In-utero exposure to antiepileptic drugs and offspring learning disability

There was something quite familiar about the findings reported by Laura Fuglslang Bech and colleagues [1] investigating any "association between in utero exposure to antiepileptic drugs and learning disabilities in the first year of compulsory education among offspring." Familiar because this class of medicines - antiepileptics - used to primarily treat/manage epilepsy and seizure disorders have been put under the spotlight in recent years as a result of various *associations* with offspring childhood developmental disorders/conditions when used during pregnancy (see here and see here).

Obviously one has to be quite careful when it comes to talking about this class of medicines. Antiepileptics, as I have mentioned before, are not typically dispensed willy-nilly, and on many occasions have proved to be not just a life-enhancer but also a lifesaver to those living with epilepsy. The balancing act comes when they are prescribed to women of child-bearing age and ability, and the possibility of them producing 'adverse' effects' on the developing child.

Bech et al focused on learning disability as a possible offspring outcome following pregnancy exposure to a range of antiepileptic medicines. One of those marvellous Scandinavian population registries provided the research starting point (based in Denmark) and lead to the participation of some 630 cases ("offspring exposed to antiepileptic drugs in utero") and 430+ controls ("unexposed offspring of mothers previously redeeming antiepileptic drug prescriptions").

Results: "Learning disabilities were identified among 7.1% cases compared with 3.7% for controls." Although not at first glance showing a huge difference between the groups, a little statistical analysis revealed that: "During any trimester, the adjusted OR [odds ratio] of the association between in utero exposure to antiepileptic drugs and learning disabilities was 2.20 (95% CI 1.16 to 4.17)." When taking into account different types of antiepileptic medicines and their possible risk profile, yet again one particular medicine stuck out: valproate. As the authors mention: "valproate carried a higher risk (OR 4.67, 95% CI 1.73 to 12.59)" compared with other antiepileptic medicines. This accords with other findings.

As with any observational study of this type, one has to be a little careful with the old 'correlation is not necessarily causation' thing. But set against a tide of research observing similar trends - particularly with respect to the use of valproate - and indeed, a rodent model of autism called the valproate rodent model of autism - it's getting ever harder to say that pregnancy valproate use in particular, is not associated with a variety of adverse offspring outcomes...

If in doubt, please speak to your prescribing physician. Please don't tinker yourself with things that you shouldn't tinker with...

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[1] Bech L. et al. In utero exposure to antiepileptic drugs is associated with learning disabilities among offspring. J Neurol Neurosurg Psychiatry. 2018 Aug 3. pii: jnnp-2018-318386.

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"evidence that in utero exposure to certain AEDs can cause developmental problems in children"

AEDs mentioned in the title of this post refer to antiepileptic drugs, a class of medicines that provide life-enhancing and sometimes life-saving relief from symptoms of various conditions headed under the term epilepsy. As I've mentioned previously on this blog, the management of epilepsy is not something to be taken lightly given what the condition(s) can mean in terms of (life-threatening) risks. AEDs provide both an important management and preventative tool. Don't ever forget that.

The results published by Arron Lacey and colleagues [1] add to a bank of peer-reviewed research observing that whilst various AEDs provide an important service with regards to the management of epilepsy, they are not however without potential risks of their own. Indeed, the risks following consumption of such medicines - or at least certain AEDs - during pregnancy when it comes to offspring outcomes are seemingly becoming more and more evident as ever more [peer-reviewed] science appears...

I should at this point mention that no medical or clinical advice is given or intended on this blog. This is even more pertinent when it comes to this topic and what epilepsy means to many, many people. If you want further information about the topic discussed today, please, speak to your prescribing physician and don't make any medication changes without their input and say-so.

OK, Lacey et al started out with the aim of investigating "the effect of AED exposure in utero on the educational attainment of children born to mothers with epilepsy using anonymised, routinely collected healthcare records and the results of a standard national educational assessment." That anonymised database was something called the Secure Anonymous Information Linkage (SAIL) databank, a resource funded by Health and Care Research Wales, thus providing a clue as to the population on which this research was carried out with.

Researchers identified women diagnosed with epilepsy - "a diagnosis of epilepsy if their GP [general practitioner] record contained an epilepsy diagnosis code as well as a record of repeat AED prescriptions" - who had children, and looked also at their child's education attainment at 7 years of age. In case you might not be familiar with measuring educational attainment here in the UK (yes, Wales is a country part of the UK), the particular assessments taken at 7 years of age are called the Key Stage 1 (KS1) SATs. Maths and English made up the core topics alongside science at the study time in question. Educational data of offspring were included in the statistical mix and results reported as a function of maternal epilepsy and corresponding prescription of AEDs.

Results: "We demonstrate through the analysis of linked data in the SAIL databank that mothers being prescribed multiple AEDs and those being prescribed sodium valproate have children with significantly poorer attainment in national tests at the age of 7." The authors once again (see here) specifically zoomed in on a role for valproate when it came to educational outcomes of offspring; where: "there was no difference seen in children exposed to carbamazepine, lamotrigine or mothers who did not take drugs during pregnancy." Importantly also, authors noted that: "We did not find a significant decrease in attainment in children born to mothers with epilepsy who were not prescribed an AED during pregnancy" indicating that maternal epilepsy was probably not a 'cause' of the results obtained. Finally, when cases of smoking during pregnancy - something that also seems to be able to affect offspring developmental and/or cognitive outcomes - were removed from the statistical mix, authors reported that the results did not notably change.

There are some important strengths associated with the study results by Lacey and colleagues. A large cohort, clinical information on the diagnosis of epilepsy and associated prescribed AEDs, and the reliance on "a standardised national assessment as a measure of performance" with "results [that] would closer reflect the learning experience of children at this age compared with an IQ test" all add up to something pretty impressive. The authors note that they did not / were not able to control for other potentially important variables such as parental characteristics that may have impacted on the study results but no investigation is perfect. That analysis based on epilepsy medicated vs. not medicated during pregnancy kinda helps matters but does not mean every potentially important variable was controlled for.

So yet again, valproate use crops up and yet again it seems to be earning its 'black triangle' status. I've lost track of the number of health-related agencies that have provided guidance on valproate use during pregnancy - one of the latest seems to be the European Medicines Agency that recently recommended "new measures to avoid exposure of babies to valproate medicines in the womb." Also going as far as noting that: "Babies exposed are at risk of malformations and developmental problems." There's even a call for it to be "compulsory to enrol all women who take valproate into a national registry" [2].

How much more evidence is required? Indeed, how much more evidence [3]...

Then the question remains: how does gestational exposure to valproate affect something like academic achievement and developmental course? Well, we have some clues (see here) but further investigations are of course implied.

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[1] Lacey AS. et al. Educational attainment of children born to mothers with epilepsy. J Neurol Neurosurg Psychiatry. 2018. March 27.

[2] Thomas RH. Valproate: life-saving, life-changing. Clin Med (Lond). 2018 Apr 1;18(Suppl 2):s1-s8.

[3] Paton C. et al. A UK clinical audit addressing the quality of prescribing of sodium valproate for bipolar disorder in women of childbearing age. BMJ Open. 2018 Apr 12;8(4):e020450.

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"... and now believe their pet has canine autism"

A recent tweet from the account of one of the most popular TV breakfast shows here in Blighty made some waves (international waves no less) for a couple of reasons. Leaving aside the insinuation that vaccination *might* correlate with certain behavioural changes in domestic pets, the idea that autism might not be something exclusive to humans was also implied from said tweet.

Needless to say that quite a few people took exception to the idea of 'canine autism'; even the British Veterinary Association (BVA) insisted that "there is currently no scientific evidence to suggest autism in dogs." But is that actually scientifically accurate? And more widely, is it possible for a non-human to have autism or present with significant autistic features?

Before progressing through the evidence around this question, I think it's worthwhile getting a few things straight. First, I appreciate that whilst autism is a label or diagnosis denoting a set of behavioural characteristics that 'significantly impact on day-to-day life' according to current diagnostic schedules, it's also a label of identity for some people. One therefore needs to be sensitive to the effect that discussions about animals also potentially 'having that label' would have to those who associate with an autistic identity. Second, there is a long, very long, history in peer-reviewed research circles, where animals have been used to model aspects of autism. Take for example, the increasingly important research emerging on a role for prenatal valproate exposure as a route to potentially increasing the risk of autism and other neurodevelopmental conditions being diagnosed (see here); an area that has also included discussions of a valproate-treated rodent model of autism (see here) being used in research. Of course, one needs to be aware that modelling autistic features in animals is not the same as autism and all its complexity presenting in humans (including the idea that autism rarely appears in some sort of diagnostic vacuum) and the resulting 'logical fallacies' that can arise (see here). But the assumption is that elements of certain core features of autism can potentially present in non-humans too, and could provide important clues as to the underlying nature of autism.

Going back to that 'no scientific evidence' statement made by the BVA in the lay press, you might be surprised to hear that actually, dogs have been the topic of some research interest in relation to their presenting with some of the features of autism. In an article titled: 'Can Dogs Have Autism?' some of that research was discussed. Starting from an article published way back in 1966 [1] observing behaviour in a dog "resembling human infantile autism" up to more recent peer-reviewed studies [2], several commentators have speculated on facets of autism being present in certain dogs and perhaps being more readily presented in certain breeds of dog. I've actually covered this topic previously in another post on this blog (see here) based on other research [3] reporting on shared biochemical parameters noted in some children and some canines: "tail-chasing Bull Terriers." This, on the basis that from a behavioural and biological point of view, humans are not a million miles away from canines and vice-verse. In short, there is a small scientific evidence base pursuing the notion that facets of autism may present in non-humans too.

Minus too many deep, philosophical musings about our relationship with animals and any evolutionary *connections* between human and animal behaviours, this topic did get me thinking about quite a few other things. It got me wondering whether there may be other behaviours and/or behaviourally-defined conditions / labels that are readily diagnosed in humans but that might also present in non-humans too. I also started to wonder about the myriad of animal-assisted 'interventions' that have been mentioned with autism in mind down the years (see here) and whether other possible research connections could be made as a result. Are we being too presumptuous by saying that the essence of autism is a uniquely human state?

And without trying to trivialise or make light of what autism means to many, many people, there is a long history of speculation when it comes to cats and autism...

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[1] Fox MW. A syndrome in the dog resembling human infantile autism. J Am Vet Med Assoc. 1966 Jun 1;148(11):1387-90.

[2] Zamzow RM. et al. Characterizing autism-relevant social behavior in poodles (Canis familiaris) via owner report. J Comp Psychol. 2017 May;131(2):139-149.

[3] Tsilioni I. et al. Elevated serum neurotensin and CRH levels in children with autistic spectrum disorders and tail-chasing Bull Terriers with a phenotype similar to autism. Transl Psychiatry. 2014 Oct 14;4:e466.

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Endogenous Retroviruses (ERVs) and autism continued

It's been a while since I last mentioned Human Endogenous Retroviruses (HERVs) in the context of autism (see here) on this blog. I still however retain an interest in how these 'fossil viruses' - remnants of our ancient battle with various viruses down the ages that are still present in the genome - *might* impact on our health and well-being for all-manner of reasons.

One name in particular has been at the forefront of the work on HERVs with particular reference to autism (and ADHD and beyond) - Emanuela Balestrieri - and alongside, quite a significant peer-reviewed research record has been built up (see here). A new paper from the Balestrieri 'research group' (if I can call it that) continues their research journey in this area, from Chiara Cipriani and colleagues [1]. The aim of the research game this time around was to look at two popular mouse models of autism - "inbred BTBR T+tf/J mice and CD-1 outbred mice prenatally exposed to valproic acid (VPA)" - and examine the transcriptional activity of various ERVs (that's ERVs not HERVs 'cos these were mice) compared with control mouse strains ("C57BL/J and CD-1 untreated mice").

From what I gather, there were two main elements to the Cipriani study: (1) assessing intracisternal A-particle elements (IAPs) and Type II early transposons (ETns) in blood and brain samples of those autism-related mouse models, and (2) evaluating "the transcriptional activity of proinflammatory cytokines (IL-1β, IL-6, TNF-α) and Toll-like receptors (TLR3 and 4)... in whole embryos and, from the offspring at different time after birth, in blood and brain samples to investigate on the hypothesised link between the ERVs transcriptional activity and the immune system." If much of that sounds like a foreign language to you, well, you're not alone. From what I gather, intracisternal A-particle elements (IAPs) are "endogenous retroviral sequences" that can "induce genomic mutations and cell transformation by disrupting gene expression." Type II early transposons (ETns) are "mobile members of the repetitive early transposon family of mouse long terminal repeat (LTR) retroelements and have caused a number of mutations by inserting into genes" [2]. Clear as mud right?

Results: "In the two distinct mouse models analysed, the transcriptional activity of the ERV families was significant higher in comparison with corresponding controls, in whole embryos, blood and brain samples." Taking the BTBR mice first, in comparison to control mice (C57BL6/J), pretty much all of the expression levels of the ERV genes looked at were higher in embryos. In both blood and brain, over the course of 120 days post-natally, ERV expression was also higher than that in control mice. I say all this acknowledging that absolute number of 'mouse participants' in this study was relatively small.

Also, compared with 'vehicle treated' control mice, those offspring embryos exposed to maternal VPA ("VPA mice were produced by treating outbred pregnant CD-1 female mice with a single dose of VPA (500 mg/kg, sc) at gestational day (GD) 10.5") also saw higher transcriptional activity of 'most' ERVs. The data from blood and brain samples were similarly interesting; in brain samples in particular, those exposed to VPA always showed higher ERV transcriptional activity than non-exposed controls, and notably so. Insofar as the inflammatory cytokine look-see side of things, well in both autism-related mouse models, "the expression levels of the proinflammatory cytokines and TLRs [Toll-like receptors] were significantly higher than controls."

What does this all mean? Well, bearing in mind that mice are mice and not humans (see here), researchers conclude that "results are in agreement with our previous data showing a distinctive expression profile of some human HERV families in blood samples from two different cohorts of young autistic patients and support the hypothesis that ERVs could be implicated in ASD." The fact that authors used not one but two mouse models of autism - including something akin to an 'acquired' autism phenotype in that VPA mouse model - and found similar things adds something a little extra to their findings. The possibility of a tie-up between ERV expression and immune system 'activation' requires more investigation save any sweeping generalisations about linkage. I am wondering if autism research in this area might however benefit from looking at some initial research on myalgic encephalomyelitis (ME) (see here) and onward some chatter about a possible link between HERV proteins acting as 'superantigens' in immune system terms.

Hopefully further research will be forthcoming sooner rather than later...

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[1] Cipriani C. et al. High expression of Endogenous Retroviruses from intrauterine life to adulthood in two mouse models of Autism Spectrum Disorders. Sci Reports. 2018; 8: 629.

[2] Baust C. et al. Structure and Expression of Mobile ETnII Retroelements and Their Coding-Competent MusD Relatives in the Mouse. Journal of Virology. 2003; 77: 11448-11458.

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Valproate use during pregnancy and/or breastfeeding and "greatest odds of adverse development"

As per other blogging occasions when I've talked about the antiepileptic drug (AED) valproate and its use specifically during pregnancy, I caution that no medical or clinical advice is given or intended on this blog. Anyone in any doubt or seeking an opinion on this other or any other AED should consult their prescribing physician. Don't mess with epilepsy. I repeat: don't mess with epilepsy.

The findings however reported by Areti Angeliki Veroniki and colleagues [1] (open-access) synthesising the available peer-reviewed evidence to compare "the safety of antiepileptic drugs (AEDs) on neurodevelopment of infants/children exposed in utero or during breast feeding" provides an all too familiar picture specifically in relation to valproate use during pregnancy. Namely: "Valproate alone or combined with another AED is associated with the greatest odds of adverse neurodevelopmental outcomes compared with control."

Utilising something called a Bayesian random-effects network meta-analysis (NMA), researchers set about synthesising and ranking various AEDs previously studied in terms of their safety when it comes to *association* with various childhood developmental diagnoses including autism and things like cognitive developmental delay. Based on the results from 29 studies reporting on AED use and 'neurological outcomes' including some 5000 patients, authors made some important observations.

Not to be alarmist but: "results suggest that AEDs generally pose a risk for infants and children exposed in utero or during breast feeding." The authors caution that their results whilst methodologically strong are not without limitations; not least that the studies in this area are observational only and therefore have "inherent biases because of confounding and shortcomings of these studies." That being said, the tide of such observational research cannot be readily ignored. If there is one or more confounding variables that is/are somehow being hidden behind something like valproate use during pregnancy and its potential risks of offspring developmental outcomes, they seem to be very well hidden indeed.

"Valproate was significantly associated with more children experiencing autism/dyspraxia, language, cognitive and psychomotor developmental delays versus children who were not exposed to AEDs." Valproate came 'top of the pops' when it came to those neurological outcomes. Other AEDs also showed associations with specific outcomes - "oxcarbazepine and lamotrigine were associated with increased occurrence of autism" - but the data pointed to valproate as potentially showing greatest risk to offspring. I should point out that there is a mouse model of autism that relies on offspring valproate exposure which, whilst subject to shortcomings (see here), kinda suggested that there may be an important association. Said animal research also reveals some potentially important avenues for perhaps mitigating any deleterious effects of valproate use on offspring too (see here) with the requirement for more experimental study.

"Future studies should assess the genetic contribution from the biological father, maternal seizures during pregnancy, exposure through breast feeding only, types of epilepsy and maternal family history." Of course the authors are right to talk about other factors that are probably important to various childhood developmental outcomes. But unlike a related area talking about medicines taken during pregnancy potentially affecting risk of something like autism and how one might tease apart medicine use from underlying health issue(s) (see here for example), I don't think it too likely that there is going to be a large bank of pregnant mums out there who present with epilepsy or other seizure disorder that is not going to be already managed via AEDs. Indeed, it would be rather unethical as well as unwise to leave epilepsy untreated under any conditions.

To close, where we're up to when it comes to government (UK) advice on AEDS such as valproate and pregnancy use. Again, if it doubt, talk to your prescribing physician.

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[1] Vernoniki AA. et al. Comparative safety of antiepileptic drugs for neurological development in children exposed during pregnancy and breast feeding: a systematic review and network meta-analysis. BMJ Open. 2017; 7: e017248.

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"Logical fallacies in animal model research"

A paper which is a bit 'out of left field' is presented for your reading pleasure today and how one should be rather careful about how animal research - "with focus on animal models of mental illness" - is translated into relevance to humans [1].

The paper by Espen Sjoberg is pertinent to various diagnostic labels including depression and schizophrenia. I would perhaps disagree with the author including autism under the specific heading of 'mental illness' (bearing in mind various mental health diagnoses can follow an autism diagnosis), but the discussions on how we should all be a little cautious about translating findings from animal research to real people ring as true for autism as they do for the other conditions discussed.

The paper is open-access but a few choice phrases are worth highlighting from the 'what can we do about this ' section of the Sjoberg paper in these days of animal models of [insert condition name here].

So: "Avoid making inferences about the animal’s thoughts, feelings, inner motivation, or understanding of the situation. We can report what the animals did, and what this means in the context of our hypothesis, but take care not to make assumptions of the inner workings of the animal." I note the words 'theory of mind' (ToM) are mentioned in another section of the paper which is interesting and potentially relevant to autism research history...

Onwards: "No matter how validated an animal model is, we cannot be certain that a newly observed effect also applies to humans." The valproate model of autism is specifically mentioned in the Sjoberg text - where prenatal exposure to valproate may have implications for offspring development - but is not the only rodent model of autism (see here). The implication is that one has to be be mindful that just because findings might talk about intestinal inflammation associated with the valproate mouse model of autism for example (see here), this does not make them directly applicable to real people without looking at real people (who were prenatally exposed to valproate). The caveat being: "Remember that the strength of an animal model is to generate new knowledge and hypotheses relevant to the target group, including the assessment of potentially useful treatments, but that these new possibilities are only hypothetical once they are discovered."

Finally: "Replicating an experiment in order to establish interval validity and reliability of an animal model is essential." Replication is a cornerstone of reliable science and so, where possible, when one finds and reports on a specific aspect of an animal model of some label or other, the experiment should be [independently] replicated. The author even goes further, bringing in another couple of 'R' words: reproduction and reconstruction ("A reconstruction involves redesigning an experiment, while maintaining the original hypothesis, in order to accommodate different species").

The bottom line: don't over-hype your [animal research] findings if you've only looked at animal models and are presenting novel findings. In particular, make sure you write any press release mindful of what you were studying and how applicable the results may/may not be (outside of animals)...

Music to close: an old favourite of this blog, Weezer and The Fonz...

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[1] Sjoberg EA. Logical fallacies in animal model research. Behavioral and Brain Functions. 2017; 13: 3.

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Sjoberg EA (2017). Logical fallacies in animal model research Behavioral and Brain Functions : 10.1186/s12993-017-0121-8

Blood glutamate levels in autism meta-analysed

"The meta-analysis provided evidence for higher blood glutamate levels in ASD [autism spectrum disorder]."

That was the research bottom-line reported by Zhen Zheng and colleagues [1] (open-access available here) who surveyed the current peer-reviewed science literature in this area and found something to see based on: "Twelve studies involving 880 participants and 446 incident cases."

Drawing on the idea that glutamate is a rather important amino acid that plays a role in various biological processes including that related to the manufacture of GABA (see here), Zheng et al observed higher circulating blood levels of the stuff; a sort-of proxy for what might also be going on with regards to brain levels of glutamate. That "excess glutamate has been shown to be a potent neurotoxin that leads to neuronal cell death and plays a role in the pathophysiology of some neuropsychiatric disorders" is an important point to make as to the potential implications from the Zheng meta-analysis.

Zheng et al do mention how important glutamate is for the purposes of GABA production and in particular, how issues with glutamate decarboxylase (GAD) - a key enzyme that converts glutamate into GABA - described in some cases of autism [2] might account for the elevated levels of glutamate yet the generally lower levels of GABA seen in autism (see here). I'd be inclined to agree that this is perhaps one of the more important implications for glutamate in autism; particularly when added to the whole 'glutamate linked to epilepsy' bit knowing how close a relationship autism and epilepsy seem to share (see here).

Where next with this research area I hear you ask? Well, I'd like to know a little more not just about glutamate but also another linked amino acid called glutamine. It has already been talked about in the autism research literature a while back (see here) but a lot more follow-up work is required on these two important compounds and what their differing ratio might mean. I'd also like to see more work done on the idea that "the mood stabilizer valproic acid, which exerts neuroprotective effects against glutamate-induced excitotoxicity, is effective in ASD [autism spectrum disorder] with seizures." Yes, I know that valproic acid a.k.a valproate is a bit of a double-edged sword when it comes to autism and other offspring developmental issues under certain circumstances (see here) but much like another research story in autism (see here) timing of exposure seems to be a key issue and one wonders whether other unrelated compounds might also exert a similar neuroprotective effect.

As to the idea that "blood glutamate levels may serve as a potential biomarker in the diagnosis of ASD" made by Zheng and colleagues, we'll wait and see...

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[1] Zheng Z. et al. Blood Glutamate Levels in Autism Spectrum Disorder: A Systematic Review and Meta-Analysis. PLoS One. 2016 Jul 8;11(7):e0158688.

[2] Yip J. et al. Decreased GAD65 mRNA levels in select subpopulations of neurons in the cerebellar dentate nuclei in autism: an in situ hybridization study. Autism Res. 2009 Feb;2(1):50-9.

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Zheng Z, Zhu T, Qu Y, & Mu D (2016). Blood Glutamate Levels in Autism Spectrum Disorder: A Systematic Review and Meta-Analysis. PloS one, 11 (7) PMID: 27390857

Epilepsy begets autism?

"Individuals with epilepsy are at increased risk of ASD [autism spectrum disorder], especially if epilepsy appears in childhood. Further, ASD is more common in the siblings and offspring of individuals with epilepsy, suggesting shared etiology."

That was the research bottom-line from Heléne Sundelin and colleagues [1] reporting results based on examination of the "Swedish Patient Register" with regards to the "risk of autism spectrum disorder (ASD) in individuals with epilepsy and in their first-degree relatives." Including one Jonas F. Ludvigsson, PhD on the authorship list (yes, he of 'gluten and autism: probably not coeliac disease but...' fame), researchers identified some 85,000 individuals diagnosed with epilepsy "as well as all their siblings (n = 80,511) and offspring (n = 98,534)." With some nifty statistical analysis including matching cases 5:1 with control participant data, they were able to conclude that around 1.6% of those with epilepsy were diagnosed with an ASD compared with 0.2% of controls. Those percentages are seemingly quite small both in real terms and also in differences between the groups but given the huge participant numbers included for study came out with a hazard ratio (HR) around 10.49 "confidence interval [CI] 9.55–11.53)." To put that HR of 10.49 in context, other work by Ludvigsson on epilepsy coinciding with coeliac disease for example, with a participant number in the tens of thousands came out with a HR of 1.42.

When also looking at what happened to siblings and offspring of those diagnosed with epilepsy, the authors also observed something of a potentially increased risk of autism being also diagnosed, although quite a bit less than risk to those themselves diagnosed with epilepsy. The results did however suggest that: "The risk in the offspring was particularly high in mothers with epilepsy." And just for good measure, the Sundelin results also noted that risk of epilepsy was "also associated with a prior diagnosis of ASD" confirming what many others have reported over the years (see here).

Although making some headlines I wasn't particularly shocked by the bi-directional associations reported by Sundelin and colleagues. Quite a few times on this blog I've talked about autistic features being potentially over-represented in cases of epilepsy (see here and see here) so to see some of those features crossing diagnostic thresholds into an actual autism diagnosis is perhaps not unsurprising. Continuing that line of thought I do wonder what might happen if the broader autism phenotype (BAP) was also analysed with epilepsy in mind (even the new DSM-5 categorisation of social communication disorder?)

Insofar as the hows and whys of the association between epilepsy and autism, well, we're still in guessing mode at the current time. I've talked about some of the various genetic syndromes that tend to include autism and epilepsy together as a diagnostic package (see here) as evidence for the more plural 'autisms'. Such syndromes suggest that mechanisms linking the two conditions are likely to be multiple and not necessarily the same for everyone. The issue of GABA and autism might also show some connection in some cases as per what is starting to be known about this neurotransmitter (see here) and where it might fit with some autism (see here) on top of epilepsy. Assuming also that epilepsy in pregnant mothers for example is being managed by medication, it is also not outside of the realms of possibility that certain preparations could also exert an effect on offspring autism risk (see here). I say this with no scaremongering intended.

I might also (speculatively) advance the idea that another research area might also be a connecting feature for some autism and some epilepsy: diet. Don't just click away yet as I will first bring your attention to the increasing peer-reviewed literature talking about the use of a ketogenic diet and autism (see here); said dietary intervention more typically indicated in 'some' cases of epilepsy. It's still early days but it strikes me that quite a bit more research is required in this area. Allied to the use of a ketogenic diet (see here) and also perhaps linking back to that other important research area frequently examined by Dr Ludvigsson (coeliac disease) I'm also inclined to ask whether some autism and some epilepsy might show a more specific connection to dietary gluten too. No, I'm not saying that a gluten-free diet nor a ketogenic diet is some sort of 'cure-all' for autism and epilepsy (please don't mess with epilepsy) but rather there may be overlapping genetics or biology potentially linked to facets of gluten metabolism that might be important for some on the autism spectrum with epilepsy. Certainly much more research on this and other less-traditional areas is indicated [2].

There are many questions that remain unanswered in this area of research. With regards to the here and now, well, the Sundelin and other data perhaps suggest that as and when epilepsy is diagnosed, preferential screening for autism could and should be offered particularly in infancy; and perhaps even offered family wide.

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[1] Sundelin HEK. et al. Autism and epilepsy: A population-based nationwide cohort study. Neurology. 2016. June 15.

[2] Frye RE. et al. A review of traditional and novel treatments for seizures in autism spectrum disorder: findings from a systematic review and expert panel. Front Public Health. 2013 Sep 13;1:31.

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Sundelin, H., Larsson, H., Lichtenstein, P., Almqvist, C., Hultman, C., Tomson, T., & Ludvigsson, J. (2016). Autism and epilepsy Neurology DOI: 10.1212/WNL.0000000000002836

On the question of valproate use and pregnancy

I very much want to stress the point that 'no medical or clinical advice is given or intended' on this blog before proceeding further with discussions based on the commentary paper by Richard Balon & Michelle Riba titled: 'Should Women of Childbearing Potential Be Prescribed Valproate?' [1].

Valproate, as in preparations like sodium valproate, has been a particular talking point in recent years as a consequence of something of an emerging body of peer-reviewed science suggesting that its use during pregnancy may place offspring at some elevated risk for various neurodevelopmental outcomes (see here). The Medicines and Healthcare Products Regulatory Agency (MHRA) here in Blighty issued some revised guidance last year (2015) 'strengthening' warnings about the use of valproate under certain circumstances. This follows some research history on how for example, a valproic acid mouse model of autism has been used as "environmentally induced ASD [autism spectrum disorder] models in rodents" [2] for quite a few years.

Balon & Riba cover various points in the debate about valproate use during pregnancy specifically focused on the known "teratogenic outcome[s]" that have been reported down the years bearing in mind that valproate serves an important (sometimes life-saving) use. I was particularly struck by the 'interference' with folic acid metabolism discussed in their commentary on the basis of some science in this area [3]. With that pinch of salt at the ready, some readers might already know that folate metabolism has some research history in autism circles (albeit not necessarily settled science) and indeed, continues to make scientific waves. Accepting that valproate might have more than one action when potential offspring outcomes are concerned (see here), I do wonder if further research focus could be directed on the folate aspect of the drug when it comes to risk of various neurodevelopmental diagnoses for example?

The question of valproate use outside of the management of epilepsy is a focus of the Balon/Riba article; specifically "used in acute mania or in prophylaxis of bipolar disorder." Bearing in mind that various other medicines are available to manage these conditions and that "unplanned pregnancies are common in this population" [4] I don't think it's out of place for the authors to "recommend that the FDA and valproate manufacturers declare valproate contraindicated in women of childbearing age and issue guidelines for counseling women of childbearing potential with bipolar disorder." Indeed, NICE here in England, seem to have taken a lead on this...

If in doubt, please consult with your medical physician.

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[1] Balon R. & Riba M. Should Women of Childbearing Potential Be Prescribed Valproate? J Clin Psychiatry. 2016; 77: 525–526.

[2] Ergaz Z. et al. Genetic and non-genetic animal models for Autism Spectrum Disorders (ASD). Reprod Toxicol. 2016 Apr 30. pii: S0890-6238(16)30077-6.

[3] Fathe K. et al. Brief report novel mechanism for valproate-induced teratogenicity. Birth Defects Res A Clin Mol Teratol. 2014 Aug;100(8):592-7.

[4] Marengo E. et al. Unplanned pregnancies and reproductive health among women with bipolar disorder. J Affect Disord. 2015 Jun 1;178:201-5.

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Balon R, & Riba M (2016). Should women of childbearing potential be prescribed valproate? a call to action. The Journal of clinical psychiatry, 77 (4), 525-6 PMID: 27137420

Pendulum swings... prenatal antidepressant exposure not linked to autism or ADHD

"Multiple studies have examined the risk of prenatal antidepressant exposure and risk for autism spectrum disorder (ASD) or attention-deficit hyperactivity disorder (ADHD), with inconsistent results."

And...

"These results suggest that prior reports of association between prenatal antidepressant exposure and neurodevelopmental disease are likely to represent a false-positive finding, which may arise in part through confounding by indication."

'These results' refers to the findings reported by Castro and colleagues [1] (open-access available here) who looked at the records of over 1200 children diagnosed with ASD and ~1700 children diagnosed with ADHD compared with over 3400 and 3700 controls respectively with regards to antidepressant exposure during pregnancy and maternal antidepressant use before pregnancy. Based on exposures identified "using e-prescribing data in the EHR [electronic health records], both inpatient and outpatient, which record number of pills, frequency and refill number, allowing calculation of exposure period" researchers were, with reasonable confidence, able to test the idea that a diagnosis of ASD or ADHD might be elevated following prenatal exposure to said pharmaceutics.

The headline that most media discussing this study picked up on was the lack of any significant association between antidepressant use during pregnancy and risk of offspring autism or ADHD. This finding kinda contrasts with other recent independent reports that have been covered on this blog (see here). Indeed the authors - including one Isaac Kohane (see here) - suggest that their results, bearing in mind certain limitations, highlight how 'false-positive' might indeed be a good description of some of the previous data in this area.

But just before any sweeping generalisations are made about this class of pharmaceutic being 'off the hook' there were some other potentially important findings also reported by Castro et al. To quote once again: "For both ASD and ADHD, pre-pregnancy antidepressant use was associated with greater risk, even after adjustment for maternal major depression." The risk reported was significant insofar as what it might mean for offspring autism and/or ADHD and also how "the requirement for maternal antidepressant treatment, rather than the medication itself, may be associated with risk for neurodevelopmental disorders in offspring".

As I've discussed before, the idea that antidepressant use during pregnancy might be linked to offspring developmental outcomes is a complicated area. That such medicines use is not generally entered into lightly is something to bear in mind given what depression can do to a person and those around them. I cannot readily account for the discrepancy between these and other reports on this topic outside of the idea that the question of a connection or not may not be as simple as 'yes' or 'no' but rather a slightly more convoluted story where genetics and other more 'environmental' factors might play some role. The idea that there may be specific phenotypes of autism associated with such medication use has received a boost in other independent studies [2] looking at other medicines. I suppose such confusion kinda sums up autism research when it comes to questions of such exposure and the range of pharmaceutics that have been correlated with offspring risk (see here and see here).

Music: Björk - It's Oh So Quiet. Shhh.

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[1] Castro VM. et al. Absence of evidence for increase in risk for autism or attention-deficit hyperactivity disorder following antidepressant exposure during pregnancy: a replication study. Transl Psychiatry. 2016 Jan 5;6:e708.

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Castro VM, Kong SW, Clements CC, Brady R, Kaimal AJ, Doyle AE, Robinson EB, Churchill SE, Kohane IS, & Perlis RH (2016). Absence of evidence for increase in risk for autism or attention-deficit hyperactivity disorder following antidepressant exposure during pregnancy: a replication study. Translational psychiatry, 6 PMID: 26731445

The ketogenic diet and autism: where are we up to?

Today I'm bringing the paper by Kamila Castro and colleagues [1] to the blogging table and their systematic review of the available peer-reviewed literature on the use of a ketogenic diet (KD) when it comes to real life autism and various mouse models trying to map the label.

Drawing on data derived from 8 studies - "three studies with animals and five studies with humans" - that met the relevant inclusion criteria for study, authors concluded that although the evidence looks promising for the ketogenic diet (high fat, low carbohydrate intake) with autism in mind, there is insufficient evidence "to attest to the practicability of the KD as a treatment for ASD [autism spectrum disorder]."

I've been following the research on the ketogenic diet and autism for some time now (see here). The paper from Evangeliou and colleagues [2] providing preliminary data on what promise a KD might hold for 'some' autism really got the research ball rolling. Subsequent studies and cases reports (some of which have been covered on this blog, see here and see here) have generally been favourable about the possibilities of the KD in a real-world setting. Other animal model based research has similarly demonstrated "attenuation of some autistic-like features" following the use of the KD specifically with the dangermouse that is the BTBR mouse (see here) and the valproic acid mouse model (see here). And yes, I know that mice are not people.

I do think the time is right for more scientifically controlled trials of the KD with autism (some autism) in mind as per suggestions for various other labels too [3]. I know for some people this will be met with a rolling of the eyes and look of disdain in light of other dietary interventions put forward with autism in mind (see here) and where that has led down the years. But, and it is perhaps an important point, the utility of a KD in [some] cases of refractory epilepsy [4] perhaps give the KD something of a grounding when it comes to the presentation of some autism on top of continuing interest in nutritional medicine in modern day psychiatry (see here). Given for example, the quite noticeable connection between autism and epilepsy (see here) perhaps even more complicated than anyone had recognised (see here), one might entertain the notion that some cases of autism(s) overlapping with epilepsy might be a good starting point for further investigations?

Music: Of Monsters And Men - Dirty Paws (a band who make some of the best music videos around these days).

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[1] Castro K. et al. Effect of a ketogenic diet on autism spectrum disorder: A systematic review. Research in Autism Spectrum Disorders. 2015; 20: 31-38.

[2] Evangeliou A. et al. Application of a ketogenic diet in children with autistic behavior: pilot study. J Child Neurol. 2003 Feb;18(2):113-8.

[3] Paoli A. et al. Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets. European Journal of Clinical Nutrition. 2013; 67: 789–796.

[4] Lefevre F. & Aronson N. Ketogenic diet for the treatment of refractory epilepsy in children: A systematic review of efficacy. Pediatrics. 2000 Apr;105(4):E46.

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Kamila Castro, Larissa Slongo Faccioli, Diego Baronio, Carmem Gottfried, Ingrid Schweigert Perry, & Rudimar dos Santos Riesgo (2015). Effect of a ketogenic diet on autism spectrum disorder: A systematic review Research in Autism Spectrum Disorders, 20, 31-38 : 10.1016/j.rasd.2015.08.005

Autism's environmental exposome (part 2)

Back in June 2012, I posted an entry on this blog titled: 'Autism's environmental exposome: fish and pharmaceuticals' covering some work by Michael Thomas & Rebecca Klaper [1] (open-access). In it, authors suggested that unmetabolized psychoactive pharmaceuticals (UPPs) - residues from certain medicines - present in drinking (or in the case of this work, swimming) water may "induce autism-like gene expression patterns in fish."

The UPPs in question were "FLX [fluoxetine], VNX [venlafaxine], and CBZ [carbamazepine] in a 3-component mixture" and the lucky fish volunteers were fathead minnows who got to swim with those UPPs. The data were interesting insofar as the potential "ability to induce ASD-like gene expression patterns in developing brains" as a function of exposure to those UPPs, albeit with concentrations used in the Thomas/Klaper study "higher than observed environmental concentrations". The idea being that drug residues are present in the environment around us and some, either alone or in combination, may potentially host some important biological effects.

Enter then further work from this group in the form of the paper by Gaurav Kaushik and colleagues [2] (open-access) who undertook some rather interesting network analysis among other things and concluded that: "protein products from gene sets with enriched expression in fish brains and human neuronal cells, due to an exposure of psychoactive pharmaceuticals, were comparatively more inter-connected to other neighboring proteins than protein products of non-enriched gene sets." Further: "these genes are more likely to experience altered expression upon exposure to PPCPs [pharmaceuticals and personal care products], causing further dysregulation of the whole interactome due to a ripple effect."

I'll be honest with you and say that I'm not altogether au fait with all the goings-on reported by Kaushik et al and their bioinformatics approach adopted so you'll have to take my interpretation with a pinch of salt.  What they appear to be suggesting is that the effects of UPP exposure may not be just centred on the gene expression patterns they previously reported but rather having something of a wider knock-on effect on how gene products are expressed and how this might map onto something like autism. Interestingly, this time around researchers also introduced valproate (VPA) into their investigations given the growing evidence base that "VPA is known to induce ASD [autism spectrum disorder]-like phenotypes in mice" (see here for more information) as it might in people [3]. They reported some potentially important connections - "enrichment effects of clinical doses of VPA are similar to those for environmental concentrations of pharmaceutical mixtures."

Accepting how the word 'chemical' has been very wrongly demonised over the years, the idea that environmental 'exposures' either singularly or as combinations, might have important effects on development and behaviour is something that requires quite a bit more investigation when it comes to something like autism. The idea that gene expression for example, can be modified by said exposures adds an extra layer of complexity to the rather too simplistic idea of 'genes vs. environment' when it comes to autism risk. One might also be minded to take into account gender/sex (see here) too particularly in light of some of the findings reported by Werling & Geschwind [4] recently...

Oh, and UPPs might not be the only pharmaceuticals requiring further research attention with wastewater and minnows in mind...

Music: Dinosaur Jr. - Freak Scene.

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[1] Thomas MA. & Klaper RD. Psychoactive pharmaceuticals induce fish gene expression profiles associated with human idiopathic autism. PLoS One. 2012;7(6):e32917.

[2] Kaushik G. et al. Psychoactive pharmaceuticals as environmental contaminants may disrupt highly inter-connected nodes in an Autism-associated protein-protein interaction network. BMC Bioinformatics 2015, 16(Suppl 7): S3.

[3] Wood AG. et al. Prospective assessment of autism traits in children exposed to antiepileptic drugs during pregnancy. Epilepsia. 2015. 11 May.

[4] Werling DM. & Geschwind DH. Recurrence rates provide evidence for sex-differential, familial genetic liability for autism spectrum disorders in multiplex families and twins. Molecular Autism 2015, 6:27.

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Gaurav Kaushik, Michael A Thomas, & Ken A Aho (2015). Psychoactive pharmaceuticals as environmental contaminants may disrupt highly inter-connected nodes in an Autism-associated protein-protein interaction network BMC Bioinformatics

Donepezil and D-cycloserine rescue behaviours in VPA exposed animals

In a post not-so-long-ago I talked about an interesting piece of research by Ahn and colleagues [1] suggesting that a ketogenic diet might yet hold some promise to "modify complex social behaviors and mitochondrial respiration" affected in the "prenatal valproic acid (VPA) rodent model of ASD [autism spectrum disorder]". The idea being that exposure to valproic acid (valproate) during the nine months that made us might carry some heightened risk for adverse effects on offspring development (see here) and a dietary change might rescue some functions.

"Daisy, Daisy, give me your answer do"

Well, the floodgates have well and truly opened when it comes to looking at various pharmacological agents that 'might' also rescue abilities thought to be affected by prenatal valproate exposure as today I discuss two papers.

First up is the paper by Wellmann and colleagues [2] which reported that: "D-cycloserine normalized the VPA-induced increase in play fighting in males and also increased social motivation in females". Second is the paper by Kim and colleagues [3] (open-access here) who observed: "Subchronic treatment of donepezil improved sociability and prevented repetitive behavior and hyperactivity of VPA-treated mice offspring".

Aside from reiterating that these were studies of rodents and not humans, I was slightly taken aback by the reported findings. Cycloserine is normally packaged as an antibiotic but, as with many medicines these days, the pharmacological effects of the compound seem to extend far beyond the intended (antimicrobial) action [4]. I've talked about D-cycloserine before on this blog (see here) and some rather interesting research linking administration to several conditions. With autism in mind, I'll bring to your attention the paper by Urbano and colleagues [5] as one example of how far and wide this pharmaceutic is venturing. As to mode of action, well, I'd be clutching at straws if I was to hazard any guess. I might suggest that something around glutamate metabolism might be something to look at [6] which coincides with one of the proposed actions of D-cycloserine [7].

Donepezil (Aricept®) falls under the category of acting as a reversible acetylcholinesterase inhibitor (AChEI). More usually indicated for dementia and particularly Alzheimer's disease [8] Kim et al describe how "prenatal exposure of valproic acid (VPA) induced dysregulation of cholinergic neuronal development, most notably the up-regulation of acetylcholinesterase (AChE) in the prefrontal cortex of affected rat and mouse offspring". You can, therefore, perhaps see the logic in using donepezil as an AChEI particularly when one takes into account how other AChE inhibitors have been studied with autistic behaviours in mind [9]. Indeed, this is not the first time that donepezil has specifically been talked about in relation to autism, mouse models of autism, as per the findings from Karvat & Kimchi [10] and their discussions based on the BTBR 'dangermouse' where: "i.p. [intraperitoneal] injection of AChEI to BTBR mice significantly relieved autism-relevant phenotypes, including decreasing cognitive rigidity, improving social preference, and enhancing social interaction, in a dose-dependent manner". And there is the promise of more to come with this medicine.

Reiterating that the Wellmann and Kim results (and the Ahn results) are based on studies of rodents not people, these are an interesting datasets crying out for further replication and study. Scientific glimmers are appearing which provide further data on what biological functions might be affected by prenatal valproate exposure and importantly, what might be done to [safely] rescue certain functions. But we're not there yet... and I haven't even mentioned epigenetics [11] ...

An unusual song from Ween to close... Push th' Little Daisies. Having said that, Ween are/were an unusual band...

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[1] Ahn Y. et al. The Ketogenic Diet Modifies Social and Metabolic Alterations Identified in the Prenatal Valproic Acid Model of Autism Spectrum Disorder. Dev Neurosci. 2014 Jul 8.

[2] Wellmann KA. et al. D-Cycloserine Ameliorates Social Alterations That Result From Prenatal Exposure To Valproic Acid. Brain Res Bull. 2014 Aug 14. pii: S0361-9230(14)00120-8.

[3] Kim JW. et al. Subchronic Treatment of Donepezil Rescues Impaired Social, Hyperactive, and Stereotypic Behavior in Valproic Acid-Induced Animal Model of Autism. PLoS One. 2014 Aug 18;9(8):e104927.

[4] Rodrigues H. et al. Does D-cycloserine enhance exposure therapy for anxiety disorders in humans? A meta-analysis. PLoS One. 2014 Jul 3;9(7):e93519.

[5] Urbano M. et al. A trial of D-cycloserine to treat stereotypies in older adolescents and young adults with autism spectrum disorder. Clin Neuropharmacol. 2014 May-Jun;37(3):69-72.

[6] Bristot Silvestrin R. et al. Animal model of autism induced by prenatal exposure to valproate: altered glutamate metabolism in the hippocampus. Brain Res. 2013 Feb 7;1495:52-60.

[7] Hashimoto K. Targeting of NMDA receptors in new treatments for schizophrenia. Expert Opin Ther Targets. 2014 Sep;18(9):1049-63.

[8] McGleenon BM. et al. Acetylcholinesterase inhibitors in Alzheimer’s disease. British Journal of Clinical Pharmacology. 1999; 48: 471-480.

[9] Ghaleiha A. et al. Galantamine efficacy and tolerability as an augmentative therapy in autistic children: A randomized, double-blind, placebo-controlled trial. J Psychopharmacol. 2013 Oct 15;28(7):677-685.

[10] Karvat G & Kimchi T. Acetylcholine elevation relieves cognitive rigidity and social deficiency in a mouse model of autism. Neuropsychopharmacology. 2014 Mar;39(4):831-40.

[11] Tordjman S. et al. Gene × Environment interactions in autism spectrum disorders: role of epigenetic mechanisms. Front Psychiatry. 2014 Aug 4;5:53.

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Wellmann KA, Varlinskaya EI, & Mooney SM (2014). D-Cycloserine Ameliorates Social Alterations That Result From Prenatal Exposure To Valproic Acid. Brain research bulletin PMID: 25130667



Kim JW, Seung H, Kwon KJ, Ko MJ, Lee EJ, Oh HA, Choi CS, Kim KC, Gonzales EL, You JS, Choi DH, Lee J, Han SH, Yang SM, Cheong JH, Shin CY, & Bahn GH (2014). Subchronic Treatment of Donepezil Rescues Impaired Social, Hyperactive, and Stereotypic Behavior in Valproic Acid-Induced Animal Model of Autism. PloS one, 9 (8) PMID: 25133713