"Childhood seizures and risk of psychiatric disorders in adolescence and early adulthood"

I want to bring the findings reported by Julie Dreier and colleagues [1] to your attention today and their observation that: "Children with epilepsy and febrile seizures-with and without concomitant epilepsy-are at increased risk of developing a broad range of psychiatric disorders in later life."

Researchers report results based on the examination of one of those ever-so-impressive Scandinavian population registries that have moved science forward in many, many different areas (see here for example). This time around it was the Danish National Patient Register and the inclusion of data from "1 291 679 individuals... born in Denmark and followed up in our population cohort (approximately 15 million person-years)." Over 43,000 individuals showed a history of febrile seizure - "fits that can happen when a child has a fever" - and over 10,000 had epilepsy. Likewise: "83 735 (6%) cohort members were identified with at least one of the psychiatric disorders of interest" including substance abuse disorders, schizophrenia, mood disorder, anxiety, and personality disorder.

Results: "The risk of any psychiatric disorder was raised in individuals with a history of febrile seizures..., epilepsy..., or both disorders." The magnitude of the risk was categorised as statistically significant in terms of elevation but ranged from between a 10-50% increased risk. Further: "Excess risk of psychiatric illness associated with childhood seizures was present across a range of different disorders, most notably schizophrenia but also anxiety and mood disorders." Authors also opine that further research is needed on this topic with regards to mechanisms pertinent to identifying "potential options for prevention."

Although some caution is always required when one variable (epilepsy) is solely correlated with another (history of recorded psychiatric diagnosis), I am interested in the Dreier findings. I'm interested not only because of the *association* being made between a condition that often has life-changing effects on other often life-changing diagnoses but also because this *association* complements other links being made with epilepsy. I speak of the various studies linking epilepsy to diagnostic labels such as autism and attention-deficit hyperactivity disorder (ADHD) of course (see here and see here for examples) whilst pointing out that ADHD and autism are not to be categorised as mental health conditions. Such links between epilepsy and neurodevelopmental diagnoses are all the more interesting because the presence of labels such as autism and ADHD are also known to manifest elevations in other psychiatric diagnoses such as mood disorder, anxiety and schizophrenia (see here and see here and see here for examples). It's not therefore unreasonable to suspect that there may be some 'over-arching' themes when it comes to epilepsy/febrile seizures 'linking' with various developmental and psychiatric diagnoses.

Minus any sweeping generalisations and being careful how I phrase this, one area that requires a lot more investigation is the neurological effect that epilepsy in particular can have. I speak of the idea that seizures can, in some cases, affect the physical nature of the brain [2] and the question of whether such 'damage' might also then affect the presentation of behaviour akin to the signs and symptoms of a neurodevelopmental or psychiatric diagnosis. I know this is not a particularly palatable line of thinking but it does require further scientific exploration. This is also pertinent to the Dreier study focusing in on childhood seizures and by inference, possible effects on the developing brain. Another area of further investigation is whether the presentation of epilepsy or seizures *might* be part-and-parcel of various syndromes also presenting with neurodevelopmental and/or psychiatric features? We do have some examples of this already (see here) and, given that various genetic syndromes are quite regularly being identified day-by-day, it's another area that could yield some important data.

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[1] Dreier JW. et al. Childhood seizures and risk of psychiatric disorders in adolescence and early adulthood: a Danish nationwide cohort study. Lancet Child Adolesc Health. 2018 Dec 6. pii: S2352-4642(18)30351-1.

[2] Bronen RA. et al. The Status of Status: Seizures Are Bad for Your Brain's Health. American Journal of Neuroradiology. 2000; 21: 1782-1783.

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"not consistent with the hypothesis that ADHD medication increases risk of seizures"

ADHD mentioned in the title of this post - "not consistent with the hypothesis that ADHD medication increases risk of seizures" - refers to attention-deficit hyperactivity disorder; said quote coming from the paper by Kelsey Wiggs and colleagues [1].

Wiggs et al report findings based on the premise that: "Individuals with attention-deficit/hyperactivity disorder (ADHD) are at increased risk of seizures" (see here) and specifically the question of whether or not "ADHD medication treatment increases risk among patients with and without preexisting seizures."

To try and answer their research question, authors relied on data from a sample including over 800,000 people diagnosed with ADHD "who had prescribed drug claims from the Truven Health MarketScan Commercial Claims and Encounters databases." I have talked about other research utilising these databases before on this blog (see here), once again looking at ADHD medicines and also including some of the authors listed on the Wiggs paper.

Wiggs reports results that were primarily two-fold: (a) assessing "overall risk of seizures among patients with ADHD" and (b) "odds of seizure events during months when a patient with ADHD received ADHD medication compared with when the same individual did not, while adjusting for antiepileptic medications."

Result: yes, yet again a diagnosis of ADHD did seem to *correlate* with a higher odds for seizure episodes when compared with (non-ADHD) controls. Similarly, use of ADHD medicines seemed to *correlate* with a lower odds of seizures, both in those with a history of seizures and those without.

With the requirement for further investigation, this are interesting findings. I note there has been previous peer-reviewed discussion on the potential risk(s) of seizure attached to certain medicines indicated for ADHD [2]. It's been a bit of a mixed bag in terms of any possible association or not, but allowing for individual medicines, the research has generally observed no significant effect of such medicines on seizure risk in cases of ADHD. Generally-speaking. Wiggs and colleagues seem to go one stage further on from suggesting no effect to observing something of a potential protective effect from such medicines in relation to seizure risk in cases of ADHD. If replicated, such findings could be rather important...

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[1] Wiggs KK. et al. Attention-deficit/hyperactivity disorder medication and seizures. Neurology. 2018 Feb 23. pii: 10.1212/WNL.0000000000005213.

[2] McAfee AT. et al. A cohort study of the risk of seizures in a pediatric population treated with atomoxetine or stimulant medications. Pharmacoepidemiol Drug Saf. 2013 Apr;22(4):386-93.

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Second seizure risk and "idiopathic autism"

Idiopathic autism refers to instances where autism is the primary diagnosis and not something secondary to another - usually genetic - condition. The paper by Asad Qadir and colleagues [1] reviewed the files of some 150 people diagnosed with an autism spectrum disorder (ASD), idiopathic ASD, and a history of at least one seizure in connection to an important issue: recurrence risk of seizure. They concluded that the average age of first seizure in their cohort was around about 7 years old and many, over 90% of participants included for review, were at serious risk of a second seizure on average just over 6 months later.

This is an important finding. We already know that epilepsy and seizure disorder(s) are not uncommon bedfellows to parts of the autism spectrum (see here) (indeed, many parts of the autism spectrum seem to be prone to unusual EEG - electroencephalographic or electroencephalogram - findings). We know that non-febrile seizures (seizures not attached to fever) are quite a bit more common in relation to autism when compared with non-autistic siblings for example (see here). And on top of all that, we know that seizures can in some instances be life-threatening (see here).

The Qadir data highlights the "short time to second seizure" as a window to appropriate management of seizure when coincidental to autism. The data suggest that even after one seemingly isolated incidence of seizure, clinicians might consider being proactive in (i) screening for signs of EEG anomalies for example, and (b) be pretty assured that initiation of appropriate treatment/management of seizure is very likely applicable insofar as the risk of recurrence in those diagnosed with an ASD. I say all that with my blogging caveat of no medical or clinical advice given or intended, in full working order.

I'd also like to think that as our knowledge about the autism spectrum increases, in particular the idea that there may be many different routes to many different types of autism (see here) so science will start to put some further flesh on the bones that what we call idiopathic autism with epilepsy at the moment, does not necessarily mean things will stay 'idiopathic' in future times. Then, other questions need answering, such as whether certain 'epileptic encephalopathy syndromes' might actually be the cause of some autism [2]...

As I've said many times before on this blog, don't mess with seizures and/or epilepsy...

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[1] Qadir AA. et al. Risk of Second Seizure in Pediatric Patients With Idiopathic Autism. J Child Neurol. 2017 Jan 1:883073817713906.

[2] Srivastava S. & Sahin M. Autism spectrum disorder and epileptic encephalopathy: common causes, many questions. J Neurodev Disord. 2017 Jun 23;9:23.

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EEG abnormalities and "high functioning" autism

I'm not a great fan of the term 'functioning' when it comes to autism (see here) hence the quote marks around high-functioning in the title of this post. Yes, I understand the message that it's trying to convey and that we don't have viable alternatives at the moment. It just however seems a little sweeping in terms of 'generalised' describing and labelling of people...

No mind. Today I'd like to bring the paper by Özdem Ertürk Çetin and colleagues [1] to your attention and the observation that their results "support the fact that EEG abnormalities are observed at a higher rate also in ASD [autism spectrum disorder] with a better functionality." EEG - electroencephalographic or electroencephalogram - refers to the recording of electrical activity in the brain. Although in small amounts, our cells use electrical signals to message each other; said activity in the brain can be picked up and recorded using some rather sensitive equipment. EEGs are the method of choice when it comes to investigating epilepsy or related seizure disorders (such conditions are epitomised by abnormal electrical activity between cells).

The connection between autism and epilepsy / seizure disorder is one that has persisted for many years (see here); even now to the point where research is starting to talk about autism / autistic traits being a feature of some cases of epilepsy (see here). Quite a bit of the research looking at autism and epilepsy has tended to suggest that epilepsy may be a little more over-represented for those towards the more severe end of the autism spectrum (i.e. in relation to presentation of symptoms and the presence of some degree of learning / intellectual disability). The Ertürk Çetin findings report that even in those with described 'better functionality' there may be disturbances in relation to the measurement of EEGs.

Looking for "the presence of EEG abnormalities in sixteen children diagnosed with high-functioning ASD" researchers reported that whilst none of the participants had clinical seizures (the overt expression of epilepsy) "5 patients (31.3%) were detected to have EEG abnormalities." Bearing in mind the quite small participant numbers and the fact that no control groups (asymptomatic or otherwise) were included for comparisons, this is quite an important finding. I agree with the authors when they say that: "The potential impact of EEG abnormalities on cognition and behavior, and the risk of epilepsy should be considered during long-term follow-up of these patients." In other words, whenever a diagnosis of autism or ASD is received, one should always consider the possibility that a heightened risk of epilepsy / seizure / abnormal EEG patterns might also be a feature of presentation irrespective of "functioning" status.

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[1] Ertürk Çetin Ö. et al. EEG abnormalities and long term seizure outcome in high functioning autism. Acta Neurol Belg. 2017 Apr 26.

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Ertürk Çetin Ö, Korkmaz B, Alev G, & Demirbilek V (2017). EEG abnormalities and long term seizure outcome in high functioning autism. Acta neurologica Belgica PMID: 28447214

Autism, ageing and comorbidity

I'm not spending too much time today on the findings published by Elizabeth Wise and colleagues [1] but did want to bring them to your attention. Looking at the presentation of "comorbidities and behavioral and neuropsychiatric symptoms" in relation to autism in the context of ageing, some important details were noted. Not least that "GI [gastrointestinal] disorders (68.9%) and seizure disorders (23%) were common, and 25.7% of the sample had a BMI [body mass index] >30" when looking at their 74 strong cohort of adults diagnosed with autism (DSM-5 autism by all accounts).

It's not new news that the label of autism rarely exists in some sort of diagnostic vacuum (see here and see here for other examples). The fact that GI disorders (whether functional or more pathological), epilepsy and/or seizure disorder and excess BMI have been picked out by Wise et al ties into an extensive peer-reviewed research body highlighting such issues. What is still missing from quite a lot of that literature is the hows-and-whys of such over-represented comorbidity and importantly, what can be done to manage/ameliorate them (see here for example) given that sometimes they can be just as 'disabling' as a diagnosis of autism itself.

Wise and colleagues also noted that: "the point prevalence of behavioral and neuropsychiatric symptoms (BNPS) declined significantly for 12 of 13 BNPS over a mean of 25 years while many other features of ASD remained stable." Accepting the relatively small cohort studied, this is an interesting finding and ties into other research looking at what happens to something like psychiatric comorbidity in the context of ageing and autism (see here). There is a caution attached to the idea that behavioural and psychiatric comorbidity might be quite fluid across the lifespan in relation to autism insofar as sex/gender potentially being an important variable (see here).

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[1] Wise EA. et al. Aging and Autism Spectrum Disorder: A Naturalistic, Longitudinal Study of the Comorbidities and Behavioral and Neuropsychiatric Symptoms in Adults with ASD. J Autism Dev Disord. 2017. Mar 16.

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Wise EA, Smith MD, & Rabins PV (2017). Aging and Autism Spectrum Disorder: A Naturalistic, Longitudinal Study of the Comorbidities and Behavioral and Neuropsychiatric Symptoms in Adults with ASD. Journal of autism and developmental disorders PMID: 28303420

8.6% of children with autism have epilepsy?

"Epilepsy was reported to co-occur in 8.6 % of ASD [autism spectrum disorder] cases."

That was the headline conclusion reported by Shiny Thomas and colleagues [1] as they drew on data from "the most recent U.S. National Survey of Children's Health, 2011-2012" to add to the extensive literature looking at how common epilepsy is when it comes to autism.

Including some 1600 children/young adults diagnosed with autism - equivalent to a prevalence of 1.8% of the entire 85,000-strong cohort - researchers "examined parent-reported prevalence of co-occurring epilepsy" and eventually came up with that 8-9% figure. Further, they also observed that: "the co-occurrence of epilepsy was associated with increasing child age, female gender, intellectual disability, speech problems and lower socioeconomic status."

This is important work. Epilepsy or seizure disorder is not something to be taken lightly under any circumstances; more so when applied to autism and the 'burden' of medical comorbidity that seems to be over-represented following a diagnosis (see here). The use of the U.S. National Survey of Children's Health (NSCH), 2011-2012 also has some significant strengths in terms of numbers of participants and has previously informed quite a few areas of autism research (see here for example).

There is another important detail attached to the Thomas paper that is also worthy of comment in relation to how their prevalence figure compares with other independent studies in terms of epilepsy appearing comorbid to autism (readers should click on the 'Supplementary material' attachment shown here). Bearing in mind their data was derived from children "ages 2-17" and includes the term 'parent-reported' (as opposed to medical records reported) the 8.6% figure seems to be quite a conservative one. I say this on the basis that previous data from NSCH has observed slightly higher rates of epilepsy (see here) and other data sources have even talked about 1 in 5 children on the autism spectrum manifesting with a seizure or seizure disorder (see here). I of course realise that the word 'epilepsy' covers quite a bit of diagnostic ground and seizures/seizure disorder can present for a variety of reasons, but nonetheless I stand by the 8.6% comorbidity figure as perhaps being one of the lower values published in the peer-review domain.

The additional observations that 'increasing age' and presence of intellectual (learning) disability might influence the presence of epilepsy in relation to autism are interesting but by no means novel findings. They do however offer something of a roadmap to monitoring those on the autism spectrum who may be at some enhanced risk of developing epilepsy and indeed, implementing the relevant strategies in a timely fashion to ensure that epilepsy is managed safely.

Many questions still remain concerning the hows and whys of epilepsy intersecting with autism (and indeed, autism intersecting with epilepsy) including those related to more 'non-traditional' aspects (see here for example). What however is abundantly clear from the peer-reviewed and other literature in this area is that epilepsy is an important part of life for quite a few people on the autism spectrum and as many resources as possible should be pumped into looking at the relationship and offsetting / averting the potentially life-changing consequences that epilepsy can have on a person and their loved ones (see here).

To close, when one mentions 'God Save the Queen' one should really specify which version one requires?

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[1] Thomas S. et al. Brief Report: Prevalence of Co-occurring Epilepsy and Autism Spectrum Disorder: The U.S. National Survey of Children's Health 2011-2012. J Autism Dev Disord. 2016 Oct 17.

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Thomas S, Hovinga ME, Rai D, & Lee BK (2016). Brief Report: Prevalence of Co-occurring Epilepsy and Autism Spectrum Disorder: The U.S. National Survey of Children's Health 2011-2012. Journal of autism and developmental disorders PMID: 27752862

Around 1 in 5 with autism will experience seizure or seizure disorder

The paper by Jennifer Jaskiewicz and colleagues [1] recently offered a further important insight into the relationship between autism and seizure or seizure disorder (i.e. epilepsy).

Based on the examination of records of nearly 50,000 children and young adults diagnosed with an autism spectrum disorder (ASD) compared with approximately quarter of a million 'not-autism' participants, authors reported some interesting trends. Concluding that some 19% of participants with autism experienced "some kind of seizure or seizure disorder", the study in particular reaffirms something of an important relationship between [some] autism and [some] epilepsy or seizure disorder.

Drawing on data derived from the US Military Health System database between 2000-2013, the records of children and young adults aged 0-18 years were the focus of analysis, where those with autism were age and sex-matched with asymptomatic (not autism) controls. Alongside the heightened risk of a general description of 'seizure or seizure disorder' in the autism group, authors also reported that specific issues such as status epilepticus and absence seizures were over-represented in the autism group. Febrile seizures - seizures that accompany fever - were also over-represented in the autism group although to a slightly lower extent than other seizure types. The authors conclude that: "Rates of epilepsy in children with autism are vastly increased in a wide variety of seizure types, known to have different etiologies, genetic and otherwise." Compare also the estimate of epilepsy or seizure disorder shown here with other population figures [2] and you get a flavour for how advanced the risk might be...

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[1] Jaskiewicz J. et al. Quantification of Risks of Seizure in Autism. Neurology. 2016; 86: suppl. S32.003.

[2] Russ SA. et al. A national profile of childhood epilepsy and seizure disorder. Pediatrics. 2012 Feb;129(2):256-64

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Jennifer Jaskiewicz, Apryl Susi, Elizabeth Hisle-Gorman, David Dennison, Gregory Gorman, Cade Nylund, & Christine Erdie-Lalena (2016). Quantification of Risks of Seizure in Autism Neurology