Abstract
Carson L, Parlatini V, Safa T, Baig B, Shetty H, Phillips-Owen J, Prasad V, Downs J. Eur Child Adolesc Psychiatry. 2022. doi:10.1007/s00787-022-02041-3
Children and young people with Autism Spectrum Disorder (ASD) have an increased risk of comorbidities, such as epilepsy and Attention-Deficit/Hyperactivity Disorder (ADHD). However, little is known about the relationship between early childhood epilepsy (below age 7) and later ADHD diagnosis (at age 7 or above) in ASD. In this historical cohort study, we examined this relationship using an innovative data source, which included linked data from routinely collected acute hospital paediatric records and childhood community and inpatient psychiatric records. In a large sample of children and young people with ASD (N = 3237), we conducted a longitudinal analysis to examine early childhood epilepsy as a risk factor for ADHD diagnosis while adjusting for potential confounders, including socio-demographic characteristics, intellectual disability, family history of epilepsy and associated physical conditions. We found that ASD children and young people diagnosed with early childhood epilepsy had nearly a twofold increase in risk of developing ADHD later in life, an association which persisted after adjusting for potential confounders (adjusted OR = 1.72, CI95% = 1.13-2.62). This study suggests that sensitive monitoring of ADHD symptoms in children with ASD who have a history of childhood epilepsy may be important to promote early detection and treatment. It also highlights how linked electronic health records can be used to examine potential risk factors over time for multimorbidity in neurodevelopmental conditions.
Commentary
What did medical science ever do before big data? Maybe the world was smaller or clearer. After all, science is blissfully more manageable when there is no way to know the unknown. But big data can bring new concepts and new questions, challenging notions of what has been accepted about neurologic and psychiatric conditions. As a field, we already know that previous conventional wisdom of the independence of psychiatry and neurology is largely spurious. Yet the simplistic notions of this approach are even more flawed when reports from large scale databases identify new associations and overlaps that may have previously been hidden from view. That is the case with Carson et al, in showing how the seemingly disparate conditions of autism, childhood onset epilepsy, and attention deficit hyperactivity disorder (ADHD), assort together so frequently that a common physiologic underpinning may be present. 1
While overlaps between epilepsy and psychiatric conditions have been recently reported so often that the idea has become de rigueur, this particular study actually shows us something new. The investigators started with a large population of individuals with Autism Spectrum Disorder, and then followed them in order to see what subsequent diagnoses emerged, as coded in medical records. The database was created from electronic health records from several institutions in the United Kingdom. Records were reviewed in order to assess the age of diagnosis of childhood onset epilepsy, then followed to assess the timing of subsequent diagnoses of ADHD. The results suggest that earlier onset epilepsy was associated with a twofold increase in subsequent diagnoses of ADHD. The approach is direct and noteworthy, especially since the sample exceeded 3200 patients.
While the overrepresentation of ADHD in epilepsy has been well established, the relationship to the timing of the diagnosis of epilepsy is not well understood. 2 Autism is presumed to start very early in life, perhaps with genetic underpinning, as with other disorders potentially reflecting aberrant neuronal architecture or migration. Superimposing additional instability as with early onset epilepsy may then yield further disruption in higher order functions, such as language or cognitive development. ADHD may be the culmination of disordered thought processing, given difficulties of sustaining attention and filtering out extraneous information. The relationships are exceedingly complex particularly given the heterogeneity in all of these conditions. However, with big data sets, we can not only assess co-occurrence but also the timing of that co-occurrence, and that may reflect a dynamic physiologic process and vulnerability to further developing pathologic conditions that have not been previously appreciated.
Carson and colleagues likely had the right idea in starting with a population with ASD to base their exploration. ASD certainly has a varied etiology, as is consistent with the spectrum nomenclature. Yet many researchers consider that autism spectrum disorders may reflect anomalous neural connectivity and hyperexcitability of those anomalous neurons. 3,4 The hyperexcitability theory posits that excess glutamatergic activity is present in autism and leads to overactive neuronal firing. In the context of additional problems with connectivity or pruning, many sources of “flash points” could be found. One could not help thinking that this pathway seems a lot like pathologic processes in epilepsy, with overactive neurons firing without sufficient inhibitory infrastructure to prevent full-blown seizures. 5 Perhaps then it is no accident, as the authors note, that autism spectrum disorder has an associated prevalence of epilepsy as high as 39%. 1 The hyperexcitability may be the common thread.
Additionally, patients with ASD independently often have unusual findings on EEGs. Several reports suggest that isolated spikes or nonspecific epileptiform discharges may be more common in ASD even if frank epilepsy is not present. 6 The same seems to be the case for ADHD as well. A sizeable amount of circumstantial evidence suggests that epileptiform abnormalities may be present in ADHD, including rolandic spikes. 7 One report suggests that up to half of patients with ADHD may have abnormal discharges identifiable on EEG. 8
To be fair, most notions of physiologic overlap and intersecting developmental pathways are speculative, but such evidence often reflects conjecture that may eventually be borne out by the facts. If a brain with hyperexcitable neurons and anomalous connectivity develops seizure activity early in life, then it may be reasonable to expect that higher order functions of sustained attention and impulse control would also be altered later in life. ADHD is often considered a condition identifiable in school-aged children, but precursors may be present earlier. The onset of epilepsy may be a key ingredient in ASD that consolidates that phenotype more efficiently and explains the pathologic process of ADHD at the same time.
We can thank Carson and colleagues for deliberately seeking associations between these conditions. Looking for symptomatic common ground is a sound albeit difficult way to learn about neuropsychiatric conditions. The field is prolific with emphasis upon mood disorder comorbidity with epilepsy and also with specific cognitive deficits associated with epilepsy syndromes. But examining early onset conditions may be simpler and prove to be even more enlightening. The common ground of hyperexcitability, whether propagated by excess glutamatergic activity or not, may suggest that epilepsy, ASD, and ADHD are simply phenotypes, all reflecting a common pathophysiologic process that is now becoming clearer. Ultimately, our paradigms may become better refined, simply by identifying aggregations of illnesses. Now we know more about where to look for them.
