Abstract
Brikell I, Ghirardi L, D'Onofrio BM, Dunn DW, Almqvist C, Dalsgaard S, Kuja-Halkola R, Larsson H. Biol Psychiatry 2018;83:173–180.
BACKGROUND: Epilepsy and attention-deficit/hyperactivity disorder (ADHD) are strongly associated; however, the underlying factors contributing to their co-occurrence remain unclear. A shared genetic liability has been proposed as one possible mechanism. Therefore, our goal in this study was to investigate the familial coaggregation of epilepsy and ADHD and to estimate the contribution of genetic and environmental risk factors to their co-occurrence. METHODS: We identified 1,899,654 individuals born between 1987 and 2006 via national Swedish registers and linked each individual to his or her biological relatives. We used logistic regression to estimate the association between epilepsy and ADHD within individual and across relatives. Quantitative genetic modeling was used to decompose the cross-disorder covariance into genetic and environmental factors. RESULTS: Individuals with epilepsy had a statistically significant increased risk of ADHD (odds ratio [OR] = 3.47, 95% confidence interval [CI] = 3.33–3.62). This risk increase extended to children whose mothers had epilepsy (OR = 1.85, 95% CI = 1.75–1.96), children whose fathers had epilepsy (OR = 1.64, 95% CI = 1.54–1.74), full siblings (OR = 1.56, 95% CI = 1.46–1.67), maternal half siblings (OR = 1.28, 95% CI = 1.14–1.43), paternal half siblings (OR = 1.10, 95% CI = 0.96–1.25), and cousins (OR = 1.15, 95% CI = 1.10–1.20). The genetic correlation was 0.21 (95% CI = 0.02–0.40) and explained 40% of the phenotypic correlation between epilepsy and ADHD, with the remaining variance largely explained by nonshared environmental factors (49%, nonshared environmental correlation = 0.36, 95% CI = 0.23–0.49). The contribution of shared environmental factors to the cross-disorder overlap was not statistically significant (11%, shared environmental correlation = 0.32, 95% CI = −0.16–0.79). CONCLUSIONS: This study demonstrates a strong and etiologically complex association between epilepsy and ADHD, with shared familial factors and risk factors unique to the individual contributing to co-occurrence of the disorders. Our findings suggest that epilepsy and ADHD may share less genetic risk as compared with other neurodevelopmental disorders.
Liu X, Carney PR, Bussing R, Segal R, Cottler LB, Winterstein AG. J Child Adolesc Psychopharmacol. 2018;28:111–116.
OBJECTIVE: To evaluate the safety of stimulants in children with epilepsy. METHODS: In a retrospective cohort study based on Medicaid Analytic eXtract billing records from 26 U.S. states from 1999 to 2010, we identified incident stimulant use among children with epilepsy through outpatient encounter claims and pharmacy claims. We established a control group of nonusers and used frequency matching to generate index dates. We followed both cohorts for 12 months and calculated hazard ratios [HRs] of current and former use of stimulants versus no use on the outcome of seizure-related hospitalization using multivariate Cox proportional hazard models.
Commentary
The links between attention-deficit/hyperactivity disorder (ADHD) and epilepsy continue to become better identified. Of course, there is much speculation about why these links exist, and the answers are not yet forthcoming. However, two recent papers have added more evidence on this topic and may even allay some fears about treatment aspects. Although etiologic pronouncements are still premature, the overlap between these two disorders cannot be ignored. Examining the recent reports from Brikell and colleagues and from Liu and colleagues, we have new energy to apply to diagnostic and treatment paradigms that may help us understand and manage both illnesses better.
First, we consider the links between the two conditions: Brikell et al. performed a comprehensive analysis of the Swedish population registry. Continuing on the recurring theme of bidirectionality often mentioned in reports over the past few years, having epilepsy makes it more likely that ADHD will eventually be diagnosed, and vice versa. The odds ratios are robust, with the lower confidence interval of 3.33. Risks for developing ADHD increased if primary family members—even half-siblings—also had epilepsy.
The study team went on to assess environmental effects, considering whether shared environment is related to the development of ADHD. As is the case for most population studies, the complexity of the analyses prevents clear-cut conclusions regarding associations. Familial relationships did not explain all the associations, so it could be posited that environmental or individual disease-specific factors also played a role. This would be intuitive, but the specific attribution ultimately may not matter. The fact that familial overlap occurs, whether environmental or primary genetic, is still notable. The authors noted that diagnostic sensitivity may play a significant role in how the associations are ultimately determined.
Thus links between ADHD and epilepsy are markedly present, more than would be expected by a random distribution. That suggests that management of epilepsy would commonly include simultaneous management of ADHD. This presents a conundrum, as the conventional wisdom is that medication treatments for ADHD may adversely affect seizure thresholds. Still present on FDA information labels for stimulant medications are strong precautions regarding seizure exacerbation. This has led to a generation of epileptologists who are legitimately hesitant about treating ADHD in the context of epilepsy. This predicament is highly unfortunate given the affirming evidence of frequent overlap of the two conditions given by Brikell and colleagues. It is still true in clinical practice that most patients with comorbid ADHD do not receive treatment for that condition.
Enter the recent report by Liu and colleagues. Clinicians are unsure about the use of stimulants in the context of pediatric epilepsy, so any evidence that evaluates the safety of such usage is welcome. Liu et al. similarly did a large-scale study addressing a broad pediatric population. Their sample was in the United States among children and adolescents who ultimately became hospitalized for seizure-related reasons. They reviewed hospital admission records of patients with epilepsy who were taking stimulants versus those who were not. The data were obtained from multiple states among those receiving public medical insurance.
Liu et al. used pharmacy records as proxies for current stimulant usage, and in that manner were also able to determine former usage of stimulants as well as no history of usage whatsoever. Three comparison groups were differentiated: current stimulant users, former stimulant users (over 6 months ago), and nonusers. Epilepsy characteristics were also obtained, such as generalized-versus localization-related seizures. Conditions such as cerebral palsy, congenital neurologic disease, or intellectual disability were also measured.
The analysis was robust, notably because a single objective measure—seizure-related hospitalization—was the outcome assessed. This outcome is exactly what clinicians need. Minor seizure exacerbations may not be meaningful or could reflect other antecedents or circumstances more significant to seizure threshold than stimulant usage. However, if hospitalization for seizures is necessary, then it could be concluded that treatment has been compromised in some way, and careful reevaluation of stimulant usage would be indicated.
The results were striking. Not only did stimulant usage in the present or recent past show no increase in seizure-related hospitalizations, it appeared that the stimulant users were actually less likely to require hospitalization. Seizure severity had a modest effect upon likelihood for hospitalizations, but other neurologic conditions, cerebral palsy, or other comorbid conditions did not change the outcome. It could then be concluded, albeit with reasonable limitations, that stimulants were actually protective against seizures that required hospitalization.
The idea that stimulant medicines are protective against seizures is completely counter to what generations of epileptologists have been taught. Yet the data continue to accumulate, suggesting that, at the very least, stimulants do not worsen seizures. According to Liu and colleagues, patients were less likely to end up in the hospital for seizure-related reasons if they were taking stimulants.
Perhaps the most valuable lesson from these two reports is that finally we can intuit combined treatment approaches for ADHD and epilepsy. Of course, this requires a paradigm shift from what the FDA and conventional wisdom have taught us. But medicine has always progressed by countering conventional wisdom. It took a generation for Helicobacter pylori to be accepted as etiologic for peptic ulcers (1). The sensibility for enriched environments to enhance brain growth in early childhood is still growing (2). Generations ago, the germ theory took a long time to accept (3).
Perhaps epilepsy and ADHD require a similar change in mind-set. We have numerous small treatment studies suggesting the safety of stimulants in the context of epilepsy. Now we have large-scale population studies suggesting that overlaps between the conditions are marked, and that stimulants do not lead to large scale seizure exacerbation. The need for effort to diagnose ADHD and the indications for stimulant treatment are clearer with these recent reports. Can we now consider ADHD and epilepsy as linked, maybe even as component parts of the same illness? Do we now consider stimulant medicine as protective against seizure exacerbation? Whether or not we accept these queries as constructed, this evidence must be acknowledged. Clinically, we can no longer avoid such decision making—it is time for us to act.