Epilepsy and Cardiovascular Events

By Robert McInnis, MD

Synopsis: This large prospective cohort study found that older adults with a lifetime history of epilepsy were more likely to experience cardiovascular events (CVEs), and that enzyme-inducing antiseizure medications (EIASMs) may account for a significant portion of this risk. The findings suggest a potential causal link between epilepsy treated with EIASMs and CVE, highlighting the need for careful medication selection in epilepsy management.

Source: Jimmy Li, Shlobin NA, Thijs RD, et al. Antiseizure medications and cardiovascular events in older people with epilepsy. JAMA Neurol. 2024;81(11):1178-1186.

Epilepsy is a chronic condition that affects approximately 1% of the population. Older adults comprise a large proportion of those living with epilepsy — a proportion that will increase substantially over time in line with worldwide demographic trends. There is growing evidence that epilepsy and its treatments are associated with increased cardiovascular comorbidity, although the nature and directionality of this relationship in older adults, who are more vulnerable to cardiovascular events (CVEs), remain poorly understood.

To address this knowledge gap, Li and colleagues conducted a prospective cohort study using participants recruited through the Canadian Longitudinal Study on Aging (CLSA). They examined medication and CVEs in participants who had a lifetime history of epilepsy, determined by participant responses to a questionnaire previously demonstrated to have a high sensitivity and specificity for epilepsy.

Participants were aged 45-85 years at the time of enrollment and were excluded if they lived in a long-term care facility, had cognitive impairment, resided in a First Nation reserve, were full-time in the Canadian Armed Forces, or could not communicate in English or French. Participants were followed over six years, with in-person visits occurring at the baseline, three years, and six years. Those with history of CVEs (stroke, transient ischemic attack [TIA], or myocardial infarction [MI]) prior to the baseline visit were excluded. The primary outcome was self-reported occurrence of a CVE, while secondary outcomes were subtypes of CVE (stroke, TIA, or MI).

Sociodemographic variables, medical comorbidities, medication variables (including the use of enzyme-inducing antiseizure medications [EIASMs]), and clinical measures of cardiovascular health (e.g., Physical Activity Score for the Elderly [PASE], waist-to-hip ratio, and blood biomarkers such as high-density lipoprotein and total cholesterol) also were recorded.

There were 27,320 participants included in the analysis, with a mean age of 62 years, 52.4% female sex, and with 431 reporting a lifetime history of epilepsy. Employing a regression model after multiple imputations adjusting for age, sex, household income, and educational level, investigators found that new CVEs were more likely to occur in those with a lifetime history of epilepsy over the six-year follow-up period (adjusted odds ratio, 2.2; 11.9% in people with epilepsy [PWE] vs. 5.4% in those without epilepsy).

Investigators then calculated the proportions of the effect of exposure of lifelong epilepsy on CVEs as mediated by EIASM exposure (strong and weak EIASM were examined separately), non-EIASM use (e.g., lamotrigine, lacosamide, levetiracetam), and cardiovascular risk factors including Framingham score, PASE score, and waist-to-hip ratio. This analysis revealed that exposure to EIASM explained nearly one-third of CVEs in those with lifelong epilepsy, with the vast majority (25%) explained by exposure to a strong EIASM.

Commentary

This large prospective cohort study enhances our understanding of the connection between epilepsy and cardiovascular disease, offering compelling evidence that PWE are at an elevated risk of CVEs. Notably, a significant portion of this risk appears to be driven by using EIASMs, particularly strong EIASMs, rather than by traditional cardiovascular risk factors.

Although the study’s strengths include its large sample size and in-person assessments, the reliance on participant self-reports may introduce some bias in the classification of epilepsy and other historical variables. Nevertheless, these findings suggest a potential causal link between epilepsy treatments and cardiovascular risk, emphasizing the need for neurologists and epileptologists to carefully consider this relationship when selecting medications for their patients.

Robert McInnis, MD, is Assistant Professor of Clinical Neurology, Weill Cornell Medical College.