Hypertension May Double Risk of Late-Onset Epilepsy

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Hypertension is associated with more than a twofold increased risk of developing late-onset epilepsy (LOE) even in patients who have not had a previous stroke, new research suggests.

After excluding individuals with normal blood pressure who were taking antihypertensive medication, investigators found hypertension was linked to an almost 2.5-fold higher risk of epilepsy.

“Our findings further expand upon our knowledge of the negative effects hypertension has on brain health and, regarding epilepsy, that effect may be starting even in midlife,” co-lead author Maria Stefanidou, MD, MSc, of Boston University School of Medicine, Boston, Massachusetts, told Medscape Medical News.

“Practicing clinicians should be vigilant to diagnose hypertension, discuss with patients all potential long-term brain health outcomes, and need for treatment. Furthermore, in those presenting with new-onset epilepsy later in life, screening for potentially undiagnosed hypertension should be included in the initial workup,” she said.

The study was published online November 17 in the journal Epilepsia.

Unknown Etiology

“New-onset epilepsy risk increases with increasing age over the age of 65 and can affect 15 to 20 per 1000 older individuals. Although the most common causes for seizures in this age group are prior history of stroke and presence of dementia, for about 30% to 40% of patients, the etiology of seizures remains unknown,” Stefanidou said.

“We wanted to study if modifiable vascular risk factors that are known to contribute both to vascular brain aging and to neurodegeneration may directly predict the development of epilepsy, even in the absence of clinical stroke or dementia,” she added.

To investigate, researchers turned to data from participants in the Offspring Cohort of the Framingham Health Study (FHS). The original FHS was an ongoing longitudinal community-based study that first began in 1948. Offspring of the original cohort and their spouses (n = 5124) were enrolled in the Offspring Cohort in 1971, with surveillance of these second-generation participants based on exam visits occurring every 4 years.

The study included participants who had attended exam 5 (1991-1995), were age 45 years or older, had available vascular risk factor (VRF) data, and available follow-up data on epilepsy status (n = 2986, mean age 58 years, 48% male).

The investigators conducted two statistical analyses. In the primary model, they adjusted for age and gender, while in a secondary model they also adjusted for prevalent and interim stroke. They also conducted an analysis that excluded participants treated with antihypertensive medication and had normal blood pressure.

Plausible Mechanisms

During a mean follow-up of 19.2 years, 55 incident epilepsy cases were identified. The mean age of these patients was 73.8 years.

In the primary model, hypertension was associated with an almost twofold higher risk of developing epilepsy (HR, 1.97; 95% CI, 1.13 – 3.45; P = .017).

Interestingly, the Framingham Stroke Risk Profile — a calculation based on an array of factors, including age/sex, systolic blood pressure antihypertensive therapy, diabetes, history of cardiovascular disease, atrial fibrillation, and cigarette smoking — was not associated with incident epilepsy, and there was no other significant associated between any of the other VRFs when looked at independently.

When the researchers adjusted for prevalent and interim stroke, they continued to find an almost twofold higher risk of developing epilepsy (HR 1.93; 95% CI, 1.10 – 3.37; P = .022). An analysis that adjusted for competing risk of death obtained similar findings (HR, 1.98; 95% CI, 1.03- 3.81; P = .042).

The model that excluded patients receiving antihypertensive treatment, whose blood pressure readings were normal (n = 2162, 50 incident epilepsy cases) showed an even stronger association (HR, 2.44; 95% CI, 1.36 – 4.35; P = .003).

“Our results are based on an epidemiological, observational study, therefore our findings point to an association between hypertension and new-onset epilepsy later in life,” said Stefanidou.

She noted that because it was an observational study, “a cause-effect relationship cannot be established based on these results, but there is growing evidence from our, as well as other, similar cohorts that hypertension, a modifiable vascular risk factor, may indeed be an independent predictor of late-onset epilepsy.”

There are “plausible mechanisms” that support both a direct, and indirect, role of hypertension — for example, through accumulation of small vessel disease in the brain — but further research will be necessary to elucidate the exact mechanisms involved in the process,” she added.

“Welcome Addition”

Requesting comment on the study, Medscape Medical News spoke to Hedley C.A. Emsley, PhD, professor of clinical neuroscience, Lancaster University, Lancaster, UK, and Jasmine Wall, MBBChir, academic clinical fellow in neurology, Lancaster University, who described it as a “welcome addition to this field,” noting that the Framingham Heart Study “lends itself well to an embedded observational study of this nature of LOE.”

Emsley and Wall, who were not involved in the research, said that the “apparent magnitude of increased LOE risk association with hypertension in the Stefanidou et al study is quite striking,” even allowing for the “relatively small sample size,” since their analysis and findings appear to “withstand exclusion of individuals who became normotensive on antihypertensive treatment.”

They note that in recent years there’s has been a growing body of evidence highlighting the importance of hypertension in LOE epileptogenesis with subclinical cerebrovascular diseases, including “otherwise occult cerebral small vessel disease believed to be a frequent cause.”

The mechanisms “remain unclear,” but they could potentially include diffuse cerebral microangiopathy, structural and physiological changes, and/or blood–brain barrier dysfunction and leakage, they suggested.

“Although there is no current consensus over an age threshold that defines ‘late-onset,’ we would argue that age thresholds used in such studies of LOE should be lower, to avoid missing younger adults at risk through vascular mechanisms,” Emsley and Wall added.

The study authors suggest that “potential pathophysiologic mechanisms can further be explored in future experimental studies and clinical trials.”

This study was funded by grants from the National Institutes of Health (NIH) and Finding a Cure for Epilepsy/Seizures (FACES). Stefanidou has disclosed relevant financial relationships. The other authors’ disclosures are listed on the original paper. Emsley and Wall have disclosed no relevant financial relationships.

Epilepsia. Published online November 17, 2021. Abstract

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