Could a Hypertension Drug Protect Against Post-Stroke Epilepsy?

LOS ANGELES — Use of angiotensin receptor blockers (ARBs) was linked to a lower risk of epilepsy after an acute ischemic stroke, according to an observational study.

Among hypertensive patients, ARB use was the only factor significantly associated with onset of post-stroke epilepsy after multivariate adjustment, reported Giacomo Evangelista, MD, of G. D’Annunzio University of Chieti-Pescara in Chieti, Italy, at the American Epilepsy Society annual meeting.

ARB users accounted for about 5% of those who developed epilepsy (two of 38) and 25% of those who didn’t develop epilepsy after their stroke (104 of 409).

The findings match up with observational findings among hypertensive persons without prior stroke, the researchers noted. One large study from Germany showed a hazard ratio of 0.77 (95% CI 0.65-0.90) for epilepsy incidence among ARB users compared with users of other antihypertensive drug classes. An even larger U.S. study showed similar adjusted hazard ratios of 0.70 to 0.75 for ARBs versus other antihypertensive classes, which appeared to be driven by a reduction with losartan.

“In our study, ARBs show a potential protective role in epilepsy development in patients with hypertension and stroke,” Evangelista concluded. “These insights can help inform clinical guidelines and therapeutic strategies, emphasizing the need for larger, prospective studies to confirm these results and further elucidate the mechanisms involved.”

Ischemic stroke is the most common cause of seizures in patients older than 60 years, Evangelista noted, as it accounts for about 6-8% of new epilepsy diagnoses in elderly patients.

“It has been postulated that the brain’s renin-angiotensin-aldosterone system plays a special mediating role in epilepsy pathology and may be associated with the hyperactivation of angiotensin II type 1 receptor and ACE [angiotensin-converting enzyme] signaling in astrocytes, oligodendrocytes, and microglia,” the researchers noted.

Potential mechanisms could include reducing neuronal loss and microglia-mediated inflammatory responses or other neuroinflammatory processes. Evangelista’s group added that ARBs “downregulate the TGF-beta-mediated signaling cascade displaying numerous neuroprotective benefits, such as diminishing neuroinflammation or reducing epilepsy severity and seizure frequency.”

Although the findings corroborate those of prior studies, Alain Lekoubou Looti, MD, of Penn State College of Medicine in Hershey, Pennsylvania, cautioned against overinterpreting the results from observational studies, which cannot account for all possible variables or make any conclusions about causality. He was not involved in the study.

“At this stage it’s too premature to just use these results to make a recommendation on antihypertensive medication prescription to prevent late-onset seizures,” he told MedPage Today. “I think at this point it’s important to start thinking about a randomized clinical trial that would test the impact of ARBs, and more specifically losartan, on preventing seizures in patients with hypertension.”

Evangelista’s retrospective study used data from 528 patients (mean age 71, 57% men) who had hypertension and a diagnosis of ischemic stroke, which had to be confirmed by clinical and neuroimaging evaluations, and who were seen at the neurology ward of a single center in Italy from January 2016 through January 2022.

All participants were followed up at a median of 24 months with a telephone interview based on a validated seizure detection questionnaire. Those who screened positive for possible epilepsy had an in-person neurological consultation and an electroencephalogram to determine the epileptic etiology of their episodes and to rule out mimic seizures.

Post-stroke epilepsy diagnosis was made according to International League Against Epilepsy criteria in 38 (7.2%) patients.

Most of the patients had pre-existing hypertension before stroke (70.3%), and each antihypertensive class was taken by 20-30% of patients. The same spread was seen post-stroke, with 34% on an ACE inhibitor, 21% on an ARB, 31% on a beta-blocker, and 28% on a calcium channel blocker. Most patients took a single antihypertensive; 37% took two or more drugs.

Unadjusted findings suggested a lower epilepsy risk with a number of the classes. The proportion of patients on each class in the epilepsy versus no-epilepsy groups were significantly lower with:

• ARBs (P=0.009)
• Beta-blockers (P=0.008)
• Calcium channel blockers (P=0.019)

However, the associations of epilepsy incidence with beta-blockers and calcium channel blockers disappeared upon multivariate adjustment.

The observational study could not draw any causal conclusions and was hampered by a limited sample size at a single institution, the researchers noted.