Zoe C. Wolcott, Brin E. Freund, William O. Tatum and Anteneh M. Feyissa*
Department of Neurology, Mayo Clinic Florida, Jacksonville, FL, United States
Edited by
Giovanni Boero, SS Annunziata Hospital, Italy
Reviewed by
Mariangela Panebianco, University of Liverpool, United Kingdom
*Correspondence
Anteneh M. Feyissa, feyissa.anteneh@mayo.edu
Received 16 June 2025
Accepted 25 June 2025
Published 08 July 2025
Citation
Wolcott ZC, Freund BE, Tatum WO and Feyissa AM (2025) Antiseizure medications for primary and secondary seizure prevention after stroke. Front. Neurol. 16:1648064. doi: 10.3389/fneur.2025.1648064
Post-stroke seizures (PSS) and post-stroke epilepsy (PSE) are serious complications of cerebrovascular disease, contributing to morbidity, delayed recovery, cognitive decline, and mortality. PSS are classified as early (within 7 days) or late (after 7 days), with late-onset seizures often signaling the development of PSE. As stroke survival improves, the incidence of PSS continues to rise. Risk factors include cortical involvement, large or severe strokes, and early seizures. Although antiseizure medications (ASMs) are central to management, their use is limited by a lack of high-quality trials and reliable predictive tools. Routine primary prophylaxis is generally discouraged, except in high-risk patients—such as those with hemorrhagic stroke or severe cortical damage—while secondary prophylaxis after unprovoked seizures remains standard. Evidence supporting specific ASMs is limited, but lamotrigine and levetiracetam are considered reasonable first-line options. ASM selection should be individualized, particularly in older adults or those with cardiovascular or cognitive comorbidities, for whom older, enzyme-inducing ASMs carry greater risks. Withdrawal is often recommended after early seizures, but managing established PSE remains challenging without validated biomarkers. High-quality trials are urgently needed to evaluate the efficacy, safety, and tolerability of ASMs in post-stroke seizure prevention. Advancing the field also requires robust validation studies, improved prediction models, and personalized treatment strategies. This minireview summarizes current approaches to ASM use in PSS, with an emphasis on clinical decision-making for initiation and discontinuation.
Keywords
antiseizure medication; early seizure; late seizure; post-stroke seizures; stroke-related epilepsy; stroke; symptomatic epilepsy
1 Introduction
Post-stroke seizures (PSS) are classified as early (within 7 days) or late (after 7 days). Early seizures, or acute symptomatic seizures (ASS), result from transient neurochemical changes post-stroke and are not typically epileptic. Late seizures, or unprovoked seizures, stem from lasting structural brain changes and signify post-stroke epilepsy (PSE). The 7-day cutoff is widely accepted and aligns with underlying pathophysiology (1). Early seizures occur in 3–6% of stroke patients, more commonly in hemorrhagic (10–16%) than ischemic strokes (2–4%) (2, 3). Stroke causes 73% of acute symptomatic seizures in adults. Late seizures affect 3–5% using the 7-day definition, with incidence up to 12%. According to the International League Against Epilepsy (ILAE), PSE can be diagnosed after a single unprovoked seizure, as it reflects an enduring brain change with a high recurrence risk (>60% over 10 years) (1). Redefining PSE to include single late seizures has raised incidence estimates to 8–12% (1).
Risk factors for PSS include cortical involvement, severe or large strokes, and early seizures (2, 4, 5). Hemorrhagic strokes carry a higher PSE risk (12.4%) than ischemic ones (6.4%). Additional predictors include ICH volume, younger age, hyponatremia, alcohol use, and premorbid disability (4). Stroke treatments, including decompressive craniectomy, craniotomy, intravenous alteplase, or endovascular treatment, are also considered risk factors (3). Routine scalp electrocephalograpm (EEG) has not reliably predicted PSE, but focal epileptiform discharges and lateralized periodic patterns may carry prognostic value (6). Prediction models like the SeLECT score exist but need further validation before widespread use (7).
Studies indicate that PSS is associated with worse functional outcomes and increased disability. Patients with PSS have significantly higher modified Rankin Scale scores and greater odds of poor outcome (3). PSE also contributes to long-term morbidity. There is growing evidence linking PSE with increased dementia risk. A 2.5-fold higher dementia incidence was reported in young stroke survivors with seizures, and pooled analyses confirm that PSS is independently associated with dementia (8). This suggests a feed-forward relationship among stroke, PSS, and neurodegeneration (8).
This minireview discusses antiseizure medication (ASM) therapies for managing PSS, including clinical considerations for initiating and discontinuing treatment.
2 Primary prophylaxis
Routine primary prophylaxis ASMs after stroke is generally not recommended due to the low incidence of PSS or PSE and the significant risk of adverse drug reactions (ADRs), especially in older adults with comorbidities (9, 10). Professional guidelines reflect this: the European Stroke Organization gives a weak recommendation against primary prophylaxis due to very low-quality evidence, and the American Heart Association/American Stroke Association similarly advises against routine ASM use, noting that potential harms outweigh benefits for most survivors (10).
For most patients, harms outweigh the benefits of preventing a first seizure. However, certain high-risk groups may warrant selective primary prophylaxis briefly. Even then, decisions must carefully weigh seizure risk against ASM tolerability and ADRs (11, 12). Tools such as the SeLECT score for ischemic stroke and the CAVE and 2HELPS2B scores for ICH help quantify seizure risk (4, 12). These models include factors like cortical involvement, NIHSS severity, early seizure, and MCA distribution infarcts. Despite this, primary prophylaxis is rarely recommended, even in high-risk patients, as efficacy evidence remains sparse and low quality (9, 11).
Evidence for primary ASM prophylaxis after hemorrhagic stroke is limited. Two randomized trials assessed this: one comparing valproate to placebo in 72 ICH patients showed no significant benefit (13), while the PEACH trial testing levetiracetam yielded mixed results—some reduction in electrographic seizures but no effect on clinical seizures (14). Both were underpowered, with the PEACH trial halted early due to poor recruitment. A Cochrane review incorporating these studies concluded ASMs do not effectively prevent post-stroke seizures, rating the evidence as low quality due to imprecision (9). No trials support long-term prophylaxis for late unprovoked seizures. Two small studies on short-term prophylaxis post-ICH were inconclusive (11, 12).
Observational studies provide important insights. A real-world study in older adults with acute ischemic stroke found higher 30-day mortality among those receiving seizure prophylaxis within 7 days, raising concerns about net benefit (15). Decision models favor secondary over primary prophylaxis. One model showed that starting ASMs after a seizure consistently yields better quality-adjusted life years (QALYs) than primary prophylaxis (11). Another model for ICH suggested short-term prophylaxis (e.g., 7 days) may benefit select high-risk patients, but long-term use generally leads to worse outcomes due to ADRs (12, 16).
In conclusion, current evidence does not support routine primary prophylaxis with ASMs, though select high-risk patients may be considered. When ASMs are indicated, lamotrigine, levetiracetam, lacosamide, and oxcarbazepine are preferred for their safety profiles (15, 17).
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