Management of Poststroke Epilepsy: An Update

Poststroke seizures are associated with poor functional outcomes, cognitive decline, and increased mortality risk.¹ Cerebrovascular disease accounts for ~50% of new-onset epilepsy cases in adults aged >65 years.² Poststroke seizures are classified into early and late seizures.³ Unprovoked seizures that occur >7 days after stroke are referred to as late seizures, also known as poststroke epilepsy (PSE).⁴ PSE commonly occurs in the first 2 years after stroke.^5,6 Early seizure (ie, a seizure within 7 days of stroke) is an independent predictor of late seizures.⁷

Although early and late seizures should ideally be distinguished based on pathophysiologic differences, not arbitrary time, a tissue-based diagnosis is currently unavailable due to the lack of a validated test or biomarker of epileptogenesis.³ A tissue-based definition of early and late seizures was recently proposed; however, tissue-based diagnosis is unavailable because it requires a validated test such as an epileptogenesis biomarker.³

To develop drugs that prevent PSE, it is imperative to understand the mechanisms of epileptogenesis in people who have experienced a stroke. The discovery and validation of PSE biomarkers will contribute to designing trials investigating antiepileptogenic agents. Biologic markers of poststroke inflammation, blood-brain barrier disruption, and electroencephalogram (EEG) alterations may be associated with active epileptogenesis.⁴ Interictal EEG data associated with epileptogenesis (eg, periodic discharges and rhythmic delta activity, fast frequencies, gamma frequencies, high-frequency oscillations) must be confirmed in a reliable biomarker research paradigm.^8-12 No validated biomarkers or proven drugs for primary prevention of epilepsy (ie, those that block epileptogenic pathways) are available.¹³

Importance of Seizure Control for Prognosis

A systematic review and meta-analysis of 71 studies involving >20,000 participants with poststroke seizures found that poststroke seizures significantly increase the risk of death (odds ratio [OR], 2.1; 95% CI, 1.8 to 2.4), poor functional outcome (OR, 2.2; 95% CI, 1.8 to 2.8), disability (standardized mean difference, 0.6; 95% CI, 0.4 to 0.7), and dementia (OR, 3.1; 95% CI, 1.3 to 7.7) in stroke survivors.¹ The analysis further indicated that people experiencing early seizures, regardless of whether the stroke was ischemic or hemorrhagic, faced an increased risk of death. Both early and late seizures were linked to poorer functional outcomes across stroke subtypes. Data on seizure frequency and their association with mortality or functional outcomes were unavailable. These findings highlight the importance of prioritizing poststroke seizure management as a critical clinical and research priority to improve prognosis.

PSE Prediction

Reliable and validated PSE prediction models are needed for future PSE prevention trials, mainly to enrich these trials with individuals who have experienced a stroke and are at higher risk of PSE. Biomarkers could also be utilized for predicting PSE or to act as surrogate end points. Scoring systems such as CAVE and SeLECT scores have been reported for predicting PSE in individuals who have experienced hemorrhagic or ischemic stroke, respectively. The CAVE score includes points for cortical lesions, age <65 years, hematoma volume >10 mL, and early seizures in individuals with cerebral hemorrhage.¹⁴ The SeLECT score includes points for stroke severity, main artery occlusion, early seizure, cortical stroke, and middle cerebral artery territory infarction.⁷ SeLECT 2.0 was recently created, which emphasizes early status epilepticus more than early seizure.¹⁵ Adding cortical superficial siderosis further improved the CAVE and SeLECT scores’ ability to predict PSE.¹⁶ PSE is more common with hemorrhagic strokes than ischemic strokes,³ and the presence of cortical superficial siderosis is strongly associated with PSE.¹⁶ Exclusive lobar cerebral microbleeds and apolipoprotein E &Epsolon;4 (APOE &Epsolon;4) genotype are also associated with PSE risk.^17-19 Furthermore, the presence of TRMP6 rs2274924, ALDH2 rs671, and CD40-1C/T genotype are associated with a greater risk of PSE, and AT1R rs12721273 and rs55707609 are associated with a lower risk of PSE.²⁰ Polygenic risk score models of PSE prediction may also help identify individuals with high risk of PSE, but the existing model needs validation.²¹

Treatment

Primary Prophylaxis

Antiepileptogenesis trials are challenging to conduct, and evidence from randomized controlled trials (RCTs) for primary prevention is lacking. Due to sparse reliable evidence, the European Stroke Organization guidelines suggest against general primary antiseizure medication (ASM) prophylaxis administration.²² Valproic acid, diazepam, and levetiracetam have been tested for primary prevention in RCTs but failed to show efficacy or safety.^23-27 Statin use appears to prevent PSE (OR, 0.60; 95% CI, 0.42 to 0.84) and early seizures (OR, 0.36; 95% CI, 0.42 to 0.84) probably due to its anti-inflammatory and other pleiotropic effects, though this has not been confirmed.^28,29

Strategies for Secondary Prophylaxis

A network meta-analysis of 15 studies, including 18,676 participants with poststroke seizures, compared 13 ASMs and suggested that lamotrigine and levetiracetam may be safe and tolerable options in this population.³⁰ Levetiracetam was associated with lower mortality risk and fewer seizure recurrences; lamotrigine demonstrated the fewest adverse events, lower drug discontinuation rates, and low mortality risk.³⁰ However, despite ASM use, the overall seizure recurrence rate remained high (24.8%), with eslicarbazepine linked to the fewest recurrences.³⁰ The analysis provided low- to very-low–quality evidence that phenytoin was associated with higher seizure recurrence (OR, 7.3; 95% CI, 3.7 to 14.5) and more adverse events (OR, 5.2; 95% CI, 1.2 to 22.9). Both phenytoin (OR, 1.9; 95% CI, 1.4 to 2.8) and carbamazepine (OR, 1.8; 95% CI, 1.5 to 2.2) were linked to high drug discontinuation rates.³⁰ In addition, the network meta-analysis provided moderate- to high-certainty evidence that both valproic acid (OR, 4.7; 95% CI, 3.6 to 6.3) and phenytoin (OR, 8.3; 95% CI, 5.7 to 11.9) were associated with increased mortality risk.³⁰ Although first-generation ASMs (eg, phenytoin, valproate, and carbamazepine) are the most widely prescribed, newer-generation ASMs have better efficacy and adverse effect profiles.^30,31 Despite their potential effectiveness, some of the newest agents (eg, perampanel and eslicarbazepine)^32-34 have not been extensively validated or evaluated.

Future Research

Many individuals with intracerebral haemorrhage are started on ASMs. Individuals who suffer early seizures (ie, a seizure within 1 week poststroke) are more likely to be started on ASMs and remain on these medications for a longer duration. Further studies are needed to determine whether these individuals should remain on ASMs.

People who have experienced a stroke struggle to resume driving because of physical and cognitive deficits like neglect and apraxia. Individuals with early seizures and other PSE predictors require guidance regarding whether they can resume driving. Schubert et al recently reported the chance of seizure in the next year (COSY) and seizure-free interval (SFI) using the SeLECT prognostic model.³¹ These study results demonstrated that stroke patients with acute symptomatic seizure and acute symptomatic status epilepticus were at a greater risk of late seizures.³¹ They noted COSY at 3 months was 2% to 91% for patients with acute symptomatic seizures and 14% to 92% amongst those with early acute status epilepticus.³¹ The study indicated that COSY <20% is considered safe for private driving.³¹ However, driving restrictions vary by state and these state regulations should be followed when assessing a stroke survivor’s ability to return to driving.³²

Lastly, emerging evidence demonstrates the prognostic importance of PSE prevention. Conducting large-scale studies of PSE prevention is challenging and collaboration between stroke and epilepsy researchers is critical. Efforts in this direction are underway through the International Poststroke Epilepsy Research Consortium.³³