Levetiracetam May Lower Seizure Risk in Spontaneous Intracerebral Hemorrhage

Treatment with levetiracetam is safe and may be effective as a primary prophylactic antiseizure medication for the improvement of neurologic outcomes in patients who experience a spontaneous intracerebral hemorrhage (ICH), according to study findings published in The Lancet Neurology.

Currently, clinical guidelines do not recommend the use of prophylactic antiseizure medication among patients who experience spontaneous ICH. However, researchers of the study sought to determine whether prophylactic levetiracetam could reduce the risk for acute seizures in this patient population during early recovery.

The parallel-group, double-blind, randomized, placebo-controlled, investigator-led, phase 3 Prevention of Epileptic seizures at the Acute phase of intraCerebral Haemorrhage trial (PEACH; ClinicalTrials.gov Identifier: NCT02631759) was conducted at 3 stroke units in France — 1 secondary and 2 tertiary health care hospitals. The primary outcome measure was the occurrence of 1 or more clinical seizure(s) within 72 hours after study inclusion or 1 or more electrographic seizure(s) recorded on continuous electroencephalogram (EEG).

Patients, aged 18 years or older, presented with spontaneous ICH within 24 hours after onset and were randomized in a 1:1 ratio to intravenous levetiracetam 500 mg every 12 hours or matching placebo. Randomization, which was performed using a web-based system, was stratified by the center and by the National Institutes of Health Stroke Scale score at baseline. Treatment of all patients continued for 6 weeks. Continuous EEG was initiated within 24 hours of study inclusion and was recorded over 48 hours. Recruitment in PEACH was stopped prematurely after 48% of the recruitment had been attained because of a low recruitment rate and the cessation of funding.

A total of 50 patients with mild to moderate ICH were enrolled in the PEACH trial between June 1, 2017 and April 14, 2020. Of these individuals, 24 were assigned to the levetiracetam group and 26 to the placebo group.

In the initial 72 hours in the modified intention-to-treat population, a clinical or electrographic seizure was observed in 16% (3 of 19) of participants in the levetiracetam group and 43% (10 of 23) of those in the placebo group (Odds ratio, 0.16; 95% CI, 0.03-0.94; P =.043). All of the seizures reported in the first 72 hours were electrographic seizures.

In the PEACH trial, anxiety and depression were evaluated with use of the Hospital Anxiety and Depression Scale at 1 month and 3 months. Disability and health-related quality of life were evaluated with the self-report questionnaire Stroke Impact Scale at
3 months, 6 months, and 12 months. Depression was recorded in 3 levetiracetam-treated patients vs 4 placebo-treated patients. Anxiety was reported in 2 participants in the levetiracetam group vs 1 participant in the placebo group.

The most common treatment-emergent adverse events reported in the levetiracetam group compared with the placebo group included headache (9 patients vs
6 patients, respectively); pain (3 patients vs 10 patients, respectively); and falls
(7 patients vs 4 patients, respectively). The most common serious adverse events included neurologic deterioration due to ICH (1 participant vs 4 participants, respectively) and severe pneumonia (2 participants vs 2 participants). No treatment-related death reported among any of the patients.

Several limitations of the PEACH trial warrant mention. To begin, recruitment was interrupted prematurely after a total of 50 patients had been included, due to cessation of funding. The small sample size was associated with some randomization imbalances between both groups in terms of demographics and baseline characteristics. Further, although brain imaging was read centrally, the imaging modalities used at admission and at 72-hour follow-up were not standardized, with computed tomography or magnetic resonance imaging (MRI) performed at the treating clinician’s discretion.

“Larger studies are needed to determine whether seizure prophylaxis improves functional outcome in patients with intracerebral haemorrhage,” the researchers concluded.

Disclosure: Some of the study authors have declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.