Original Article: Ruijter B, Keijzer M, et al. Treating Rhythmic and Periodic EEG Patterns in Comatose Survivors of Cardiac Arrest. NEJM (2022). DOI: 10.1056/NEJMoa2115998

Summary

Spontaneous intracerebral hemorrhage (ICH) accounts for 15% of all strokes and a significant burden of neurological morbidity and mortality affecting 2 million people per year. While organized neurological systems of care have improved outcomes, ICH remains stubbornly resistant to medical interventions. Seizure occurs in 6-15% of ICH patients with recent data reporting up to 30% when continuous EEG (cEEG) is used to identify subclinical seizures. Current literature is mixed on whether seizures affect long-term outcome.  Prior studies were limited as they depended on clinical seizures, failing to capture subclinical seizures, and utilized older antiseizure medications (ASM) that have unfavorable side effect profiles which may themselves affect outcome.  This study sought to evaluate the safety and efficacy of levetiracetam for primary prevention of seizures in a parallel-group, double-blind, randomized, placebo-controlled trial.

Methods

The trial included patients >18 years with a spontaneous ICH presenting within 24 hours. Patients with known seizures, seizure after presentation but before intervention, current ASM use, psychiatric history, or terminal illness were excluded. Levetiracetam 500mg twice daily or placebo was given within 24 hours of randomization and patients were monitored on cEEG for 48 hours. Treatment was continued for 30 days followed by a 2-week taper. Primary efficacy outcome was the occurrence of one clinical seizure within 72 hours or one electrographic seizure on cEEG. Secondary efficacy outcomes included the number and duration of seizures on cEEG, paroxysmal interictal patterns, change in ICH volume or midline shift at 72 hours, seizures during the follow up period, and function and quality of life measures. Secondary safety outcomes were medication side effects, psychiatric symptoms measured by the Hospital Anxiety and Depression Scale (HADS), and all-cause mortality.  Analysis was performed using modified intention-to-treat analysis utilizing logistic regression, adjusted for randomization factors.

Results

50 patients were enrolled in the study, 24 assigned to levetiractem and 26 to placebo.  For the endpoint analysis, 19 were included in the treatment group and 23 in the placebo group. Patients were excluded because of issues with cEEG access or other technical issues.  Any patient who initiated treatment was included in the safety analysis.  The treatment group had more women (38% vs 27%), was older (77.5, IQR 72.5-81, vs 66.5, IQR 53-86), had more baseline disability (mRS 0 in 71% of treatment and 92% of placebo), and had a lower NIHSS (7.5, IQR 5-13.5, vs. 12.5, IQR 8-15).  Median GCS was 15 (IQR 14-15) in both groups.  Treatment group also had higher percentage of lobar hemorrhage compared to placebo (42% vs 19%).  Median hematoma volume was 9.2 (IQR 3.1-24.4) in the treatment group and 18 (IQR 7.2-27) in the placebo group.  Seizures occurred in 3 patients in the treatment arm and 10 in placebo (16% vs 43%; OR 0.16, 95% CI, 0.03-0.94; P=.043). Median duration of seizures was lower in the treatment group compared to the placebo (67 sec, IQR 46-300, vs 780 sec, IQR 380-1980, p=0.028).  These differences did not translate into any difference in the number of seizures within 30 days, 12 months, the mRS change between inclusion and 3 or 6 months follow-up, or 12 month mortality. No statistical difference was found in changes in ICH volume nor in midline shift at 72 hours between the two groups. There was no difference in adverse events between the two groups nor in depression or anxiety at followup.

Commentary

This parallel-group, double-blind, randomized, placebo-controlled trial suggests that that levetiracetam is safe and may reduce seizures after ICH. Interestingly, this effect on seizure frequency in the acute phase did not translate to lower risk of late onset seizures nor to improved functional outcome, quality of life, or mortality. However, this study has significant limitations due to the small sample size and unbalanced groups, given the number of differences in the age, prestrike mRS, gender, ICH volume and NIHSS between the two groups.. Additionally, the treatment group had higher rates of diabetes (33% vs 8%) and HTN (73% vs 50%). Most importantly, ICH location was more often lobar and ICH volume was smaller in the levetiracetam group both of which may influence seizure risk as well as outcome, which may have had differential effects that washed out any true difference between the levetiractem and placebo groups.  

This study reinforces the emerging data showing seizure occurrence has been underestimated and further supports current AHA/ASA and the American Clinical Neurophysiology Society recommendations for EEG monitoring in supratentorial ICH with altered mental status, although this can be challenging in limited resource settings. Some studies have shown that seizures may worsen outcomes due to hematoma expansion and impaired brain-oxygenation with one prospective study showing a worse functional outcome with early seizures, however this study did not find a difference in hematoma expansion nor midline shift from baseline between the two groups. As such, this data is compelling despite the limitations and warrants a larger study powered to evaluate outcomes.