Be a PEACH and Hand Me That Levetiracetam: Seizure Prophylaxis for Spontaneous Intracerebral Hemorrhage

Abstract

Safety and Efficacy of Prophylactic Levetiracetam for Prevention of Epileptic Seizures in the Acute Phase of Intracerebral Haemorrhage (PEACH): A Randomised, Double-Blind, Placebo-Controlled, Phase 3 Trial

Peter-Derex L, Philippeau F, Garnier P, André-Obadia N, Boulogne S, Catenoix H, Convers P, Mazzola L, Gouttard M, Esteban M, Fontaine J, Mechtouff L, Ong E, Cho T-H, Nighoghossian N, Perreton N, Termoz A, Haesebaert J, Schott A-M, Rabilloud M, Pivot C, Dhelens C, Filip A, Berthezène Y, Rheims S, Boutitie F, Derex L. Lancet Neurol. 2022;21(9):781-791. doi:10.1016/S1474-4422(22)00235-6

Background:

The incidence of early seizures (occurring within 7 days of stroke onset) after intracerebral haemorrhage reaches 30% when subclinical seizures are diagnosed by continuous EEG. Early seizures might be associated with haematoma expansion and worse neurological outcomes. Current guidelines do not recommend prophylactic antiseizure treatment in this setting. We aimed to assess whether prophylactic levetiracetam would reduce the risk of acute seizures in patients with intracerebral haemorrhage.

Methods:

The double-blind, randomised, placebo-controlled, phase 3 PEACH trial was conducted at three stroke units in France. Patients (aged 18 years or older) who presented with a non-traumatic intracerebral haemorrhage within 24 h after onset were randomly assigned (1:1) to levetiracetam (intravenous 500 mg every 12 h) or matching placebo. Randomisation was done with a web-based system and stratified by centre and National Institutes of Health Stroke Scale (NIHSS) score at baseline. Treatment was continued for 6 weeks. Continuous EEG was started within 24 h after inclusion and recorded over 48 h. The primary endpoint was the occurrence of at least one clinical seizure within 72 h of inclusion or at least one electrographic seizure recorded on continuous EEG, analysed in the modified intention-to-treat population, which comprised all patients who were randomly assigned to treatment and who had a continuous EEG performed. This trial was registered at ClinicalTrials.gov, NCT02631759, and is now closed. Recruitment was prematurely stopped after 48% of the recruitment target was reached due to a low recruitment rate and cessation of funding. Findings Between June 1, 2017, and April 14, 2020, 50 patients with mild-to-moderate severity intracerebral haemorrhage were included: 24 were assigned to levetiracetam and 26 to placebo. During the first 72 h, a clinical or electrographic seizure was observed in three (16%) of 19 patients in the levetiracetam group versus ten (43%) of 23 patients in the placebo group (odds ratio 0.16, 95% CI 0.03–0.94, p = 0.043). All seizures in the first 72 h were electrographic seizures only. No difference in depression or anxiety reporting was observed between the groups at 1 month or 3 months. Depression was recorded in three (13%) patients who received levetiracetam versus four (15%) patients who received placebo, and anxiety was reported for two (8%) patients versus one (4%) patient. The most common treatment-emergent adverse events in the levetiracetam group versus the placebo group were headache (nine [39%] vs six [24%]), pain (three [13%] vs ten [40%]), and falls (seven [30%] vs four [16%]). The most frequent serious adverse events were neurological deterioration due to the intracerebral haemorrhage (one [4%] vs four [16%]) and severe pneumonia (two [9%] vs two [8%]). No treatment-related death was reported in either group.

Interpretation:

Levetiracetam might be effective in preventing acute seizures in intracerebral haemorrhage. Larger studies are needed to determine whether seizure prophylaxis improves functional outcome in patients with intracerebral haemorrhage.

Commentary

Spontaneous intracerebral hemorrhage (ICH) causes acute electrographic and/or electroclinical seizures in nearly one third of patients monitored with continuous video electroencephalography. ^1,2 Acute seizures can cause subsequent expansion of an ICH with increased morbidity and mortality. ¹ With expanding utilization of continuous video EEG, electrographic seizures have been discovered with high frequency in neurologic injury, suggesting that the overall occurrence of seizures in the setting of ICH potentially remains an underestimate. ² There are currently no universally accepted guidelines for pharmacologic management to prevent acute seizures (occurring within the first 7 days of symptom onset) in patients with spontaneous ICHs. The major risk of harm results from increased sedation with the addition of an anti-seizure medication. ^3,4 Furthermore, whether controlling acute seizures results in better long-term outcomes remains unknown, particularly when recorded seizures are electrographic-only and not electroclinical, as some evidence suggests that outcomes are independent of presence or absence of acute seizures. ⁵

Peter-Derex and colleagues designed and conducted a phase III randomized controlled trial Prevention of Epileptic seizures at the Acute phase of intraCerebral Haemorrhage (PEACH) at 3 hospitals in France to examine whether low-dose (500 mg twice a day) levetiracetam over 6 weeks reduced the incidence of electrographic and electroclinical seizures in the acute phase of ICH compared to placebo. ⁶ Adults were enrolled who presented within 24 hours of symptom onset. Those with underlying structural causes as well as patients with a history of severe psychiatric disorder were excluded given the risk of levetiracetam resulting in exacerbation in these individuals. Patients underwent continuous EEG monitoring within 24 hours of enrollment and continued on placebo or levetiracetam for 30 days then a taper was initiated. The primary outcome was presence of at least one electrographic or electroclinical seizure in the first 72 hours following inclusion in the study.

Unfortunately, enrollment was halted early because of challenges with cost and slow recruitment. Despite these limitations, the number of patients who had electrographic or electroclinical seizures within the first 72 hours of study inclusion was found to be significantly smaller in the active treatment arm (16%) compared to the control arm (43%, P = .043) of the study. A total of 6 seizures were captured in 3 patients receiving low-dose levetiracetam compared to 158 seizures in 10 patients receiving a placebo. All seizures captured were electrographic only. The number of electrographic seizures was larger in the control arm as well as duration compared to the treatment arm. There was also a large proportion of patients in each study arm with interictal epileptiform activity (63% in each group). Long-term outcomes were not evaluated.

For the purpose of the study, electrographic seizures were defined as “rhythmic discharges or spike and wave patterns with definite evolution in frequency, location, or morphology lasting at least 10 seconds” which is not identical to the new American Clinical Neurophysiology Society’s Standardized Critical Care EEG Terminology ⁷ which also defines electrographic seizures as “epileptiform discharges averaging >2.5 Hz for ≥10 seconds (>25 discharges in 10 seconds).” Applying these stricter criteria, even more patients with spontaneous ICH may be candidates for anti-seizure medication prophylaxis based on the results of the trial.

In this study, continuous EEG was obtained without video recording and not shared with the clinical team in order to blind the investigators to the presence or absence of seizures during a 48-hour recording and was later interpreted by a board-certified neurophysiologist also blinded to the study arm of the participant. This methodology may not be approved in the United States as acute ICH with altered mental status has been described as a clinical indication for continuous video EEG monitoring by expert opinion. ⁸ In addition, lack of video interpretation limits the ability of investigators to differentiate electrographic from electroclinical seizures with subtle clinical changes.

The findings from this study have led to several opportunities for further investigation. How soon was the interictal epileptiform activity seen (in 63% of patients in both study arms) during the EEG recording? Were the patients who later had seizures, the same patients who were seen to have interictal epileptiform activity early during the EEG recording? If interictal epileptiform activity was identified early during the recordings and was followed by seizures in up to 43% of patients, this finding may guide the clinical decision as to which patients should receive continuous video EEG and prophylactic levetiracetam in this setting. If so, it may be reasonable to obtain a routine EEG in all patients with spontaneous ICH (with or without altered mental status) within the first 24 hours of presentation. If the routine EEG showed interictal epileptiform activity, the treating team could begin low-dose prophylactic levetiracetam and monitor with continuous video EEG for 72 hours. If no electroclinical or electrographic seizures occur, they could then taper levetiracetam and if they did occur, titrate accordingly. An algorithm like this would be especially useful for medical centers with limited continuous video EEG resources to allow for optimal triage.

Likely because of the small number of participants randomized to each study arm, there were baseline characteristics and demographics that were significantly different between study arms. Participants in the control arm were younger, less likely to have diabetes or hypertension, and less likely to be taking antithrombotic medications. However, baseline hematoma volume was twice as large in patients in the control arm (18 mL) compared to the levetiracetam arm (9.2 mL), increasing the risk of neurologic deterioration. ¹ As the authors pointed out, larger clinical trials are needed to understand which of these factors is significant in determining seizure risk.

The optimal prophylactic anti-seizure medication to prescribe, dosing, and duration was beyond the scope of this study. In addition, it remains to be determined whether acute anti-seizure prophylaxis reduces risks of morbidity and mortality, neurologic deterioration, or chronic epilepsy. Finally, whether interictal epileptiform discharges versus electrographic versus electroclinical seizures predict worse long-term outcome with or without prophylactic anti-seizure medication also remains unknown. Findings from this study indicate that these questions warrant further investigation.

Mackenzie C. Cervenka, MD
Department of Neurology, Epilepsy Division, Johns Hopkins University