Centre for Sleep Medicine and Respiratory Diseases, Croix-Rousse Hospital, Lyon University Hospital, Lyon, France; Lyon Neuroscience Research Centre, CNRS UMR 5292, INSERM U1028, Lyon, France.
Stroke Unit, Department of Neurology, Fleyriat Hospital, Bourg en Bresse, France.
Lancet Neurol. 2022 Sep;21(9):781-791. doi: 10.1016/S1474-4422(22)00235-6.
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.
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.
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.
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.
French Ministry of Health.
通过连续脑电图诊断亚临床发作时，脑出血后早期发作（发病后 7 天内发生）的发生率达到 30%。早期发作可能与血肿扩大和更差的神经功能结局有关。目前的指南不建议在此情况下预防性使用抗癫痫药物。我们旨在评估左乙拉西坦是否会降低脑出血患者急性发作的风险。
这项双盲、随机、安慰剂对照、3 期 PEACH 试验在法国的三个卒中单元进行。发病后 24 小时内出现非创伤性脑出血的患者（年龄 18 岁或以上）被随机分配（1:1）接受左乙拉西坦（静脉 500mg，每 12 小时一次）或匹配的安慰剂。随机分配是通过一个基于网络的系统进行的，并按中心和基线国家卫生研究院卒中量表（NIHSS）评分进行分层。治疗持续 6 周。在纳入后 24 小时内开始进行连续脑电图，并记录 48 小时。主要终点是在纳入后 72 小时内至少发生一次临床发作或连续脑电图上记录到至少一次脑电图发作，在改良意向治疗人群中进行分析，该人群包括所有随机分配至治疗且进行连续脑电图检查的患者。这项试验在 ClinicalTrials.gov 上注册，NCT02631759，现已关闭。由于招募率低和资金停止，在达到 48%的招募目标后提前停止招募。
2017 年 6 月 1 日至 2020 年 4 月 14 日，共纳入 50 例轻度至中度脑出血患者：24 例分配至左乙拉西坦组，26 例分配至安慰剂组。在最初的 72 小时内，左乙拉西坦组有 3 名（16%）患者发生临床或脑电图发作，安慰剂组有 10 名（43%）患者发生（比值比 0.16，95%CI 0.03-0.94，p=0.043）。前 72 小时内所有发作均为脑电图发作。在 1 个月或 3 个月时，两组的抑郁或焦虑报告无差异。在接受左乙拉西坦治疗的患者中，有 3 名（13%）出现抑郁，4 名（15%）接受安慰剂的患者出现抑郁，有 2 名（8%）接受左乙拉西坦治疗的患者出现焦虑，1 名（4%）接受安慰剂的患者出现焦虑。左乙拉西坦组与安慰剂组中最常见的治疗中出现的不良事件分别为头痛（9[39%]例 vs 6[24%]例）、疼痛（3[13%]例 vs 10[40%]例）和跌倒（7[30%]例 vs 4[16%]例）。最常见的严重不良事件是脑出血引起的神经功能恶化（1[4%]例 vs 4[16%]例）和严重肺炎（2[9%]例 vs 2[8%]例）。两组均未报告与治疗相关的死亡。
左乙拉西坦可能有效预防脑出血后的急性发作。需要更大规模的研究来确定抗癫痫药物预防是否能改善脑出血患者的功能结局。
法国卫生部。
