Department of Neurology, Hospital of Merano (SABES-ASDAA), Merano-Meran, Italy.
Department of Neuropsychiatry, Alex Ekwueme Federal University Teaching Hospital (AEFUTHA), Abakaliki, Nigeria.
Cochrane Database Syst Rev. 2022 Feb 21;2(2):CD013028. doi: 10.1002/14651858.CD013028.pub3.
Epilepsy is one of the most common neurological disorders worldwide, with an age-adjusted prevalence of 4 to 8 per 1000 population and an age-adjusted incidence of 44 per 100,000 person-years in developed countries. Monotherapy represents the best therapeutic option in people with newly diagnosed epilepsy. This is an updated version of the original Cochrane Review published in 2019, Issue 11.
To assess the efficacy and tolerability of oral clonazepam used as monotherapy for newly diagnosed epilepsy, compared with placebo or a different anti-seizure medication.
For the latest update of this review we searched the following databases on 14 September 2021: the Cochrane Register of Studies (CRS Web) and MEDLINE (Ovid) (1946 to 13 September 2021). CRS Web includes randomized controlled trials (RCTs) or quasi-RCTs from PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the Specialized Registers of Cochrane Review Groups, including Epilepsy.
We included RCTs or quasi-RCTs comparing oral clonazepam used as monotherapy treatment versus placebo or a different anti-seizure medication (active comparator) in people of any age with newly diagnosed epilepsy, defined according to the clinical practical definition proposed by the International League Against Epilepsy (ILAE).
The following outcomes were considered: proportion of participants seizure-free at one, three, six, 12, and 24 months after randomization; proportion of responders (those with at least a 50% reduction in seizure frequency from baseline to end of treatment); proportion of participants with treatment-emergent adverse events (TEAEs) during the treatment period or leading to discontinuation during the treatment period; proportion of dropouts/withdrawals due to side effects, lack of efficacy or other reasons; and improvement in quality of life, as assessed by validated and reliable rating scales. Two review authors independently screened all titles and abstracts to assess the eligibility of publications identified by the searches. We independently extracted data from trial reports and cross-checked them for accuracy. Any disagreements between the two authors regarding data extraction were resolved by discussion and consensus. We scrutinized trials and evaluated the methodological quality of all included studies. We used GRADE assessment criteria to evaluate the certainty of the evidence.
Two randomized controlled trials had already been included in the previous version of the review, with a total of 115 participants. One study compared clonazepam to carbamazepine as monotherapy for participants with newly diagnosed psychomotor epilepsy (a condition corresponding to what is now termed mesial temporal lobe epilepsy). One study (published as an abstract) compared clonazepam to ethosuximide as monotherapy for children with absence seizures. Based on the available data and the details on methodology provided, we judged both studies as being at unclear or high risk of bias for the domains assessed (apart from the selective reporting (reporting bias) domain - we judged one study as being at low risk of bias and the other study at high risk of bias). In the study comparing clonazepam to carbamazepine, no difference was found between the groups regarding the proportion of participants who were seizure-free at one month after randomization (risk ratio (RR) 1.97, 95% confidence interval (CI) 0.99 to 3.94; 30 participants; very low-certainty evidence), three months after randomization (RR 1.19, 95% CI 0.62 to 2.29; 26 participants; very low-certainty evidence), and six months after randomization (RR 0.50, 95% CI 0.09 to 2.73; 9 participants; very low-certainty evidence). No statistical difference was found between clonazepam and carbamazepine in terms of proportion of participants with TEAEs leading to discontinuation (RR 2.61, 95% CI 0.80 to 8.52; 36 participants; very low-certainty evidence) and in terms of dropouts/withdrawals due to side effects, lack of efficacy or other reasons (RR 1.56, 95% CI 0.61 to 4.02; 36 participants; very low-certainty evidence). The study did not provide any information on our other prespecified outcomes of interest. The study comparing clonazepam to ethosuximide did not provide any data on efficacy. The proportion of dropouts/withdrawal was higher in the group receiving clonazepam compared to the group receiving ethosuximide (RR 3.63, 95% CI 1.12 to 11.74; 79 participants; very low-certainty evidence). No information on other outcomes of interest was provided in this study.
AUTHORS' CONCLUSIONS: We did not find any new studies since the last version of this review. There is only limited and very low-certainty evidence from randomized controlled trials on the efficacy and tolerability of clonazepam used in monotherapy for the treatment of epilepsy. No difference in efficacy and tolerability was found in a small trial comparing clonazepam to carbamazepine for the treatment of mesial temporal lobe epilepsy. Clonazepam was less well tolerated than ethosuximide in a trial of children with absence seizures, however no comparative data on efficacy were provided. There is currently insufficient evidence to support the use of clonazepam as monotherapy treatment for epilepsy.
癫痫是全世界最常见的神经系统疾病之一，在发达国家，其年龄调整患病率为每 1000 人 4 至 8 例，年龄调整发病率为每 100000 人 44 例。对于新诊断的癫痫患者，单药治疗是最佳治疗选择。这是 2019 年原始 Cochrane 综述的更新版本，第 11 期。
评估新诊断癫痫患者使用氯硝西泮口服单药治疗与安慰剂或其他抗癫痫药物相比的疗效和耐受性。
为了更新本综述，我们于 2021 年 9 月 14 日在以下数据库中进行了检索：Cochrane 研究注册库（CRS Web）和 MEDLINE（Ovid）（1946 年至 2021 年 9 月 13 日）。CRS Web 包括来自 PubMed、Embase、ClinicalTrials.gov、世界卫生组织国际临床试验注册平台（ICTRP）、Cochrane 中心对照试验注册库（CENTRAL）和 Cochrane 各专业组（包括癫痫）的随机对照试验（RCT）或准 RCT。
我们纳入了 RCT 或准 RCT，比较了新诊断癫痫患者使用氯硝西泮口服单药治疗与安慰剂或其他抗癫痫药物（阳性对照）的疗效，定义为根据国际抗癫痫联盟（ILAE）提出的临床实用定义。
考虑了以下结局：随机分组后 1、3、6、12 和 24 个月时无癫痫发作的参与者比例；应答者（与基线相比，癫痫发作频率至少减少 50%的参与者）比例；治疗期间出现治疗相关不良事件（TEAEs）并导致治疗期间停药的参与者比例；因不良反应、疗效不佳或其他原因而脱落/退出的参与者比例；以及通过经过验证和可靠的评分量表评估的生活质量改善。两位综述作者独立筛选所有标题和摘要，以评估搜索结果中出版物的入选资格。我们独立地从试验报告中提取数据，并交叉核对其准确性。对于数据提取存在的任何分歧，两位作者均通过讨论和达成共识进行解决。我们对试验进行了审查，并对所有纳入研究的方法学质量进行了评估。我们使用 GRADE 评估标准来评估证据的确定性。
本次更新纳入了两项随机对照试验，共有 115 名参与者。一项研究比较了氯硝西泮与卡马西平作为新诊断的精神运动性癫痫（现在称为内侧颞叶癫痫）患者的单药治疗。另一项研究（作为摘要发表）比较了氯硝西泮与乙琥胺作为儿童失神性癫痫患者的单药治疗。根据可用数据和提供的方法学细节，我们判断这两项研究在评估的领域均存在不确定或高偏倚风险（除了选择性报告（报告偏倚）领域——我们判断其中一项研究为低偏倚风险，另一项研究为高偏倚风险）。在比较氯硝西泮与卡马西平的研究中，在随机分组后 1 个月（风险比（RR）1.97，95%置信区间（CI）0.99 至 3.94；30 名参与者；极低确定性证据）、3 个月（RR 1.19，95%CI 0.62 至 2.29；26 名参与者；极低确定性证据）和 6 个月（RR 0.50，95%CI 0.09 至 2.73；9 名参与者；极低确定性证据）时，两组之间无癫痫发作的参与者比例无差异。氯硝西泮与卡马西平在导致停药的 TEAEs 比例（RR 2.61，95%CI 0.80 至 8.52；36 名参与者；极低确定性证据）和因不良反应、疗效不佳或其他原因而脱落/退出的比例（RR 1.56，95%CI 0.61 至 4.02；36 名参与者；极低确定性证据）方面无统计学差异。该研究未提供我们其他预先指定的疗效结局的任何信息。比较氯硝西泮与乙琥胺的研究未提供任何疗效数据。接受氯硝西泮治疗的组与接受乙琥胺治疗的组相比，脱落/退出的比例更高（RR 3.63，95%CI 1.12 至 11.74；79 名参与者；极低确定性证据）。该研究未提供其他感兴趣结局的任何信息。
自上次更新以来，我们没有发现任何新的研究。目前，关于氯硝西泮单药治疗癫痫的疗效和耐受性仅有有限的、极低确定性证据，来自随机对照试验。在一项比较氯硝西泮与卡马西平治疗内侧颞叶癫痫的小型试验中，两者在疗效和耐受性方面无差异。在一项儿童失神性癫痫的试验中，氯硝西泮的耐受性不如乙琥胺，但未提供疗效的比较数据。目前，没有足够的证据支持氯硝西泮作为癫痫的单药治疗。
