Strozzi Isabella, Nolan Sarah J, Sperling Michael R, Wingerchuk Dean M, Sirven Joseph
Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK, L9 7LJ.
Cochrane Database Syst Rev. 2015 Feb 11;2015(2):CD001902. doi: 10.1002/14651858.CD001902.pub2.
Epilepsy is a chronic neurological disorder which affects millions of people around the world. Antiepileptic drugs (AED) are the main interventions used to prevent seizures and control epilepsy. Although effective in most cases, AEDs are related to long-term adverse effects, such as cognitive and behavioural alterations. Thus when epilepsy is in remission, it may be in the individual's best interest to discontinue medication. However, the optimal timing of AED discontinuation is still unknown.This is an updated version of the original Cochrane review published in Issue 3, 2001.
(1) To quantify and compare risk of seizure recurrence, status epilepticus and mortality after early and late AED discontinuation in adult and pediatric epilepsy patients.(2) To assess which variables modify the risk of seizure recurrence.(3) To define a subpopulation in which early AED discontinuation is safe.
We searched the Cochrane Epilepsy Group Specialised Register (June 2014); CENTRAL (Issue 5, The Cochrane Library, May 2014); MEDLINE (1946 to June 2014); CINAHL (23 June 2014); Scopus (1823 to June 2014); ClinicalTrials.gov (23 June 2014); and WHO International Clinical Trials Registry Platform (23 June 2014). We also checked the reference lists of studies found through the electronic searches.
Randomised controlled trials that evaluate withdrawal of AEDs after varying periods of seizure remission in adults and children with epilepsy. Included studies compared an early AED discontinuation time (defined as a period of remission of seizures of less than two years) versus a late AED discontinuation time (defined as a period of remission of seizures of more than two years).
Two authors independently extracted data and assessed trial quality. Risk ratio (RR) with 95% confidence interval (CI) was calculated for each trial. Summary RRs and 95% CIs for dichotomous data were calculated using a fixed-effect model. A test of statistical heterogeneity was conducted for each pooled risk ratio calculation. Each included study underwent a 'Risk of bias' assessment, based on the Cochrane Handbook recommendations, and we examined the overall quality of information through the GRADE system, presented in two 'Summary of Findings' tables.
Five trials were included in this review, representing 924 randomised children with epilepsy, all under 16 years of age at randomisation, with a median follow-up of 5.6 years. No eligible trial evaluated adults or assessed mortality or status epilepticus as outcomes. The pooled risk ratio for seizure relapse after AED withdrawal was 1.34 (95% CI 1.13 to 1.59, P = 0.0007). Conforming to this estimate, the number needed to harm, that is expose an individual to a higher risk of seizure relapse because of early withdrawal of AED, is 8 (95% CI 5 to 20). Early discontinuation was associated with greater relapse rates in people with partial seizures with a pooled risk ratio of 1.51 (95% CI 0.97 to 2.35, P = 0.07). Absence type epilepsy showed a lower risk of relapse. Variables associated with higher risk of seizure relapse were abnormal EEG findings (pooled RR 1.44, 95% CI 1.13 to 1.83, P = 0.003), especially epileptiform activity (RR 2.58, 95% CI 2.03 to 3.28, P < 0.0001); epilepsy onset before 2 years or after 10 years of age; history of status epilepticus; intellectual disability (IQ < 70); and high seizure frequency before and during treatment. Gender and family history did not show any significant influence over seizure relapse. Overall, the included trials were classified as low or unclear risk of bias where methodological information was not reported and could not be provided by original study authors.
AUTHORS' CONCLUSIONS: There is evidence to support waiting for at least two seizure-free years before discontinuing AEDs in children, particularly if individuals have an abnormal EEG or partial seizures, or both. There is insufficient evidence to establish when to withdraw AEDs in children with generalised seizures. There is no evidence to guide the timing of withdrawal of AEDs in seizure-free adults. Further high-quality randomised controlled trials are needed, particularly recruiting adults and recruiting those with generalised seizure types, to identify the optimal timing of AED withdrawal and risk factors predictive of relapse.
癫痫是一种慢性神经系统疾病，影响着全球数百万人。抗癫痫药物（AED）是预防癫痫发作和控制癫痫的主要干预措施。尽管在大多数情况下有效，但AEDs与长期不良反应有关，如认知和行为改变。因此，当癫痫缓解时，停药可能符合个体的最大利益。然而，AED停药的最佳时机仍然未知。这是2001年第3期发表的原始Cochrane系统评价的更新版本。
（1）量化并比较成人和儿童癫痫患者早期和晚期停用AED后癫痫复发、癫痫持续状态和死亡率的风险。（2）评估哪些变量会改变癫痫复发的风险。（3）确定一个早期停用AED安全的亚组人群。
我们检索了Cochrane癫痫小组专业注册库（2014年6月）；CENTRAL（《Cochrane图书馆》2014年第5期）；MEDLINE（1946年至2014年6月）；CINAHL（2014年6月23日）；Scopus（1823年至2014年6月）；ClinicalTrials.gov（2014年6月23日）；以及世界卫生组织国际临床试验注册平台（2014年6月23日）。我们还检查了通过电子检索找到的研究的参考文献列表。
评估癫痫成人和儿童在不同癫痫缓解期后停用AED的随机对照试验。纳入的研究比较了早期AED停药时间（定义为癫痫发作缓解期少于两年）与晚期AED停药时间（定义为癫痫发作缓解期超过两年）。
两位作者独立提取数据并评估试验质量。计算每个试验的风险比（RR）及其95%置信区间（CI）。使用固定效应模型计算二分数据的汇总RR和95%CI。对每个合并风险比计算进行统计异质性检验。根据Cochrane手册的建议，对每项纳入研究进行“偏倚风险”评估，并通过两个“结果总结”表中的GRADE系统检查信息的总体质量。
本评价纳入了5项试验，共924例随机分组的癫痫儿童，随机分组时均未满16岁，中位随访时间为5.6年。没有符合条件的试验评估成人或评估死亡率或癫痫持续状态作为结局。停用AED后癫痫复发的汇总风险比为1.34（95%CI 1.13至1.59，P = 0.0007）。根据这一估计，因早期停用AED而使个体面临更高癫痫复发风险所需伤害的人数为8（95%CI 5至20）。部分性癫痫患者早期停药与更高的复发率相关，汇总风险比为1.51（95%CI 0.97至2.35，P = 0.07）。失神发作型癫痫的复发风险较低。与癫痫复发风险较高相关的变量包括脑电图异常结果（汇总RR 1.44，95%CI 1.13至1.83，P = 0.003），尤其是癫痫样活动（RR 2.58，95%CI 2.03至3.28，P < 0.0001）；癫痫发作起始于2岁之前或10岁之后；癫痫持续状态病史；智力残疾（智商<70）；以及治疗前和治疗期间癫痫发作频率高。性别和家族史对癫痫复发未显示出任何显著影响。总体而言，纳入的试验在未报告方法学信息且原始研究作者无法提供的情况下，被归类为低或不清楚的偏倚风险。
有证据支持在儿童停用AED之前至少等待两年无癫痫发作，特别是如果个体脑电图异常或有部分性癫痫发作，或两者皆有。没有足够的证据确定全身性癫痫发作儿童停用AED的时间。没有证据指导无癫痫发作成人停用AED的时机。需要进一步开展高质量的随机对照试验，特别是纳入成人以及全身性癫痫发作类型的患者，以确定AED停药的最佳时机和预测复发的危险因素。
