Ayuga Loro Fernando, Gisbert Tijeras Enrique, Brigo Francesco
University Hospital of Toledo, Toledo, Spain.
University of Verona, Department of Neurological and Movement Sciences. Section of Clinical Neurology, P.le L.A. Scuro, 10, Verona, Italy, 37134.
Cochrane Database Syst Rev. 2020 Jan 23;1(1):CD005003. doi: 10.1002/14651858.CD005003.pub3.
The ideal objective of treating a person with epilepsy is to induce remission (free of seizures for some time) using antiepileptic drugs (AEDs) and withdraw the AEDs without causing seizure recurrence. Prolonged usage of AEDs may have long-term adverse effects. Hence, when a person with epilepsy is in remission, it is logical to attempt to discontinue the medication. The timing of withdrawal and the mode of withdrawal arise while contemplating withdrawal of AEDs. This review examines the evidence for the rate of withdrawal of AEDs (whether rapid or slow tapering) and its effect on seizure recurrence. This is an updated version of the original Cochrane Review published in 2006, Issue 2.
To quantify risk of seizure recurrence after rapid (tapering period of three months or less) or slow (tapering period of more than three months) discontinuation of antiepileptic drugs in adults and children with epilepsy who are in remission, and to assess which variables modify the risk of seizure recurrence.
For the latest update, on 9 April 2019, we searched: Cochrane Register of Studies (CRS Web, which includes the Cochrane Epilepsy Group Specialized Register, CENTRAL, and ClinicalTrials.gov), MEDLINE (Ovid; 8 April 2019), the WHO International Clinical Trials Registry Platform, and SCOPUS. There were no language restrictions.
Randomized controlled trials that evaluate withdrawal of AEDs in a rapid or slow tapering after varying periods of seizure control in people with epilepsy.
Review authors independently assessed the trials for inclusion and extracted the data. The outcomes assessed included seizure freedom after one, two, or five years of AED withdrawal; time to recurrence of seizure following withdrawal; occurrence of status epilepticus; mortality; morbidity due to seizure, such as injuries, fractures, and aspiration pneumonia; and quality of life (assessed by validated scale).
In this review update, we have included one new study. The new study randomized 57 children with epilepsy with seizure freedom for at least two years to taper the AED during over one or six months. The study was not blinded and there were no details of randomization. Over the period of 54 months of follow-up, 20/30 participants in the one-month group remained seizure-free compared to 15/27 participants in the six-month group (no evidence of a difference). There was no information on time of seizure recurrence for each group to allow a comparison. One trial had already been included in the previous version of the review; it involved 149 children. There was a non-significant trend toward a lower risk of seizure recurrence after one year of AED withdrawal in participants allocated to slow tapering (risk ratio (RR) 0.76, 95% confidence interval (CI) 0.58 to 1.01; P= 0.06; very low-certainty evidence). At the end of two years, 30 participants were seizure free in the rapid-tapering group and 29 participants in the slow-tapering group (RR 0.87, 95% CI 0.58 to 1.29; P = 0.48; very low-certainty evidence). At the end of five years, 10 participants were seizure free in the rapid-tapering group and six participants in the slow-tapering group (RR 1.40, 95% CI 0.54 to 3.65; P = 0.49; very low-certainty evidence). There were no data for the other outcomes. Due to the methodological heterogeneity and the difference in the duration of tapering we did not perform a quantitative synthesis of these studies.
AUTHORS' CONCLUSIONS: Since the last version of this review was published, we found one new pediatric study. In view of methodological deficiencies, and small sample size of the two included studies, we cannot draw any reliable conclusions regarding the optimal rate of tapering of AEDs. Using GRADE, we assessed the certainty of the evidence as very low for outcomes for which data were available. We judged both studies to be at high risk of bias. Further studies are needed in adults and children to investigate the optimal rate of withdrawal of AEDs and to study the effects of variables such as seizure types, etiology, mental retardation, electroencephalography abnormalities, presence of neurologic deficits, and other comorbidities on the rate of tapering.
治疗癫痫患者的理想目标是使用抗癫痫药物（AEDs）诱导缓解（一段时间无癫痫发作）并停用AEDs而不引起癫痫复发。长期使用AEDs可能有长期不良影响。因此，当癫痫患者处于缓解期时，尝试停药是合理的。在考虑停用AEDs时会出现停药时机和停药方式的问题。本综述考察了AEDs停药速度（快速或缓慢减量）的证据及其对癫痫复发的影响。这是2006年第2期发表的原始Cochrane综述的更新版本。
量化癫痫缓解期的成人和儿童快速（减量期三个月或更短）或缓慢（减量期超过三个月）停用抗癫痫药物后癫痫复发的风险，并评估哪些变量可改变癫痫复发风险。
为获取最新更新内容，我们于2019年4月9日进行了检索：Cochrane研究注册库（CRS网络版，包括Cochrane癫痫小组专业注册库、CENTRAL和ClinicalTrials.gov）、MEDLINE（Ovid；2019年4月8日）、世界卫生组织国际临床试验注册平台和SCOPUS。无语言限制。
评估癫痫患者在不同癫痫控制期后快速或缓慢减量停用AEDs的随机对照试验。
综述作者独立评估试验是否纳入并提取数据。评估的结局包括停用AEDs一年、两年或五年后的无癫痫发作情况；停药后癫痫复发时间；癫痫持续状态的发生情况；死亡率；癫痫所致的发病率，如受伤、骨折和吸入性肺炎；以及生活质量（通过有效量表评估）。
在本次综述更新中，我们纳入了一项新研究。该新研究将57例至少两年无癫痫发作的癫痫儿童随机分为在一个月或六个月内逐渐减量停用AEDs组。该研究未设盲，且无随机化细节。在54个月的随访期内，一个月组的30名参与者中有20名仍无癫痫发作，而六个月组的27名参与者中有15名仍无癫痫发作（无差异证据）。没有关于每组癫痫复发时间的信息可供比较。之前版本的综述已纳入一项试验；该试验涉及149名儿童。在分配至缓慢减量组的参与者中，停用AEDs一年后癫痫复发风险有降低的趋势，但无统计学意义（风险比（RR）0.76，95%置信区间（CI）0.58至1.01；P = 0.06；极低确定性证据）。在两年末，快速减量组有30名参与者无癫痫发作，缓慢减量组有29名参与者无癫痫发作（RR 0.87，95%CI 0.58至1.29；P = 0.48；极低确定性证据）。在五年末，快速减量组有10名参与者无癫痫发作，缓慢减量组有6名参与者无癫痫发作（RR 1.40，95%CI 0.54至3.65；P = 0.49；极低确定性证据）。其他结局无数据。由于方法学异质性以及减量持续时间的差异，我们未对这些研究进行定量综合分析。
自本综述的上一版本发表以来，我们发现了一项新的儿科研究。鉴于方法学缺陷以及两项纳入研究的样本量较小，我们无法就AEDs的最佳减量速度得出任何可靠结论。使用GRADE，我们将现有数据结局的证据确定性评估为极低。我们判断两项研究均存在高偏倚风险。需要在成人和儿童中开展进一步研究，以调查AEDs的最佳停药速度，并研究癫痫类型、病因、智力发育迟缓、脑电图异常、神经功能缺损的存在以及其他合并症等变量对减量速度的影响。
