托吡酯添加治疗难治性部分性癫癇疗效及安全性Meta分析

Evaluation of the efficacy and safety of topiramate as adjunctive drug in the treatment of refractory partial seizures with Meta-analysis

研究背景癫癇是中枢神经系统神经元异常放电所致慢性神经系统疾病。在过去20年中,涌现出约10余种新型抗癫癇药物,为癫癇患者的治疗提供了新的选择,其中托吡酯主要用于难治性部分性发作之添加治疗,本研究拟对其疗效和安全性进行系统评价,以期进一步对临床用药提供参考和借鉴。方法分别以托吡酯、妥泰、部分性发作、难治性、癫癇痫,以及topiramate、Topamax、add-ontreatment、adjunctive treatment、add-on therapy、adjunctive therapy、refractory partial seizure、refractorypartial epilepsy等中英文词汇为检索词,计算机检索美国国立医学图书馆（1995-2014年）、Cochrane临床对照试验中心注册库（1995-2014年）、Cochrane系统评价数据库（1995-2014年）、中国知网中国知识基础设施工程（1995-2014年）、万方数据库（1999-2014年）等,收集所有关于托吡酯添加治疗难治性部分性癫癇的随机双盲对照临床试验,经方法学质量评价后行Meta分析。结果共纳入13项随机对照试验,包括1622例难治性部分性发作患者。分析显示：托吡酯每周部分性发作减少率≥50%（OR=3.710,95%CI：2.870~4.810;P=0.000）、≥75%（OR=7.220,95%CI：3.310~15.750;P=0.000）及完全不发作（OR=3.380,95%CI：1.720~6.640;P=0.000）的患者比例均高于对照组;停药率除200 mg/d组外（OR=2.170,95%CI：0.470~9.950;P=0.320）,其余各亚组均高于对照组（600 mg/d：OR=2.090,95%CI：1.020~4.270,P=0.040;800 mg/d：OR=8.000,95%CI：1.390~46.140,P=0.020）。常见不良反应包括嗜睡、厌食、共济失调、注意力下降、头晕、疲劳、恶心、思维异常、肢体麻木和体重减轻,托吡酯组不良反应发生率均高于对照组。结论托吡酯添加治疗难治性部分性癫癇疗效显著,剂量维持在200 mg/d停药率与对照组相近;轻至中度不良反应较对照组常见,主要为中枢神经系统不良反应,其次为消化系统。

Background pilepsy is a chronic neurological condition characterized by paroxysm ofseizures due to abnormal electrical discharge from central nervous system neurons. Several newantiepileptic drugs（AEDs） were listed over the past two decades, and they were believed to be equallyeffective and have better tolerability and side effect profiles. This paper aims to evaluate the efficacy andsafety of adjunctive topiramate in refractory partial seizures.MethodsRelevant research articles aboutrandomized controlled trials of adjunctive topiramate in refractory partial seizures, with topiramate,Topamax, add- on treatment, adjunctive treatment, add- on therapy, adjunctive therapy, refractory partial seizure, refractory partial epilepsy both in Chinese and English as retrieval words, were retrieved from Pub Med（1995-2014）, Cochrane Central Register of Controlled Trials（CENTRAL, 1995-2014）, The Cochrane Database of Systematic Reviews（CDSR, 1995-2014）, China National Knowledge Infrastructure（CNKI, 1995-2014） and Wanfang Data（1999-2014）. Two reviewers independently evaluated the quality of the included articles and abstracted the data. A Meta-analysis was conducted using Rev Man 5.0 software.Results According to the enrollment criteria, 13 prospective, randomized controlled clinical trials with a total of 1622 patients were finally selected. The proportions of patients with reduction in seizure frequency ≥ 50%（OR = 3.710, 95% CI： 2.870-4.810; P = 0.000）, ≥ 75%（OR = 7.220, 95% CI：3.310-15.750; P = 0.000） and seizure free（OR = 3.380, 95%CI： 1.720-6.640; P = 0.000） in topiramate group were significantly higher than that in control group. The treatment withdrawal ratio was significantly higher compared to placebo in 600 mg/d and 800 mg/d subgroups, but not in 200 mg/d subgroup（200 mg/d： OR =2.170, 95%CI： 0.470-9.950, P = 0.320; 600 mg/d： OR = 2.090, 95%CI： 1.020-4.270, P = 0.040; 800 mg/d：OR = 8.000, 95%CI： 1.390-46.140, P = 0.020）. The common side effects included somnolence, anorexia,ataxia, aprosexia, dizziness, fatigue, nausea, thinking abnormality, paraesthesia and weight loss. The occurrence rate of side effects in topiramate group was higher than that in control group.Conclusions Topiramate is effective when added to existing therapy in patients with refractory partial seizures. The withdrawal rate of 200 mg/d topiramate is similar to control group. Compared with the control group,adverse effects are more common but mild or moderate, mainly related with the central nervous system.However, trials included in this study are of relatively short duration, and provide no evidence for the longterm efficacy of topiramate.