Mbizvo Gashirai K, Dixon Pete, Hutton Jane L, Marson Anthony G
Institute for Ageing and Chronic Disease, University of Liverpool, Liverpool, UK.
Cochrane Database Syst Rev. 2012 Sep 12;2012(9):CD001901. doi: 10.1002/14651858.CD001901.pub2.
Epilepsy is an important neurological condition and drug resistance in epilepsy is particularly common in individuals with focal seizures. In this review, we summarise the current evidence regarding a new antiepileptic drug, levetiracetam, when used as add-on treatment for controlling drug-resistant focal epilepsy. This is an update to a Cochrane Review that was originally published in 2001.
To evaluate the effectiveness of levetiracetam, added on to usual care, in treating drug-resistant focal epilepsy.
We searched the Cochrane Epilepsy Group's Specialized Register (August 2012), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library Issue 7, 2012), and MEDLINE (1946 to August week 1, 2012). We also contacted the manufacturers of levetiracetam and researchers in the field to seek any ongoing or unpublished trials.
Randomised, placebo-controlled trials of add-on levetiracetam treatment in people with drug-resistant focal epilepsy.
Two review authors independently selected trials for inclusion, assessed trials for bias, extracted data, and evaluated the overall quality of evidence. Outcomes investigated included 50% or greater reduction in focal seizure frequency (response); less than 50% reduction in focal seizure frequency (non-response); treatment withdrawal; adverse effects (including a specific analysis of changes in behaviour); cognitive effects and quality of life (QoL). Risk ratios (RR) with 95% confidence intervals (CIs) were used as measures of effect (99% CIs for adverse effects). Primary analyses were Intention-to-Treat (ITT). Dose response and inter-trial heterogeneity were evaluated in regression models.
Eleven trials (1861 participants) were included. They predominantly possessed low risks of bias. Participants were adults in nine trials (1565 participants) and children in the remaining two trials (296 participants). The dose of levetiracetam tested was 1000 to 4000 mg/day in adults, and 60 mg/kg/day in children. Treatment ranged from 12 to 24 weeks. For the 50% or greater reduction in focal seizure frequency outcome, the RR was significantly in favour of levetiracetam at all doses. The naive estimates, ignoring dose, showed children (52% responded) as better responders than adults (39% responded) on levetiracetam. 25% of children and 16% of adults responded to placebo. The Number Needed to Treat for an additional beneficial outcome for children and adults was four (95% CI three to seven) and five (95% CI four to six), respectively. The significant levels of statistical heterogeneity between trials on adults precluded valid provision of an overall RR (ignoring dose). Results for the two trials that tested levetiracetam 2000 mg on adults were sufficiently similar to be combined to give an RR for 50% or greater reduction in focal seizure frequency of 4.91 (95% CI 2.75 to 8.77), with an RR of 0.68 (95% CI 0.60 to 0.77) for non-response. At this dose, 37% and 8% of adults were responders in the levetiracetam and placebo groups, respectively. Regression analysis demonstrated that much of the heterogeneity between adult trials was likely to be explained by different doses of levetiracetam tested and different years of trial publication. There was no evidence of statistical heterogeneity between trials on children. For these trials, the RR for 50% or greater reduction in focal seizure frequency was 1.91 (95% CI 1.38 to 2.63), with an RR of 0.68 (95% CI 0.56 to 0.81) for non-response. 27% of children responded. Participants were not significantly more likely to have levetiracetam withdrawn (RR 0.98; 95% CI 0.73 to 1.32 and RR 0.80; 95% CI 0.43 to 1.46 for adults and children, respectively). For adults, somnolence (RR 1.51; 99% CI 1.06 to 2.17) and infection (RR 1.76; 99% CI 1.03 to 3.02) were significantly associated with levetiracetam. Accidental injury was significantly associated with placebo (RR 0.60; 99% CI 0.39 to 0.92). No individual adverse effect was significantly associated with levetiracetam in children. Changes in behaviour were negligible in adults (1% affected; RR 1.79; 99% CI 0.59 to 5.41) but significant in children (23% affected; RR 1.90; 99% CI 1.16 to 3.11). Cognitive effect and QoL outcomes suggested that levetiracetam had a positive effect on cognition and some aspects of QoL in adults. In children, levetiracetam did not appear to alter cognitive function but there was evidence of worsening in certain aspects of child behaviour. The overall quality of evidence used was high.
AUTHORS' CONCLUSIONS: This update adds seven more trials to the original review, which contained four trials. At every dose analysed, levetiracetam significantly reduced focal seizure frequency relative to placebo. This indicates that levetiracetam can significantly reduce focal seizure frequency when it is used as an add-on treatment for both adults and children with drug-resistant focal epilepsy. As there was evidence of significant levels of statistical heterogeneity within this positive effect it is difficult to be precise about the relative magnitude of the effect. At a dose of 2000 mg, levetiracetam may be expected to be 3.9 times more effective than placebo; with 30% of adults being responders at this dose. At a dose of 60 mg/kg/day, levetiracetam may be expected to be 0.9 times more effective than placebo; with 25% of children being responders at this dose. When dose was ignored, children were better responders than adults by around 4% to 13%. The results grossly suggest that one child or adult may respond to levetiracetam for every four or five children or adults, respectively, that have received levetiracetam rather than placebo. The drug seems to be well tolerated in both adults and children although non-specific changes in behaviour may be experienced in as high as 20% of children. This aspect of the adverse-effect profile of levetiracetam was analysed crudely and requires further investigation and validation. It seems reasonable to continue the use of levetiracetam in both adults and children with drug-resistant focal epilepsy. The results cannot be used to confirm longer-term or monotherapy effects of levetiracetam or its effects on generalised seizures. The conclusions are largely unchanged from those in the original review. The most significant contribution of this update is the addition of paediatric data into the analysis.
癫痫是一种重要的神经系统疾病，耐药性在局灶性癫痫患者中尤为常见。在本综述中，我们总结了关于新型抗癫痫药物左乙拉西坦作为附加治疗用于控制耐药性局灶性癫痫的现有证据。这是对2001年首次发表的Cochrane综述的更新。
评估在常规治疗基础上加用左乙拉西坦治疗耐药性局灶性癫痫的有效性。
我们检索了Cochrane癫痫小组专业注册库（2012年8月）、Cochrane对照试验中心注册库（CENTRAL，Cochrane图书馆2012年第7期）和MEDLINE（1946年至2012年8月第1周）。我们还联系了左乙拉西坦的制造商和该领域的研究人员，以查找任何正在进行或未发表的试验。
关于左乙拉西坦附加治疗耐药性局灶性癫痫患者的随机、安慰剂对照试验。
两位综述作者独立选择纳入试验、评估试验偏倚、提取数据并评估证据的整体质量。研究的结局包括局灶性癫痫发作频率降低50%或更多（有反应）；局灶性癫痫发作频率降低少于50%（无反应）；治疗撤药；不良反应（包括对行为变化的具体分析）；认知效应和生活质量（QoL）。采用风险比（RR）及95%置信区间（CI）作为效应量度（不良反应采用99%CI）。主要分析为意向性分析（ITT）。在回归模型中评估剂量反应和试验间异质性。
纳入11项试验（1861名参与者）。这些试验大多偏倚风险较低。9项试验（1565名参与者）的参与者为成年人，其余2项试验（296名参与者）的参与者为儿童。成人左乙拉西坦的试验剂量为1000至4000mg/天，儿童为60mg/kg/天。治疗时间为12至24周。对于局灶性癫痫发作频率降低50%或更多这一结局，所有剂量下RR均显著有利于左乙拉西坦。忽略剂量的粗略估计显示，接受左乙拉西坦治疗的儿童（52%有反应）比成人（39%有反应）反应更好。25%的儿童和16%的成人对安慰剂有反应。儿童和成人获得额外有益结局的需治疗人数分别为4（95%CI 3至7）和5（95%CI 4至6）。成人试验间显著的统计学异质性使得无法有效提供总体RR（忽略剂量）。两项对成人使用2000mg左乙拉西坦的试验结果足够相似，可合并得出局灶性癫痫发作频率降低50%或更多的RR为4.91（95%CI 2.75至8.77），无反应的RR为0.68（95%CI 0.60至0.77）。在此剂量下，左乙拉西坦组和安慰剂组分别有37%和8%的成人有反应。回归分析表明，成人试验间的大部分异质性可能由所测试的左乙拉西坦不同剂量和试验发表年份不同所解释。儿童试验间无统计学异质性证据。对于这些试验，局灶性癫痫发作频率降低50%或更多的RR为1.91（95%CI 1.38至2.63），无反应的RR为0.68（95%CI 0.56至0.81）。27%的儿童有反应。参与者停用左乙拉西坦的可能性无显著增加（成人RR 0.98；95%CI 0.73至1.32，儿童RR 0.80；95%CI 0.43至1.46）。对于成人，嗜睡（RR 1.51；99%CI 1.06至2.17）和感染（RR 1.76；99%CI 1.03至3.02）与左乙拉西坦显著相关。意外伤害与安慰剂显著相关（RR 0.60；99%CI 0.39至0.92）。儿童中没有个体不良反应与左乙拉西坦显著相关。成人行为变化可忽略不计（1%受影响；RR 1.79；99%CI 0.59至5.41），但儿童中显著（23%受影响；RR 1.90；99%CI 1.16至3.11）。认知效应和QoL结局表明，左乙拉西坦对成人认知和QoL的某些方面有积极影响。在儿童中，左乙拉西坦似乎未改变认知功能，但有证据表明儿童行为的某些方面有所恶化。所使用证据的整体质量较高。
本次更新在原综述（包含4项试验）基础上增加了7项试验。在分析的每个剂量下，相对于安慰剂，左乙拉西坦均显著降低局灶性癫痫发作频率。这表明左乙拉西坦作为附加治疗用于耐药性局灶性癫痫的成人和儿童时，均可显著降低局灶性癫痫发作频率。由于在这一积极效应中有显著的统计学异质性证据，因此难以精确确定效应的相对大小。在2000mg剂量下，预计左乙拉西坦比安慰剂有效3.9倍；此剂量下30%的成人有反应。在60mg/kg/天的剂量下，预计左乙拉西坦比安慰剂有效0.9倍；此剂量下25%的儿童有反应。忽略剂量时，儿童比成人反应好约4%至13%。结果大致表明，接受左乙拉西坦而非安慰剂治疗的儿童或成人中，分别约每四个或五个儿童或成人中有一个可能对左乙拉西坦有反应。该药物在成人和儿童中似乎耐受性良好，尽管高达20%的儿童可能会出现非特异性行为变化。左乙拉西坦不良反应的这一方面分析较为粗略，需要进一步研究和验证。对于耐药性局灶性癫痫的成人和儿童继续使用左乙拉西坦似乎是合理的。结果不能用于证实左乙拉西坦的长期或单药治疗效果或其对全身性癫痫发作的影响。结论与原综述基本一致。本次更新最显著的贡献是在分析中增加了儿科数据。
