Levetiracetam add-on for drug-resistant focal epilepsy: an updated Cochrane Review

Background 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. Objectives To evaluate the effectiveness of levetiracetam, added on to usual care, in treating drug-resistant focal epilepsy. Search methods 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 We also contacted the manufacturers of levetiracetam and researchers in the field to seek any ongoing or unpublished trials. Selection criteria Randomised, placebo-controlled trials of add-on levetiracetam treatment in people with drug-resistant focal epilepsy. Data collection and analysis 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. Main results 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