Levetiracetam add-on for drug-resistant focal epilepsy

This is an updated version of the Cochrane Review first published in 2001 and last updated in Issue 9, 2012 of the Cochrane Database of Systematic Reviews.

Background and objective

Epilepsy is a one of the most common disorders of the brain, affecting over 70 million people worldwide. Levetiracetam is an antiepileptic drug widely used around the world. In this review, we summarised the current evidence regarding its effectiveness when used as a treatment added on to usual care in people experiencing focal epilepsy that responds poorly to medication.

Methods

The evidence is current to 26 November 2018. Fourteen studies in which people were randomly assigned to either levetiracetam or a dummy tablet (placebo) were included, with a total of 2455 participants (296 of whom were children). Everybody had their usual medications continued, meaning that nobody was left without taking an antiepileptic medicine. Among other things, we looked at how many people had their frequency of seizures reduced by 50% or more when taking levetiracetam versus when taking the placebo tablet. We combined the results of all of these people in order to increase our confidence in how effective levetiracetam is.

Key results

Levetiracetam significantly reduced the frequency of seizures in both adults and children. Just over half of children responded to levetiracetam, and 34% of adults also responded. These responses were much higher than in the placebo groups, indicating that levetiracetam was better than placebo. The most effective doses were those of 1000 mg to 3000 mg levetiracetam. For every 1000 mg increase in dose, the chances that levetiracetam would reduce seizures (fits) appeared to improve by 40%. We noticed that the results were very different in each study we looked at. Therefore, although we could see that levetiracetam works, it was difficult for us to be certain about how large that effect actually is.

Levetiracetam was generally tolerated well by adults and children. Most people managed to complete their course of levetiracetam during the studies. There were very few side effects with levetiracetam. The only side effect that was significantly associated with levetiracetam was somnolence (sleepiness). However, we also noticed that the behaviour of some children taking levetiracetam could worsen significantly.

Overall, it seems reasonable to add levetiracetam to a patient's usual antiepileptic medications if they have focal epilepsy that has responded poorly to other medications.

Authors' conclusions: 

Overall, this review update finds that in both adults and children with drug-resistant focal epilepsy, levetiracetam added on to usual care is more effective than placebo at reducing seizure frequency, it is unlikely to be stopped by patients, and it has minimal adverse effects outside of potential worsening behaviour in children. These findings are unchanged from the previous review update in 2012. This review update contributes two key additional findings: 1. a 500 mg daily dose of levetiracetam is no more effective than placebo at reducing seizures; and 2. the odds of response (50% reduction in seizure frequency) are increased by nearly 40% for each 1000 mg increase in dose of levetiracetam.

It seems reasonable to continue the use of levetiracetam in both adults and children with drug-resistant focal epilepsy.

Read the full abstract...
Background: 

Drug resistance is common in focal epilepsy. In this update, we summarised the current evidence regarding add-on levetiracetam in treating drug-resistant focal epilepsy. The original review was published in 2001 and last updated in 2012.

Objectives: 

To evaluate the effectiveness of levetiracetam when used as an add-on treatment for people with drug-resistant focal epilepsy.

Search strategy: 

We searched the Cochrane Register of Studies (CRS Web, which includes the Cochrane Epilepsy Group Specialized Register and CENTRAL), MEDLINE Ovid, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform (ICTRP) to November 2018. We 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 certainty of the evidence. Outcomes investigated included 50% or greater reduction in focal seizure frequency (response), treatment withdrawal, adverse effects (including a specific analysis of changes in behaviour), cognitive effects, and quality of life (QoL). Primary analysis was intention-to-treat. We performed meta-analysis for all outcomes using a Mantel-Haenszel approach and calculated risk ratios (RR), with 95% confidence intervals (CI) for all estimates apart from adverse effects (99% CIs). We assessed heterogeneity using a Chi² test and the I² statistic.

Main results: 

This update included 14 trials (2455 participants), predominantly possessing low risks of bias. Participants were adults in 12 trials (2159 participants) and children in the remaining two (296 participants). The doses of levetiracetam tested were 500 mg/day to 4000 mg/day in adults, and 60 mg/kg/day in children. Treatment ranged from 12 to 24 weeks. When individual doses were examined, levetiracetam at either 500 mg/day or 4000 mg/day did not perform better than placebo for the 50% or greater reduction in seizure frequency outcome (500 mg: RR 1.60, 95% CI 0.71 to 3.62; P = 0.26; 4000 mg: RR 1.64, 95% CI 0.59 to 4.57; P = 0.34). Levetiracetam was significantly better than placebo at all other individual doses (1000 mg to 3000 mg). RR was significantly in favour of levetiracetam compared to placebo when results were pooled across all doses (RR 2.37, 95% CI 2.02 to 2.78; 14 studies, 2455 participants; moderate-certainty evidence). Dose–response analysis demonstrated that the odds of achieving response (50% or greater reduction in seizure frequency) were increased by nearly 40% (odds ratio (OR) 1.39, 95% CI 1.23 to 1.58) for each 1000 mg increase in dose of levetiracetam. There were important levels of heterogeneity across multiple comparisons.

Participants were not significantly more likely to experience treatment withdrawal with levetiracetam than with placebo (pooled RR 1.11, 95% CI 0.89 to 1.40; 13 studies, 2428 participants; high-certainty evidence).

Somnolence was the most common adverse effect, affecting 13% of participants, and it was significantly associated with levetiracetam compared to placebo (pooled RR 1.62, 99% CI 1.19 to 2.20; 13 studies, 2423 participants; moderate-certainty evidence). 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). Levetiracetam had a positive effect on some aspects of cognition and QoL in adults and worsened certain aspects of child behaviour.

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