Elsevier

The Lancet Neurology

Volume 10, Issue 11, November 2011, Pages 961-968
The Lancet Neurology

Articles
Risk of sudden unexpected death in epilepsy in patients given adjunctive antiepileptic treatment for refractory seizures: a meta-analysis of placebo-controlled randomised trials

https://doi.org/10.1016/S1474-4422(11)70193-4Get rights and content

Summary

Background

Sudden unexpected death in epilepsy (SUDEP) represents the main cause of death in patients with refractory epilepsy. No evidence-based intervention to prevent SUDEP exists. We postulated that pooling data from randomised placebo-controlled trials in patients with refractory epilepsy might show a lower incidence of SUDEP in patients receiving antiepileptic drugs (AEDs) at efficacious doses than in those receiving placebo.

Methods

We searched Medline and the Cochrane Library for randomised trials investigating any AED in the add-on treatment of drug-resistant epilepsy in adults. We extracted the number and causes of death in patients allocated to AEDs at doses that were more efficacious than placebo against seizures, AEDs at non-efficacious doses, and placebo. In our primary analysis, we compared the occurrence of definite or probable SUDEP between patients given efficacious AED doses and those given placebo using the Mantel-Haenszel method, with exclusion of trials with no event.

Findings

Data of 33 deaths, including 20 deemed as SUDEP, were extracted from 112 eligible randomised trials. 18 deaths were classified as definite or probable SUDEP and two as possible SUDEP. Definite or probable SUDEP, all SUDEP, and all causes of death were significantly less frequent in the efficacious AED group than in the placebo group, with odds ratios of 0·17 (95% CI 0·05–0·57, p=0·0046), 0·17 (0·05–0·57, p=0·0046), and 0·37 (0·17–0·81, p=0·0131), respectively. Rates of definite or probable SUDEP per 1000 person-years were 0·9 (95% CI 0·2–2·7) in patients who received efficacious AED doses and 6·9 (3·8–11·6) in those allocated to placebo.

Interpretation

Treatment with adjunctive AEDs at efficacious doses may have reduced the incidence of definite or probable SUDEP by more than seven times compared with placebo in patients with previously uncontrolled seizures. This result provides evidence in favour of active treatment revision for patients with refractory epilepsy.

Funding

None.

Introduction

Mortality is increased in patients with uncontrolled seizures,1, 2 mainly owing to sudden unexpected death in epilepsy (SUDEP). Incidence of SUDEP is between 3·5 and 9·3 per 1000 person-years in refractory epilepsy,3 and at least 12% of patients with childhood epilepsy and no terminal 5-year remission will die of SUDEP by the age of 40 years.1, 2 Indeed, most SUDEP victims are young adults with a mean age at the time of death of about 35 years.2, 4, 5 SUDEP is typically unwitnessed and occurs during sleep, but SUDEP that is observed is usually triggered by a seizure through mechanisms that remain uncertain.3 Some potentially preventable risk factors have been identified,3, 4, 6, 7, 8, 9 suggesting that a significant proportion of SUDEP could be avoidable with optimal care.10, 11 However, despite an urge to develop such a strategy, no intervention has yet been assessed in a controlled study.

Meta-analysis of randomised placebo-controlled trials done in patients with refractory epilepsy offers a unique opportunity to investigate this issue. These trials assess the potency of adjunctive antiepileptic drugs (AEDs) to reduce frequency of seizures, a risk factor for SUDEP.4, 7, 9 However, because polytherapy might also promote SUDEP,3, 4, 7, 8, 9 the net effect of adding another AED cannot be predicted. Although SUDEP rarely occurs during such randomised trials, pooling of data across a large number of trials might allow to detect the effect of adjunctive AED treatment on the risk of SUDEP. More specifically, we hypothesised that the incidence of definite and probable SUDEP would be lower in patients receiving AEDs at efficacious doses than in those receiving placebo. Our secondary aims were to compare the rate of all SUDEP (possible, probable, or definite), deaths from causes other than SUDEP, and the total number of deaths between the two groups.

Section snippets

Search strategy and selection criteria

We selected double-blind, placebo-controlled randomised trials of add-on AEDs done in adult patients with uncontrolled partial or primary generalised tonic-clonic seizures. Two electronic databases (Medline and the Cochrane Library) were searched from Jan 1, 1960, to Dec 31, 2010. We looked for additional studies in the register of the ISRCTN, the metaRegister of Controlled Trials, ClinicalTrials.gov, Cochrane meta-analyses of AEDs, and references of all identified publications. The detailed

Results

Our search initially retrieved 6718 reports and eventually led to the identification of 112 eligible trials, including 106 (95%) in refractory partial epilepsy and six (5%) in refractory primary generalised tonic-clonic seizures (figure 1, webappendix p 3). According to our criteria, we could exclude a reporting bias for the occurrence of deaths in 97 (87%) of these 112 trials, whereas the possibility of such bias was judged unclear in six (5%), and present in nine (8%) trials (ie, non-reported

Discussion

This meta-analysis shows that adult patients with refractory epilepsy enrolled in double-blind randomised trials of add-on AEDs are less likely to die of a SUDEP if allocated to AEDs at efficacious doses rather than if allocated to placebo. To the best of our knowledge, this post-hoc analysis offers the first controlled evidence that an intervention may modify the risk of SUDEP.

Addressing the issue of SUDEP in the setting of double-blind randomised trials in epilepsy is challenging, because of

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    These authors contributed equally to the study

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