ArticlesRisk of sudden unexpected death in epilepsy in patients given adjunctive antiepileptic treatment for refractory seizures: a meta-analysis of placebo-controlled randomised trials
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
References (43)
- et al.
Mortality in adults with newly diagnosed and chronic epilepsy: a retrospective comparative study
Lancet Neurol
(2006) - et al.
Sudden unexpected death in epilepsy: current knowledge and future directions
Lancet Neurol
(2008) - et al.
Sudden unexpected death in epilepsy: evidence-based analysis of incidence and risk factors
Epilepsy Res
(2005) - et al.
Risk factors for sudden unexpected death in epilepsy: a case-control study
Lancet
(1999) - et al.
Sudden death in epilepsy: a wake-up call for management
Lancet
(2002) - et al.
Lamotrigine: a six-month, placebo-controlled, safety and tolerance study
J Epilepsy
(1995) - et al.
A placebo-controlled, double-blind cross-over trial of adjunctive one month remacemide hydrochloride treatment in patients with refractory epilepsy
Seizure
(2000) - et al.
A randomized, double-blind, placebo-controlled trial of topiramate in adults with epilepsy and intellectual disability: impact on seizures, severity, and quality of life
Epilepsy Behav
(2005) - et al.
Remacemide hydrochloride as an add-on therapy in epilepsy: a randomized, placebo-controlled trial of three dose levels (300, 600 and 1200 mg/day) in a Q.I.D. regimen
Seizure
(2002) - et al.
Gabapentin in generalized seizures
Epilepsy Res
(1996)
Dose-response effect of levetiracetam 1000 and 2000 mg/day in partial epilepsy
Epilepsy Res
The pharmacological treatment of epilepsy in adults
Lancet Neurol
Long-term mortality in childhood-onset epilepsy
N Engl J Med
Case-control study of SUDEP
Neurology
A prospective study on sudden unexpected in epilepsy
Ann Neurol
Incidence and risk factors in sudden unexpected death in epilepsy: a prospective cohort study
Neurology
Combined analysis of risk factors for SUDEP
Epilepsia
Epilepsy in the WHO European Region
Sudden unexpected death in epilepsy: terminology and definitions
Epilepsia
United States perspective on definitions and classifications
Epilepsia
Chapter 8: Assessing risk of bias in included studies
Cited by (0)
- †
These authors contributed equally to the study