Ethosuximide, sodium valproate or lamotrigine for absence seizures in children and adolescents

Background

Epilepsy is a disorder where seizures are caused by abnormal electrical discharges from the brain. Absence epilepsy involves seizures that cause a sudden loss of awareness. It often starts in childhood or adolescence. Three antiepileptic drugs are often used for absence epilepsy: valproate, ethosuximide and lamotrigine.

This review aims to determine which of these three antiepileptic drugs is the best choice for the treatment of absence seizures in children and adolescents.

Results

The review found some evidence (based on eight small trials) that individuals taking lamotrigine are more likely to be seizure free than those using placebos. The review found robust evidence that patients taking ethosuximide or valproate are more likely to be seizure free than those using lamotrigine. However, because of the lower risk of adverse effects, the use of ethosuximide is preferred over valproate in patients with absence childhood epilepsy.

With regards to both efficacy and tolerability, ethosuximide represents the optimal initial empirical monotherapy for children and adolescents with absence seizures.

The evidence is current to 1 September 2016.

Authors' conclusions: 

With regards to both efficacy and tolerability, ethosuximide represents the optimal initial empirical monotherapy for children and adolescents with absence seizures. However, if absence and generalised tonic-clonic seizures coexist, valproate should be preferred, as ethosuximide is probably inefficacious on tonic-clonic seizures.

Read the full abstract...
Background: 

This is an updated version of the original Cochrane review originally published in 2003, Issue 3, and updated in 2005, Issue 4.

Absence seizures are brief epileptic seizures which present in childhood and adolescence. Depending on clinical features and electroencephalogram (EEG) findings they are divided into typical, atypical absences, and absences with special features. Typical absences are characterised by sudden loss of awareness and an EEG typically shows generalised spike wave discharges at three cycles per second. Ethosuximide, valproate and lamotrigine are currently used to treat absence seizures. This review aims to determine the best choice of antiepileptic drug for children and adolescents with typical absence seizures.

Objectives: 

To review the evidence for the effects of ethosuximide, valproate and lamotrigine as treatments for children and adolescents with absence seizures, when compared with placebo or each other.

Search strategy: 

We searched the Cochrane Epilepsy Group's Specialized Register (1 September 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO, 1 September 2016), MEDLINE (Ovid, 1946 to 1 September 2016), ClinicalTrials.gov (1 September 2016) and the WHO International Clinical Trials Registry Platform ICTRP (1 September 2016). Previously we searched Embase (1988 to March 2005) and SCOPUS (1823 to 31 March 2014). No language restrictions were imposed. In addition, we contacted Sanofi Winthrop, Glaxo Wellcome (now GlaxoSmithKline) and Parke Davis (now Pfizer), manufacturers of sodium valproate, lamotrigine and ethosuximide respectively.

Selection criteria: 

Randomised parallel group monotherapy or add-on trials which include a comparison of any of the following in children or adolescents with absence seizures: ethosuximide; sodium valproate; lamotrigine; or placebo.

Data collection and analysis: 

Outcome measures were: (1) proportion of individuals seizure free at one, three, six, 12 and 18 months post randomisation; (2) people with a 50% or greater reduction in seizure frequency; (3) normalisation of EEG and/or negative hyperventilation test; and (4) adverse effects. Data were independently extracted by two review authors. Results are presented as risk ratios (RR) with 95% confidence intervals (95% CIs).

Main results: 

Eight small trials were found (three of them not included in the previous version of the review). Six of them were of poor methodological quality and seven recruited less than 50 participants. There are no placebo-controlled trials for ethosuximide or valproate, and hence, no evidence from randomised controlled trials to support a specific effect on absence seizures for either of these two drugs. Due to the differing methodologies used in the trials comparing ethosuximide, lamotrigine and valproate, we thought it inappropriate to undertake a meta-analysis. One large randomised, parallel double-blind controlled trial comparing ethosuximide, lamotrigine and sodium valproate in children with newly diagnosed childhood absence epilepsy found that at 12 months, the freedom-from-failure rates for ethosuximide and valproic acid (VPA) were similar and were higher than the rate for lamotrigine. The frequency of treatment failures due to lack of seizure control (P < 0.001) and intolerable adverse events (P < 0.037) was significantly different among the treatment groups, with the largest proportion of lack of seizure control in the lamotrigine cohort, and the largest proportion of adverse events in the VPA group. Overall, this large study demonstrates the superior effectiveness of ethosuximide and VPA compared to lamotrigine as initial monotherapy aimed to control seizures without intolerable adverse effects in children with childhood absence epilepsy.

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