Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy

Abstract

Background: Childhood absence epilepsy, the most common pediatric epilepsy syndrome, is usually treated with ethosuximide, valproic acid, or lamotrigine. The most efficacious and tolerable initial empirical treatment has not been defined.

Methods: In a double-blind, randomized, controlled clinical trial, we compared the efficacy, tolerability, and neuropsychological effects of ethosuximide, valproic acid, and lamotrigine in children with newly diagnosed childhood absence epilepsy. Drug doses were incrementally increased until the child was free of seizures, the maximal allowable or highest tolerable dose was reached, or a criterion indicating treatment failure was met. The primary outcome was freedom from treatment failure after 16 weeks of therapy; the secondary outcome was attentional dysfunction. Differential drug effects were determined by means of pairwise comparisons.

Results: The 453 children who were randomly assigned to treatment with ethosuximide (156), lamotrigine (149), or valproic acid (148) were similar with respect to their demographic characteristics. After 16 weeks of therapy, the freedom-from-failure rates for ethosuximide and valproic acid were similar (53% and 58%, respectively; odds ratio with valproic acid vs. ethosuximide, 1.26; 95% confidence interval [CI], 0.80 to 1.98; P=0.35) and were higher than the rate for lamotrigine (29%; odds ratio with ethosuximide vs. lamotrigine, 2.66; 95% CI, 1.65 to 4.28; odds ratio with valproic acid vs. lamotrigine, 3.34; 95% CI, 2.06 to 5.42; P<0.001 for both comparisons). There were no significant differences among the three drugs with regard to discontinuation because of adverse events. Attentional dysfunction was more common with valproic acid than with ethosuximide (in 49% of the children vs. 33%; odds ratio, 1.95; 95% CI, 1.12 to 3.41; P=0.03).

Conclusions: Ethosuximide and valproic acid are more effective than lamotrigine in the treatment of childhood absence epilepsy. Ethosuximide is associated with fewer adverse attentional effects. (ClinicalTrials.gov number, NCT00088452.)

Figure 1. Kaplan–Meier Curves for Freedom from Treatment Failure in the Three Study Groups

The log-rank test of time to treatment failure through the visit at 16 or 20 weeks showed significant differences according to treatment (P<0.001). The hazard ratio for treatment failure was 1.63 (95% confidence interval [CI], 1.20 to 2.20) for lamotrigine as compared with ethosuximide and 0.81 (95% CI, 0.58 to 1.14) for valproic acid as compared with ethosuximide. Patients remained in the study unless they met a criterion for treatment failure. Treatment failure due to drug toxicity or a generalized tonic–clonic seizure could occur at any time; treatment failure attributable to the persistence of absence seizures could occur only on or after the visit at week 16. The rates of freedom from treatment failure at 20 weeks were estimated to be 58% for ethosuximide (95% CI, 50 to 65), 39% for lamotrigine (95% CI, 31 to 47), and 66% for valproic acid (95% CI, 57 to 73).