Long-term outcomes of generalized tonic-clonic seizures in a childhood absence epilepsy trial

Abstract

Objective: To determine incidence and early predictors of generalized tonic-clonic seizures (GTCs) in children with childhood absence epilepsy (CAE).Methods: Occurrence of GTCs was determined in 446 children with CAE who participated in a randomized clinical trial comparing ethosuximide, lamotrigine, and valproate as initial therapy for CAE.Results: As of June 2014, the cohort had been followed for a median of 7.0 years since enrollment and 12% (53) have experienced at least one GTC. The median time to develop GTCs from initial therapy was 4.7 years. The median age at first GTC was 13.1 years. Fifteen (28%) were not on medications at the time of their first GTC. On univariate analysis, older age at enrollment was associated with a higher risk of GTCs (p 5 20.0009), as was the duration of the shortest burst on the baseline EEG (p 5 0.037). Failure to respond to initial treatment (p , 0.001) but not treatment assignment was associated with a higher rate of GTCs. Among patients initially assigned to ethosuximide, 94% (15/16) with GTCs experienced initial therapy failure (p , 0.0001). A similar but more modest effect was noted in those initially treated with valproate (p 5 0.017) and not seen in those initially treated with lamotrigine. Conclusions:The occurrence of GTCs in a well-characterized cohort of children with CAE appears lower than previously reported. GTCs tend to occur late in the course of the disorder. Children initially treated with ethosuximide who are responders have a particularly low risk of developing subsequent GTCs. Neurology ® 2015;85:1108-1114 GLOSSARY AED 5 antiepileptic drug; CAE 5 childhood absence epilepsy; CI 5 confidence interval; GTC 5 generalized tonic-clonic seizure; HR 5 hazard ratio; IQR 5 interquartile range; JAE 5 juvenile absence epilepsy; RCT 5 randomized controlled trial.Childhood absence epilepsy (CAE) is the most common childhood-onset epilepsy syndrome, accounting for 10%-17% of all childhood-onset epilepsy.1,2 Although the core seizure type in CAE is absence seizures, studies have reported that generalized tonic-clonic seizures (GTCs) occur in 30%-60% of children with CAE.3,4 Lack of clarity about the homogeneity of these reports' study populations means the incidence of GTCs remains unclear. The timing of GTC onset in children with CAE is also imprecise but GTCs tend to occur late in the course of CAE with latencies of 5-10 years after syndrome onset. 3,4 A double-blind randomized controlled trial (RCT) of initial therapy for children with CAE enrolled 446 children with newly diagnosed CAE (without a history of GTCs) and randomized them to ethosuximide, lamotrigine, or valproate. 5,6 This cohort was well-characterized with pretreatment and subsequent prospective longitudinal assessment of seizure status, EEG, cognition, and behavioral status. The RCT identified ethosuximide as the optimal initial therapy due to superior efficacy compared with lamotrigine and similar efficacy but fewer attentional side effects when compared to valproic acid. 5,6 The results of th...

Experimental Treatment Options in Absence Epilepsy

“…This seems in contrast to what has been found in children with AE: in a retrospective clinical study, ETX was found to be associated with a high rate of complete remission [5]. Spontaneous remission and or a transition to more severeforms of genetic generalized epilepsy [51] were never reported in any genetic model of AE. This seems to be a real difference between the rodent models and clinical conditions.…”

“…Berg et al (2014) proposed that ETX might have a disease-modifying effect and a high remission rate [5]. In addition, children who were succesfully treated with ETX as the first medication, had a particular low risk of developing subsequent generalized tonic clonic seizures [51]. Despite these rather favorable outcomes for ETX, therapy with this drug was found to fail in 47% of subjects due to seizures, intolerable side-effects oreven withdrawal from the study [2].…”

Out of thin air: Hyperventilation-triggered seizures

“…Also, relative to CAE, patients with JAE are more likely to present with additional, different seizure types at the time of diagnosis. Specifically, Trinka et al reported that nearly 95% of JAE patients eventually develop generalized tonic clonic seizures (GTCS), compared to 69% of CAE patients; other reports suggest that GTCS prevalence in the CAE population may be much lower (Shinnar, 2015). …”

Second monotherapy in childhood absence epilepsy

“…Most tolerable side effects occur early in therapy; the proportion of new occurrences after the first 16-20 weeks is fairly low except weight gain. The number of GTC seizures on initial valproate (n 5 6) and lamotrigine (n 5 1) monotherapy was very low 22 and therefore unlikely to introduce bias. Few studies have examined response to second therapy.…”