What Is the Best First-Line Treatment for Young Women with Generalized Epilepsy?

By Robert McInnis, MD

Assistant Professor of Clinical Neurology, Weill Cornell Medical College

SYNOPSIS: Valproate is a highly efficacious drug for treating idiopathic generalized epilepsy (IGE) but is not an option for many young women because of known teratogenic risks. This retrospective, multicenter study examined women with IGE who were treated initially with either levetiracetam or lamotrigine monotherapy, demonstrating superior efficacy of levetiracetam, although exclusively in women with juvenile myoclonic epilepsy.

SOURCE: Irelli EC, Cocchi E, Morano A, et al, for the Women With Epilepsy Treatment Options and Research (WETOR) Study Group. Levetiracetam vs lamotrigine as first-line antiseizure medication in female patients with idiopathic generalized epilepsy. JAMA Neurol 2023;80:1174-1181.

Valproate, a broad-spectrum anti-seizure medication (ASM), has been recognized as a drug of choice for idiopathic generalized epilepsy (IGE) syndromes, given its demonstrated efficacy across multiple generalized seizure types when compared head-to-head with other ASMs, including lamotrigine (LTG), levetiracetam (LEV), and topiramate. For women diagnosed with IGE, the higher incidence of structural and cognitive teratogenesis that occurs with valproate disqualifies it as an option in many cases. As a result, women with IGE may be exposed to more breakthrough seizures and their associated risks. Unfortunately, there is a paucity of quality evidence to guide alternative ASM selection for women of childbearing age with IGE.

To address this knowledge gap, Irelli and colleagues performed a multicenter, retrospective study comparing LEV or LTG as initial therapy in eligible female patients of childbearing age with IGE. LEV and LTG were selected specifically because of prior evidence that they are the least teratogenic among the ASMs considered effective for generalized seizure types.

Data were pooled from 22 epilepsy centers over a retrospective period of 30 years from 1991 to 2022. To be included, patients had to be of female sex, to have received a diagnosis of IGE according to International League Against Epilepsy criteria, to have been prescribed either LEV of LTG as a first ASM, be between the ages of 10 and 50 years, and to have received a minimum of 12 months of follow-up after treatment initiation, unless there was treatment failure (TF).

The primary outcome was time from prescription to TF, defined as either stopping the ASM in favor of another as the result of ineffectiveness or adverse effects, or adding a second ASM as the result of ineffectiveness. Seizure freedom also was measured after 12 months of follow-up, and patients were considered seizure-free only if remission was achieved on the first monotherapy trial.

There were 543 female patients of childbearing age who were included in the analysis, after excluding patients who had insufficient duration of follow-up. The median age at the time of prescription was 17 years, and the median duration of follow-up was 60 months (range 24-108 months). Of those included in the analysis, 312 (57.5%) were treated with LEV and 231 (42.5%) were treated with LTG. There were 259 (47.7%) patients categorized as juvenile myoclonic epilepsy (JME), 175 (32.2%) with generalized tonic-clonic seizures alone, and 109 (20.1%) with absence epilepsy.

Other demographic and clinical factors were tracked and included as covariates, although there were no significant differences between the two treatment groups except for a diagnosis of absence epilepsy, which was less common in the group treated with LEV (15.4% vs. 26.4%). Propensity score analysis with inverse probability of treatment weighting was applied as a method to control for the effect of confounding factors on outcomes.

Mean initial maintenance doses were 1,197 mg for the LEV group and 239 mg for the LTG group. During the follow-up period, there were significantly fewer TFs in those treated with LEV, which was confirmed by multivariate adjusted analysis. A subgroup analysis was performed by stratifying by IGE subsyndrome, which redemonstrated significantly superior effectiveness as well as ASM retention for LEV, but only for those with JME; no significant differences were observed for the other IGE subtypes.

Seizure freedom in the entire study population at 12 months was modest at only 40%, although it was significantly higher in the LEV group. Adverse events were observed more frequently in the LEV group, but this ultimately did not associate with a higher rate of TF. Myoclonic seizures were uncommon overall but found to occur significantly more frequently in those treated with LTG.

COMMENTARY

This is a well-executed retrospective analysis that aims to address a critical knowledge gap in treating women with IGE. The results suggest that initial monotherapy with LEV is more successful than that of LTG in women with IGE, but only in women with JME. Given that JME is the most common subsyndrome encountered in adults with IGE, this evidence is practical and may be applied regularly in neurology clinics.

Although the retrospective design introduced a risk for bias and precludes more certain causative conclusions, the authors employed sound methodological approaches to account for the non-random assortment of factors that may have confounded outcomes. In the absence of a randomized controlled trial comparing LTG to LEV, the study provides some of the best evidence currently available for women presenting with a JME phenotype of IGE. The study did not track the use of estrogen-containing oral contraceptives, which may be a methodological weakness, given that this contraceptive method may have been common in this cohort and would have preferentially decreased the efficacy of LTG.

The rather disappointing rate of seizure freedom at 12 months in this population underscores the importance of continued focus on optimizing treatment strategies for women with IGE, as well as new drug development.