By Hai Chen, MD, PhD
Synopsis: After failure of first-line anti-seizure medication, women with idiopathic generalized epilepsy may receive either substitution monotherapy or add-on therapy. There were no significant differences in effectiveness or safety between substitution monotherapy and add-on therapy in this retrospective comparative study.
Source: Cerulli Irelli E, Cocchi E, Gesche J, et al. Second-line medications for women aged 10 to 50 years with idiopathic generalized epilepsy. JAMA Netw Open. 2025;8(3):e250354.
Patients who have not achieved seizure control with first-line anti-seizure medication (ASM) need either ASM substitution or add-on therapy. Idiopathic generalized epilepsy (IGE) is seen commonly in clinical practice, and valproic acid (VPA) is effective in treatment of IGE. However, VPA use in women often is restricted because of the negative effect on pregnancy. This study examines the effectiveness of different treatment strategies for women with IGE after the first-line ASM (other than VPA) failure.
In this study, the authors identified women of childbearing age with IGE who did not achieve seizure control with a first-line ASM (other than VPA). Patients who were prescribed a second ASM, either as add-on or substitution monotherapy with at least 12-month follow-up duration, were included in the study. The primary outcome was the time from the initiation of a second-line ASM to treatment failure (TF) of this second ASM. TF was defined as the need to switch to another ASM or to add an adjunctive ASM because of a lack of adequate responses.
The study included 249 patients. Three syndromes, juvenile myoclonic epilepsy (JME), absence epilepsy, and generalized tonic-clonic seizures alone (GTCA), were observed in the study population. The commonly prescribed first-line ASMs in the cohort were levetiracetam (LEV, n = 109) and lamotrigine (LTG, n = 108), followed by topiramate, ethosuximide, and zonisamide.
After first-line monotherapy failure, 146 women (58.6%) were prescribed an add-on regimen, and 103 women (41.4%) received substitution monotherapy. There was no difference in baseline characteristics, such as age, history of febrile seizure, or status epilepticus, between the two treatment groups. In the group with substituted monotherapy (n = 103), commonly used ASMs included LEV (n = 30), LTG (n = 30), VPA (n = 22), and others. Among 146 patients receiving an add-on regimen, the most frequent ASM combination was LEV plus LTG (n = 68, 46.6%).
In total, 84 TF events were observed in the cohort. There was no significant difference in TF between the two groups who received an add-on therapy (48 of 146 participants, 32.9%) or substitution monotherapy (36 of 103 subjects, 35%). For secondary outcomes, there were no significant differences in seizure freedom between the add-on regimen group (68 of 146 patients, 50.4%) and substitution monotherapy group (60 of 103 patients, 58.8%). ASM withdrawal as the result of ineffectiveness or adverse effects occurred in 36 patients (24.7%) using an add-on regimen and 29 patients (28.2%) in the substitution monotherapy group. Regarding specific IGE syndromes, the add-on regimen had a nonsignificant lower rate of TF in patients with GTCA and JME compared with substitution monotherapy.
The authors then evaluated the effectiveness of individual agents, either prescribed as substitution monotherapy or as part of an add-on therapy. VPA was associated with a significantly lower risk of TF (8 of 48 patients, 16.7%) compared with all other ASMs (76 of 201 patients, 37.8%), except for LEV. When considering the effectiveness of each ASM combination among patients using an add-on regimen, LEV plus LTG was associated with a significantly reduced risk of TF compared with LEV plus others and LTG plus others. But LEV plus LTG showed nonsignificant lower effectiveness compared with VPA plus LEV or VPA plus LTG.
Finally, the study compared ASM withdrawal because of adverse effects in two groups. In total, ASM discontinuation occurred in 22 patients (8.9%), including 13 patients (9.0%) in the add-on therapy group and nine patients (8.7%) in the substitution monotherapy group. There were no significant differences in ASM withdrawal between the two groups.
Commentary
Management of IGE in childbearing-age women who have failed initial treatment poses significant challenges, and there is limited knowledge about the most effective treatment strategies in this population.
In this study, substitution monotherapy and add-on therapy did not show significant differences in terms of TF, seizure freedom, or discontinuation rates because of adverse effects. These findings suggest both substitution monotherapy and add-on therapy are viable second-line treatments for women with IGE after first-line ASM failure. Additionally, this study confirmed that VPA was the most effective ASM in seizure control as a second-line treatment.
Despite its effectiveness, prenatal exposure to VPA is associated with an elevated risk of congenital malformations and neurodevelopmental disorders. Therefore, the benefit and risk must be carefully considered, and clinicians should make individualized treatment decisions in women of childbearing age with IGE after initial treatment failure.
Hai Chen, MD, PhD, is Assistant Professor of Clinical Neurology, Weill Cornell Medical College.
After failure of first-line anti-seizure medication, women with idiopathic generalized epilepsy may receive either substitution monotherapy or add-on therapy. There were no significant differences in effectiveness or safety between substitution monotherapy and add-on therapy in this retrospective comparative study.
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