Second-Line Medications for Women Aged 10 to 50 Years With Idiopathic Generalized Epilepsy
Authors: Emanuele Cerulli Irelli, Enrico Cocchi, Joanna Gesche, Javier Peña-Ceballos, Roberto H. Caraballo, Simona Lattanzi, Gionata Strigaro, Alessandra Morano, Patrick B. Moloney, Edoardo Ferlazzo, Angelo Pascarella, Adolfo Mazzeo, Alfredo D’Aniello, Chiara Pizzanelli, Chiara Milano, Loretta Giuliano, Veronica Viola, Barbara Mostacci, Francesco Fortunato, Patrizia Pulitano, Margherita Burani, Stefano Meletti, Pietro Pignatta, Marco Perulli, Domenica Battaglia, Eleonora Rosati, Norman Delanty, Giancarlo Di Gennaro, Antonio Gambardella, Angelo Labate, Francesca F. Operto, Anna T. Giallonardo, Christoph P. Beier, Carlo Di Bonaventura, Betul Baykan, Daniela Fatuzzo, Giulio Pastorelli, Pierpaolo Quarato, Cecilia Catania, Sara Casciato, Chiara Martellino, Giorgia Atanasio, Emanuela Viglietta, Vittoria Cianci, Irene Bagnasco, Erica Cognolato, Edoardo Pronello, Francesca Bisulli, Giuseppe Pontrelli, Giovanni Boero, Francesca Gilio, Francesca Gragnani, Carla Marini, Sara Gasparini, Irene Pappalardo
Journal: JAMA Network Open (2025)

Importance Women with idiopathic generalized epilepsy (IGE) face challenges in treatment due to limited options that are both effective and safe. Objective To evaluate the effectiveness and safety of substitution monotherapy vs add-on therapy as second-line options for women who might become pregnant with IGE after failure of first-line antiseizure medications (ASMs) other than valproic acid. Design, Setting, and Participants Multicenter retrospective comparative effectiveness cohort study at 18 primary, secondary, and tertiary adult and children epilepsy centers across 4 countries, analyzing data from 1995 to 2023. Participants were women aged 10 to 50 years diagnosed with IGE who were prescribed a second line of ASM. Main Outcomes and Measures Treatment failure (TF), defined as the replacement or addition of a second ASM due to ineffectiveness, was compared between patients receiving ASM add-on or substitution monotherapy using inverse probability of treatment weighting (IPTW)–adjusted Cox proportional hazards regression. Exploratory analyses were also conducted to assess the effectiveness of individual ASMs and various ASM combinations. Results This study included 249 women with a median (IQR) age of 18.0 (15.5-22.0) years. Among them, 146 (58.6%) received an add-on regimen, and 103 (41.4%) received substitution monotherapy. During follow-up, TF occurred in 48 patients (32.9%) receiving add-on therapy and 36 (35.0%) using substitution monotherapy, with no significant differences between groups (IPTW-adjusted hazard ratio [HR], 0.89; 95% CI, 0.53-1.51; P = .69). ASM discontinuation due to ineffectiveness or adverse effects occurred in 36 patients (24.7%) receiving add-on therapy and 29 (28.2%) receiving substitution monotherapy, showing no significant differences (IPTW-adjusted HR, 0.97; 95% CI, 0.57-1.65; P = .92). Rates of ASM discontinuation due to adverse effects only were low in both groups, occurring in 13 patients (9.0%) receiving add-on therapy and 9 (8.7%) receiving a substitution monotherapy. Among add-on regimens other than valproic acid, the combination of levetiracetam and lamotrigine demonstrated a lower risk of TF compared with other combinations with levetiracetam plus other ASM (adjusted HR, 2.41; 95% CI, 1.12-5.17; P = .02) and lamotrigine plus other ASM (adjusted HR, 4.03; 95% CI, 1.73-9.39; P = .001). However, valproic acid remained the most effective second-line ASM when considering individual agents. Conclusions and relevance In this comparative effectiveness study of second-line treatment strategies for women with IGE, no significant differences were observed between substitution monotherapy and add-on therapy.