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Multicenter Study
. 2025 Mar 3;8(3):e250354.
doi: 10.1001/jamanetworkopen.2025.0354.

Second-Line Medications for Women Aged 10 to 50 Years With Idiopathic Generalized Epilepsy

Emanuele Cerulli Irelli  1 , Enrico Cocchi  2 , Joanna Gesche  3 , Javier Peña-Ceballos  4 , Roberto H Caraballo  5 , Simona Lattanzi  6 , Gionata Strigaro  7 , Alessandra Morano  1 , Patrick B Moloney  4 , Edoardo Ferlazzo  8   9 , Angelo Pascarella  8   9 , Adolfo Mazzeo  10 , Alfredo D'Aniello  10 , Chiara Pizzanelli  11 , Chiara Milano  11 , Loretta Giuliano  12 , Veronica Viola  13 , Barbara Mostacci  13 , Francesco Fortunato  14 , Patrizia Pulitano  1 , Margherita Burani  15 , Stefano Meletti  15 , Pietro Pignatta  16 , Marco Perulli  17 , Domenica Battaglia  17 , Eleonora Rosati  18 , Norman Delanty  4   19   20 , Giancarlo Di Gennaro  10 , Antonio Gambardella  14 , Angelo Labate  21 , Francesca F Operto  22 , Anna T Giallonardo  1 , Christoph P Beier  3 , Carlo Di Bonaventura  1   23   24 ; Women with Epilepsy Treatment Options and Research (WETOR) study group
Collaborators, Affiliations
Multicenter Study

Second-Line Medications for Women Aged 10 to 50 Years With Idiopathic Generalized Epilepsy

Emanuele Cerulli Irelli et al. JAMA Netw Open. .

Abstract

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Cerulli Irelli reported receiving travel support from Angelini, UCB, and GW; and personal fees from Lusofarmaco outside the submitted work. Dr Peña-Ceballos reported receiving personal fees from Angelini and LivaNova PLC outside the submitted work. Dr Lattanzi reported receiving speaker or consultancy fees from Angelini, Eisai, GW Pharmaceuticals, Medscape, and UCB; and has served on advisory boards for Angelini Pharma, Arvelle Therapeutics, BIAL, Eisai, GW Pharmaceuticals, and Rapport Therapeutics outside the submitted work. Dr Strigaro reported receiving personal fees from Eisai and Angelini outside the submitted work. Dr Morano reported receiving personal fees from Jazz Pharmaceuticals, EISAI, Angelini, Lusofarmaco Takeda, Ecupharma, and UCB outside the submitted work. Dr Ferlazzo reported receiving personal fees from UCB, EISAI, and Angelini outside the submitted work. Dr D'Aniello reported receiving grants from UCB and speaker fees from Eisai, UCB, Angelini, and Lusofarmaco outside the submitted work. Dr Pizzanelli reported receiving speaking fees from Angelini and Eisai outside the submitted work. Dr Giuliano reported personal fees from Angelini, Eisai, and Lusofarmaco; and nonfinancial support from Ecupharma outside the submitted work. Dr Mostacci reported receiving personal fees from Livanova, Angelini, Eisai, Lusofarmaco, Sanofi, and Dr Schar; and being an investigator in trials for which their institution received compensation from Livanova, Xenon, and Takeda outside the submitted work. Dr Pulitano reported receiving speaker fees from Angelini and Eisai and serving as a consultant for UCB’s advisory board outside the submitted work. Dr Meletti reported receiving personal fees from UCB and Eisai outside the submitted work. Dr Rosati reported receiving personal fees from Eisai, UCB, Jazz Pharmaceutical, Angelini, Ecupharma, and Livanova outside the submitted work. Dr Delanty reported receiving personal fees from Actio Biosciences, Angelini, Eisai, Jazz, Livanova, Radius, and UNEEG Medical; and grants from Angelini and UNEEG Medical outside the submitted work. Dr Di Gennaro reported receiving personal fees from Angelini, Eisai, UCB, Jazz Pharmaceutical, Lusofarmaco, and Livanova; and has served as an advisor for the advisory boards of UCB, Arvelle Therapeutics, Angelini Pharma, and Neuraxpharma outside the submitted work. Dr Beier reported receiving personal fees from Angellini, EISAI, Jazz Pharmaceutical, and UCB; and grants from the Lundbeck Foundation and Independent Research Council outside the submitted work. Dr Di Bonaventura reported receiving personal fees from UCB, Eisai, GW Pharmaceuticals, JAZZ Pharmaceuticals, Angelini, Lusofarmaco, and Ecupharma outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Overview of Second Antiseizure Medication (ASM) Types and Combination Therapies
AZM indicates acetazolamide; ESM, ethosuximide; LEV, levetiracetam; LTG, lamotrigine; PB, phenobarbital; PER, perampanel; SCB, sodium channel blocker (includes 8 lacosamide and 3 carbamazepine); TPM, topiramate; VPA, valproic acid; ZNS, zonisamide.
Figure 2.
Figure 2.. Inverse Probability of Treatment Weighting (IPTW)–Adjusted Curves of Treatment Failure and Antiseizure Medication (ASM) Withdrawal Between Add-On Regimen and Substitution Monotherapy
A, IPTW-adjusted survival curves; B, IPTW-adjusted survival curves, considering both adverse effects and ineffectiveness.
Figure 3.
Figure 3.. Adjusted Time-to-Event Curves of Treatment Failure Based on Specific Antiseizure Medications Used as Second Regimen
Survival curves for treatment failure based on specific antiseizure medications (ASMs) used as the second regimen, either as an add-on or substitution monotherapy, adjusted for epilepsy syndrome and the type of regimen used. Only ASMs prescribed to at least 10 patients are included. Each ASM is represented by a specific color, compared with reference ASM (ie, valproic acid). LEV indicates levetiracetam; LTG, lamotrigine; SCB, sodium channel blocker (8 lacosamide, 3 carbamazepine); TPM, topiramate; VPA, valproic acid.
Figure 4.
Figure 4.. Adjusted Time-to-Event Curves of Treatment Failure Based on Specific Combinations of Antiseizure Medications in Patients Using an Add-On Regimen
Survival curves for treatment failure based on specific antiseizure medication (ASM) combination, adjusted for epilepsy syndrome. Each ASM combination is represented by a specific color, compared with reference ASM combination (ie, lamotrigine [LTG] plus levetiracetam [LEV]). VPA indicates valproic acid.
See this image and copyright information in PMC

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