Second-Line Treatments for Women With Epilepsy Show Comparable Outcomes

Among women with idiopathic generalized epilepsy (IGE), there are no significant differences between add-on therapy and substitution monotherapy as a second-line treatment, according to study results published in JAMA Network Open.

First-line antiseizure medications (ASMs) fail to provide adequate seizure control for more than half of patients, requiring a second-line ASM. While valproic acid is considered the preferred treatment for IGE due to its broad efficacy for various types of seizures, it is strongly discouraged for women who may become pregnant. Current guideline recommendations for second-line ASMs provide inadequate guidance for treatment selection, especially for women who face additional selection constraints.

Researchers conducted a multicenter retrospective comparative effectiveness study of women aged 10 to 50 years (N=249; age, 10-50 years) who were diagnosed with IGE and prescribed a second-line ASM. The researchers included data from 18 primary, secondary, and tertiary epilepsy treatment centers in 4 countries between 1995 and 2023.

The primary outcome was second-line treatment failure, defined as discontinuation of medication or switch to another ASM. Treatment discontinuation due to adverse effects or consideration for future pregnancy were not considered as treatment failure and excluded from analysis.

Of the total cohort, 109 patients (43.8%) received levetiracetam, 108 (43.4%) received lamotrigine, 18 (7.2%) received topiramate, 10 (4.0%) received ethosuximide, and 4 (1.6%) received zonisamide as first-line monotherapy. The most common second ASM was levetiracetam (30.5%), followed by lamotrigine (22.5%), valproic acid (19.3%), and topiramate (9.6%).

Among those with add-on therapy, the most common combination was levetiracetam plus lamotrigine (46.6%). The women who used add-on (58.6%) and substitution (41.4%) therapies as second-line treatment were mean age 20.13 and 18.59 years.

Treatment failure occurred in 32.9% of patients receiving add-on therapy and 35% using substitution monotherapy (hazard ratio [HR], 0.92; 95% CI, 0.58-1.46; P =.92); seizure freedom with a second-line ASM occurred in 50.4% and 58.8%, respectively, showing no significant differences (inverse probability of treatment weighting [IPTW]-adjusted odds ratio [aOR], 0.80; 95% CI, 0.44-1.45; P =.47).

ASM discontinuation due to ineffectiveness or adverse effects occurred in 24.7% of patients receiving add-on therapy and 28.2% of patients receiving substitution monotherapy (IPTW-adjusted HR, 0.97; 95% CI, 0.57-1.65; P =.92).

Stratified by individual agents, valproic acid was associated with a lower treatment failure rate (16.7%) than all other ASMs (37.8%), except for levetiracetam (adjusted hazard ratio [aHR], 1.75; 95% CI, 0.69-4.50; P =.24).

Among drug combinations, levetiracetam plus lamotrigine had a lower treatment failure rate than levetiracetam plus other ASMs (aHR, 2.41; 95% CI, 1.12-5.17; P =.02) or lamotrigine plus other ASMs (aHR, 4.03; 95% CI, 1.73-9.39; P =.001), but not compared with valproic acid plus levetiracetam or lamotrigine (aHR, 0.14; 95% CI, 0.02-1.07; P =.06). Levetiracetam combined with lamotrigine emerged as the most commonly prescribed option, accounting for approximately half of women receiving combination therapy.

Withdrawal due to adverse events was observed among 9.0% of patients using add-on regimens and 8.7% using substitution monotherapy. No regimen-specific trends in safety were observed.

The major limitations of this study include the retrospective nature of the study, subjective decisions of individual physicians when substituting ASMs, the relatively small sample size, and the preclusion of more specific ASM combinations.

“The combination of levetiracetam and lamotrigine emerges as a promising alternative for add-on therapy, offering a balance between efficacy and safety,” the researchers concluded.

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.