Levetiracetam Outperforms Lamotrigine as First-Line Treatment for Females With Juvenile Myoclonic Epilepsy

Carlo Di Bonaventura, MD, PhD

Findings from a comparative effectiveness research study showed that use of levetiracetam and lamotrigine as first-line treatments have similar efficacy on idiopathic generalized epilepsy (IGE) syndromes in females; however, levetiracetam was more effective in treating juvenile myoclonic epilepsy (JME). Further studies are still needed to identify the most effective antiseizure medication (ASM) alternative in other IGE syndromes.

Published in JAMA Neurology, the trial included 543 patients from 22 primary, secondary, and tertiary adult and child epilepsy centers who were prescribed either levetiracetam (57.5%) or lamotrigine (42.5%). Followed up for a median of 60 (24-108) months, the trial featured only females of childbearing age, diagnosed with IGE according to International League Against Epilepsy (2022) criteria. The 4 distinct IGE syndromes include childhood absence epilepsy (CAE; n = 2), juvenile absence epilepsy (JAE; n = 107), JME (n = 259), and idiopathic generalized epilepsy with generalized tonic-clonic seizures alone (GTCA; n = 175).

Senior investigator Carlo Di Bonaventura, MD, PhD, adjunct professor, Sapienza University of Rome, and colleagues used inverse probability of treatment weighting (IPTW)-adjusted Cox proportional hazards regression to compare treatment failure (TF) among patients who received either therapy. During follow-up, there were 238 TF events in 114 participants in the levetiracetam group and in 117 participants in the lamotrigine group (unadjusted HR, 0.74; 95% CI, 0.57-0.96; P = .02). Following multivariable Cox analysis, findings confirmed that levetiracetam was associated with a reduced risk of TF after adjustment for all baseline variables compared with lamotrigine (IPTW-adjusted HR, 0.77; 95% CI, 0.59-0.99; P = .04).

After stratification of different IGE subsyndromes, the higher effectiveness of levetiracetam was confirmed only in patients with JME (IPTW-adjusted HR, 0.47; 95% CI, 0.32-0.68; P <.001) whereas no significant differences were found in absence epilepsy (IPTW-adjusted HR, 1.17; 95% CI, 0.69-1.99; P = .60) and GTCA (IPTW-adjusted HR, 1.02; 95% CI, 0.58-1.77; P = .90). “In light of these results, clinicians should particularly take into account patients’ comorbidities in the choice of the first-line ASM in IGE syndromes other than JME,” the study authors wrote.

Among those who had information on seizure outcomes at 12 months (n = 519), 40.1% (n = 208) achieved seizure freedom at this time point. In the sensitivity analysis, levetiracetam use was associated with a higher likelihood of seizure freedom at 12 months both in univariable analysis (unadjusted OR, 2.06; 95% CI, 1.38-3.08; P <.001) and after adjusting for baseline confounders (IPTW-adjusted OR, 1.68; 95% CI, 1.15-2.44; P = .006). In addition, treating clinicians more frequently reported worsening of myoclonic seizures among patients treated with lamotrigine (4 of 97 [3.3%]; 95% CI, 0-2.2) than those on levetiracetam (1 of 162 [0.6%]; 95% CI, 1.3-6.8; P = .03).

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Between the 2 treatment groups, there were no significant differences in either ASM retention (IPTW-adjusted HR, 0.91; 95% CI, 0.65-1.23; P = .60) or ASM withdrawal because of adverse events only (IPTW-adjusted HR, 1.15; 95% CI, 0.64-2.09; P = .60). Among those experiencing TF, an add-on ASM regimen was used in 112 patients (48.5%; 95% CI, 41.9-55.1) whereas substitution monotherapy was used in 119 patients (51.5%; 95% CI, 44.9-58.1).

In terms of safety, AEs were more frequent among levetiracetam-treated patients than those on lamotrigine (28.2% [95% CI, 22.8-34.2] vs 18.1% [95% CI, 13.1-23.9; P = .01) whereas the 2 ASMs had similar retention rates during follow-up (IPTW-adjusted HR, 0.91; 95% CI, 0.65-1.23; P = .60). Notably, 6.4% (13 of 204) of patients on lamotrigine experienced skin rashes and other dermatologic AEs.

Di Bonaventura et al wrote, "Accordingly, our data suggest that the use of lamotrigine may be preferable in absence epilepsy and GTCA in the presence of psychiatric comorbidities, based on the comparable effectiveness of lamotrigine and levetiracetam in these specific syndromes and their tolerability profile." They added, “a small but relatively higher number of patients taking lamotrigine showed worsening of myoclonic seizures during follow-up (3.3% of patients), confirming the potentially detrimental effect of sodium-channel blockers on this seizure type and further supporting the use of levetiracetam as initial alternative monotherapy in patients with JME."

REFERENCE
1. Cerulli Ireli E, Cocchi E, Morano A, et al. Levetiracetam vs lamotrigine as first-line antiseizure medication in female patients with idiopathic generalized epilepsy. JAMA Netw Open. Published online October 2, 2023. doi:10.1001/jamaneurol.2023.3400