The response to anti-seizure medications and the development of pharmacoresistant epilepsy in malformations of cortical development

Abstract

Background: Malformations of cortical development (MCD) are a group of congenital brain malformation disorders commonly associated with pharmacoresistant epilepsy (PRE). While studies often focus on surgery outcomes, the pharmacological treatment is still imperative and the odyssey to PRE remains underexplored. We aim to investigate the influence of anti-seizure medications (ASMs) on the development of PRE in this specific patient population.

Methods: We retrospectively included a cohort of epilepsy patients with MRI-confirmed MCD due to abnormal cell proliferation and apoptosis (group I, mainly FCD II), and abnormal neuronal migration (group II, mainly heterotopia, lissencephaly, and polymicrogyria) from March 2013 to June 2023. The clinical features of group I and group II were compared. Factors associated with PRE were analyzed. The time to development of PRE with different ASMs was assessed using Kaplan-Meier survival analysis.

Results: Of 259 enrolled patients with epilepsy and MRI-confirmed MCD (group I, n = 121; group II, n = 138), 73.4% met the criteria for PRE. The median duration of follow-up from seizure onset to the last visit or surgery was 103 months (IQR 45-174), with group I showing a significantly higher PRE rate than group II (90.1% vs. 58.7%, p = 0.000). Binomial regression analysis identified the significant predictors of PRE in MCD patients: high pretreatment seizure frequency (OR = 2.506), group II patients (OR = 0.248), and failure of the first ASM (OR = 5.885). Sodium channel blockers (SCBs) were the most prescribed initial ASMs and demonstrated a higher response rate than other ASMs. Kaplan-Meier analysis revealed that using SCBs as the first ASM significantly prolongs the time to PRE, with a median of 72 months for SCB users versus 48 months for non-SCB users.

Conclusions: Our findings indicate a high prevalence of PRE that varies among different subtypes of MCD. Early appropriate selection of ASMs, particularly SCBs, can significantly delay the time to PRE onset, offering a promising strategy for managing this complex patient population. Tailoring pharmacological approaches is crucial for optimizing outcomes, and further research is warranted to optimize treatment strategies.

Keywords: Malformations of cortical development; Pharmacoresistant epilepsy; Sodium channel blockers.

Fig. 1

Flow diagram of enrolled patients

Fig. 2

Response rates to the first ASM are illustrated, detailing the distribution of initial ASM types used among all MCD patients (a), MCD group I patients (b), and MCD group II patients (c). a SCBs show a significantly higher response rate than other ASMs (p < 0.001). b A greater response rate for SCBs compared to other ASMs among group I patients (p = 0.002). c SCBs exhibited a higher response rate than other initial ASMs in group II patients (p = 0.020)

Fig. 3

Kaplan–Meier PRE estimates: a selecting SCBs as the first ASM (green curve) significantly prolongs the time to developing PRE compared to those who did not (purple curve); b patients who failed to respond to SCBs as the first ASM experienced the earliest onset of PRE (blue curve) compared to patients who responded successfully to SCBs as the first ASM (red curve)

Fig. 4

Kaplan–Meier PRE estimates in subgroups: Among the patients who received SCBs as their first ASM, patients in group I who failed to respond to SCBs had the earliest time to PRE (red curve) and patients in group II who responded successfully to SCBs had the latest time to PRE (green curve)