Sirolimus for epileptic seizures associated with focal cortical dysplasia type II

Abstract

Abstract Objective To determine whether sirolimus, a mechanistic target of rapamycin (mTOR) inhibitor, reduces epileptic seizures associated with focal cortical dysplasia (FCD) type II. Methods Sixteen patients (aged 6–57 years) with FCD type II received sirolimus at an initial dose of 1 or 2 mg/day based on body weight (FCDS‐01). In 15 patients, the dose was adjusted to achieve target trough ranges of 5–15 ng/mL, followed by a 12‐week maintenance therapy period. The primary endpoint was a lower focal seizure frequency during the maintenance therapy period. Further, we also conducted a prospective cohort study (RES‐FCD) in which 60 patients with FCD type II were included as an external control group. Results The focal seizure frequency reduced by 25% in all patients during the maintenance therapy period and by a median value of 17%, 28%, and 23% during the 1–4‐, 5–8‐, and 9–12‐week periods. The response rate was 33%. The focal seizure frequency in the external control group reduced by 0.5%. However, the background characteristics of external and sirolimus‐treated groups differed. Adverse events were consistent with those of mTOR inhibitors reported previously. The blood KL‐6 level was elevated over time. Interpretation The reduction of focal seizures did not meet the predetermined level of statistical significance. The safety profile of the drug was tolerable. The potential for a reduction of focal seizures over time merit further investigations.