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Sirolimus for epileptic seizures associated with focal cortical dysplasia type II
Mitsuhiro Kato1, Akiko Kada2, Hideaki Shiraishi3
1Department of Pediatrics, Showa University School of Medicine, Tokyo, Japan.
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.
Insights
Sirolimus showed a 25% reduction in focal cortical dysplasia (FCD) type II seizures, but did not reach statistical significance. Further investigation into this mechanistic target of rapamycin (mTOR) inhibitor is warranted.
Area of Science:
- Neurology
- Pharmacology
- Medical Science
Background:
- Focal cortical dysplasia (FCD) type II is a malformation of cortical development associated with refractory epilepsy.
- Mechanistic target of rapamycin (mTOR) inhibitors, such as sirolimus, are being investigated for their potential therapeutic effects in neurological disorders.
Purpose of the Study:
- To evaluate the efficacy of sirolimus in reducing epileptic seizures in patients with FCD type II.
- To assess the safety and tolerability of sirolimus in this patient population.
Main Methods:
- A 12-week open-label trial (FCDS-01) involving 16 patients with FCD type II treated with sirolimus, with dose adjustments to achieve target trough ranges.
- A prospective external control group (RES-FCD) of 60 patients with FCD type II was used for comparison.
Main Results:
- Sirolimus treatment resulted in a 25% reduction in focal seizure frequency during the maintenance period.
- A 33% response rate was observed, with a median seizure reduction of 17-28% across different time points.
- The external control group showed only a 0.5% reduction in seizure frequency; however, group characteristics differed.
Conclusions:
- While sirolimus demonstrated a trend towards reducing focal seizures in FCD type II, the primary endpoint was not met statistically.
- The drug was generally well-tolerated, with adverse events consistent with known mTOR inhibitor side effects.
- Further research is recommended to explore the potential of sirolimus for seizure reduction in FCD type II.
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