Sirolimus for epileptic seizures associated with focal cortical dysplasia type II.

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.

• Authors: Mitsuhiro Kato, Akiko Kada, Hideaki Shiraishi, Jun Tohyama, Eiji Nakagawa, Yukitoshi Takahashi, Tomoyuki Akiyama, Akiyoshi Kakita, Noriko Miyake, Atsushi Fujita, Akiko M Saito, Yushi Inoue
• Journal: Annals of clinical and translational neurology (Ann Clin Transl Neurol) Vol. 9 Issue 2 Pg. 181-192 (02 2022) ISSN: 2328-9503 [Electronic] United States
• PMID: 35040598 (Publication Type: Clinical Trial, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.

Chemical References

• Protein Kinase Inhibitors
• MTOR protein, human
• TOR Serine-Threonine Kinases
• Sirolimus

Topics

• Adolescent
• Adult
• Child
• Epilepsy (complications)
• Humans
• Malformations of Cortical Development, Group I (complications)
• Middle Aged
• Outcome Assessment, Health Care
• Protein Kinase Inhibitors (administration & dosage, adverse effects, pharmacology)
• Seizures (drug therapy, etiology)
• Sirolimus (administration & dosage, adverse effects, pharmacology)
• TOR Serine-Threonine Kinases (antagonists & inhibitors)
• Young Adult