Abstracts

Rationale: TS is characterized by hamartoma formation in multiple organ systems and disabling neurological disorders including epilepsy, mental retardation, and autism. Neurosurgical resection with its associated complications and comorbidities is the current standard treatment for intractable epilepsy associated with TS. Recently, an open-label, phase II trial (NCT00411619) of everolimus, an orally bioavailable selective mTOR inhibitor, demonstrated a significant reduction in both subependymal giant-cell astrocytoma (SEGA) and tuber volume and was well tolerated. Secondary endpoints included potential changes in seizure frequency in patients treated with everolimus. Methods: Patients ?3 years of age with a definitive TS diagnosis and evidence of serial SEGA growth (on MRI) were treated with everolimus 3 mg/m²/d orally (titrated to tolerability to achieve target trough concentrations of 5-15 ng/mL). The primary efficacy endpoint was change in SEGA volume from baseline to 6 months. Results: Twenty-eight patients were enrolled; median duration of treatment was 21.5 months (range 4.7-34.4). After 6 months of treatment, 21 patients (75%) had ?30% reduction in primary SEGA volume. Based on caregiver observation, the proportion of patients with daily seizures was reduced from 7 of 26 patients (26.9%) at baseline to 2 of 25 patients (8.0%) at month 6 and 1 of 25 patients (4.0%) at month 12. Of 16 patients with uncontrolled epilepsy for whom video-electroencephalogram data were available, captured electroclinical and electrographic seizures were diminished at month 6 compared with baseline (average 2.75 vs. 6.30 per 24-hour period, respectively; p = 0.022); 9 patients had decreases in seizure frequency (across all types of seizure), 6 had no change (all were event-free at both time points), and 1 had an increase. Interictal epileptiform activity during the first 15 minutes of stage II sleep also was reduced compared with baseline (median change -20.0 [range, -227 to 201]). Of the 9 patients who experienced a reduction in seizure frequency, evaluation of antiepileptic drug concentrations in the blood demonstrated minimal variations between pre- and posttreatment despite adjustments in dosage. Changes in seizure frequency would therefore appear to be attributable to everolimus therapy. Conclusions: Everolimus significantly reduced seizure frequency in patients with TS. Based on these findings, everolimus may be a viable alternative to surgical resection for the treatment of intractable epilepsy in patients with TS, and additional research is warranted.