Abstracts

Rationale: Tuberous Sclerosis Complex (TSC) is caused by mutations in the TSC1 or TSC2 genes thereby causing disinhibition of the mammalian target of rapamycin (mTOR ) pathway. The mTOR pathway controls protein synthesis regulating cell growth and division, and mediating long term potentiation and inhibition. Seizures are the most common neurological manifestation in tuberous sclerosis complex (TSC) and are often intractable. In animal models treatment with mTOR inhibitors prevents the development of seizures in young animals and controls seizures in older ones. Methods: Retrospective chart review of patients with TSC treated with rapamycin that included neurologic history, seizure onset, seizure type, anti-epileptic treatment, and sirolimus blood levels. Seizure frequency was determined retrospectively as part of the chart review Results: 7 patients with active seizures received treatment with rapamycin, none of them was treated with intention of diminishing seizure frequency. 5/15 patients who participated in the clincal trial: “A phase II multicenter study of rapamycin for treating kidney angiomyolipomas” {NCT00126672, clinical trials.gov} were experiencing seizures at the time of sirolimus initiation. Two were felt to have non-epileptic seizures; in both the frequency was reduced during sirolimus treatment. Generalized tonic clonic seizure frequency decreased in one and increased in one. Complex partial seizure (CPS) frequency increased in one. 7 study patients had been seizure free for more than 5 years at the time of initiation of rapamycin treatment. None of the patients who were seizure free at trial onset experienced seizures during rapamycin treatment. One patient, who was being treated with rapamycin with the intention to decrease the size of a subependymal giant cell tumor, had stable CPS frequency throughout the rapamycin treatment. His SGCT decreased in size with resolution of optic edema. One patient was treated with rapamycin to reduce severe impulsive and self injurious behavioral problems. Complex partial seizure frequency increased and behavior improved. None of the patients experienced a dramatic reduction in seizure frequency during the time of treatment with rapamycin. Reported seizure frequency was slightly decreased in 3 patients, somewhat increased in 3 patients, and was unchanged in 1 patient at last follow-up visit. Conclusions: Rapamycin treatment did not appear to significantly reduce seizure frequency in the majority of our cohort of TSC patients. Our study is limited due to its small size, the retrospective nature, and by the fact that patients had longstanding refractory epilepsy. Based on evidence from mouse models that mTOR inhibitors effectively decrease seizures (Meikle et al., 2008, Zeng et al., 2008) and improve cognition and memory (Ehninger et al., 2008) along with concerns regarding the potential toxicity of mTOR inhibitor treatment, we conclude that efficacy and tolerability of mTOR inhibitors for neurologic manifestations of TSC should be evaluated in well controlled clinical trials.