Mechanistic target of rapamycin (mTOR) in tuberous sclerosis complex-associated epilepsy.

BACKGROUND: Tuberous sclerosis complex is a multiorgan disease resulting from a mutation of one of two TSC genes. The two gene products form a functional complex that regulates the mTOR signaling pathway (mTOR initially represented mammalian target of rapamycin, but increasingly the term mechanistic target of rapamycin is used to reflect the ubiquitous occurrence of mTOR). Epilepsy is the most common neurological symptom of tuberous sclerosis complex, occurring in 80% to 90% of affected individuals over the course of their lifetimes and causing significant morbidity and mortality. The mechanistic target of rapamycin (mTOR) signaling pathway is intricately involved in multiple cellular functions--including protein synthesis, cell growth and proliferation, and synaptic plasticity--which may influence neuronal excitability and precipitate epileptogenesis. Recent preclinical and clinical studies have increased interest in the potential role of mTOR inhibitors for the treatment of tuberous sclerosis complex-related epilepsy.
METHODS: Medline and PubMed database searches were used to identify relevant studies and other information on tuberous sclerosis complex-related epilepsies, the mTOR pathway, and current advances in treatment approaches.
RESULTS: Although current management strategies that provide symptomatic relief are effective at reducing the frequency of seizures in individuals with tuberous sclerosis complex, there is further room for the exploration of therapies that directly address hyperactive mTOR signaling--the underlying etiology of the disease. The role of the antiepileptic effect of mTOR inhibition was first demonstrated in knockout TSC1 mouse models. Additionally, several case studies demonstrated a positive effect on seizure frequency and severity in patients with pharmacoresistant epilepsy. In a phase 1/2 clinical trial with 28 patients, clinically relevant reduction in overall seizure frequency was documented in individuals treated with the mTOR inhibitor everolimus. In a phase 3 trial evaluating the role of everolimus in subependymal giant cell astrocytoma, seizures were a secondary end point. Because the median seizure frequency was zero in this study, the analysis was inconclusive.
CONCLUSION: Various preclinical models provide substantial evidence for the role of mTOR inhibition in the treatment of epilepsy in individuals with tuberous sclerosis complex. Preliminary clinical studies provide supportive evidence for a role of mTOR inhibition in the management of tuberous sclerosis complex-associated epilepsy and pave the way for new randomized placebo-controlled studies. This article reviews current treatment recommendations for the management of tuberous sclerosis complex-associated epilepsy as well as the rationale and evidence to support the use of mTOR inhibitors.