Everolimus for the treatment of refractory seizures associated with tuberous sclerosis complex (TSC): current perspectives
2019
textabstractUp to 90% of patients with tuberous sclerosis complex (TSC) have epilepsy, and
in over half of patients seizure control cannot be achieved by regular antiepileptic drugs. The
underlying problem is mTOR hyperactivation due to loss of function of the TSC proteins.
Treatment with everolimus, an mTOR inhibitor, has been shown to be of great benefit to TSC
patients, both in reducing tumor growth and as a treatment for intractable epilepsy. Up to
40% of TSC patients with intractable epilepsy show a clinically relevant seizure response to
everolimus. It has not yet fully lived up to its promise as a disease-modifying drug, however,
as half of TSC patients with intractable epilepsy do not show a clinically relevant seizure
frequency reduction. There is no evidence yet of a positive effect on the cognitive and
neuropsychiatric deficits in TSC patients. In preclinical studies, mTOR inhibition can rescue
abnormal neuronal migration and synapse formation that is caused by mTOR hyperactivation. These studies show a critical time window that suggests that mTOR inhibition may be
most beneficial in young children. The trials done so far have not studied treatment in
children under 2 years of age, although case series suggest that the safety profile is similar to
that in older children. Further studies into the optimal time window, dosing schedules and
possibly combination with other drugs may further improve the benefit of everolimus for
TSC patients.
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