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Everolimus for the treatment of refractory seizures associated with tuberous sclerosis complex (TSC): current perspectives

Authors Overwater IE, Rietman AB, van Eeghen AM, de Wit MCY

Received 9 April 2019

Accepted for publication 26 May 2019

Published 26 July 2019 Volume 2019:15 Pages 951—955

DOI https://doi.org/10.2147/TCRM.S145630

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Melinda Thomas

Peer reviewer comments 2

Editor who approved publication: Professor Garry Walsh


Iris E Overwater,1 André B Rietman,2 Agnies M van Eeghen,3 Marie Claire Y de Wit1

1Department of Pediatric Neurology and ENCORE Expertise Center, Erasmus MC, Rotterdam, the Netherlands; 2Department of Child and Adolescent Psychiatry/Psychology and ENCORE Expertise Center, Erasmus MC, Rotterdam, the Netherlands; 3Heeren Loo Care Group and ENCORE Expertise Center, Erasmus MC, Rotterdam, the Netherlands

Abstract: Up 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.

Keywords: mTOR, epileptogenesis, epilepsy

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