Medical treatment of tuberous sclerosis-related epilepsy
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ANNUAL ISSUE PAPER
Medical treatment of tuberous sclerosis-related epilepsy Shimrit Uliel-Sibony 1,2
&
Veronika Chernuha 1 & Hadas Meirson 1 & Aviva Fattal-Valevski 1
Received: 15 May 2020 / Accepted: 23 June 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Epilepsy is one of the most frequent CNS manifestations of tuberous sclerosis, and for most patients, it is the major debilitating factor. In up to 70% of the cases, the epilepsy is refractory and usually associated with significant behavioral as well as developmental consequences. Therefore, controlling seizures is one of the biggest medical and surgical challenges. Understanding the cellular mechanism involved in the disease empowered targeted research aimed toward early intervention in the epileptogenicity process. In this review, we present an update on the pharmacological treatments in tuberous sclerosisrelated epilepsy. Keywords Tuberous sclerosis . Epilepsy . Drug therapy
Background Tuberous sclerosis (TSC) is an autosomal dominant, multisystemic, neurocutaneous disorder. The diagnostic criteria for TSC were recently revised to include genetic testing and have simplified the clinical diagnostic classes to either definite or possible TSC [43]. The clinical manifestations of TSC vary widely, but predominantly involve benign tumors (hamartomas) in multiple organ systems. In the brain, it presents as congenital malformations which include tubers, subependymal nodules, subependymal giant cell astrocytomas, and white matter radial migration lines [52]. Up to 90% of the cases are caused by mutation in either TSC1 or TSC2 genes that cause upregulation of the mammalian target of rapamycin (mTOR) pathway, which is responsible for protein synthesis, cell growth, differentiation, synaptic plasticity, proliferation, and migration. The hyperactivated mTOR plays critical role in epileptogenesis, derived by physiological and structural mechanisms; it leads to an abnormal neuronal * Shimrit Uliel-Sibony [email protected] 1
Pediatric Neurology Institute, Dana-Dwek Children’s Hospital, Tel Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel Aviv, Israel
2
Pediatric Neurology institute, Dana-Dwek Children’s Hospital, Tel-Aviv Sourasky Medical Center, 6 Weizmann Street, 64239 Tel Aviv, Israel
structure supported by stereoelectroencephalographic studies that found a striking similarity between the organization of tubers with focal epileptogenic zone and type II focal cortical dysplasia [41]. It also regulates the inhibitory and excitatory neurotransmitter balance, causing a decreased inhibition of γaminobutyric acid receptors in giant cells and dysplastic neurons, and an increased excitation of glutamate receptors in dysplastic neurons [6]. The hyperactivation of this pathway observed in TSC leads to global disturbances in the architecture and connectivity of the brain. Epilepsy is the most common neurological symptom in patients with TSC, and significantly accounts for morbidity and mortality. It affects up to 85% of the
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