@article{8653f755830c4894a4ffc2581652bb01,
title = "Modifying genetic epilepsies – Results from studies on tuberous sclerosis complex",
abstract = "Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder affecting approximately 1 in 6,000 in general population and represents one of the most common genetic causes of epilepsy. Epilepsy affects 90% of the patients and appears in the first 2 years of life in the majority of them. Early onset of epilepsy in the first year of life is associated with high risk of cognitive decline and neuropsychiatric problems including autism. Recently TSC has been recognized as a model of genetic epilepsies. TSC is a genetic condition with known dysregulated mTOR pathway and is increasingly viewed as a model for human epileptogenesis. Moreover, TSC is characterized by a hyperactivation of mTOR (mammalian target of rapamycin) pathway, and mTOR activation was showed to be implicated in epileptogenesis in many animal models and human epilepsies. Recently published studies documented positive effect of preventive or disease modifying treatment of epilepsy in infants with high risk of epilepsy with significantly lower incidence of epilepsy and better cognitive outcome. Further studies on preventive treatment of epilepsy in other genetic epilepsies of early childhood are considered.",
keywords = "Children, Disease modification, Epileptogenesis, Prevention, Tuberous sclerosis complex",
author = "Sergiusz Jozwiak and Katarzyna Kotulska and Michael Wong and Martina Bebin",
note = "Funding Information: The EPISTOP project (Clinical- Trials.gov Identifier NCT02098759), a large collaborative study funded by European Union within 7th Frame Programme to examine the risk factors and biomarkers of epilepsy has addressed this issue. In the clinical part of the project, a clinical trial comparing preventive and standard antiepileptic treatments has been carried out. Ninety-seven infants with definite TSC were included and followed from birth up to the age of 24 months with serial EEG, imaging, and laboratory tests. In the randomized part of the study, children were randomly assigned to either preventive or standard antiepileptic treatment with vigabatrin. Preventive treatment was introduced after the onset of spikes on EEG but prior to seizures. The results of the study are currently in preparation. Funding Information: While controlled preventive clinical trials of vigabatrin for epilepsy in TSC are ongoing, comparable preventive clinical trials of mTOR inhibitors are still under development. However, the mTOR inhibitor, everolimus, has been tested rigorously in clinical trials for conventional antiseizure effects in TSC patients with drug-resistant epilepsy. Initial suggestion for a potential effect of everolimus against seizures in TSC patients was derived from the clinical trials of everolimus for tumors in patients who had concurrent epilepsy (Kotulska et al., 2013; Krueger et al., 2010). Open-label drug studies further supported that everolimus decreased seizure frequency in TSC patients, independent of treatment of tumors (Krueger et al., 2013; Sadowski et al., 2016). Most definitively, a recent double-blind, randomized, placebo-controlled trial (EXIST-3) showed that everolimus was significantly more effective than placebo in reducing focal seizures in TSC patients with drug-resistant epilepsy (French et al., 2016). A high exposure everolimus group had a median reduction in seizure frequency of 40% compared with 15% in the placebo group. Longer term follow-up of this study indicates that everolimus has a sustained effect on seizure frequency (Franz et al., 2018).This work was supported by the 7th Framework Programme of European Commission within the Large-scale Integrating Project EPISTOP (Proposal No: 602391–2; Proposal title: “Long term, prospective study evaluating clinical and molecular biomarkers of epileptogenesis in a genetic model of epilepsy – tuberous sclerosis complex”; www.EPISTOP.eu), the Polish Ministerial funds for science (years 2014–2018) for the implementation of international co-financed project and the grant EPIMARKER of the Polish National Center for Research and Development No STRATEGMED3/306306/4/2016 (SJ, KK) and by National Institutes of Health IH R01 NS056872 (MW). Funding Information: This work was supported by the 7th Framework Programme of European Commission within the Large-scale Integrating Project EPISTOP (Proposal No: 602391–2 ; Proposal title: “Long term, prospective study evaluating clinical and molecular biomarkers of epileptogenesis in a genetic model of epilepsy – tuberous sclerosis complex”; www.EPISTOP.eu ), the Polish Ministerial funds for science (years 2014–2018) for the implementation of international co-financed project and the grant EPIMARKER of the Polish National Center for Research and Development No STRATEGMED3/306306/4/2016 (SJ, KK) and by National Institutes of Health IH R01 NS056872 (MW). Publisher Copyright: {\textcopyright} 2019 The Authors",
year = "2020",
month = apr,
doi = "10.1016/j.neuropharm.2019.107908",
language = "English",
volume = "166",
journal = "Neuropharmacology",
issn = "0028-3908",
}