{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T22:20:13Z","timestamp":1792016413520,"version":"4.4.0"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,4,29]],"date-time":"2022-04-29T00:00:00Z","timestamp":1651190400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005632","name":"Narodowe Centrum Badan i Rozwoju","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005632","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Epilepsy develops in 70\u201390% of children with Tuberous Sclerosis Complex (TSC) and is often resistant to medication. Treatment with mTOR pathway inhibitors is an important therapeutic option in drug-resistant epilepsy associated with TSC. Our study evaluated the antiepileptic effect of rapamycin in the pediatric population of patients diagnosed with TSC.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This single center, open-label study evaluated safety and anti-epileptic efficacy of 12 months of rapamycin treatment in 32 patients aged from 11 months to 14 years with drug-resistant TSC- associated epilepsy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>After the first 6 months of treatment, the improvement in seizure frequency, defined as at least a 50% reduction in the number of seizures per week compared to baseline, was seen in 18 individuals (56.25%). We observed no change in 12 individuals (37.5%) and worsening, defined as increase in the number of seizures\u2014in 2 patients (6.25%). The overall improvement defined as at least a 50% reduction in seizure frequency was found in 65.6% of all patients after 12 months with 28% of patients obtaining complete remission. Another five patients experienced at least an 80% reduction in the frequency of seizures. Concomitant treatment with vigabatrin, and to a much lesser extent topiramate and levetiracetam, was an additional favorable prognostic factor for the success of the therapy. A linear relationship between the cumulative dose of rapamycin and its therapeutic effect was observed. The safety profile of the drug was satisfactory. In none of the observed cases did the adverse events reach the level that required withdrawal of the rapamycin treatment. The reason for dropouts was insufficient drug efficacy in 3 cases.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Long-term use of rapamycin, especially in combination with vigabatrin, might be a beneficial therapeutic option in the treatment of drug-resistant epilepsy in children with TSC.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fneur.2022.704978","type":"journal-article","created":{"date-parts":[[2022,4,29]],"date-time":"2022-04-29T07:29:52Z","timestamp":1651217392000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":19,"title":["Antiepileptic Effect and Safety Profile of Rapamycin in Pediatric Patients With Tuberous Sclerosis Complex"],"prefix":"10.3389","volume":"13","author":[{"given":"Krzysztof","family":"Sadowski","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamil","family":"Sijko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorota","family":"Doma\u0144ska-Pakie\u0142a","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julita","family":"Borkowska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dariusz","family":"Chmielewski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agata","family":"Ulatowska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergiusz","family":"J\u00f3zwiak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katarzyna","family":"Kotulska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,4,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"16035","DOI":"10.1038\/nrdp.2016.35","article-title":"Tuberous sclerosis complex","volume":"2","author":"Henske","year":"2016","journal-title":"Nat Rev Dis Primers"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1305","DOI":"10.1016\/0092-8674(93)90618-z","article-title":"Identification and characterization of the tuberous sclerosis gene on chromosome 16","volume":"75","author":"European","year":"1993","journal-title":"Cell"},{"key":"B3","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1126\/science.277.5327.805","article-title":"Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34","volume":"277","author":"van Slegtenhorst","year":"1997","journal-title":"Science"},{"key":"B4","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1016\/s1097-2765(02)00568-3","article-title":"Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase\/akt pathway","volume":"10","author":"Manning","year":"2002","journal-title":"Mol Cell"},{"key":"B5","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1016\/j.pediatrneurol.2013.08.001","article-title":"Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference","volume":"49","author":"Northrup","year":"2013","journal-title":"Pediatr Neurol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1236","DOI":"10.1111\/j.1528-1167.2009.02474.x","article-title":"The natural history of epilepsy in tuberous sclerosis complex","volume":"51","author":"Chu-Shore","year":"2010","journal-title":"Epilepsia"},{"key":"B7","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1093\/ndt\/gfv249","article-title":"Everolimus for renal angiomyolipoma in patients with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis: extension of a randomized controlled trial","volume":"31","author":"Bissler","year":"2016","journal-title":"Nephrol Dial Transplant"},{"key":"B8","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1186\/s13023-016-0553-5","article-title":"TuberOus SClerosis registry to increase disease Awareness (TOSCA) - baseline data on 2093 patients","volume":"12","author":"Kingswood","year":"2017","journal-title":"Orphanet J Rare Dis"},{"key":"B9","doi-asserted-by":"publisher","first-page":"e20164040","DOI":"10.1542\/peds.2016-4040","article-title":"Presentation and diagnosis of tuberous sclerosis complex in infants","volume":"140","author":"Davis","year":"2017","journal-title":"Pediatrics"},{"key":"B10","doi-asserted-by":"publisher","first-page":"735","DOI":"10.1016\/j.yebeh.2011.08.037","article-title":"Long-term neurological outcome in children with early-onset epilepsy associated with tuberous sclerosis","volume":"22","author":"Cusmai","year":"2011","journal-title":"Epilepsy Behav"},{"key":"B11","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/j.yebeh.2017.02.007","article-title":"Influence of seizures on early development in tuberous sclerosis complex","volume":"70","author":"Capal","year":"2017","journal-title":"Epilepsy Behav"},{"key":"B12","doi-asserted-by":"publisher","first-page":"582","DOI":"10.1016\/j.ejpn.2012.05.004","article-title":"Management of epilepsy associated with tuberous sclerosis complex (TSC): clinical recommendations","volume":"16","author":"Curatolo","year":"2012","journal-title":"Eur J Paediatr Neurol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"738","DOI":"10.1016\/j.ejpn.2018.05.006","article-title":"Management of epilepsy associated with tuberous sclerosis complex: updated clinical recommendations","volume":"22","author":"Curatolo","year":"2018","journal-title":"Eur J Paediatr Neurol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1046\/j.1365-2133.2002.04968.x","article-title":"Carbon dioxide and pulsed dye laser treatment of angiofibromas in 29 patients with tuberous sclerosis","volume":"147","author":"Papadavid","year":"2002","journal-title":"Br J Dermatol"},{"key":"B15","doi-asserted-by":"publisher","first-page":"2021","DOI":"10.2147\/NDT.S51789","article-title":"Optimal management of seizures associated with tuberous sclerosis complex: current and emerging options","volume":"10","author":"Wang","year":"2014","journal-title":"Neuropsychiatr Dis Treat"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1239","DOI":"10.1111\/epi.13050","article-title":"Epilepsy in children with tuberous sclerosis complex: chance of remission and response to antiepileptic drugs","volume":"56","author":"Overwater","year":"2015","journal-title":"Epilepsia"},{"key":"B17","doi-asserted-by":"publisher","first-page":"919","DOI":"10.1056\/NEJMra1004418","article-title":"Drug-resistant epilepsy","volume":"365","author":"Kwan","year":"2011","journal-title":"N Engl J Med"},{"key":"B18","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1016\/S0140-6736(12)61134-9","article-title":"Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial","volume":"381","author":"Franz","year":"2013","journal-title":"Lancet"},{"key":"B19","doi-asserted-by":"publisher","first-page":"817","DOI":"10.1016\/S0140-6736(12)61767-X","article-title":"Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial","volume":"381","author":"Bissler","year":"2013","journal-title":"Lancet"},{"key":"B20","doi-asserted-by":"publisher","first-page":"2153","DOI":"10.1016\/S0140-6736(16)31419-2","article-title":"Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study","volume":"388","author":"French","year":"2016","journal-title":"Lancet"},{"key":"B21","doi-asserted-by":"publisher","first-page":"e27","DOI":"10.1053\/j.ajkd.2006.05.018","article-title":"Antitumoral activity of rapamycin in renal angiomyolipoma associated with tuberous sclerosis complex","volume":"48","author":"Wienecke","year":"2006","journal-title":"Am J Kidney Dis"},{"key":"B22","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1177\/0883073808324535","article-title":"Rapamycin reduces seizure frequency in tuberous sclerosis complex","volume":"24","author":"Muncy","year":"2009","journal-title":"J Child Neurol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"490","DOI":"10.1002\/ana.20784","article-title":"Rapamycin causes regression of astrocytomas in tuberous sclerosis complex","volume":"59","author":"Franz","year":"2006","journal-title":"Ann Neurol"},{"key":"B24","doi-asserted-by":"publisher","first-page":"1195","DOI":"10.1016\/j.jpeds.2013.12.053","article-title":"Mammalian target of rapamycin inhibitors for intractable epilepsy and subependymal giant cell astrocytomas in tuberous sclerosis complex","volume":"164","author":"Cardamone","year":"2014","journal-title":"J Pediatr"},{"key":"B25","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1007\/s00381-013-2185-6","article-title":"Rapamycin has a beneficial effect on controlling epilepsy in children with tuberous sclerosis complex: results of 7 children from a cohort of 86","volume":"30","author":"Canpolat","year":"2014","journal-title":"Childs Nerv Syst"},{"key":"B26","doi-asserted-by":"publisher","first-page":"1011","DOI":"10.1212\/WNL.0000000000003077","article-title":"Sirolimus for epilepsy in children with tuberous sclerosis complex: a randomized controlled trial","volume":"87","author":"Overwater","year":"2016","journal-title":"Neurology"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1069","DOI":"10.1111\/j.1528-1167.2009.02397.x","article-title":"Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies","volume":"51","author":"Kwan","year":"2010","journal-title":"Epilepsia"},{"key":"B28","unstructured":"GagolewskiP\n          R Package Stringi: Character String Processing Facilities"},{"key":"B29","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v067.i01","article-title":"Fitting linear mixed-effects models using lme4","volume":"67","author":"Bates","year":"2015","journal-title":"J Stat Softw"},{"key":"B30","first-page":"1","article-title":"DALEX: explainers for complex predictive models in R","volume":"19","author":"Biecek","year":"2018","journal-title":"J Mach Learn Res"},{"key":"B31","doi-asserted-by":"publisher","first-page":"e57445","DOI":"10.1371\/journal.pone.0057445","article-title":"Vigabatrin inhibits seizures and mTOR pathway activation in a mouse model of tuberous sclerosis complex","volume":"8","author":"Zhang","year":"2013","journal-title":"PLoS ONE"},{"key":"B32","doi-asserted-by":"publisher","first-page":"536","DOI":"10.1016\/j.pharep.2016.01.005","article-title":"Management of side effects of mTOR inhibitors in tuberous sclerosis patients","volume":"68","author":"Sadowski","year":"2016","journal-title":"Pharmacol Rep"},{"key":"B33","doi-asserted-by":"publisher","first-page":"13571","DOI":"10.1073\/pnas.202476899","article-title":"Tuberous sclerosis complex-1 and\u22122 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling","volume":"99","author":"Tee","year":"2002","journal-title":"Proc Natl Acad Sci USA"},{"key":"B34","doi-asserted-by":"publisher","first-page":"444","DOI":"10.1002\/ana.21331","article-title":"Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex","volume":"63","author":"Zeng","year":"2008","journal-title":"Ann Neurol"},{"key":"B35","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1002\/ana.23960","article-title":"Everolimus treatment of refractory epilepsy in tuberous sclerosis complex","volume":"74","author":"Krueger","year":"2013","journal-title":"Ann Neurol"},{"key":"B36","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1016\/S2352-4642(18)30099-3","article-title":"Adjunctive everolimus for children and adolescents with treatment-refractory seizures associated with tuberous sclerosis complex: post-hoc analysis of the phase 3 EXIST-3 trial","volume":"2","author":"Curatolo","year":"2018","journal-title":"Lancet Child Adolesc Health"},{"key":"B37","doi-asserted-by":"publisher","first-page":"1550","DOI":"10.1093\/neuonc\/nov152","article-title":"Differentiating the mTOR inhibitors everolimus and sirolimus in the treatment of tuberous sclerosis complex","volume":"17","author":"MacKeigan","year":"2015","journal-title":"Neuro Oncol"}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2022.704978\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,29]],"date-time":"2022-04-29T07:30:02Z","timestamp":1651217402000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2022.704978\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,29]]},"references-count":37,"alternative-id":["10.3389\/fneur.2022.704978"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2022.704978","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,29]]},"article-number":"704978"}}