Альманах клинической медицины. 2020; 48: 1-6
Ретроспективный анализ эффективности и переносимости лечения эверолимусом фармакорезистентной эпилепсии, ассоциированной с туберозным склерозом
https://doi.org/10.18786/2072-0505-2020-48-003Аннотация
Обоснование. Туберозный склероз (TC) представляет собой аутосомно-доминантное мультисистемное заболевание, характеризующееся гамартомами многих органов. Фармакорезистентная эпилепсия (ФЭ) встречается у 60% пациентов с ТС. Pезультаты исследования ЕXIST-3 показали эффективность терапии ФЭ ингибитором mTOR эверолимусом у больных ТС. В Российской Федерации препарат одобрен с 2017 г. для лечения ФЭ, ассоциированной с ТС, у пациентов старше 2 лет. Цель – оценить эффективность эверолимуса для лечения фармакорезистентных судорог, опосредованных с комплексом ТС. Материал и методы. Проведен ретроспективный анализ данных медицинской документации – историй болезни 89 пациентов с TC, госпитализированных с ФЭ в отделение психоневрологии и эпилептологии НИКИ педиатрии им. Ю.Е. Вельтищева с ноября 2016 по декабрь 2018 года. Пациенты были распределены в 3 группы в зависимости от показания, по которому получали эверолимус: 1) ФЭ – 17 пациентов, 2) субэпендимальная гигантоклеточная астроцитома диаметром более 1 см в сочетании с ФЭ (ФЭ + СЭГА) – 64, 3) почечная ангиомиолипома более 3 см в диаметре в сочетании с ФЭ (ФЭ + AМЛ) – 8. Средний возраст составил 7,9 года (от 2 до 34 лет). Мужчин было 45 (50,6%), женщин – 44 (49,4%). Продолжительность терапии составила от 6 месяцев до 5 лет. Доза препарата – 8 мг/м2 . Фокальная эпилепсия преобладала над эпилептическими спазмами: 60 (67,4%) и 29 (32,6%) человек соответственно. Результаты. Процент респондеров в группе ФЭ составил 9/17 (52,9%), в группе ФЭ + СЭГА 16/64 (25%), в группе ФЭ + АМЛ – 4/8 (50%). Наиболее частым нежелательным явлением был стоматит (от легкой до умеренной степени) – 40,5%. Заключение. Эверолимус представляется новым важным препаратом для лечения рефрактерной эпилепсии у пациентов с ТС. Лечение эверолимусом безопасно и хорошо переносится.
Список литературы
1. Белоусова ЕД, Дорофеева МЮ, Пивоварова АМ, Катышева ОВ. Диагностика туберозного склероза. Журнал неврологии и психиатрии им. С.С. Корсакова. 2015;115(10): 89–95. doi: 10.17116/jnevro201511510189-95.
2. Franz DN, Lawson JA, Yapici Z, Ikeda H, Polster T, Nabbout R, Curatolo P, de Vries PJ, Dlugos DJ, Voi M, Fan J, Vaury A, Pelov D, French JA. Everolimus for treatment-refractory seizures in TSC: Extension of a randomized controlled trial. Neurol Clin Pract. 2018;8(5):412–20. doi: 10.1212/CPJ.0000000000000514.
3. Li M, Zhou Y, Chen C, Yang T, Zhou S, Chen S, Wu Y, Cui Y. Efficacy and safety of mTOR inhibitors (rapamycin and its analogues) for tuberous sclerosis complex: a meta-analysis. Orphanet J Rare Dis. 2019;14(1):39. doi: 10.1186/s13023-019-1012-x.
4. Franz DN, Capal JK. mTOR inhibitors in the pharmacologic management of tuberous sclerosis complex and their potential role in other rare neurodevelopmental disorders. Orphanet J Rare Dis. 2017;12(1):51. doi: 10.1186/s13023017-0596-2.
5. Overwater IE, Rietman AB, van Eeghen AM, de Wit MCY. Everolimus for the treatment of refractory seizures associated with tuberous sclerosis complex (TSC): current perspectives. Ther Clin Risk Manag. 2019;15:951–5. doi: 10.2147/TCRM.S145630.
6. Curatolo P, Moavero R, de Vries PJ. Neurological and neuropsychiatric aspects of tuberous sclerosis complex. Lancet Neurol. 2015;14(7): 733–45. doi: 10.1016/S1474-4422(15)00069-1.
7. Overwater IE, Bindels-de Heus K, Rietman AB, Ten Hoopen LW, Vergouwe Y, Moll HA, de Wit MC. Epilepsy in children with tuberous sclerosis complex: Chance of remission and response to antiepileptic drugs. Epilepsia. 2015;56(8):1239–45. doi: 10.1111/epi.13050.
8. Lipton JO, Sahin M. The neurology of mTOR. Neuron. 2014;84(2):275–91. doi: 10.1016/j.neuron.2014.09.034.
9. Wong M. A critical review of mTOR inhibitors and epilepsy: from basic science to clinical trials. Expert Rev Neurother. 2013;13(6):657–69. doi: 10.1586/ern.13.48.
10. Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med. 2000;342(5): 314–9. doi: 10.1056/NEJM200002033420503.
11. Chu-Shore CJ, Major P, Camposano S, Muzykewicz D, Thiele EA. The natural history of epilepsy in tuberous sclerosis complex. Epilepsia. 2010;51(7):1236–41. doi: 10.1111/j.1528-1167.2009.02474.x.
12. Curatolo P. Mechanistic target of rapamycin (mTOR) in tuberous sclerosis complex-associated epilepsy. Pediatr Neurol. 2015;52(3):281–9. doi: 10.1016/j.pediatrneurol.2014.10.028.
13. Stafstrom CE, Hagerman PJ, Pessah IN. Pathophysiology of epilepsy in autism spectrum disorders. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, editors. Jasper's Basic Mechanisms of the Epilepsies [Internet]. 4 th edition. Bethesda (MD): National Center for Biotechnology Information (US); 2012. Available from: https://www.ncbi.nlm.nih.gov/books/NBK98169/.
14. Krueger DA, Care MM, Holland K, Agricola K, Tudor C, Mangeshkar P, Wilson KA, Byars A, Sahmoud T, Franz DN. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med. 2010;363(19):1801–11. doi: 10.1056/NEJMoa1001671.
15. Wang S, Fallah A. Optimal management of seizures associated with tuberous sclerosis complex: current and emerging options. Neuropsychiatr Dis Treat. 2014;10:2021–30. doi: 10.2147/NDT.S51789.
16. French JA, Lawson JA, Yapici Z, Ikeda H, Polster T, Nabbout R, Curatolo P, de Vries PJ, Dlugos DJ, Berkowitz N, Voi M, Peyrard S, Pelov D, Franz DN. Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study. Lancet. 2016;388(10056): 2153–63. doi: 10.1016/S0140-6736(16)31419-2.
17. Krueger DA, Wilfong AA, Holland-Bouley K, Anderson AE, Agricola K, Tudor C, Mays M, Lopez CM, Kim MO, Franz DN. Everolimus treatment of refractory epilepsy in tuberous sclerosis complex. Ann Neurol. 2013;74(5):679–87. doi: 10.1002/ana.23960.
Almanac of Clinical Medicine. 2020; 48: 1-6
A retrospective analysis of the efficacy and tolerability of treatment with everolimus in treatment-refractory epilepsy associated with tuberous sclerosis
https://doi.org/10.18786/2072-0505-2020-48-003Abstract
Rationale: Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem disorder characterized by multiple multi-organ hamartomas. Medically refractory epilepsy (MRE) occurs in up to 60% of TSC patients. The results of the EXIST-3 study have shown the efficacy of MRE treatment with an mTOR inhibitor everolimus. In the Russian Federation, the drug has been approved since 2017 for the treatment of TSC-associated MRE in patients above 2 years of age. Aim: To assess the efficacy of everolimus for treatment of medically refractory seizures associated with TSC. Materials and methods: We retrospectively analyzed medical files from 89 patients with TSC who had been admitted with MRE to the Department of Psychoneurology and Epileptology, Research and Clinical Institute for Pediatrics (Moscow, Russia) from November 2016 to December 2018. The patients were divided into three groups depending on their indications for everolimus: 1) 17 patients received with MRE; 2) 64 patients with MRE and subependymal giant cell astrocytoma (SEGA) of > 1 cm in diameter; 3) 8 patients with MRE and renal angiomyolipoma (AML) of > 3 cm in diameter. Their median age was 7.9 year (range, from 2 to 34 years). There were 45 (50.6%) male and 44 (49.4%) female patients. Their treatment lasted from 6 months to 5 years; the dose of everolimus was 8 mg/m2 . Focal seizures were more prevalent than epileptic spasms: 60 (67.4%) and 29 (32.6%) patients, respectively. Results: There were 9/17 (52.9%) responders in the MRE group, 16/64 (25%) in the MRE + SEGA group, and 4/8 (50%) in the MRE + AML group. Mild to moderate stomatitis was the most frequent side effect (40.5%). Conclusion: Everolimus is a new important agent for MRE in TSC patients. Treatment with everolimus is safe and well tolerated.
References
1. Belousova ED, Dorofeeva MYu, Pivovarova AM, Katysheva OV. Diagnostika tuberoznogo skleroza. Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova. 2015;115(10): 89–95. doi: 10.17116/jnevro201511510189-95.
2. Franz DN, Lawson JA, Yapici Z, Ikeda H, Polster T, Nabbout R, Curatolo P, de Vries PJ, Dlugos DJ, Voi M, Fan J, Vaury A, Pelov D, French JA. Everolimus for treatment-refractory seizures in TSC: Extension of a randomized controlled trial. Neurol Clin Pract. 2018;8(5):412–20. doi: 10.1212/CPJ.0000000000000514.
3. Li M, Zhou Y, Chen C, Yang T, Zhou S, Chen S, Wu Y, Cui Y. Efficacy and safety of mTOR inhibitors (rapamycin and its analogues) for tuberous sclerosis complex: a meta-analysis. Orphanet J Rare Dis. 2019;14(1):39. doi: 10.1186/s13023-019-1012-x.
4. Franz DN, Capal JK. mTOR inhibitors in the pharmacologic management of tuberous sclerosis complex and their potential role in other rare neurodevelopmental disorders. Orphanet J Rare Dis. 2017;12(1):51. doi: 10.1186/s13023017-0596-2.
5. Overwater IE, Rietman AB, van Eeghen AM, de Wit MCY. Everolimus for the treatment of refractory seizures associated with tuberous sclerosis complex (TSC): current perspectives. Ther Clin Risk Manag. 2019;15:951–5. doi: 10.2147/TCRM.S145630.
6. Curatolo P, Moavero R, de Vries PJ. Neurological and neuropsychiatric aspects of tuberous sclerosis complex. Lancet Neurol. 2015;14(7): 733–45. doi: 10.1016/S1474-4422(15)00069-1.
7. Overwater IE, Bindels-de Heus K, Rietman AB, Ten Hoopen LW, Vergouwe Y, Moll HA, de Wit MC. Epilepsy in children with tuberous sclerosis complex: Chance of remission and response to antiepileptic drugs. Epilepsia. 2015;56(8):1239–45. doi: 10.1111/epi.13050.
8. Lipton JO, Sahin M. The neurology of mTOR. Neuron. 2014;84(2):275–91. doi: 10.1016/j.neuron.2014.09.034.
9. Wong M. A critical review of mTOR inhibitors and epilepsy: from basic science to clinical trials. Expert Rev Neurother. 2013;13(6):657–69. doi: 10.1586/ern.13.48.
10. Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med. 2000;342(5): 314–9. doi: 10.1056/NEJM200002033420503.
11. Chu-Shore CJ, Major P, Camposano S, Muzykewicz D, Thiele EA. The natural history of epilepsy in tuberous sclerosis complex. Epilepsia. 2010;51(7):1236–41. doi: 10.1111/j.1528-1167.2009.02474.x.
12. Curatolo P. Mechanistic target of rapamycin (mTOR) in tuberous sclerosis complex-associated epilepsy. Pediatr Neurol. 2015;52(3):281–9. doi: 10.1016/j.pediatrneurol.2014.10.028.
13. Stafstrom CE, Hagerman PJ, Pessah IN. Pathophysiology of epilepsy in autism spectrum disorders. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, editors. Jasper's Basic Mechanisms of the Epilepsies [Internet]. 4 th edition. Bethesda (MD): National Center for Biotechnology Information (US); 2012. Available from: https://www.ncbi.nlm.nih.gov/books/NBK98169/.
14. Krueger DA, Care MM, Holland K, Agricola K, Tudor C, Mangeshkar P, Wilson KA, Byars A, Sahmoud T, Franz DN. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med. 2010;363(19):1801–11. doi: 10.1056/NEJMoa1001671.
15. Wang S, Fallah A. Optimal management of seizures associated with tuberous sclerosis complex: current and emerging options. Neuropsychiatr Dis Treat. 2014;10:2021–30. doi: 10.2147/NDT.S51789.
16. French JA, Lawson JA, Yapici Z, Ikeda H, Polster T, Nabbout R, Curatolo P, de Vries PJ, Dlugos DJ, Berkowitz N, Voi M, Peyrard S, Pelov D, Franz DN. Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study. Lancet. 2016;388(10056): 2153–63. doi: 10.1016/S0140-6736(16)31419-2.
17. Krueger DA, Wilfong AA, Holland-Bouley K, Anderson AE, Agricola K, Tudor C, Mays M, Lopez CM, Kim MO, Franz DN. Everolimus treatment of refractory epilepsy in tuberous sclerosis complex. Ann Neurol. 2013;74(5):679–87. doi: 10.1002/ana.23960.
