Head and Neck TumorsHead and Neck TumorsОпухоли головы и шеи2222-14682411-4634Publishing House ABV Press81910.17650/2222-1468-2022-12-3-102-113ORIGINAL REPORTОРИГИНАЛЬНОЕ ИССЛЕДОВАНИЕFeatures of epileptiform activity in patients with diagnosed glioblastoma: from genetic and biochemical mechanisms to clinical aspectsОсобенности эпилептиформной активности у пациентов с диагностированной глиобластомой: от генетических и биохимических механизмов к клиническим аспектамhttps://orcid.org/0000-0002-5074-6391TyagunovaE. E.ТягуноваЕ. Е.
Russian Federation

Ekaterina Evgenievna Tyagunova 

 

Екатерина Евгеньевна Тягунова 

119991 Москва, ул. Трубецкая, 8, стр. 2

katerina.tyagunova@yandex.ruhttps://orcid.org/0000-0002-4004-7474ZakharovA. S.ЗахаровА. С.
Russian Federation

9 Vysokovoltnaya St., Ryazan 390026

390026 Рязань, ул. Высоковольтная, 9

https://orcid.org/0000-0002-2835-5992GlukhovA. I.ГлуховА. И.
Russian Federation

Bld. 2, 8 Trubetskaya St., Moscow 119991

1 Leninskie Gory, Moscow 119991

119991 Москва, ул. Трубецкая, 8, стр. 2

119991 Москва,  Ленинские горы, 1

https://orcid.org/0000-0001-5889-392XDobrokhotovaV. Z.ДоброхотоваВ. З.
Russian Federation

Bld. 2, 8 Trubetskaya St., Moscow 119991

24 Kashirskoe Shosse, Moscow 115522

119991 Москва, ул. Трубецкая, 8, стр. 2

115522 Москва, Каширское шоссе, 24

https://orcid.org/0000-0002-4446-1357ShlapakovT. I.ШлапаковаТ. И.
Russian Federation

Bld. 2, 8 Trubetskaya St., Moscow 119991

119991 Москва, ул. Трубецкая, 8, стр. 2

https://orcid.org/0000-0002-2389-3820KozlovV. V.КозловВ. В.
Russian Federation

Bld. 2, 8 Trubetskaya St., Moscow 119991

119991 Москва, ул. Трубецкая, 8, стр. 2

https://orcid.org/0000-0001-7974-2450KorotkovaN. V.КоротковаН. В.
Russian Federation

9 Vysokovoltnaya St., Ryazan 390026

390026 Рязань, ул. Высоковольтная, 9

https://orcid.org/0000-0002-3532-430XTyagunovaT.  E. ТягуноваТ. Е.
Russian Federation

15 Karl Marks St., Kasimov 391000

391000 Касимов, ул. Карла Маркса, 15

I.M. Sechenov First Moscow State Medical University, Ministry of Health of RussiaФГАОУ ВО Первый Московский государственный медицинский университет им. И. М. Сеченова Минздрава РоссииPavlov Ryazan State Medical University, Ministry of Health of RussiaФГБОУ ВО «Рязанский государственный медицинский университет им. акад. И. П. Павлова» Минздрава РоссииM.V. Lomonosov Moscow State UniversityФГБОУ ВО «Московский государственный университет им. М. В. Ломоносова»N. N. Blokhin National Research Institute of Oncology, Ministry of Health of RussiaФГБУ «Национальный медицинский исследовательский центр онкологии им. Н. Н. Блохина» Минздрава РоссииLLC “Klassny Doctor”ООО «Классный доктор»141020221231021131312202213122022Copyright ©; 2022, Tyagunova E.E., Zakharov A.S., Glukhov A.I., Dobrokhotova V.Z., Shlapakov T.I., Kozlov V.V., Korotkova N.V., Tyagunova T.E.Copyright ©; 2022, Тягунова Е.Е., Захаров А.С., Глухов А.И., Доброхотова В.З., Шлапакова Т.И., Козлов В.В., Короткова Н.В., Тягунова Т.Е.2022Tyagunova E.E., Zakharov A.S., Glukhov A.I., Dobrokhotova V.Z., Shlapakov T.I., Kozlov V.V., Korotkova N.V., Tyagunova T.E.Тягунова Е.Е., Захаров А.С., Глухов А.И., Доброхотова В.З., Шлапакова Т.И., Козлов В.В., Короткова Н.В., Тягунова Т.Е.https://creativecommons.org/licenses/by/4.0https://ogsh.abvpress.ru/jour/article/view/819

Introduction. glioblastomas multiforme (grade Iv gliomas) are common and the most aggressive primary tumors of the brain with very unfavorable prognosis. In all previously published papers on epileptiform activity in glioblastomas, not enough information on encephalogram results is presented.

Aim. To study the features of epileptiform activity in patients with glioblastomas and development of a plan for further study of these patients.

Materials and methods. An analysis of articles from Elsevier, Embase, Scopus, The Cochrane Library, global Health, Russian Science Citation Index (RSCI) databases, Scholar, google, web of Science, pubmed search engines and scientific electronic library CyberLeninka was performed. materials were selected considering journal indexing system and citations, scientific novelty of the studies, statistical significance of the results. publications repeating data from previous articles or describing animal experiments were excluded from analysis.

Results. During the study, data on mechanisms of epileptiform activity pathogenesis, predisposing factors (tumor location in the temporal, frontal or parietal lobes, IDH-1 and / or IDH-2 gene mutations), treatment options in patients with glioblastomas were systemized. Additionally, and original plan of data accumulation for clinical studied taking into account limitations of the previous studies was developed to increase quality of results interpretation.

Conclusion. Epileptiform symptoms in glioblastomas negatively affect patients’ quality of life and lifespan. Currently, researchers actively search for an effective method of treatment of epileptic seizures in patients with glioblastomas. The most effective is combination of temozolomide with valproate and levetiracetam due to good control of seizure frequency, low toxicity, and pharmacological synergy between the drugs.

Введение. Мультиформные глиобластомы (глиомы Iv степени) – часто встречающиеся наиболее агрессивные первичные опухоли головного мозга с крайне неблагоприятным прогнозом. Во всех опубликованных ранее статьях об эпилептиформной активности при глиобластомах содержится недостаточно информации о результатах электроэнцефалограмм.

Цель – разностороннее изучение особенностей эпилептиформной активности у пациентов с глиобластомами и разработка плана дальнейшего исследования таких больных.

Материалы и методы. Представлен анализ статей из баз данных Elsevier, Embase, Scopus, The Cochrane Library, global Health, Российской базы научного цитирования (Russian Science Citation Index, RSCI), поисковых систем Scholar, google, web of Science, pubmed и научной электронной библиотеки CyberLeninka. при отборе материала учитывались системы индексирования журналов и цитируемость, научная новизна исследований, статистическая значимость полученных результатов. публикации, в которых дублировались данные предыдущих работ или использовались эксперименты на животных, исключались из анализа.

Результаты. В ходе исследования были систематизированы сведения о механизмах патогенеза эпилептиформной активности у пациентов с глиобластомами, предрасполагающих факторах (локализация опухоли в височной, лобной и теменной долях, наличие мутаций в генах IDH-1 и / или IDH-2), особенностях лечения таких больных. Кроме того, предложен оригинальный план сбора данных для проведения клинических исследований, учитывающий недостатки предыдущих работ, что способствует повышению качества интерпретации полученных результатов.

Заключение. Эпилептиформная симптоматика при глиобластомах негативно влияет на качество и продолжительность жизни пациентов. В настоящее время ведутся активные поиски эффективного метода лечения эпилептических припадков у больных глиобластомой. Наиболее действенным оказалось комбинирование темозоломида с вальпроатом и леветирацетамом в связи с хорошими показателями контроля над частотой приступов, низкой токсичностью и фармакодинамическим синергизмом данных лекарственных препаратов.

glioblastomaepilepsyreactive astrocytesisocitrate dehydrogenaseIDH-1IDH-2questionnaireглиобластомаэпилепсияреактивные астроцитыизоцитратдегидрогеназаIDH-1, IDH-2анкетированиеShlapakova T.I., Tyagunova E.E., Kostin R.K., Danilova D.A. Targeted antitumor drug delivery to glioblastoma multiforme cells. Russ J Bioorg Chem 2021;47(2):376–79. DOI: 10.1134/ S1068162021020254Bogoyavlenskaya T.A., Tyagunova E.E., Kostin R.K. et al. Glioblastoma break-in; try something new. Int J Cancer Manag 2021;14(1):e109054. DOI: 10.5812/ijcm.109054Shlapakova T.I., Tyagunova E.E., Kostin R.K., Danilova D.A. Targeted delivery of antitumor drugs to glioblastoma multiforme cells. Bioorganicheskaya himiya = Bioorganic Chemistry 2021;47(3):299–303. (In Russ.). DOI: 10.31857/S0132342321020251Шлапакова Т.И., Тягунова Е.Е., Костин Р.К., Данилова Д.А. Адресная доставка противоопухолевых препаратов к клеткам мультиформной глиобластомы. Биоорганическая химия 2021;47(3):299–303. DOI: 10.31857/S0132342321020251Climans S.A., Brandes A.A., Cairncross J.G. et al. Temozolomide and seizure outcomes in a randomized clinical trial of elderly glioblastoma patients. J Neurooncol 2020;149(1):65–71. DOI: 10.1007/s11060-020-03573-xAvila E.K., Chamberlain M., Schiff D. et al. Seizure control as a new metric in assessing efficacy of tumor treatment in low-grade glioma trials. Neuro Oncol 2017;19(1):12–21. DOI: 10.1093/ neuonc/now190Perry J.R., Laperriere N., O’Callaghan C.J. et al. Short-course radiation plus temozolomide in elderly patients with glioblastoma. N Engl J Med 2017;376(11):1027–37. DOI: 10.1056/NEJMoa1611977Vecht C.J., Kerkhof M., Duran-Pena A. Seizure prognosis in brain tumors: new insights and evidence-based management. Oncologist 2014;19(7):751–9. DOI: 10.1634/theoncologist. 2014-0060Vecht C.J., Kerkhof M., Duran-Pena A. Seizure prognosis in brain tumors: new insights and evidence-based management. Oncologist 2014;19(7):751–9. DOI: 10.1634/theoncologist. 2014-0060Bruna J., Miró J., Velasco R. Epilepsy in glioblastoma patients: basic mechanisms and current problems in treatment. Expert Rev Clin Pharmacol 2013;6(3):333–44. DOI: 10.1586/ecp.13.12Forsgren L., Bucht G., Eriksson S., Bergmark L. Incidence and clinical characterization of unprovoked seizures in adults: a prospective population-based study. Epilepsia 1996;37(3):224–9. DOI: 10.1111/j.1528-1157.1996.tb00017.xPerucca P., Camfield P., Camfield C. Does gender influence susceptibility and consequences of acquired epilepsies. Neurobiol Dis 2014;72(Pt. B):125–30. DOI: 10.1016/j.nbd.2014.05.016Maugeri R., Schiera G., Di Liegro C.M. et al. Aquaporins and brain tumors. Int J Mol Sci 2016; 17(7):1029. DOI: 10.3390/ ijms17071029Wolburg H., Noell S., Fallier-Becker P. et al. The disturbed blood–brain barrier in human glioblastoma.Mol Asp Med 2012;33(5–6): 579–89. DOI: 10.1016/j.mam.2012.02.003Vecht C., Royer-Perron L., Houillier C., Huberfeld G. Seizures and anticonvulsants in brain tumours: frequency, mechanisms and antiepileptic management. Curr Pharm Des 2017;23(42):6464–87. DOI: 10.2174/1381612823666171027130003Vecht C., Royer-Perron L., Houillier C., Huberfeld G. Seizures and anticonvulsants in brain tumours: frequency, mechanisms and antiepileptic management. Curr Pharm Des 2017;23(42):6464–87. DOI: 10.2174/1381612823666171027130003Yuen T.I., Morokoff A.P., Bjorksten A. et al. Glutamate is associated with a higher risk of seizures in patients with gliomas. Neurology 2012;79(9):883–9. DOI: 10.1212/WNL.0b013e3186fa89Lo M., Wang Y.-Z., Gout P.W. The x(c)-cystine/glutamate antiporter: a potential target for therapy of cancer and other diseases. J Cell Physiol 2008;215(3):593–602. DOI: 10.1002/jcp. 21366Buccoliero A.M., Caporalini C., Scagnet M. et al. Angiocentric glioma-associated seizures: the possible role of EATT2, pyruvate carboxylase and glutamine synthetase. Seizure 2021;86:152–4. DOI: 10.1016/j.seizure.2021.02.014Lange F., Hörnschemeyer J., Kirschstein T. Glutamatergic mechanisms in glioblastoma and tumor-associated epilepsy. Cells 2021;10(5):1226. DOI: 10.3390/cells10051226Pallud J., Le Van Quyen M., Bielle F. et al. Cortical GABAergic excitation contributes to epileptic activities around human glioma. Sci Transl Med 2014;6(244):244ra89. DOI: 10.1126/ scitranslmed.3008065Tönjes M., Barbus S., Park Y.J. et al. BCAT1 promotes cell proliferation through amino acid catabolism in gliomas carrying wild-type IDH1. Nat Med 2013;19(7):901–8. DOI: 10.1038/ nm.3217Zhang B., Chen Y., Shi X. et al. Regulation of branchedchain amino acid metabolism by hypoxia-inducible factor in glioblastoma. Cell Mol Life Sci 2021;78(1):195–206. DOI: 10.1007/s00018-020-03483-1Marcus H.J., Carpenter K.L.H., Price S.J., Hutchinson P.J. In vivo assessment of high-grade glioma biochemistry using microdialysis: a study of energy-related molecules, growth factors and cytokines. J Neurooncol 2010;97(1):11–23. DOI: 10.1007/s11060-009-9990-5Venkataramani V., Tanev D.I., Strahle C. et al. Glutamatergic synaptic input to glioma cells drives brain tumour progression. Nature 2019;573(7775):532–8. DOI: 10.1038/s41586-019-1564-xVenkatesh H.S., Morishita W., Geraghty A.C. et al. Electrical and synaptic integration of glioma into neural circuits. Nature 2019;573(7775):539–45. DOI: 10.1038/s41586-019-1563-yIshiuchi S., Yoshida Y., Sugawara K. et al. Ca2+-permeable AMPA receptors regulate growth of human glioblastoma via Akt activation. J Neurosci 2007;27(30):7987–8001. DOI: 10.1523/JNEUROSCI.2180-07.2007Buckingham S.C., Campbell S.L., Haas B.R. et al. Glutamate release by primary brain tumors induces epileptic activity. Nat Med 2011;17(10):1269–74. DOI: 10.1038/nm.2453Intlekofer A.M., Dematteo R.G., Venneti S. et al. Hypoxia induces production of L-2-Hydroxyglutarate. Cell Metab 2015;22(2): 304–11. DOI: 10.1016/j.cmet.2015.06.023Madala H.R., Punganuru S.R., Arutla V. et al. Beyond brooding on oncometabolic havoc in IDH-mutant gliomas and AML: current and future therapeutic strategies. Cancers (Basel) 2018;10(2):49. DOI: 10.3390/cancers10020049Toplak M., Brunner J., Schmidt J., Macheroux P. Biochemical characterization of human D-2-hydroxyglutarate dehydrogenase and two disease related variants reveals the molecular cause of D-2-hydroxyglutaric aciduria. Biochim Biophys Acta Proteins Proteom 2019;1867(11):140255. DOI: 10.1016/j.bbapap.2019.07.008Toplak M., Brunner J., Schmidt J., Macheroux P. Biochemical characterization of human D-2-hydroxyglutarate dehydrogenase and two disease related variants reveals the molecular cause of D-2-hydroxyglutaric aciduria. Biochim Biophys Acta Proteins Proteom 2019;1867(11):140255. DOI: 10.1016/j.bbapap.2019.07.008Flavahan W.A., Drier Y., Liau B.B. et al. Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature 2016;529(7584):110–4. DOI: 10.1038/nature16490Losman J.A., Kaelin W.G. What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer. Genes Dev 2013;27(8):836–52. DOI: 10.1101/gad.217406.113Rasmussen K.D., Helin K. Role of TET enzymes in DNA methylation, development, and cancer. Genes Dev 2016;30(7): 733–50. DOI: 10.1101/gad.276568.115Xu W., Yang H, Liu Y. et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell 2011;19(1):17–30. DOI: 10.1016/j. ccr.2010.12.014Xu W., Yang H, Liu Y. et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell 2011;19(1):17–30. DOI: 10.1016/j. ccr.2010.12.014Huberfeld G., Vecht C.J. Seizures and gliomas--towards a single therapeutic approach. Nat Rev Neurol 2016;12(4):204–16. DOI: 10.1038/nrneurol.2016.26McBrayer S.K., Mayers J.R., DiNatale G.J. et al. Transaminase inhibition by 2-Hydroxyglutarate impairs glutamate biosynthesis and redox homeostasis in glioma. Cell 2018;175(1):101–16.e25. DOI: 10.1016/j.cell.2018.08.038Bady P., Sciuscio D., Diserens A.C. et al. MGMT methylation analysis of glioblastoma on the Infinium methylation BeadChip identifies two distinct CpG regions associated with gene silencing and outcome, yielding a prediction model for comparisons across datasets, tumor grades, and CIMP-status. Acta Neuropathol 2012;124(4):547–60. DOI: 10.1007/s00401-012-1016-2Aldape K., Zadeh G., Mansouri S. et al. Glioblastoma: pathology, molecular mechanisms and markers. Acta Neuropathol 2015;129(6):829–48. DOI: 0.1007/s00401-015-1432-1Berghoff A.S., Kiesel B., Widhalm G. et al. Correlation of immune phenotype with IDH mutation in diffuse glioma. Neuro Oncol 2017;19(11):1460–8. DOI: 10.1093/neuonc/nox054Mu L., Long Y., Yang C. et al. The IDH1 Mutation-induced oncometabolite, 2-Hydroxyglutarate, may affect DNA methylation and expression of PD-L1 in gliomas. Front Mol Neurosci 2018;11:82. DOI: 10.3389/fnmol.2018.00082Reuss D.E., Sahm F., Schrimpf D. et al. ATRX and IDH1-R132H immunohistochemistry with subsequent copy number analysis and IDH sequencing as a basis for an “integrated” diagnostic approach for adult astrocytoma, oligodendroglioma and glioblastoma. Acta Neuropathol 2015;129(1):133–46. DOI: 10.1007/s00401-014-1370-3Kerkhof M., Benit C., Duran-Pena A., Vecht C.J. Seizures in oligodendroglial tumors. CNS Oncol 2015;4(5):347–56. DOI: 10.2217/cns.15.29Van Meir E. G., Hadjipanayis C.G., Norden A.D. et al. Exciting new advances in neuro-oncology. CA Cancer J Clin 2010;60(3): 166–93. DOI: 10.3322/caac.20069Heiland H.D., Ravi V.M., Behringer S.P. et al. Tumor-associated reactive astrocytes aid the evolution of immunosuppressive environment in glioblastoma. Nat Commun 2019;10(1):2541. DOI: 10.1038/s41467-019-10493-6Darmanis S., Sloan S.A., Croote D. et al. Single-cell RNA-Seq analysis of infiltrating neoplastic cells at the migrating front of human glioblastoma. Cell Rep 2017;21(5):1399–410. DOI: 10.1016/j.celrep.2017.10.030Zhang Y., Chen K., Sloan S.A. et al. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci 2014;34(36):11929–47. DOI: 10.1523/JNEUROSCI.1860-14.2014Zhang Y., Sloan S.A., Clarke L.E. et al. Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse. Neuron 2016;89(1):37–53. DOI: 10.1016/j.neuron.2015.11.013Liddelow S.A., Barres B.A. Reactive astrocytes: production, function, and therapeutic potential. Immunity 2017;46(6):957–67. DOI: 10.1016/j.immuni.2017.06.006Liddelow S.A., Guttenplan K.A., Clarke L.E. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 2017;541(7638):481–7. DOI: 10.1038/nature21029Zamanian J.L., Xu L., Foo L.C. et al. Genomic analysis of reactive astrogliosis. J Neurosci 2012;32(18):6391–410. DOI: 10.1523/JNEUROSCI.6221-11.2012Yun S.P., Kam T.-I., Panicker N. et al. Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson’ s disease. Nat Med 2018;24(7):931–8. DOI: 10.1038/s41591-018-0051-5Hatcher A., Yu K., Meyer J. et al. Pathogenesis of peritumoral hyperexcitability in an immunocompetent CRISPR-based glioblastoma model. J Clin Investig 2020;130(5):2286–300. DOI: 10.1172/JCI133316Lu V.M., Jue T.R., Phan K., McDonald K.L. Quantifying the prognostic significance in glioblastoma of seizure history at initial presentation: a systematic review and meta-analysis. Clin Neurol Neurosurg 2018;164:75–80. DOI: 10.1016/j.clineuro.2017.11.015Sherman J.H., Moldovan K., Yeoh H. K. et al. Impact of temozolomide chemotherapy on seizure frequency in patients with low-grade gliomas. J Neurosurg 2011;114(6):1617–21. DOI: 10.3171/2010.12.JNS101602Koekkoek J., Dirven L., Reijneveld J.C. et al. Epilepsy in the end of life phase of brain tumor patients: a systematic review. Neurooncol Pract 2014;1(3):134–40. DOI: 10.1093/nop/npu018Koekkoek J., Dirven L., Reijneveld J.C. et al. Epilepsy in the end of life phase of brain tumor patients: a systematic review. Neurooncol Pract 2014;1(3):134–40. DOI: 10.1093/nop/npu018Rudà R., Soffietti R. What is new in the management of epilepsy in gliomas? Curr Treat Options Neurol 2015;17(6):351. DOI: 10.1007/s11940-015-0351-8Haggiagi A., Avila E.K. Seizure response to temozolomide chemotherapy in patients with WHO grade II oligodendroglioma: a single-institution descriptive study. Neurooncol Pract 2019;6(3):203–8. DOI: 10.1093/nop/npy029Climans S.A., Brandes A.A., Cairncross J.G. et al. Temozolomide and seizure outcomes in a randomized clinical trial of elderly glioblastoma patients. J Neurooncol 2020;149(1):65–71. DOI: 10.1007/s11060-020-03573-xKerkhof M., Dielemans J.C., van Breemen M.S. et al. Effect of valproic acid on seizure control and on survival in patients with glioblastoma multiforme. Neuro Oncol 2013;15(7):961–7. DOI: 10.1093/neuonc/not057Kerkhof M., Dielemans J.C., van Breemen M.S. et al. Effect of valproic acid on seizure control and on survival in patients with glioblastoma multiforme. Neuro Oncol 2013;15(7):961–7. DOI: 10.1093/neuonc/not057Redjal N., Reinshagen C., Le A. et al. Valproic acid, compared to other antiepileptic drugs, is associated with improved overall and progression-free survival in glioblastoma but worse outcome in grade II/III gliomas treated with temozolomide. J Neurooncol 2016;127(3):505–14. DOI: 10.1007/s11060-016-2054-8Bobustuc G.C., Baker C.H., Limaye A.et al. Levetiracetam enhances p53-mediated MGMT inhibition and sensitizes glioblastoma cells to temozolomide. Neuro Oncol 2010;12(9): 917–27. DOI: 10.1093/neuonc/noq044Ni X.R., Guo C.C., Yu Y.J. et al. Combination of levetiracetam and IFN-α increased temozolomide efficacy in MGMT-positive glioma. Cancer Chemother Pharmacol 2020;86(6):773–82. DOI: 10.1007/s00280-020-04169-yRyu C.H., Yoon W.S., Park K.Y. et al. Valproic acid downregulates the expression of MGMT and sensitizes temozolomide-resistant glioma cells. J Biomed Biotechnol 2012;2012:987495. DOI: 10.1155/2012/987495Maschio M., Albani F., Jandolo B. et al. Temozolomide treatment does not affect topiramate and oxcarbazepine plasma concentrations in chronically treated patients with brain tumor-related epilepsy. J Neurooncol 2008;90(2):217–21. DOI: 10.1007/s11060-008-9651-0Cardona A.F., Rojas L., Wills B. et al. Efficacy and safety of Levetiracetam vs. other antiepileptic drugs in Hispanic patients with glioblastoma. J Neurooncol 2018;136(2):363–71. DOI: 10.1007/s11060-017-2660-0Krauze A.V., Mackey M., Rowe L. et al. Late toxicity in long-term survivors from a phase 2 study of concurrent radiation therapy, temozolomide and valproic acid for newly diagnosed glioblastoma. Neurooncol Pract 2018;5(4):246–50. DOI: 10.1093/nop/npy009Shlapakova T.I., Kostin R.K., Tyagunova, E.E. Reactive Oxygen Species: Participation in Cellular Processes and Progression of Pathology. Russ J Bioorg Chem 2020;46(5):657–74. DOI: 10.1134/S1068162020050222Nikolenko V.N., Gridin L.A., Oganesyan M.V. et al. The posterior perforated substance: a brain mystery wrapped in an enigma. Curr Top Med Chem 2019;19(32):2991–8. DOI: 10.2174/1568026619666191127122452Shlapakova T.I., Kostin R.K., Tyagunova E.E. Reactive oxygen species: participation in cellular processes and the development of pathology. Bioorganicheskaya himiya = Bioorganic Chemistry 2020;46(5):466–85. (In Russ.). DOI: 10.31857/S013234232005022XШлапакова Т.И., Костин Р.К., Тягунова Е.Е. Активные формы кислорода: участие в клеточных процессах и развитии патологии. Биоорганическая химия 2020;46(5):466–85. DOI: 10.31857/S013234232005022XBerg A.T., Berkovic S.F., Brodie M.J. et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005–2009. Epilepsia 2010;51(4):676–85. DOI: 10.1111/j.1528-1167.2010.02522.xWieser H.G., Blume W.T., Fish D. et al. ILAE Commission report. Proposal for a new classification of outcome with respect to epileptic seizures following epilepsy surgery. Epilepsia 2001;42(2):282–6.