Epilepsy and paroxysmal conditions

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Treatment of epilepsy associated with primary and metastatic brain tumors

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There is a number of unsolved issues in management of epilepsy associated with primary and metastatic brain tumors (BTs). In particular, no consensus approaches to treatment of patients with epilepsy associated with BTs have been proposed regarding use of current anti-epileptic drugs (AEDs). The review presents the relevant data on epidemiology, features of clinically manifested epilepsy at varying stages of BTs, aspects of drug-drug interaction between AEDs and anti-tumor agents, AED-related effects on cognitive functions as well as quality of life in patients with epilepsy associated with BTs. Levetiracetam and valproic acid comprise the first-line drugs for treating seizures in patients with BTs. It is unreasonable to use AEDs acting as hepatic microsomal enzyme inducers for therapy of epileptic seizures in BTs, because it may decrease efficacy of chemotherapy agents and glucocorticoids along with elevated rate of side effects. Perampanel acting as a selective noncompetitive AMPA receptor antagonist, may be one of the drugs of choice for the adjunctive therapy of epileptic seizures associated with BTs.

About the Authors

A V. Lebedeva
Pirogov Russian National Research Medical University; Research Institute of Healthcare Organization and Medical Management
Russian Federation

Anna V. Lebedeva – Dr. Med. Sc., Professor, Chair of Neurology, Neurosurgery and Medical Genetics, Faculty of Medicine; Head of Organizational and Methodological Department of Neurology

1 Ostrovityanov Str., Moscow 117997

9 Sharikopodshipnikovskaya Str., Moscow 115088

RSCI SPIN-code: 3515-2408

S. G. Burd
Pirogov Russian National Research Medical University; Federal Center for Brain and Neurotechnology
Russian Federation

Sergey G. Burd – Dr. Med. Sc., Professor, Chair of Neurology, Neurosurgery and Medical Genetics, Faculty of Medicine; Head of Department of Epilepsy and Paroxysmal Conditions

1 Ostrovityanov Str., Moscow 117997

1 bld. 10 Ostrovityanov Str., Moscow 117513

RSCI SPIN-code: 1484-0178

P. N. Vlasov
Yevdokimov Moscow State University of Medicine and Dentistry
Russian Federation

Pavel N. Vlasov – Dr. Med. Sc., Professor, Chair of Nervous Diseases

20/1 Delegatskaya Str., Moscow 127473

Scopus Author ID: 7101688064

RSCI SPIN-code: 9357-2284

N. A. Ermolenko
Burdenko Voronezh State Medical University; Voronezh Regional Children's Clinical Hospital No. 1
Russian Federation

Natalia A. Ermolenko – Dr. Med. Sc., Chief of Chair of Neurology No. 1; Head of Neurological Department No. 2

10 Studencheskaya Str., Voronezh 394036

1 Burdenko Str., Voronezh 394024

RSCI SPIN-code: 8604-1145

I. A. Zhidkova
Yevdokimov Moscow State University of Medicine and Dentistry
Russian Federation

Irina A. Zhidkova – Dr. Med. Sc., Professor, Chair of Nervous Diseases

20/1 Delegatskaya Str., Moscow 127473

RSCI SPIN-code: 5498-6921

S. K. Zyryanov
Peoples’ Friendship University of Russia; City Clinical Hospital No. 24
Russian Federation

Sergey K. Zyryanov – Dr. Med. Sc., Professor, Chief of Chair of General and Clinical Pharmacology; Deputy Chief Physician for Therapy

8 corp. 2 Miklukho-Maklay Str., Moscow 117198

10 Pistsovaya Str., Moscow 127015

RSCI SPIN-code: 2725-9981

I. Yu. Kovaleva
Pirogov Russian National Research Medical University
Russian Federation

Irina Yu. Kovaleva – MD, PhD, Professor, Chair of Neurology, Neurosurgery and Medical Genetics, Faculty of Medicine

1 Ostrovityanov Str., Moscow 117997


D. R. Naskhletashvili
Blokhin National Medical Research Center of Oncology
Russian Federation

David R. Naskhletashvili – MD, PhD, Senior Researcher, Neurosurgical Department, Research Institute of Clinical Oncology

24 Kashirskoye Hwy, Moscow 115478

RSCI SPIN-code: 3038-5710

N. Yu. Perunova
Medical Center "Neurology
Russian Federation

Natalia Yu. Perunova – Dr. Med. Sc., Neurologist, Epileptologist, Neurology Medical Center

52 Amundsen Str., Ekaterinburg 620146


I. G. Rudakova
Vladimirskiy Moscow Regional Research Clinical Institute
Russian Federation

Irina G. Rudakova – Dr. Med. Sc., Professor, Chair of Neurology

61/2 bld. 6 Shchepkin Str., Moscow 129110

RSCI SPIN-code: 3832-4770

R. K. Shikhkerimov
Polyclinic No. 4, Department of Affairs of the President of the Russian Federation; City Polyclinic No. 166
Russian Federation

Rafiz K. Shikhkerimov – Dr. Med. Sc., Neurologist

20 Kutuzovskiy Ave, Moscow 121151

9 Domodedovskaya Str., Moscow 115551

RSCI SPIN-code: 6191-5433

M. A. Yamin
Regional Consultative and Diagnostic Center; Rostov State Medical University
Russian Federation

Maksim A. Yamin – MD, PhD, Head of Regional Epileptology Center; Assistant Professor, Chair of Personalized and Translational Medicine

127 Pushkinskaya Str., Rostov-on-Don 344000

29 Nakhichevanskiy Aly,Rostov-on-Don 344022

RSCI SPINcode: 3726-5656


1. DeAngelis L.M. Brain tumors. N Engl J Med. 2001; 344 (2): 114–23.

2. Ostrom Q.T., Gittleman H., Liao P., et al. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2010–2014. Neuro Oncol. 2017; 19 (Suppl. 5): v1–88.

3. Englot D.J., Chang E.F., Vecht C.J. Epilepsy and brain tumors. Handb Clin Neurol. 2016; 134: 267–85.

4. Cancer Research UK. Statistics by cancer type. URL: (дата обращения 07.06.2021).

5. Giulioni M., Rubboli G., Marucci G., et al. Seizure outcome of epilepsy surgery in focal epilepsies associated with temporomesial glioneuronal tumors: lesionectomy compared with tailored resection. J Neurosurg. 2009; 111 (6): 1275–82.

6. American Association of Neurological Surgeons. Metastatic brain tumors. URL: (дата обращения 07.06.2021).

7. Fox B.D., Cheung V.J., Patel A.J., et al. Epidemiology of metastatic brain tumors. Neurosurg Clin N Am. 2011; 22 (1): 1–6.

8. Chen D.Y., Chen C.C., Crawford J.R., Wang S.W. Tumor related epilepsy epidemiology, pathogenesis and management. J Neurooncol. 2018; 139 (1): 13–21.

9. Maschio M. Brain tumor-related epilepsy. Curr Neuropharmacol. 2012; 10 (2): 124–33.

10. Sperling M.R., Ko J. Seizures and brain tumors. Semin Oncol. 2006; 33 (3): 333–41.

11. Pascual-Castroviejo I., Hernández- Moneo J.L., Pascual-Pascual S.I., et al. Significance of tuber size for complications of tuberous sclerosis complex. Neurologia. 2013; 28 (9): 550–7.

12. Switon K., Kotulska K., Janusz-Kaminska A., et al. Tuberous sclerosis complex: from molecular biology to novel therapeutic approaches. IUBMB Life. 2016; 68 (12): 955–62.

13. Olafsson E., Ludvigsson P., Gudmundsson G., et al. Incidence of unprovoked seizures and epilepsy in Iceland and assessment of the epilepsy syndrome classification: a prospective study. Lancet Neurol. 2005; 4 (10): 627–34.

14. Marcus L.P., McCutcheon B.A., Noorbakhsh A., et al. Incidence and predictors of 30-day readmission for patients discharged home after craniotomy for malignant supratentorial tumors in California (1995–2010). J Neurosurg. 2014; 120 (5): 1201–11.

15. Wang Y., Qian T., You G., et al. Localizing seizure-susceptible brain regions associated with low-grade gliomas using voxel-based lesion-symptom mapping. Neuro Oncol. 2015; 17 (2): 282–8.

16. Chang E.F., Potts M.B., Keles G.E., et al. Seizure characteristics and control following resection in 332 patients with low-grade gliomas. J Neurosurg. 2008; 108 (2): 227–35.

17. Goodman M., Lamm S.H., Engel A., et al. Cortical tuber count: a biomarker indicating neurologic severity of tuberous sclerosis complex. J Child Neurol. 1997; 12 (2): 85–90.

18. Haines S.J. Decerebrate posturing misinterpreted as seizure activity. Am J Emerg Med. 1988; 6 (2): 173–7.

19. Arik Y., Leijten F.S., Seute T., et al. Prognosis and therapy of tumorrelated versus non-tumor-related status epilepticus: a systematic review and meta-analysis. BMC Neurol. 2014; 14: 152.

20. Karlov V.А., Madzhidov N.М., Bova V.Е. Jacksonian seizure. Tashkent: Meditsina Uz SSR; 1988: 144 p. (in Russ.).

21. Mukhacheva M.V., Bein B.N., Shishkina E.S. Clinical features of epileptic syndrome in patients with brain tumors. Medical Almanac. 2016; 5 (45): 154–8 (in Russ.).

22. Pallud J., Audureau E., Blonski M., et al. Epileptic seizures in diffuse low-grade gliomas in adults. Brain. 2014; 137 (Pt. 2): 449–62.

23. Lote K., Stenwig A.E., Skullerud K., Hirschberg H. Prevalence and prognostic significance of epilepsy in patients with gliomas. Eur J Cancer. 1998; 34 (1): 98–102.

24. Glantz M.J., Cole B.F., Forsyth P.A., et al. Practice parameter: anticonvulsant prophylaxis in patients with newly diagnosed brain tumors. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2000; 54 (10): 1886–93.

25. Sirven J.I., Wingerchuk D.M., Drazkowski J.F., et al. Seizure prophylaxis in patients with brain tumors: a meta-analysis. Mayo Clin Proc. 2004; 79 (12): 1489–94.

26. Perucca E. Optimizing antiepileptic drug treatment in tumoral epilepsy. Epilepsia. 2013; 54 (Suppl. 9): 97–104.

27. Moots P.L., Maciunas R.J., Eisert D.R., et al. The course of seizure disorders in patients with malignant gliomas. Arch Neurol. 1995; 52 (7): 717–24.

28. Micali G., Linthicum K., Han N., West D.P. Increased risk of erythema multiforme major with combination anticonvulsant and radiation therapies. Pharmacotherapy. 1999; 19 (2): 223–7.

29. van Breemen M.S., Wilms E.B., Vecht C.J. Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management. Lancet Neurol. 2007; 6 (5): 421–30.

30. Buckingham 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.

31. Marcus H.J., Carpenter K.L., 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.

32. Pallud J., Capelle L., Huberfeld G. Tumoral epileptogenicity: how does it happen? Epilepsia. 2013; 54 (Suppl. 9): 30–4.

33. Yuen 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.

34. Neal A., Yuen T., Bjorksten A.R., et al. Peritumoural glutamate correlates with post-operative seizures in supratentorial gliomas. J Neurooncol. 2016; 129 (2): 259–67.

35. Sørensen M.F., Heimisdóttir S.B., Sørensen M.D., et al. High expression of cystine-glutamate antiporter xCT (SLC7A11) is an independent biomarker for epileptic seizures at diagnosis in glioma. J Neurooncol. 2018; 138 (1): 49–53.

36. Pallud 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.

37. Vecht C.J., Kerkhof M., Duran-Pena A. Seizure prognosis in brain tumors: new insights and evidence-based management. Oncologist. 2014; 19 (7): 751–9.

38. Izumoto S., Miyauchi M., Tasaki T., et al. Seizures and tumor progression in glioma patients with uncontrollable epilepsy treated with perampanel. Anticancer Res. 2018; 38 (7): 4361–6.

39. Maschio M., Aguglia U., Avanzini G., et al. Management of epilepsy in brain tumors. Neurol Sci. 2019; 40 (10): 2217–34.

40. Lockney D.T., Vaziri S., Walch F., et al. Prophylactic antiepileptic drug use in patients with brain tumors undergoing craniotomy. World Neurosurg. 2017; 98: 28–33.

41. Lobos-Urbina D., Kittsteiner-Manubens L., Peña J. Is primary prevention with antiepileptic drugs effective in brain tumors or brain metastases? Medwave. 2017; 17 (Suppl. 1): e6871.

42. Spena G., Schucht P., Seidel K., et al. Brain tumors in eloquent areas: a European multicenter survey of intraoperative mapping techniques, intraoperative seizures occurrence, and antiepileptic drug prophylaxis. Neurosurg Rev. 2017; 40 (2): 287–98.

43. Das R.R., Artsy E., Hurwitz S., et al. Outcomes after discontinuation of antiepileptic drugs after surgery in patients with low grade brain tumors and meningiomas. J Neurooncol. 2012; 107 (3): 565–70.

44. Villanueva V., Saiz-Diaz R., Toledo M., et al. NEOPLASM study: real-life use of lacosamide in patients with brain tumor-related epilepsy. Epilepsy Behav. 2016; 65: 25–32.

45. Vecht C., Royer-Perron L., Houillier C., Huberfeld G. Seizures and anticonvulsants in brain tumours: frequency, mechanisms and anti-epileptic management. Curr Pharm Des. 2017; 23 (42): 6464–87.

46. Maschio M., Sperati F., Dinapoli L., et al. Weight of epilepsy in brain tumor patients. J Neurooncol. 2014; 118 (2): 385–93.

47. Kerkhof M., Vecht C.J. Seizure characteristics and prognostic factors of gliomas. Epilepsia. 2013; 54 (Suppl. 9): 12–7.

48. Vecht C., Duran-Peña A., Houillier C., et al. Seizure response to perampanel in drug-resistant epilepsy with gliomas: early observations. J Neurooncol. 2017; 133 (3): 603–7.

49. Stupp R., Brada M., van den Bent M.J., et al. High-grade glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014; 25 (Suppl. 3): iii93–101.

50. Blaheta R.A., Cinatl J. Jr. Anti-tumor mechanisms of valproate: a novel role for an old drug. Med Res Rev. 2002; 22 (5): 492–511.

51. Huberfeld G., Vecht C.J. Seizures and gliomas – towards a single therapeutic approach. Nat Rev Neurol. 2016; 12 (4): 204–16.

52. Bénit C.P., Vecht C.J. Spectrum of side effects of anticonvilsants in patients with brain tumors. Eur Assoc Neurooncol Mag. 2012; 2 (1): 15–24.

53. Gilliam F. Optimizing health outcomes in active epilepsy. Neurology. 2002 23; 58 (8 Suppl. 5): S9–20.

54. Gilliam F.G., Fessler A.J., Baker G., et al. Systematic screening allows reduction of adverse antiepileptic drug effects: a randomized trial. Neurology. 2004; 62 (1): 23–7.

55. Australian New Zealand Clinical Trials Registry. Perampanel for the control of glioma associated seizures – efficacy and safety: a pilot phase II randomised controlled trial. URL: (дата обращения 07.06.2021).

56. Australian New Zealand Clinical Trials Registry. Perampanel for the prevention of glioma associated seizures – efficacy and safety: a pilot phase II randomised controlled trial. URL: (дата обращения 07.06.2021).

57. Instruction for the medical use of Faycompa® (perampanel) as amended on 07.12.2020 (RU-LP-002200 of 23.08.2013). Available at: (in Russ.) (accessed 07.06.2021)

58. Coppola A., Zarabla A., Maialetti A., et al. Perampanel confirms to be effective and well tolerated as an add on treatment in patients with brain tumor related epilepsy (PERADET Study). Front Neurol. 2020; 11: 592.

59. Barker C.A., Bishop A.J., Chang M., et al. Valproic acid use during radiation therapy for glioblastoma associated with improved survival. Int J Radiat Oncol Biol Phys. 2013; 86 (3): 504–9.

60. Kim Y.H., Kim T., Joo J.D., et al. Survival benefit of levetiracetam in patients treated with concomitant chemoradiotherapy and adjuvant chemotherapy with temozolomide for glioblastoma multiforme. Cancer. 2015; 121 (17): 2926–32.

61. Happold C., Gorlia T., Chinot O., et al. Does valproic acid or levetiracetam improve survival in glioblastoma? A pooled analysis of prospective clinical trials in newly diagnosed glioblastoma. J Clin Oncol. 2016; 34 (7): 731–9.

62. Bénit C.P., Vecht C.J. Seizures and cancer: drug interactions of anticonvulsants with chemotherapeutic agents, tyrosine kinase inhibitors and glucocorticoids. Neurooncol Pract. 2016; 3 (4): 245–60.

63. Fowler T., Bansal A.S., Lozsádi D. Risks and management of antiepileptic drug induced skin reactions in the adult out-patient setting. Seizure. 2019; 72: 61–70.

64. Loring D.W., Marino S., Meador K.J. Neuropsychological and behavioral effects of antiepilepsy drugs. Neuropsychol Rev. 2007; 17 (4): 413–25.

65. Hamed S.A. The aspects and mechanisms of cognitive alterations in epilepsy: the role of antiepileptic medications. CNS Neurosci Ther. 2009; 15 (2): 134–56.

66. Klein M., Taphoorn M.J., Heimans J.J., et al. Neurobehavioral status and health related quality of life in newly diagnosed high grade glioma patients. J Clin Oncol. 2001; 19 (20): 4037–47.

67. Bosma I., Vos M.J., Heimans J.J., et al. The course of neurocognitive functioning in high grade glioma patients. Neuro Oncol. 2007; 9 (1): 53–62.

68. de Groot M., Douw L., Sizoo E.M., et al. Levetiracetam improves verbal memory in high-grade glioma patients. Neuro Oncol. 2013; 15 (2): 216–23.

69. Zaccara G., Gangemi P.F., Cincotta M. Central nervous system adverse effects of new antiepileptic drugs: a meta-analysis of placebocontrolled studies. Seizure. 2008; 17 (5): 405–21.

70. Meador K.J., Yang H., Piña Garza J.E., et al. Cognitive effects of adjunctive perampanel for partial onset seizures: a randomized trial. Epilepsia. 2016; 57 (2): 243–51.

71. Karlov V.A., Khabibova A.O. Modern methods of diagnosis and treatment of epilepsy. Smolensk; 1997: 76–7 (in Russ.).

72. The World Health Organization Quality of Life assessment (WHOQOL): position paper from the World Health Organization. Soc Sci Med. 1995; 41 (10): 1403–9.

73. Naughton M.J., Wiklund I. A critical review of dimension-specific measures of health-related quality of life in cross-cultural research. Qual Life Res. 1993; 2 (6): 397–432.

74. Osoba D. Current applications of health-related quality-of-life assessment in oncology. Support Care Cancer. 1997; 5 (2): 100–4.

75. Gorbunova V.A., Breder V.V. Quality of life of cancer patients. In: Collection of materials of the IV Russian Oncological Conference. Мoscow: 2016 (in Russ.).

76. Randazzo D., Peters K.B. Psychosocial distress and its effects on the health-related quality of life of primary brain tumor patients. CNS Oncol. 2016; 5 (4): 241–9.

77. Klein M., Engelberts N.H., van der Ploeg H.M., et al. Epilepsy in low grade gliomas: the impact on cognitive function and quality of life. Ann Neurol. 2003; 54 (4): 514–20.

78. Shan X., Fan X., Liu X., et al. Clinical characteristics associated with postoperative seizure control in adult low-grade gliomas: a systematic review and meta-analysis. Neuro Oncol. 2018; 20 (3): 324–31.

79. Rahman Z., Wong C.H., Dexter M., et al. Epilepsy in patients with primary brain tumors: the impact on mood, cognition, and HRQOL. Epilepsy Behav. 2015; 48: 88–95.

80. Venkatesh H.S., Johung T.B., Caretti V., et al. Neuronal activity promotes glioma growth through neuroligin-3 secretion. Cell. 2015; 161 (4): 803–16.

81. Piao Y., Lu L., de Groot J. AMPA receptors promote perivascular glioma invasion via β1 integrin dependent adhesion to the extracellular matrix. Neuro Oncol. 2009; 11 (3): 260–73.

82. Brocke K.S., Staufner C., Luksch H., et al. Glutamate receptors in pediatric tumors of the central nervous system. Cancer Biol Ther. 2010; 9 (6): 455–68.

83. Oh M.C., Kim J.M., Safaee M., et al. Overexpression of calcium permeable glutamate receptors in glioblastoma derived brain tumor initiating cells. PLoS One. 2012; 7 (10): e47846.

84. Di Bonaventura C., Labate A., Maschio M., et al. AMPA receptors and perampanel behind selected epilepsies: current evidence and future perspectives. Expert Opin Pharmacother. 2017; 18 (16): 1751–64.

For citation:

Lebedeva A.V., Burd S.G., Vlasov P.N., Ermolenko N.A., Zhidkova I.A., Zyryanov S.K., Kovaleva I.Yu., Naskhletashvili D.R., Perunova N.Yu., Rudakova I.G., Shikhkerimov R.K., Yamin M.A. Treatment of epilepsy associated with primary and metastatic brain tumors. Epilepsy and paroxysmal conditions. 2021;13(3):286-304. (In Russ.)

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ISSN 2311-4088 (Online)