Эпилепсия у больных с глиомами: механизмы, лечение и влияние противосудорожной терапии

Эпилептические припадки являются общепризнанным симптомом первичных опухолей головного мозга, при их возникновении широко используются противосудорожные препараты. Данная статья посвящена опухоль-ассоциированной эпилепсии и применению противоэпилептических препаратов (ПЭП) у пациентов с глиомами. Рассмотрены общая частота и механизмы эпилептогенеза. Факторы, которые следует учитывать при использовании противоэпилептических препаратов, включая течение болезни и ее профилактику, наряду с ПЭП основной линии выбора (например, возможные побочные эффекты, фармакокинетика, явные побочные эффекты и влияние таких препаратов на общую выживаемость пациентов с опухоль-ассоциированной эпилепсией). Наконец, рассмотрены области будущих исследований патофизиологии и использования противосудорожных препаратов у пациентов с глиомами.

1. Pignatti F, van den Bent M, Curran D, et al. Prognostic factors for survival in adult patients with cerebral low-grade glioma. J Clin Oncol. 2002;20(8):2076–2084.

2. Stockhammer F, Misch M, Helms HJ, et al. IDH1/2 mutations in WHO grade II astrocytomas associated with localization and seizure as the initial symptom. Seizure. 2012;21(3):194–197.

3. Beaumont A, Whittle IR. The pathogenesis of tumour associated epilepsy. Acta Neurochir (Wien). 2000;142(1):1–15.

4. Iuchi T, Hasegawa Y, Kawasaki K, Sakaida T. Epilepsy in patients with gliomas: incidence and control of seizures. J Clin Neurosci. 2015;22(1):87–91.

5. Kerkhof M, Vecht CJ. Seizure characteristics and prognostic factors of gliomas. Epilepsia. 2013;54(Suppl 9):12–17.

6. Kerkhof M, Dielemans JC, van Breemen MS, et al. Effect of valproic acid on seizure control and on survival in patients with glioblastoma multiforme. Neuro Oncol. 2013;15(7):961–967.

7. van Breemen MS, Wilms EB, Vecht CJ. Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management. Lancet Neurol. 2007;6(5):421–430.

8. Chaichana KL, Parker SL, Olivi A, QuinonesHinojosa A. Long-term seizure outcomes in adult patients undergoing primary resection of malignant brain astrocytomas. Clinical article. J Neurosurg. 2009;111(2):282–292.

9. Vecht CJ, Kerkhof M, Duran-Pena A. Seizure prognosis in brain tumors: new insights and evidencebased management. Oncologist. 2014;19(7):751–759.

10. Chang EF, Potts MB, Keles GE, et al. Seizure characteristics and control following resection in 332 patients with low-grade gliomas. J Neurosurg. 2008;108(2):227–235.

11. Ruda R, Bello L, Duffau H, Soffietti R. Seizures in low-grade gliomas: natural history, pathogenesis, and outcome after treatments. Neuro Oncol. 2012;14(Suppl 4): iv55–iv64.

12. Koekkoek JA, Dirven L, Heimans JJ, et al. Seizure reduction in a low-grade glioma: more than a beneficial side effect of temozolomide. J Neurol Neurosurg Psychiatry. 2015;86(4):366–373.

13. Ruda R, Magliola U, Bertero L, et al. Seizure control following radiotherapy in patients with diffuse gliomas: a retrospective study. Neuro Oncol. 2013;15(12):1739– 1749.

14. Soffietti R, Baumert BG, Bello L, et al. Guidelines on management of low-grade gliomas: report of an EFNSEANO Task Force. Eur J Neurol. 2010;17(9):1124–1133.

15. Kohling R, Senner V, Paulus W, Speckmann EJ. Epileptiform activity preferentially arises outside tumor invasion zone in glioma xenotransplants. Neurobiol Dis. 2006;22(1):64–75.

16. de Groot M, Reijneveld JC, Aronica E, Heimans JJ. Epilepsy in patients with a brain tumour: focal epilepsy requires focused treatment. Brain. 2012;135(Pt 4):1002– 1016.

17. Giulioni M, Rubboli G, Marucci G, et al. Focal epilepsies associated with glioneuronal tumors: review article. Panminerva Med. 2013; 55(2):225–238.

18. Nowell M, Miserocchi A, McEvoy AW. Tumors in epilepsy. Semin Neurol. 2015;35(3):209–217.

19. Pallud J, Capelle L, Huberfeld G. Tumoral epileptogenicity: how does it happen? Epilepsia. 2013;54(Suppl 9):30–34.

20. Lieu AS, Howng SL. Intracranial meningiomas and epilepsy: incidence, prognosis and influencing factors. Epilepsy Res. 2000;38(1):45–52.

21. Marchi N, Angelov L, Masaryk T, et al. Seizurepromoting effect of blood-brain barrier disruption. Epilepsia. 2007;48(4):732–742.

22. Shamji MF, Fric-Shamji EC, Benoit BG. Brain tumors and epilepsy: pathophysiology of peritumoral changes. Neurosurg Rev. 2009; 32(3):275–284 discussion 84–6.

23. Aronica E, Gorter JA, Jansen GH, et al. Expression of connexin 43 and connexin 32 gap-junction proteins in epilepsy-associated brain tumors and in the perilesional epileptic cortex. Acta Neuropathol (Berl). 2001;101(5):449–459.

24. Goldring S, Gregorie EM. Experience with lesions that mimic gliomas in patients presenting with a chronic seizure disorder. Clin Neurosurg. 1986;33:43–70.

25. Moody W. Effects of intracellular H+ on the electrical properties of excitable cells. Ann Rev Neurosci. 1984;7:257–258.

26. Pasternack M, Bountra C, Voipio J, Kaila K. Influence of extracellular and intracellular pH on GABAgated chloride conductance in crayfish muscle fibres. Neuroscience. 1992;47(4):921–929.

27. Tang CM, Dichter M, Morad M. Modulation of the N-methyl-D-aspartate channel by extracellular H+. Proc Natl Acad Sci USA. 1990;87(16):6445–6449.

28. Marco P, Sola RG, Cajal R, DeFelipe J. Loss of inhibitory synapses on the soma and axon initial segment of pyramidal cells in human epileptic peritumoural neocortex: implications for epilepsy. Brain Res Bull. 1997;44:47–66.

29. Petroff OA, Rothman DL, Behar KL, Mattson RH. Initial observations on effect of vigabatrin on in vivo 1H spectroscopic measurements of gamma-aminobutyric acid, glutamate, and glutamine in human brain. Epilepsia. 1995;36(5):457–464.

30. Bianchi L, DeMicheli E, Bricolo A, et al. Extracellular levels of amino acids and choline in human high grade gliomas: an intraoperative microdialysis study. Neurochem Res. 2004;29(1):325–334.

31. Wolf HK, Roos D, Blumcke I, Pietsch T, Wiestler OD. Perilesional neurochemical changes in focal epilepsies. Acta Neuropathol (Berl). 1996;91:376 –384.

32. Haglund MM, Berger MS, Kunkel DD, et al. Changes in gamma-aminobutyric acid and somatostatin in epileptic cortex associated with low-grade gliomas. J Neurosurg. 1992;77(2):209–216.

33. Olson JM, McNeel W, Young AB, Mancini WR. Localization of the peripheral-type benzodiazepine binding site to mitochondria of human glioma cells. J Neurooncol. 1992;13(1):35–42.

34. Buckingham SC, Robel S. Glutamate and tumor-associated epilepsy: glial cell dysfunction in the peritumoral environment. Neurochem Int. 2013;63(7):696–701.

35. Terunuma M, Vargas KJ, Wilkins ME, et al. Prolonged activation of NMDA receptors promotes dephosphorylation and alters postendocytic sorting of GABAB receptors. Proc Natl Acad Sci USA. 2010;107(31):13918–13923.

36. Conti L, Palma E, Roseti C, et al. Anomalous levels of Cltransporters cause a decrease of GABAergic inhibition in human peritumoral epileptic cortex. Epilepsia. 2011;52(9):1635–1644.

37. Beaumont A, Clarke M, Whittle IR. The effects of malignant glioma on the EEG and seizure thresholds: an experimental study. Acta Neurochir (Wien). 1996;138(4):370–381.

38. Aronica E, Yankaya B, Jansen GH, et al. Ionotropic and metabotropic glutamate receptor protein expression in glioneuronal tumours from patients with intractable epilepsy. Neuropathol Appl Neurobiol. 2001;27:223–237.

39. Obrenovitch TD, Urenjak J, Zilkha E. Evidence disputing the link between seizure activity and high extracellular glutamate. J Neurochem. 1996;66:2446– 2456.

40. Yuen TI, Morokoff AP, Bjorksten A, et al. Glutamate is associated with a higher risk of seizures in patients with gliomas. Neurology. 2012;79(9):883–889.

41. Kim JY, Kanai Y, Chairoungdua A, et al. Human cystine/glutamate transporter: cDNA cloning and upregulation by oxidative stress in glioma cells. Biochim Biophys Acta. 2001;1512(2):335–344.

42. Schousboe A, Waagepetersen HS. Role of astrocytes in glutamate homeostasis: implications for excitotoxicity. Neurotox Res. 2005;8(3–4):221–225.

43. Lee JW, Norden AD, Ligon KL, et al. Tumor associated seizures in glioblastomas are influenced by survival gene expression in a region-specific manner: A gene expression imaging study. Epilepsy Res.

44. ;108(5):843–852. 44. You G, Yan W, Zhang W, et al. Significance of miR-196b in tumor-related epilepsy of patients with gliomas. PLoS One. 2012;7(9):e46218.

45. Kong B, Yang T, Chen L, et al. Protein-protein interaction network analysis and gene set enrichment analysis in epilepsy patients with brain cancer. J Clin Neurosci. 2014;21(2):316–319.

46. Isoardo G, Morra I, Chiarle G, et al. Different aquaporin-4 expression in glioblastoma multiforme patients with and without seizures. Mol Med. 2012;18:1147–1151.

47. Niesen CE, Xu J, Fan X, et al. Transcriptomic profiling of human peritumoral neocortex tissues revealed genes possibly involved in tumor-induced epilepsy. PLoS One. 2013;8(2):e56077.

48. Robert SM, Buckingham SC, Campbell SL, et al. SLC7A11 expression is associated with seizures and predicts poor survival in patients with malignant glioma. Sci Transl Med. 2015;7(289):289ra86.

49. Zhong Z, Wang Z, Wang Y, et al. IDH1/2 mutation is associated with seizure as an initial symptom in lowgrade glioma: A report of 311 Chinese adult glioma patients. Epilepsy Res. 2015;109:100–105.

50. Ohka F, Ito M, Ranjit M, et al. Quantitative metabolome analysis profiles activation of glutaminolysis in glioma with IDH1 mutation. Tumour Biol. 2014;35(6):5911–5920.

51. Junqueira D, Brusque AM, Porciuncula LO, et al. In vitro effects of D-2-hydroxyglutaric acid on glutamate binding, uptake and release in cerebral cortex of rats. J Neurol Sci. 2004;217(2):189–194.

52. Kolker S, Pawlak V, Ahlemeyer B, et al. NMDA receptor activation and respiratory chain complex V inhibition contribute to neurodegeneration in d-2hydroxyglutaric aciduria. Eur J Neurosci. 2002;16(1):21– 28.

53. Yamamoto HA, Mohanan PV. Effect of alphaketoglutarate and oxaloacetate on brain mitochondrial DNA damage and seizures induced by kainic acid in mice. Toxicol Lett. 2003;143(2):115–122.

54. Xu W, Yang H, Liu Y, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alphaketoglutarate-dependent dioxygenases. Cancer Cell. 2011;19(1):17–30.

55. Bullmore E, Sporns O. Complex brain networks: graph theoretical analysis of structural and functional systems. Nat Rev Neurosci. 2009;10(3):186–198.

56. Rubinov M, Sporns O. Complex network measures of brain connectivity: uses and interpretations. Neuroimage. 2010;52(3):1059–1069.

57. Franaszczuk PJ, Bergey GK. Application of the directed transfer function method to mesial and lateral onset temporal lobe seizures. Brain Topogr. 1998;11(1):13–21.

58. Kramer MA, Kolaczyk ED, Kirsch HE. Emergent network topology at seizure onset in humans. Epilepsy Res. 2008;79(2–3):173–186.

59. Percha B, Dzakpasu R, Zochowski M, Parent J. Transition from local to global phase synchrony in small world neural network and its possible implications for epilepsy. Phys Rev E Stat Nonlin Soft Matter Phys. 2005;72(3 Pt 1):031909.

60. Morgan RJ, Soltesz I. Nonrandom connectivity of the epileptic dentate gyrus predicts a major role for neuronal hubs in seizures. Proc Natl Acad Sci USA. 2008;105(16):6179–6184.

61. Bartolomei F, Bosma I, Klein M, et al. Disturbed functional connectivity in brain tumour patients: evaluation by graph analysis of synchronization matrices. Clin Neurophysiol. 2006;117(9):2039–2049.

62. Bartolomei F, Bosma I, Klein M, et al. How do brain tumors alter functional connectivity? A magnetoencephalo graphy study. Ann Neurol. 2006;59(1):128–138.

63. Douw L, de Groot M, van Dellen E, et al. Local MEG networks: the missing link between protein expression and epilepsy in glioma patients? Neuroimage. 2013;75:195–203.

64. Douw L, van Dellen E, de Groot M, et al. Epilepsy is related to theta band brain connectivity and network topology in brain tumor patients. BMC Neurosci. 2010;11:103.

65. Ruda R, Soffietti R. What is new in the management of epilepsy in gliomas? Curr Treat Options Neurol. 2015;17(6):351.

66. Weller M, Stupp R, Wick W. Epilepsy meets cancer: when, why, and what to do about it? Lancet Oncol. 2012;13(9):e375–e382.

67. Sherman JH, Moldovan K, Yeoh HK, et al. Impact of temozolomide chemotherapy on seizure frequency in patients with low-grade gliomas. J Neurosurg. 2011;114(6):1617–1621.

68. Rogers LR, Morris HH, Lupica K. Effect of cranial irradiation on seizure frequency in adults with lowgrade astrocytoma and medically intractable epilepsy. Neurology. 1993;43(8):1599–1601.

69. Wychowski T, Wang H, Buniak L, et al. Considerations in prophylaxis for tumor-associated epilepsy: prevention of status epilepticus and tolerability of newer generation AEDs. Clin Neurol Neurosurg. 2013;115(11):2365–2369.

70. Maschio M. Brain tumor-related epilepsy. Curr Neuropharmacol. 2012;10(2):124–133.

71. Foy PM, Copeland GP, Shaw MD. The incidence of postoperative seizures. Acta Neurochir (Wien). 1981;55(3–4):253–264.

72. Pallud J, Audureau E, Blonski M, et al. Epileptic seizures in diffuse low-grade gliomas in adults. Brain. 2014;137(Pt 2):449–462.

73. Siomin V, Angelov L, Li L, Vogelbaum MA. Results of a survey of neurosurgical practice patterns regarding the prophylactic use of anti-epilepsy drugs in patients with brain tumors. J Neurooncol. 2005;74(2):211–215.

74. North JB, Penhall RK, Hanieh A, et al. Phenytoin and postoperative epilepsy. A double-blind study. J Neurosurg. 1983;58(5):672–677.

75. Franceschetti S, Binelli S, Casazza M, et al. Influence of surgery and antiepileptic drugs on seizures symptomatic of cerebral tumours. Acta Neurochir (Wien). 1990;103(1–2):47–51.

76. Lee ST, Lui TN, Chang CN, et al. Prophylactic anticonvulsants for prevention of immediate and early postcraniotomy seizures. Surg Neurol. 1989;31(5):361– 364.

77. Kuijlen JM, Teernstra OP, Kessels AG, et al. Effectiveness of antiepileptic prophylaxis used with supratentorial craniotomies: a meta-analysis. Seizure. 1996; 5(4):291–298.

78. Komotar RJ, Raper DM, Starke RM, et al. Prophylactic antiepileptic drug therapy in patients undergoing supratentorial meningioma resection: a systematic analysis of efficacy. J Neurosurg. 2011;115(3):483–490.

79. Pulman J, Greenhalgh J, Marson AG. Antiepileptic drugs as prophylaxis for post-craniotomy seizures. Cochrane Database Syst Rev. 2013;2:CD007286.