THE FORMATION OF COGNITIVE AND MENTAL DISORDERS IN EPILEPSY: THE ROLE OF VARIOUS FACTORS ASSOCIATED WITH DISEASE AND TREATMENT (A REVIEW OF LITERATURE AND CASE REPORTS)

Cognitive and mental disorders often occur in patients with epilepsy and significantly reduce the quality of life of patients and their families. Approximately in 35 % of patients, despite treatment, various violations of intelligence, behavior, affective sphere of different degree of seve rity are preserved. In general, mental (affective, anxious and psychotic) disorders occur in epilepsy 2–3 times more often than in the general population. The most common is depression: the occurrence of depression and anxiety in epilepsy varies from 20 to 55 % (and more than 50 % of patients with refractory focal epilepsy, especially epilepsy of the temporal lobe of the brain). Children are a particularly vulnerable category of patients: in addition to persistent intellectual disabilities (mental retardation), they may have specific impairments in the form of mental and speech development delay, learning difficulties, attention deficit hyperactivity disorder.

Causes of cognitive and mental disorders in epilepsy can directly be the factor underlying epilepsy (genetic disease, structural brain defect, etc.), epileptic seizures, interictal epileptiform activity, side effects of antiepileptic drugs (AED). In many cases, a patient with epilepsy combines several of these causes, and it is often difficult to determine which one cause is leading. The contribution of specific factors is difficult to estimate, because different factors can have an independent different effect on cognitive impairment. Some of causes underlying cognitive and mental disorders in epilepsy can be influenced and thus reduce the existing risk. Such measures include early diagnosis and effective adequate treatment of epileptic encephalopathy, as early as possible control of seizures, justified appointment of AED in children with cognitive impairment of unknown etiology and frequent epileptiform discharges on the electroencephalogram, careful monitoring of cognitive side effects of AED and assessment of benefit–risk ratio, early surgical treatment of patients with resistance to therapy. Of course, the use of AED with the most favorable profile of influence on cognitive functions plays an important role in the treatment of epilepsy. In the treatment of epilepsy in children, it’s especially important to give preference to AED, which doesn’t negatively influence on the cognitive sphere. 

1. Воронкова К.В., Петрухин А.С., Пылаева О.А., Холин А.А. Рациональная антиэпилептическая фармакотерапия. М.: Бином, 2007. 275 с. [Voronkova K.V., Petrukhin A.S., Pylaeva O.A., Kholin A.A. Rational antiepileptic pharmacotherapy. Moscow: Binom, 2007. 275 p. (In Russ.)].

2. Зенков Л.Р. Бессудорожные эпилептические энцефалопатии с психиатрическими, коммуникативными и поведенческими расстройствами. Вестник эпилептологии 2004;2:7–11. [Zenkov L.R. Anxiety epileptic encephalopathy with psychiatric, communicative and behavioral disorders. Vestnik epileptologii = Bulletin of Epileptology 2004;2:7–11. (In Russ.)].

3. Иванова И.В., Мухин К.Ю., Пылаева О.А. и др. Мутации в гене ARX: клинические, электроэнцефалографические и нейровизуализационные особенности у 3 пациентов. Русский журнал детской неврологии 2017;12(4):58–67. [I.V. Ivanova, K.Yu. Mukhin, O.A. Pylaeva et al. Mutations in the ARX gene: clinical, electroencephalographic and neuroimaging features in 3 patients. Russkiy zhurnal detskoy nevrologii = Russian Journal of Child Neurology 2017;12(4):58–67. (In Russ.)].

4. Карлов В.А. Эпилепсия у детей и взрослых женщин и мужчин. М.: Медицина, 2010. 720 с. [Karlov V.A. Epilepsy in children and adult women and men. Мoscow: Meditsina, 2010. 720 p. (In Russ.)].

5. Мухин К.Ю. Когнитивная эпилептиформная дезинтеграция: дефиниция, диагностика, терапия. Русский журнал детской неврологии 2012;7(1):3–20. [Mukhin K.Yu. Cognitive epileptiform disintegration: definition, diagnosis, treatment. Russkiy zhurnal detskoy nevrologii = Russian Journal of Child Neurology 2012;7(1):3–20. (In Russ.)].

6. Мухин К.Ю. Синдром Ландау–Клеффнера (приобретенная эпилептическая афазия) с фокусом на электроэнцефалографические критерии. Русский журнал детской неврологии 2016;11(3): 8–21. [Mukhin K.Yu. Landau–Kleffner syndrome (acquired epileptic aphasia) with focus on electroencephalographic criteria. Russkiy zhurnal detskoy nevrologii = Russian Journal of Child Neurology 2016;11(3):8–21. (In Russ.)].

7. Мухин К.Ю. Фокальные кортикальные дисплазии: клинико-электро-нейровизуализационные характеристики. Русский журнал детской неврологии 2016;11(2):8–24. [Mukhin K.Yu. Focal cortical dysplasia: clinical-electroneuroimaging characteristics. Russkiy zhurnal detskoy nevrologii = Russian Journal of Child Neurology 2016;11(2): 8–24. (In Russ.)].

8. Мухин К.Ю., Глухова Л.Ю. Эпилепсия с электрическим эпилептическим статусом в фазу медленного сна с фокусом на электроэнцефалографические критерии. Русский журнал детской неврологии 2017;12(2):21–35. [Mukhin K.Yu., Glukhova L.Yu. Epilepsy with electrical epileptic status in the phase of slow-wave sleep with focus on electroencephalographic criteria. Russkiy zhurnal detskoy nevrologii = Russian Journal of Child Neurology 2017;12(2):21–35. (In Russ.)].

9. Мухин К.Ю., Головтеев А.Л. Приобретенный эпилептический лобный синдром. Русский журнал детской неврологии 2008;3(1):21–9. [Mukhin K.Yu., Golovteev A.L. Acquired epileptic frontal syndrome. Russkiy zhurnal detskoy nevrologii = Russian Journal of Child Neurology 2008;3(1):21–9. (In Russ.)].

10. Мухин К.Ю., Миронов М.Б., Тысячина М.Д. и др. Электроклиническая характеристика больных симптоматической фокальной эпилепсией с феноменом вторичной билатеральной синхронизации на электроэнцефалограмме. Русский журнал детской неврологии 2006;1(1):6–17. [Mukhin K.Yu., Mironov M.B., Tysiachina M.D. Electroclinical characteristics of patients with symptomatic focal epilepsy with the phenomenon of secondary bilateral synchronization on the electroencephalogram. Russkiy zhurnal detskoy nevrologii = Russian Journal of Child Neurology 2006;1(1):6–17. (In Russ.)].

11. Мухин К.Ю., Пылаева О.А. Применение перампанела в лечении эпилепсии: обзор литературы и описание клинического случая. Русский журнал детской неврологии 2016;11(2):52–62. [Mukhin K.Yu., Pylaeva O.A. Use of perampanel in the treatment of epilepsy: a review of literature and a case report. Russkiy zhurnal detskoy nevrologii = Russian Journal of Child Neurology 2016;11(2):52–62. (In Russ.)].

12. Пылаева О.А., Мухин К.Ю., Петрухин А.С. Побочные эффекты антиэпилептической терапии. М.: Гранат, 2016. 236 с. [Pylaeva O.A., Mukhin K.Yu., Petrukhin A.S. Side effects of antiepileptic therapy. Moscow: Granat, 2016. 236 p. (In Russ.)].

13. Эпилептология детского возраста: руководство для врачей. Под ред. А.С. Петрухина. М.: Медицина, 2000. 624 c. [Epileptology of childhood: a guide for doctors. Ed. A.S. Petrukhin. Moscow: Meditsina, 2000. 624 p. (In Russ.)].

14. Aldenkamp A., Besag F., Gobbi G. et al. Psychiatric and behavioural disorders in children with epilepsy (ILAE Task Force Report): adverse cognitive and behavioral effects of antiepileptic drugs in children. Epileptic Disord 2016 May 16. DOI: 10.1684/epd.2016.0817.

15. Alsaadi T., El Hammasi K., Shahrour T.M. et al. Prevalence of depression and anxiety among patients with epilepsy attending the epilepsy clinic at Sheikh Khalifa Medical City, UAE: a cross-sectional study. Epilepsy Behav 2015;52(Pt A):194–9. DOI: 10.1016/j.yebeh.2015.09.008.

16. Andersohn F., Schade R., Willich S.N. et al. Use of antiepileptic drugs in epilepsy and the risk of self-harm or suicidal behavior. Neurology 2010;75(4):335–40. DOI: 10.1212/WNL.0b013e3181ea157e.

17. Arif H., Buchsbaum R., Weintraub D. et al. Patient-reported cognitive side effects of antiepileptic drugs: predictors and comparison of all commonly used antiepileptic drugs. Epilepsy Behav 2009;14(1):202–9. DOI: 10.1016/j. yebeh.2008.10.017.

18. Arzimanoglou A., Guerrini R., Aicardi J. Aicardi’s epilepsy in children. 3rd edn. Philadelphia: Lippincott, 2004. Pp. 176–87.

19. Aurich-Barrera B., Wilton L., Brown D. et al. Paediatric post-marketing pharmacovigilance: comparison of the adverse event profile of vigabatrin prescribed to children and adults. Pharmacoepidemiol Drug Saf 2011;20(6):608–18. DOI: 10.1002/ pds.2105.

20. Barabas G., Matthews W.S. Barbiturate anticonvulsants as a cause of severe depression. Pediatrics 1988;82(2):284–5. PMID: 3399308.

21. Ben-Menachem E., Scheepers B., Stodieck S. Epilepsy: from consensus to daily practice. Acta Neurologica Scandinavica 2003;108:5–15. PMID: 14510815.

22. Berg A.T. Epilepsy, cognition and behavior: the clinical picture epilepsia. Epilepsia 2011;52(suppl 1):7–12. DOI: 10.1111/j.1528-1167.2010.02905.x.

23. Besag F., Gobbi G., Aldenkamp A. et al. Behavioural and psychiatric disorders associated with epilepsy syndromes. In: Psychiatric and behavioural disorders in children with epilepsy. Eds.: F. Besag, A. Aldenkamp, R. Caplan et al. Montrouge: J.L. Eurotext, 2016. Pp. 46–62.

24. Boylan L.S., Flint L.A., Labovitz D.L. Depression but not seizure frequency predicts quality of in treatment-resistant epilepsy. Neurology 2004;62(2):258–61. PMID: 14745064.

25. Braun K.P. Preventing cognitive impairment in children with epilepsy. Curr Opin Neurol 2017;30(2):140–7. DOI: 10.1097/ WCO.0000000000000424.

26. Brent D.A., Crumrine P.K., Varma R. et al. Phenobarbital treatment and major depressive disorder in children with epilepsy. Pediatrics 1987;80(6):909–17. PMID: 3684404.

27. Calandre E.P., Dominguez-Granados R., Gomez-Rubio M. et al. Cognitive effects of long-term treatment with phenobarbital and valproic acid in school children. Acta Neur Scand 1990;81(6):504–6. PMID: 2220307.

28. Cook M., Shorvon S. The pharmacokinetics and clinical therapeutics of antiepileptic drugs. In: Oxford textbook of epilepsy and epileptic seizures. Oxford: Oxford university press, 2013. Pp. 279–289.

29. Craig I., Tallis R. Impact of valproate and phenytoin on cognitive function in elderly patients: results of a single-blind randomized comparative study. Epilepsia 1994;35(2):381–90. PMID: 8156961.

30. Cramer J.A., Hammer A.E., Kustra R.P. Improved mood states with lamotrigine in patients with epilepsy. Epilepsy Behav 2004;5(5):702–7. DOI: 10.1016/j. yebeh.2004.07.005.

31. Deonna Th., Roulet-Perez E. Mental retardation and epilepsy. In: Mental retardation. Eds.: D. Riva et al. Montrouge: J.L. Eurotext, 2007. Pp. 19–32.

32. Doose H. EEG in childhood epilepsy. Hamburg: John Libbey, 2003. Pp. 218–27.

33. Dulac O., Pinard J.-M., Plouin P. Infantile spasms associated with cortical dysplasia and tuberous sclerosis. In: Dysplasias of cerebral cortex and epilepsy. Eds.: R. Guerrini, F. Andermann, R. Canapicchi et al. Philadelphia: Lippincott Raven Publishers, 1996. Pp. 217–225.

34. Ettinger A.B., LoPresti A., Yang H. et al. Psychiatric and behavioral adverse events in randomized clinical studies of the noncompetitive AMPA receptor antagonist perampanel. Epilepsia 2015;56(8): 1252–63. DOI: 10.1111/epi.13054.

35. Fiest K.M., Dykeman J., Patten S.B. et al. Depression in epilepsy: a systematic review and meta-analysis. Neurology 2013;80(6):590–9. DOI: 10.1212/ WNL.0b013e31827b1ae0.

36. Fisher R.S., Acevedo C., Arzimanoglou A. et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia 2014;55(4):475–82. DOI: 10.1111/ epi.12550.

37. Galanopoulou A.S., Bojko A., Lado F., Moshe S.L. The spectrum of neuropsychiatric abnormalities associated with electrical status epilepticus in sleep. Brain Dev 2000;22(5):279–95. PMID: 10891635.

38. Gallassi R., Morreale A., Di Sarro R. et al. Cognitive effects of antiepileptic drug discontinuation. Epilepsia 1992;33(suppl 6): 41–4. PMID: 1486836.

39. Grevers E., Breuer L.E., Ijff D.M., Aldenkamp A. Mental slowing in relation to epilepsy and antiepileptic medication. Acta Neurol Scand 2016;134(2):116–22. DOI: 10.1111/ane.12517.

40. Harbord M.G. Significant anticonvulsant side-effects in children and adolescents. J Clin Neurosci 2000;7(3):213–6. DOI: 10.1054/jocn.1999.0190.

41. Hirashima Y., Morimoto M., Nishimura A. et al. Alternative psychosis and dysgraphia accompanied by forced normalization in a girl with occipital lobe epilepsy. Epilepsy Behav 2008;12(3):481–5. DOI: 10.1016/j.yebeh.2007.11.002.

42. Holmes G.L. Effect of seizures on the developing brain and cognition. Semin Pediatr Neurol 2016;23(2):120–6. DOI: 10.1016/j.spen.2016.05.001.

43. Holthausen H., Fogarasi A., Arzimanoglou A., Kahane Ph. Structural (symptomatic) focal epilepsies of childhood. In: Epileptic syndromes in infancy, childhood and adolescence. Eds.: M. Bureau, P. Genton, C. Dravet et al. 5th edn. Paris: John Libbey Eurotext, 2012. Pp. 455–505.

44. Ibrahim G.M., Cassel D., Morgan B.R. et al. Resilience of developing brain networks to interictal epileptiform discharges is associated with cognitive outcome. Brain 2014;137(Pt 10):2690– 702. DOI: 10.1093/brain/awu214.

45. Ijff D.M., Aldenkamp A. Cognitive side effects of antiepileptic drugs in children. Handb Clin Neurol 2013;111:707–18. DOI: 10.1016/B978-0-444-52891-9.00073-7.

46. Ijff D.M., van Veenendaal T.M., Debeij van Hall M.H. et al. The cognitive profile of ethosuximide in children. Paediatr Drugs 2016;18(5):379–85. DOI: 10.1007/ s40272-016-0187-z.

47. Jaimes-Bautista A.G., Rodriguez-Camacho M., Martinez-Juarez I.E., Rodriguez-Agudelo Y. Quantitative and qualitative analysis of semantic verbal fluency in patients with temporal lobe epilepsy. Neurologia 2017;S0213-4853(17) 30235–9. DOI: 10.1016/j.nrl.2017.07.001.

48. Josephson C.B., Jette N. Psychiatric comorbidities in epilepsy. Int Rev Psychiatry 2017;29(5):409–24. DOI: 10.1080/09540261.2017.1302412.

49. Kalinin V.V. Suicidality and antiepileptic drugs: is there a link? Drug Saf 2007;30(2):123–42. PMID: 17253878.

50. Kaufman K.R., Struck P.J. Activation of suicidal ideation with adjunctive rufinamide in bipolar disorder. Epilepsy Behav 2011;20(2):386–9. DOI: 10.1016/j.yebeh.2010.11.014.

51. Kleffner F.R., Landau W.M. The Landau– Kleffner syndrome. Epilepsia 2009;50(suppl 7):3. DOI: 10.1111/j.1528-1167.2009.02208.x.

52. Korman B., Krsek P., Duchowny M. et al. Early seizure onset and dysplastic lesion extent independently disrupt cognitive networks. Neurology 2013;81(8):745–51. DOI: 10.1212/WNL.0b013e3182a1aa2a.

53. Levinson D.F., Devinsky O. Psychiatric adverse events during vigabatrin therapy. Neurology 1999;53(7):1503–11. PMID: 10534259.

54. Machado R.A., Espinosa A.G., Melendrez D. et al. Suicidal risk and suicide attempts in people treated with antiepileptic drugs for epilepsy. Seizure 2011;20(4):280–4. DOI: 10.1016/j.seizure.2010.12.010.

55. Mastrangelo M. Lennox–Gastaut syndrome: a state of the art review. Neuropediatrics 2017;48(3):143–51. DOI: 10.1055/s-0037-1601324.

56. Meador K. Neurodevelopmental impact of antiepileptic drugs. In: Neuropsychology in the care of people with epilepsy. Eds.: Ch. Helmstaedter et al. UK: J.L. Eurotext, 2011. Pp. 179–87.

57. Miller L.A., Galioto R., Tremont G. et al. Cognitive impairment in older adults with epilepsy: characterization and risk factor analysis. Epilepsy Behav 2016;56:113–7. DOI: 10.1016/j.yebeh.2016.01.011.

58. Moavero R., Santarone M.E., Galasso C., Curatolo P. Cognitive and behavioral effects of new antiepileptic drugs in pediatric epilepsy. Brain Dev 2017;39(6):464–69. DOI: 10.1016/j. braindev.2017.01.006.

59. Mula M., Sander J.W. Negative effects of antiepileptic drugs on mood in patients with epilepsy. Drug Saf 2007;30(7): 555–67. PMID: 17604407.

60. Nass R., Gross A., Devinsky O. Autism and autistic epileptiform regression with occipital spikes. Dev Med Child Neurol 1998;40(7):453–8. PMID: 9698058.

61. Olesen J.B., Hansen P.R., Erdal J. et al. Antiepileptic drugs and risk of suicide: a nationwide study. Pharmacoepidemiol Drug Saf 2010;19(5):518–24. DOI: 10.1002/pds.1932.

62. Overwater I.E., Verhaar B.J.H., Lingsma H.F. et al. Interdependence of clinical factors predicting cognition in children with tuberous sclerosis complex. J Neurol 2017;264(1): 161–7. DOI: 10.1007/s00415-016-8335-5.

63. Panayiotopoulos C.P. A clinical guide to epileptic syndromes and their treatment. 2nd edn. London: Springer, 2010. Pp. 45–49, 325–335.

64. Perucca E. Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience. CNS Drugs 2002;16(10):695–724. PMID: 12269862.

65. Poindexter A.R., Kolstoe P.D. Effects of barbiturate withdrawal on behavior. Results from a barbiturate discontinuation program. Habilitative Mental Healthcare Newsletter 1998;11:63–70.

66. Prevey M.L., Delaney R.C., Cramer J.A. et al. Effect of valproate on cognitive function. Comparison with carbamazepine. The Department of Veterans Affairs Epilepsy Cooperative Study 264 Group. Arch Neurol 1996;53(10):1008–16. PMID: 8859063.

67. Reilly C., Atkinson P., Krishna B.D. et al. Neurobehavioral comorbidities in children with active epilepsy: a population-based study. Pediatrics 2014;133(6):1586–93. DOI: 10.1542/peds.2013-3787.

68. Rohracher A., Brigo F., Hofler J. et al. Perampanel for the treatment of primary generalized tonic-clonic seizures in idiopathic generalized epilepsy. Expert Opin Pharmacother 2016;17(10):1403–11. DOI: 10.1080/14656566.2016.1195810.

69. Rugg-Gunn F. Adverse effects and safety profile of perampanel: a review of pooled data. Epilepsia 2014;55(suppl 1):13–5. DOI: 10.1111/epi.12504.

70. Sabers A., Moller A., Dam M. et al. Cognitive function and anticonvulsant therapy: effect of monotherapy in epilepsy. Acta Neurol Scand 1995;92(1):19–27. PMID: 7572056.

71. Sanchez-Fernandez I.S., Loddenkemper T. Continuous spike-and-wave during sleep including Landau–Kleffner syndrome. In: Wyllie’s treatment of epilepsy. Principles and practice. Ed. E. Wyllie. Philadelphia: Wolters Kluwer, 2015. Pp. 284–292.

72. Sankar R., Holmes G.L. Mechanisms of action for the commonly used antiepileptic drugs: relevance to antiepileptic drug-associated neurobehavioral adverse effects. J Child Neurol 2004;19(suppl 1):6– 14. DOI: 10.1177/088307380401900102.

73. Scheffer I.E., Berkovic S., Capovilla G. et al. ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology. Epilepsia 2017;58(4):512–21. DOI: 10.1111/ epi.13709.

74. Schoenberg M.R., Rum R.S., Osborn K.E., Werz M.A. A randomized, double-blind, placebo-controlled crossover study of the effects of levetiracetam on cognition, mood and balance in healthy older adults. Epilepsia 2017; 58(9):1566–74. DOI: 10.1111/epi.13849.

75. Schubert R. Attention deficit disorder and epilepsy. Pediatr Neurol 2005;32(1):1–10. DOI: 10.1016/j.pediatrneurol.2004.06.007.

76. Straussberg R., Kivity S., Weitz R. et al. Reversible cortical atrophy and cognitive decline induced by valproic acid. Eur J Paediatr Neurol 1998;2(4):213–8. PMID: 10726594.

77. Swaiman K.F., Ashwal S., Ferriero D.M. et al. Swaiman’s pediatric neurology. Principles and practice. 6th edn. Philadelphia: Elsevier, 2017. 2969 p.

78. Tassinari C.A., Cantaluppo G., Dalla Bernardina B. et al. Encephalopathy related to status epilepticus during slow sleep (ESES) including Landau–Kleffner syndrome. In: Epileptic syndromes in infancy, childhood and adolescence. Eds.: M. Bureau, P. Genton, C. Dravet et al. 5th edn. Paris: John Libbey Eurotext, 2012. Pp. 255–75.

79. Thompson P.J., Huppert F.A., Trimble M.R. Phenytoin and cognitive functions: effects on normal volunteers and implications for epilepsy. British Journ Clin Psychol 1981;20(Pt 3):155–62. PMID: 7284649.

80. Thompson P.J., Huppert F., Trimble M.R. Anticonvulsant drugs, cognitive function and memory. Acta Neurol Scand 1980;80:75–81. PMID: 6937084.

81. Thompson P.J., Trimble M.R. Sodium valproate en cognitive functioning in normal volunteers. Br J Clin Pharmacol 1981;12(6):819–24. PMID: 6803819.

82. Trimble M.R., Schmitz B. Seizures, affective disorders and anticonvulsant drugs. Guildford: Clarus Press Ltd., 2002. 199 p.

83. Van Bogaert P. Epileptic encephalopathy with continious spike–waves during slowwave sleep including Landau–Kleffner syndrome: what determines the outcome? In: Outcome of childhood epilepsies. Eds.: W.F. Arts, A. Arzimanoglou, O.F. Brouwer, C. Camfield, P. Camfield. Montrouge: J.L. Eurotext, 2013. Pp. 141–148.

84. Van Veenendaal T.M., Ijff D.M., Aldenkamp A. et al. Glutamate concentrations vary with antiepileptic drug use and mental slowing. Epilepsy Behav 2016; 64(Pt A):200–5. DOI: 10.1016/j.yebeh.2016.08.027.

85. Vining E.P. Use of barbiturates and benzodiazepines in treatment of epilepsy. Neurol Clin 1986;4(3):617–32. PMID: 3528811.

86. Vinten J., Bromley R.L., Taylor J. et al. The behavioral consequences of exposure to antiepileptic drugs in utero. Epilepsy Behav 2009;14(1):197–201. DOI: 10.1016/j.yebeh.2008.10.011.

87. Williams A.E., Giust J.M., Kronenberger W.G., Dunn D.W. Epilepsy and attention-deficit hyperactivity disorder: links, risks and challenges. Neuropsychiatr Dis Treat 2016;12:287–96. DOI: 10.2147/NDT.S81549.

88. Witt J.-A., Helmstaedter Ch. Assessing cognitive antiepileptic drug effects in the individual patient. In: Neuropsychology in the care of people with epilepsy. Eds.: Ch. Helmstaedter et al. UK: J.L. Eurotext, 2011. Pp. 163–177.

89. Witt J.A., Elger C.E., Helmstaedter C. Impaired verbal fluency under topiramate – evidence for synergistic negative effects of epilepsy, topiramate and polytherapy. Eur J Neurol 2013;20(1):130–7. DOI: 10.1111/j.1468-1331.2012.03814.x.