Cognitive Disorders in Juvenile Myoclonic Epilepsy

Olga S. Shilkina, PhD*; Ivan P. Artyukhov, PhD, ScD; Polina Moskaleva; Irina Strotskaya; Natalia A. Shnayder, PhD, ScD

V.F. Voino-Yasenetsky Krasnoyarsk State Medical University; Krasnoyarsk, the Russian Federation

*Corresponding author: Olga Shilkina, MD; V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, Krasnoyarsk, the Russian Federation. Email:

Published: March 17, 2017.  doi: 10.21103/Article7(1)_RA1


Cognitive disorders are often associated with epilepsy and are a result of a combination of various factors. This review describes scientific advances in the field of cognitive disorders in patients with juvenile myoclonic epilepsy (JME), the most common form of idiopathic generalized epilepsy. Data in this review were collected through an extensive literature search of available full-text publications in PubMed and eLIBRARY.RU databases. We selected four theories of the origin of cognitive impairment in JME patients for discussion, based on the analysis of available studies. Our findings highlight the etiological heterogeneity of cognitive disorders in JME and the importance early screening for them.

juvenile myoclonic epilepsy ● cognitive disorders ● epileptiform discharges ● antiepileptic drugs

1. O'Muircheartaigh J, Vollmar C, Barker GJ, Kumari V, Symms MR, Thompson P, et al. Abnormal thalamocortical structural and functional connectivity in juvenile myoclonic epilepsy. Brain. 2012;135 (Pt 12):3635-44. doi: 10.1093/brain/aws296.
2. Janz D. Juvenile myoclonic epilepsy. Epilepsy with impulsive petit mal. Cleve Clin J Med. 1989;56 Suppl Pt 1:S23-33; discussion S40-2.
3. Proposal for revised classification of epilepsies and epileptic syndromes. Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia. 1989;30(4):389-99.
4. Krauss GL. Cognitive Activation of "Hyperexcitable Cortex" in JME: Can It Trigger Seizures? Epilepsy Curr. 2011;11(6):184-5. doi: 10.5698/1535-7511-11.6.184
5. da Silva Sousa P, Lin K, Garzon E, Sakamoto A, Yacubian EM. Self-perception of factors that precipitate or inhibit seizures in juvenile myoclonic epilepsy. Seizure. 2005;14(5):340–6.
6.Giorgi FS, Guida M, Caciagli L, Pagni C, Pizzanelli C, Bonanni E, et al. Social cognition in Juvenile Myoclonic Epilepsy. Epilepsy Res. 2016;128:61-67. doi: 10.1016/j.eplepsyres.2016.10.017.
7. Lin JJ, Dabbs K, Riley JD, Jones JE, Jackson DC, Hsu DA, et al. Neurodevelopment in new-onset juvenile myoclonic epilepsy over the first 2 years. Ann Neurol. 2014;76(5):660-8. doi: 10.1002/ana.24240.
8. Kim JH, Lee JK, Koh SB, Lee SA, Lee JM, Kim SI, Kang JK.  Regional grey matter abnormalities in juvenile myoclonic epilepsy: a voxel-based morphometry study. Neuroimage. 2007;37(4):1132-7.
9. Kim EH, Ko TS. Cognitive impairment in childhood onset epilepsy: up-to-date information about its causes. Korean J Pediatr. 2016; 59(4):155–64. doi:  10.3345/kjp.2016.59.4.155
10. Loughman A, Bowden SC, D'Souza W. Cognitive functioning in idiopathic generalised epilepsies: a systematic review and meta-analysis. Neurosci Biobehav Rev. 2014;43:20-34. doi: 10.1016/j.neubiorev.2014.02.012.
11. Wandschneider B, Thompson PJ, Vollmar C, Koepp MJ. Frontal lobe function and structure in juvenile myoclonic epilepsy: a comprehensive review of neuropsychological and imaging data. Epilepsia. 2012;53(12):2091-8. doi: 10.1111/epi.12003.
12. Lee JM, Kim SY, Hwang YH, Lee HW, Suh CK, Park SP. Longitudinal Assessment of Cognitive Function in Patients with Juvenile Myoclonic Epilepsy. J Korean Epilepsy Soc. 2008;12(2):85-91. Korean.
13. Motamedi M, Nasergivehch S, Karamghadiri N, Noroozian M. Juvenile Myoclonic Epilepsy (JME): Neuropsychological Profile and Related Factors with Cognitive Dysfunction. Iran J Psychiatry. 2014;9(1):14-9.
14. Mosby's Medical Dictionary, 9th edition. © 2009, Elsevier.
15. Holmes GL, Lenck-Santini PP. Role of interictal epileptiform abnormalities in cognitive impairment. Epilepsy Behav. 2006 ;8(3):504-15.
16. Dodrill CB. Correlates of generalized tonic-clonic seizures with intellectual, neuropsychychological, emotional, and social function in patients with epilepsy. Epilepsia. 1986;27:399–411.
17. Bornstein RA, Pakalnis A, Drake ME Jr, Suga LJ. Effects of seizure type and waveform abnormality on memory and attention. Arch Neurol. 1988;45(8):884–7.
18. Binnie CD. Cognitive impairment during epileptiform discharges: is it ever justifiable to treat the EEG? Lancet Neurol. 2003;2(12):725-30.
19. Lavandier N, De Toffol B, Gillet P, Hommet C, Corcia P, Autret A. Syndrome dysexecutif, epilepsie myoclonique juvenile et anomalies paroxystiques intercritiques. Rev Neurol. 2002;158:164-5.
20. Carvalho KC, Uchida CG, Guaranha MS, Guilhoto LM, Wolf P, Yacubian EM. Cognitive performance in juvenile myoclonic epilepsy patients with specific endophenotypes. Seizure. 2016; 40:33-41. doi: 10.1016/j.seizure.2016.06.002.
21. Meador KJ. Cognitive effects of epilepsy and of antiepileptic medications. In:Wyllie E, editor. The treatment of epilepsy: principles and practices. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:1185–95.
22. Martin R, Kuzniecky R, Ho S, Hetherington H, Pan J, Sinclair K, et al. Cognitive effects of topiramate, gabapentin, and lamotrigine in healthy young adults. Neurology 1999;52(2):321–7.
23. Seidel WT, Mitchell WG. Cognitive and behavioral effects of carbamazepine in children: Data from benign rolandic epilepsy. J Child Neurol 1999;14(11):716–23.
24. Frost JD Jr, Hrachovy RA, Glaze DG, Rettig GM. Alpha rhythm slowing during initiation of carbamazepine therapy: Implications for future cognitive performance. J Clin Neurophysiol 1995;12(1):57–63.
25. Hanson JW, Smith DW. The fetal hydantoin syndrome. J Pediatr 1975;87(2):285–90.
26. Shapiro S, Hartz SC, Siskind V, Mitchell AA, Slone D, Rosenberg L, et al. Anticonvulsants and parental epilepsy in the development of birth defects. Lancet 1976;1(7954):272–5.
27. Moore SJ, Turnpenny P, Qinn A, Glover S, Lloyd DJ, Montgomery T, Dean JC. A clinical study of 57 children with fetal anticonvulsant syndromes. J Med Genet. 2000;37(7):489–97.
28. Shapiro S, Hartz SC, Siskind V, Mitchell AA, Slone D, Rosenberg L, et al. Anticonvulsants and parental epilepsy in the development of birth defects. Lancet. 1976;1(7954):272–5.
29. Reinisch JM, Sanders SA, Mortensen EL, Rubin DB. In utero exposure to phenobarbital and intelligence deficits in adult men. JAMA 1995;274(19):1518–25.
30. Harden CL, Lazar LM, Pick LH, Nikolov B, Goldstein MA, Carson D, et al. A beneficial effect on mood in partial epilepsy patients treated with gabapentin. Epilepsia. 1999;40(8):1129–34.
31. Pressler RM, Binnie CD, Coleshill SG, Chorley GA, Robinson RO. Effect of lamotrigine on cognition in children with epilepsy. Neurology. 2006;66(10):1495-9.
32. Park SP, Hwang YH, Lee HW, Suh CK, Kwon SH, Lee BI. Long-term cognitive and mood effects of zonisamide monotherapy in epilepsy patients. Epilepsy Behav .2008;12(1):102–8.
33. Piazzini A, Chifari R, Canevini MP, Turner K, Fontana SP, Canger R. Levetiracetam: an improvement of attention and of oral fluency in patients with partial epilepsy. Epilepsy Res. 2006;68(3):181–8.
34. Bootsma HP, Coolen F, Aldenkamp AP, Arends J, Diepman L, Hulsman J, et al. Topiramate in clinical practice: Long-term experience in patients with refractory epilepsy referred to a tertiary epilepsy center. Epilepsy Behav. 2004;5(3):380–7.
35.Thomas RH, Walsh J, Church C, Sills GJ, Marson AG, Baker GA, Rees MI. A comprehensive neuropsychological description of cognition in drug-refractory juvenile myoclonic epilepsy. Epilepsy Behav. 2014;36:124-9. doi: 10.1016/j.yebeh.2014.04.027.  
36. Gomer B, Wagner K, Frings L, Saar J, Carius A, Harle M, et al.The influence of antiepileptic drugs on cognition: a comparison of levetiracetam with topiramate. Epilepsy Behav. 2007; 10(3):486–94.
37. Roebling R, Scheerer N, Uttner I, Gruber O, Kraft E, Lerche H. Evaluation of cognition, structural, and functional MRI in juvenile myoclonic epilepsy. Epilepsia. 2009;50(11):2456-65. doi: 10.1111/j.1528-1167.2009.02127.x.
38. Hessen E, Lossius MI, Reinvang I, Gjerstad L. Influence of major antiepileptic drugs on attention, reaction time, and speed of information processing: results from a randomized, double-blind, placebo-controlled withdrawal study of seizure-free epilepsy patients receiving monotherapy. Epilepsia. 2006;47(12):2038–45.
39. Valente KD, Rzezak P, Moschetta SP, de Vincentiis S, Coan AC, Guerreiro CA. Delineating behavioral and cognitive phenotypes in juvenile myoclonic epilepsy: Are we missing the forest for the trees? Epilepsy Behav. 2016;54:95-9. doi:10.1016/j.yebeh.2015.10.022.
40. Hamed SA.  The aspects and mechanisms of cognitive alterations in epilepsy: the role of antiepileptic medications. CNS Neurosci Ther. 2009;15(2):134-56. doi: 10.1111/j.1755-5949.2008.00062.x.
41. Elger CE, Helmstaedter C, Kurthen M. Chronic epilepsy and cognition. Lancet Neurol. 2004;3(11):663–72.
42. Delgado-Escueta AV. Advances in genetics of juvenile myoclonic epilepsies. Epilepsy Curr. 2007;7(3):61–7.
43. Nicoletti A, Reggio A, Bartoloni A, Failla G, Sofia V, Bartalesi F, et al. Prevalence of epilepsy in rural Bolivia: a door-to-door survey. Neurology. 1999;53(9):2064–9.
44. Delgado-Escueta AV, Koeleman BP, Bailey JN, Medina MT, Durón RM. The quest for juvenile myoclonic epilepsy genes. Epilepsy Behav. 2013;28 Suppl 1:S52-7. doi: 10.1016/j.yebeh.2012.06.033.
45. Levav M, Mirsky AF, Herault J, Xiong L, Amir N, Andermann E. Familial association of neuropsychological traits in patients with generalized and partial seizure disorders. J Clin Exp Neuropsychol. 2002;24(3):311-26.
46. Iqbal N, Caswell HL, Hare DJ, Pilkington O, Mercer S, Duncan S. Neuropsychological profiles of patients with juvenile myoclonic epilepsy and their siblings: a preliminary controlledexperimental video-EEG case series. Epilepsy Behav. 2009;14(3):516-21. doi: 10.1016/j.yebeh.2008.12.025.
47. Wandschneider B, Kopp UA, Kliegel M, Stephani U, Kurlemann G, Janz D, Schmitz B. Prospective memory in patients with juvenile myoclonic epilepsy and their healthy siblings. Neurology. 2010;75(24):2161-7. doi: 10.1212/WNL.0b013e318202010a.
48. Escayg A, De Waard M, Lee DD, Bichet D, Wolf P, Mayer T, et al. Coding and noncoding variation of the human calcium-channel beta4-subunit gene CACNB4 in patients with idiopathic generalized epilepsy and episodic ataxia. Am J Hum Genet. 2000;66(5):1531–9.
49. Kapoor A, Satishchandra P, Ratnapriya R, Reddy R, Kadandale J, Shankar SK, Anand A. An idiopathic epilepsy syndrome linked to 3q13.3-q21 and missense mutations in the extracellular calcium sensing receptor gene. Ann Neurol. 2008;64(2):158–67. doi: 10.1002/ana.21428.
50. Cossette P, Liu L, Brisebois K, Dong H, Lortie A, Vanasse M, et al. Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy. Nat Genet. 2002;31(2):184–9.
51.  Dibbens LM, Feng HJ, Richards MC, Harkin LA, Hodgson BL, Scott D, et al. GABRD encoding a protein for extra- or peri-synaptic GABAA receptors is a susceptibility locus for generalized epilepsies. Hum Mol Genet. 2004;13(13):1315–9.
52.  Suzuki T, Delgado-Escueta AV, Aguan K, Alonso ME, Shi J, Hara Y, et al. Mutations in EFHC1 cause juvenile myoclonic epilepsy. Nat Genet. 2004;36(8):842–9.
53.  Pal DK, Evgrafov OV, Tabares P, Zhang F, Durner M, Greenberg DA. BRD2 (RING3) is a probable major susceptibility gene for common juvenile myoclonic epilepsy. Am J Hum Genet. 2003;73(2):261–70.
54. Mas C, Taske N, Deutsch S, Guipponi M, Thomas P, Covanis A, et al. Association of the connexin36 gene with juvenile myoclonic epilepsy. J Med Genet. 2004;41(7):e93.
55. Greenberg DA, Cayanis E, Strug L, Marathe S, Durner M, Pal DK, et al. Malic enzyme 2 may underlie susceptibility to adolescent-onset idiopathic generalized epilepsy. Am J Hum Genet. 2005;76(1):139–46.
56. Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV. The next decade of research in the basic mechanisms of the epilepsies. In: Noebeles JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, editors. Jasper's basic mechanisms of the epilepsies. Oxford University Press; 2012:3–11.
57.Cordell HJ. Epistasis: what it means, what it doesn’t mean, and statistical methods to detect it in humans. Hum Mol Genet. 2002;11(20):2463-8.
58.Harden C. Juvenile myoclonic epilepsy-what does the future look like? Epilepsy Curr. 2014;14(3):150-1. doi: 10.5698/1535-7597-14.3.150.
59. Chachua T, Goletiani C, Maglakelidze G, Sidyelyeva G, Daniel M, Morris E, et al. Sex-specific behavioral traits in the Brd2 mouse model of juvenile myoclonic epilepsy. Genes Brain Behav. 2014;13(7):702-12. doi: 10.1111/gbb.12160.
60. Mencke HJ, Janz D. Neuropathological findings in primary generalized epilepsy: a study of eight cases. Epilepsia. 1984;25(1):8-21.
61. Woermann FG, Free SL, Koepp MJ, Sisodiya SM, Duncan JS. Abnormal cerebral structure in juvenile myoclonic epilepsy demonstrated with voxel-based analysis of MRI. Brain. 1999;122 (Pt 11):2101-8.
62. Tae WS, Kim SH, Joo EY, Han SJ, Kim IY, Kim SI, et al. Cortical thickness abnormality in juvenile myoclonic epilepsy. J Neurol. 2008;255(4):561-6. doi: 10.1007/s00415-008-0745-6.
63. Kim SH, Lim SC, Kim W, Kwon OH, Jeon S, Lee JM, Shon YM. Extrafrontal structural changes in juvenile myoclonic epilepsy: a topographic analysis of combined structural and microstructural brain imaging. Seizure. 2015;30:124-31. doi: 10.1016/j.seizure.2015.06.009.
64. Shnayder NA, Shilkina OS, Petrov KV, Chernykh IA, Diuzhakova AV. Clinical and genetic heterogenity of juvenile myoclonic epilepsy. Epilepsy and Paroxyzmal Conditions. 2016;8(2):20-36. doi:10.17749/2077-8333.2016.8.2.020-036. [Article in Russian].

The fully formatted PDF version is available.
Download Article
International Journal of Biomedicine. 2017;7(1):9-14. © 2017 International Medical Research and Development Corporation. All rights reserved.