J Clin Neurol.  2009 Dec;5(4):178-185. 10.3988/jcn.2009.5.4.178.

Increased EEG Current-Source Density in the High Beta Frequency Band Induced by Levetiracetam Adjunctive Therapy in Refractory Partial Epilepsy

• Park SP
• Kwon OY

• KMID: 2287647
• DOI: http://doi.org/10.3988/jcn.2009.5.4.178

Abstract

BACKGROUND AND PURPOSE
Levetiracetam (LEV) is an antiepileptic drug (AED) that has favorable effects on cognition. Although neuropsychological studies have demonstrated these favorable outcomes on cognition, there are few electrophysiologic data describing the functional changes exerted by LEV. The purpose of this study was to determine the effects of LEV adjunctive therapy on the current-source density (CSD) in the high beta frequency band (22-30 Hz) of EEG background activity in refractory partial epilepsy (RPE). METHODS: We conducted a 24-week, open-label, prospective study in 24 patients with RPE. Scalp electroencephalography and neuropsychological tests (NPTs) were conducted twice, once before the LEV trial and then again after 24 weeks of medication. RESULTS: The CSD in the 22-30 Hz band of EEG background activity increased in the bilateral anterior cingulate gyri, left parahippocampal gyrus, and a small area of the right anterior parahippocampal gyrus after the LEV trial. Neither seizure freedom nor the dosage increment of LEV elicited meaningful CSD changes. Verbal memory and executive function were improved after the 24-week LEV trial. CONCLUSIONS: To our knowledge, this is the first study to examine the changes in CSD induced by LEV adjunctive therapy in RPE patients. The CSD changes and NPT results suggest that LEV enhances the activities of the neuronal networks in the prefrontal cortex and left hippocampus.

Keyword

electroencephalography; current-source analysis; levetiracetam; adjunctive therapy; refractory partial epilepsy; neuropsychological tests

MeSH Terms

Cognition
Electroencephalography
Epilepsies, Partial
Executive Function
Freedom
Hippocampus
Humans
Memory
Neurons
Neuropsychological Tests
Parahippocampal Gyrus
Piracetam
Prefrontal Cortex
Prospective Studies
Scalp
Seizures
Piracetam

Figure

• 

  Fig. 1 Statistical nonparametric maps (SnPMs) of the 22-30 Hz frequency band with an add-on trial of levetiracetam (LEV) in patients with refractory partial epilepsy (RPE)(n=24). The current-source density (CSD) after 24 weeks of the LEV trial compared with that at baseline was increased in the bilateral anterior cingulate gyri, left parahippocampal gyrus, and a small area of the right anterior parahippocampal gyrus (p<0.05).

• 

  Fig. 2 SnPMs of the 22-30 Hz frequency band with an add-on trial of LEV in patients with RPE (n=24). A: The CSD in a small area of the bilateral superior parietal gyri was higher for seizure freedom (n=8) than for no freedom from seizures (n=16, p<0.05). B: The CSD in a small area of the bilateral precunei was higher for an LEV dosage of at least 2,000 mg/day (n=15) than for one of less than 2,000 mg/day (n=9, p<0.05). SnPMs: statistical nonparametric maps, LEV: levetiracetam, RPE: refractory partial epilepsy, CSD: current-source density.

Reference

1. Park SP, Kwon SH. Cognitive effects of antiepileptic drugs. J Clin Neurol. 2008. 4:99–106.

2. Loring DW, Marino S, Meador KJ. Neuropsychological and behavioral effects of antiepilepsy drugs. Neuropsychol Rev. 2007. 17:413–425.

3. Lee HW, Jung DK, Suh CK, Kwon SH, Park SP. Cognitive effects of low-dose topiramate monotherapy in epilepsy patients: A 1-year follow-up. Epilepsy Behav. 2006. 8:736–741.

4. 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. 12:102–108.

5. Cereghino JJ, Biton V, Abou-Khalil B, Dreifuss F, Gauer LJ, Leppik I. Levetiracetam for partial seizures: results of a double-blind, randomized clinical trial. Neurology. 2000. 55:236–242.

6. Berkovic SF, Knowlton RC, Leroy RF, Schiemann J, Falter U. Levetiracetam N01057 Study Group. Placebo-controlled study of levetiracetam in idiopathic generalized epilepsy. Neurology. 2007. 69:1751–1760.

7. Meador KJ, Gevins A, Loring DW, McEvoy LK, Ray PG, Smith ME, et al. Neuropsychological and neurophysiologic effects of carbamazepine and levetiracetam. Neurology. 2007. 69:2076–2084.

8. 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. 68:181–188.

9. Zhou B, Zhang Q, Tian L, Xiao J, Stefan H, Zhou D. Effects of levetiracetam as an add-on therapy on cognitive function and quality of life in patients with refractory partial seizures. Epilepsy Behav. 2008. 12:305–310.

10. Neyens LG, Alpherts WC, Aldenkamp AP. Cognitive effects of a new pyrrolidine derivative (levetiracetam) in patients with epilepsy. Prog Neuropsychopharmacol Biol Psychiatry. 1995. 19:411–419.

11. Ciesielski AS, Samson S, Steinhoff BJ. Neuropsychological and psychiatric impact of add-on titration of pregabalin versus levetiracetam: a comparative short-term study. Epilepsy Behav. 2006. 9:424–431.

12. Aldenkamp AP, Overweg J, Gutter T, Beun AM, Diepman L, Mulder OG. Effect of epilepsy, seizures and epileptiform EEG discharges on cognitive function. Acta Neurol Scand. 1996. 93:253–259.

13. Coq JO, Xerri C. Acute reorganization of the forepaw representation in the rat SI cortex after focal cortical injury: neuroprotective effects of piracetam treatment. Eur J Neurosci. 1999. 11:2597–2608.

14. Kristeva-Feige R, Feige B, Makeig S, Ross B, Elbert T. Oscillatory brain activity during a motor task. Neuroreport. 1993. 4:1291–1294.

15. Pulvermüller F, Eulitz C, Pantev C, Mohr B, Feige B, Lutzenberger W, et al. High-frequency cortical responses reflect lexical processing: an MEG study. Electroencephalogr Clin Neurophysiol. 1996. 98:76–85.

16. Bhattacharya J, Petsche H, Pereda E. Long-range synchrony in the gamma band: role in music perception. J Neurosci. 2001. 21:6329–6337.

17. Tallon C, Bertrand O, Bouchet P, Pernier J. Gamma-range activity evoked by coherent visual stimuli in humans. Eur J Neurosci. 1995. 7:1285–1291.

18. Pulvermüller F. Hebb's concept of cell assemblies and the psychophysiology of word processing. Psychophysiology. 1996. 33:317–333.

19. Pantev C. Evoked and induced gamma-band activity of the human cortex. Brain Topogr. 1995. 7:321–330.

20. Fell J, Fernández G, Klaver P, Elger CE, Fries P. Is synchronized neuronal gamma activity relevant for selective attention? Brain Res Brain Res Rev. 2003. 42:265–272.

21. Koles ZJ. Trends in EEG source localization. Electroencephalogr Clin Neurophysiol. 1998. 106:127–137.

22. Pascual-Marqui RD, Michel CM, Lehmann D. Low resolution electromagnetic tomography: a new method for localizing electrical activity in the brain. Int J Psychophysiol. 1994. 18:49–65.

23. Talairach J, Tournoux P. Co-planar sterotaxic atlas of the human brain: 3-dimensional proportional system-an approach to cerebral imaging. 1988. New York: Thieme Medical Publisher.

24. Towle VL, Bolaños J, Suarez D, Tan K, Grzeszczuk R, Levin DN, et al. The spatial location of EEG electrodes: locating the best-fitting sphere relative to cortical anatomy. Electroencephalogr Clin Neurophysiol. 1993. 86:1–6.

25. Pascual-Marqui RD. Review of methods for solving the EEG inverse problem. Interantional Journal of Bioelectromagnetism. 1999. 1:75–86.

26. Williams JM. Memory Assessment Scales profesional manual. 1991. Odessa, FL: Psychological Assessment Resources.

27. Wechsler D. Wechsler Memory Scale-Revised manual. 1987. San Antonio, TX: Psychological Corp..

28. Reitan RM, Wolfson D. The Halstead-Retan Neuropsychological Test Battery: theory and clinical interpretation. 1993. 2nd ed. Tucson, AZ: Neuropsychology Press.

29. Goodglass H, Kaplan E, Barresi B. Boston Diagnostic Aphasia Examination. 2000. 3rd ed. (BDAE-3). San Antonio, TX: Psychhological Corp..

30. Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J. An inventory for measuring depression. Arch Gen Psychiatry. 1961. 4:561–571.

31. Beck AT, Steer RA. Manual for the Beck Anxiety Inventory. 1990. San Antonio, TX: Psychological Corp..

32. Wagner GL, Wilms EB, Van Donselaar CA, Vecht ChJ. Levetiracetam: preliminary experience in patients with primary brain tumours. Seizure. 2003. 12:585–586.

33. Mecarelli O, Vicenzini E, Pulitano P, Vanacore N, Romolo FS, Di Piero V, et al. Clinical, cognitive, and neurophysiologic correlates of short-term treatment with carbamazepine, oxcarbazepine, and levetiracetam in healthy volunteers. Ann Pharmacother. 2004. 38:1816–1822.

34. Helmstaedter C, Witt JA. The effects of levetiracetam on cognition: a non-interventional surveillance study. Epilepsy Behav. 2008. 13:642–649.

35. Flicker L, Grimley Evans J. Piracetam for dementia or cognitive impairment. Cochrane Database Syst Rev. 2000. CD001011.

36. Schindler U. Pre-clinical evaluation of cognition enhancing drugs. Prog Neuropsychopharmacol Biol Psychiatry. 1989. 13:Suppl. S99–S115.

37. Genton P, Van Vleymen B. Piracetam and levetiracetam: close structural similarities but different pharmacological and clinical profiles. Epileptic Disord. 2000. 2:99–105.

38. Salinsky MC, Binder LM, Oken BS, Storzbach D, Aron CR, Dodrill CB. Effects of gabapentin and carbamazepine on the EEG and cognition in healthy volunteers. Epilepsia. 2002. 43:482–490.

39. Salinsky MC, Spencer DC, Oken BS, Storzbach D. Effects of oxcarbazepine and phenytoin on the EEG and cognition in healthy volunteers. Epilepsy Behav. 2004. 5:894–902.

40. Salinsky M, Storzbach D, Oken B, Spencer D. Topiramate effects on the EEG and alertness in healthy volunteers: a different profile of antiepileptic drug neurotoxicity. Epilepsy Behav. 2007. 10:463–469.

41. Veauthier J, Haettig H, Meencke HJ. Impact of levetiracetam add-on therapy on different EEG occipital frequencies in epileptic patients. Seizure. 2009. 18:392–395.

42. Devinsky O, D'Esposito M. Neurology of cognitive and behavioral disorders. 2004. 1st ed. New York: Oxford;275–329.

43. Krings T, Chiappa KH, Cuffin BN, Cochius JI, Connolly S, Cosgrove GR. Accuracy of EEG dipole source localization using implanted sources in the human brain. Clin Neurophysiol. 1999. 110:106–114.

44. Michel CM, Murray MM, Lantz G, Gonzalez S, Spinelli L, Grave de Peralta R. EEG source imaging. Clin Neurophysiol. 2004. 115:2195–2222.

45. Zumsteg D, Friedman A, Wennberg RA, Wieser HG. Source localization of mesial temporal interictal epileptiform discharges: correlation with intracranial foramen ovale electrode recordings. Clin Neurophysiol. 2005. 116:2810–2818.

46. Zumsteg D, Friedman A, Wieser HG, Wennberg RA. Propagation of interictal discharges in temporal lobe epilepsy: correlation of spatiotemporal mapping with intracranial foramen ovale electrode recordings. Clin Neurophysiol. 2006. 117:2615–2626.

47. Merlet I, Garcia-Larrea L, Grégoire MC, Lavenne F, Mauguiére F. Source propagation of interictal spikes in temporal lobe epilepsy. Correlations between spike dipole modelling and [18F]fluorodeoxy-glucose PET data. Brain. 1996. 119:377–392.

48. Cuffin BN, Schomer DL, Ives JR, Blume H. Experimental tests of EEG source localization accuracy in realistically shaped head models. Clin Neurophysiol. 2001. 112:2288–2292.