Cognitive Effects of Treatment of Interictal Discharges

Condition(s) targeted: Epilepsy

Intervention: levetiracetam (Drug); Lamotrigine (Drug)

Phase: N/A

Status: Recruiting

Sponsored by: Massachusetts General Hospital

Official(s) and/or principal investigator(s):
Daniel B Hoch, M.D., Ph.D., Principal Investigator, Affiliation: Massachusetts General Hospital

Overall contact:
Christine M Arsnow, B.S., Phone: 781-864-6525, Email: carsnow@partners.org

The purpose of this study is to determine if levetiracetam (for patients with focal seizures) or lamotrigine (for patients with generalized seizures) reduces the occurrence of interictal discharges. The study investigates the possible correlation between reduction of interictal discharges and improved cognitive performance.

Official title: Cognitive Effects of Treatment of Interictal Discharges

Study design: Treatment, Non-Randomized, Open Label, Parallel Assignment, Efficacy Study

Primary outcome:

Reduction of focal interictal discharges. The proposed study tests the hypothesis that treatment with levetiracetam will reduce focal interictal epileptiform activity.

Reduction of generalized interictal discharges. The proposed study tests the hypothesis that treatment with lamotrigine will reduce generalized interictal epileptiform activity.

The study will evaluate the hypothesis that reduction of focal and generalized interictal epileptiform activity is associated with improved performance on neuropsychological batteries and computerized cognitive testing.

Detailed description: Subjects newly diagnosed with seizures will be studied with electroencephalography (EEG) and offered medication for prevention of recurrent seizures. Those with focal seizures will be treated with levetiracetam, and those with generalized seizures will be treated with lamotrigine. Subjects will undergo repeated EEG with concurrent cognitive testing before and after initiation of treatment. The proposed study tests 3 hypotheses: 1. that treatment with levetiracetam will reduce focal interictal epileptiform activity, 2. that treatment with lamotrigine will reduce generalized interictal epileptiform activity, and 3. that the extent of interictal epileptiform activity is inversely associated with performance on neuropsychological batteries and computerized cognitive testing. Repeated cognitive/neuropsychological testing obtained at steady state of the study drug and again after approximately 2 months on the final dosage will serve to evaluate the timecourse of potential cognitive benefits.

Minimum age: 18 Years. Maximum age: 55 Years. Gender(s): Both.

Criteria:

Inclusion Criteria

- 18-55 years of age

- Normal IQ (≥ 80) as estimated by the Wechsler Test of Adult Reading (WTAR)

- Able to give consent

- Newly diagnosed focal or generalized epilepsy, based on clinical history and EEG

- The subject's treating physician is planning to prescribe levetiracetam for focal or

lamotrigine for generalized seizure prevention

- Untreated with antiepileptic medications at the time of enrollment

- Either symptomatic or idiopathic seizures.

Exclusion Criteria:

- Non-native English speaking and/or multilingual

- Frequent seizures, since seizures themselves impair cognitive function and present a

confounding variable. Subjects may have no more than one seizure or one cluster of seizures per month, with a cluster of seizures including more than one seizure, but between which the patient returns to baseline. The cluster may occur over no more than two consecutive days in one month.

- The sentinel seizure(s) must not have occurred within 3 days of enrollment and

testing.

- Those with focal seizures who have evidence of renal disease (creatinine clearance

less than 80) will be excluded from participation, as levetiracetam is cleared by the kidney.

- Those with focal seizures who have neutrophil counts <1000/uL will be excluded from

participation, as levetiracetam may lower white blood cell counts.

- Those with focal seizures and irritability or mood swings will not be eligible for

participation, as levetiracetam may exacerbate these symptoms. This will be determined by self-report, information obtained from the referring physician and medical record.

- Those with generalized seizures who have moderate to severe liver dysfunction

(Child-Pugh Grades B and C) will be excluded from participation, as lamotrigine is cleared by the liver and the proposed dosing may not be tolerable in this population. This will be determined by self-report, information obtained from the referring physician, a comprehensive metabolic panel (routinely obtained in new-onset seizures) and the medical record.

- Subjects who are pregnant will not be eligible to take part in the study, as

levetiracetam and lamotrigine are classified as Pregnancy Category C drugs and may pose risk to the fetus. Women of childbearing potential will have a urine pregnancy test prior to participation in the study. The urine pregnancy test will be repeated at the final study visit. Subjects with epilepsy who are of childbearing potential must use acceptable methods of birth control during the study, to be continued until one month after discontinuation of the study drug. If a subject does become pregnant during this time period, she must notify the investigators.

- Women who are breastfeeding may not participate in this study. Levetiracetam and

lamotrigine may pass into the breastmilk of nursing mothers, posing a risk to the baby.

- Hypersensitivity to lamotrigine, levetiracetam or any components of these products

Christine M Arsnow, B.S., Phone: 781-864-6525, Email: carsnow@partners.org

Massachusetts General Hospital, Boston, Massachusetts 02114, United States; Recruiting
Daniel B Hoch, M.D., Ph.D., Principal Investigator

Related publications:

Aarts JH, Binnie CD, Smit AM, Wilkins AJ. Selective cognitive impairment during focal and generalized epileptiform EEG activity. Brain. 1984 Mar;107 ( Pt 1):293-308.

Browne TR, Penry JK, Proter RJ, Dreifuss FE. Responsiveness before, during, and after spike-wave paroxysms. Neurology. 1974 Jul;24(7):659-65. No abstract available.

Dodrill CB, Wilkus RJ. Relationships between intelligence and electroencephalographic epileptiform activity in adult epileptics. Neurology. 1976 Jun;26(6 PT 1):525-31.

Gallagher MJ, Eisenman LN, Brown KM, Erbayat-Altay E, Hecimovic H, Fessler AJ, Attarian HP, Gilliam FG. Levetiracetam reduces spike-wave density and duration during continuous EEG monitoring in patients with idiopathic generalized epilepsy. Epilepsia. 2004 Jan;45(1):90-1. No abstract available.

Goode DJ, Penry JK, Dreifuss FE. Effects of paroxysmal spike-wave on continuous visual-motor performance. Epilepsia. 1970 Sep;11(3):241-54. No abstract available.

Hermann BP, Seidenberg M, Schoenfeld J, Peterson J, Leveroni C, Wyler AR. Empirical techniques for determining the reliability, magnitude, and pattern of neuropsychological change after epilepsy surgery. Epilepsia. 1996 Oct;37(10):942-50.

HOVEY HB, KOOI KA. Transient disturbances of thought processes and epilepsy. AMA Arch Neurol Psychiatry. 1955 Sep;74(3):287-91. No abstract available.

Kasteleijn-Nolst Trenité DG, Riemersma JB, Binnie CD, Smit AM, Meinardi H. The influence of subclinical epileptiform EEG discharges on driving behaviour. Electroencephalogr Clin Neurophysiol. 1987 Aug;67(2):167-70.

KOOI KA, HOVEY HB. Alterations in mental function and paroxysmal cerebral activity. AMA Arch Neurol Psychiatry. 1957 Sep;78(3):264-71. No abstract available.

Lee, S., Sziklas, V., Andermann, F., Farnham, S., Risse, G., Gustafson, M., Gates, J., Penovich, P., Al-Asmi, A., Dubeau, F., and Jones-Gotman, M. The effects of topiramate on cognitive functioning in patients with epilepsy. Epilepsia 2003; 44:339-347.

Lutz MT, Helmstaedter C. EpiTrack: tracking cognitive side effects of medication on attention and executive functions in patients with epilepsy. Epilepsy Behav. 2005 Dec;7(4):708-14. Epub 2005 Nov 2.

Meador KJ, Loring DW, Vahle VJ, Ray PG, Werz MA, Fessler AJ, Ogrocki P, Schoenberg MR, Miller JM, Kustra RP. Cognitive and behavioral effects of lamotrigine and topiramate in healthy volunteers. Neurology. 2005 Jun 28;64(12):2108-14.

Selldén U. Psychotechnical performance related to paroxysmal discharges in EEG. Clinical Electroencephalography 1971; 2:18-27.

Shewmon DA, Erwin RJ. The effect of focal interictal spikes on perception and reaction time. I. General considerations. Electroencephalogr Clin Neurophysiol. 1988 Apr;69(4):319-37.

Shewmon DA, Erwin RJ. The effect of focal interictal spikes on perception and reaction time. II. Neuroanatomic specificity. Electroencephalogr Clin Neurophysiol. 1988 Apr;69(4):338-52.

Stodieck S, Steinhoff BJ, Kolmsee S, van Rijckevorsel K. Effect of levetiracetam in patients with epilepsy and interictal epileptiform discharges. Seizure. 2001 Dec;10(8):583-7.

Stroup E, Langfitt J, Berg M, McDermott M, Pilcher W, Como P. Predicting verbal memory decline following anterior temporal lobectomy (ATL). Neurology. 2003 Apr 22;60(8):1266-73.

TIZARD B, MARGERISON JH. THE RELATIONSHIP BETWEEN GENERALIZED PAROXYSMAL E.E.G. DISCHARGES AND VARIOUS TEST SITUATIONS IN TWO EPILEPTIC PATIENTS. J Neurol Neurosurg Psychiatry. 1963 Aug;26:308-13. No abstract available.

Tizard B, Margerison JH. Psychological functions during wave-spike discharge. British Journal of Social and Clinical Psychology 1963b; 3:6-15.

Tromp SC, Weber JW, Aldenkamp AP, Arends J, vander Linden I, Diepman L. Relative influence of epileptic seizures and of epilepsy syndrome on cognitive function. J Child Neurol. 2003 Jun;18(6):407-12.

Starting date: January 2007
Ending date: January 2010
Last updated: June 5, 2009