Cognitive Effects of Treatment of Interictal Discharges

Epilepsy Clinical Trial

Official title:

Cognitive Effects of Treatment of Interictal Discharges

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00916149
• Other study ID #: LMC111754
• Status: Completed
• Phase: N/A
• Start date: January 2007
• Est. completion date: October 2012

Study information

• Verified date: September 2018
• Source: Massachusetts General Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

Subjects 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 31
• Est. completion date: October 2012
• Est. primary completion date: October 2012
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

Inclusion Criteria

• 18-55 years of age

• Normal Intelligence Quotient (IQ = 80) as estimated by the Wechsler Test of Adult Reading (WTAR)

• Able to give consent

• The subject's treating physician is planning to prescribe levetiracetam for focal or lamotrigine for generalized seizure prevention

• 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.

• 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/microliter 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

Related Conditions & MeSH terms

• Epilepsy

Intervention

Drug:
• levetiracetam
The dosage of levetiracetam will begin at 500mg twice per day (bid) for the first 4 days, and increase by 500mg every 5 days thereafter until a goal of 1500mg bid is reached. The subject will then remain on levetiracetam at 1500mg bid for 8 weeks, until the conclusion of the study. Medication will be supplied in 500mg tablets, to be taken orally.
• Lamotrigine
The drug will be supplied in 25, 100 and 150mg tablets, to be taken orally per the titration schedule below: The regimen will begin at 25mg once per day for the first two weeks, and increase to 50mg once per day during weeks 3 and 4. In week 5, the subject will take 50mg twice per day (bid). The dosage will increase to 50mg in the morning and 100mg at night during week 6. During week 7 the subject will take 100mg bid. During week 8, the subject will take 100mg in the morning and 150mg at night. At week 9, the subject will reach the target dose of 150mg bid. The subject will then remain on lamotrigine at 150mg bid for 7 weeks, until the conclusion of the study.

Locations

Country	Name	City	State
United States	Massachusetts General Hospital	Boston	Massachusetts

Sponsors (5)

Lead Sponsor	Collaborator
Massachusetts General Hospital	GlaxoSmithKline, National EpiFellows Foundation, UCB Pharma, UCB Young Investigator Research Program

Country where clinical trial is conducted

United States, 

References & Publications (23)

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. — View Citation

Browne TR, Penry JK, Proter RJ, Dreifuss FE. Responsiveness before, during, and after spike-wave paroxysms. Neurology. 1974 Jul;24(7):659-65. — View Citation

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

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. — View Citation

Goode DJ, Penry JK, Dreifuss FE. Effects of paroxysmal spike-wave on continuous visual-motor performance. Epilepsia. 1970 Sep;11(3):241-54. — View Citation

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. — View Citation

HOVEY HB, KOOI KA. Transient disturbances of thought processes and epilepsy. AMA Arch Neurol Psychiatry. 1955 Sep;74(3):287-91. — View Citation

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. — View Citation

KOOI KA, HOVEY HB. Alterations in mental function and paroxysmal cerebral activity. AMA Arch Neurol Psychiatry. 1957 Sep;78(3):264-71. — View Citation

Lee S, Sziklas V, Andermann F, Farnham S, Risse G, Gustafson M, Gates J, Penovich P, Al-Asmi A, Dubeau F, Jones-Gotman M. The effects of adjunctive topiramate on cognitive function in patients with epilepsy. Epilepsia. 2003 Mar;44(3):339-47. — View Citation

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. — View Citation

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. — View Citation

Schwab RS. Research Publications. Reaction time in petit mal epilepsy. Association for Research in Nervous and Mental Disease 1947; 26:339-341.

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Synder, P.J. Epilepsy. In Snyder, P.J. & Nussbaum, P.D, Clinical neuropsychology: a pocket handbook for assessment. 1998, Washington DC: American Psychological Association.

The Psychological Corporation. Wechsler Test of Adult Reading. 2001, San Antonio, TX: Harcourt Assessment

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

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. — View Citation

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. — View Citation

* Note: There are 23 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Mean Change in Focal Interictal Discharges (IEDs) Per Hour, Pre to Post Treatment	This descriptive analysis examined the change in interictal discharge rates pre to post-treatment with levetiracetam in subjects with epilepsy and with no treatment in healthy controls.	1 and 11 weeks
Secondary	Performance on Neuropsychological Batteries and Computerized Cognitive Testing: CVLT Trial 1 Learning Score	Change in California Verbal Learning Test (CVLT) Trial 1 learning score (range 0-16; higher score indicates better memory)	1 and 11 weeks
Secondary	Performance on Neuropsychological Batteries and Computerized Cognitive Testing: CVLT Total Learning	Change in California Verbal Learning Test (CVLT) Total Learning Score (the total learning score is summed across 5 learning trials, range 0-80). Higher scores indicate better memory. Scores on the CVLT reflect the number of words recalled.	1 and 11 weeks
Secondary	Performance on Neuropsychological Batteries and Computerized Cognitive Testing: CVLT Short Delay	Change in California Verbal Learning Test (CVLT) Short Delay Recall Score (the score ranges from 0-16, reflecting the number of words recalled)	1 and 11 weeks
Secondary	Performance on Neuropsychological Batteries and Computerized Cognitive Testing: CVLT Long Delay	Change in California Verbal Learning Test (CVLT) Long Delay Recall score (the score ranges from 0-16, reflecting the number of words recalled)	1 and 11 weeks
Secondary	Performance on Neuropsychological Batteries and Computerized Cognitive Testing: BVMT-R Learning	Change in Brief Visuospatial Memory Test-Revised (BVMT-R) Learning score (the score ranges from 0-6, reflecting the number of shapes recalled on the initial learning trial)	1 and 11 weeks
Secondary	Performance on Neuropsychological Batteries and Computerized Cognitive Testing: BVMT-R Total Learning	Change in Brief Visuospatial Memory Test-Revised (BVMT-R) Total Learning score (the score is summed across 3 learning trials, score range 0-18, reflecting the total number of shapes recalled)	1 and 11 weeks
Secondary	Performance on Neuropsychological Batteries and Computerized Cognitive Testing: BVMT-R Delayed Recall	Change in Brief Visuospatial Memory Test-Revised (BVMT-R) Delayed Recall score (the score ranges from 0-6, reflecting the number of shapes recalled after a 25 minute delay)	1 and 11 weeks
Secondary	Performance on Neuropsychological Batteries and Computerized Cognitive Testing: QOLIE	Change in Quality of Life Inventory in Epilepsy-89 score (QOLIE; score ranges from 0-100; higher scores reflect better quality of life)	1 and 11 weeks
Secondary	Performance on Neuropsychological Batteries and Computerized Cognitive Testing: LNS	Change in Letter-Number Sequencing score (LNS; score ranges from 0-21; higher scores indicate better performance). The score reflects the number of items that the subject can correctly recall and place in proper alphabetical and numerical sequence.	1 and 11 weeks
Secondary	Performance on Neuropsychological Batteries and Computerized Cognitive Testing: Spatial Span	Change in Spatial Span score (score ranges from 0-32; higher scores indicate better performance). Scores indicate the number of spatial sequences correctly recalled, forwards and backwards.	1 and 11 Weeks
Secondary	Performance on Neuropsychological Batteries and Computerized Cognitive Testing: Digit Span	Change in Digit Span score (score ranges from 0-30; higher scores indicate better performance). Scores indicate the number of digit sequences correctly recalled, forwards and backwards.	1 and 11 weeks
Secondary	Performance on Neuropsychological Batteries and Computerized Cognitive Testing: Verbal Fluency	Change in Verbal Fluency score (Score range: lowest score = 0, with no upper limit, reflecting total number of words generated. Higher scores indicate better performance.)	1 and 11 weeks
Secondary	Performance on Neuropsychological Batteries and Computerized Cognitive Testing: Stroop	Change in Stroop score (The score is the time for completion in seconds; less time reflects better performance.)	1 and 11 weeks
Secondary	Performance on Neuropsychological Batteries and Computerized Cognitive Testing: Design Fluency	Change in Design Fluency score (Score range: lowest score = 0; there is no upper limit. A higher score reflects more designs generated, hence better performance.)	1 and 11 weeks
Secondary	Performance on Neuropsychological Batteries and Computerized Cognitive Testing: Trails Test	Change in Trails Test score (The score is the time for completion in seconds. A lower score reflects better performance.)	1 and 11 weeks
Secondary	Performance on Neuropsychological Batteries and Computerized Cognitive Testing: Grooved Pegboard	Change in Grooved Pegboard Score (The score is the time for completion. A lower score reflects better performance.)	1 and 11 weeks
Secondary	Performance on Neuropsychological Batteries and Computerized Cognitive Testing: Digit Symbol	Change in Digit Symbol Score (The score is the number of items completed. A higher score reflects better performance.)	1 and 11 weeks
Secondary	Performance on Neuropsychological Batteries and Computerized Cognitive Testing: CPT Accuracy	Change in Continuous Performance Test Score - Accuracy (CPT; score ranges from 0-100% correct)	1 and 11 weeks
Secondary	Performance on Neuropsychological Batteries and Computerized Cognitive Testing: CPT Reaction Time (CPT RT)	Change in Continuous Performance Test Score - Reaction Time, measured in seconds (CPT RT; less time reflects better performance)	1 and 11 weeks
Secondary	Performance on Neuropsychological Batteries and Computerized Cognitive Testing: Choice Accuracy	Change in Choice Accuracy Score (indicate if red or blue stimulus; accuracy 0-100%)	1 and 11 weeks
Secondary	Performance on Neuropsychological Batteries and Computerized Cognitive Testing: Choice Reaction Time	Change in Choice Reaction Time Score, with reaction time measured in seconds (indicate if red or blue stimulus; lower reaction time suggests better performance)	1 and 11 weeks
Secondary	Performance on Neuropsychological Batteries and Computerized Cognitive Testing: Verbal Working Memory Accuracy	Change in Verbal Working Memory Accuracy Score (range 0-100%)	1 and 11 weeks
Secondary	Performance on Neuropsychological Batteries and Computerized Cognitive Testing: Verbal Working Memory Reaction Time	Change in Verbal Working Memory Reaction Time Score, with reaction time measured in seconds (indicates processing speed)	1 and 11 weeks
Secondary	Performance on Neuropsychological Batteries and Computerized Cognitive Testing: Non-verbal Working Memory Accuracy	Change in Non-verbal Working Memory Accuracy Score (accuracy ranges from 0-100%)	1 and 11 weeks
Secondary	Performance on Neuropsychological Batteries and Computerized Cognitive Testing: Non-verbal Working Memory Reaction Time	Change in Non-verbal Working Memory Reaction Time Score (indicates processing speed, with reaction time measured in seconds)	1 and 11 weeks
Secondary	Performance on Neuropsychological Batteries and Computerized Cognitive Testing: Verbal Recognition Accuracy	Change in Verbal Recognition Accuracy Score (accuracy ranges from 0-100%)	1 and 11 weeks
Secondary	Performance on Neuropsychological Batteries and Computerized Cognitive Testing: Verbal Recognition Reaction Time	Change in Verbal Recognition Reaction Time Score (indicates processing speed, with reaction time measured in seconds)	1 and 11 weeks
Secondary	Performance on Neuropsychological Batteries and Computerized Cognitive Testing: Facial Recognition Accuracy	Change in Facial Recognition Accuracy Score (accuracy ranges from 0-100%)	1 and 11 weeks
Secondary	Performance on Neuropsychological Batteries and Computerized Cognitive Testing: Facial Recognition Reaction Time	Change in Facial Recognition Reaction Time Score (indicates processing speed, with reaction time measured in seconds)	1 and 11 weeks
Secondary	Performance on Neuropsychological Batteries and Computerized Cognitive Testing: NDDIE	Change in Neurological Disorders Depression Inventory for Epilepsy (NDDIE) score (scores range from 0-24; higher scores indicate greater depressive symptoms)	1 and 11 weeks
Secondary	Performance on Neuropsychological Batteries and Computerized Cognitive Testing: Adverse Events Profile (AEP)	Change in Adverse Events Profile score (scores range from 19-76; higher scores indicate greater side effects)	1 and 11 weeks