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Clinical Trial
. 2021 Nov 1;78(11):1345-1354.
doi: 10.1001/jamaneurol.2021.3310.

Effect of Levetiracetam on Cognition in Patients With Alzheimer Disease With and Without Epileptiform Activity: A Randomized Clinical Trial

Keith Vossel  1   2   3   4   5 , Kamalini G Ranasinghe  1 , Alexander J Beagle  1 , Alice La  1 , Kasey Ah Pook  2 , Madelyn Castro  2 , Danielle Mizuiri  6 , Susanne M Honma  6 , Nisha Venkateswaran  2   4 , Mary Koestler  1 , Wenbo Zhang  7   8 , Lennart Mucke  1   5 , Michael J Howell  8 , Katherine L Possin  1 , Joel H Kramer  1 , Adam L Boxer  1 , Bruce L Miller  1 , Srikantan S Nagarajan  6 , Heidi E Kirsch  6   9
Affiliations
Clinical Trial

Effect of Levetiracetam on Cognition in Patients With Alzheimer Disease With and Without Epileptiform Activity: A Randomized Clinical Trial

Keith Vossel et al. JAMA Neurol. .

Abstract

Importance: Network hyperexcitability may contribute to cognitive dysfunction in patients with Alzheimer disease (AD).

Objective: To determine the ability of the antiseizure drug levetiracetam to improve cognition in persons with AD.

Design, setting, and participants: The Levetiracetam for Alzheimer's Disease-Associated Network Hyperexcitability (LEV-AD) study was a phase 2a randomized double-blinded placebo-controlled crossover clinical trial of 34 adults with AD that was conducted at the University of California, San Francisco, and the University of Minnesota, Twin Cities, between October 16, 2014, and July 21, 2020. Participants were adults 80 years and younger who had a Mini-Mental State Examination score of 18 points or higher and/or a Clinical Dementia Rating score of less than 2 points. Screening included overnight video electroencephalography and a 1-hour resting magnetoencephalography examination.

Interventions: Group A received placebo twice daily for 4 weeks followed by a 4-week washout period, then oral levetiracetam, 125 mg, twice daily for 4 weeks. Group B received treatment using the reverse sequence.

Main outcomes and measures: The primary outcome was the ability of levetiracetam treatment to improve executive function (measured by the National Institutes of Health Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research [NIH-EXAMINER] composite score). Secondary outcomes were cognition (measured by the Stroop Color and Word Test [Stroop] interference naming subscale and the Alzheimer's Disease Assessment Scale-Cognitive Subscale) and disability. Exploratory outcomes included performance on a virtual route learning test and scores on cognitive and functional tests among participants with epileptiform activity.

Results: Of 54 adults assessed for eligibility, 11 did not meet study criteria, and 9 declined to participate. A total of 34 adults (21 women [61.8%]; mean [SD] age, 62.3 [7.7] years) with AD were enrolled and randomized (17 participants to group A and 17 participants to group B). Thirteen participants (38.2%) were categorized as having epileptiform activity. In total, 28 participants (82.4%) completed the study, 10 of whom (35.7%) had epileptiform activity. Overall, treatment with levetiracetam did not change NIH-EXAMINER composite scores (mean difference vs placebo, 0.07 points; 95% CI, -0.18 to 0.32 points; P = .55) or secondary measures. However, among participants with epileptiform activity, levetiracetam treatment improved performance on the Stroop interference naming subscale (net improvement vs placebo, 7.4 points; 95% CI, 0.2-14.7 points; P = .046) and the virtual route learning test (t = 2.36; Cohen f2 = 0.11; P = .02). There were no treatment discontinuations because of adverse events.

Conclusions and relevance: In this randomized clinical trial, levetiracetam was well tolerated and, although it did not improve the primary outcome, in prespecified analysis, levetiracetam improved performance on spatial memory and executive function tasks in patients with AD and epileptiform activity. These exploratory findings warrant further assessment of antiseizure approaches in AD.

Trial registration: ClinicalTrials.gov Identifier: NCT02002819.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Vossel reported receiving grants from the Alzheimer’s Association and the National Institute on Aging, National Institutes of Health and donations from the Fineberg Foundation, the N. Bud and Beverly Grossman Foundation, and the S. D. Bechtel, Jr. Foundation during the conduct of the study. Dr Mucke reported receiving grants from the S. D. Bechtel, Jr. Foundation during the conduct of the study and research funding for an independent project from Cure Network Dolby Acceleration Partners; personal fees from Eisai and Takeda Pharmaceutical; and serving on the scientific advisory boards of Acumen, Alkahest, Arvinas, Biogen, and Dolby Family Ventures outside the submitted work. Dr Possin reported receiving grants from the Global Brain Health Institute, the National Institutes of Health, the Rainwater Charitable Foundation, and Quest Diagnostics during the conduct of the study and personal fees from ClearView Healthcare Partners and Vanguard outside the submitted work. Dr Boxer reported receiving grants from the Alzheimer’s Association, the Alzheimer’s Drug Discovery Foundation, the Association for Frontotemporal Degeneration, Biogen, the Bluefield Project to Cure Frontotemporal Dementia, Eisai, Eli Lilly and Company, the National Institutes of Health, the Rainwater Charitable Foundation, Regeneron Pharmaceuticals, and the State of California; personal fees from Alector, Applied Genetic Technologies, Arkuda Therapeutics, Arvinas, AZTherapies, GlaxoSmithKline, Humana, Lundbeck, Oligomerix, Roche, the Roissy Foundation, Stealth BioTherapeutics, Transposon Therapeutics, TrueBinding, UCB, and Wave Pharma; and nonfinancial support from Eli Lilly and Company and Novartis; and serving as a consultant for Applied Genetic Technologies, Alector, Arkuda Therapeutics, Arvinas, Asceneuron, AZTherapies, BioAge Labs, GlaxoSmithKline, Humana, Oligomerix, Ono Pharmaceutical, Roche, Samumed, Sangamo Therapeutics, Stealth BioTherapeutics, Third Rock Ventures, Transposon Therapeutics, and Wave Pharma outside the submitted work. Dr Miller reported receiving grants from the Bluefield Project to Cure Frontotemporal Dementia and royalties from the Cambridge University Press, Guilford Press, John Hopkins Press, and Oxford University Press; being the editor-in-chief of Neurocase and a section editor of Frontiers in Neurology; serving as a scientific advisor, consultant, or board member for the Bluefield Project to Cure Frontotemporal Dementia, Biogen, the Buck Institute for Research on Aging, the National Institute for Health Research Cambridge Biomedical Research Centre and its Biomedical Research Unit in Dementia, the John Douglas French Alzheimer’s Foundation, the Larry L. Hillblom Foundation, the Massachusetts General Hospital/Harvard Medical School Alzheimer’s Disease Research Center, the Rainwater Charitable Foundation, SafelyYou, the Stanford Alzheimer’s Disease Research Center, The University of Texas at Dallas Center for BrainHealth, and the University of Washington Alzheimer’s Disease Research Center outside the submitted work. Dr Nagarajan reported receiving grants from RICOH MEG outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Enrollment and Randomization of Participants
aGroup A received placebo twice daily for 4 weeks followed by a 4-week washout period, then levetiracetam, 125 mg, twice daily for 4 weeks. Group A included 6 patients with Alzheimer disease (AD) and epileptiform activity and 11 patients with AD and no epileptiform activity. bGroup B received levetiracetam, 125 mg, twice daily for 4 weeks followed by a 4-week washout period, then placebo twice daily for 4 weeks. Group B included 7 patients with AD and epileptiform activity and 10 patients with AD and no epileptiform activity. cOf 15 patients from group A included in the primary analysis, 5 had AD with epileptiform activity, and 10 had AD without epileptiform activity. dOf 13 patients from group B included in the primary analysis, 5 had AD with epileptiform activity, and 8 had AD without epileptiform activity.
Figure 2.
Figure 2.. Differences in Cognitive Outcomes Among Patients With Alzheimer Disease by Epileptiform Subgroup
A, Differences in interference naming performance on the Stroop Color and Word Test after 4 weeks of levetiracetam (LEV) compared with 4 weeks of placebo among 9 participants with epileptiform (EPI) activity and 13 participants without EPI activity. P = .046 for comparison within patients with EPI activity after receiving LEV vs placebo (derived from repeated-measures analysis of variance), and P = .04 for comparison between patients with vs without EPI activity (derived from t test). Middle horizontal bars represent means, and lines connecting dots represent differences between placebo and levetiracetam for individual participants. B, Linear fits from a linear mixed-effects model estimating the difference in spatial navigation performance on a virtual route learning test (VRLT) among 5 patients with EPI activity before and after placebo vs before and after LEV treatment. Shaded areas represent SEs of the mean.
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Comment in

References

    1. GBD 2016 Dementia Collaborators . Global, regional, and national burden of Alzheimer’s disease and other dementias, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019;18(1):88-106. doi:10.1016/S1474-4422(18)30403-4 - DOI - PMC - PubMed
    1. Vossel KA, Beagle AJ, Rabinovici GD, et al. . Seizures and epileptiform activity in the early stages of Alzheimer disease. JAMA Neurol. 2013;70(9):1158-1166. doi:10.1001/jamaneurol.2013.136 - DOI - PMC - PubMed
    1. Mendez M, Lim G. Seizures in elderly patients with dementia: epidemiology and management. Drugs Aging. 2003;20(11):791-803. doi:10.2165/00002512-200320110-00001 - DOI - PubMed
    1. Vossel KA, Tartaglia MC, Nygaard HB, Zeman AZ, Miller BL. Epileptic activity in Alzheimer’s disease: causes and clinical relevance. Lancet Neurol. 2017;16(4):311-322. doi:10.1016/S1474-4422(17)30044-3 - DOI - PMC - PubMed
    1. Amatniek JC, Hauser WA, DelCastillo-Castaneda C, et al. . Incidence and predictors of seizures in patients with Alzheimer’s disease. Epilepsia. 2006;47(5):867-872. doi:10.1111/j.1528-1167.2006.00554.x - DOI - PubMed

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