Incidence and impact of subclinical epileptiform activity in Alzheimer's disease

Keith A. Vossel, Kamalini G. Ranasinghe, Alexander J. Beagle, Danielle Mizuiri, Susanne M. Honma, Anne F. Dowling, Sonja M. Darwish, Victoria Van Berlo, Deborah E. Barnes, Mary Mantle, Anna M. Karydas, Giovanni Coppola, Erik D. Roberson, Bruce L. Miller, Paul A. Garcia, Heidi E. Kirsch, Lennart Mucke, Srikantan S. Nagarajan

Research output: Contribution to journalArticlepeer-review

241 Scopus citations


Objective: Seizures are more frequent in patients with Alzheimer's disease (AD) and can hasten cognitive decline. However, the incidence of subclinical epileptiform activity in AD and its consequences are unknown. Motivated by results from animal studies, we hypothesized higher than expected rates of subclinical epileptiform activity in AD with deleterious effects on cognition. Methods: We prospectively enrolled 33 patients (mean age, 62 years) who met criteria for AD, but had no history of seizures, and 19 age-matched, cognitively normal controls. Subclinical epileptiform activity was assessed, blinded to diagnosis, by overnight long-term video-electroencephalography (EEG) and a 1-hour resting magnetoencephalography exam with simultaneous EEG. Patients also had comprehensive clinical and cognitive evaluations, assessed longitudinally over an average period of 3.3 years. Results: Subclinical epileptiform activity was detected in 42.4% of AD patients and 10.5% of controls (p = 0.02). At the time of monitoring, AD patients with epileptiform activity did not differ clinically from those without such activity. However, patients with subclinical epileptiform activity showed faster declines in global cognition, determined by the Mini–Mental State Examination (3.9 points/year in patients with epileptiform activity vs 1.6 points/year in patients without; p = 0.006), and in executive function (p = 0.01). Interpretation: Extended monitoring detects subclinical epileptiform activity in a substantial proportion of patients with AD. Patients with this indicator of network hyperexcitability are at risk for accelerated cognitive decline and might benefit from antiepileptic therapies. These data call for more sensitive and comprehensive neurophysiological assessments in AD patient evaluations and impending clinical trials. Ann Neurol 2016;80:858–870.

Original languageEnglish (US)
Pages (from-to)858-870
Number of pages13
JournalAnnals of Neurology
Issue number6
StatePublished - Dec 1 2016

Bibliographical note

Funding Information:
This study was supported by NIH grants K23 AG038357 (K.A.V.), P50 AG023501 and P01 AG19724 (B.L.M.), R21 NS76171 (S.S.N.), R01 DC010145 (S.S.N.), NS066654 (S.S.N.), and NS64060 (S.S.N.), a University of California San Francisco Alzheimer's Disease Research Center pilot project grant (K.A.V.), National Science Foundation grant BCS-1262297 (S.S.N.), a grant from the Alzheimer's Association (PCTRB-13-288476) made possible by Part the Cloud™ (K.A.V.), the John Douglas French Alzheimer's Foundation (K.A.V.), the S.D. Bechtel Jr. Foundation (L.M.), the McBean Family Foundation (K.A.V.), and the Larry L. Hillblom Foundation (K.G.R.). This study was also supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, NIH, through University of California San Francisco–Clinical and Translational Science Institute (CTSI) grant numbers UL1 RR024131 and UL1 TR000004. We thank Jeanne Paz for helpful comments on the manuscript; Mary Betinis for LTM-EEG oversight; the CTSI Clinical Research Services for nursing, coordination, and biospecimen support; Averill Cantwell, Pia Ghosh, Matthew Growdon, Jung Jang, Baber Khan, and Teresa Wu for coordination support; Joe Hesse, Albert Lee, and Charlie Toohey for database support; Ryan Fitch for support with biospecimens; Joel Kramer for oversight of neuropsychological testing; Manu Hegde for assistance with MEG reading; Coleman Garrett for MEG acquisition support; EEG technicians for excellent technical support; Grisell Diaz-Ramirez, Clifford Anderson-Bergman, and Elissaios Karageorgiou for advice on statistical analysis; William Jagust and Gil Rabinovici for providing the amyloid imaging; Lea Grinberg, Eric Huang, and William Seeley for neuropathological assessments; Crystal Herron and Stephen Ordway for editorial assistance; Giovanni Maki and Benedicte Rossi for graphics support; and Monica Dela Cruz and Amy Cheung for administrative assistance. We are deeply grateful to all study participants and caregivers who contributed to this study.

Publisher Copyright:
© 2016 American Neurological Association


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