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

Abstract

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.

Conflict of interest statement

POTENTIAL CONFLICTS OF INTERESTS Nothing to report.

© 2016 American Neurological Association.

Figures

FIGURE 1

Flowchart of participant recruitment and enrollment. AD = Alzheimer’s disease; MEG = magnetoencephalography.

FIGURE 2

Proportion of participants with subclinical epileptiform activity. Subclinical epileptiform activity in patients with Alzheimer’s disease (AD) and age-matched controls detected by long-term monitoring with video-EEG (LTM-EEG, overnight), magnetoencephalography with simultaneous EEG (M/EEG), or both. EEG = electroencephalogram.

FIGURE 3

Subclinical epileptiform activity in Alzheimer’s disease (AD) patients. (A) Subclinical epileptiform spike detected by overnight long-term monitoring with video-EEG (LTM-EEG). The maximum negativity is isopotential between the Fp2 and F4 electrodes, corresponding neuroanatomically with the right frontal lobe (D, patient 3). (B) Subclinical epileptiform sharp wave observed on magnetoencephalography (MEG, left panel), localized in the left temporal lobe (B, middle panel and D, patient 4), and corresponding slow wave on EEG (right panel). (C and D) Distribution of predominant regions of subclinical epileptiform activity by recording modality and patient. Patients 4 and 6 had bilateral localization of epileptiform activity. A = anterior; EEG = electroencephalogram; L = left; μV = microvolts; P = posterior; pT = picotesla; R = right.

FIGURE 4

Averaged power spectral density estimates for different frequency bands during resting magnetoencephalography. Alzheimer’s disease (AD) patients with (n = 14) or without (n = 19) epileptiform activity had decreased power of alpha (α), beta (β), and gamma (γ) oscillations compared to age-matched controls (n = 19). p < 0.05 for each AD group vs. controls at each frequency band by ANOVA and Dunnett’s test. Spectral data were derived from posterior-based sensors over 60 seconds. Shaded areas are standard error of the mean. dB = decibels; Hz = hertz.

FIGURE 5

Subclinical epileptiform activity and brain atrophy in Alzheimer’s disease (AD). Patterns of brain atrophy in AD patients without (top images) or with (bottom images) subclinical epileptiform activity revealed by voxel-based morphometry. Atrophy maps are based on comparisons with age- and sex-matched controls from the UCSF Memory and Aging Center database. Regions of gray matter atrophy are shown on the 3-dimensional rendering of the Montreal Neurological Institute standard template brain. n = 16 AD patients without epileptiform activity, n = 10 AD patients with epileptiform activity, and n = 75 controls. The images were thresholded at p < 0.001, uncorrected.

FIGURE 6

Subclinical epileptiform activity and longitudinal change in cognition in Alzheimer’s disease (AD). Estimates from linear mixed-effects models of the longitudinal change in cognitive functions. (A) Mini-Mental State Examination (MMSE) score. n = 34–55 observations from 10–15 patients per group (7 observations included in the model occurred after 60 months, and these data are provided in Supplementary Table S6). (B) Composite measure of executive function (z score). n = 11–34 observations from 4–11 patients per group. Shaded areas are 95% confidence intervals.