Original Investigation |

Seizures and Epileptiform Activity in the Early Stages of Alzheimer Disease

Keith A. Vossel, MD, MSc1,2; Alexander J. Beagle, BA2; Gil D. Rabinovici, MD2; Huidy Shu, MD, PhD2,5; Suzee E. Lee, MD2; Georges Naasan, MD2; Manu Hegde, MD, PhD3; Susannah B. Cornes, MD3; Maya L. Henry, PhD2; Alexandra B. Nelson, MD, PhD1,2; William W. Seeley, MD2; Michael D. Geschwind, MD, PhD2; Maria L. Gorno-Tempini, MD2; Tina Shih, MD3; Heidi E. Kirsch, MD, MS3,4; Paul A. Garcia, MD3; Bruce L. Miller, MD2; Lennart Mucke, MD1,2
[+] Author Affiliations
1Gladstone Institute of Neurological Disease, San Francisco, California
2Memory and Aging Center, Department of Neurology, University of California, San Francisco, California
3Epilepsy Center, Department of Neurology, University of California, San Francisco, California
4Department of Radiology and Biomedical Imaging, University of California, San Francisco, California
5currently at the Pali Momi Medical Center, Aiea, Hawaii
JAMA Neurol. 2013;70(9):1158-1166. doi:10.1001/jamaneurol.2013.136.
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Importance  Epileptic activity associated with Alzheimer disease (AD) deserves increased attention because it has a harmful impact on these patients, can easily go unrecognized and untreated, and may reflect pathogenic processes that also contribute to other aspects of the illness. We report key features of AD-related seizures and epileptiform activity that are instructive for clinical practice and highlight similarities between AD and transgenic animal models of the disease.

Objective  To describe common clinical characteristics and treatment outcomes of patients with amnestic mild cognitive impairment (aMCI) or early AD who also have epilepsy or subclinical epileptiform activity.

Design  Retrospective observational study from 2007 to 2012.

Setting  Memory and Aging Center, University of California, San Francisco.

Patients  We studied 54 patients with a diagnosis of aMCI plus epilepsy (n = 12), AD plus epilepsy (n = 35), and AD plus subclinical epileptiform activity (n = 7).

Main Outcomes and Measures  Clinical and demographic data, electroencephalogram (EEG) readings, and treatment responses to antiepileptic medications.

Results  Patients with aMCI who had epilepsy presented with symptoms of cognitive decline 6.8 years earlier than patients with aMCI who did not have epilepsy (64.3 vs 71.1 years; P = .02). Patients with AD who had epilepsy presented with cognitive decline 5.5 years earlier than patients with AD who did not have epilepsy (64.8 vs 70.3 years; P = .001). Patients with AD who had subclinical epileptiform activity also had an early onset of cognitive decline (58.9 years). The timing of seizure onset in patients with aMCI and AD was nonuniform (P < .001), clustering near the onset of cognitive decline. Epilepsies were most often complex partial seizures (47%) and more than half were nonconvulsive (55%). Serial or extended EEG monitoring appeared to be more effective than routine EEG at detecting interictal and subclinical epileptiform activity. Epileptic foci were predominantly unilateral and temporal. Of the most commonly prescribed antiepileptics, treatment outcomes appeared to be better for lamotrigine and levetiracetam than for phenytoin.

Conclusions and Relevance  Common clinical features of patients with aMCI- or AD-associated epilepsy at our center included early age at onset of cognitive decline, early incidence of seizures in the disease course, unilateral temporal epileptic foci detected by serial/extended EEG, transient cognitive dysfunction, and good seizure control and tolerability with lamotrigine and levetiracetam. Careful identification and treatment of epilepsy in such patients may improve their clinical course.

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Figure 1.
Seizure Onset in Relation to Disease Course

A, Seizures were coincident with, or followed the onset of, nonepileptic symptoms of Alzheimer disease (AD) in all but 4 cases. The yearly distribution of new-onset seizures relative to the year of amnestic mild cognitive impairment (aMCI) or AD onset was nonuniform (P < .001, χ2 test) and clustered near the onset of cognitive decline. B, Seizure onset generally occurred prior to neurodegenerative diagnosis or early into the disease course. C, Mini-Mental State Examination (MMSE) scores obtained nearest the time of the first seizure were clustered toward the upper end of the range (2 missing data points for patients with aMCI and 4 missing data points for patients with AD).

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Figure 2.
Distribution of Electroencephalogram Epileptiform Activity

Of the 31 cases who had spikes or sharp waves on electroencephalogram, epileptiform activity was predominantly unilateral and most commonly temporal (8 left, 4 right, and 1 bitemporal), followed by frontotemporal (5 left and 4 right), frontal (2 left, 1 right, and 1 bifrontal), central (1 left central and 2 central frontal), and generalized (2). L indicates left, and R, right.

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Figure 3.
Right-Handed, 53-Year-Old Woman Who Presented With 3.5 Years of Progressive Expressive Language Difficulties and Executive Dysfunction

Her Mini-Mental State Examination score was 23 of 30. Her speech was effortful with word-finding pauses, and she had difficulty repeating. Her comprehension was relatively preserved. She also had ocular apraxia and optic ataxia. Brain magnetic resonance imaging showed diffuse cortical atrophy, greatest in the left parietal lobe. Her apoE genotype was E3/E3. Carbon 11–labeled Pittsburgh compound B positron emission tomography (A, left image) showed amyloid deposits throughout the neocortex, as indicated by the red signal, and fluorodeoxyglucose positron emission tomography (A, right image) revealed reduced glucose metabolism in the temporoparietal lobes (left > right) and left frontal lobe, as indicated by reduction in the yellow signal and white arrows. Both findings support a diagnosis of Alzheimer disease. At age 54 years, she drove into a parked car that she did not see on her right side. She was not injured. The accident prompted a routine electroencephalogram (EEG) evaluation, which showed intermittent left frontotemporal slowing. Long-term video EEG monitoring (B) revealed epileptiform spikes, occurring as frequently as every few minutes, centered in the left frontal lobe with phase reversal at F3, corresponding neuroanatomically to a language region that was clinically impaired and hypometabolic on fluorodeoxyglucose positron emission tomography. She started treatment with levetiracetam, with a final dose of 1000 mg twice daily. Her Mini-Mental State Examination score at age 54 years was 20 of 30. Routine EEG during levetiracetam treatment showed diffuse theta slowing with no asymmetry and no epileptiform activity. At the age of 55 years, she developed occasional arm myoclonus but remained otherwise seizure free.

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