Seizures and Alzheimer's Disease: Who's at Risk?
Abstract & Commentary
By Cynthia L. Harden, MD, Associate Professor, Neurology and Neurosciences, Weill Cornell Medical Center, Cornell University. Dr. Harden does research for Schwarz, GlaxoSmithKline, UCB, Ortho, and Ivax, is a consultant for Cyberonics and GlaxoSmithKline, and is on the speaker's bureau for Cyberonics, GlaxoSmithKline, UCB, Novartis, Pfizer, and Ortho.
Synopsis: Seizure occurrence in AD is higher than expected in the general population, and patients with onset of AD in the sixth decade have a greatly increased risk.
Source: Amatniek JC, et al. Incidence and Predictors of Seizures in Patients with Alzheimer's Disease. Epilepsia. 2006;47:867-872.
Seizure incidence is dramatically increased in patients with Alzheimer's disease (AD), according to a recent report of 233 subjects with mild AD from 3 centers, who were followed for a median of 6 years. Unprovoked seizures developed in 12 patients, for a cumulative incidence of almost 8%, which is greatly increased compared to age-specific population norms. In the youngest age group studied, ages 50-59 years, the risk of a seizure in AD patients was 87 times greater than expected, and was 3 times greater than expected in the oldest age group, age 85+ years.
Independent predictors of seizure incidence were younger age, more severe dementia, focal epileptiform abnormalities on electroencephalogram (EEG), and African-American ethnic background. Not all subjects had EEGs (114/233). Furthermore, only 15 African-Americans were in the cohort, and this factor was not significant in a multivariate analysis, when EEG findings were also included. Family history of AD was not recorded.
Factors protective of seizure incidence were history of hypertension, depression based on a Hamilton depression scale score, and a slow posterior dominant rhythm on EEG, which is an abnormal finding consistent with mild diffuse cerebral dysfunction, but is not considered an epileptiform EEG feature.
This article is provocative due to several findings. The risk of seizures in the younger and more severely affected patients suggests this group includes familial AD (FAD) cases. FAD, which typically has an early onset in the sixth decade, is caused by one of 3 separate mutations; the presenilin 1 gene (PSEN1), located on chromosome 14, the amyloid-beta protein precursor (APP) on chromosome 21, and the presenilin 2 genes on chromosome 1. One of these forms of FAD, caused by a specific mutation in PSEN1 identified as PS1 [E280A], is associated with CA1 hippocampal neuronal loss.1 Of the 8 FAD subjects described in this report,1 5 had a history of recurrent seizures as well. CA1 hippocampal neuronal loss appears to be present in this form of FAD and is also often present in intractable temporal lobe epilepsy. Therefore, the hippocampal neuropathology may be related to seizure occurrence in these FAD subjects.
Further, this study may actually underestimate seizure occurrence. The determination of whether a seizure had occurred was by patient and family interview, as well as chart review. A recent large treatment trial of epilepsy in subjects over age 65 has found that seizures in this age group can be particularly subtle, without significant motor involvement and, therefore, difficult to detect.2
Seizure occurrence in AD is higher than expected in the general population, and patients with onset of AD in the sixth decade have a greatly increased risk. Seizures may be a more frequent clinical feature of FAD, but further study of phenotype of FAD-causative mutations is needed. Careful surveillance for seizures in the mature age group, with the use of video-EEG when necessary, is appropriate.
1. Velez-Pardo C, et al. CA1 Hippocampal Neuronal Loss in Familial Alzheimer's Disease Presenilin-1 E280A Mutation is Related to Epilepsy. Epilepsia. 2004;45:751-756.
2. Rowan AJ, et al. New Onset Geriatric Epilepsy: A Randomized Study of Gabapentin, Lamotrigine, and Carbamazepine. Neurology. 2005;64:1868-1873.