Seizures and Alzheimer's Disease

Abstract & Commentary

By Steven Karceski, MD, Cornell Comprehensive Epilepsy Center, Weill Cornell Medical College. Dr. Karceski reports no financial relationships relevant to this field of study.

Synopsis: The incidence of epileptic seizures is much higher in elderly patients with Alzheimer's disease than those who are elderly but non-demented.

Source: Irizarry MC, et al. Incidence of new-onset seizures in mild to moderate Alzheimer's disease. Arch Neurol 2012;69:368-372.

Alzheimer's disease (ad) is a slowly progressive neurodegenerative disease that causes a gradual loss of higher cognitive functions. In AD, β-amyloid gradually accumulates in the brain and is deposited between nerve cells, accumulating into regions which, under a microscope, are called amyloid plaques. In addition, as Alzheimer's progresses, there is an accumulation of neurofibrillary tangles inside of the nerve cells. These tangles are made up of insoluble twisted "tau" fibers that are normally part of the microtubule system of nerve cells. The microtubule system helps to transport nutrients and other important substances from one part of the nerve cell to another. In AD, however, the tau protein is abnormal. More research is needed to determine exactly how this process occurs. However, most scientists believe that it is the combination of amyloid and neurofibrillary tangles that cause damage to the brain, loss of neurons, and leads to the cognitive problems. If true, these same changes may be responsible for the increased risk of seizures in patients with AD.

For many years, neurologists have noticed an association between AD and seizures. Several epidemiological studies have shown this, including the Rochester, Minnesota study by Hesdorffer and Hauser.1 Looking at patients between 1975 and 1984, their study showed that dementia was a major risk factor for seizures, with an odds ratio of 6.2. In the Northern Manhattan Study, Shinnar et al found an increased risk in elderly people with a hazard ratio of 1.96.2 Finally, a collaboration between Columbia University, Johns Hopkins, and Massachusetts General Hospital studied 453 patients with mild AD, and found that there was eight-fold increase in the incidence of seizures in people with AD.3

Although many studies have shown this association, the risk ratios vary widely, because the studies looked at people who had different degrees of AD severity; some people were mildly affected, and others were severe in the late course of their illness. To better understand how often seizures occur in mild or moderate AD (earlier in the course of the illness), Irizarry and colleagues pooled data from 10 studies of AD from the Alzheimer's Disease Cooperative Study between 1995 and 2010.

By using pooled data, Irizarry and colleagues were able to look at a large group of patients (n = 3078). Because these were patients in clinical trials, each person had been rigorously screened for AD using NIH criteria for diagnosis, giving the investigators confidence that all patients had either mild or moderate dementia. In the study group, the average duration of AD was 4.3 years. All patients were over the age of 50. Seventy-two percent were taking an acetycholinesterase inhibitor (Ach-I). Of those who had genetic testing, 64% carried the Apo E4 allele.

Eighteen people were found to have seizures, and these were correlated with a younger age at the onset of AD, and a lower score on the Mini Mental Status Exam (MMSE), suggesting that these patients had more advanced AD. In addition, they found that people who were taking memantine or an antipsychotic medication were more likely to have seizures. Memantine (NMDA receptor inhibitor) is used in moderate AD, but not mild AD. Antipsychotics are more often needed in more advanced cases of AD, and the association between these medications and seizures suggests that seizures are more likely to occur in more advanced cases of AD.

Irizarry found that the rate of seizures in mild-to-moderate AD was 484 per 100,000 patient-years. This was slightly higher, but similar to other published studies in mild AD: 418/100,000. This is a much higher rate than the rate of a first unprovoked seizure in older people who do not have AD. In the Minnesota study, the rate of an unprovoked seizure in 65-74 year olds was 120/100,000 patient-years. This increased to 280/100,000 for those over 75. In the Northern Manhattan Study, the rate of a first unprovoked seizure was 45/100,000 in 65-74 years olds, and was 144.7/100,000 in those between 75-84.

Commentary

There are some weaknesses in this study due to the use of pooled study data. First, most people who are enrolled in studies must be generally "healthy." Those who have many medical problems are often excluded from clinical trials to minimize bias and to make the population more uniform. By doing so, the "healthy" patients may not accurately reflect the general population of those with AD. This may mean that the incidence of 484/100,000 actually underestimates the rate of seizures in less-healthy people with AD.

In addition, half of the people with AD in these studies were given some treatment (like an ACH-I, memantine, or valproate) and half were given placebo. All were analyzed in the same pool. In a study where valproate was given as a neuroprotective agent, one might expect that seizures would occur less in the treated group, since valproate also acts as an antiepileptic. By using patients in clinical treatment trials, one cannot be certain whether the administered treatment could have caused or stopped seizures. Despite the potential pitfalls, however, studies like this are helpful in better understanding the association between illnesses.

References

1. Hesdorffer DC, et al. Dementia and adult-onset unprovoked seizures. Neurology 1996;46:727-730.

2. Shinnar SA, et al. Incidence of epilepsy in a racially diverse, community-dwelling, elderly cohort: Results from the Einstein aging study Epilepsy Res 2006;71:195-205.

3. Scarmeas N, et al. Seizures in Alzheimer disease: Who, when, and how common? Arch Neurol 2009;66:992-997.