Epilepsy in Patients With Alzheimer's Disease

Epidemiology

Epilepsy in the elderly is frequently associated with progressive neurodegenerative disorders such as Alzheimer’s disease (AD). A person with dementia has a 5 to 10 times higher incidence of seizures compared to an elderly person without dementia.1 An estimated 10% to 22% of patients with AD dementia have at least 1 unprovoked seizure in their lifetime.2

The incidence of epilepsy in patients who also have AD is not entirely known, and studies have shown variable incidence of seizure in persons with AD.2-4 In 1 study, there was increased risk of seizures in patients of all ages with AD, although it was highest in the youngest patient group studied, who were between 50 and 59.3 In another study, it was shown that epilepsy occurs more commonly in the later stages of AD but can also be seen in younger patients with a known genetic etiology of AD.4 Others found no correlation between seizure occurrence and patient age at the time of dementia onset.2 These different findings could be partially explained by differences in the populations studied. The true incidence of epilepsy in the population of patients with dementia is likely underestimated both because of the subtle presentation of some seizure types and the limited available history that is common in the setting of cognitive impairment.

Diagnosing Seizures in the Elderly

Making a diagnosis of a seizure disorder in elderly patients with dementia can be challenging due to factors previously mentioned. Localization-related epilepsy with origin in the temporal lobes with semiology of altered awareness is the most common seizure type in this setting.5,6 African American ethnicity, lower Mini-Mental Status Examination (MMSE) score at initial evaluation, longer symptom duration, lower level of education attained, and focal epileptiform findings on EEG are all predictors of unprovoked seizures in persons with AD.3 Other etiologies that cause patients to present with transient loss of awareness (eg, syncope, transient global amnesia, transient ischemic attack, and metabolic encephalopathy) should be considered when evaluating these patients.

As an additional consideration in this population, seizures can be mistaken for progression of dementia. Confusion and altered awareness during or following an unrecognized complex partial seizure may be attributed to symptoms of dementia or delirium.1

The consequences of unprovoked seizures for patients with dementia could be significant. Seizures in this patient population worsen their cognitive abilities, increase the risk of injury, and possibly increase mortality.1 Therefore, any suspicion for a concomitant seizure disorder should prompt timely and thorough evaluation. Evaluation usually includes diagnostic imaging such as brain MRI or CT, metabolic blood tests, and EEG. Extended EEG that captures sleep may offer higher diagnostic yield. In a small study, 48-hour EEG recordings from 5 patients with AD, who also had epilepsy, found higher incidence of epileptiform discharges, both ictal and intraictal, during nonREM sleep compared to wakefulness or REM sleep.7 A larger-scale study from France compared the diagnostic value of standard EEG to long-term EEG in patients over age 65, with and without dementia, who had nonconvulsive seizures. This study found that long-term EEG was higher yield than standard EEG.8 Furthermore, the use of provocative EEG techniques might increase the yield of the study further. Hyperventilation is commonly excluded in EEG studies of elderly patients; however, hyperventilation may increase the likelihood of detecting epileptiform discharges in APOE4 allele carriers.6

Pathophysiology

Not only do patients with dementia have a higher risk of developing seizures, patients with epilepsy have a higher risk of developing cognitive impairment. This bidirectional relationship is likely rooted in the localization of pathology in medial temporal lobe structures. Seizures transiently affect cognition, and if uncontrolled, can cause more permanent damage of hippocampal structures.9 The exact mechanism of how AD and other dementias increase the frequency of seizures is not completely understood. We do know that the accumulation of Aß in AD leads to synaptic degradation, circuit remodeling, pathologic synchronization, and hyperexcitability within the hippocampal region.9 Patients are at risk of accelerated cognitive decline due to more pronounced neuronal loss when AD and epilepsy occur together.6,9

Treatment

There are no specific guidelines for managing epilepsy in patients with AD. The application of more general guidelines for management of epilepsy in elderly patients is generally recommended (Table). Providers should keep in mind age-related changes in drug metabolism due to decline in hepatic and renal functions, decrease in plasma albumin level, altered volume of distribution, and potential for toxicity related to drug interactions in the setting of polypharmacy. Antiepileptic drugs (AEDs) should be started at low doses and titrated slowly. Whenever possible, monotherapy should be used. Agents such as levetiracetam that do not affect cytochrome p450 function, with low protein binding, and minimal cognitive effects are generally preferred. Careful consideration should be given when prescribing medications that are known to lower seizure threshold. These medications include typical and atypical antipsychotics, tricyclic antidepressants, and cholinesterase inhibitors.1 Physicians should consider risks and benefits of these agents when prescribing. Lastly, careful monitoring for side effects is required, as up to a third of patients may experience dose-related cognitive side effects or worsening of behavioral problems.5

Fortunately, epilepsy in the setting of dementia is frequently responsive to pharmacotherapy, and seizure control has a positive effect on cognitive function with as much as 79% of patients with epilepsy in the setting of dementia having an excellent response to AEDs, defined as 95% reduction in seizures or fewer than 3 seizures annually.

Conclusion

Because of the high incidence of epilepsy, the subtle nature of seizures, and limited available history, providers should have a high index of suspicion for seizure disorders in patients with AD. Extended EEG recording is reasonable to clarify the diagnosis and initiate appropriate treatment in a timely fashion. Patients with risk factors or pathology with higher incidence of comorbid epilepsy such as early-onset AD, amyloid precursor protein or presenillin mutations, African American ethnicity, and rapid or more severe disease course should be identified by the clinician and may require a more thorough evaluation. Epilepsy in patients with AD is generally responsive to medical therapy, but patients are often frail with multiple comorbidities and are also particularly sensitive to cognitive side effects of AEDs.

1. Hommet C, Mondon K, Camus V, De Toffol B, Constans T. Epilepsy and dementia in the elderly. Dement Geriatr Cogn Disord. 2008;25(4):293-300.

2. Mendez M, and Lim G. Seizures in elderly patients with dementia: epidemiology and managment. Drugs Aging. 2003;20:791-803.

3. Amatniek JC, Hauser WA, Del Castillo-Castaneda C, et al. Incidence and predictors of seizures in patients with Alzheimer’s disease. Epilepsia. 2006;47:867-872.

4. Gaitatzis A, Sisodiya SM, and Sander JW. The somatic comorbidity of epilepsy: A weighty but often unrecognized burden. Epilpesia. 2012;53(8):1282-1293.

5. Rao, SC, Dove G, Cascino GD, Petersen RC. Recurrent seizures in patients with dementia: frequency, seizure types and treatment outcome. Epilepsy Behav. 2009;14(1):118-120.

6. Vossel KA, Beagle AJ, Rabinovici GD, et al. Seizures and epileptiform activity in the early stages of Alzheimer disease. JAMA Neurol. 2013;70(9):1158-1166.

7. Horváth A, Szucs A, Barcs G, Noebels JL, Kamondi A. ID 84–EEG monitoring of sleep is important in the detection of dementia-associated epilepsy. Clin Neurophys. 2016;27(3):e101.

8. Chochoi M, Tyvaert L, Derambure P, Szurhaj W. Is long-term electroencephalogram more appropriate than standard electroencephalogram in the elderly? Clinical Neurophysiol. 2017;128(1):270-274.

9. Noebels JL. A perfect storm: converging paths of epilepsy and Alzheimer’s dementia intersect in the hippocampal formation. Epilepsia. 2011;53(Suppl 1):39-46.

G. Peter Gliebus, MD

Interim Chairman, Department of Neurology
Assistant Professor of Neurology
Director, Memory and Cognitive Disorder Center
Director, Behavioral Neurology and Neuropsychiatry
Fellowship
Drexel Neurosciences Institute
Drexel University College of Medicine
Philadelphia, PA

Ahmad Al-Sibai, MD

Resident in Neurology
Drexel University College of Medicine
Philadelphia, PA

Michelle L. Dougherty, MD

Assistant Professor of Neurology
Director of Epilepsy Program
Director of Neurology Residency Program
Drexel University College of Medicine
Philadelphia, PA