ARTICLE IN BRIEF
Investigators reported that 6- to 7-percent of patients with Alzheimer's disease and/or amnestic mild cognitive impairment had a diagnosed seizure disorder or subclinical epileptiform activity early in the course of their disease.
Insights from an animal model with pathological features of Alzheimer's disease (AD) as well as seizures and epileptiform activity led a team of scientists at the University of California, San Francisco (UCSF) to wonder whether the phenotype was present in patients with Alzheimer's disease and mild cognitive impairment (MCI).
Based on a review of clinic charts from patients with AD and MCI, the investigators reported that, in fact, seizure disorders can occur early in the disease course. The study was published July 8 online ahead of the print edition of the Journal of the American Medical Association Neurology.
While it is known that convulsive seizures are common among AD patients in the later stages of the disease, there has been a dearth of research showing signs of abnormal brain wave activity earlier in the AD course.
Keith A. Vossel, MD, an assistant professor of neurology and a staff scientist at the UCSF Gladstone Institutes, had been working on the transgenic mouse model developed by Gladstone scientist Lennart Mucke, MD — the J20 line mutant human amyloid precursor protein mouse — and as a clinician wondered whether he might find a similar phenotype in AD patients.
He and his colleagues, including Dr. Mucke, reviewed the charts of 233 amnestic MCI (aMCI) patients and 1,024 patients who had been diagnosed with AD between 2007 and 2012. They found that 6- to 7-percent of the patients had a diagnosed seizure disorder or subclinical epileptiform activity. When they excluded those patients with brain tumors, strokes, or a decades-long history of epilepsy, they found that 4- to 5-percent of MCI and AD patients suffered from seizures or a subclinical disorder that showed up on an EEG.
Surprisingly, Dr. Vossel said, most of the patients with seizure disorders developed their first seizures around the same time they experienced a change in cognition. “Such patients are often excluded from prospective studies because their seizures preceded the diagnosis of neurodegenerative disease,” he said.
Those patients with epilepsy developed cognitive declines five to seven years earlier than those without evidence of seizure activity, he pointed out. The patients with aMCI and seizures developed cognitive symptoms 6.8 years earlier than those who did not have epilepsy (64.3 vs 71.1 years; p = .02). Patients with AD and epilepsy were diagnosed with cognitive decline 5.5 years earlier than patients with AD who did not have epilepsy (64.8 vs 70.3 years; p = .001). And patients with AD who had subclinical abnormal electrical activity also had an early onset of cognitive decline (58.9 years).
Forty-seven percent had complex partial seizures and more than half (55 percent) were non-convulsive (55 percent), the scientists reported.
Dr. Vossel added that earlier studies have shown that having a diagnosis of AD increases the risk of developing a seizure disorder six-fold, with a higher incidence in early-onset and familial cases. By contrast, epilepsy patients have roughly a 1.5-fold risk of cognitive decline associated with dementia over the course of their disease. Previous studies have also shown that AD patients with seizure disorders have a faster decline in language function than those who do not have seizures.
“We hope our study will raise awareness that seizures can occur early in the disease process,” said Dr. Vossel.
The investigators are now conducting a prospective study in people with the first signs of cognitive problems; they are following them over time to better understand the relationship between epileptic activity and cognitive impairments. They have enrolled 50 patients to date and are doing 36-hour video-EEG recordings and magnetoencephalography to look for subclinical epileptic activity.
The investigators are also planning to study whether AD patients who have epileptic activity could benefit cognitively from antiepileptic treatments. They have chosen to study levetiracetam because the medication worked best in J20-hAPP mice. In a report last October in the Proceedings of the National Academy of Sciences, Dr. Vossel and colleagues reported that levetiracetam effectively reduced abnormal spike activity detected by EEG in hAPP mice; chronic treatment with the drug also reversed hippocampal remodeling, behavioral abnormalities, synaptic dysfunction, and deficits in learning and memory.
EXPERTS WEIGH IN
“I am happy that this study was put in the context of epilepsy in the presence of AD,” said Imad Najm, MD, director of the Epilepsy Center at the Cleveland Clinic. “It is interesting that the scientists report epileptic discharges and seizures early on in the AD process. They are two separate diseases but it makes us think that patients with cognitive declines in early stages of the disease may also have an underlying seizure disorder that could contribute to AD.”
Still, he said, the small numbers — 5 to 7 percent of AD patients had abnormal electrical activity on a brain scan — does not warrant blanket EEG testing for all AD patients.
The study findings offer an intriguing opportunity to sample these clinic patients longitudinally to see whether a greater proportion of them went on to develop AD. “The other question I would really like to see answered is whether anti-epileptic medicines might be effective at slowing the progression of AD.”
John C. Morris, MD, director of the Knight Alzheimer's Disease Research Center at Washington University in St. Louis, added: “There has always been a recognition that AD patients at the end of their disease can suffer from seizures. But these researchers found that the seizures are independent of the severity of the changes in AD,” he said.
“Seizures may be under-recognized and under-reported,” Dr. Morris added. “People don't expect to see it and thus don't look for it.”
He said that one of the limitations of the study is that the scientists did not have pathological proof that the patients in the study who had seizures truly had AD.
“Seizures are relatively rare in AD [compared with other AD manifestations such as behavioral symptoms] but AD is clearly a risk factor for seizures,” said Nikolaos Scarmeas, MD, an associate professor of neurology at Columbia University Medical Center. “It is noteworthy that a significant proportion of seizures were non-convulsive. Convulsive seizures are commonly noted in previous studies, a bias that actually underestimates true seizure frequency.”
LINK UP FOR MORE INFORMATION:
•. Vossel KA, Beagle AJ, Rabinovici GD, et al. Seizures and epileptiform activity in the early stages of Alzheimer disease. JAMA Neurol 2013; E-pub 2013 Jul 8.
•. Sanchez PE, Zhu L, Verret L, et al. Proc Natl Acad Sci USA 2012:109(42):E2895–2903.
•. Chin J, Scharfman H. Shared cognitive and behavioral impairments in epilepsy and Alzheimer's disease and potential underlying mechanisms. Epilepsy Behav