November/December 2013

New Target for Therapy
in AD Patients

By Jamie Santa Cruz
Today’s Geriatric Medicine
Vol. 6 No. 6 P. 24

For the 5 million patients currently suffering from Alzheimer’s disease (AD), there is a frustrating lack of options for slowing the disease’s progression. But a growing body of research into the connection between AD and epilepsy is providing a glimmer of hope.

Recent studies suggest that epilepsy may be an important contributor to cognitive decline in AD patients, and that antiepileptic drugs offer the potential to slow or even reverse cognitive losses associated with the disease, especially in patients with the most aggressive forms, according to Lennart Mucke, MD, who directs neurological research at the Gladstone Institutes, an independent biomedical-research nonprofit based in San Francisco.

Silent Seizures
Researchers have known for some time that patients with AD have an elevated risk of seizures compared with other patients of the same age without AD. Several studies have suggested that patients with early onset or inherited forms of the disease, which typically are thought to be more aggressive, were at greater risk of seizures.1-6

But, according to Mucke, who also is a professor of neurology at the University of California, San Francisco (UCSF), most early research on epileptic activity in AD patients focused only on convulsive seizures, and many neurologists previously had assumed that seizures are a “late burnout” phenomenon caused by the neurodegeneration that occurs as part of the disease’s course.

However, in 2007, Mucke’s team at the Gladstone Institutes made a significant discovery challenging that assumption. While studying mouse models of AD, the researchers observed seizure activity in the mice but, surprisingly, not convulsive activity. Instead, most of the seizures were subclinical “silent” seizures evident only via electroencephalography (EEG) monitoring. Although the seizures lacked any overt manifestations, they were strongly associated with cognitive decline. The findings, published in Neuron, raised the possibility that nonconvulsive seizures could play a more important role in AD than previously thought.7

According to Daniel Friedman, MD, an assistant professor of neurology at the Comprehensive Epilepsy Center at NYU Langone Medical Center, the findings marked a pivotal moment in AD and epilepsy research. Scientists began to question the possibility that, if animal models of AD showed evidence of subclinical seizure activity, were human AD patients also experiencing unrecognized nonconvulsive seizures? If so, how early in the course of the disease might the seizures be occurring, and what impact might they be having on brain function?

Human Theoretical Applications
The questions prompted Mucke’s team to undertake a new study this year, now focusing on human patients with AD or amnestic mild cognitive impairment (aMCI), which often leads to AD. Their retrospective analysis, published in September in JAMA Neurology, focused on patients with a dual diagnosis of AD or aMCI with epilepsy.8 “It wasn’t our experience that patients had to be in the later stages to have seizures,” Mucke says, “so we wanted to formally address what the seizures are really like and how early they can occur.”

As it turned out, among the patients studied, seizure activity indeed occurred early in the course of AD. Keith Vossel, MD, MSc, a staff scientist at the Gladstone Institutes and the lead author of the JAMA Neurology paper, says the group was surprised to find that seizures frequently preceded a diagnosis of neurodegenerative disease by a few years. In fact, seizures often began around the same time symptoms of neurodegeneration first appeared. Rather than a late burnout phenomenon, the group’s results suggested that epilepsy onset may even precede clinical recognition of AD—a striking reversal of earlier thinking.

Equally important was the finding, consistent with earlier discoveries in Gladstone’s animal models, that 55% of the epilepsy cases in their patients were nonconvulsive. Instead, episodes were marked by transient cognitive symptoms such as aphasia, amnestic spells, sensory phenomena, or déjà vu.

Friedman, who was not involved in the study, believes the Gladstone researchers’ findings point to the fact that seizures probably are much more common in AD patients than anyone has realized. “My feeling is that we’re probably underrecognizing seizures in patients, especially with Alzheimer’s disease,” he says. “There’s often no obvious motor manifestation.”

Vossel’s JAMA Neurology study focused on patients already known to have epilepsy, but there currently are no data available on the percentage of the general AD population who may be experiencing subclinical epileptiform activity. To address this, Mucke’s team has undertaken a prospective study for the purpose of establishing the incidence of epilepsy more concretely. Using a combination of extended EEG monitoring and highly sensitive magnetoencephalography, the team is studying patients in the Memory and Aging Center and the Epilepsy Center of UCSF (most of whom are early onset cases) who are not known to have epilepsy but who have a diagnosis of either aMCI or early AD.

Final results are not yet available but, according to Vossel, who also is an assistant professor of neurology at UCSF, the preliminary findings are striking. “We’re actually detecting epileptic activity in almost half of our patients with Alzheimer’s,” he says, “so there could be a pretty sizable population who are having epileptic activity.”

Reversing Cognitive Decline
Although it seems likely that seizures occur in the early stages of AD with greater frequency than previously thought, questions remain about whether epileptic activity actually contributes to cognitive decline. “People with more aggressive disease are more likely to have seizures,” Friedman says, but “we don’t know if that’s a chicken-or-egg phenomenon: Does the presence of seizures accelerate the course of their Alzheimer’s disease or is the more aggressive Alzheimer’s disease the cause of their seizures?”

If seizures do accelerate the disease, it raises the possibility that suppressing seizure activity could improve the clinical course for AD patients. And while the evidence is not yet conclusive, several telling indications suggest this is a real possibility.

After their discovery that AD animal models frequently showed evidence of subclinical seizures, Mucke and his team conducted further studies last year to explore whether suppressing seizures in animal models using a range of antiepileptic drugs would lead to improved cognitive function. Their findings, reported online in the Proceedings of the National Academy of Sciences, were encouraging.9 Mice showed significantly reduced seizure activity when treated with one drug in particular, levetiracetam (Keppra). At the same time their seizures plummeted, the mice demonstrated what Vossel describes as “miraculous improvement” in learning and memory.

The results from these animal models were consistent with the findings of a small clinical trial conducted at Johns Hopkins University just a few months prior.10 In this trial, the results of which were published in Neuron, researchers administered low doses of levetiracetam to patients who were not known to have had seizures but who had been diagnosed with aMCI. After receiving the drug, patients showed reversal of brain network abnormalities on functional MRI and modest improvement of learning and memory in a cognitive test.

Large-scale trials are needed to confirm these findings but, according to Mucke, both studies appear to indicate that abnormal neuronal network activity contributes to cognitive impairment, and that antiepileptic medications may improve cognitive functioning.

Clinical Implications
Mucke cautions that it’s too early for physicians to place early-onset AD patients on a course of antiepileptic drug treatment, but he believes there are key takeaways for clinicians from the research available so far.

His first recommendation simply is that physicians remain alert for symptoms of epilepsy early in the course of AD. “If I see an early-onset Alzheimer’s patient, I should not be thinking, ‘I don’t need to worry about the possibility of epilepsy in this patient because he is in such an early stage,’” Mucke says. “Wrong. It’s especially around the onset of the disease that one needs to worry about the possibility of epileptiform activity.”

It’s also a mistaken assumption that seizures will manifest with obvious convulsions, and that patients or family members will understand the importance of reporting them. On the contrary, physicians should be prepared to ask about strange psychic phenomena, such as déjà vu experiences, a feeling of being flushed, or a rising feeling in the stomach. “You have to really be aware of it to question about suspicious types of experiences people may have and to investigate them carefully,” Mucke says.

If there is reason to suspect a seizure, Vossel encourages using an extended EEG over a period of at least two hours rather than relying on routine EEGs for detection. In his team’s experience, longer EEGs are more likely to pick up markers of epileptic activity that could be missed in a routine EEG, which lasts for only 20 minutes.

And for patients who have confirmed seizure activity, the best treatments seem to be levetiracetam or lamotrigine (Lamictal), both of which are newer antiepileptic medications. In the Gladstone Institutes’ studies on both animal models and human populations, these two medications appeared to be more effective and better tolerated than phenytoin (Dilantin), which still is commonly prescribed.

“Not every antiepileptic drug is the same when you treat epilepsy in association with Alzheimer’s disease,” Mucke says. But so far, levetiracetam in particular “works like a charm,” at least in mouse models of the disease. Plans for more extensive human trials of this drug are in the works.

— Jamie Santa Cruz is a freelance writer based in New York City.

References
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