Subclinical Seizures Linked to Memory Loss?

Megan Brooks

May 05, 2017

Researchers at Massachusetts General Hospital (MGH) in Boston, Massachusetts, have observed clinically silent seizures and epileptic activity in the hippocampus of two patients with early Alzheimer's disease (AD) and no history of seizures.

These alterations in the brain's electrical activity were absent on standard scalp electroencephalography (EEG) but were evident using bilateral electrodes inserted through the foramen ovale (FO) targeting the mesial temporal lobe (mTL). 

These observations suggest that clinically silent mTL seizures and spikes can occur early in the course of AD in the absence of substantial scalp EEG abnormalities and may predominate during sleep, a time critical for memory consolidation, the researchers say.

"While the primary finding of epileptic discharge in mesial temporal structures in patients with AD is fascinating, the observation that these events occur preferentially during sleep is particularly provocative as it suggests epileptic activity may specifically disrupt memory consolidation known to occur during sleep," senior author, Andrew Cole, MD, professor of neurology, Harvard Medical School, and director, MGH Epilepsy Center, Boston, told Medscape Medical News.

"Our findings challenge the widely held view that epilepsy occurs only as a late sequela of neurodegeneration in AD, to be treated symptomatically once clinical seizures arise," Dr Cole and colleagues write in their report, published online May 1 in Nature Medicine.  

Patient 1

The first patient was a 67-year-old woman with no seizure history who developed cognitive decline over 1 year, characterized by confusional episodes. Neuropsychological testing demonstrated amnestic mild cognitive impairment. Scalp EEG performed during sleep showed normal sleep architecture and no evidence of focal slowing or epileptiform discharges. 

On the basis of a high index of suspicion for occult seizures, the patient was implanted with bilateral FO electrodes targeting the mTL. Intracranial recordings from these electrodes revealed abundant mTL spiking (approximately 400 spikes per hour during wakefulness and up to 850 spikes per hour during sleep). Most (95%) of the spikes detected on the FO electrodes were not seen on scalp EEG.

During the first 12 hours of recording, the patient had three subclinical seizures arising from the left mTL, all of which occurred during sleep. Scalp EEG during these seizures showed no ictal activity.

The patient was treated with the antiepileptic drug levetiracetam, which has reduced abnormal spiking activity in animal models of AD and reduce hippocampal hyperactivity in humans with amnestic MCI.

After initiation of levetiracetam (1500 mg/d), no further seizures were captured on the FO electrodes over the following 48 hours before  removal of the electrodes, and the spike frequency was reduced by 65%.  In the following year, the patient experienced only one episode of confusion, which occurred after she missed several doses of her antiseizure medication.

Patient 2

The second patient was initially evaluated at age 58 years for gradual cognitive decline, including repetitive questioning, misplacing objects, and social withdrawal. She had no history of seizures. Within 5 years, she had severe dementia.

Continuous video-EEG monitoring demonstrated rare multifocal epileptiform discharges occurring independently over the right temporal, left temporal, and bifrontal regions (roughly 2 discharges per hour during wakefulness and about 12 discharges per hour during sleep).

Bilateral FO electrode recordings showed frequent right mTL spikes (about 16 spikes per hour during wakefulness and up to 190 spikes per hour during sleep). Like the first patient, over 95% of the spikes detected on the FO electrodes were not evident on a scalp EEG. A trial of levetiracetam (1000 mg/d) was not tolerated because of worsening mood.

"Our findings reveal a specific form of network dysfunction in patients with AD that may contribute directly to some of the most troubling symptoms of AD," Dr Cole told Medscape Medical News. "This observation highlights a specific physiology that can be targeted for treatment with new and existing drugs. Additionally, because neuronal activity may drive release of amyloid beta and promote tau production and metabolism, it is possible that the activity we have recognized may have a role in underlying disease progression," he said.

The next step, said Dr Cole, is to validate these observations in a larger cohort to understand how prevalent it is in patients with AD, whether it occurs in other neurodegenerative disorders, and how it responds to treatment.

"New analytical tools that can be applied to scalp EEG signals or that incorporate functional neuroimaging strategies will ultimately lead to broader recognition of this aspect of the disease and will facilitate development and clinical trials of new targeted treatments," he said.

Interpret Cautiously

Reached for comment, Cyrus A. Raji, MD, PhD, from the University of California, San Francisco, said, "This short report importantly describes what could be a new component of our better understanding Alzheimer's pathology. The authors described how seizures in the hippocampus may link Alzheimer's with epilepsy — another brain disorder that also targets the hippocampus. More work needs to be done in developing this potential connection."

Asked for his thoughts on this research, Ronald Petersen, MD, PhD, director, Mayo Clinic Alzheimer's Disease Research Center, Rochester, Minnesota, said, "We know there is an increased number of seizure disorders in people with Alzheimer's disease, and one would think so insofar as Alzheimer's disease is a neurodegenerative disease and in some people that may elicit a seizure."

The "cautionary note" with this report, said Dr Petersen, is that it includes only two patients. "I would be cautious in extrapolating this to say that maybe people with Alzheimer's disease are having subclinical seizures or seizure discharges in the hippocampus and that this is compounding their memory problems. But it does raise the question whether that could be the case in some people."

"My epilepsy colleagues," he added, "said the likelihood that there is major seizure activity or electrical spiking going on in the hippocampus that is absolutely not reflected on the surface with a typical EEG is really quite low."

This research, Dr Petersen concluded, is "certainly very interesting and raises some questions, but it's far from conclusive and you really need to study a broader population of people."

The study was supported by grants from the National Institute of Neurological Disorders and Stroke, Citizens United for Research in Epilepsy, and the Blue Bird Circle Foundation. The authors have disclosed no relevant financial relationships.

Nat Med. Published online May 2, 2017. Abstract

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