Even while measurements taken from atop the scalp registered calm skies in the brain, an all-out electrical storm was raging deep in the hippocampi of two women in different stages of Alzheimer’s disease. Researchers led by Andrew Cole at Massachusetts General Hospital in Boston picked up these so-called silent seizures via probes inserted into the brain via the foramen ovale, a narrow opening between the back of the jaw and the ear. The epileptic activity fired up as the patients slept, and resolved in one after she received treatment with the anticonvulsant levetiracetam. It is unclear how widespread these sleepytime seizures are in people with AD, but Cole speculated they could underlie spells of memory loss and anxiety, or even accelerate neurodegeneration.
“This instructive report nicely demonstrates in Alzheimer’s disease (AD) patients what is well recognized in the epilepsy field, but widely underappreciated in AD research,” commented Lennart Mucke of the University of California, San Francisco. “The absence of obvious seizure activity by clinical observation and routine scalp EEG does not exclude the presence of frequent epileptic events, particularly in the medial temporal lobes and during sleep.”
Researchers have long noted that people with AD have a higher incidence of epileptic activity. This can range from overt seizures that trigger convulsions to non-convulsive seizures and the epileptic spikes that pop up in between them. While the latter two are often considered “subclinical,” researchers have previously associated these hidden discharges with faster cognitive decline in people with mild cognitive impairment and AD (see July 2013 news; Vossel et al., 2016).
Electrodes placed on the scalp remain limited in their ability to detect these abnormal currents, even though their sensitivity has improved with overnight video electroencephalograms (EEGs) as well as magnetoencephalography (MEG), a technique that picks up electrical spikes emanating from multiple directions. Still, probes threaded inside the brain “hear” even more. Electrodes inserted via a needle through the foramen ovale have been used to pinpoint the source of seizures in people with epilepsy. With the patient under general anesthesia, surgeons insert a needle into the upper cheek and through the foramen ovale using fluoroscopic guidance. They then thread the electrodes through the needle, positioning them in the ambient cistern, a fluid-filled space on the surface of the brain, adjacent to the medial temporal lobes. Patients stay at the clinic for monitoring for several days, before the electrodes are gently removed through wires still protruding from the cheeks. Though less invasive than procedures that require opening the skull, FO electrodes are not commonly used on people without overt signs of seizures (see Karakis et al., 2011).
In this study, first author Alice Lam and colleagues hypothesized that intermittent seizure activity in the medial temporal lobe (mTL) could explain why people with AD experience episodic bursts of confusion, memory loss, or anxiety. Reasoning that scalp measurements might miss this subcortical activity, the researchers implanted FO probes into two patients with fluctuating cognitive symptoms.
The first volunteer was a 67-year-old woman whose cognition had been waning over a year, punctuated by episodes of intense confusion. Neuropsychological testing indicated amnestic MCI, and brain MRI and FDG-PET scans showed diffuse brain atrophy and hypometabolism in her left tempoparietal lobe. Cerebrospinal fluid concentrations of Aβ, tau, and p-tau suggested AD as the cause for her symptoms. She carried one ApoE4 allele, but no autosomal-dominant AD mutations. A routine 35-minute scalp EEG, obtained as she slept, found no signs of epileptic activity, but when the researchers conducted continuous video EEG over several hours, hints of abnormality emerged from the left temporal lobe. About 40-70 epileptic spikes per hour popped up as she slept, compared to about two blips per hour while she was awake.
The scalp recordings were but the tip of the iceberg, it turned out. From their position next to the medial temporal lobes, the FO electrodes picked up about 400 and 850 spikes per hour from the left mTL during waking and sleeping, respectively. A simultaneous scalp EEG failed to detect 95 percent of these spikes, and it recorded nary a blip during any of the three seizures the FO electrodes detected during the first 12 hours of monitoring. With the electrodes still in place, the patient started taking 1,500mg/day of the anticonvulsant levetiracetam. No further seizures occurred, and spikes dropped by 65 percent during the following two days. At that time the researchers removed the electrodes. The woman’s cognition continued to decline. It is unclear whether levetiracetam slowed this process, but the woman reported a spell of confusion a year later after she had missed several consecutive doses of the drug.
Silent Storm. Though readings from scalp EEG (top six panels) failed to notice, deeper readings from a nearby (LFO) electrode caught a seizure (arrow) in the left medial temporal lobe. [Image courtesy of Lam et al., Nature Medicine, 2017.]
The second patient, a 63-year-old woman with dementia, had declined rapidly over the previous five years. Brain atrophy and CSF biomarkers indicated she had early onset AD, though no genetic testing was done. Dramatic fluctuations in anxiety brought her to the researchers’ attention. Similar to the first patient, video EEG recordings picked up some signs of epileptic activity, but the FO probes uncovered substantially more. Again, only about 5 percent of the spikes detected intracranially also registered scalpside. This patient did not tolerate levetiracetam due to her worsening mood.
The findings demonstrate that abundant epileptic activity can occur in the hippocampus in different stages of AD, and that it is largely undetected via scalp EEG, Cole concluded. Whether this phenomenon occurs in a significant proportion of people with AD is unclear, especially since hippocampal seizures also have been documented in people without AD (Höller and Trinka, 2014).
“That the seizures are only picked up with foramen ovale electrodes and not scalp EEG is known to sometimes occur in people with or without dementia, who have temporal lobe seizures,” commented David Holtzman of Washington University in St. Louis. More extensive studies would be needed to determine if the phenomenon occurs more frequently in AD, he added.
Regardless of whether mTL spikes and seizures occur in the context of AD, their predominance during sleep could make them prone to affect cognition, commented Brendan Lucey, also of WashU. Studies have indicated that non-REM, slow-wave sleep is prime time for memory consolidation. “If someone is having subclinical seizures every night, this could certainly impair memory,” he said.
Cole agreed. “That these discharges happen during sleep ups the ante for their potential significance to cognition,” he said.
To further probe the relationship between AD, seizures, and cognitive decline, subcortical epileptic activity would need to be monitored in large numbers of people. But is widespread monitoring via FO electrodes feasible, or required, to accomplish this? Not necessarily, according to Keith Vossel of the University of Minnesota in Minneapolis. Vossel pointed out that some abnormalities did pop up on extended video EEGs in this study. Furthermore, Vossel’s studies, conducted at UCSF, used both extended video EEG and MEG, and found that AD patients had higher levels of epileptic activity emanating from the temporal lobes and other regions, and that this correlated with accelerated cognitive decline. Vossel is using these scalp measurements for an ongoing trial testing the cognitive benefits of low doses of levetiracetam in patients with or without epileptic activity.
Cole added that researchers in his lab are working to make scalp EEG more sensitive using computational tools. Even if scalp methods only pick up a fraction of spikes in the hippocampus, it is possible they could be used to screen patients for trials, he said. Researchers also mentioned that besides being more invasive than scalp EEG, placement of FO electrodes is a specialized procedure not available at most clinics.
András Horváth of the National Institute of Clinical Neuroscience in Budapest, published a paper in February about epileptiform activity in AD (Horváth et al., 2017). He called the use of this semi-invasive technique in AD patients a “brilliant idea,” but added a word of caution. “While foramen ovale implantation proved to be generally safe in the assessment of epilepsy, we have to emphasize that strict patient selection is essential because previous experience is absent in the elderly population,” Horváth wrote to Alzforum (see full comment below).
Regarding the potential relationship between epileptic activity and AD, Cole and commentators pointed to Mucke’s hypothesis, whereby Aβ and tau pathology could trigger network dysfunction that could spark epileptic activity. This, in turn, could promote release of more Aβ, exacerbate tau pathology, and trigger more network dysfunction and seizures (Sept 2007 news). If such a vicious cycle indeed exists, then anti-epileptic therapies such as levetiracetam could slow disease progression, rather than just soothe symptoms, researchers commented.
In a joint comment to Alzforum, Michela Gallagher of Johns Hopkins University in Baltimore and Richard Mohs of AgeneBio, Inc., drew a distinction between the epileptic spikes and seizures reported in Cole’s paper and the stable neuronal hyperactivity observed in other studies. “The new study …. uses a novel electrophysiological technique to measure epileptiform activity during sleep, while previous studies used fMRI to measure activity during waking hours,” they wrote (see full comment below). “The relationship of these measures should be explored and their relationship to one another, if any, needs to be evaluated.”
Regarding levetiracetam treatment, they added that early clinical studies demonstrated low doses of levetiracetam can ameliorate hyperactivity and improve cognition (see Mar 2015 news). Cole used higher doses. “It does not appear that they tested lower doses, which might have the desired effect on neuronal overactivity in the medial temporal regions with very few side effects,” they added.—Jessica Shugart
- Epilepsy in Alzheimer’s Can Be Early and Subtle
- Do "Silent" Seizures Cause Network Dysfunction in AD?
- More Evidence That Epilepsy Drug Calms Neurons and Boosts Memory
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