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 newsVossel 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.

Going Deep.

Inserted through the foramen ovale between the jaw and the ear, bilateral electrodes lie adjacent to each medial temporal lobe, primed to pick up epileptic spikes. [Courtesy of Lam et al., Nature Medicine 2017.]

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

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  1. This instructive report by Lam et al. nicely demonstrates in Alzheimer’s disease (AD) patients what is well recognized in the epilepsy field, but widely underappreciated in AD research: 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.

    These illustrative cases also suggest that our recent study, in which we detected subtle, non-convulsive epileptiform activity in 42 percent of AD patients by overnight scalp EEG recordings and magnetoencephalography, may well have underestimated the actual extent and prevalence of the problem.

    As highlighted by the findings of Lam and colleagues, even more sensitive approaches would have to be applied to obtain more accurate estimates. In agreement with their findings, most of the AD-associated epileptic activity we detected in our study occurred during sleep (see Vossel et al., 2016). 

    References:

    . Incidence and impact of subclinical epileptiform activity in Alzheimer's disease. Ann Neurol. 2016 Dec;80(6):858-870. Epub 2016 Nov 7 PubMed.

  2. This paper provides additional support for the growing body of data indicating that neuronal overactivity in the medial temporal regions of the brain are an integral part of the pathophysiology of early Alzheimer’s disease and probably play a role in driving subsequent neurodegeneration. This is a small study in two patients, and the specific findings will need to be investigated in other patients. Studies using fMRI have consistently found hippocampal overactivity in patients with clinically identified mild cognitive impairment; they have also shown that this phenomenon is stable rather than fluctuating, and is associated with the deposition of amyloid plaques and progression of cognitive decline (Huijbers et al., 2015). This is consistent with data from animal models showing neural overactivity associated with Aβ overexpression, neuronal dysfunction, and cognitive deficits (Sanchez et al., 2012); all of these abnormalities were positively affected by a low dose of levetiracetam. In humans with MCI, low doses, but not higher doses, of levetiracetam diminished hippocampal overactivity and improved performance on a memory task (Bakker et al., 2015). 

    This new study by Lam et al. uses a novel electrophysiological technique to measure epileptiform activity during sleep, while previous studies used fMRI to measure activity during waking hours. The relationship of these measures should be explored and their relationship to one another, if any, needs to be evaluated.

    Previous work on hippocampal overactivity showed the most benefit came from low doses of levetiracetam, while those used in the Lam et al. paper are within the usual antiepileptic dose range. 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. Note that in animal AD models, a dissociation has been observed between the efficacy of antiepileptics on aberrant epileptiform activity and cognitive benefit (Nygaard et al., 2015). Overall, this paper is a very useful addition to the literature on the relationship of AD dementia to neuronal overactivity.

    References:

    . Response of the medial temporal lobe network in amnestic mild cognitive impairment to therapeutic intervention assessed by fMRI and memory task performance. Neuroimage Clin. 2015;7:688-98. Epub 2015 Feb 21 PubMed.

    . Amyloid-β deposition in mild cognitive impairment is associated with increased hippocampal activity, atrophy and clinical progression. Brain. 2015 Apr;138(Pt 4):1023-35. Epub 2015 Feb 11 PubMed.

    . Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer's disease model. Proc Natl Acad Sci U S A. 2012 Oct 16;109(42):E2895-903. PubMed.

    . Brivaracetam, but not ethosuximide, reverses memory impairments in an Alzheimer's disease mouse model. Alzheimers Res Ther. 2015;7(1):25. Epub 2015 May 5 PubMed.

  3. The association of seizures and epilepsy with Alzheimer’s disease (AD) is well established. However, there is increasing recognition that seizures may occur in milder stages of the disease (Vossel et al., 2016; Zarea et al., 2016), and that this may be a consequence of the altered brain network hyperexcitibility related to AD pathology (Palop and Mucke, 2016).

    Lam and colleagues provide an interesting addition to this area of research by reporting on two cases of young-onset, nonfamilial AD that had bilateral mesial temporal lobe intracranial electrodes placed through the foramen ovale. In both cases, they found a high level of clinically silent hippocampal seizures and epileptiform discharges that were far more common than those identified using scalp electrodes. In one case, levetiracetam resulted in a significant improvement of seizure activity, whereas in the other case it was not tolerated. They also report that cognitive decline continued over one year in the one patient who tolerated levetiracetam.

    The number of subclinical seizures and epileptiform activity identified in one of these cases was striking and certainly suggests that a component of the cognitive and clinical impairment characteristic of AD could be from epileptiform activity. Further, it clearly supports more research into the causes, clinical manifestations, and treatment of altered network dynamics in AD.

    However, the ultimate utility of this procedure for screening for seizures in AD patients is likely limited. As the authors point out, epileptiform activity was identified in one of the patients using a video EEG with scalp electrodes, and recent work by Vossel and colleagues has identified a high prevalence of epileptiform activity in AD using noninvasive techniques. Rather, this technique might be better employed to more precisely study the mechanisms underlying the network hyperexcitibility, the time of onset relative to Aβ, tau pathology and synaptic protein alterations, the impact on clinical progression, and treatment options beyond levetiracetam. 

    References:

    . Incidence and impact of subclinical epileptiform activity in Alzheimer's disease. Ann Neurol. 2016 Dec;80(6):858-870. Epub 2016 Nov 7 PubMed.

    . Seizures in dominantly inherited Alzheimer disease. Neurology. 2016 Aug 30;87(9):912-9. Epub 2016 Jul 27 PubMed.

    . Network abnormalities and interneuron dysfunction in Alzheimer disease. Nat Rev Neurosci. 2016 Dec;17(12):777-792. Epub 2016 Nov 10 PubMed.

  4. This report adds to the growing body of evidence that epileptic activity is an important and early concomitant condition of Alzheimer’s disease. Epilepsy, especially epileptic spikes, could be a remarkable contributor in the accelerated progression of AD, and non-convulsive seizures might resemble the commonly seen alterations in the cognitive performance of AD patients (Vossel et al., 2016). However, recognition of epileptic seizures and interictal discharges is complicated because EEG is not part of the routine assessment of cognitive disorders. Another important aspect of the problem is that routine electroencephalography (EEG) shows limited sensitivity in capturing epileptic signs, while the presence of epileptiform potentials seems to be related to the non-REM sleep period (Horváth et al., 2017). 

    The hippocampus is a primary affected structure of pathological protein misfolding in AD; however, it is also the most epileptogenic area of the brain. We know that capturing epileptic seizures or interictal discharges could be difficult in mesiotemporal lobe epilepsy because epileptic activity arising from the deep brain structures such as hippocampus could remain hidden on scalp electrodes. In epilepsy studies, approximately 70 percent of epileptiform discharges could be captured only by deep electrodes. Thus, to examine AD patients with a semi-invasive foramen ovale electrode technique is a brilliant idea.

    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. However, the findings are fascinating as well; seemingly, epilepsy could be hidden on scalp electrodes but detectable even in the early phase of AD. This might have positive consequences since previous reports revealed promising results on the use of antiepileptic drugs (especially levetiracetam) in the early phase of Alzheimer’s disease. Since we also apply foramen ovale implantation in AD-related epilepsy, I believe that epileptic activity is an important concomitant condition in neurocognitive disorders and the introduction of foramen ovale measurements could lead to new therapeutic strategies and could open new perspectives in the research of dementia.

    References:

    . Incidence and impact of subclinical epileptiform activity in Alzheimer's disease. Ann Neurol. 2016 Dec;80(6):858-870. Epub 2016 Nov 7 PubMed.

    . Sleep EEG Detects Epileptiform Activity in Alzheimer's Disease with High Sensitivity. J Alzheimers Dis. 2017;56(3):1175-1183. PubMed.

  5. I agree with Dr. Gallagher. The hyperactivity in the dentate and CA3 hippocampal subregions observed in humans and aged animal models is entirely consistent with these new observations. Most importantly, the use of higher concentrations of anti-epilepsy medications may exacerbate the memory deficits associated with aMCI and AD. Therefore, the lowest clinically effective doses should be used.

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References

News Citations

  1. Epilepsy in Alzheimer’s Can Be Early and Subtle
  2. Do "Silent" Seizures Cause Network Dysfunction in AD?
  3. More Evidence That Epilepsy Drug Calms Neurons and Boosts Memory

Therapeutics Citations

  1. AGB101

Paper Citations

  1. . Incidence and impact of subclinical epileptiform activity in Alzheimer's disease. Ann Neurol. 2016 Dec;80(6):858-870. Epub 2016 Nov 7 PubMed.
  2. . Foramen ovale electrodes in the evaluation of epilepsy surgery: conventional and unconventional uses. Epilepsy Behav. 2011 Oct;22(2):247-54. Epub 2011 Jul 22 PubMed.
  3. . What do temporal lobe epilepsy and progressive mild cognitive impairment have in common?. Front Syst Neurosci. 2014;8:58. Epub 2014 Apr 16 PubMed.
  4. . Sleep EEG Detects Epileptiform Activity in Alzheimer's Disease with High Sensitivity. J Alzheimers Dis. 2017;56(3):1175-1183. PubMed.

External Citations

  1. trial 

Further Reading

Papers

  1. . Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer's disease model. Proc Natl Acad Sci U S A. 2012 Oct 16;109(42):E2895-903. PubMed.
  2. . Brivaracetam, but not ethosuximide, reverses memory impairments in an Alzheimer's disease mouse model. Alzheimers Res Ther. 2015;7(1):25. Epub 2015 May 5 PubMed.

Primary Papers

  1. . Silent hippocampal seizures and spikes identified by foramen ovale electrodes in Alzheimer's disease. Nat Med. 2017 Jun;23(6):678-680. Epub 2017 May 1 PubMed.