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Subclinical Epileptic Spikes Seen in 42 Percent of Alzheimer's Patients, Suggesting Role of Network Hyperexcitability as Potentially Modifiable Risk Factor

ARTICLE IN BRIEF

Researchers has found that in patients with early Alzheimer's disease (AD) who had EEG done, 42.4 percent had subclinical epileptiform spikes, compared to 10.5 percent of healthy controls. They said the findings lend support an emerging hypothesis that network hyperexcitability plays an important and potentially modifiable role in the progression, and perhaps even development, of AD.

The first study to apply highly sensitive noninvasive testing of brain rhythms to patients with early Alzheimer's disease (AD) has found that 42.4 percent had subclinical epileptiform spikes, compared to 10.5 percent of healthy controls, a significant difference (p=0.02).

The findings, published in the December Annals of Neurology, involved only 33 patients and 19 age-matched controls. But the new study confirms the results of previous research involving mouse models of AD. The study authors authors and neurologists familiar with the research said it lends support to an emerging hypothesis that network hyperexcitability plays an important and potentially modifiable role in the progression, and perhaps even development, of AD.

The study authors, as well as another team based at Johns Hopkins, are already in the midst of randomized clinical trials of low-dose levetiracetam aimed at reducing the epileptiform activity and improving functioning.

“There's healthy skepticism among my neurology dementia colleagues about the significance of these epileptiform spikes,” the study's first author, Keith A. Vossel, MD, assistant professor of neurology at the University of California, San Francisco Memory and Aging Center, told Neurology Today. “The question now is whether suppressing this activity is going to benefit patients without harming them. It's not far-fetched that a network stabilizing drug could be disease-modifying. The group from Hopkins is geared up to do a phase 3 trial with the same dose of levetiracetam we're using, but they're looking longitudinally for a disease-modifying effect.”

STUDY DETAILS

Dr. Vossel and colleagues prospectively enrolled 33 patients whose mean age was 62 years and who met criteria for AD but had no history of seizures. They were compared to 19 age-matched cognitively normal controls.

Subclinical epileptiform activity was assessed by blinded clinicians via overnight long-term video-electroencephalography (EEG) and one-hour resting magnetoencephalography exam with simultaneous EEG. Patients and controls also had comprehensive clinical and cognitive evaluations, assessed longitudinally over an average period of 3.3 years.

At the time of initial monitoring, AD patients with epileptiform activity did not differ clinically from those without such activity. “However,” according to the study, “patients with subclinical epileptiform activity showed faster declines in global cognition” determined by the Mini–Mental State Examination (3.9 points/year in patients with epileptiform activity vs 1.6 points/year in patients without; p=0.006), and in executive function (p=0.01).

The frequency of spikes and sharp waves ranged from as few as 0.03 to as high as 5.18 per hour on overnight EEG and from one to 20 per hour on magnetoencephalography exam. Overall, 90.1 percent of the discharges occurred during sleep. Indeed, nine of the 14 AD patients with epileptiform activity, or 64.3 percent, had epileptiform discharges exclusively during sleep.

The activity seen in AD patients was not related to differences in carrier status for the apolipoprotein E4 allele, or to the MAPT (tau) haplotype. Nor, the study reported, “was it related to age, duration of disease symptoms, atypical presentations, history of mild head trauma or myoclonus, clinical fluctuations, blood prolactin levels, or concomitant medications, although there was a trend toward younger age in the patients with epileptiform activity. Two of the patients had a single first-degree relative with epilepsy; both patients were in the non-epileptiform group.”

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DR. KEITH A. VOSSEL: “Theres healthy skepticism among my neurology dementia colleagues about the significance of these epileptiform spikes. The question now is whether suppressing this activity is going to benefit patients without harming them. Its not far-fetched that a network stabilizing drug could be disease-modifying.”

Although researchers have speculated that subclinical epileptic spikes could be the cause of the clinical fluctuations seen in patients with AD, the spikes seen in the study were not associated with clinical fluctuations.

The finding that 10.5 percent of controls also showed spontaneous epileptiform activity was higher than expected, since previous studies had found rates of spontaneous epileptiform activity in 0 to 6.6 percent of healthy adults of all ages. The higher rate seen in the study, Dr. Vossel's team theorized, could be due to the use of long-term overnight EEG and magnetoencephalography, and perhaps by the older age of the population than in previous investigations.

A coauthor of the paper pointed out that the medial temporal lobes show the most prominent neuropathological alterations during early stages of AD and that epileptic activity in this brain region are especially difficult to detect by noninvasive means.

“We suspect that the incidence of epileptiform activity may be even higher than what we detected,” said Lennart Mucke, MD, director of the Gladstone Institute of Neurological Disease and Joseph B. Martin Distinguished Professor of Neuroscience and Professor of Neurology at the University of California, San Francisco.

EXPERTS COMMENT

On the other hand, the true rate of epileptiform activity might be lower than that seen in the study, said Daniel Friedman, MD, associate professor of neurology at New York University Medical Center, and co-director of its video-EEG laboratory, who was not involved with the study.

“The raters were blinded to whether they were looking at recordings of AD patients or controls, but they were not, I presume, blinded to the study hypothesis,” Dr. Friedman said. “That may have made them more amenable to calling discharges as epileptiform. They might have been a little overly sensitive in their interpretations. Probably the real rate of epileptiform activity in patients with AD lies somewhere below 40 percent. But I do still think, as this study shows, that it's higher than previously recognized.”

The first study to detect spontaneous non-convulsive EEG spikes and seizures in a mouse model of AD was published in a 2007 paper in Neuron coauthored by Jeffrey L. Noebels, MD, PhD, who holds the Cullen Trust for Health Care Endowed Chair and is professor of neurology, neuroscience and molecular and human genetics at Baylor College of Medicine.

“When we first published, Alzheimer's neurologists would sometimes say to me, ‘None of my patients have seizures,’” Dr. Noebels said. “But how could they know? Seizures limited to the hippocampus are not obvious, require longer term monitoring, and are not usually even visible in a routine scalp EEG.”

In a 2011 paper in Epilepsia, Dr. Noebels described how epilepsy and AD can interact pathologically. “Since neuronal hyperexcitability amplifies the synaptic release of amyloid-beta,” he wrote, “seizures create a vicious spiral that accelerates cell death and cognitive decline in the AD brain.”

In 2012, another study from Dr. Mucke's group that was also coauthored by Dr. Vossel in the Proceedings of the National Academy of Sciences found that among a variety of antiepileptic drugs tested in hAPP transgenic mice, only levetiracetam suppressed epileptiform discharges in mice. Chronic treatment also reversed hippocampal remodeling, behavioral abnormalities, synaptic dysfunction, and deficits in learning and memory in the mice.

Studies of clinically obvious seizures in AD have found rates as low as 1.5 percent to as high as 22 percent, with autosomal dominant patients having even higher rates. But a growing body of evidence suggests that subclinical epileptiform activity is, at the very least, associated with earlier onset and swifter progression of cognitive loss.

One limitation of the new paper, acknowledged in the discussion, is that the sample size was not large enough to search for genetic or other factors that could promote neural network hyperexcitability. Nor was it possible to determine inter-rater reliability between readers of the neurophysiological readings.

David Spencer, MD, FAAN, director of the comprehensive epilepsy center at Oregon Health & Science University, said that another limitation of the paper is the relatively young mean age of the AD patients, at 61 years, and the fact that they were all drawn from tertiary care AD centers.

“We always have the concerns that it's a unique group that has ended up at this research center,” Dr. Spencer said. “The overall AD population may not have quite such high rates of epileptiform activity.”

Nikolaos Scarmeas, MD, PhD, associate professor of neurology at the National and Kapodistrian University of Athens as well as at Columbia University, has previously studied the incidence of seizures in AD, and said much remains to be learned about the relationship between the two.

“It is a very well done study that produces really novel findings and moves the field forward,” he said. “But it is still not clear what the real cause and effect relationship is.”

Taking note of the wide variation in rates of epileptiform activity seen between patients, Dr. Scarmeas said: “Of course there are understandable power limitations, but it would be important to know whether higher frequencies of epileptiform activities were somehow related to cognitive performance, cognitive decline, or other characteristics.”

He also noted that the clinical presentation and age of onset of the AD patients with epileptiform activity, at about 53 years, was quite unusual. “We know that in autosomal dominant AD the frequency of seizures (and possibly epileptiform activity) is quite high,” Dr. Scarmeas said. “Of course these are not autosomal dominant AD patients, but I suspect it is an AD population possibly enriched with subjects with high genetic susceptibility for AD. It would be important to know whether the findings hold in AD patients with a more typical clinical presentation and age.”

He said it remains to be seen whether reducing epileptiform activity with an antiepileptic drug such as levetiracetam will produce more benefit than harm in a large clinical trial. It could be, he said in an email, that the epileptiform discharges “are a manifestation of a more aggressive form of underlying AD pathology, which is the cause of faster cognitive decline (and not the epileptiform discharges themselves).”

Even if the discharges are causing the cognitive problems, he added, it is debatable whether antiepileptic drugs can safely suppress epileptiform discharges and improve clinical outcomes. That uncertainty was anticipated by Dr. Vossel, even as he proceeds with a phase 1 clinical trial of low-dose levetiracetam.

“The question is what level of activity suppression is going to benefit patients without harming them,” Dr. Vossel said. “If people are sleepy, if you induce strong suppression of brain activity, you can put them into a state in which they're not engaged with the world. Fortunately, seizures in AD are often treatable with low doses of antiseizure drugs that do not affect alertness, and the same may be true for treating more silent forms of network hyperexcitability.”

Hoping to answer that and other questions, Dr. Vossel's ongoing clinical trial seeks to enroll 36 patients with early AD to a trial of levetiracetam, 125 mg twice daily, for 12 weeks. Patients will spend four weeks randomized to drug or placebo, followed by a four-week break, and then the opposite of their initial treatment group.

“We're nearly halfway through,” he said. “We're including people without epileptiform activity to see if they might also respond to the drug.”

At Johns Hopkins, a phase 3 clinical trial of the same low dose of levetiracetam is being led by Michela Gallagher, PhD, the Krieger-Eisenhower Professor of Psychological and Brain Sciences and Neuroscience. Her group previously published the results of a small clinical trial in 2015 involving the drug given to patients with mild cognitive impairment, finding significant improvement in memory task performance relative to placebo.

In September of 2015, the NIH announced a $7.5 million grant to Dr. Gallagher's group to test the 125 mg dose of levetiracetam in a formulation developed by a biotechnology company she founded, AgeneBio. Because of her ownership stake, she is not participating in the clinical aspects of the study.

EXPERTS: ON EPILEPTIFORM ACTIVITY IN ALZHEIMER'S DISEASE

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DR. DANIEL FRIEDMAN: “The raters were blinded to whether they were looking at recordings of AD patients or controls, but they were not, I presume, blinded to the study hypothesis. That may have made them more amenable to calling discharges as epileptiform. They might have been a little overly sensitive in their interpretations. Probably the real rate of epileptiform activity in patients with AD lies somewhere below 40 percent. But I do still think, as this study shows, that its higher than previously recognized.”

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DR. NICHOLAOS SCARMEAS said it remains to be seen whether reducing epileptiform activity with an antiepileptic drug such as levetiracetam will produce more benefit than harm in a large clinical trial. It could be that the epileptiform discharges “are a manifestation of a more aggressive form of underlying AD pathology, which is the cause of faster cognitive decline (and not the epileptiform discharges themselves).”

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DR. JEFFREY L. NOEBELS first detected epileptiform activity in a mouse model of Alzheimers disease: “When we first published, Alzheimers neurologists would sometimes say to me, ‘None of my patients have seizures.’ But how did they know? None of them had ordered an EEG.”

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DR. DAVID SPENCER said that a limitation of the paper is the relatively young mean age of the AD patients, at 61 years, and the fact that they were all drawn from tertiary care AD centers. “We always have the concerns that its a unique group that has ended up at this research center. The overall AD population may not have quite such high rates of epileptiform activity.”

LINK UP FOR MORE INFORMATION:

• Vossel KA, Ranasighe KG, Beagle AJ, et al. Incidence and impact of subclinical epileptiform activity in Alzheimer's disease http://onlinelibrary.wiley.com/doi/10.1002/ana.24794/abstract. Ann Neurol 2016;80(6):858–870.
• Sanchez PE, Zhu L, Verret L, et al. Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer's disease model http://www.pnas.org/content/109/42/E2895.abstract. Proc Natl Acad Sci USA 2012; 109(42):E2895–2903.
• Vossel KA, Beagle AJ, Rabinovici GD, et al. Seizures and epileptiform activity in the early stages of Alzheimer's disease http://jamanetwork.com/journals/jamaneurology/fullarticle/1709572. JAMA Neurol 2013; 70(9):1158–1166.
• Spencer D. Seizures and epileptiform activity in early Alzheimer disease: How hard should we be looking http://epilepsycurrents.org/doi/full/10.5698/1535-7597-14.2.73?code=amep-site. Epilepsy Curr 2014; 14(2):73–75.
• Scarmeas N, Honig LS, Choi H, et al. Seizures in Alzheimer disease: Who, when, and how common http://jamanetwork.com/journals/jamaneurology/fullarticle/797760. Arch Neurol 2009; 66: 992–997.
• Palop JJ, Chin J, Roberson ED, et al. Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer's disease http://www.sciencedirect.com/science/article/pii/S0896627307005703. Neuron 2007; 55(5):697–711.
• Noebels JL. A perfect storm: Converging paths of epilepsy and Alzheimer's dementia intersect in the hippocampal formation http://onlinelibrary.wiley.com/doi/10.1111/j.1528-1167.2010.02909.x/abstract. Epilepsia 2011; 52 (Suppl 1): 39–46.
• Palop JJ. Mucke L. Network abnormalities and interneuron dysfunction in Alzheimer disease http://www.nature.com/nrn/journal/v17/n12/abs/nrn.2016.141.html. Nat Rev Neurosci 2016; 17: 777–792.