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:
Vossel KA, Ranasinghe KG, Beagle AJ, Mizuiri D, Honma SM, Dowling AF, Darwish SM, Van Berlo V, Barnes DE, Mantle M, Karydas AM, Coppola G, Roberson ED, Miller BL, Garcia PA, Kirsch HE, Mucke L, Nagarajan SS.
Incidence and impact of subclinical epileptiform activity in Alzheimer's disease.
Ann Neurol. 2016 Dec;80(6):858-870. Epub 2016 Nov 7
PubMed.
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:
Bakker A, Albert MS, Krauss G, Speck CL, Gallagher M.
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.
Huijbers W, Mormino EC, Schultz AP, Wigman S, Ward AM, Larvie M, Amariglio RE, Marshall GA, Rentz DM, Johnson KA, Sperling RA.
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.
Sanchez PE, Zhu L, Verret L, Vossel KA, Orr AG, Cirrito JR, Devidze N, Ho K, Yu GQ, Palop JJ, Mucke L.
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.
Nygaard HB, Kaufman AC, Sekine-Konno T, Huh LL, Going H, Feldman SJ, Kostylev MA, Strittmatter SM.
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.
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:
Vossel KA, Ranasinghe KG, Beagle AJ, Mizuiri D, Honma SM, Dowling AF, Darwish SM, Van Berlo V, Barnes DE, Mantle M, Karydas AM, Coppola G, Roberson ED, Miller BL, Garcia PA, Kirsch HE, Mucke L, Nagarajan SS.
Incidence and impact of subclinical epileptiform activity in Alzheimer's disease.
Ann Neurol. 2016 Dec;80(6):858-870. Epub 2016 Nov 7
PubMed.
Zarea A, Charbonnier C, Rovelet-Lecrux A, Nicolas G, Rousseau S, Borden A, Pariente J, Le Ber I, Pasquier F, Formaglio M, Martinaud O, Rollin-Sillaire A, Sarazin M, Croisile B, Boutoleau-Bretonnière C, Ceccaldi M, Gabelle A, Chamard L, Blanc F, Sellal F, Paquet C, Campion D, Hannequin D, Wallon D, PHRC GMAJ Collaborators.
Seizures in dominantly inherited Alzheimer disease.
Neurology. 2016 Aug 30;87(9):912-9. Epub 2016 Jul 27
PubMed.
Palop JJ, Mucke L.
Network abnormalities and interneuron dysfunction in Alzheimer disease.
Nat Rev Neurosci. 2016 Dec;17(12):777-792. Epub 2016 Nov 10
PubMed.
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:
Vossel KA, Ranasinghe KG, Beagle AJ, Mizuiri D, Honma SM, Dowling AF, Darwish SM, Van Berlo V, Barnes DE, Mantle M, Karydas AM, Coppola G, Roberson ED, Miller BL, Garcia PA, Kirsch HE, Mucke L, Nagarajan SS.
Incidence and impact of subclinical epileptiform activity in Alzheimer's disease.
Ann Neurol. 2016 Dec;80(6):858-870. Epub 2016 Nov 7
PubMed.
Horváth A, Szűcs A, Barcs G, Kamondi A.
Sleep EEG Detects Epileptiform Activity in Alzheimer's Disease with High Sensitivity.
J Alzheimers Dis. 2017;56(3):1175-1183.
PubMed.
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.
Comments
Gladstone Institutes/UCSF
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:
Vossel KA, Ranasinghe KG, Beagle AJ, Mizuiri D, Honma SM, Dowling AF, Darwish SM, Van Berlo V, Barnes DE, Mantle M, Karydas AM, Coppola G, Roberson ED, Miller BL, Garcia PA, Kirsch HE, Mucke L, Nagarajan SS. Incidence and impact of subclinical epileptiform activity in Alzheimer's disease. Ann Neurol. 2016 Dec;80(6):858-870. Epub 2016 Nov 7 PubMed.
View all comments by Lennart MuckeGlobal Alzheimer's Platform Foundation
Johns Hopkins University
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:
Bakker A, Albert MS, Krauss G, Speck CL, Gallagher M. 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.
Huijbers W, Mormino EC, Schultz AP, Wigman S, Ward AM, Larvie M, Amariglio RE, Marshall GA, Rentz DM, Johnson KA, Sperling RA. 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.
Sanchez PE, Zhu L, Verret L, Vossel KA, Orr AG, Cirrito JR, Devidze N, Ho K, Yu GQ, Palop JJ, Mucke L. 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.
Nygaard HB, Kaufman AC, Sekine-Konno T, Huh LL, Going H, Feldman SJ, Kostylev MA, Strittmatter SM. 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.
View all comments by Michela GallagherWashington University
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:
Vossel KA, Ranasinghe KG, Beagle AJ, Mizuiri D, Honma SM, Dowling AF, Darwish SM, Van Berlo V, Barnes DE, Mantle M, Karydas AM, Coppola G, Roberson ED, Miller BL, Garcia PA, Kirsch HE, Mucke L, Nagarajan SS. Incidence and impact of subclinical epileptiform activity in Alzheimer's disease. Ann Neurol. 2016 Dec;80(6):858-870. Epub 2016 Nov 7 PubMed.
Zarea A, Charbonnier C, Rovelet-Lecrux A, Nicolas G, Rousseau S, Borden A, Pariente J, Le Ber I, Pasquier F, Formaglio M, Martinaud O, Rollin-Sillaire A, Sarazin M, Croisile B, Boutoleau-Bretonnière C, Ceccaldi M, Gabelle A, Chamard L, Blanc F, Sellal F, Paquet C, Campion D, Hannequin D, Wallon D, PHRC GMAJ Collaborators. Seizures in dominantly inherited Alzheimer disease. Neurology. 2016 Aug 30;87(9):912-9. Epub 2016 Jul 27 PubMed.
Palop JJ, Mucke L. Network abnormalities and interneuron dysfunction in Alzheimer disease. Nat Rev Neurosci. 2016 Dec;17(12):777-792. Epub 2016 Nov 10 PubMed.
View all comments by Eric McDadeNational Institute of Clinical Neurosciences
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:
Vossel KA, Ranasinghe KG, Beagle AJ, Mizuiri D, Honma SM, Dowling AF, Darwish SM, Van Berlo V, Barnes DE, Mantle M, Karydas AM, Coppola G, Roberson ED, Miller BL, Garcia PA, Kirsch HE, Mucke L, Nagarajan SS. Incidence and impact of subclinical epileptiform activity in Alzheimer's disease. Ann Neurol. 2016 Dec;80(6):858-870. Epub 2016 Nov 7 PubMed.
Horváth A, Szűcs A, Barcs G, Kamondi A. Sleep EEG Detects Epileptiform Activity in Alzheimer's Disease with High Sensitivity. J Alzheimers Dis. 2017;56(3):1175-1183. PubMed.
View all comments by András HorváthBoston University Chobanian & Avedisian School of Medicine
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.
View all comments by Marcia RatnerMake a Comment
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