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Seizures and epileptiform activity in the early stages of Alzheimer disease.

ABSTRACT: Epileptic activity associated with Alzheimer disease (AD) deserves increased attention because it has a harmful impact on these patients, can easily go unrecognized and untreated, and may reflect pathogenic processes that also contribute to other aspects of the illness. We report key features of AD-related seizures and epileptiform activity that are instructive for clinical practice and highlight similarities between AD and transgenic animal models of the disease.To describe common clinical characteristics and treatment outcomes of patients with amnestic mild cognitive impairment (aMCI) or early AD who also have epilepsy or subclinical epileptiform activity.Retrospective observational study from 2007 to 2012. SETTING Memory and Aging Center, University of California, San Francisco.We studied 54 patients with a diagnosis of aMCI plus epilepsy (n = 12), AD plus epilepsy (n?=?35), and AD plus subclinical epileptiform activity (n?=?7).Clinical and demographic data, electroencephalogram (EEG) readings, and treatment responses to antiepileptic medications.Patients with aMCI who had epilepsy presented with symptoms of cognitive decline 6.8 years earlier than patients with aMCI who did not have epilepsy (64.3 vs 71.1 years; P?=?.02). Patients with AD who had epilepsy presented with cognitive decline 5.5 years earlier than patients with AD who did not have epilepsy (64.8 vs 70.3 years; P?=?.001). Patients with AD who had subclinical epileptiform activity also had an early onset of cognitive decline (58.9 years). The timing of seizure onset in patients with aMCI and AD was nonuniform (P?

SUBMITTER: Vossel KA

PROVIDER: S-EPMC4013391 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Seizures and epileptiform activity in the early stages of Alzheimer disease.

Vossel Keith A KA Beagle Alexander J AJ Rabinovici Gil D GD Shu Huidy H Lee Suzee E SE Naasan Georges G Hegde Manu M Cornes Susannah B SB Henry Maya L ML Nelson Alexandra B AB Seeley William W WW Geschwind Michael D MD Gorno-Tempini Maria L ML Shih Tina T Kirsch Heidi E HE Garcia Paul A PA Miller Bruce L BL Mucke Lennart L

JAMA neurology 20130901 9

<h4>Importance</h4>Epileptic activity associated with Alzheimer disease (AD) deserves increased attention because it has a harmful impact on these patients, can easily go unrecognized and untreated, and may reflect pathogenic processes that also contribute to other aspects of the illness. We report key features of AD-related seizures and epileptiform activity that are instructive for clinical practice and highlight similarities between AD and transgenic animal models of the disease.<h4>Objective ...[more]

PMID: 23835471

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Project description:AimsIntracerebral hemorrhage (ICH) is a known risk factor for the development of acute symptomatic as well as late unprovoked seizures. The underlying pathophysiology of post-ICH seizures is incompletely understood and there are no reliable predictive biomarkers. An animal model to study post-ICH seizures is currently lacking. The aim of this study was to investigate (1) the occurrence of seizures and interictal epileptiform activity in the ICH rat collagenase model using long-term video-EEG monitoring (VEM) and (2) whether seizure occurrence was associated with interictal epileptiform activity and histological features.MethodsMale Sprague-Dawley rats were implanted with epidural electrodes. After 1 week of baseline VEM, collagenase was injected in left striatum to induce an ICH. VEM was continued for 180 days to assess the occurrence of post-ICH seizures and interictal epileptiform activity (spikes and epileptiform discharges). At the end of the experiment, animals were euthanized for histological characterization of the hemorrhagic lesion, using cresyl violet, Prussian blue and immunofluorescence staining.ResultsAcute symptomatic seizures occurred in 4/12 animals between 46 and 80 h after ICH induction. Late unprovoked seizures were present in 2/12 animals and started at 90 and 103 days post-ICH. Animals with late unprovoked seizures did not have acute symptomatic seizures. All electrographic seizures were accompanied by clear behavioral changes. Interictal spikes and epileptiform discharges were observed in all animals but occurred more frequently in rats with late seizures (p = 0.019 and p < 0.001, respectively). Animals with acute symptomatic seizures had more extended hemorrhagic lesions and hemosiderin deposits in the piriform cortex.ConclusionBoth acute symptomatic and late unprovoked seizures were observed in the rat collagenase model. Interictal epileptiform activity was more frequently seen in animals with late seizures. Rats with acute symptomatic seizures showed more extensive lesions and hemosiderin deposits in the piriform cortex. This model could be used to further explore possible biomarkers for epileptogenesis.

Project description:ImportanceNetwork hyperexcitability may contribute to cognitive dysfunction in patients with Alzheimer disease (AD).ObjectiveTo determine the ability of the antiseizure drug levetiracetam to improve cognition in persons with AD.Design, setting, and participantsThe Levetiracetam for Alzheimer's Disease-Associated Network Hyperexcitability (LEV-AD) study was a phase 2a randomized double-blinded placebo-controlled crossover clinical trial of 34 adults with AD that was conducted at the University of California, San Francisco, and the University of Minnesota, Twin Cities, between October 16, 2014, and July 21, 2020. Participants were adults 80 years and younger who had a Mini-Mental State Examination score of 18 points or higher and/or a Clinical Dementia Rating score of less than 2 points. Screening included overnight video electroencephalography and a 1-hour resting magnetoencephalography examination.InterventionsGroup A received placebo twice daily for 4 weeks followed by a 4-week washout period, then oral levetiracetam, 125 mg, twice daily for 4 weeks. Group B received treatment using the reverse sequence.Main outcomes and measuresThe primary outcome was the ability of levetiracetam treatment to improve executive function (measured by the National Institutes of Health Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research [NIH-EXAMINER] composite score). Secondary outcomes were cognition (measured by the Stroop Color and Word Test [Stroop] interference naming subscale and the Alzheimer's Disease Assessment Scale-Cognitive Subscale) and disability. Exploratory outcomes included performance on a virtual route learning test and scores on cognitive and functional tests among participants with epileptiform activity.ResultsOf 54 adults assessed for eligibility, 11 did not meet study criteria, and 9 declined to participate. A total of 34 adults (21 women [61.8%]; mean [SD] age, 62.3 [7.7] years) with AD were enrolled and randomized (17 participants to group A and 17 participants to group B). Thirteen participants (38.2%) were categorized as having epileptiform activity. In total, 28 participants (82.4%) completed the study, 10 of whom (35.7%) had epileptiform activity. Overall, treatment with levetiracetam did not change NIH-EXAMINER composite scores (mean difference vs placebo, 0.07 points; 95% CI, -0.18 to 0.32 points; P = .55) or secondary measures. However, among participants with epileptiform activity, levetiracetam treatment improved performance on the Stroop interference naming subscale (net improvement vs placebo, 7.4 points; 95% CI, 0.2-14.7 points; P = .046) and the virtual route learning test (t = 2.36; Cohen f2 = 0.11; P = .02). There were no treatment discontinuations because of adverse events.Conclusions and relevanceIn this randomized clinical trial, levetiracetam was well tolerated and, although it did not improve the primary outcome, in prespecified analysis, levetiracetam improved performance on spatial memory and executive function tasks in patients with AD and epileptiform activity. These exploratory findings warrant further assessment of antiseizure approaches in AD.Trial registrationClinicalTrials.gov Identifier: NCT02002819.

Project description:Transient receptor potential vanilloid 1 (TRPV1) is a cation-permeable ion channel found in the peripheral and central nervous systems. The membrane surface expression of TRPV1 is known to occur in neuronal cell bodies and sensory neuron axons. TRPV1 receptors are also expressed in the hippocampus, the main epileptogenic region in the brain. Although, previous studies implicate TRPV1 channels in the generation of epilepsy, suppression of ongoing seizures by TRPV1 antagonists has not yet been attempted. Here, we evaluate the role of TRPV1 channels in the modulation of epileptiform activity as well as the anti-convulsant properties of capsazepine (CZP), an established TRPV1 competitive antagonist, using in vitro and in vivo models. To this end, we used 4-aminopyridine (4-AP) to trigger seizure-like activity. We found that CZP suppressed 4-AP induced epileptiform activity in vitro (10-100?M) and in vivo (50mg/kg s.c.). In contrast, capsaicin enhanced 4-AP induced epileptiform activity in vitro (1-100?M) and triggered bursting activity in vivo (100?M dialysis perfusion), which was abolished by the TRPV1 antagonist CZP. To further investigate the mechanisms of TRPV1 modulation, we studied the effect of capsaicin and CZP on evoked potentials. Capsaicin (1-100?M) and CZP (10-100?M) increased and decreased, respectively, the amplitude of extracellular field evoked potentials in a concentration-dependent manner. Additional in vitro studies showed that the effect of the TRPV1 blocker on evoked potentials was similar whether the response was orthodromic or antidromic, suggesting that the effect involves interference with membrane depolarization on cell bodies and axons. The fact that CZP could act directly on axons was confirmed by decreased amplitude of the compound action potential and by an increased delay of both the antidromic potentials and the axonal response. Histological studies using transgenic mice also show that, in addition to the known neural expression, TRPV1 channels are widely expressed in alvear oligodendrocytes in the hippocampus. Taken together, these results indicate that activation of TRPV1 channels leads to enhanced excitability, while their inhibition can effectively suppress ongoing electrographic seizures. These results support a role for TRPV1 channels in the suppression of convulsive activity, indicating that antagonism of TRPV1 channels particularly in axons may possibly be a novel target for effective acute suppression of seizures.

Dataset Information

Seizures and epileptiform activity in the early stages of Alzheimer disease.

Publications

Seizures and epileptiform activity in the early stages of Alzheimer disease.

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