Philip A. Williams

Development of spontaneous recurrent seizures after kainate-induced status epilepticus

Acquired epilepsy (i.e., after an insult to the brain) is often considered to be a progressive disorder, and the nature of this hypothetical progression remains controversial. Antiepileptic drug treatment necessarily confounds analyses of progressive changes in human patients with acquired epilepsy. Here, we describe experiments testing the hypothesis that development of acquired epilepsy begins as a continuous process of increased seizure frequency (i.e., proportional to probability of a spontaneous seizure) that ultimately plateaus. Using nearly continuous surface cortical and bilateral hippocampal recordings with radiotelemetry and semiautomated seizure detection, the frequency of electrographically recorded seizures (both convulsive and nonconvulsive) was analyzed quantitatively for ∼100 d after kainate-induced status epilepticus in adult rats. The frequency of spontaneous recurrent seizures was not a step function of time (as implied by the “latent period”); rather, seizure frequency increased as a sigmoid function of time. The distribution of interseizure intervals was nonrandom, suggesting that seizure clusters (i.e., short interseizure intervals) obscured the early stages of progression, and may have contributed to the increase in seizure frequency. These data suggest that (1) the latent period is the first of many long interseizure intervals and a poor measure of the time frame of epileptogenesis, (2) epileptogenesis is a continuous process that extends much beyond the first spontaneous recurrent seizure, (3) uneven seizure clustering contributes to the variability in occurrence of epileptic seizures, and (4) the window for antiepileptogenic therapies aimed at suppressing acquired epilepsy probably extends well past the first clinical seizure.

Efficient unsupervised algorithms for the detection of seizures in continuous EEG recordings from rats after brain injury

Long-term EEG monitoring in chronically epileptic animals produces very large EEG data files which require efficient algorithms to differentiate interictal spikes and seizures from normal brain activity, noise, and, artifact. We compared four methods for seizure detection based on (1) EEG power as computed using amplitude squared (the power method), (2) the sum of the distances between consecutive data points (the coastline method), (3) automated spike frequency and duration detection (the spike frequency method), and (4) data range autocorrelation combined with spike frequency (the autocorrelation method). These methods were used to analyze a randomly selected test set of 13 days of continuous EEG data in which 75 seizures were imbedded. The EEG recordings were from eight different rats representing two different models of chronic epilepsy (five kainate-treated and three hypoxic-ischemic). The EEG power method had a positive predictive value (PPV, or true positives divided by the sum of true positives and false positives) of 18% and a sensitivity (true positives divided by the sum of true positives and false negatives) of 95%, the coastline method had a PPV of 78% and sensitivity of 99.59, the spike frequency method had a PPV of 78% and a sensitivity of 95%, and the autocorrelation method yielded a PPV of 96% and a sensitivity of 100%. It is possible to detect seizures automatically in a prolonged EEG recording using computationally efficient unsupervised algorithms. Both the quality of the EEG and the analysis method employed affect PPV and sensitivity.

EEG spike activity precedes epilepsy after kainate-induced status epilepticus

Purpose:  Chronic epilepsy frequently develops after brain injury, but prediction of which individual patient will develop spontaneous recurrent seizures (i.e., epilepsy) is not currently possible. Here, we use continuous radiotelemetric electroencephalography (EEG) and video monitoring along with automated computer detection of EEG spikes and seizures to test the hypothesis that EEG spikes precede and are correlated with subsequent spontaneous recurrent seizures.

The course of cellular alterations associated with the development of spontaneous seizures after status epilepticus

Chronic epilepsy, as a consequence of status epilepticus, has been studied in animal models in order to analyze the cellular mechanisms responsible for the subsequent occurrence of spontaneous seizures. Status epilepticus, induced by either kainic acid or pilocarpine or by prolonged electrical stimulation, causes a characteristic pattern of neuronal death in the hippocampus; which is followed--after an apparent latent period--by the development of chronic, recurrent, spontaneous seizures. The question most relevant to this conference is the degree to which the subsequent chronic seizures contribute further to epileptogenesis and brain damage. This article addresses the temporal and anatomical parameters that must be understood in order to address this question. (1) How does one evaluate experimentally whether the chronic epileptic seizures that follow status epilepticus contribute to epileptogenesis and lead to brain damage? To answer this question, we must first know the time course of the development of the chronic epileptic seizures, and whether the interval between subsequent individual chronic seizures is a relevant factor. (2) What anatomical parameters are most relevant to the progression of epilepsy? For instance, how does loss of inhibitory interneurons potentially influence seizure generation and the progressive development of epileptogenesis? Does axon sprouting and formation of new synaptic connections represent a form of seizure-induced brain damage? These specific issues bear directly on the general question of whether seizures damage the brain during the chronic epilepsy that follows status epilepticus.

Effects of Fluoxetine and TFMPP on Spontaneous Seizures in Rats with Pilocarpine‐induced Epilepsy

Summary:  Purpose: Fluoxetine is a selective serotonin [5‐hydroxytryptamine (5‐HT)] reuptake inhibitor (SSRI) commonly used to treat depression. Some uncontrolled clinical studies have reported that SSRIs increase seizures, but animal experiments with evoked‐seizure models have suggested that SSRIs at therapeutic doses decrease seizure susceptibility. We tested the hypothesis that fluoxetine and trifluoromethylphenylpiperazine (TFMPP, a nonselective 5‐HT–receptor agonist) reduce the frequency of spontaneous motor seizures in pilocarpine‐treated rats.

Use of chronic epilepsy models in antiepileptic drug discovery: The effect of topiramate on spontaneous motor seizures in rats with kainate-induced epilepsy

Summary:  Purpose: Potential antiepileptic drugs (AEDs) are typically screened on acute seizures in normal animals, such as those induced in the maximal electroshock and pentylenetet‐razole models. As a proof‐of‐principle test, the present experiments used spontaneous epileptic seizures in kainate‐treated rats to examine the efficacy of topiramate (TPM) with a repeated‐measures, crossover protocol.

Epilepsy and synaptic reorganization in a perinatal rat model of hypoxia-ischemia.

Summary:  Purpose: One of the potential consequences of perinatal hypoxia–ischemia (H‐I) is the development of epilepsy, and synaptic reorganization in the hippocampus has been associated with epilepsy after an injury. We tested the hypothesis that perinatal H‐I will induce spontaneous motor seizures, hippocampal lesions, and synaptic reorganization in the dentate gyrus.

Development of Spontaneous Seizures after Experimental Status Epilepticus: Implications for Understanding Epileptogenesis

Summary:  This report examines several concepts concerning the latent period to the first convulsive seizure, subsequent increases in seizure frequency, and possible mechanisms of epileptogenesis after kainate‐induced status epilepticus. Previous data concerning the latent period and seizure progression from intermittent and continuous behavioral monitoring are compared, and hypothetical mechanisms of acquired epilepsy are discussed. Data involving electrographic recordings with tethered animals or with radiotelemetry are assessed in terms of their potential for addressing different hypotheses concerning the latent period and progressive changes in seizure frequency. Experimental analyses of the time course of occurrence of spontaneous seizures are interpreted in terms of possible cellular mechanisms underlying epileptogenesis.

Semilunar Granule Cells: Glutamatergic Neurons in the Rat Dentate Gyrus with Axon Collaterals in the Inner Molecular Layer

Synaptic reorganization of the dentate gyrus inner molecular layer (IML) is a pathophysiological process that may facilitate seizures in patients with temporal-lobe epilepsy. Two subtypes of IML neurons were originally described by Ramón y Cajal (1995), but have not been thoroughly studied. We used two-photon imaging, infrared-differential interference contrast microscopy and patch clamp recordings from rat hippocampal slices to define the intrinsic physiology and synaptic targets of spiny, granule-like neurons in the IML, termed semilunar granule cells (SGCs). These neurons resembled dentate granule cells but had axon collaterals in the molecular layer, significantly larger dendritic arborization in the molecular layer, and a more triangular cell body than granule cells. Unlike granule cells, SGCs fired throughout long-duration depolarizing steps and had ramp-like depolarizations during interspike periods. Paired recordings demonstrated that SGCs are glutamatergic and monosynaptically excite both hilar interneurons and mossy cells. Semilunar granule cells appear to represent a distinct excitatory neuron population in the dentate gyrus that may be an important target for mossy fiber sprouting in patients and rodent models of temporal lobe epilepsy.

NMDA receptor-mediated long-term alterations in epileptiform activity in experimental chronic epilepsy

When epileptiform activity is acutely induced in vitro, transient partial blockade of N-methyl-d-aspartic acid (NMDA) receptor-mediated calcium influx leads to selective long-term depotentiation of the synapses involved in the epileptic activity as well as a reduction in the probability of further epileptiform activity. If such selective depotentiation occurred within foci of epileptic activity in vivo, the corresponding long-term reduction in seizure probability could form the basis for a novel treatment of epilepsy. Continuous radiotelemetric EEG monitoring demonstrated modest acute anticonvulsant effects but no long-term reductions in the probability of spontaneous seizures after transient partial blockade of NMDA receptors (NMDAR) during ictal and interictal activity in the kainate animal model of chronic epilepsy. In vitro, depotentiation was induced when NMDAR were partially blocked during epileptiform activity in hippocampal slices from control animals, but not in slices from chronically epileptic rats. However in slices from epileptic animals, depotentiation during epileptiform activity was induced by partial block of NMDAR using NR2B- but not NR2A-selective antagonists. These results suggest that chronic epileptic activity is associated with changes in NMDA receptor-mediated signaling that is reflected in the pharmacology of activity- and NMDA receptor-dependent depotentiation.