Development of Spontaneous Recurrent Seizures after Kainate-Induced Status Epilepticus

Abstract

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 ϳ100 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.

Mechanisms of physiological and epileptic HFO generation

“…Perhaps the most commonly used chronic models of TLE rely on a period of status epilepticus lasting over 40 min (typically 1-2 h) with may be induced, in rat or in some cases in mouse, by one of kainic acid (KA, intrahippocampal or intraperitoneal) (Ben-Ari et al, 1980;Cavalheiro et al, 1982;Dudek et al, 2006), pilocarpine (intraperitoneal) (Cavalheiro et al, 2006;Curia et al, 2008) or electrical stimulation (intracerebral) (Gorter et al, 2001;Walker et al, 1999). In each of these models the induced status epilepticus is followed by a latent period of days to a couple of weeks before spontaneous seizures start, and then recur for the rest of the lifetime of the animal (Bortel et al, 2010;Lévesque et al, 2011;Williams et al, 2009). The latent period is not silent, as originally thought, but rather is characterized by progressive electrographic abnormalities that culminate in seizures (Bortel et al, 2010;Bragin et al, 1999b;White et al, 2010).…”

Staged anticonvulsant screening for chronic epilepsy

“…The second stage of screening was also accomplished in a matter of weeks. The final, in vivo stage of screening was by far the most labor‐intensive, requiring at least 2 months to develop chronic epilepsy with an adequate seizure rate after kainate treatment,9 2 months to execute the crossover trial, and several months to analyze the electrographic data with blind procedures. The speed of the first stage can be further enhanced by parallelization, so that this staged analysis could also be applied to medicinal chemistry optimization of lead compounds.…”

“…A description of the methods for and characteristics of the repeated, low‐dose kainate model have been published in detail elsewhere 9, 10, 37. Briefly, convulsive status epilepticus was induced in adult male Sprague–Dawley rats (180–200 g) with repeated (i.e., approximately every 30 min), low‐dose (7.5 mg/kg), intraperitoneal (IP) injections of kainic acid (Tocris Bioscience, Bristol, UK).…”

“…While not benign,7 spikes are not the target of anticonvulsants 8. Actual seizure activity in experimental epilepsy is rare, unpredictable, and develops slowly after an inciting brain injury 9. Morbidity and mortality are significant once seizure frequencies are sufficiently high for screening studies 10.…”

“…Repeat biochemical as well as electrophysiological confirmation in vitro comprised the second stage of screening. The final stage was comprised of double blind, crossover controlled, in vivo testing in the kainate model of severe chronic epilepsy9, 32 with seizure quantification by continuous electrographic monitoring 33…”