ReviewThe time course of acquired epilepsy: Implications for therapeutic intervention to suppress epileptogenesis
Highlights
► The classical view of the development of epileptogenesis is a step-function of time after the brain injury. Based on nearly-continuous electrographic (EEG) recordings, seizure frequency was a sigmoid function of time after the insult in two different animal models of acquired epilepsy. ► Spontaneous recurrent seizures often occurred in clusters, even shortly after the first spontaneous seizure. ► The data suggest that (1) epileptogenesis is a continuous process, (2) seizure clusters can obscure this continuous process, and (3) the potential time for administration of a therapy to suppress acquired epilepsy extends well past the first clinical seizure.
Introduction
In order to develop strategies for preventing epileptogenesis, it is critical to understand the temporal features of acquired epilepsy. Brain insults such as traumatic brain injury, stroke, status epilepticus, and infection/inflammation are some of the causes of acquired epilepsy, which usually occurs after a latent period and is often progressive (i.e., the seizures become more frequent and severe over time). Because many patients receive antiepileptic drugs (AEDs) to suppress the symptomatic or “early” seizures directly associated with the brain injury, and most patients are treated with AEDs after one or a few “late” (i.e., “epileptic”) clinical seizures, it is virtually impossible to analyze quantitatively the temporal features of acquired epileptogenesis in humans (i.e., the time-dependent development of spontaneous recurrent seizures), independent of the effects of AEDs. In order to study the effects of potential antiepileptogenic or disease-modifying drugs on acquired epileptogenesis in a quantitative manner, one needs to know the time-course of development of spontaneous recurrent seizures after a brain injury. Animal models of acquired epilepsy provide a means to assess how different types of brain injury lead to an epileptic state, independent of the effects of AEDs. The studies summarized here have analyzed the time course of the development of spontaneous recurrent seizures in two animal models of acquired epilepsy, one of temporal lobe epilepsy and the other of perinatal stroke. These studies are based on nearly continuous electrographic (EEG) recordings with radiotelemetry and correlated video monitoring in kainate-treated rats [41] and in an animal model of hypoxic–ischemic brain damage in immature rats [31], [40].
Numerous hypothetical mechanisms have been proposed to account for, or at least contribute to, epileptogenesis after a brain injury. Molecular and cellular studies have been oriented towards analyses of changes that would occur during the latent period, which is the time from a brain injury to the first clinical seizure. Although it is widely believed that the latent period marks the duration of epileptogenesis, relatively little is known about when the different possible mechanisms of epileptogenesis occur. For example, we do not know if these processes are completed before the first clinical seizure or whether they continue beyond this time point, and if so for how long. The present studies aimed to provide information on the frequency and pattern of spontaneous recurrent seizures as a function of time after the brain injury. One important rationale for the research is that the time course of the development of epileptogenesis is fundamental to an understanding of the mechanisms of acquired epilepsy, and may place constraints on which possible mechanisms are likely to contribute to epileptogenesis after brain injury. In addition, understanding the time course of epileptogenesis is important for deciding when a hypothetical disease-modifying or antiepileptogenic therapy should be administered.
Section snippets
Issues relevant to studies aimed at preventing epileptogenesis
A fundamental question is whether acquired epilepsy is optimally described as a step function (i.e., all or none) or a continuous function (e.g., a sigmoid curve) of time after the brain injury [41]. The second hypothesis implies a slow, gradual and progressive development of epilepsy after the brain injury. Both hypotheses are illustrated in Fig. 1; they may be considered as two extremes along a continuum. Another set of important questions are: What is the duration of the latent period, and
Animal models
Most animal models of temporal lobe epilepsy with spontaneous recurrent seizures are based on status epilepticus, which has been induced with either electrical stimulation or administration of a chemo-convulsant drug. The present studies used the repeated low-dose kainate model of status epilepticus [6], [10], [11], [26], [27]. Hypoxic–ischemic brain injury in immature rats [30], [35], [40] was used as an animal model of perinatal stroke, which is a major cause of intractable epilepsy in
Electrophysiological and histopathological methods
EEG recordings were obtained with a three-channel implantable, radiotelemetry system (Data Sciences International). For kainate-treated rats, two electrodes were positioned bilaterally in the dorsal dentate gyrus, and another recording channel provided a surface EEG. In the postnatal day 7 hypoxic–ischemic animals, one electrode was located over the anticipated infarct region, another was located ipsilaterally in the nearby neocortex, and the third electrode was located in the contralateral
Is acquired epileptogenesis progressive?
Numerous studies have provided data on the question of whether acquired epilepsy is progressive. As introduced above, one view is that acquired epilepsy (e.g., temporal lobe epilepsy) is generally static after a latent period; that is, seizure frequency and severity are variable over time, but do not progressively increase to any major degree (i.e., the step-function hypothesis, Fig. 1). An opposing view is that acquired epilepsy is always progressive, but limitations in the measurement of
Does the latent period mark the time of epileptogenesis?
One of the most interesting and difficult concepts in research on acquired epilepsy is that of the latent period, the time from the brain insult to the observation of the first clinical seizure (Fig. 1). This period in humans can be as short as a few months or as long as many years. One particular difficulty in the field is to explain the mechanistic basis for the cases of exceptionally long latent periods (i.e., many years). Bertram and Cornett [4], [5], using a model based on electrically
The possible significance of seizure clusters?
Many patients with acquired epilepsy, particularly those that are intractable, have seizures that occur in clusters [22], [23], [24], [25]. Similarly, apparent clusters of seizures have been observed in both the kainate [21] and the pilocarpine [18] models of chronic epilepsy. If the occurrence of seizures was random, one could still expect to observe apparent seizure clusters by chance. Williams and co-workers [41] measured successive inter-seizure intervals for the first 100 days after
Progression of epileptogenesis
Although many human patients with acquired epilepsy may not appear to demonstrate progressive epileptogenesis, many others clearly show an increase in seizure frequency and/or severity over time, particularly when considered over several decades [13], [14], [15], [16]. In the present studies, nearly continuous electrographic monitoring for prolonged periods (i.e., months) in rats with kainate-induced epilepsy clearly showed a consistent increase in seizure frequency. This increase in seizure
Conclusions
An improved understanding of the time course of acquired epilepsy is likely to be extremely useful in terms of deciding when to administer anti-epileptogenesis or disease-modifying therapies, and for determining how to assess the potential effects of these therapies. The concepts associated with the step-function hypothesis seem to lead to an exclusive focus on either preventing or reversing the changes associated with acquired epilepsy. To prevent epileptogenesis, therapy administration would
Acknowledgements
Supported by the NINDS and the American Heart Association. These data were derived from collaborative experiments with Phil Williams, Shilpa Kadam, Andrew White, D.J. Ferraro, Suzanne Clark, and Walde Swiercz.
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