Research reportTopiramate reduces neuronal injury after experimental status epilepticus
Introduction
Status epilepticus is a neurologic emergency characterized by prolonged or rapidly recurring seizures. It is estimated that between 126,000 and 195,000 episodes of status epilepticus occur annually in the United States [3]. Thirty-five percent of patients are refractory to the best available initial treatment [20]. Despite advances in diagnosis and the development of specific treatment protocols, the mortality associated with status epilepticus is approximately 20% in adults [19], with rates as high as 35% in adults over age 65 [18]. The duration of status epilepticus is a significant determinant of mortality, underscoring the need for rapid treatment [19]. Delayed treatment substantially reduces the likelihood that status epilepticus will respond to initial therapy [11]. Unfortunately, limitations in access to treatment can result in significant delays [8].
In humans dying after status epilepticus, a characteristic pattern of neuronal death has been observed 2, 10, 14. In the hippocampus, neurons in the dentate hilus and pyramidal neurons in regions CA1 and CA3 are particularly vulnerable. Data from experimental models indicate that seizure-induced death of vulnerable neurons is the result of numerous, simultaneous intracellular events which occur after excessive exposure to the excitatory amino acid glutamate [21].
A substantial proportion of seizure-induced neuronal death is delayed for several hours 12, 15. This delay provides a potential therapeutic window during which neuroprotective agents could be administered. Since patients with prolonged status epilepticus are at greatest risk for morbidity and mortality, a need exists for treatments to minimize neuronal injury in this setting.
Topiramate is an anticonvulsant compound that has multiple mechanisms of action including blockade of voltage-gated sodium channels [24], antagonism of non-NMDA glutamate receptors [16], and enhancement of GABA-mediated chloride conductance [22]. Since multiple mechanisms are involved in neuronal injury associated with excessive excitation 1, 21, we hypothesized that topiramate may reduce neuronal injury when administered after experimental status epilepticus.
We used an electrogenic model of limbic status epilepticus in the rat to test the hypothesis that administration of topiramate after 140 min of status epilepticus would reduce hippocampal neuronal injury. This model permits direct control over the duration of status epilepticus, and results in extensive, reproducible hippocampal neuronal injury in a distribution resembling that seen in other models [6]. Since this model does not result in self-sustaining seizures, potential neuroprotective drugs can be administered after status epilepticus has ended, thereby eliminating the confounding influence of anticonvulsant activity.
Section snippets
Materials and methods
All procedures involving animals were in accordance with the National Institutes of Health guide for the care and use of laboratory animals and were approved by the University of Louisville Institutional Animal Care and Use Committee.
EEG parameters
All animals received continuous stimulation for 140 min after the onset of status epilepticus. All animals entered status epilepticus and progressed through a characteristic sequence of EEG stages as described previously [6]. Status epilepticus ended no more than 10 min after stopping stimulation. The afterdischarge threshold, the maximum current needed to induce status epilepticus, the time required to reach status epilepticus and the total duration of ictal EEG activity for each group are
Discussion
The purpose of this study was to test the hypothesis that topiramate, an anticonvulsant compound with multiple mechanisms of action, would prevent seizure-induced hippocampal neuronal death. In order to isolate the potential neuroprotective actions of topiramate from its known anticonvulsant actions, a model of limbic status epilepticus was used in which the duration of status epilepticus was under direct control. This permitted us to administer topiramate or vehicle after status epilepticus
Acknowledgements
Supported by the Jewish Hospital Foundation and an Oak Ridge Associated Universities Junior Faculty Enhancement Award. A preliminary report was presented at the annual meeting of the American Epilepsy Society, San Diego, CA, 1998.
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