Human absence epilepsy: The WAG/Rij rat as a model

Abstract

Human absence epilepsy is characterized by a generalized 3 Hz spike-wave activity in the electroencephalogram. This non-convulsive type of epilepsy is associated with mild myoclonic twitches. Main clinical characteristics are brief lapses in the patient's ability to maintain contact with the environment, with a lowering in vigilance and with a suppression in cognitive functioning. Absence seizures mainly occur during states of drowsiness and during light slow wave sleep. Typical anti-absence drugs are ethosuximide and valproate. There is evidence for an autosomal dominant inheritance. The WAG/Rij strain of rats is considered as an appropriate genetic animal model for this type of epilepsy. The WAG/Rij strain is an inbred strain of albino rats. Electrophysiological studies have indicated that the paroxysms are bilateral symmetrical, with a spike-wave frequency of about 8 Hz. There is a circadian modulation in the number of spike-wave discharges and they mainly occur during passive wakefulness and light slow wave sleep and at transitions of sleep states. This emphasizes the prevalence for spike-wave discharges to breakthrough at unstable periods of vigilance, just as sleep spindles having the same frequency. Thus, the hypothesis that spike-wave discharges are related to sleep spindles is a leading hypothesis. Pharmacological studies have shown a close agreement between man and rat after the administration of clinically effective anti-epileptic drugs. Studies with new compounds have emphasized the role of the GABAergic and glutamatergic systems in this type of epilepsy. Also the dopaminergic and opioidergic systems are involved in absence epilepsy. The role of ion-channels such as sodium and calcium channels is under investigation. Genetic data show a relative simple inheritance factor of one gene regulating being epileptic or not, while other genes determine the number and duration. This is again in good agreement with the scarce human data. Cognitive studies have shown two important features of epilepsy in the WAG/Rij strain. The modulation of the number of spike-wave discharges by mental and physical activity and the disruption of cognitive activity by these discharges. Taking into account all electrophysiological, pharmacological, genetical and behavioural data, it may be concluded that the WAG/Rij strain is an adequate model for absence epilepsy in man, showing face, predictive and, presumably, construct validity. The model may be profitable for gaining further basic insights in the genesis of epilepsy and can also be helpful in the screening and development of putative anti-epileptic drugs.