Absence Epilepsy: The Tail WAGs the Rat.

Commentary If there is any " sure thing " in epilepsy, the syndrome of childhood absence epilepsy (CAE) may come close to fitting the bill. The characteristic seizure semiology (staring spells), response to specific medications (ethosuximide or valproate), and prognosis (often outgrown by late adolescence) are about as close as we get to a well-defined syndrome with reproducible clinical features and response to specific treatment. CAE is a subtype of generalized genetic epilepsy. The underlying pathophysiology of CAE involves abnormal thalamocorti-cal firing as a result of aberrant T-type calcium channels in thalamocortical and thalamic reticular neurons, giving rise to the responsiveness of absence seizures to the T-type calcium channel blocker, ethosuximide. However, emerging information suggests that many of these presumptions are overly simplified. For example, children with absence epilepsy often express comorbidities including cognitive and psychiatric impairments such as depression and attentional difficulties, albeit less severe than those present in most epilepsies (1). It is not known why seizures begin at a certain age. Despite the purportedly specific action of ethosuximide as a blocker of the T-type calcium channel in thalamic neurons, this drug does not always work. Finally, brain regions outside the thalamocortical axis likely also participate in abnormal rhythm generation and some microscopic structural changes have been documented in the brains of patients with CAE (2, 3). Animal models of absence epilepsy may be helpful in sorting out some of these uncertainties. Several animal models recapitulate salient clinical and electrophysiological aspects of absence epilepsy, one of the most prominent being the WAG/ Rij rat (Wistar Albino Glaxo rats from Rijswijk). The WAG/Rij rat strain has been studied in detail by investigators in the Nether-lands (4) and elsewhere (5). This rat model has provided many insights into generalized epilepsy of the absence type. WAG/ Rij rats exhibit age-related onset of spike-wave discharges (SWD) (7–8 Hz) that correlate with absence-like clinical spells and behavioral arrest. The SWD develop in an age-dependent fashion, emerging around 3 months of age and becoming fully established by 5 to 6 months of age when virtually all rats express SWD. However, unlike many children with CAE, WAG/ Rij rats have persistent SWD and absence seizures throughout their adult life span. Previous studies have shown that seizures and SWD in WAG/Rij rats respond briskly to treatment with ethosuximide at a dose that blocks SWD but does not cause toxic effects; SWD were not decreased by drugs …