Abstracts

RATIONALE: The traditional animal models of seizures used to screen for AED efficacy and investigate mechanisms of epileptogenesis have limited relevance to medically refractory pediatric epilepsy syndromes. We sought to create such a model by inducing atypical absence epilepsy in rats that had dysplastic brains.
METHODS: Pregnant Long Evans rats were treated at embryonic day 15 with methylazoxymethanol (MAM), a teratogenic compound known to induce cortical dysplasias. The resultant pups were then treated sequentially with AY 9944 (AY) in the first 3 postnatal weeks of life. AY is a cholesterol synthesis inhibitor known to induce life-long atypical absence epilepsy (Cortez et al, Neurology 2001;56:341-9). At postnatal day 55, unrestrained animals had EEG video recordings made from epidural electrodes to quantitate the duration and frequency of atypical absence seizures.
RESULTS: AY treatment resulted in spontaneous, bilaterally synchronous slow spike-and-wave discharges (SWD) which were frequent, recurrent, prolonged, and life long. MAM induced cortical dysplasias that were apparent on histological examination of brain. The SWD duration and SWD burst frequency was significantly (P [lt] 0.01) greater in AY treated rats with MAM-induced cortical dysplasias than in AY treated control animals.
CONCLUSIONS: Our experiments demonstrate that the induction of a chronic epileptic state in an abnormal brain during development results in recurrent seizures that are likely to be more severe than those that occur during the same epileptic state induced in a normal brain. This same phenomenon is often observed clinically in medically refractory pediatric epilepsy. Hit 1 creates the brain abnormality and hit 2 induces the seizures. Therefore, in the MAM (hit 1)-AY (hit 2) model the seizures are a result of a pre- and postnatal perturbation of brain. This approach differs from the seizure-induced brain injury which typifies the pilocarpine and kainate rodent models of epilepsy. Our model appears to be more clinically relevant in chilren because seizure-induced brain injury which, in turn, leads to medically refractory epilepsy is not a common occurrence in children. The [dsquote]2 hit[dsquote] concept has the potential to lead to animal models that are clinically relevant to malignant pediatric epilepsy syndromes, such as Lennox Gastaut.
Support: Canadian Institutes of Health Research; Bloorview Childrens Hospital Foundation