Abstracts

RATIONALE: Cortical dysplasia (CD)-associated seizures are often resistant to pharmacologic intervention, necessitating surgical excision of dysplastic tissue. A number of animal models of cerebrocortical dysgenesis have been developed to study CD-associated epilepsy, but prior investigations have emphasized mechanisms of epileptogenesis and have failed to examine the issue of antiepileptic drug (AED) resistance. Here we used rats exposed to methylazoxymethanol acetate (MAM) in utero, to investigate the AED sensitivity of CD-associated seizures.
METHODS: Pregnant S-D rats were injected with MAM (25 mg/kg i.p.) or vehicle on E15. Horizontal hippocampal slices (450 [mu]m) were prepared at P40-P50, using standard techniques and perfused with artificial CSF containing 100 [mu]M 4-aminopyridine. Epileptiform-like interictal bursting developed within 30 min. CA1 field recordings were used to monitor epileptiform activity. For in vitro experiments, 5 standard AEDs were tested: phenobarbital-PHB, 25-400 [mu]M; carbamazepine-CBZ, 25-200 [mu]M; valproate-VPA, 0.19 to 2 mM; ethosuximide-ETX, 0.5-8 mM; and lamotrigine-LMT, 49-390 [mu]M. For in vivo studies, seizure latencies were measured after kainate administration (15 mg/kg, i.p.) with and without pretreatment with valproate (400 mg/kg i.p.) or lamotrigine (15 mg/kg i.p.)
RESULTS: 4-AP-induced epileptiform bursting occurred with shorter latencies in slices from MAM (n = 75; mean = 6.4 min) vs. control rats (n = 97; mean = 18.8 min; p [lt] 0.05), but had similar burst characteristics in both tissue types. AEDs demonstrated dose-dependent burst suppression in control slices, but bursting in MAM slices was relatively AED resistant. Even at the highest doses, VPA, ETX and LMT had no effect on burst amplitude. Evoked epileptiform activity, elicited via stimulation in stratum radiatum, was also not altered by AEDs in MAM slices. Latency to kainate-induced seizures was similar in MAM (n = 6; mean = 61 [plusminus] 20 min) and control rats (n = 8; mean = 68 [plusminus] 15 min). Pretreatment with VPA prolonged latency in controls (n = 8; mean = 105 [plusminus] 15 min), but had no effect in MAM animals (n = 6; mean = 72 [plusminus] 14 min). Pretreatment with LMT slightly prolonged seizure latency in controls (n = 6, mean = 80 [plusminus] 20 min), but shortened seizure latency in MAM animals (n = 7; mean = 37 [plusminus] 10 min).
CONCLUSIONS: Taken together, our findings suggest that standard AEDs (at clinically relevant doses) have no effect in animals with CD. These findings are qualitatively similar to what has been reported for children with CD-associated epileptic syndromes. Because of the similarities with the human condition (e.g., seizure susceptibility, neuronal heterotopia, vascular abnormalities, and pharmaco-resistance), MAM rats may ultimately prove useful in the design and testing of novel treatment options for CD-associated epilepsy.
Support: NIH NRSA fellowship [MDS], March of Dimes & Sandler Family Supporting Foundation [SCB].