756 Cellular and Network Mechanisms of Epileptogenesis in Cortical Dysplasia: A Combined Clinical, Pathological, and Electrophysiological Study

Abstract

INTRODUCTION: Epileptogenesis in cortical dysplasia (CD) is unknown but could be caused by cytomegalic neurons and balloon cells acting as “pacemakers” and/or changes in excitatory and inhibitory synaptic transmission. This study addressed this question using a combined clinical-pathological-electrophysiological approach in pediatric epilepsy surgery patients with CD. METHODS: In vitro electrophysiology determined intrinsic membrane properties and spontaneous glutamatergic and GABAergic synaptic activity for normal-pyramidal neurons, cytomegalic neurons, and balloon cells (n = 360) from 67 neocortical sites from 43 CD patients (age range, 0.2–14 yr). Magnetic resonance imaging (MRI), fluorodeoxyglucose-positron emission tomography (FDG-PET), and electrocorticography (ECoG) graded sample sites from least to worst CD abnormality. RESULTS: Cytomegalic neurons were observed in 60% and balloon cells in 53% of pathological specimens. Cytomegalic neurons and/or balloon cells were most frequent in areas of severe CD compared with mild or normal CD regions as assessed by FDG-PET/MRI, and the presence of cytomegalic neurons (but not balloon cells) correlated with the worse ECoG scores. Using voltage-clamp techniques, cytomegalic neurons, when depolarized, generated large oscillatory voltage-gated calcium spikes, and 25 to 30% of normal-pyramidal and all tested cytomegalic neurons showed decreased magnesium sensitivity and loss of NR2B subunit expression. In current clamp, however, cytomegalic and normal-pyramidal neurons displayed similar active membrane properties without intrinsic bursting. Balloon cells were electrically silent using similar techniques. Normal-pyramidal neurons displayed decreased spontaneous glutamatergic synaptic activity in the areas of most severe hypometabolism by FDG-PET compared with normal regions, and there were no changes in GABAergic synaptic activity based on FDG-PET/MRI abnormalities. CONCLUSION: In CD, these findings indicate that cytomegalic and normal-pyramidal neurons but not balloon cells could be candidate epileptogenic neurons but are not likely to be “pacemaker” cells. Instead, epileptogenic neurons and abnormal synaptic circuits working together probably contribute to seizure generation in CD tissue.