Brain tissue from 4 children with intractable epilepsy and subcortical or periventricular nodular heterotopia of different etiologies (megalencephaly, cortical dysplasia, polymicrogyria) was examined at the University of Oxford, Radcliffe Infirmary, UK. Histological and carbocyanine dye (DiI) tracing techniques showed fibers surrounding nodules and connectivity between adjacent nodules. Immunohistochemical tests for calretinin and neuropeptide Y (NPY), normally expressed in GABAergic cortical interneurons, found numerous calretinin-positive neurons (CPN) within nodules with incomplete differentiation, abnormal clusters of CPN in the overlying cortical plate, and many cell processes positive for NPY. Heterotopic nodules were associated with malformation in the overlying cortex and had limited connectivity with other brain regions. Abnormal connectivity could affect the balance of excitation and inhibition in neuronal circuits, leading to epileptogenic activity. 
COMMENT. The abnormal structure, composition, and connections between nodules and the overlying cortex may explain the epileptogenicity of neuronal heterotopias and its propagation to other brain regions.