Cellular development and differentiation in human cerebral cortical dysplasia

Human cerebral cortical dysplasia results from the abnormal development and migration of neurons comprising the cerebral cortex. The disorder often manifests as a pediatric or childhood seizure disorder. In cases resistant to pharmacological intervention, the effectiveness of cortical resection to reduce seizure frequency and severity has led to its increased use. Our studies of resected cerebral cortical tissue have attempted to describe the associated neuropathology and more fully understand that pathology in terms of insults which might lead to such malformations. We have used immunohistochemistry, electron microscopy and molecular biology in addition to basic histologic protocols to study resected cerebral tissue.; Our studies have focused on two aberrant cell types which we have shown to be present in subsets of the resection specimens. We have encountered abnormally large cells of apparent neuronal morphology with great intracytoplasmic accumulations of cytoskeletal elements, which we refer to as hypertrophic neurons. We have also observed large swollen cells with glassy, eosinophilic cytoplasm. These cells appear to exist in a state of abnormal differentiation exhibiting features common to both neurons and astrocytes. We refer to this cell as a "balloon" cell in reference to its appearance.; In our studies, we have demonstrated that the profound brain malformations associated with hemimegalencephaly and polymicrogyria share many cytopathologic features with cases described more generally as cortical dysplasia. These features include the presence of the two cell types on which we have concentrated. We demonstrated that the intracytoplasmic neurofilamentous accumulations of hypertrophic neurons bear a close resemblance to the neurofibrillary tangles (NFTs) associated with Alzheimer disease but lack the paired helical filaments which define NFTs ultrastructurally.; Within the balloon cells, we have demonstrated immunoreactivity for neuronal and astrocytic markers using synaptophysin and neurofilament antibodies in concert with antibodies directed against glial fibrillary acidic protein. We have also analyzed their proliferative state using a silver stain commonly used in grading neoplastic lesions demonstrating a cell more like neurons than astrocytes in terms of proliferative potential. Finally we continue to attempt to define the origin and differentiation state of the balloon cell with further double labeling experiments, antibodies to markers of oligodendrocyte differentiation and radial glia, and in situ hybridization.