Contralateral hemimicrencephaly and clinical-pathological correlations in children with hemimegalencephaly.

In paediatric epilepsy surgery patients with hemimegalencephaly (HME; n = 23), this study compared clinical, neuroimaging and pathologic features to discern potential mechanisms for suboptimal post-hemispherectomy developmental outcomes and structural pathogenesis. MRI measured affected and non-affected cerebral hemisphere volumes for HME and non-HME cases, including monozygotic twins where one sibling had HME. Staining against neuronal nuclei (NeuN) determined grey and white matter cell densities and sizes in HME and autopsy cases, including the non-affected side of a HME surgical/autopsy case. By MRI, the affected hemisphere was larger and the non-affected side smaller in HME compared with non-HME children. The affected HME side showed enlarged abnormal deep grey and white matter structures and/or T2-weighted hypointensity in the subcortical white matter in 75% of cases, suggestive of excessive pre-natal neurogenesis and heterotopias. Histopathological examination of the affected HME side revealed immature-appearing neurons in 70%, polymicrogyria (PMG) in 61% and balloon cells in 45% of cases. Compared with autopsy cases, in HME children NeuN cell densities on the affected side were increased in the molecular layer and upper cortex (+244 to +18%), decreased in lower cortical layers (-35%) and increased in the white matter (+139 to +149%). Deep grey matter MRI abnormalities and/or T2-weighted white matter hypointensity correlated with the presence of immature-appearing neurons and PMG on histopathology, decreased NeuN cell densities in lower cortical layers and a positive history of infantile spasms. Post-surgery seizure control was associated with decreased NeuN densities in the molecular layer. In young children with HME and epilepsy, these findings indicate that there are bilateral cerebral hemispheric abnormalities and contralateral hemimicrencephaly is a likely explanation for poorer post-surgery seizure control and cognitive outcomes. In addition, our findings support the hypothesis that HME pathogenesis probably involves somatic mutations that affect each developing cerebral hemisphere differently with more neurons than expected on the HME side.

A hypothesis regarding the pathogenesis and epileptogenesis of pediatric cortical dysplasia and hemimegalencephaly based on MRI cerebral volumes and NeuN cortical cell densities.

This study compared MRI cerebral volumes and Neuronal-Nuclei (NeuN) cell densities in pediatric epilepsy surgery patients with cortical dysplasia (CD; n = 25) and hemimegalencephaly (HME; n = 14). Our purpose was to deduce possible mechanisms of pathogenesis and epileptogenesis based on an understanding of normal developmental corticoneurogenesis. We used MRI to measured cerebral hemisphere volumes, and NeuN staining to determine grey and white matter cell densities and cell sizes in the molecular layer, grey, and white matter. CD and HME surgical cases were compared with autopsy or non-CD cases (n = 20). Total MRI brain volumes were similar between non-CD, CD, and HME cases. However, in HME patients, the affected cerebral hemisphere was larger and the nonaffected side smaller than non-CD cases. Compared with autopsy cases, NeuN cell densities and cell sizes in CD and HME patients were increased in the molecular layer, upper grey matter, and white matter. In CD and HME cases, total cerebral hemisphere volumes were normal in size and there were more cortical neurons in upper layers than expected. The increase in cortical neuronal densities is consistent with the hypothesis that CD and HME pathogenesis involves increased neurogenesis in the late (not early) phases of cortical formation. In addition, more neurons in the molecular layer and white matter supports the concept that CD and HME pathogenesis also involves incomplete programmed cell death in the remnant cells occupying the preplate and subplate regions. Based on our anatomical and previous electrophysiological findings, we propose that in CD and HME seizure generation is the consequence of incomplete cerebral development with abnormal interactions between immature and mature cells and cellular networks.

Human cortical dysplasia and epilepsy: an ontogenetic hypothesis based on volumetric MRI and NeuN neuronal density and size measurements.

In epilepsy patients with cortical dysplasia (CD), this study determined the probable ontogenetic timing of pathogenesis based on the number, location and appearance of neurons. Magnetic resonance imaging (MRI) determined gray and white matter volumes of affected and non-affected cerebral hemispheres, and gray and white matter neuronal-nuclear protein (NeuN) densities and sizes were assessed in epilepsy surgery patients (0.2-38 years) with CD (n = 25) and non-CD etiologies (n = 14), and compared with autopsy cases (n = 13; 0-33 years). Pathology group, seizure type and age at surgery were compared against MRI and NeuN data. CD patients demonstrated increased MRI cerebral (3%) and gray matter (8%) volumes of the affected compared with non-affected cerebral hemisphere, and increased layer 1 (131%), upper cortical (9-23%) and white matter (28-77%) NeuN densities compared with autopsy cases. Non-CD cases showed decreased cerebral volumes of the affected hemisphere (14-18%) without changes in NeuN densities. Compared with autopsy cases, in CD and non-CD patients, cortical neurons were hypertrophied. Patients with a history of infantile spasms had a 40% increase in the size of layer 1 neurons compared with cases without spasms. By age, regardless of pathology group, there were logarithmic increases in MRI cerebral and white matter volumes, logarithmic increases in the size of lower gray and superficial white matter neurons, and logarithmic decreases in gray and white matter neuronal densities. These results support the concept that there were more neurons than expected in layer 1, gray, and white matter of CD patients compared with non-CD and autopsy cases. In addition, the location and appearance of neurons are consistent with the hypothesis that CD is the consequence of abnormalities occurring late in corticoneurogenesis that involve excessive neurogenesis with retention of pre-plate cells in the molecular layer and subplate regions.