Brain Advance Access originally published online on November 16, 2005
Brain 2006 129(2):352-365; doi:10.1093/brain/awh681
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Contralateral hemimicrencephaly and clinical–pathological correlations in children with hemimegalencephaly
Divisions of 1 Neurosurgery, 2 Neuroradiology, and 3 Neuropathology and 4 Department of Neurology, 5 The Brain Research Institute and 6 The Mental Retardation Research Center, David Geffen School of Medicine, University of California, Los Angeles, CA, USA and 7 Departments of Pathology and 8 Neurology, Ribeirão Preto School of Medicine, University of São Paulo, Ribeirão Preto, SP, Brazil
Correspondence to: Gary W. Mathern, MD, Reed Neurological Research Center, 710 Westwood Plaza, Room 2123, Los Angeles, CA 90095-1769, USA E-mail: gmathern{at}ucla.edu
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.
Key Words: seizures; MRI volumetric; cortical dysplasia; malformations of cortical development; unilateral megalencephaly; cell cycle; neurogenesis; corticogenesis; tuberous sclerosis complex
Abbreviations: HME = hemimegalencephaly; NeuN = neuronal nuclei; PMG = polymicrogyria
Received May 23, 2005. Revised September 7, 2005. Accepted September 28, 2005.
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