Human Cortical Dysplasia and Epilepsy: An Ontogenetic Hypothesis Based on Volumetric MRI and NeuN Neuronal Density and Size Measurements

Division of Neurosurgery, University of California, Los Angeles, CA 90005, USA.
Cerebral Cortex (Impact Factor: 8.67). 03/2005; 15(2):194-210. DOI: 10.1093/cercor/bhh122
Source: PubMed


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.

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Available from: Carlos Cepeda, Oct 05, 2015
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    • "Neurons, activated astrocytes and microglia were counted in coronal brain sections. All labeled cells within three squares of 0.15 mm2 each were counted in coronal sections using a BX-51 Olympus (Tokyo, Japan) microscope (200× magnification: 10× ocular and 20× objective) as described [19]. Six sections from each brain were analyzed and averaged. "
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    Journal of Neuroinflammation 02/2014; 11(1):28. DOI:10.1186/1742-2094-11-28 · 5.41 Impact Factor
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    • "Concerning the lower neocortical layers, our investigations revealed that in some patients neither SMI32-positive pyramidal cells nor ER81-positive cells of layers V and VI respected the gray/white matter border, but were detected in the white matter. This subcortical occurrence points to a local migratory failure or to an incomplete regression of subplate neurons [38]. Interestingly, invasion of white matter was common to all different FCD types, independent of their localization and is most likely the cellular correlate of a blurred gray/white matter boundary seen in MR imaging [6]. "
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    ABSTRACT: Focal cortical dysplasias (FCD) are local disturbances of neocortical architecture and a common cause of pharmaco-resistant focal epilepsy. Little is known about the pathomechanisms leading to architectural abnormalities associated with FCD. In the present study we compared 52 FCD cases originating from the frontal or temporal lobe with or without Ammon's horn sclerosis (AHS) with regard to structural and molecular differences. We applied layer-specific (ER81, RORß, SMI32, TLE4) and interneuron (calbindin, parvalbumin) markers by means of immunohistochemistry, in situ hybridization (ISH), and real time RT-PCR and correlated our findings with clinical parameters. We found that: (1) Structural abnormalities were most prominent in layers III-VI including changed morphology of individual neurons or dispersion, blurring and thinning of layers. These alterations were most pronounced in isolated frontal FCD, whereas the most homogeneous group was FCD IIIa. (2) Numbers of calbindin- and parvalbumin-positive interneurons varied considerably within the different FCD groups, but were not generally reduced. A significant decrease was only found for calbindin-positive interneurons in frontal FCD, and for parvalbumin-positive interneurons in FCD IIIa. (3) Interestingly, FCD IIIa presented with significant changes in the numbers of calbindin- or TLE4-positive neurons when compared to isolated FCD or controls. (4) Correlations between clinical and cellular parameters strongly depended on FCD localisation and age of the patients. In summary, our data suggest that late cortical development is disturbed in FCD, yet most likely by different causes depending on brain region, FCD type and FCD severity.
    08/2013; 1(1):47. DOI:10.1186/2051-5960-1-47
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    • "Regional blurring is an established marker of focal cortical neuropathology, particularly in the radiological diagnosis of focal cortical dysplasia (FCD) (Barkovich et al., 2001; Colombo et al., 2003; Huppertz et al., 2005; Thesen et al., 2011). In addition to histological abnormalities in gray matter, such as large dysmorphic neurons and balloon cells, which can lead to cortical thickening in FCD (Blümcke et al., 2011), there is a greater density of white matter neurons just adjacent to the gray–white boundary (Andres et al., 2005; Sisodiya et al., 2009). Together with hypomyelination and gliosis, this can result in blurring of the gray– white boundary in the dysplastic region (Bernasconi et al., 2011). "
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