Young-Jong Woo

Atypical teratoid/rhabdoid tumor of the central nervous system: clinico-pathological study.

Atypical teratoid/rhabdoid tumor (AT/RT) is a new entity among malignant pediatric brain tumors. This study was performed to investigate the clinicopathologic and cytogenetic features of the tumor. Five cases from a series of the brain tumors were studied. Clinical features of the patients were assessed with age, sex, location of the tumors, treatments and survival periods. Histopathologic features were analyzed by routine HE stain and immunohistochemical stains for epithelial membrane antigen, cytokeratin, vimentin, smooth muscle actin, desmin, GFAP, S‐100 protein, neurofilament protein, synaptophysin and α‐feto protein. Cytogenetic studies for karyotype analysis and fluorescent in situ hybridization were available in three cases. Mean age of patients was 5.6 years, and maximal survival periods were less than 13 months despite surgical and radiation therapy. The tumors were located in infratentorial and supratentorial areas. Histopathologically, the tumors were chiefly composed of rhabdoid cells, modified rhabdoid cells and undifferentiated small cells, mixed with epithelial, mesenchymal, and neural tumor‐like areas. These polyphenotypic features of the tumor cells were supported by diverse immunoreaction. Monosomy of chromosome 22 was demonstrated in two cases of the tumor. These results suggest that AT/RT may be a unique clinicopathologic entity, and histopathologic diagnosis of it should be made judiciously by differentiating other polymorphous tumors of the brain.

Clinical features and epileptogenesis of dysembryoplastic neuroepithelial tumor

IntroductionDysembryoplastic neuroepithelial tumor (DNT) frequently causes medically intractable epilepsy.ObjectiveThe aim of this study was to investigate the basic mechanism of epileptogenecity of the tumor.Materials and methodsClinicopathological data in 13 cases of DNT and immunohistochemical changes of ionotropic glutamate receptor subunits in the tumor and peritumoral epileptogenic cortex were studied.ConclusionsMagnetic resonance imaging combined with electroencephalography (EEG), electrocorticography, and depth-electrode EEG was valuable to localize complicated epileptogenic zones of the patients with DNT. Neuropathological examinations of the peritumoral cerebral cortex presenting abnormal spikes showed different histopathological grades of neuronal migration disorder (NMD). The tumor cells in DNT disclosed increased immunopositivities of N-methyl-d-aspartate receptor 1 (NR1) and NR2A/B, and peritumoral epileptogenic NMD revealed increased immunopositivities of GluR2 and GluR3. The amplification of ionotropic glutamate receptor subunits in the tumor and peritumoral NMD may be the underlying cause of epileptic seizures in DNT patients.

Pathophysiologic characteristics of balloon cells in cortical dysplasia

ObjectsBalloon cells are histopathological hallmarks of cortical malformations, i.e., focal cortical dysplasia (FCD) of the Taylor type or the cortical tubers of tuberous sclerosis, and they are believed to be the epileptogenic substrate and cause therapeutic drug resistant epilepsy in man. This study was carried out to investigate the developmental histogenesis and epileptogenesis of balloon cells in FCD.Materials and methodsWe used an immunohistochemical approach to examine the expressions of primitive neuroepithelial cell antigens (CD34, nestin, and vimentin), ionotrophic glutamate receptor subunits (NR1, NR2A/B, GluR1, GluR2, GluR3, GluR4, and GluR5/6/7), and P-glycoprotein in balloon cells from FCD and normal cerebral cortex epileptogenic lesions.ConclusionBalloon cells presented in clusters or as scattered cells throughout FCD lesions involving the gray and white matter. We found the balloon cells to be classifiable into three subtypes based on glial fibrillary acidic protein (GFAP) and neurofilament protein (NF-L) immunohistochemistry, i.e., as neuronal, astrocytic, and uncommitted. Immunopositivity for nestin, CD34, and vimentin in balloon cells of FCD suggests that they may be derived from the abnormal development and differentiation of neural stem cells. Moreover, it appears that epileptogenesis in cortical dysplasia is partly caused by the upregulations of some glutamate receptor subunit proteins (NR1, NR2A/B, GluR1, and GluR3) in balloon cells and dysplastic neurons. We speculate that the presence of the drug resistance protein P-glycoprotein in balloon cells might explain medically refractory epilepsy in FCD.

Immunohistochemical analysis of developmental neural antigen expression in the balloon cells of focal cortical dysplasia.

Balloon cells (BC) are the histological hallmarks of focal cortical dysplasia (FCD). Expression of the neural stem cell surface marker CD133 and other developmental markers was studied in the BC of FCD using formalin-fixed paraffin-embedded tissue from nine patients with FCD. Labeling indexes were calculated for all antibodies. BC were easily identified at the gray-white matter junction and they extended into the white matter. Immunoreactivity in BC was found for the following antigens in nine patients: CD133 (six patients; 22.2 ± 7.7%), CD34 (two patients; 0.4 ± 0.3%), nestin (nine patients; 37.6 ± 8.5%), vimentin (eight patients; 59.2 ± 8.7%), glial fibrillary acid protein (six patients; 34.3 ± 10.4%), microtubule-associated protein 2 (four patients; 8.3 ± 5.0%), neurofilament-middle/high (five patients; 10.2 ± 4.6%) and synaptophysin (three patients; 4.2 ± 3.3%). Neuronal nuclei (NeuN, neuron specific nuclear protein) was not expressed in BC of any patient. The results of this study suggest that BC in patients with FCD originate from glioneuronal precursor cells and that developmental defects of neuronal and glial specifications are important in the histogenesis of FCD.

Stem Cell Dynamics in an Experimental Model of Stroke

We investigated the migration of endogenous neural stem cells (NSCs) toward an infarct lesion in a photo-thrombotic stroke model. The lesions produced by using rose bengal dye (20 mg/kg) with cold light in the motor cortex of Sprague-Dawley rats were also evaluated with sequential magnetic resonance imaging (MRI) from 30 minutes through 8 weeks. Migration of NSCs was identified by immunohistochemistry for nestin monoclonal antibody in the lesion cortex, subventricular zone (SVZ), and corpus callosum (CC). The contrast to noncontrast ratio (CNR) on MRI was greatest at 12 hours in DWI and decreased over time. By contrast, T1-weighted and T2-weighted images showed a constant CNR from the beginning through 8 weeks. MRI of the lesional cortex correlated with histopathologic findings, which could be divided into three stages: acute (edema and necrosis) within 24 hours, subacute (acute and chronic inflammatory cell infiltration) at 2 to 7 days, and chronic (gliofibrosis) at 2 to 4 weeks. The volume of the infarct was significantly reduced by reparative gliofibrosis. The number of nestin+ NSCs in the contralateral SVZ was similar to that of the ipsilateral SVZ in each group. However, the number of nestin+ NSCs in the ipsilateral cortex and CC increased at 12 hours to 3 days compared with the contralateral side (p<0.01) and was reduced significantly by 7 days (p<0.01). Active emigration of internal NSCs from the SVZ toward the infarct lesion may also contribute to decreased volume of the infarct lesion, but the self-repair mechanism by endogenous NSCs is insufficient to treat stroke causing extensive neuronal death. Further studies should be focused on amplification technologies of NSCs to enhance the collection of endogenous or transplanted NSCs for the treatment of stroke.

Advance Organizers in a Gross Anatomy Dissection Course and Their Effects on Academic Achievement

We presented two kinds of advance organizers (AOs), video clips and prosection, for a gross anatomy dissection course and compared their effects on academic achievement and student perception of the learning experience. In total, 141 students at Chonnam National University Medical School were randomly assigned to two groups: Group 1 (n = 70) was provided with video clips AO, whereas Group 2 (n = 71) was provided with prosection AO, the use of cadaveric specimens dissected by the course instructor. Student self‐assessment scores regarding the learning objectives of upper limb anatomy improved significantly in both groups. Academic achievement scores in Group 2 were significantly higher than those in Group 1, although the self‐assessment scores were not significantly different between the groups. Additionally, students in Group 2 responded significantly more positively to the statements about perception of the learning experience such as helping them understand the course content and concepts, decreasing anxiety about the dissection course, and participating actively in the dissection. It would seem that the application of prosection as an AO improved academic achievement and increased student engagement and satisfaction. This study will contribute to designing effective AOs and developing a teaching and learning strategy for a gross anatomy dissection course. Clin. Anat. 2013.

Bilateral perisylvian ulegyria: clinicopathological study of patients presenting with pseudobulbar palsy and epilepsy.

Structural abnormalities related with pseudobulbar palsy have been gaining attention because of their characteristic symptoms and unique pathogenesis. We present five cases of bilateral perisylvian ulegyria (BPU) presenting epilepsy and pseudobulbar palsy with pathogenesis different from previously reported syndromes. All patients showed medically intractable seizures, complex partial seizures with secondary generalization and clinical symptoms of pseudobulbar palsy, including dysarthria, limitation of tongue movement and drooling. MRI revealed BPU in all patients, and BPU associated with hippocampal sclerosis in four patients. Intracranial EEG recording with subdural grip and stripe was helpful for localizing the area of ictal generation. Resective surgeries, including the temporal lobe, central area and parietal lobe, were performed depending on the localizing information. The surgical outcome was favorable after 9.8 years of follow‐up. Characteristic features of ulegyria were confirmed on pathological examination. Ulegyria is considered to be another important perinatal or postnatal structural abnormality which can explain the etiological heterogeneity for pseudobulbar palsy, which results from bilateral perisylvian lesions. Awareness of this disorder can provide a useful strategy for evaluation and treatment which differs from that in perisylvian polymicrogyria.

Upregulation of glutamate receptors in rat cerebral cortex with neuronal migration disorders.

Neuronal migration disorders (NMDs) constitute the main pathologic substrate of medically intractable epilepsy in human. This study is designed to investigate the changes in expression of glutamate receptor subtypes on radiation-induced NMD in rats. The lesion was produced by intrauterine irradiation (240 cGy) on E17 rats, and then 10 weeks old rats were used for the study. The pathologic and immunohistochemical findings for glutamate receptor subunit proteins on NMD cortex were correlated with development of behavioral seizures and EEG abnormality. Spontaneous seizures uncommonly occurred in NMD rats (5%); however, clinical stages of seizures were significantly increased in NMD rats by an administration of kainic acid. Brains taken from irradiated rats revealed gross and histopathologic features of NMD. Focal cortical dysplasia was identified by histopathology and immunohistochemistry with neurofilament protein (NF-M/H). Significantly strong NR1 and NR2A/B immunoreactivities were demonstrated in cytomegalic and heterotopic neurons of NMD rats. The results of the present study indicate that epileptogenesis of NMD might be caused by upregulation of glutamate receptor expression in dysplastic neurons of the rat cerebral cortex with NMDs.

Neurotoxicity Screening in a Multipotent Neural Stem Cell Line Established from the Mouse Brain

Neural stem cells (NSCs) have mainly been applied to neurodegeneration in some medically intractable neurologic diseases. In this study, we established a novel NSC line and investigated the cytotoxic responses of NSCs to exogenous neurotoxicants, glutamates and reactive oxygen species (ROS). A multipotent NSC line, B2A1 cells, was established from long-term primary cultures of oligodendrocyte-enriched cells from an adult BALB/c mouse brain. B2A1 cells could be differentiated into neuronal, astrocytic and oligodendroglial lineages. The cells also expressed genotypic mRNA messages for both neural progenitor cells and differentiated neuronoglial cells. B2A1 cells treated with hydrogen peroxide and L-buthionine-(S,R)-sulfoximine underwent 30-40% cell death, while B2A1 cells treated with glutamate and kainate showed 25-35% cell death. Cytopathologic changes consisting of swollen cell bodies, loss of cytoplasmic processes, and nuclear chromatin disintegration, developed after exposure to both ROS and excitotoxic chemicals. These results suggest that B2A1 cells may be useful in the study of NSC biology and may constitute an effective neurotoxicity screening system for ROS and excitotoxic chemicals.

Increased expression of l-amino acid transporters in balloon cells of tuberous sclerosis

ObjectsTuberous sclerosis complex (TSC) is a dysgenetic syndrome involved in multiple organs, and the pathognomonic cortical tuber act as an epileptic substrate. The amino acid transport system L (LAT) is a major nutrient transport system, and LAT1 is highly expressed in malignant tumors to support tumor cell growth. To study the life-long epilepsy from the cortical tuber, the expression of LAT1 in balloon cells and dysplastic neurons of the cortical tuber is investigated.Materials and methodsLAT1 expression was investigated by LAT1 mRNA using reverse transcription-polymerase chain reaction and immunohistochemical staining with anti-human LAT1 antibody in nine patients with TSC and three control brains.ConclusionLAT1 mRNA was detectable only in fresh-frozen tissues of TSC, and it was upregulated in the cortical tuber lesion. While the LAT1 immunopositivity of control brains was limited in the capillary endothelial cells in the gray matter, increased LAT1 immunopositivity was noted in balloon cells of the cortical tubers in addition to the capillary endothelial cells as shown in control brains. Linear and strong immunopositivity along the cell membrane and cytoplasm of the balloon cells, and weakly granular immunopositivity in their cytoplasm were noted. Increased expression of LAT1 in the balloon cells is important for the active transport of large neutral amino acids into the balloon cells, and that the biologic process may play an important role in the active protein synthesis with metabolic maintenance of balloon cells in cortical tubers of patients with TSC.