Biomedical subjects

Ingmar Blümcke

Publications and source records attributed to Ingmar Blümcke.

At least 37 records · Page 2Linked to original sources

PubMed2004

CD34-immunoreactive balloon cells in cortical malformations.

Balloon cells are histopathological hallmarks of various cortical malformations, i.e., focal cortical dysplasia (Taylor's type, FCD IIb), hemimegalencephaly (HME) or cortical tubers (tuberous sclerosis, TSC). Whether this intriguing cell type results from similar pathogenetic pathways remains to be shown. Here, we analyzed the immunohistochemical distribution pattern of the CD34 epitope in surgical specimens from 34 patients with FCD IIb, compared to that of 6 patients with TSC and 3 patients with HME. In normal brain, CD34 occurs only transiently during neurulation, but cannot be detected in mature neuroectodermal cell progenies. In contrast, 58% of our patients showed CD34 immunoreactivity within a subpopulation of balloon cells. Interestingly, CD34-positive balloon cells were confined to the white matter, but never observed in neocortical layers. Furthermore, balloon cells expressing neurofilament protein were also restricted to white matter, whereas GFAP-positive balloon cells were observed either in white or gray matter location. Clinical characteristics did not significantly differ between patients with CD34-positive versus CD34-negative lesions. No significant correlation was found between CD34 expression and genetic alterations of the TSC1 gene, which is affected in many FCD and TSC patients and which plays a role in the regulation of cell size. Further studies are warranted to clarify the restricted expression of CD34 in balloon cells of the white matter.

Adolescent↗

PubMed2004

Microtubule-associated protein-2 immunoreactivity: a useful tool in the differential diagnosis of low-grade neuroepithelial tumors.

Complex and variable morphological phenotypes pose a major challenge to the histopathological classification of neuroepithelial tumors. This applies in particular for low-grade gliomas and glio-neuronal tumors. Recently, we and others have identified microtubule-associated protein-2 (MAP2) as an immunohistochemical marker expressed in the majority of glial tumors. Characteristic cell morphologies can be recognized by MAP2 immunoreactivity in different glioma entities, i.e., process sparse oligodendroglial versus densely ramified astrocytic elements. Here, we describe MAP2-immunoreactivity patterns in a large series of various neuroepithelial tumors and related neoplasms (n = 960). Immunohistochemical analysis led to the following conclusions: (1) specific pattern of MAP2-positive tumor cells can be identified in 95% of glial neoplasms; (2) ependymal tumors do not express MAP2 in their rosette-forming cell component; (3) tumors of the pineal gland as well as malignant embryonic tumors are also characterized by abundant MAP2 immunoreactivity; (4) virtually no MAP2 expression can be observed in the neoplastic glial component of glio-neuronal tumors, i.e. gangliogliomas; (5) malignant glial tumor variants (WHO grade III or IV) exhibit different and less specific MAP2 staining patterns compared to their benign counterparts (WHO grade I or II); (6) with the exception of melanomas and small cell lung cancers, MAP2 expression is very rare in metastatic and non-neuroepithelial tumors; (7) glial MAP2 expression was not detected in 56 non-neoplastic lesions. These data point towards MAP2 as valuable diagnostic tool for pattern recognition and differential diagnosis of low-grade neuroepithelial tumors.

Biomarkers, Tumor↗

PubMed2004

Analysis of chromosomal instability in focal cortical dysplasia of Taylor's balloon cell type.

Focal cortical dysplasias (FCD) represent a frequent finding in patients with chronic intractable epilepsy. Neuropathological hallmarks include localized dyslamination of the neocortex and neuronal heterotopias in white matter. Balloon cells, similar to those occurring in cortical tubers of patients with tuberous sclerosis (TSC) are observed in numerous patients. These lesions were classified as FCD type IIb (FCD IIb). Recent findings indicate an accumulation of TSC1 polymorphisms as well as loss of heterozygosity (LOH) and/or microsatellite instability (MSI) at the TSC1 locus on chromosome 9q in FCD IIb. Here, we tested the hypothesis of whether chromosomal instability constitutes a genome-wide phenomenon in this patient cohort. Seven microsatellite markers based on a reference panel recommended by the international workshop on microsatellite instability were analyzed in 14 surgical FCD IIb specimens. DNA from single laser-microdissected cells, i.e., balloon cells versus control neurons obtained from adjacent cortex was harvested for PCR amplification and subsequent fluorescent fragment length gel electrophoresis. Our analysis revealed only rare instances of LOH and MSI at genomic loci on 2p and 17q, whereas no alterations were found at informative markers on chromosomes 1p, 5q and 18q. In addition, no loss of repair protein expression (MSH2 or MLH1) has been identified in balloon cell nuclei of FCD IIb specimens. The present data suggest solitary LOH and MSI events at genomic localizations others than the TSC1 locus to occur in FCD IIb. Our findings lend further support to the hypothesis that the molecular pathogenesis of FCD IIb is associated with TSC1.

Chromosomal Instability↗

PubMed2004

An isomorphic subtype of long-term epilepsy-associated astrocytomas associated with benign prognosis.

The semi-benign nature of diffuse astrocytomas is characterized by an increased risk for tumor recurrence and malignant transformation. In patients with intractable seizures, however, length of history and clinical follow-up studies indicate a better prognosis of this tumor entity. Here, we present a clinico-neuropathological study of 19 patients with chronic seizures and diffuse astrocytomas. In 6 patients, long-term survival and lack of tumor progression after a maximal follow-up time of 13 years appeared to correlate with a histologically isomorphic phenotype. Cytological hallmarks comprise low cellularity, lack of mitotic activity and highly differentiated astroglial elements infiltrating into adjacent brain parenchyma. Compared to "classical" variants of diffuse astrocytomas (WHO grade II), immunohistochemical reactions revealed a cellular proliferation below 1%, absence of nuclear p53 accumulation, and a lack of glial MAP2 and CD34 expression. Histopathologically, the isomorphic astrocytoma subtype can be distinguished from gangliogliomas, pilocytic astrocytomas and dysembryoplastic neuroepithelial tumors as well as from cortical dysplasia or reactive gliosis. Our data support the concept of a rare variant of diffuse astrocytomas occurring in young adults with long-term epilepsy and a favorable prognosis, which corresponds to WHO grade I.

Adolescent↗

PubMed2004

Analysis of different types of resection for pediatric patients with temporal lobe epilepsy.

OBJECTIVE: Resection strategies for the treatment of temporal lobe epilepsy (TLE) are a matter of discussion. Few data on the significance of resection type are available for pediatric patients with TLE. METHODS: Data for a series of 89 children who were surgically treated for TLE were analyzed. A first cohort of patients were mainly surgically treated with anterior temporal lobectomies. For a second cohort, resections were preoperatively "tailored" to the lesion and presumed epileptogenic area. RESULTS: The follow-up period was 46 months (range, 14-118 mo). Seventy-seven patients (87%) attained satisfactory seizure control (82% Engel Class I and 5% Class II). For 12 patients (13%), seizure control was unsatisfactory (8% Class III and 5% Class IV). Anterior temporal lobectomies resulted in 94% satisfactory seizure control (33 patients), whereas the success rates were only 74% (20 patients) for amygdalohippocampectomy (AH) (P = 0.023) and 77% (13 patients) for lesionectomy plus hippocampectomy (not significant). All patients who underwent purely lateral temporal lesionectomies became seizure-free (14 patients). Logistic regression revealed the factors of AH (P = 0.021) and left-side surgery (P = 0.017) as significant predictors of unsatisfactory seizure control. Satisfactory seizure control was not dependent on the histopathological diagnoses. There was a low rate of verbal memory deterioration after left-side operations. Neuropsychological deterioration was rare after right temporal resections. Attentional and contralateral functions improved after surgery. CONCLUSION: Surgery for the treatment of juvenile TLE is successful and safe, but the resection type may influence outcomes. Results after AHs were disappointing, probably because of difficulties in precise localization of the epileptogenic focus among children. Neuropsychological results demonstrated minimal rates of deterioration and significant improvements in contralateral functions. Surgical treatment of juvenile TLE should be encouraged, but the use of especially left AH should possibly be restricted.

Adolescent↗

PubMed2004

Evidence for a clinically distinct new subtype of grade II astrocytomas in patients with long-term epilepsy.

OBJECTIVE: The authors tested the hypothesis that among Grade II astrocytomas with a particularly long seizure history, a subgroup is hidden with a different prognosis and possibly histological characteristics. To do so, clinical and histological characteristics of two groups of World Health Organization Grade II astrocytoma patients were analyzed: the long-term epilepsy-associated tumor (LEAT) astrocytoma group, with a mean duration of 12.5 years of seizures (n = 19), and the ordinary astrocytomas (n = 87), with a mean length of seizure history of 1.5 years (Non-LEAT). METHODS: All astrocytomas operated on between 1988 and 1999 were collected and followed up for 2 to 13 years (median, 7.0 yr). The 19 LEAT astrocytomas belonged to a group of 207 long-term epilepsy-associated tumors from the epilepsy surgery program. The 87 Non-LEAT cases were 60 so-called ordinary or diffuse World Health Organization Grade II astrocytomas and 27 oligoastrocytomas without long-term epilepsy operated on during the same time period. All tumor cases have been reviewed and partly reclassified as a result of the use of modern immunohistochemical techniques. Statistical analyses for possible discriminating factors included chi(2) test, Fisher's exact test, Kaplan-Meier curves, and multifactorial analysis. RESULTS: Histological subtyping revealed a possible new isomorphic astrocytoma subtype in seven patients. By use of Kaplan-Meier curves, this isomorphic subtype had 50% fewer recurrences at 7.5 years and an estimated long-term survival of 80%. LEAT astrocytomas differed from ordinary Non-LEAT astrocytomas in overall length of history, younger age at first seizure, and higher percentage of 10-year survivors (80%). Temporal location did not influence outcome, and the presence of epilepsy per se was also not a prognostic factor. CONCLUSION: Differences between astrocytomas with a very long seizure history and those with a very short seizure history do exist. Significant factors for prognosis were age at surgery and presence of postoperative tumor residue but not the presence of epilepsy per se. A new subtype of astrocytomas, provisionally called isomorphic LEA astrocytoma, has putatively been identified with significantly better survival and lower recurrence rate. The negative prognostic factor of a gemistocytic differentiation pattern in diffuse astrocytomas was confirmed.

Adolescent↗

PubMed2003

Cellular pathology of amygdala neurons in human temporal lobe epilepsy.

The amygdala complex substantially contributes to the generation and propagation of focal seizures in patients suffering from temporal lobe epilepsy (TLE). A cellular substrate for increased excitability in the human amygdala, however, remains to be identified. Here, we analyzed the three-dimensional morphology of 264 neurons from different subregions of the amygdaloid complex obtained from 17 "en bloc" resected surgical specimens using intracellular Lucifer Yellow (LY) injection and confocal laser scanning microscopy. Autopsy samples from unaffected individuals ( n=3, 20 neurons) served as controls. We have identified spine-laden, spine-sparse and aspinous cells in the lateral, basal, accessory basal and granular nuclei. Semiquantitative analysis points to significant changes in neuronal soma size, number of dendrites and spine densities in specimens from epilepsy patients compared to controls. Neuronal somata in the epilepsy group were smaller compared to controls ( P<0.01), neurons had fewer first-order dendrites ( P<0.01), whereas the maximum density of spines per dendritic segment in these cells was increased in TLE patients ( P<0.01). There were also dendritic alterations such as focal constrictions or spine bifurcations. These changes were consistent between amygdaloid subregions. The dendritic morphology of amygdaloid neurons in TLE patients points to substantial changes in synaptic connectivity and would be compatible with altered neuronal circuitries operating in the epileptic human amygdala. Although the morphological alterations differ from those described in hippocampal subregions of a similar cohort of TLE patients, they appear to reflect a characteristic pathological substrate associated with seizure activity/propagation within the amygdaloid complex.

Adult↗

PubMed2003

Heterotopias, cortical dysplasias and glioneural tumors participate in cognitive processing in patients with temporal lobe epilepsy.

Focal brain lesions such as cortical dysplasia and glioneural tumors generate epileptic activity and thus may be synaptically connected with normal cortex. To test this hypothesis, we compared event-related potentials recorded directly from the medial temporal lobe (MTL) and a dysplastic lesion in eight patients with intractable temporal lobe epilepsy. The P3 component, related to visual target detection, showed different peak latencies in four patients and a larger intralesional amplitude compared to established anterior-MTL-generators in two patients. Semantic processing was identified by the N400 component and showed a different latency in four patients and larger intralesional amplitudes in two patients. These results are compatible with the hypothesis that cortical lesions interact with synaptic pathways related to cognitive functions such as visual target detection, and verbal processing.

Adult↗

PubMed2003

Consequences of a novel caveolin-3 mutation in a large German family.

Mutations in the human caveolin-3 gene (cav-3) on chromosome 3p25 have been described in limb girdle muscular dystrophy, rippling muscle disease, hyperCKemia, and distal myopathy. Here, we describe the genetic, myopathological, and clinical findings in a large German family harboring a novel heterozygous mutation (GAC-->GAA) in codon 27 of the cav-3 gene. This missense mutation causes an amino acid change from asparagine to glutamate (Asp27Glu) in the N-terminal region of the Cav-3 protein, which leads to a drastic decrease of Cav-3 protein expression in skeletal muscle tissue. In keeping with an autosomal dominant mode of inheritance, this novel cav-3 mutation was found to cosegregate with neuromuscular involvement in the reported family. Ultrastructural analysis of Cav-3-deficient muscle showed an abnormal folding of the plasma membrane as well as multiple vesicular structures in the subsarcolemmal region. Neurological examination of all nine subjects from three generations harboring the novel cav-3 mutation showed clear evidence of rippling muscle disease. However, only two of these nine patients showed isolated signs of rippling muscle disease without muscle weakness or atrophy, whereas five had additional signs of a distal myopathy and two fulfilled the diagnostic criteria of a coexisting limb girdle muscular dystrophy. These findings indicate that mutations in the human cav-3 gene can lead to different and overlapping clinical phenotypes even within the same family. Different clinical phenotypes in caveolinopathies may be attributed to so far unidentified modifying factors/genes in the individual genetic background of affected patients.

Biopsy↗

PubMed2003

The spectrum of long-term epilepsy-associated tumors: long-term seizure and tumor outcome and neurosurgical aspects.

PURPOSE: To describe the histologic spectrum and clinical characteristics of patients with neuroepithelial tumors and drug-resistant epilepsy and to analyze clinical data and treatment related to seizure outcome and survival. METHODS: Data were analyzed from 207 consecutive patients with intractable epilepsy (aged 2-54 years), who between 1988 and 1999 had >or=50% resection of supratentorial, neuroepithelial tumors. Extent of resection was assessed on postoperative magnetic resonance imaging (MRI); seizure outcome was classified according to Engel's outcome scale; and follow-up data were prospectively updated. RESULTS: Median follow-up was eight years (range, 2-14 years). Histologic examination revealed 154 classic epilepsy-associated tumors (ganglioglioma, dysembryoplastic neuroepithelial tumor, pleomorphic xanthoastrocytoma, and pilocytic astrocytomas) and 53 others (astrocytomas and oligodendrogliomas). Four World Health Organization (WHO) grade III tumors were found (astrocytoma, n = 3; ganglioglioma, n = 1). After surgery, 82% of the patients were seizure free (class I). The following factors were associated with improved seizure outcome: Short duration of epilepsy before surgery, single EEG focus, absence of additional hippocampal sclerosis or cortical dysplasia, transsylvian approach, other than astrocytomas, and complete tumor resection. After 5 years, only nine (4%) patients had tumor recurrence, four (2%) with malignant transformation and death. None of the four patients with anaplastic tumors died. Even patients with astrocytomas of WHO grade II or III showed 10-year recurrence of only 25% and 10-year survival of 90%. CONCLUSIONS: Tumors associated with long-term epilepsy should be removed early for two different reasons: high rate of seizure freedom and rare but potential risk of malignant tumor progression. The unexpected long survival of these astrocytomas should be investigated by using immunohistochemistry and molecular biology.

Adolescent↗

PubMed2003

Correlated stage- and subfield-associated hippocampal gene expression patterns in experimental and human temporal lobe epilepsy.

Epileptic activity evokes profound alterations of hippocampal organization and function. Genomic responses may reflect immediate consequences of excitatory stimulation as well as sustained molecular processes related to neuronal plasticity and structural remodeling. Using oligonucleotide microarrays with 8799 sequences, we determined subregional gene expression profiles in rats subjected to pilocarpine-induced epilepsy (U34A arrays, Affymetrix, Santa Clara, CA, USA; P < 0.05, twofold change, n = 3 per stage). Patterns of gene expression corresponded to distinct stages of epilepsy development. The highest number of differentially expressed genes (dentate gyrus, approx. 400 genes and CA1, approx. 700 genes) was observed 3 days after status epilepticus. The majority of up-regulated genes was associated with mechanisms of cellular stress and injury - 14 days after status epilepticus, numerous transcription factors and genes linked to cytoskeletal and synaptic reorganization were differentially expressed and, in the stage of chronic spontaneous seizures, distinct changes were observed in the transcription of genes involved in various neurotransmission pathways and between animals with low vs. high seizure frequency. A number of genes (n = 18) differentially expressed during the chronic epileptic stage showed corresponding expression patterns in hippocampal subfields of patients with pharmacoresistant temporal lobe epilepsy (n = 5 temporal lobe epilepsy patients; U133A microarrays, Affymetrix; covering 22284 human sequences). These data provide novel insights into the molecular mechanisms of epileptogenesis and seizure-associated cellular and structural remodeling of the hippocampus.

Animals↗

PubMed2003

Functional network integration of embryonic stem cell-derived astrocytes in hippocampal slice cultures.

Embryonic stem (ES) cells provide attractive prospects for neural transplantation. So far, grafting strategies in the CNS have focused mainly on neuronal replacement. Employing a slice culture model, we found that ES cell-derived glial precursors (ESGPs) possess a remarkable capacity to integrate into the host glial network. Following deposition on the surface of hippocampal slices, ESGPs actively migrate into the recipient tissue and establish extensive cell-cell contacts with recipient glia. Gap junction-mediated coupling between donor and host astrocytes permits widespread delivery of dye from single donor cells. During maturation, engrafted donor cells display morphological, immunochemical and electrophysiological properties that are characteristic of differentiating native glia. Our findings provide the first evidence of functional integration of grafted astrocytes, and depict glial network integration as a potential route for widespread transcellular delivery of small molecules to the CNS.

Animals↗

PubMed2002

Transcriptional profiling in human epilepsy: expression array and single cell real-time qRT-PCR analysis reveal distinct cellular gene regulation.

Highly parallel expression monitoring by microarrays is a powerful tool to study human brain disorders. In contrast to various nonneuronal tissues, the CNS is composed of a multitude of different cell types. Changed mRNA levels in neuropathological conditions may simply reflect altered tissue composition, rather than specific gene transcription regulation. Therefore, it is crucial, to supplement expression array data of histologically heterogeneous brain samples with a detailed analysis at the cellular level. Here, we have used a two-step approach to identify specific changes in hippocampal gene expression in patients with a hippocampal seizure focus (TLE) and marked neuronal damage. Using comparative expression array hybridization, 21 genes appeared to be differentially regulated. Expression alterations of a subset of these genes, i.e. (up-regulation of ataxin-3 and glial fibrillary acid protein (GFAP) as well as down-regulation of calmodulin) was confirmed in an extended series of individuals by real-time quantitative RT-PCR (qRT-PCR). In order to determine the cellular localization of these mRNAs, we performed real-time qRT-PCR of individual laser-microdissected neurons and glial cells. While ataxin-3 was expressed only in hippocampal neurons, GFAP was detected in reactive astrocytes. The differential calmodulin expression found on the tissue level was not observed in mRNA analyses from single neurons, suggesting that lower calmodulin mRNA levels are a consequence of segmental cell loss and do not indicate reduced cellular expression. Ataxin-3 has been related to neuronal maintenance. Its functional role for TLE has to be further evaluated.

Ataxin-3↗

PubMed2002

Mutational and expression analysis of the reelin pathway components CDK5 and doublecortin in gangliogliomas.

Gangliogliomas represent highly differentiated glioneuronal tumors frequently occurring in young patients with focal epilepsies. Dysplastic neurons are a neuropathological hallmark of this neoplasm. Here, we have analyzed two major components of the reelin pathway associated with neuronal migration and cortical cytoarchitecture in gangliogliomas, i.e., cyclin-dependent kinase 5 (CDK5) and doublecortin (DCX). The genomic structure of human CDK5 was identified by an " in silico" cloning approach using the "high throughput genomic sequencing" (htgs) databank, NCBI BLAST 2.1. DNA sequence analysis of CDK5 and DCX was carried out in tissue samples obtained from 23 patients and compared with control DNA from non-affected individuals ( n=100). For gene expression analysis of CDK5 and DCX, a quantitative real time reverse transcription-PCR TaqMan assay was used with mRNA from gangliogliomas ( n=22) and non-lesional central nervous tissue control tissue ( n=7). The human CDK5 gene is located on chromosome 7q36 and contains 12 exons. Its coding sequence reveals 90.1% homology to the mouse counterpart. A novel pseudogene of CDK5 was found on chromosome 8. While the mutational analysis of CDK5 and DCX did not reveal any sequence alterations in gangliogliomas, a lower expression was observed for both genes in tumor compared to control tissue samples. The present data indicate that mutations of CDK5 and DCX genes are not involved in the development of gangliogliomas. A novel pseudogene on chromosome 8 has to be taken into account for future studies on CDK5.

Animals↗

PubMed2002

Focal cortical dysplasia of Taylor's balloon cell type: mutational analysis of the TSC1 gene indicates a pathogenic relationship to tuberous sclerosis.

Focal cortical dysplasia (FCD) is characterized by a localized malformation of the neocortex and underlying white matter. Balloon cells, similar to those observed in tuberous sclerosis, are present in many cases (FCD(bc)). In these patients, a hyperintense funnel-shaped subcortical lesion tapering toward the lateral ventricle was the characteristic finding on fluid-attenuated inversion recovery magnetic resonance imaging scans. Surgical lesionectomy results in complete seizure relief. Although the pathogenesis of FCD(bc) remains uncertain, histopathological similarities indicate that FCD(bc) may be related pathogenetically to tuberous sclerosis. Here, we studied alterations of the TSC1 and TSC2 genes in a cohort of patients with chronic, focal epilepsy and histologically documented FCD(bc) (n = 48). DNA was obtained after microdissection and laser-assisted isolation of balloon cells, dysplastic neurons, and nonlesional cells from adjacent normal brain tissue. Sequence alterations resulting in amino acid exchange of the TSC1 gene product affecting exons 5 and 17 and silent base exchanges in exons 14 and 22 were increased in patients with FCD(bc) compared with 200 control individuals (exon 5, 2.3% FCD(bc) vs 0% C; exon 17, 35% FCD(bc) vs 1.0% C; exon 14, 37.8% FCD(bc) vs 15% C; exon 22, 45% FCD(bc) vs 23.8% C). Sequence alterations could be detected in FCD(bc) and in adjacent normal cells. In 24 patients, DNA was suitable to study loss of heterozygosity at the TSC1 gene locus in microdissected FCD(bc) samples compared with control tissue. Eleven FCD(bc) cases exhibited loss of heterozygosity. In the TSC2 gene, only silent polymorphisms were detected at similar frequencies as in controls. Our findings indicate that FCD(bc) constitutes a clinicopathological entity with distinct neuroradiological, neuropathological, and molecular genetic features. These data also suggest a role of the TSC1 gene in the development of FCD(bc) and point toward a pathogenic relationship between FCD(bc) and the tuberous sclerosis complex.

Amino Acid Substitution↗

PubMed2002

Functional genomics in experimental and human temporal lobe epilepsy: powerful new tools to identify molecular disease mechanisms of hippocampal damage.

The human genome project is a milestone for molecular genetic studies on complex, sporadic disorders in the human central nervous system (CNS). Functional analysis and tissue-/cell-specific expression profiles will be of particular importance anticipating the magnitude of expressed genes in the brain and their dynamic epigenetic modifications. The recent progress in microarray technologies allows expression studies for a large number of genes. In combination with laser-microdissection and quantitative reverse transcription-polymerase chain reaction technologies, such large-scale expression analyses can be successfully addressed in well-defined tissue specimens or cellular subpopulations. Complex, sporadic diseases, such as temporal lobe epilepsy (TLE), are challenging for functional genomics. Issues of particular importance in this field include molecular mechanisms of neurodevelopmental abnormalities, neuronal plasticity and hyperexcitability as well as neuronal cell damage in affected CNS areas. The availability of anatomically well-preserved surgical specimens, i.e. hippocampus obtained from epilepsy patients with Ammon's horn sclerosis or focal lesions not affecting the hippocampus proper as well as comparisons with experimental TLE models may help to elucidate specific molecular-pathological mechanisms during epileptogenesis and in chronic conditions of the disease.

Animals↗

PubMed2002

Focal cortical dysplasia of Taylor's balloon cell type: a clinicopathological entity with characteristic neuroimaging and histopathological features, and favorable postsurgical outcome.

BACKGROUND AND PURPOSE: Focal cortical dysplasia of Taylor's balloon-cell type (FCD-BC) are a frequent cause of pharmacoresistant epilepsy in young patients. In order to characterize FCD-BC, we coupled MRI and histopathology, and analyzed the clinical outcome following epilepsy surgery. METHODS: From an epilepsy data bank with 547 histological specimens, 17 FCD-BC were re-evaluated of which high resolution MRI was available. Five additional FCD-BC were prospectively identified by MRI. Histopathological and immunohistochemical features were related to MRI. Outcome following lesionectomy was analyzed as determined on routine examinations 3, 6 and 12 months following surgery. RESULTS: All but one lesion were located outside the temporal lobe. A markedly hyperintense funnel-shaped subcortical zone tapering towards the lateral ventricle was the characteristic finding on FLAIR MRI. Histopathologically, the subcortical zone of the FCD-BC displayed hypomyelinated white matter with radially oriented balloon cells and gliosis. Dysplastic neurons were found in the adjacent, disorganized cortex. All patients with complete lesionectomy were seizure free one year following surgery. CONCLUSION: Focal cortical dysplasias of Taylor's balloon-cell type (FCD-BC) have characteristic MRI and histopathological findings. MRI recognition is important, since outcome following resective surgery is favorable.

Adolescent↗

PubMed2002

Disorganization of the desmin cytoskeleton and mitochondrial dysfunction in plectin-related epidermolysis bullosa simplex with muscular dystrophy.

Mutations of the human plectin gene (Plec1) cause autosomal recessive epidermolysis bullosa simplex with muscular dystrophy (EBS-MD). Here, we report on molecular mechanisms leading to severe dystrophic muscle alterations in EBS-MD. Analysis of a 25-yr-old EBS-MD patient carrying a novel homozygous 16-bp insertion mutation (13803ins16/13803ins16) close to the intermediate filament (IF) binding site of plectin showed severe disorganization of the myogenic IF cytoskeleton. Intermyofibrillar and subsarcolemmal accumulations of assembled but highly unordered desmin filaments may be attributed to impaired desmin binding capability of the mutant plectin. This IF pathology was also associated with severe mitochondrial dysfunction, suggesting that the muscle pathology of EBS-MD caused by IF disorganization leads not only to defects in mechanical force transduction but also to metabolic dysfunction. Beyond EBS-MD, our data may contribute to the understanding of other myopathies characterized by sarcoplasmic IF accumulations such as desminopathies or alpha-B-crystallinopathies.

Adult↗