PubMed Health⌕ Search

Biomedical subjects

S M Sisodiya

Publications and source records attributed to S M Sisodiya.

At least 19 recordsLinked to original sources
PubMed2006

Vascular colocalization of P-glycoprotein, multidrug-resistance associated protein 1, breast cancer resistance protein and major vault protein in human epileptogenic pathologies.

Multidrug transporters, such as P-glycoprotein (P-gp), multidrug-resistance associated protein 1 (MRP1) and breast cancer resistance protein (BCRP), are associated with multidrug resistance in cancers; other molecules, such as major vault protein (MVP), have a similar association with drug-resistant cancer. These proteins are postulated to generate drug resistance in epilepsy. They have been shown individually to be up-regulated in epileptogenic brain tissue. In any consideration of the function, inhibition or evasion of the activity of such proteins, the colocalization of such proteins needs to be understood. We systematically determined the presence of such colocalization, focusing on microvascular endothelium from epileptogenic human brain tissue. Double labelling immunofluorescence and confocal laser scanning microscopy were used to determine colocalization of P-gp, MRP1, BCRP and MVP in one case of hippocampal sclerosis and two cases of focal cortical dysplasia type IIb. Endothelial colocalization was examined with double labelling using antibodies to CD34 and Factor VIII. The presence of P-gp, BCRP and MVP in microvascular endothelium was confirmed. P-gp, BCRP and MVP colocalized in microvascular endothelium, though not all proteins appeared to be identically distributed within this tissue. MRP1 did not colocalize to endothelium. These findings were not unexpected but required formal confirmation. The demonstrated colocalization of P-gp, BCRP and MVP in microvascular endothelium in epileptogenic human brain tissue has important implications for functional experiments (including single knock-out mice studies), work with specific and broad-spectrum inhibitors of transport function, and any eventual trials of treatment of refractory epilepsy involving modulation of the function of these proteins.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Methodological aspects of 3D and automated 2D analyses of white matter neuronal density in temporal lobe epilepsy.

White matter neuronal density has been correlated with clinical outcome after temporal lobectomy for refractory epilepsy. Both morphometric 2D (two-dimensional) and stereological 3D (three-dimensional) analyses of neuronal density have been performed. 3D analyses are thought to be more accurate than 2D counts, but more time-consuming. We compared 3D and automated 2D measurements in the same specimens. Adjacent 20-microm (for 3D analyses) and 5-microm (for 2D analyses) sections from 10 temporal lobectomies were stained for NeuN immunohistochemistry. Analysis of 100% of a region of interest (ROI) in deep white matter was performed using an image analysis system (Histometrix, Kinetic Imaging, UK). 3D analyses were undertaken using x 63 magnification (6 h/case). Automated 2D analyses were undertaken using automatic neuronal identification at x 10 magnification with three to four repeats (1.5 h/case). The range of neuronal densities for 3D measurements was 2120-4910 neurones/mm(3), and for automated 2D measurements 17.4-47.1 neurones/mm2. There was a linear correlation between the two methods with an r2 of 0.58. [corrected] Count-recount variability was 1.4-9.9% for the 3D and 5.1-36.6% for the automated 2D measurements. We found a wide range of white matter neuronal densities using either analysis. The low agreement between methods, and the high count-recount variability for the automated 2D analyses, indicate that despite being more time-consuming, rigorous 3D stereological analyses have to be performed to obtain reliable results. These findings have implications for studies requiring neuronal counts in normal and disease states.

Adult↗
PubMed2005

Cortical neuronal densities and lamination in focal cortical dysplasia.

Focal cortical dysplasia (FCD) is considered to represent a malformation due to abnormal cortical development (MCD) and is an important cause of focal epilepsy. The histopathological features include abnormal laminar architecture, the presence of hypertrophic and dysmorphic neurones in FCD type IIA and additional balloon cells in FCD type IIB. The events causing these sporadic lesions are unknown, but abnormal progenitor cell proliferation occurring late in corticogenesis has been proposed. FCD-like lesions have, however, also been described following a cerebral injury early in life. We carried out a stereological assessment on 15 cases of FCD on NeuN- and Nissl-stained sections from patients with a wide age range, and identified a significant reduction in the neuronal density in all cases in the region of dysplasia compared to the adjacent unaffected cortex (mean neuronal densities 19.2x10(3)/mm3 in the region of dysplasia; 42.8x10(3)/mm3 in the adjacent cortex). Relative differences in neuronal density and size in FCD cases between the superficial (layer I and II) and deep cortical laminae (layer V and VI) were similar to that observed in other pathologies including mild MCD, temporal neocortex adjacent to hippocampal sclerosis as well as in a non-epilepsy surgical control group. The lower overall neuronal densities observed in FCD may reflect neuropil expansion, a local failure of neuronal migration, proliferation or secondary neuronal loss. The preservation of relative differences in neuronal densities between cortical layers and laminar patterns of neurofilament staining in FCD would support the view that the temporal sequence of lamination is not affected.

Adolescent↗
PubMed2005

Mcm2 labelling of balloon cells in focal cortical dysplasia.

Balloon cells (BC) are the prominent and defining cellular component of type IIB Focal Cortical Dysplasia (FCD), a common cause of focal epilepsy in patients undergoing surgical treatment. BC are considered immature cells of uncommitted cellular differentiation having immunophenotypical characteristics of both neurones and glia. They are often located in the lower cortical layers and white matter underlying the dysplastic cortex, suggesting migratory arrest during development. We investigated the proliferative potential of BC in 15 cases of FCD from patients with a wide range of ages using immunohistochemistry for Mcm2 (mini chromosome maintenance protein) and Ki67. In the majority of cases, BC showed Mcm2 nuclear positivity. In addition, cells with intermediate neuronal-glial characteristics were labelled whilst the dysmorphic or hypertrophic pyramidal neuronal components of FCD were not. Ki67 labelled only occasional BC. These findings support the view that BC cells represent a pool of less differentiated glial cells with proliferative capacity which may have potential for delayed neuronal differentiation. Furthermore, as Mcm2 specifically identifies BC populations, this marker may be of diagnostic value in the subtyping of FCD lesions in patients with epilepsy.

Adolescent↗
PubMed2004

The -1021C->T DBH gene variant is not associated with epilepsy or antiepileptic drug response.

Dopamine beta-hydroxylase (DBH) catalyzes the conversion of dopamine to norepinephrine (NE). Animal studies show that genes in the NE pathway are candidates for susceptibility to epilepsy and antiepileptic drug (AED) response. The authors genotyped the -1021C-->T major functional polymorphism in the DBH gene in 675 patients with epilepsy and 1,087 controls. The authors found no association with epilepsy, several epilepsy subtypes, or AED response. The results suggest that the -1021C-->T variant does not contribute to epilepsy.

Anticonvulsants↗
PubMed2004

Cognitive functioning in humans with mutations of the PAX6 gene.

Fourteen patients with PAX6 gene mutations and previously identified MRI abnormalities were administered tests of cognitive functioning. No deficits were found. A subgroup with agenesis of the anterior commissure performed significantly more poorly on measures of working memory than those without this abnormality, suggesting the anterior commissure may play a role in cognitive processing in addition to an earlier identified role in sensory development and processing.

Adolescent↗
PubMed2004

Defective auditory interhemispheric transfer in a patient with a PAX6 mutation.

Heterozygous PAX6 mutation is associated with an absent or hypoplastic anterior commissure and a reduction in the area of the corpus callosum. The authors found deficient auditory interhemispheric transfer in a 53-year-old woman with a PAX6 mutation who had an absent anterior commissure but normal callosal volume.

Auditory Pathways↗
PubMed2004

Misdiagnosis of seizures: insulinoma presenting as adult-onset seizure disorder.

Once diagnosed with a refractory seizure disorder, patients often receive aggressive and escalating pharmacotherapy. However, a significant proportion of patients referred to neurologists do not have epilepsy. Toxic and metabolic causes of seizures should always be considered as they are potentially curable, and may be fatal if untreated. The following case report highlights the need for careful reassessment of all seizures that are atypical and refractory to medication.

Adult↗
PubMed2003

Cajal-Retzius cells, inhibitory interneuronal populations and neuropeptide Y expression in focal cortical dysplasia and microdysgenesis.

Focal cortical dysplasia (FCD) and microdysgenesis (MD) are likely to represent abnormalities of radial neuronal migration during cortical development. We investigated the distribution of reelin-positive Cajal-Retzius cells, known to be important in the later stages of radial neuronal migration and cortical organization, in 12 surgical cases of both MD and FCD. Quantitation revealed significantly higher numbers of these cells in MD cases compared to controls. As the majority of cortical interneurones arise via tangential rather than radial migration, we studied the distribution and morphology of inhibitory interneuronal subsets immunolabelled for calbindin, parvalbumin and calretinin within these malformations. Frequent findings were a reduction of inhibitory interneurones in the region of FCD and abnormally localised hypertrophic or multipolar calbindin-positive interneurones in both FCD and MD. Neuropeptide Y immunostaining showed a striking increase in the density of the superficial plexus of fibres in both MD and FCD cases in addition to labelling of dysplastic neurones, which may represent an adaptive anti-convulsant mechanism to dampen down seizure propagation.

Adolescent↗
PubMed2003

A longitudinal study of brain morphometrics using quantitative magnetic resonance imaging and difference image analysis.

Serial quantitative magnetic resonance imaging (MRI) allows the detection of subtle volumetric changes in brain volume. We used serial volumetry and voxel-based difference image analysis to quantify and characterize longitudinal changes in the hippocampus, cerebellum, and neocortex in younger and middle-age individuals. Paired volumetric MRI brain scans 3.5 years apart were performed on 90 healthy subjects 14 to 77 years old. Quantitative assessment of registered images included hippocampal volumetry, cerebellar volumetry, and automatically determined regional brain volumes. Longitudinal volume changes in three age epochs (<35, 35-54, >54 years) were compared and neocortical changes beyond regions of interest were visualized using filtered difference images. Cross-sectional analysis revealed a significant association between age and reduction in all brain volumes except hippocampal volume. Changes in normalized hippocampal and white matter volume were significantly different among the three groups. Individual analysis revealed 5 subjects with significant longitudinal volume changes lying outside the normative range. Difference image analysis showed global involutional changes in the >54 age group. Our findings suggest that cross-sectional observations in intracranial volume, cerebellar volume, and gray matter volume are likely to reflect uniform rates of volume loss or secular changes. Accelerated brain atrophy was seen from the age of 35-54 and increased rates of hippocampal atrophy from the age of 54. Our findings emphasize the importance of controlling for age effects when studying pathological brain changes over a wide age range.

Adolescent↗
PubMed2003

Epilepsy and perisylvian polymicrogyria in a patient with Kabuki syndrome.

Kabuki syndrome is a dysmorphogenic syndrome which has been reported in over 300 patients since it was first described in Japan in 1981. In addition to its cardinal features (typical facies, mild-to-moderate learning disability, short stature, skeletal anomalies, and dermatoglyphic abnormalities with persistent foetal fingerpads), neurological anomalies are frequently reported, including epilepsy in 8% of those with the syndrome. We present here a 22-year-old white female patient with refractory partial epilepsy, Kabuki syndrome, and bilateral perisylvian polymicrogyria on MRI: the first reported case of this association. The aetiology of the syndrome, including the diverse genetic changes recognized, is then discussed.

Abnormalities, Multiple↗
PubMed2002

Bilateral isolated hippocampal malformation in temporal lobe epilepsy.

Hippocampal malformations in patients with epilepsy usually are reported in the context of widespread cortical malformations. Isolated hippocampal malformations are more rarely identified in MRI studies with little documentation of their pathologic appearance. Postmortem examination revealed abnormal position and complex convolutional malformations isolated to the hippocampal formation in an adult with temporal lobe epilepsy in whom MRI demonstrated bilateral hippocampal abnormalities.

Epilepsy, Complex Partial↗
PubMed2002

Anterior commissure absence without callosal agenesis: a new brain malformation.

The authors report a novel human brain malformation characterized by the absence of the anterior commissure without callosal agenesis, but associated with gross unilateral panhemispheric malformation incorporating subependymal heterotopia, subcortical heterotopia, and gyral abnormalities including temporal malformation and polymicrogyria. In contrast, a normal anterior commissure was found in 125 control subjects and in 113 other subjects with a range of brain malformations.

Adolescent↗
PubMed2002

Drug resistance in epilepsy: human epilepsy.

The basis of drug resistance in human epilepsy is not understood. Parallels with resistance in cancer suggest that drug resistance proteins may have a role. To examine this possibility, we have studied human brain tissue containing pathologies capable of causing refractory epilepsy. Using immunohistochemistry for P glycoprotein (Pgp) and multidrug resistance-associated protein 1 (MRP1), we examined both pathological tissue and control tissue. We demonstrate expression of Pgp and MRP1 in glia from cases of malformation of cortical development studied both before and after the onset of epilepsy, as well as in cases of hippocampal sclerosis and dysembryoplastic neuroepithelial tumours. In one particular type of malformation, we also demonstrate that dysplastic neurons express MRP1. The pattern of immunolabelling suggests overexpression is concentrated particularly around vessels in most of the pathologies. The timing shows that expression may be constitutive in some pathologies. These findings suggest that drug resistance proteins may contribute to drug resistance in refractory epilepsy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Drug resistance in epilepsy: expression of drug resistance proteins in common causes of refractory epilepsy.

Epilepsy is resistant to drug treatment in about one-third of cases, but the mechanisms underlying this drug resistance are not understood. In cancer, drug resistance has been studied extensively. Amongst the various resistance mechanisms, overexpression of drug resistance proteins, such as multi-drug resistance gene-1 P-glycoprotein (MDR1) and multidrug resistance-associated protein 1 (MRP1), has been shown to correlate with cellular resistance to anticancer drugs. Previous studies in human epilepsy have shown that MDR1 and MRP1 may also be overexpressed in brain tissue from patients with refractory epilepsy; expression has been shown in glia and neurones, which do not normally express these proteins. We examined expression of MDR1 and MRP1 in refractory epilepsy from three common causes, dysembryoplastic neuroepithelial tumours (DNTs; eight cases), focal cortical dysplasia (FCD; 14 cases) and hippocampal sclerosis (HS; eight cases). Expression was studied immunohistochemically in lesional tissue from therapeutic resections and compared with expression in histologically normal adjacent tissue. With the most sensitive antibodies, in all eight DNT cases, reactive astrocytes within tumour nodules expressed MDR1 and MRP1. In five of eight HS cases, reactive astrocytes within the gliotic hippocampus expressed MDR1 and MRP1. Of 14 cases of FCD, MDR1 and MRP1 expression was noted in reactive astrocytes in all cases. In five FCD cases, MRP1 expression was also noted in dysplastic neurones. In FCD and DNTs, accentuation of reactivity was noted around lesional vessels. Immunoreactivity was always more frequent and intense in lesional reactive astrocytes than in glial fibrillary acidic protein-positive reactive astrocytes in adjacent histologically normal tissue. MDR1 is able to transport some antiepileptic drugs (AEDs), and MRP1 may also do so. The overexpression of these drug resistance proteins in tissue from patients with refractory epilepsy suggests one possible mechanism for drug resistance in patients with these pathologies. We propose that overexpressed resistance proteins lower the interstitial concentration of AEDs in the vicinity of the epileptogenic pathology and thereby render the epilepsy caused by these pathologies resistant to treatment with AEDs.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Mutations in the X-linked filamin 1 gene cause periventricular nodular heterotopia in males as well as in females.

Periventricular heterotopia (PH) is a human neuronal migration disorder in which many neurons destined for the cerebral cortex fail to migrate. Previous analysis showed heterozygous mutations in the X-linked gene filamin 1 (FLN1), but examined only the first six (of 48) coding exons of the gene and hence did not assess the incidence and functional consequences of FLN1 mutations. Here we perform single-strand conformation polymorphism (SSCP) analysis of FLN1 throughout its entire coding region in six PH pedigrees, 31 sporadic female PH patients and 24 sporadic male PH patients. We detected FLN1 mutations by SSCP in 83% of PH pedigrees and 19% of sporadic females with PH. Moreover, no PH females (0/7 tested) with atypical radiographic features showed FLN1 mutations, suggesting that other genes may cause atypical PH. Surprisingly, 2/24 males analyzed with PH (9%) also carried FLN1 mutations. Whereas FLN1 mutations in PH pedigrees caused severe predicted loss of FLN1 protein function, both male FLN1 mutations were consistent with partial loss of function of the protein. Moreover, sporadic female FLN1 mutations associated with PH appear to cause either severe or partial loss of function. Neither male could be shown to be mosaic for the FLN1 mutation in peripheral blood lymphocytes, suggesting that some neurons in the intact cortex of PH males may be mutant for FLN1 but migrate adequately. These results demonstrate the sensitivity and specificity of DNA testing for FLN1 mutations and have important functional implications for models of FLN1 protein function in neuronal migration.

Abnormalities, Multiple↗
PubMed2001

Multidrug-resistance protein 1 in focal cortical dysplasia.

Drug resistance in epilepsy is poorly understood. We used routine immunohistochemistry to assess overexpression of a multidrug-resistance protein in dysplastic neurons, glia, and around vessels in surgically resected epileptogenic human brain tissue. We showed non-tumoral overexpression of this multidrug-resistance protein, which might contribute to drug resistance in epilepsy caused by focal cortical dysplasia.

ATP Binding Cassette Transporter, Subfamily B, Mem↗