Biomedical subjects

M Thom

Publications and source records attributed to M Thom.

At least 37 records · Page 2Linked to original sources

PubMed2001

Neocortical abnormalities of [11C]-flumazenil PET in mesial temporal lobe epilepsy.

OBJECTIVE: To characterize abnormalities in neocortical central benzodiazepine receptor (cBZR) binding in patients with mesial temporal lobe epilepsy (mTLE) with unilateral hippocampal sclerosis (HS) using [(11)C]-flumazenil-(FMZ) PET and complementary voxel-based and quantitative volume-of-interest (VOI) methods. METHODS: The authors studied 13 control subjects and 15 patients with refractory mTLE and unilateral HS with [(11)C]-FMZ PET. Data were corrected for partial volume effect in the interactively outlined hippocampus and in 28 cortical VOI using an individualized template. A voxel-based analysis was also performed using statistical parametric mapping (SPM). RESULTS: Fourteen patients with mTLE had reduced [(11)C]-FMZ volume distribution (V(d)) in the hippocampus ipsilateral to the EEG focus, extending into the amygdala in four. Five patients showed additional significant neocortical abnormalities of [(11)C]-FMZ binding: temporal neocortical increases (1), extratemporal decreases (2), extratemporal increases only (1), and temporal and extratemporal neocortical increases (1). Group VOI analysis revealed significant reductions only in the ipsilateral hippocampus. SPM showed decreased [(11)C]-FMZ-V(d) in the ipsilateral hippocampus in 13 of 15 patients, extending into the amygdala in eight. Five patients showed additional neocortical abnormalities: temporal neocortical increases only (3), extratemporal decreases (1), or both temporal neocortical and extratemporal decreases (1). Group analysis showed significant reductions in the ipsilateral hippocampus only. CONCLUSIONS: A combination of VOI- and voxel-based analysis of [(11)C]-FMZ PET detected extrahippocampal changes of cBZR binding in eight of 15 patients with mTLE due to HS. The finding of abnormalities in patients who were thought to have unilateral HS only based on MRI suggests that more widespread abnormalities are present in HS.

Adult↗

PubMed2001

GABA(B(1)) mRNA expression in hippocampal sclerosis associated with human temporal lobe epilepsy.

GABA(B) receptors act to inhibit neurotransmitter release from presynaptic terminals, and mediate the late inhibitory postsynaptic potential. Studies of GABA(B) receptor function in rodent models of temporal lobe epilepsy (TLE) suggest that GABA(B) receptor expression and/or function may be perturbed. GABA(B(1)) mRNA levels were investigated in 10 hippocampal resection samples obtained at surgery from intractable hippocampal sclerosis (HS) associated TLE patients and five neurologically normal post-mortem (PM) control samples. In situ hybridisation with a 35S-dATP-labelled oligonucleotide was carried out to measure mRNA levels, along with three-dimensional cell counting, for assessment of neuronal density in hippocampal subregions. GABA(B(1)) mRNA was significantly up-regulated in the subiculum of HS samples as compared with PM controls. When adjusted for the characteristic neuronal density changes observed in HS, GABA(B(1)) mRNA was significantly up-regulated in CA1, hilus and dentate gyrus granule cell layer of HS samples as compared with PM controls. The possibility of increased GABA(B(1)) expression suggests that changes in GABA(B) receptor mechanisms may be involved in the pathogenesis of human HS-associated TLE.

Adult↗

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↗

PubMed2001

GABA(B) receptor autoradiography in hippocampal sclerosis associated with human temporal lobe epilepsy.

1. Metabotropic gamma-aminobutyric acid receptors (GABA(B)) exist both pre- and postsynaptically throughout the brain, mediating the suppression of neurotransmitter release and late inhibitory postsynaptic potentials. Investigation of GABA(B) receptors in rodent models of temporal lobe epilepsy (TLE) suggests that expression or function of these receptors may be altered in the disorder. 2. The aim of the present study was to investigate the expression of GABA(B) receptors in samples of hippocampus surgically resected from patients with hippocampal sclerosis (HS) related intractable TLE, and compare this expression with samples of neurologically normal post-mortem (PM) control hippocampal tissue. Appropriate measures of neuronal loss associated with HS were investigated for comparison with receptor binding data. 3. Receptor autoradiography with [(3)H]-GABA in the presence of isoguvacine, and quantitative densitometric analysis were used to investigate GABA(B) receptor expression (B(max)) and affinity (K(D)) in 11 HS samples and eight controls. A three-dimensional cell counting technique was used to assess neuronal density in both groups. 4. GABA(B) receptor density was significantly reduced in CA1, CA2, CA3, hilus and dentate gyrus, and increased in the subiculum, of HS cases as compared with PM controls. Neuronal loss was significant in all regions measured. When adjusted for neuronal loss, CA1 GABA(B) receptor expression appeared significantly upregulated (P:<0.05). 5. In HS/TLE, GABA(B) receptor expression per remaining neurone appears increased in CA1. This finding, and increased [(3)H]-GABA affinity at CA3 and hilar GABA(B) receptors, suggests altered GABA(B) receptor function may occur in human HS/TLE, possibly as a result of synaptic reorganization.

Adult↗

PubMed2001

Bilateral hippocampal granule cell dispersion: autopsy study of 3 infants.

Recent morphologic studies of Ammon's horn sclerosis (AHS) have recorded granule cell dispersion (GCD) in a significant proportion of temporal lobes surgically resected for temporal lobe epilepsy (TLE). We report the first post-mortem descriptions of GCD in three unrelated infants. GCD was bilateral in all three and there were also migrational defects, heterotopias or polymicrogyria. Only one child, a 2.5-year-old boy, presented with a severe seizural disorder and exhibited bilateral AHS. But in the two younger children, deceased at 12 weeks and 5 months, respectively, no seizures were observed and hippocampal neuronal populations were intact. To date, GCD has only been reported in association with epilepsy and has not been observed bilaterally or in neurologically normal individuals. The present observations bring into question the hypothesis that GCD is causally related to seizure activity in early life, suggesting an opposing view that it is an independent developmental disorder.

Cadaver↗

PubMed2001

Microdysgenesis in temporal lobe epilepsy. A quantitative and immunohistochemical study of white matter neurones.

Microdysgenesis is a microscopic cortical malformation considered to act as a substrate for seizures in some patients with generalized epilepsy. It is also recognized to involve the temporal lobe in a proportion of patients with intractable temporal lobe epilepsy, but the incidence of this abnormality, its relationship to mesial temporal lobe sclerosis and relevance to epileptogenesis remain unknown. This is partly due to a lack of well-defined quantitative pathological diagnostic criteria. To begin to address these issues, we have carried out a rigorous quantitative analysis, using three-dimensional cell counting methods, of several components of microdysgenesis in temporal lobectomy specimens. White matter, cortical and layer I neuronal densities (NDs) were measured using immunohistochemistry for the neuronal markers neuronal nuclear antigen and calbindin D-28-K. Patients with a seizure-free outcome (Class I) showed significantly more microdysgenetic features including higher white matter ND (P < 0.05), particularly of small (<10 microm diameter) neurones (P < 0.01), higher layer I ND (P < 0.05) and increased numbers of Cajal-Retzius-like calbindin-positive neurones (P < 0.05). We also demonstrated that white matter ND was independent of the degree of temporal lobe gliosis as assessed by quantitation of glial fibrillary acidic protein-immunoreactive cells. These findings suggest that microdysgenesis may be a significant lesion in temporal lobe epilepsy in terms of post-surgical prognosis.

Adult↗

PubMed2001

Persistent reelin-expressing Cajal-Retzius cells in polymicrogyria.

Cajal-Retzius (CR) cells are early-developing cells important in mammalian corticogenesis. Reelin, a protein secreted by CR cells, is essential for completion of neuronal migration and cortical lamination. Lack of reelin causes the 'reeler' phenotype in mice and autosomal recessive lissencephaly with cerebellar hypoplasia in man. Focal increases in reelin and CR cells are associated with thickening and local invaginations of the marginal zone and microgyria in animal studies. It has been suggested that abnormalities of reelin expression may be involved in human polymicrogyria. We have studied CR cells and reelin expression in pathological sections of human polymicrogyria to explore this possibility. Occurrence, distribution, morphology and reelin expression in CR cells were studied in 12 cases of human polymicrogyria, ranging from 21 gestational weeks to 10 years of age. Findings were compared with age-matched controls. Large, reelin-positive CR-like cells were more numerous in the majority of the polymicrogyria cases and persisted for longer than usual, up to 10 years of age. The CR-like cells tended to cluster and were most frequent in fused molecular layers in the polymicrogyria. Reelin-expressing CR-like cells were also found in bridges between the molecular layer and overlying leptomeningeal heterotopia and within the heterotopia itself. Clusters of CR-like cells were also found in adjacent non-polymicrogyric cortex. No clusters were seen in the control subjects. Increased numbers of CR-like cells were seen in both familial and acquired cases. In contrast to previous reports, the findings show that large CR-like cells persisted for longer than usual, up to 10 years of age, and that they may continue to express reelin. Their maximal aggregation in regions of polymicrogyria and overlying leptomeningeal heterotopia suggest an association between the presence of these cells and polymicrogyria, which we interpret in the light of recent findings concerning the roles of reelin and its downstream signalling pathway in neuronal and glial developmental dynamics and post-developmental function.

Aging↗

PubMed2001

Relapsing intracranial Rosai-Dorfman disease.

Two patients presenting with recurrent visual impairment due to relapsing intracranial Rosai-Dorfman disease are described. In both patients a preoperative diagnosis of meningioma was made. Histological examination disclosed the characteristic picture of S100 and CD68 positive histiocytosis with prominent lymphophagocytosis. In both patients complete tumour removal by surgery was impossible with residual tissue being the origin of relapsing disease. Low dose radiation led to partial recovery of vision and resolution of the intracranial mass. Review of the literature on intracranial Rosai-Dorfman disease leads to the suggestion that postoperative radiotherapy may be advisable in all cases.

Aged↗

PubMed2001

Infundibulohypophysitis in a man presenting with diabetes insipidus and cavernous sinus involvement.

Infundibulohypophysitis is an unusual inflammatory condition that affects the infundibulum, the pituitary stalk, and the neurohypophysis and may be part of a range that includes lymphocytic hypophysitis. Lymphocytic hypophysitis occurs mainly in women and most often presents in the later stages of pregnancy. Infundibulohypophysitis usually presents with diabetes insipidus and the cause remains unclear. The case of a 46 year old man with a 12 week history of polyuria and polydipsia is reported. Cranial diabetes insipidus was diagnosed on the basis of a water deprivation test. Initial cranial and pituitary imaging studies were normal. He subsequently developed symptoms of panhypopituitism over a period of 6-9 months and then, more acutely, developed diplopia secondary to a fourth nerve palsy. Further brain imaging studies disclosed an enhancing pituitary stalk and a left cavernous sinus lesion. An initial trial of immunosuppressive treatment did not help symptoms significantly. The diagnosis of infundibulohypophysitis was made on histological evidence. The patient was treated with prednisolone and methotrexate. At 9 months he is well, without symptoms, and the radiological abnormalities have resolved.

Anti-Inflammatory Agents↗

PubMed2000

Sulcogyral variation in NMDA receptor 2A/B subunit immunoreactivity in human brain.

NMDA receptors (NR) are important in many neurological processes. Using a large series of human brain tissue, we show that the distribution of NR2A/B immunoreactivity varies according to position along a gyrus. For pyramidal neurons in laminae II and III, immunoreactivity is most marked at gyral crown and gyral lips, diminishes along sulcal wall, and is barely detectable in sulcal floor cortex. In contrast, in some cases, immunoreactivity in laminae V and VI pyramidal neurons shows the reverse pattern. Neurofilament and calretinin immunoreactivity do not show this phenomenon. The findings suggest novel functional regionalization at the sulcogyral level in normal human brain.

Adolescent↗

PubMed2000

Cortical myoclonus and cerebellar pathology.

OBJECTIVE: To study the electrophysiologic and pathologic findings in three patients with cortical myoclonus. In two patients the myoclonic ataxic syndrome was associated with proven celiac disease. BACKGROUND: The pathologic findings in conditions associated with cortical myoclonus commonly involve the cerebellar system, but there has only been one report of cerebellar pathology in a patient in whom cortical myoclonus was physiologically characterized antemortem. METHODS: Cortical somatosensory evoked potentials (SEPs) were recorded and EEG activity was averaged preceding myoclonic electromyographic activity. In one patient cortico-cortical inhibition was tested using two paired ipsilateral magnetic stimuli over the motor strip. Neuropathologic examination was carried out, including linear Purkinje cell densities/millimeter calculations for different regions of the cerebellum. RESULTS: The electrophysiology showed evidence of dysfunction of the sensorimotor cortex with enlarged SEPs and a time-locked cortical potential preceding the action myoclonus. In addition, motor cortical inhibition was abnormal in one case. Pathology showed unremarkable primary sensory, motor, and premotor cerebral cortices, except for unilateral gliosis of the motor cortex in one case. The cerebellum showed patchy atrophy and ongoing degeneration. A striking feature was the greater severity of Purkinje cell loss and Bergmann gliosis in the outer aspects than in the depths of the folia. CONCLUSIONS: Pathologic abnormalities are paradoxically mainly located in the cerebellum in some patients with cortical myoclonus, despite clear electrophysiologic evidence of cortical dysfunction. This observation suggests that enhanced excitability of the sensorimotor cortex may arise as a distant effect of cerebellar pathology.

Adult↗

PubMed2000

Imaging and radiological-pathological correlation in histologically proven cases of focal cortical dysplasia and other glial and neuronoglial malformative lesions in adults.

Focal cortical dysplasia (FCD) is a pathological entity first described in 1971. Other more subtle cortical malformations found in patients with epilepsy include microdysgenesis (MD), and glioneuronal hamartias. Although these glial and neuronoglial malformations have distinct histological features, there is terminological confusion in the radiological literature. Few cases have been reported in adults with both imaging and histology. We address these issues, giving a radiological-pathological correlation of histologically proven cortical malformations in adults. We describe clinical, radiological and histological features of 12 cases (five FCD, five MD with glioneuronal hamartias, and two hamartomas), unassociated with other conditions, and discuss them in the light of the literature. FCD is usually seen on MRI as cortical thickening, with or without signal change, which may extend into the adjacent white matter. On histology, abnormal neurons and/or glial cells, blurring of the grey-white matter interface, myelin pallor, demyelination, and gliosis may be found. Glioneuronal hamartias and hamartomas usually appear as complex masses on MRI. FCD and hamartias may be associated, and a combination of imaging findings may be seen on MRI. Atrophy of the ipsilateral hippocampus may be present on MRI in patients with hamartias, and minor cell loss on histology, but not definitive hippocampal sclerosis. Although the imaging findings of cortical malformations are protean, some characteristic MRI features, with histological correlates, may be found. The relevance of most of these observations remains unclear.

Adult↗

PubMed2000

Patterns of cerebellar atrophy in patients with chronic epilepsy: a quantitative neuropathological study.

Cerebellar atrophy occurring in patients with chronic epilepsy is considered either to be a sequel of cumulative seizure-mediated cell loss or a side effect of phenytoin treatment but there is little neuropathological data regarding the distribution of this cerebellar damage. We aimed to address if there is any relationship between the localisation of the cortical pathology in symptomatic epilepsy and the pattern of neocerebellar atrophy. A quantitative neuropathological post mortem analysis of the lobular distribution of hemispheric cerebellar atrophy in 16 patients with chronic epilepsy and four controls was carried out. Cerebellar atrophy, as measured by significant reductions in hemispheric linear Purkinje cell densities was confirmed in the epilepsy patients (P = 0.015) and even where the cerebellum appeared macroscopically normal, Purkinje cell loss was evident (P = 0.062). Two distinct patterns of atrophy were observed, predominantly involving either the anterior or posterior cerebellar lobes. Posterior lobe atrophy was more often associated with old fronto-temporal contusions and may be post traumatic in aetiology rather than a result of excitotoxic damage mediated via cerebro cerebellar pathways. As the majority of patients showing either pattern of atrophy had received phenytoin treatment, we concluded that it is unlikely that this drug acts alone in inducing the Purkinje cell loss.

Adult↗

PubMed2000

Microdysgenesis with abnormal cortical myelinated fibres in temporal lobe epilepsy: a histopathological study with calbindin D-28-K immunohistochemistry.

Microdysgenesis is a microscopic cortical malformation reported to occur with varying incidence in surgical lobectomies from patients with temporal lobe epilepsy (TLE). It may act as a substrate for the seizures. Four patients are reported with TLE, hippocampal sclerosis and cortical microdysgenesis which was also characterized by the presence of abnormal myelinated fibres running tangentially in the superficial cortical laminae and closely associated with abnormal clusters of neurones. Similar abnormal cortical fibres have been described in other malformations of cortical development including polymicrogyria and focal cortical dysplasia and it is therefore likely that these fibres represent part of the microdysgenetic malformation not hitherto reported. The possibility is discussed that they may also be of functional significance in terms of influencing local seizure propagation and the secondary cortical neuronal loss observed, predominantly affecting layer II. Studies of calbindin interneuronal populations showed preservation of these cells in the microdysgenetic cortex, when compared with non-malformed temporal lobes, despite an overall reduction in cortical neuronal density. In addition, prominent numbers of neurogliaform calbindin-positive nerve cells were observed in the microdysgenesis cases and the nature of these cells is speculated upon.

Adult↗

PubMed2000

Spinal neurenteric cysts without associated malformations. Are they the same as those presenting in spinal dysraphism?

Spinal neurenteric cysts are rare intradural developmental lesions, usually composed of a thin-walled cyst whose lining mimicks gastro-intestinal or respiratory epithelium. A detailed review of the literature revealed 80 cases of solitary spinal neurenteric cysts (including a new case of ours), which were analysed and compared, regarding clinical and pathological aspects, with 56 such cases of those with concomitant evidence of dysraphism. Older age and cervical location were found to be statistically characteristic of the solitary cysts in contrast to younger age and lumbosarcal location for the 'dysraphic' cases. Magnetic resonance imaging is the diagnostic modality of choice. Good evidence of the developmental origin of incomplete separation of notochord and endoderm was given by the fact that histologically solitary cysts were mainly composed by endodermal derivatives, while 'dysraphic' had also mesenchymal and ectodermal elements. Thus, it seems that additional spinal dysraphic changes are more likely to be found when ectodermal and mesenchymal elements co-exist with endodermal ones, possibly indicating an earlier error in development than in other cases containing only endodermal elements.

Humans↗

PubMed1999

Evidence for nodular epileptogenicity and gender differences in periventricular nodular heterotopia.

OBJECTIVE: To determine whether clinical differences between the sexes seen in periventricular nodular heterotopia (PNH) have structural correlates on imaging. BACKGROUND: PNH is the most common dysgenesis associated with hippocampal sclerosis (HS). Women with PNH have normal intellect; men may have mental retardation and other changes. Familial PNH, seen in women, is linked to Xq28-a region also abnormal in a sporadic male infant with PNH and retardation-suggesting sexual differences in gene expression. Epilepsy associated with PNH may be refractory to drugs, and surgery for associated HS does not stop seizures, suggesting intrinsic epileptogenicity of PNH. METHODS: Quantitative MRI analysis was performed using established techniques for detecting subtle structural changes in 13 female patients (11 sporadic and two familial) and four male patients (sporadic). RESULTS: There is structural heterogeneity in PNH, even in patients with bilateral PNH. On MRI, men have more cerebral abnormalities beyond PNH than control subjects or female patients (p < 0.005). CONCLUSIONS: The findings support the concept of intrinsic epileptogenicity of PNH. There may be additional structural abnormalities relevant to seizure generation, especially in men. Structural heterogeneity, and widespread abnormalities, may need consideration when patients are referred for surgical treatment or when additional studies of patients with PNH are conducted.

Adolescent↗

PubMed1999

A case of sporadic Pick disease with onset at 27 years.

BACKGROUND: Pick disease is an uncommon cause of dementia in middle age, and young-onset cases have rarely been reported. SETTING: A specialist hospital. PATIENT: Patient with onset of cognitive impairment at the age of 27 years whose cerebral biopsy specimen demonstrated Pick cells and tau-positive Pick bodies. CONCLUSION: Pick disease should be considered in the differential diagnosis of dementia in young adults.

Adult↗

PubMed1999

Hippocampal sclerosis with hypertrophy of end folium pyramidal cells.

Mesial temporal lobectomy for the treatment of intractable temporal lobe seizures may show dual pathologies for example hippocampal sclerosis (HCS) combined with a malformation. In a lobectomy specimen from a 40-year-old female with typical radiological and pathological features of HCS, an additional histopathological finding was the presence of hypertrophic pyramidal cells in the dentate hilus, in which cytoplasmic accumulations of phosphorylated neurofilament were demonstrated. Although these cells closely resembled dysplastic nerve cells of cortical dysplasia, we argue that the cytoskeletal abnormalities observed are a result of ongoing alterations to hippocampal circuitry in an evolving HCS.

Adult↗