Manfred Schmidbauer

Multiple Sclerosis and Chronic Autoimmune Encephalomyelitis : A Comparative Quantitative Study of Axonal Injury in Active, Inactive, and Remyelinated Lesions

Recent magnetic resonance (MR) studies of multiple sclerosis lesions indicate that axonal injury is a major correlate of permanent clinical deficit. In the present study we systematically quantified acute axonal injury, defined by immunoreactivity for beta-amyloid-precursor-protein in dystrophic neurites, in the central nervous system of 22 multiple sclerosis patients and 18 rats with myelin-oligodendrocyte glycoprotein (MOG)-induced chronic autoimmune encephalomyelitis (EAE). The highest incidence of acute axonal injury was found during active demyelination, which was associated with axonal damage in periplaque and in the normal appearing white matter of actively demyelinating cases. In addition, low but significant axonal injury was also observed in inactive demyelinated plaques. In contrast, no significant axonal damage was found in remyelinated shadow plaques. The patterns of axonal pathology in chronic active EAE were qualitatively and quantitatively similar to those found in multiple sclerosis. Our studies confirm previous observations of axonal destruction in multiple sclerosis lesions during active demyelination, but also indicate that ongoing axonal damage in inactive lesions may significantly contribute to the clinical progression of the disease. The results further emphasize that MOG-induced EAE may serve as a suitable model for testing axon-protective therapies in inflammatory demyelinating conditions.

The relation between inflammation and neurodegeneration in multiple sclerosis brains

Some recent studies suggest that in progressive multiple sclerosis, neurodegeneration may occur independently from inflammation. The aim of our study was to analyse the interdependence of inflammation, neurodegeneration and disease progression in various multiple sclerosis stages in relation to lesional activity and clinical course, with a particular focus on progressive multiple sclerosis. The study is based on detailed quantification of different inflammatory cells in relation to axonal injury in 67 multiple sclerosis autopsies from different disease stages and 28 controls without neurological disease or brain lesions. We found that pronounced inflammation in the brain is not only present in acute and relapsing multiple sclerosis but also in the secondary and primary progressive disease. T- and B-cell infiltrates correlated with the activity of demyelinating lesions, while plasma cell infiltrates were most pronounced in patients with secondary progressive multiple sclerosis (SPMS) and primary progressive multiple sclerosis (PPMS) and even persisted, when T- and B-cell infiltrates declined to levels seen in age matched controls. A highly significant association between inflammation and axonal injury was seen in the global multiple sclerosis population as well as in progressive multiple sclerosis alone. In older patients (median 76 years) with long-disease duration (median 372 months), inflammatory infiltrates declined to levels similar to those found in age-matched controls and the extent of axonal injury, too, was comparable with that in age-matched controls. Ongoing neurodegeneration in these patients, which exceeded the extent found in normal controls, could be attributed to confounding pathologies such as Alzheimers or vascular disease. Our study suggests a close association between inflammation and neurodegeneration in all lesions and disease stages of multiple sclerosis. It further indicates that the disease processes of multiple sclerosis may die out in aged patients with long-standing disease.

Widespread Demyelination in the Cerebellar Cortex in Multiple Sclerosis

Neocortical demyelination in the forebrain has recently been identified as an important pathological feature of multiple sclerosis (MS). Here we describe that the cerebellar cortex is a major predilection site for demyelination, in particular in patients with primary and secondary progressive MS. In these patients, on average, 38.7% of cerebellar cortical area is affected, reaching in extreme examples up to 92%. Cerebellar cortical demyelination occurs mainly in a band‐like manner, affecting multiple folia. The lesions are characterized by primary demyelination with relative axonal and neuronal preservation, although some axonal spheroids and a moderate reduction of Purkinje cells are present. Although cortical demyelination sometimes occurs together with demyelination in the adjacent white matter (leukocortical lesions), in most instances, the cortex was affected independently from white matter lesions. We found no correlation between demyelination in the cortex and the white matter, and in some cases, extensive cortical demyelination was present in the near absence of white matter lesions. Our data identify cortical demyelination as a potential substrate of cerebellar dysfunction in MS.

Expression of major histocompatibility complex class I molecules on the different cell types in multiple sclerosis lesions.

Multiple sclerosis is considered to be an immune‐mediated disease of the central nervous system, characterized by chronic inflammation, primary demyelination and axonal damage. The mechanisms of demyelination and axonal injury are heterogeneous and complex. One possible mechanism is direct damage of oligodendrocytes and neurons by Class I MHC restricted cytotpxic T‐cells. In this study we analyzed the expression of functional MHC class I molecule complex, consisting of α‐chain and β2‐microglobulin, in a large sample of human autopsy material, containing 10 cases of acute MS, 10 cases of chronic active MS, 10 cases of chronic inactive MS and 21 controls. To examine the expression of MHC class I and II molecules on the different cell‐types in brain, we used quantitative immunohistochemical techniques, double staining and confocal laser microscopy scans on paraffin embedded sections. We found constitutive expression of MHC class I molecule on microglia and endothelial cells. A hierarchical up‐regulation of MHC class I was present on astrocytes, oligodendrocytes, neurons and axons, depending upon the severity of the disease and the activity of the lesions MHC class II molecules were expressed on microglia and macrophages, but not on astrocytes. These data indicate that in MS lesions all cells of the central nervous system are potential targets for Class I MHC restricted cytotoxic T‐cells.

Late-onset metachromatic leukodystrophy: Genotype strongly influences phenotype

Background: P426L and I179S are the two most frequent mutations in juvenile and adult metachromatic leukodystrophy (late-onset MLD), which, in contrast to infantile MLD, show marked phenotypic heterogeneity. Objective: To search for genotype–phenotype correlations in late-onset MLD. Methods: The authors reviewed the clinical course of 22 patients homozygous for mutation P426L vs 20 patients heterozygous for mutation I179S, in which the second arylsulfatase A (ASA) mutation had also been determined. Results: P426L homozygotes principally presented with progressive gait disturbance caused by spastic paraparesis or cerebellar ataxia; mental disturbance was absent or insignificant at the onset of disease but became more apparent as the disease evolved. In contrast, compound heterozygotes for I179S presented with schizophrenia-like behavioral abnormalities, social dysfunction, and mental decline, but motor deficits were scarce. Reduced peripheral nerve conduction velocities and less residual ASA activity were present in P426L homozygotes vs I179S heterozygotes. Conclusion: The characteristic clinical differences between homozygous P426L and compound heterozygous I179S patients establish a distinct genotype–phenotype correlation in late-onset metachromatic leukodystrophy.

Suprasellar meningioma with expression of glial fibrillary acidic protein: a peculiar variant

A 24-year-old female presented with a 3-year history of a suprasellar and intraventricular solid midline process measuring about 3×4 cm. At surgery, this tumour was sharply delineated and of stone-like firmness and was removed completely. Histology suggested meningioma, featuring nests and cords of epithelium-like cells with prominent cytoplasm amidst abundant fibrous stroma with prominent lymphoplasmocellular infiltration. Immunocytochemically, the tumour cells expressed vimentin, S-100 protein, epithelial membrane antigen, cytokeratins, and most surprisingly, glial fibrillary acidic protein (GFAP). Ultrastructural investigation revealed abundant intermediate filaments and occasionally dense secretory granules in tumour cells with short, finger-like cytoplasmic processes joined by very rare small, but well-developed desmosomes. This tumour most likely represents a peculiar variant of meningioma with prominent production of GFAP, as previously described [Budka H (1986) Acta Neuropathol (Berl) 72: 43–54].

Cytomegalovirus (CMV) disease of the brain in AIDS and connatal infection: a comparative study by histology, immunocytochemistry and in situ DNA hybridization.

SummaryBrain tissues from 45 patients with AIDS and two brains with connatal cytomegalic inclusion body disease were investigated for a cytomegalovirus (CMV) etiology of encephalitic lesions. Nineteen brains showed evidence of CMV infection by histology, immunocytochemistry (ICC) using two different antibodies (mono- and polyclonal), and in situ hybridization (ISH). Fourteen cases with typical cytomegalic cells in conventional histology [eight with focally necrotizing encephalitis/ventriculitis including the two connatal infections and six with nodular encephalitis (NE)] revealed CMV with any method. In 5 of 15 AIDS cases of NE without cytomegalic cells, CMV infection was established by ISH, whereas ICC remained negative in these cases. Typical lesions of human immunodeficiency virus (HIV)-induced multifocal giant cell encephalitis (HIV encephalitis) in 13 brains were never labeled for CMV. In necrotizing encephalitis/ventriculitis, cell types which labeled for CMV, with and without cytomegalic change, comprised neurons, astrocytes, oligodendrocytes, ependyma, choroid plexus, endothelia, and cells in periand endoneurium, and in leptomeninges. Both ISH and ICC were able to detect widespread non-cytomegalic CMV-infected cells in normal parenchyma, well beyound the necrotizing lesions, in two AIDS cases. Labeling patterns of nuclei versus cytoplasms varied between the three methods for CMV detection. We conclude that in CNS tissues with cytomegalic cells, ICC and ISH are of comparable sensitivity; however, a diagnosis of CMV disease is possible in such cases by conventional histology. For an in situ diagnosis of CMV infection in NE without cytomegalic cells in AIDS, ISH is the method of choice. A selective vulnerability to CMV infection of any specific cell type of the human CNS is absent. With our detection methods, typical lesions of HIV encephalitis do not show local co-infection by CMV.

Progressive multifocal leukoencephalopathy (PML) in AIDS and in the pre-AIDS era - A neuropathological comparison using immunocytochemistry and in situ DNA hybridization for virus detection

SummaryTwenty-five brains with definite, and three brains with possible, progressive multifocal leukoencephalopathy (PML), including six brains of AIDS patients, were studied with special regard to the detection of papovaviruses. Formalin-fixed serial paraffin sections were immunostained with monospecific anti-JC virus (JCV) and genus-specific anti-simian virus (SV) 40 antisera, and hybridized in situ with DNA probes for JCV and SV 40, respectively. Immunocytochemistry (ICC) and in situ hybridization (ISH) were similarly sensitive in detecting virus in classical PML lesions. In all but one definite PML cases at least one method detected virus (96%). Possible PML tissue was never labeled. Labeling patterns were generally similar in ICC and ISH: mainly oligodendroglia and, less frequently, astroglia harbored virus, whereas labeling of neurons and endothelia was absent. Bizarre giant astrocytes were occasionally labeled by ICC and ISH. Burnt-out lesions harbored JCV DNA but not virus antigens. SV 40 DNA was never detectable. PML morphology in AIDS cases did not usually differ from the disease process seen in the pre-AIDS era. However, two AIDS brains presented extremely extended and, in one case, unusually necrotizing PML damage; in the latter case, PML lesions contained large amounts not only of JCV, but also of human immunodeficiency virus (HIV) antigens. We conclude that ICC and ISH are methods of comparable sensitivity for detection of papovavirus in flourishing PML lesions. In burnt-out PML lesions only ISH may detect virus. The possibility of an exceptional non-JCV (e.g., SV 40) etiology of PML could be neither confirmed for disproved. In AIDS, massive coinfection by HIV of PML lesions may increase damage to tissue, resulting in unusually extended and necrotizing PML.

Posterior ischemic optic neuropathy following bilateral radical neck dissection

A patient is presented with posterior ischemic optic neuropathy (PION) after bilateral radical neck dissection, probably caused by hemodynamic hypotension, combined with other factors. A postmortem histologic study of the optic nerve was performed to analyze the pathogenic mechanism of blindness. To prevent this complication, one should favor a two-stage procedure, avoiding drug-induced hypotension, overtransfusion, and anemia. During the postoperative period, visual acuity should be monitored regularly, and proper positioning of the patients head is necessary.

Serum Melatonin Levels: A New Neurodiagnostic Tool in Pineal Region Tumors?

The pineal hormone melatonin (MLT) is secreted in a circadian rhythm with high serum levels during nighttime and low serum levels during daytime. Several authors have reported an altered secretion pattern of MLT in patients with pineal tumors and have proposed that MLT may be used as a tumor marker. In nine patients, a pineal region tumor was diagnosed by computer-assisted tomography. Before and after surgical removal of the tumor, several day- and nighttime serum samples were collected and MLT concentrations were estimated by radioimmunoassay. Before operation, five patients presented a normal circadian pattern of MLT secretion. In the remaining four subjects, MLT levels were undetectable or at the limit of detection, with no signs of a circadian secretion pattern. Eight patients were reexamined after tumor resection, when all but one had undetectable or very low MLT levels. The remaining subject, with a pineomesencephalic pilocytic astrocytoma, dislocating but not involving the pineal gland, presented a normal circadian secretion pattern of MLT after operation; in this case, tumor resection was possible without damaging the pineal gland. Thus, before operation, MLT deficiency rather than exaggerated serum levels may be used as a marker for pineal tumors that destroy the pineal gland. After tumor resection, serum MLT may serve to demonstrate complete pinealectomy.