Helmut Rauschka

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.

Inflammation in the nervous system: The human perspective

Many basic aspects of brain inflammation, recently disclosed in experimental models, are reflected in the pathology of human inflammatory brain diseases. Examples include the key role of T lymphocytes in immune surveillance and in the regulation of the inflammatory response, the essential contributions of adhesion molecules, proinflammatory cytokines, chemokines, and proteases in the recruitment of inflammatory cells into the nervous tissue, the modulating effect of glia cells on the inflammatory process and the termination of T‐cell‐mediated inflammation by apoptotic cell death. Despite this progress in our understanding of the pathogenesis of brain inflammation, there are still major unresolved questions. Because of technical constraints, most of our knowledge on central nervous system inflammation so far relates to the role of a specific T‐cell subset, the so‐called T‐helper‐1 cells. Other T‐cell subsets, in particular cytotoxic class I MHC‐restricted T lymphocytes, however, appear to be of major importance in human disease. Furthermore, the detailed mechanisms, which are responsible for the profound differences in the patterns of tissue damage in different human inflammatory brain diseases, such as multiple sclerosis or various forms of virus encephalitis, are largely unresolved. We discuss the open questions to be addressed in the future, which, when answered, may help to design novel therapeutic strategies. GLIA 36:235–243, 2001.

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.

An Optimized Immunohistochemistry Technique Improves NMO-IgG Detection: Study Comparison with Cell-Based Assays

Cell-based assays (CBA) have increased the sensitivity of the neuromyelitis optica (NMO)-IgG/aquaporin-4-antibody detection compared to classical tissue-based indirect assays. We describe the sensitivity of an optimized immunohistochemistry (IHC-o) to detect NMO-IgG/aquaporin-4-antibody in comparison with that of two CBA: an in-house (CBA-ih) and a commercial (CBA-c) assay (Euroimmun, Germany). Coded serum from 103 patients with definite NMO and 122 inflammatory controls were studied by IHC-o, CBA-ih, and CBA-c. IHC-o used the same protocol described to detect antibodies against cell surface antigens. CBA-ih used live cells transfected with the aquaporin-4-M23-isoform. The sensitivity of the IHC-o was 74.8% (95% confidence interval [CI] 65-83) and was similar to that of the CBA-ih 75.7% (95% CI 66-84) and the CBA-c 73.8% (95% CI 64-82). The specificity of the three assays was 100% (95% CI 97-100). Interassay concordance was high, 100 of 103 samples were coincident in all techniques. The optimized immunohistochemistry proves to be as sensitive and specific as the cell-based assays. This assay extends the available tools for NMO-IgG/aquaporin-4-antibody detection.

Neuromyelitis Optica in Austria in 2011: To Bridge the Gap between Neuroepidemiological Research and Practice in a Study Population of 8.4 Million People

Background In 2008 the Austrian Task Force for Neuromyelitis Optica (NMO) started a nation-wide network for information exchange and multi-centre collaboration. Their aim was to detect all patients with NMO or NMO spectrum disorders (NMO-SD) in Austria and to analyse their disease courses and response to treatment. Methods (1) As of March 2008, 1957 serum samples (of 1557 patients) have been tested with an established cell based immunofluorescence aquaporin-4 antibody (AQP4-ab) assay with a high sensitivity and specificity (both >95%). All tests were performed in a single reference laboratory (Clinical Dept. of Neurology of the Innsbruck Medical University). (2) A nation-wide survey with several calls for participation (via email newsletters, articles in the official journal of the Austrian Society of Neurology, and workshops) was initiated in 2008. All collected data will be presented in a way that allows that every individual patient can be traced back in order to ensure transparency and to avoid any data distortion in future meta-analyses. The careful and detailed presentation allows the visualization and comparison of the different disease courses in real time span. Failure and response to treatment are made visible at one glance. Database closure was 31 December 2011. All co-operators were offered co-authorship. Results All 71 NMO- or NMO-SD patients with AQP4-ab positivity (age range 12.3 to 79.6 years) were analysed in detail. Sex ratio (m:f = 1:7) and the proportion of patients without oligoclonal bands in cerebrospinal fluid (86.6%) were in line with previously published results. All identified patients were Caucasians. Conclusions A nationwide collaboration amongst Austrian neurologists with good network communications made it possible to establish a database of 71 AQP4-ab positive patients with NMO/NMO-SD. This database is presented in detail and provides the basis for further studies and international cooperation in order to investigate this rare disease.

Rolipram does not normalize very long-chain fatty acid levels in adrenoleukodystrophy protein-deficient fibroblasts and mice

In its severe form, X-linked adrenoleukodystrophy (X-ALD) is a lethal neurodegenerative disorder with inflammatory demyelination, in which defective peroxisomal β-oxidation causes accumulation of very long-chain fatty acids (VLCFA) in tissues and plasma, in particular in the nervous system and adrenal glands. Recently, several drugs have been reported to reduce VLCFA in cultured human fibroblasts of X-ALD patients, and therefore to be potential candidates for novel therapeutic treatments in X-ALD. Among the most promising of these substances is the antidepressant rolipram, because of favourable adverse event profile in clinical studies and its additionally reported anti-inflammatory action. To further elucidate the effects of rolipram on peroxisomal β-oxidation and VLCFA accumulation, we administered rolipram orally in the diet to ALD protein-deficient mice and ALD protein-deficient cultured human and mouse fibroblasts and assayed the accumulation of VLCFA. In contrast to the previously reported reduction of VLCFA, our data did not demonstrate a decrease in VLCFA content either in vivo or in vitro. NMR spectroscopic analysis verified the structural integrity and purity of the rolipram used here, thus excluding inauthenticity as a reason for the discrepancy. We therefore suggest that rolipram should be excluded from the current list of potential therapeutic agents for X-ALD.

CROP - The Clinico-Radiologico-Ophthalmological Paradox in Multiple Sclerosis: Are Patterns of Retinal and MRI Changes Heterogeneous and Thus Not Predictable?

Background To date, no direct scientific evidence has been found linking tissue changes in multiple sclerosis (MS) patients, such as demyelination, axonal destruction or gliosis, with either steady progression and/or stepwise accumulation of focal CNS lesions. Tissue changes such as reduction of the retinal nerve fiber layer (RNFL) and the total macular volume (TMV), or brain- and spinal cord atrophy indicates an irreversible stage of tissue destruction. Whether these changes are found in all MS patients, and if there is a correlation with clinical disease state, remains controversial. The objective of our study was to determine, whether there was any correlation between the RNFL or TMV of patients with MS, and: (1) the lesion load along the visual pathways, (2) the ratios and absolute concentrations of metabolites in the normal-appearing white matter (NAWM), (3) standard brain atrophy indices, (4) disease activity or (5) disease duration. Methods 28 MS patients (RRMS, n = 23; secondary progressive MS (SPMS), n = 5) with moderately-high disease activity or long disease course were included in the study. We utilised: (1) magnetic resonance imaging (MRI) and (2) -spectroscopy (MRS), both operating at 3 Tesla, and (3) high-resolution spectral domain-OCT with locked reference images and eye tracking mode) to undertake the study. Results There was no consistency in the pattern of CNS metabolites, brain atrophy indices and the RNFL/TMV between individuals, which ranged from normal to markedly-reduced levels. Furthermore, there was no strict correlation between CNS metabolites, lesions along the visual pathways, atrophy indices, RNFL, TMV, disease duration or disability. Conclusions Based on the findings of this study, we recommend that the concept of ‘clinico-radiologico paradox’ in multiple sclerosis be extended to CROP–‘clinico-radiologico-ophthalmological paradox’. Furthermore, OCT data of MS patients should be interpreted with caution.

Susac's syndrome: clinical course and epidemiology in a Central European population

Abstract Objective: Susacs syndrome is characterized by inflammation and occlusion of pre-capillary arterioles with the clinical triad of branch retinal artery occlusion (BRAO), encephalopathy and hearing loss. No epidemiological data are available for the disease. Methods: All neurology departments in Austria were addressed to report adult patients who were on immunosuppressive treatment for a diagnosis of Susacs syndrome between 1 August 2010 and 1 August 2015. Clinical course, treatment regimens, period and point prevalence rates, and annual incidence of Susacs syndrome in Austria in people over 19 years of age are reported. Results: Ten patients with Susacs syndrome were identified, and eight of them were newly diagnosed within the five-year timeframe. Minimum five-year period prevalence of the disease is 0.148/100,000 (95% confidence interval (CI) 0.071–0.272), annual incidence is 0.024/100,000 (95% CI 0.010–0.047). Minimum point prevalence rates varied from 0.030/100,000 (95% CI 0.004–0.108) to 0.088/100,000 (95% CI 0.032–0.192). Of all 10 patients, 8 showed typical callosal or internal capsule magnetic resonance imaging lesions at first presentation, 7 presented with BRAO and 5 had hearing loss or tinnitus at the beginning of the disease. Four patients developed the complete clinical triad of Susacs syndrome during the observation period. Conclusions: We provide for the first time population-based data about the clinical course, prevalence and incidence of Susacs syndrome.

Subacute brainstem angioencephalopathy: a case report and review of the literature

A previously healthy 69-year-old man developed a progressive neurological illness with bulbar signs and ataxic paraparesis. Repeated MRI examinations revealed a large space occupying lesion in the lower brain stem with patchy contrast enhancement. MRI angiography was unremarkable and CSF had normal cell count but raised protein content. A brainstem tumor was suspected and a course of intravenous glucocorticosteroids was started. No improvement occurred and the patient died of pneumonia 11 weeks after onset. Neuropathology revealed confluent areas of complete or incomplete necrosis with marked edema in the lower brainstem. Predominantly venous meningeal vessels of the brainstem showed extensive fibromuscular thickening of all layers with luminal narrowing. In addition, intramural mononuclear infiltration was found. With the exception of localisation, this case exhibits all pathologic features of subacute diencephalic angioencephalopathy (SDAE), a rare fatal disease of unknown aetiology. In addition, the clinical features of typical age, male sex, disease duration and raised CSF proteins are shared. A common disease entity is suggested and the pathogenetic relevance of inflammation and venous outflow obstruction is discussed.