[COVID-19 and the central and peripheral nervous system]. / COVID-19: Auswirkungen auf das zentrale und periphere Nervensystem.

The health effects of coronavirus disease 2019 (COVID-19) caused by the infection of SARS-CoV­2 (severe acute respiratory syndrome coronavirus 2) are becoming increasingly clear as the pandemic spreads. In addition to the lungs, other organs are also affected, which can significantly influence morbidity and mortality. In particular, neurological symptoms involving the central nervous system can lead to acute or long-term consequences. The mechanisms of this neuropathogenesis of SARS-CoV­2 infection and its relation to acute and chronic neurological symptoms are the subject of current studies investigating a potential direct and indirect viral infection of the nervous system. The following review summarizes the current status of neuropathological manifestations, molecular pathogenesis, possible infection pathways in the nervous system, and systemic effects. In addition, an overview of the Germany-wide CNS-COVID19 registry and collaborations is presented, which should contribute to a better understanding of the neurological symptoms of COVID-19.

Late-onset leukoencephalopathy with cerebral calcifications and cysts: case report and review of the literature.

BACKGROUND: Leukoencephalopathy with calcifications and cysts (LCC or Labrune disease) is a relatively recently defined and exceptionally rare disease in which parenchymal cysts and calcifications within a widespread leukoencephalopathy can cause a broad spectrum of neurological symptoms. The cause of the disease is unknown. Manifestation is usually in childhood or adolescence, while onset in adulthood has been described in 19 cases. CASE PRESENTATION: Here we report a case of an adult-onset LCC of a Caucasian woman who became symptomatic at age 70 as confirmed by typical neuroimaging and neuropathological findings. After resection of left mesioparietal space-occupying cystic brain tissue the patient has so far remained clinically stable during one year of follow-up with a continuous treatment with glucocorticosteroids. CONCLUSION: To our knowledge this report of a patient who became symptomatic at age 70 represents the oldest age-at-onset case of LCC described so far.

Evaluation of Study and Patient Characteristics of Clinical Studies in Primary Progressive Multiple Sclerosis: A Systematic Review.

BACKGROUND: So far, clinical studies in primary progressive MS (PPMS) have failed to meet their primary efficacy endpoints. To some extent this might be attributable to the choice of assessments or to the selection of the study population. OBJECTIVE: The aim of this study was to identify outcome influencing factors by analyzing the design and methods of previous randomized studies in PPMS patients without restriction to intervention or comparator. METHODS: A systematic literature search was conducted in MEDLINE, EMBASE, BIOSIS and the COCHRANE Central Register of Controlled Trials (inception to February 2015). Keywords included PPMS, primary progressive multiple sclerosis and chronic progressive multiple sclerosis. Randomized, controlled trials of at least one year's duration were selected if they included only patients with PPMS or if they reported sufficient PPMS subgroup data. No restrictions with respect to intervention or comparator were applied. Study quality was assessed by a biometrics expert. Relevant baseline characteristics and outcomes were extracted and compared. RESULTS: Of 52 PPMS studies identified, four were selected. Inclusion criteria were notably different among studies with respect to both the definition of PPMS and the requirements for the presence of disability progression at enrolment. Differences between the study populations included the baseline lesion load, pretreatment status and disease duration. The rate of disease progression may also be an important factor, as all but one of the studies included a large proportion of patients with a low progression rate. In addition, the endpoints specified could not detect progression adequately. CONCLUSION: Optimal PPMS study methods involve appropriate patient selection, especially regarding the PPMS phenotype and progression rate. Functional composite endpoints might be more sensitive than single endpoints in capturing progression.

Analysis of CD4+ CD8+ double-positive T cells in blood, cerebrospinal fluid and multiple sclerosis lesions.

T cells with a CD4(+) CD8(+) double-positive (DP) phenotype are present in small numbers in the peripheral blood of healthy humans and may have anti-viral capacities. Here we investigate numbers and function of DP T cells in patients with relapsing-remitting multiple sclerosis (MS), either treatment-naive or under therapy with natalizumab. Flow cytometry analysis revealed that frequencies of circulating DP T cells in treatment-naive and natalizumab-treated MS patients are comparable to healthy controls. These cells have a memory phenotype with cytotoxic potential, express high levels of CD49d and are similarly functional in treatment-naive as well as natalizumab-treated MS patients. DP T cells were enriched in the cerebrospinal fluid, but do not invade acutely inflamed MS lesions. In conclusion, DP T cells are functional in MS and may play a role in the immune surveillance of the central nervous system, but do not display functional impairment under natalizumab therapy.

ß-catenin-independent WNT signaling in basal-like breast cancer and brain metastasis.

A role of WNT signaling for primary breast cancers of the basal-like subtype and as a predictor of brain metastasis has been described. However, a responsible WNT ligand has not been identified. To further clarify this question, we comparatively investigated 22 human breast cancer brain metastases as well as the highly invasive human breast cancer cell line MDA-MB-231 and the weakly motile MCF-7 as models for the basal-like and the luminal A subtype. WNT5A and B were found overexpressed in MDA-MB-231 cells as compared with MCF-7. This corresponded to reduction of MDA-MB-231 invasiveness by WNT inhibitors, whereas MCF-7 invasion was enhanced by recombinant WNT5B and abolished by WNT and Jun-N-terminal kinase antagonists. Expression and subcellular distribution of ß-catenin remained uninfluenced. Consistently, ß-catenin was not localized in the nuclei of brain metastases while there was strong nuclear c-Jun staining. Similar to MDA-MB-231, metastases showed expression of WNT5A/B and the alternative WNT receptors ROR1 and 2. These findings were validated using external gene expression datasets (Gene Expression Omnibus) of different breast cancer subtypes and brain metastases. Hierarchical cluster analysis yielded a close relation between basal-like cancers and brain metastases. Gene set enrichment analyses confirmed WNT pathway enrichment not only in basal-like primaries but also in cerebral metastases of all subtypes. In conclusion, WNT signaling seems highly relevant for basal-like and other subtypes of breast cancers metastasizing into the brain. ß-catenin-independent WNT signaling, presumably via ROR1-2, plays a major role in this context.

Absence of Epstein-Barr virus in the brain and CSF of patients with multiple sclerosis.

OBJECTIVE: Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus that becomes latent in B-lymphocytes and has been implicated in the pathogenesis of multiple sclerosis (MS). We searched for latent and active EBV infection in MS brain and CSF. METHODS: Nested and non-nested real-time PCR were used to detect cell-specific and EBV-specific transcripts in 15 fresh-frozen and 5 formalin-fixed paraffin-embedded MS plaques and in single MS CSF B-lymphocytes and plasma cells. Intrathecal anti-EBV antibody synthesis was measured by ELISA. Immunocytochemistry was used to detect binding of MS CSF and recombinant antibodies (rAbs) generated from clonally expanded plasma cells in MS CSF to EBV-infected cells. RESULTS: No EBV RNA was found in MS CSF B-lymphocytes or plasma cells. In active MS plaques, EBV-encoded RNA (EBER)-1 was the only and rarely detected transcript. The frequency of detected intrathecal anti-EBV antibody synthesis in patients with MS did not differ from that in non-MS inflammatory CNS disease control patients. Anti-EBV antibodies were detected in the CSF of patients with MS, but MS rAbs did not react with EBV. CONCLUSIONS: Application of real-time PCR to multiple sclerosis brain and single B-lymphocytes in CSF did not reveal any evidence of active Epstein-Barr virus infection.

Recent advances in the neuropathology of multiple sclerosis.

Important insights from multiple sclerosis (MS) pathology have broadened our view of the disease during the last years. Details of the inflammatory response as well as mechanisms of demyelination were elucidated. Damage to neuronal processes was identified as the major predictor of persistent disability in MS patients. Abortive repair mechanisms are increasingly studied, and our increased understanding will pave the way to new therapeutic strategies. This overview highlights some of the current views on MS pathogenesis derived from human neuropathology.

Myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis in the common marmoset reflects the immunopathology of pattern II multiple sclerosis lesions.

Pathomorphological studies described pathological heterogeneity in patients with multiple sclerosis (MS). Different effector mechanisms might therefore be responsible for lesion formation in MS. The present report shows that myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) in common marmoset monkeys reflects one specific lesional subtype of MS, namely MS pattern II lesions with antibody/complement-mediated damage. MOG-induced EAE in marmoset monkeys will, therefore, provide an ideal model for therapeutic approaches directed against B-cell/antibody/complement in MS.

The neuroprotective effect of inflammation: implications for the therapy of multiple sclerosis.

Autoreactive T cells are a regular component of the healthy immune system. It has been proposed that some of these autoreactive T cells even might have a protective function. Recent studies support this notion by demonstrating that: a) myelin-autoreactive T cells show neuroprotective effects in vivo, and b) activated antigen-specific human T cells and other immune cells produce bioactive brain-derived neurotrophic factor (BDNF) and other neurotrophic factors in vitro. Furthermore, BDNF is expressed in different types of inflammatory cells in brain lesions of patients with acute disseminated leukoencephalopathy or multiple sclerosis. It seems plausible that the immune cell-mediated import of BDNF and other neurotrophic factors into the central nervous system has functional consequences and implications for the therapy of multiple sclerosis and other neuroimmunological diseases.

[Recent advances in pathogenesis and therapy of multiple sclerosis]. / Fortschritte in Pathogeneseforschung und Therapie der Multiplen Sklerose.

In this article, recent advances in the research on pathogenesis and therapy of multiple sclerosis (MS) will be summarized. New evidence from clinical studies, imaging, histopathology and experimental models are discussed with a focus on neurodegenerative aspects and evidence from recent therapeutic studies. During the last decade, important advances in immunotherapy have been achieved, which proved especially useful for patients with relapsing remitting MS. The introduction of interferons and glatiramer acetate into MS therapy often leads to a stabilization of the disease course if administered adequately and early. The pathogenetic insights presented here may open new avenues for innovative immunomodulatory approaches and lead to an individualized MS therapy in the future. Neuroprotective treatment strategies aim at the protection of glial and neuronal cells.

Neuroprotective effects and intracellular signaling pathways of erythropoietin in a rat model of multiple sclerosis.

In multiple sclerosis (MS), long-term disability is primarily caused by axonal and neuronal damage. We demonstrated in a previous study that neuronal apoptosis occurs early during experimental autoimmune encephalomyelitis, a common animal model of MS. In the present study, we show that, in rats suffering from myelin oligodendrocyte glycoprotein (MOG)-induced optic neuritis, systemic application of erythropoietin (Epo) significantly increased survival and function of retinal ganglion cells (RGCs), the neurons that form the axons of the optic nerve. We identified three independent intracellular signaling pathways involved in Epo-induced neuroprotection in vivo: Protein levels of phospho-Akt, phospho-MAPK 1 and 2, and Bcl-2 were increased under Epo application. Using a combined treatment of Epo together with a selective inhibitor of phosphatidylinositol 3-kinase (PI3-K) prevented upregulation of phospho-Akt and consecutive RGC rescue. We conclude that in MOG-EAE the PI3-K/Akt pathway has an important influence on RGC survival under systemic treatment with Epo.

Lessons from the neuropathology of atypical forms of multiple sclerosis.

Multiple sclerosis (MS) is characterized by multiple demyelinated inflammatory lesions disseminated in the central nervous system (CNS). Additional features of MS pathology include axonal loss and gliosis. Remyelination may take place predominantly in the early stages of lesion formation. Pathologically, important inter-individual differences have been observed with respect to oligodendrocyte preservation. Furthermore, different mechanisms of demyelination, such as T-cell/macrophage-mediated demyelination, antibody/complement-mediated demyelination, and primary damage of the oligodendrocyte have been observed in individual MS patients. Atypical MS forms, such as Marburg's acute MS, Devic's neuromyelits optica, Balò's concentric sclerosis, and Schilder's diffuse sclerosis share key aspects of MS pathology, however, each of them harbors characteristic discriminative features. Devic's neuromyelitis optica may represent the prototypical disease with antibody/complement-mediated demyelination, whereas cases with Balò's concentric sclerosis show oligodendrocyte dystrophy. Acute disseminated encephalomyelitis (ADEM) may be regarded as a related condition lacking extensive demyelination. Thus, atypical MS forms may help to elucidate pathogenic mechanisms in MS.

Inflammation and degeneration in multiple sclerosis.

Multiple (MS) sclerosis is a chronic inflammatory demyelinating disease of the central nervous system with the pathological hallmarks of inflammation, demyelination, axon loss and gliosis. In the initial relapsing-remitting phase of the disease, the inflammatory-demyelinating component seems to predominate, whereas the progressive disease appears to be characterized by a neurodegenerative component leading to extensive neuroaxonal damage in the MS brain. Axon loss most likely determines the persistent neurological deficit in progressive MS. Recent studies pointed out that axon damage occurs early in the disease and during lesion development. Two different phases of axon degeneration were characterized, the first occurring during active myelin breakdown and the second in chronic demyelinated plaques in which the naked axon seems more susceptible to further damage. The exact mechanisms and effector molecules of axonal degeneration, however, are not yet defined, and an axon-protective therapy has not yet been established.

Expression of death-related proteins in dentate granule cells in human bacterial meningitis.

Neuronal apoptosis in the dentate gyrus has been observed in animal models of bacterial meningitis and in humans dying in the course of the disease. To evaluate the mechanisms of neuronal cell death, hippocampal sections of 20 patients dying from bacterial meningitis were investigated by immunohistochemistry using antibodies against the proform of caspase-3 and the active enzyme, bcl-2, bax and p53. In the dentate granule cell layer, the median density of neurons with an apoptotic morphology was 7.6/mm2 (0-15.6/mm2). The median density of immunoreactive neurons was 2.3/mm2 (procaspase-3), 0.9/mm2 (activated caspase-3), 1.8/mm2 (bcl-2), 1.1/mm2 (bax) and 0.4/mm2 (p53). 80% of neurons immunoreactive for active caspase-3 had an apoptotic morphology, whereas only 10% of all procaspase-3 stained neurons showed signs of apoptosis. Apoptotic cell death is present in humans dying in the course of bacterial meningitis in the dentate gyrus of the Formatio hippocampi. Neuronal expression of caspase-3, bcl-2 and bax suggests an involvement of these proteins in neuronal death.