[Thromboembolism - A common cause of stroke]. / Thromboembolien ­ Eine häufige Ursache des Schlaganfalls.

In the field of neurology, thromboembolic events are responsible for approximately 40% of ischemic strokes 1. The embolisms are differentiated according to their origin: One group includes emboli that occur in the heart, e.g. due to atrial fibrillation (cardioembolic stroke). Another group includes emboli, which are caused by arteriosclerotic plaques, e.g. in the area of the carotid bifurcation in the large vessels supplying the brain. After the acute therapy of the ischemic stroke, further diagnostics are essential to determine the exact cause of the ischemic stroke. Targeted therapy to prevent further strokes can only be initiated if the cause is known (secondary prevention). In the following - in addition to the current diagnostics and therapy of thromboembolic strokes - new guideline recommendations and COVID-19 will be discussed.

When your cat takes you to the ICU: Miller Fisher/ Guillain-Barré-overlap-syndrome caused by Pasteurella multocida infection resembling wound botulism.

BACKGROUND: Pasteurella multocida can cause serious soft tissue infections and, less commonly, septic arthritis, osteomyelitis, and sepsis especially in immunocompromised hosts. P. multocida can cause meningitis or meningoencephalitis, occasionally with the formation of abscesses, but is rarely the cause of other neurological diseases. Miller Fisher Syndrome (MFS) is a parainfectious autoimmune disorder presenting with ophthalmoplegia, ataxia and areflexia. CASE PRESENTATION: We present the case of a 59-year-old immunocompetent patient who developed an atypical Miller Fisher/ Guillain-Barré-overlap-syndrome associated with a phlegmon caused by P. multocida, an associated bacteremia and sepsis leading to long intensive care treatment. Initial differential diagnosis was wound botulism. Patient was treated by antibiotics, wound cleansing with VAC pump and intravenous immunoglobulins. CONCLUSION: With this case we were able to show that a P. multocida infection can trigger atypical Miller Fisher/ Guillain-Barré-overlap-syndrome and that this is an important differential diagnosis of wound botulism.

Update on Paraneoplastic Cerebellar Degeneration.

Purpose of review: To provide an update on paraneoplastic cerebellar degeneration (PCD), the involved antibodies and tumors, as well as management strategies. Recent findings: PCD represents the second most common presentation of the recently established class of immune mediated cerebellar ataxias (IMCAs). Although rare in general, PCD is one of the most frequent paraneoplastic presentations and characterized clinically by a rapidly progressive cerebellar syndrome. In recent years, several antibodies have been described in association with the clinical syndrome related to PCD; their clinical significance, however, has yet to be determined. The 2021 updated diagnostic criteria for paraneoplastic neurologic symptoms help to establish the diagnosis of PCD, direct cancer screening, and to evaluate the presence of these newly identified antibodies. Recognition of the clinical syndrome and prompt identification of a specific antibody are essential for early detection of an underlying malignancy and initiation of an appropriate treatment, which represents the best opportunity to modulate the course of the disease. As clinical symptoms can precede tumor diagnosis by years, co-occurrence of specific symptoms and antibodies should prompt continuous surveillance of the patient. Summary: We provide an in-depth overview on PCD, summarize recent findings related to PCD, and highlight the transformed diagnostic approach.

[Update 2021: COVID-19 from the perspective of neurology]. / Update 2021: COVID-19 aus Sicht der Neurologie.

Neurological complications, direct affection of neuronal structures in the course of infections with SARS-CoV-2 and long-term effects ("long COVID") are evident. This article aims to summarize and evaluate the current literature on this topic.

[COVID-19: A neurological point-of-view]. / COVID-19 aus Sicht der Neurologie.

Evidence of neurological complications and direct affection of neuronal structures in the course of infections with SARS-CoV-2 is actually emerging. Therefore adequate medical care for neurological patients must also be guaranteed as part of the current SARS-CoV-2 pandemic. Multiple, peripheral and central neurological affections have been described, such as particular headache, consciousness disorders, cranial nerve disorders, peripheral nerve damage, epileptic seizures and ischemic events. Since abundant information on COVID-19 is published on a daily basis, this article aims to summarize and evaluate the current literature on this topic.

[Pancreatic Cancer in the Year 2018 - Room for Precision Medicine?] / Pankreaskarzinom 2018 ­ reif für personalisierte Therapiekonzepte?

In Germany, an estimated 19 000 people will develop pancreatic carcinoma in 2018. The 5-year survival rate of all pancreatic carcinoma patients is very low at around 6 %, and the potentially curative operation is only possible in 15 - 20 % of patients. More frequent use and combination of systemic chemotherapeutic agents has led to improved life expectancy in recent years. In this article we will summarize recent therapeutic strategies depending on tumor status and current approaches to personalized medicine in pancreatic carcinoma.

Knockdown of ApoL1 in Zebrafish Larvae Affects the Glomerular Filtration Barrier and the Expression of Nephrin.

APOL1, a secreted high-density lipoprotein, is expressed in different human tissues. Genetic variants of APOL1 are described to be associated with the development of end stage renal diseases in African Americans. In human kidney, APOL1 is mainly expressed in podocytes that are responsible for proper blood filtration. Since mice do not express ApoL1, the zebrafish is an ideal model to study the role of ApoL1. Injection of morpholinos against zApoL1 into zebrafish eggs and larvae, respectively, induces severe edema indicating a leakage of the filtration barrier. This was demonstrated in zApoL1 knockdown larvae by intravascular injection of fluorescently-labeled 10- and 500-kDa dextrans and by clearance of the vitamin D-binding protein from the circulation. Immunohistochemistry and RT-PCR revealed the reduction of nephrin, a podocyte-specific protein essential for blood filtration. Coinjection of human nephrin mRNA rescued the zApoL1 knockdown induced phenotype. Reduced APOL1 and nephrin levels were also found in biopsies of patients suffering from end stage renal diseases. Our results demonstrate that zApoL1 is essential for proper blood filtration in the zebrafish glomerulus and that zApoL1 affects the expression of nephrin.

The role of ion channels in malignant brain tumors.

Malignant gliomas are the most common primary brain tumors and have poor clinical prognosis, despite multimodal therapeutic strategies. In recent years, ion channels have emerged as major players in tumor pathophysiology regarding all hallmarks of cancer. Since ion channels are easily accessible structures, they may prove to be effective targets for canner therapy, although their broad expression pattern and role in physiological processes should be taken into consideration. This review summarizes the current knowledge on the role of ion channels in the pathophysiology of malignant gliomas, especially glioblastoma, and evaluates their potential role in targeted antiglioma therapy.

Two-photon microscopy reveals stationary podocytes in living zebrafish larvae.

Podocytes are an essential component of the glomerular filtration barrier and cover the outer aspect of glomerular capillaries. They form a complex actin-based cytoskeleton in vivo and show prominent motility in vitro, but whether podocytes are stationary or mobile in vivo is debated. To address this question, the pronephros of translucent zebrafish larvae (casper) expressing enhanced green fluorescent protein (eGFP) specifically in podocytes (wt1a:eGFP larvae) was observed by intravital two-photon microscopy over extended periods of time. Podocyte cell bodies and the interdigitating branching pattern of major processes could be resolved with a resolution of approximately 1 µm in the xy-plane. Time-lapse imaging of zebrafish larvae at 5-7 days after fertilization demonstrated that podocytes neither migrated nor changed the branching pattern of their major processes over a time period of up to 23 hours. In summary, we show by extended intravital two-photon microscopy that podocytes are stationary cells in the intact glomerulus of a translucent zebrafish with fluorescently-labeled podocytes.

Increased cortical curvature reflects white matter atrophy in individual patients with early multiple sclerosis.

OBJECTIVE: White matter atrophy occurs independently of lesions in multiple sclerosis. In contrast to lesion detection, the quantitative assessment of white matter atrophy in individual patients has been regarded as a major challenge. We therefore tested the hypothesis that white matter atrophy (WMA) is present at the very beginning of multiple sclerosis (MS) and in virtually each individual patient. To find a new sensitive and robust marker for WMA we investigated the relationship between cortical surface area, white matter volume (WMV), and whole-brain-surface-averaged rectified cortical extrinsic curvature. Based on geometrical considerations we hypothesized that cortical curvature increases if WMV decreases and the cortical surface area remains constant. METHODS: In total, 95 participants were enrolled: 30 patients with early and advanced relapsing-remitting MS; 30 age-matched control subjects; 30 patients with Alzheimer's disease (AD) and 5 patients with clinically isolated syndrome (CIS). RESULTS: 29/30 MS and 5/5 CIS patients showed lower WMV than expected from their intracranial volume (average reduction 13.0%, P < 10(- 10)), while the cortical surface area showed no significant differences compared with controls. The estimated WMV reductions were correlated with an increase in cortical curvature (R = 0.62, P = 0.000001). Discriminant analysis revealed that the curvature increase was highly specific for the MS and CIS groups (96.7% correct assignments between MS and control groups) and was significantly correlated with reduction of white matter fractional anisotropy, as determined by diffusion tensor imaging and the Expanded Disability Status Scale. As expected by the predominant gray and WM degeneration in AD, no systematic curvature increase was observed in AD. CONCLUSION: Whole-brain-averaged cortical extrinsic curvature appears to be a specific and quantitative marker for a WMV-cortex disproportionality and allows us to assess "pure" WMA without being confounded by intracranial volume. WMA seems to be a characteristic symptom in early MS and can already occur in patients with CIS and should thus be considered in future MS research and clinical studies.

Evans syndrome associated with sterile inflammation of the central nervous system: a case report.

INTRODUCTION: Evans syndrome is a rare hematological disease commonly defined as Coombs-positive hemolytic anemia and immune thrombocytopenia. Pathophysiology of this disease involves decreased cluster of differentiation (CD)4+ T-helper cell counts, increased CD8+ T-suppressor cell counts, a decreased CD4/CD8 ratio, and reduced serum immunoglobulin G, M and A levels - indicating a complex immune dysregulation. Association with other autoimmune diseases has been described although involvement of the central nervous system has not been reported so far. CASE PRESENTATION: We here present a case of a 28-year-old woman of Turkish origin with progressive, disseminated, partly mass-forming lymphoplasmacellular infiltration (CD3+ and CD138+ cells) of the brain in association with Evans syndrome. No other central nervous system disorder could be identified on neuropathological evaluation. Although treatment with rituximab was effective to normalize erythrocyte and thrombocyte levels in her peripheral blood, it failed to dampen the inflammation in her central nervous system or prevent clinical progression. Initiation of treatment with cyclophosphamide resulted in stabilization of her central nervous system inflammation and the disease course. CONCLUSIONS: The complex immune dysregulation resulting in the antibody-mediated pathologies that can be regarded as the cause of both lymphoplasmacellular encephalitis and Evans syndrome renders this association to be of clinical relevance for both neurologists and hematologists. Our experience also sheds light on the effectiveness of different treatments for both disorders and we advise clinicians to take a closer look when encountering a combination of peripheral blood diseases with affection of the central nervous system.

Glatiramer acetate attenuates pro-inflammatory T cell responses but does not directly protect neurons from inflammatory cell death.

Glatiramer acetate (GA) is a synthetic, random, basic copolymer capable of modulating adaptive T cell responses. In animal models of various inflammatory and degenerative central nervous system disorders, GA-induced T cells cross the blood-brain barrier, secrete high levels of anti-inflammatory cytokines and neurotrophins, and thus both reduce neuronal damage and promote neurogenesis. Recently, it has been suggested that GA itself may permeate the (impaired) blood-brain-barrier and directly protect neurons under conditions of inflammation-mediated neurodegeneration. To test this hypothesis, we examined the direct effects of GA on neuronal functionality and T cell-mediated neuronal apoptosis in culture, acute brain slices, and focal experimental autoimmune encephalomyelitis. GA caused a depolarization of the resting membrane potential and led to an immediate impairment of action potential generation in neurons. Moreover, GA-incubated neurons underwent dose-dependent apoptosis. Apoptosis of ovalbumin peptide-loaded major histocompatibility complex class I-expressing neurons induced by ovalbumin-specific effector T cells could be reduced by pre-incubation of T cells, but not neurons with GA. Similar results could be found using acute brain slices. In focal experimental autoimmune encephalomyelitis, lesion size and neuronal apoptosis could be limited by pretreating rats with GA, whereas intracerebral GA application into the inflammatory lesion had no effect on neuronal survival. Our data suggest that GA attenuates adaptive pro-inflammatory T cell responses, but does not exert direct neuroprotective effects.

Regulatory T cells exhibit enhanced migratory characteristics, a feature impaired in patients with multiple sclerosis.

Migration of immune cells characterizes inflammation and plays a key role in autoimmune diseases such as MS. CD4(+)Foxp3(+) regulatory T cells (Treg) have the potential to dampen immune responses but show functional impairment in patients with MS. We here show that murine Treg exhibit higher constitutive cell motility in horizontal migration on laminin, surpass non-Treg in transwell assays through microporous membranes as well as across primary brain endothelium and are present in the naïve CNS to a significantly higher extent compared to spleen, lymph nodes and blood. Likewise, human Treg from healthy donors significantly exceed non-Treg in migratory rates across primary human brain endothelium. Finally, we investigated whether the propensity to migrate is impaired as a feature of autoimmunity and therefore tested patients with MS. Treg from patients with stable relapsing-remitting MS show significantly impaired migratory capacity under non-inflammatory conditions compared to healthy donors. We hypothesize that the enhanced propensity to migrate is a feature of Treg that allows for an equilibrium in parenchymal immune surveillance, e.g. of the CNS. Impaired Treg migration across the intact blood-brain barrier, as observed for Treg from patients with MS, indicates a broader functional deficiency hypothetically contributing to early CNS lesion development or phases of MS remissions.

Cytotoxic CD8+ T cell-neuron interactions: perforin-dependent electrical silencing precedes but is not causally linked to neuronal cell death.

Cytotoxic CD8(+) T cells are considered important effector cells contributing to neuronal damage in inflammatory and degenerative CNS disorders. Using time-lapse video microscopy and two-photon imaging in combination with whole-cell patch-clamp recordings, we here show that major histocompatibility class I (MHC I)-restricted neuronal antigen presentation and T cell receptor specificity determine CD8(+) T-cell locomotion and neuronal damage in culture and hippocampal brain slices. Two separate functional consequences result from a direct cell-cell contact between antigen-presenting neurons and antigen-specific CD8(+) T cells. (1) An immediate impairment of electrical signaling in single neurons and neuronal networks occurs as a result of massive shunting of the membrane capacitance after insertion of channel-forming perforin (and probably activation of other transmembrane conductances), which is paralleled by an increase of intracellular Ca(2+) levels (within <10 min). (2) Antigen-dependent neuronal apoptosis may occur independently of perforin and members of the granzyme B cluster (within approximately 1 h), suggesting that extracellular effects can substitute for intracellular delivery of granzymes by perforin. Thus, electrical silencing is an immediate consequence of MHC I-restricted interaction of CD8(+) T cells with neurons. This mechanism is clearly perforin-dependent and precedes, but is not causally linked, to neuronal cell death.

TASK1 modulates inflammation and neurodegeneration in autoimmune inflammation of the central nervous system.

We provide evidence that TWIK-related acid-sensitive potassium channel 1 (TASK1), a member of the family of two-pore domain potassium channels relevant for setting the resting membrane potential and balancing neuronal excitability that is expressed on T cells and neurons, is a key modulator of T cell immunity and neurodegeneration in autoimmune central nervous system inflammation. After induction of experimental autoimmune encephalomyelitis, an experimental model mimicking multiple sclerosis, TASK1(-/-) mice showed a significantly reduced clinical severity and markedly reduced axonal degeneration compared with wild-type controls. T cells from TASK1(-/-) mice displayed impaired T cell proliferation and cytokine production, while the immune repertoire is otherwise normal. In addition to these effects on systemic T cell responses, TASK1 exhibits an independent neuroprotective effect which was demonstrated using both a model of acutely prepared brain slices cocultured with activated T cells as well as in vitro cultivation experiments with isolated optic nerves. Anandamide, an endogenous cannabinoid and inhibitor of TASK channels, reduced outward currents and inhibited effector functions of T cells (IFN-gamma production and proliferation); an effect completely abrogated in TASK1(-/-) mice. Accordingly, preventive blockade of TASK1 significantly ameliorated experimental autoimmune encephalomyelitis after immunization. Therapeutic application of anandamide significantly reduced disease severity and was capable of lowering progressive loss of brain parenchymal volume as assessed by magnetic resonance imaging. These data support the identification and characterization of TASK1 as potential molecular target for the therapy of inflammatory and degenerative central nervous system disorders.

Detrimental contribution of the immuno-inhibitor B7-H1 to rabies virus encephalitis.

Rabies virus is the etiological agent of an acute encephalitis, which in absence of post exposure treatment is fatal in almost all cases. Virus lethality rests on its ability to evade the immune response. In this study, we analyzed the role of the immuno-inhibitory molecule B7-H1 in this virus strategy. We showed that in the brain and spinal cord of mice, rabies virus infection resulted in significant up-regulation of B7-H1 expression, which is specifically expressed in infected neurons. Correlatively, clinical rabies in B7-H1(-/-) mice is markedly less severe than in wild-type mice. B7-H1(-/-) mice display resistance to rabies. Virus invasion is reduced and the level of migratory CD8 T cells increases into the nervous system, while CD4/CD8 ratio remains unchanged in the periphery. In vivo, neuronal B7-H1 expression is critically depending on TLR3 signaling and IFN-beta, because TLR3(-/-) mice--in which IFN-beta production is reduced--showed only a limited increase of B7-H1 transcripts after infection. These data provide evidence that neurons can express the B7-H1 molecule after viral stress or exposure to a particular cytokine environment. They show that the B7-H1/PD-1 pathway can be exploited locally and in an organ specific manner--here the nervous system--by a neurotropic virus to promote successful host invasion.

TWIK-related acid-sensitive K+ channel 1 (TASK1) and TASK3 critically influence T lymphocyte effector functions.

Two major K(+) channels are expressed in T cells, (i) the voltage-dependent K(V)1.3 channel and (ii) the Ca(2+)-activated K(+) channel KCa 3.1 (IKCa channel). Both critically influence T cell effector functions in vitro and animal models in vivo. Here we identify and characterize TWIK-related acid-sensitive potassium channel 1 (TASK1) and TASK3 as an important third K(+) conductance on T lymphocytes. T lymphocytes constitutively express TASK1 and -3 protein. Application of semi-selective TASK blockers resulted in a significant reduction of cytokine production and cell proliferation. Interference with TASK channels on CD3(+) T cells revealed a dose-dependent reduction ( approximately 40%) of an outward current in patch clamp recordings indicative of TASK channels, a finding confirmed by computational modeling. In vivo relevance of our findings was addressed in an experimental model of multiple sclerosis, adoptive transfer experimental autoimmune encephalomyelitis. Pretreatment of myelin basic protein-specific encephalitogenic T lymphocytes with TASK modulators was associated with significant amelioration of the disease course in Lewis rats. These data introduce K(2)P channels as novel potassium conductance on T lymphocytes critically influencing T cell effector function and identify a possible molecular target for immunomodulation in T cell-mediated autoimmune disorders.

CNS inflammation and neuronal degeneration is aggravated by impaired CD200-CD200R-mediated macrophage silencing.

Multiple sclerosis is a chronic disabling CNS disorder, characterized by autoimmune inflammatory demyelination and neurodegeneration. CD200, broadly expressed on neurons and endothelial cells, mediates inhibitory signals through its receptor, CD200R, on cells of myeloid origin. Antibody-mediated blockade of CD200R leads to an aggravated clinical course of rodent experimental autoimmune encephalomyelitis in vivo, accompanied by profoundly augmented cellular infiltrates consisting of T cells and activated iNOS(+) macrophages in inflammatory spinal cord lesions. In vitro blockade of CD200R on macrophages leads to enhanced IFN-gamma-induced release of IL6 and neuronal cell death in co-cultures with hippocampal neurons expressing CD200. CD200 and its receptor could also be detected on neurons and macrophages in human MS plaques. Therefore the CD200-CD200R pathway seems of critical relevance for macrophage-mediated damage in autoimmune inflammation of the CNS.