[Telemedicine in stroke-pertinent to stroke care in Germany]. / Telemedizin in der Schlaganfallversorgung ­ versorgungsrelevant für Deutschland.

BACKGROUND AND OBJECTIVE: Telemedical stroke networks improve stroke care and provide access to time-dependent acute stroke treatment in predominantly rural regions. The aim is a presentation of data on its utility and regional distribution. METHODS: The working group on telemedical stroke care of the German Stroke Society performed a survey study among all telestroke networks. RESULTS: Currently, 22 telemedical stroke networks including 43 centers (per network: median 1.5, interquartile range, IQR, 1-3) as well as 225 cooperating hospitals (per network: median 9, IQR 4-17) operate in Germany and contribute to acute stroke care delivery to 48 million people. In 2018, 38,211 teleconsultations (per network: median 1340, IQR 319-2758) were performed. The thrombolysis rate was 14.1% (95% confidence interval 13.6-14.7%) and transfer for thrombectomy was initiated in 7.9% (95% confidence interval 7.5-8.4%) of ischemic stroke patients. Financial reimbursement differs regionally with compensation for telemedical stroke care in only three federal states. CONCLUSION: Telemedical stroke care is utilized in about 1 out of 10 stroke patients in Germany. Telemedical stroke networks achieve similar rates of thrombolysis and transfer for thrombectomy compared with neurological stroke units and contribute to stroke care in rural regions. Standardization of network structures, financial assurance and uniform quality measurements may further strengthen the importance of telestroke networks in the future.

[Left atrial appendage occlusion in patients with nonvalvular atrial fibrillation : Present evidence, ongoing studies, open questions]. / Verschluss des linken Vorhofohrs bei nichtvalvulärem Vorhofflimmern : Datenlage, aktuelle Studien, offene Fragen.

About every fifth ischemic stroke is caused by atrial fibrillation. Oral anticoagulation is highly effective in secondary stroke prevention, but a relevant portion of patients with atrial fibrillation is not (permanently) anticoagulated for a variety of reasons. Based on present evidence, no general recommendation can be given for left atrial appendage occlusion in patients with nonvalvular atrial fibrillation. However, left atrial appendage occlusion is a treatment option after severe anticoagulation-related bleeding, if the cause of bleeding is not treatable. Left atrial appendage occlusion is critical in patients with a relative contraindication for oral anticoagulation or lack of adherence to given medication. It seems to be important that further randomized studies confirm a benefit of left atrial appendage occlusion in selected patients with nonvalvular atrial fibrillation. In addition, it is vital to clarify whether discontinuation of antiplatelets is feasible after catheter-based left atrial appendage occlusion, as antiplatelets are associated with a risk of bleeding. Within this review article, we discuss present evidence, gaps of knowledge and provide an overview on ongoing clinical studies. In addition, we summarize the design of the CLOSURE-AF study. This randomized multicenter study will start recruitment soon and is funded by the German Center for Cardiovascular Research e. V.

[Left atrial appendage closure in non-valvular atrial fibrillation]. / Verschluss des linken Vorhofohrs bei nichtvalvulärem Vorhofflimmern.

Atrial fibrillation is the most frequent cardiac arrhythmia worldwide, causing approximately 20% of all ischemic strokes. Therefore, oral anticoagulation is recommended in patients with atrial fibrillation with at least a moderate risk of stroke; however, there is a significant proportion of patients who cannot undergo long-term oral anticoagulation. As the left atrial appendage is of major relevance for atrial fibrillation-induced thrombus formation, catheter-based or surgical closure of the left atrial appendage appears to be a promising therapeutic option. Large registry studies including patients with catheter-based left atrial appendage closure have proven its effectiveness and a decreasing procedure-related complication rate. This review article summarizes the current knowledge and introduces major ongoing randomized studies, which will investigate the impact of left atrial appendage closure on stroke prevention. The authors hope that the results of the randomized CLOSURE AF trial, which is funded by the German Center for Cardiovascular Research e. V. and is now recruiting patients in Germany, will help to solve many of the currently prevalent clinical questions.

[ESC guidelines on atrial fibrillation 2016 : Summary of the most relevant recommendations and modifications]. / ESC-Leitlinien zum Vorhofflimmern 2016 : Zusammenfassung der wichtigsten Empfehlungen und Neuerungen.

The first European Society of Cardiology (ESC) guidelines on atrial fibrillation (AF) developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS) were published in August 2016. These guidelines replace the revised guidelines from 2012 and contain some interesting new aspects. The topics range from the pathophysiology through diagnostics, therapy and stroke prevention up to special clinical situations, such as atrial fibrillation in cardiopathy, sport and pregnancy. Early screening, patient informed consent, individualized therapy and the modification of factors promoting atrial fibrillation are of particular importance. The guidelines recommend the establishment of AF heart teams, containing specialists from various disciplines. The guidelines also underline the importance of non-vitamin K­dependent oral anticoagulants (NOAC) for stroke prevention compared to standard anticoagulants with vitamin K antagonists. For symptomatic and especially paroxysmal atrial fibrillation, the guidelines emphasize the importance of an antiarrhythmic treatment with catheter ablation and/or pharmaceutical antiarrhythmic therapy in addition to a frequency regulating therapy.

[Neurological aspects of chronic heart failure]. / Neurologische Aspekte bei chronischer Herzinsuffizienz.

Chronic heart failure (CHF) is one of the leading causes of hospitalization, morbidity and mortality. Moreover, there is a high rate of neurological as well as neuropsychological comorbidities, namely ischemic stroke, structural brain alterations, cognitive impairment, sleep apnea and possible side-effects of HF medication such as delirium or (intracerebral) hemorrhage. The higher stroke risk in patients with HF increases further with age, concomitant arterial hypertension or atrial fibrillation (AF). In women the stroke risk increases with reduced ejection fraction (EF). In general stroke in HF patients is associated with a poor outcome and higher mortality, which is increased more than 2-fold. Furthermore, approximately 25-80% of all patients with CHF experience cognitive impairments such as decreased attention and concentration, memory loss, diminished psychomotor reaction time and decreased executive functions. Cognitive impairment in patients with HF has been linked to losses in gray matter, (silent) ischemic strokes, decreased cerebral perfusion and higher mortality. Moreover, sleep apnea occurs in more than half of all patients with CHF and reduced EF. However, prospective studies are needed to test whether early detection and optimal treatment of HF reduces the burden of neurological and neuropsychological sequelae.

The protein tyrosine kinase inhibitor AG126 prevents the massive microglial cytokine induction by pneumococcal cell walls.

Central nervous system (CNS) infections caused by Streptococcus pneumoniae still have a disastrous outcome. Underlying immunological and CNS cellular events are largely enigmatic. We used pneumococcal cells walls (PCW) to investigate microglial responses as these cells are prominent sensors and effectors during neuropathological changes. PCW stimulation of mouse microglia in vitro evoked the release of the cyto- and chemokines, TNF-alpha, IL-6, IL-12, KC, MCP-1, MIP-1alpha, MIP-2 and RANTES as well as soluble TNF receptor II, a potential TNF-alpha antagonist. The release induction followed extremely steep dose-response relations, and short exposure periods (15 min) were already sufficient to trigger substantial responses. PCW signaling controlling the release depended on both p38 and p42/p44 (ERK2/ERK1) MAP kinase activities. The kinase inhibitor, tyrphostin AG126 prevented the PCW-inducible phosphorylation of p42/p44(MAPK), potently blocked cytokine release and drastically reduced the bioavailable TNF-alpha, since it only marginally affected the release of soluble TNF receptors. Moreover, in an in vivo model of pneumococcal meningitis, AG126 significantly attenuated the PCW-induced leukocyte influx to the cerebrospinal fluid. The findings imply that pneumococcal CNS infection can cause a rapid and massive microglial activation and that ERK/MAPK pathway(s) are potential targets for pharmacological interventions.

beta-adrenergic receptor stimulation selectively inhibits IL-12p40 release in microglia.

The cytokine interleukin-12 (IL-12) is mainly produced in response to bacterial or parasitic infections. We examined the capacity of mouse brain microglia to release IL-12 forms upon challenge with bacterial lipopolysaccharide (LPS) and studied its modulation by sympathomimetics. LPS evoked the release of IL-12p40 whereas the heterodimeric form, IL-12p70 was virtually undetectable. Sympathomimetics such as salbutamol dose-dependently inhibited IL-12p40 release, whereas the production of IL-6, TNFalpha and MIP-1alpha was only marginally influenced. The inhibitory effect of salbutamol could be abolished by beta-antagonists, such as oxprenolol. The cAMP-elevating agent forskolin could mimic the effects of beta-agonists, indicating that IL-12p40 release inhibition involves intracellular cAMP accumulation. While microglial IL-12p40 may play a role in the regulation of IL-12p70 bioactivity, microglial release is itself modulated by IL-12p70. Recombinant IL-12p70 was found to enhance the LPS-evoked release of MIP-1alpha and to have a biphasic effect on both TNFalpha and MIP-1alpha with release augmentation at lower and attenuation at higher doses. Finally, no functional correlation was found between the release of IL-12p40 and the induction of Kv1.3 potassium channels, another marker of microglial activation. Taken together, beta(2)-adrenoreceptor-mediated effects on microglial cyto- and chemokine release via cAMP accumulation could modulate inflammatory cascades during bacterial infections.

Biochemical analysis of proteasomes from mouse microglia: induction of immunoproteasomes by interferon-gamma and lipopolysaccharide.

The 20S proteasome is a multicatalytic threonine protease and serves to process peptides that are subsequently presented as antigenic epitopes by MHC class I molecules. In the brain, microglial cells are the major antigen presenting cells and they respond sensitive to pathologic events. We used cultured mouse microglia and a microglial cell line, the BV-2 line, as a model to study the correlation between microglial activation parameters and structural plasticity of the 20S/26S proteasome. Lipopolysaccharide (LPS)- or interferon-gamma (IFN-gamma)-stimulated microglia or BV-2 cells exhibit properties of activated microglia such as high levels of TNFalpha and IL-6 release. In response to IFN-gamma or LPS, three constitutive beta subunits (beta1/Delta, beta2/MC14, beta5/MB1) were replaced by the immunoproteasome subunits ibeta1/LMP2, ibeta2/MECL-1, and ibeta5/LMP7, indicating that activated microglia adapts its proteasomal subunit composition to the requirements of an optimized MHC class I epitope processing. Induction of immunoproteasomes in BV-2 cells was solely provoked by IFN-gamma, but not by LPS. Moreover, LPS (but not IFN-gamma) triggered the expression of a novel protein of approximately 50 kD as part of the proteasome activator PA700, that is the substrate-recognizing and unfolding unit of the 26S proteasome. These results indicate that both the 20S core protease as well as the proteasome activator PA700 are targets of modulatory subunit replacements or transient association of regulatory components in the course of microglial activation.