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1.
J Chem Neuroanat ; : 102036, 2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34626771

RESUMO

Surfactant protein C (SP-C) modulates cerebrospinal fluid (CSF) rheology. During ageing, its declining levels are accompanied by an increased burden of white matter lesions. Pulmonary SP-C intermediates harbouring the BRICHOS-domain prevent protein misfolding in the lungs. Thus, cerebral SP-C intermediates may counteract cerebral ß-amyloidosis, a hallmark of Alzheimer's disease (AD). However, data on the molecular neuroanatomy of SP-C and its alterations in wildtype and triple transgenic (3xTg) mice, featuring essential elements of AD-neuropathology, are lacking. Therefore, this study investigated SP-C-containing structures in murine forebrains and their spatial relationships with vascular, glial and neuronal components of the neurovascular unit. Fluorescence labelling demonstrated neuronal SP-C in the medial habenula, the indusium griseum and the hippocampus. Glial counterstaining elucidated astrocytes in the corpus callosum co-expressing SP-C and S100ß. Notably, perineuronal nets were associated with SP-C in the nucleus reticularis thalami, the lateral hypothalamus and the retrosplenial cortex. In the hippocampus of aged 3xTg mice, an increased number of dot-like depositions containing SP-C and Reelin, but devoid of BRICHOS-immunoreactivity were observed apart from AD-like lesions. Wildtype and 3xTg mice revealed an age-dependent increase of such deposits markedly pronounced in about 24-month-old 3xTg mice. SP-C levels of the intracellular and extracellular compartments in each group revealed an inverse correlation of SP-C and Reelin, with reduced SP-C and increased Reelin in an age-dependent fashion especially in 3xTg mice. Taken together, extracellular SP-C, as modulator of glymphatic clearance and potential ligand of PNs, declines in 3xTg mice, which show an accumulation of extracellular Reelin depositions during ageing.

2.
Neurol Res Pract ; 3(1): 53, 2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34503568

RESUMO

INTRODUCTION: Post stroke management has moved into the focus as it represents the only way to secure acute treatment effects in the long term. Due to individual courses, post stroke management appears rather challenging and is hindered by existing barriers between treatment sectors. As a novel concept, the PostStroke-Manager combines digital and sensor-based technology with personal assistance to enable intersectoral cooperation, best possible reduction of stroke-related disability, optimal secondary prevention, and detection of physical and psychological comorbidities. METHODS: This prospective single-center observational study aims to investigate the feasibility of the PostStroke-Manager concept in an outpatient setting. Ninety patients who have suffered an ischemic or hemorrhagic stroke or transient ischemic attack will be equipped with a tablet and mobile devices recording physical activity, blood pressure, and electrocardiographic signals. Through a server-based platform, patients will be connected with the primary care physician, a stroke pilot and, if necessary, other specialists who will use web-based platforms. Via the tablet, patients will have access to an application with 10 newly designed components including, for instance, a communication tool, medication schedule, medical records platform, and psychometric screenings (e.g., depression, anxiety symptoms, quality of life, adherence, cognitive impairment). During the 1-year follow-up period, clinical visits are scheduled at three-month intervals. In the interim, communication will be secured by an appropriate tool that includes text messenger, audio, and video telephony. As the primary endpoint, feasibility will be measured by a 14-item questionnaire that addresses digital components, technical support, and personal assistance. The PostStroke-Manager will be judged feasible if at least 50% of these aspects are rated positively by at least 75% of patients. Secondary endpoints include feedback from professionals and longitudinal analyses on clinical and psychometric parameters. PERSPECTIVE: This study will answer the question of whether combined digital and personal support is a feasible approach to post stroke management. Furthermore, the patient perspective gained regarding digital support may help to specify future applications. This study will also provide information regarding the potential use of remote therapies and mobile devices in situations with limited face-to-face contacts. TRIAL REGISTRATION: German Register for Clinical Trials ( DRKS00023213 .), registered 27 April 2021.

3.
Anaesthesist ; 70(10): 874-887, 2021 Oct.
Artigo em Alemão | MEDLINE | ID: mdl-34212230

RESUMO

Focused treatment of epileptic emergencies, and in particular status epilepticus (SE), require a reliable differentiation of epileptic syndromes. In these cases, and especially in cases with predominant non-motor symptoms, clinical and electroencephalographic expertise is necessary. In 2020 the German guidelines for the management of SE were updated, which adhere to a strict stage-based treatment algorithm. The staged approach includes the administration of benzodiazepines, antiepileptic drugs and anesthetic agents. So far, efforts failed to determine the most effective and safest antiepileptic drug without interaction potential. Therefore, for the differentiated treatment of SE, individual pre-existing medical conditions and concomitant circumstances must be considered, added by the experience of the medical team. Therapeutic interventions especially for refractory forms of SE have been shown to be complex with relevant implications concerning intensive care aspects. Consequently, the modern treatment strategy of SE is characterized by an interdisciplinary approach. Future research is needed to define the optimal treatment of non-convulsive SE, in particular regarding the time point and degree of treatment escalation with associated ethical considerations.

4.
Front Cell Neurosci ; 15: 701673, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34267628

RESUMO

Microglia are the brain's immunocompetent macrophages with a unique feature that allows surveillance of the surrounding microenvironment and subsequent reactions to tissue damage, infection, or homeostatic perturbations. Thereby, microglia's striking morphological plasticity is one of their prominent characteristics and the categorization of microglial cell function based on morphology is well established. Frequently, automated classification of microglial morphological phenotypes is performed by using quantitative parameters. As this process is typically limited to a few and especially manually chosen criteria, a relevant selection bias may compromise the resulting classifications. In our study, we describe a novel microglial classification method by morphological evaluation using a convolutional neuronal network on the basis of manually selected cells in addition to classical morphological parameters. We focused on four microglial morphologies, ramified, rod-like, activated and amoeboid microglia within the murine hippocampus and cortex. The developed method for the classification was confirmed in a mouse model of ischemic stroke which is already known to result in microglial activation within affected brain regions. In conclusion, our classification of microglial morphological phenotypes using machine learning can serve as a time-saving and objective method for post-mortem characterization of microglial changes in healthy and disease mouse models, and might also represent a useful tool for human brain autopsy samples.

5.
Mol Neurobiol ; 58(8): 4051-4069, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33931805

RESUMO

In the setting of ischemic stroke, the neurofilament subunit NF-L and the microtubule-associated protein MAP2 have proven to be exceptionally ischemia-sensitive elements of the neuronal cytoskeleton. Since alterations of the cytoskeleton have been linked to the transition from reversible to irreversible tissue damage, the present study investigates underlying time- and region-specific alterations of NF-L and MAP2 in different animal models of focal cerebral ischemia. Although NF-L is increasingly established as a clinical stroke biomarker, MAP2 serum measurements after stroke are still lacking. Therefore, the present study further compares serum levels of MAP2 with NF-L in stroke patients. In the applied animal models, MAP2-related immunofluorescence intensities were decreased in ischemic areas, whereas the abundance of NF-L degradation products accounted for an increase of NF-L-related immunofluorescence intensity. Accordingly, Western blot analyses of ischemic areas revealed decreased protein levels of both MAP2 and NF-L. The cytoskeletal alterations are further reflected at an ultrastructural level as indicated by a significant reduction of detectable neurofilaments in cortical axons of ischemia-affected areas. Moreover, atomic force microscopy measurements confirmed altered mechanical properties as indicated by a decreased elastic strength in ischemia-affected tissue. In addition to the results from the animal models, stroke patients exhibited significantly elevated serum levels of MAP2, which increased with infarct size, whereas serum levels of NF-L did not differ significantly. Thus, MAP2 appears to be a more sensitive stroke biomarker than NF-L, especially for early neuronal damage. This perspective is strengthened by the results from the animal models, showing MAP2-related alterations at earlier time points compared to NF-L. The profound ischemia-induced alterations further qualify both cytoskeletal elements as promising targets for neuroprotective therapies.

6.
Lancet Neurol ; 20(6): 426-436, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34022169

RESUMO

BACKGROUND: Systematic electrocardiogram (ECG) monitoring improves detection of covert atrial fibrillation in stroke survivors but the effect on secondary prevention is unknown. We aimed to assess the effect of systematic ECG monitoring of patients in hospital on the rate of oral anticoagulant use after 12 months. METHODS: In this investigator-initiated, randomised, open-label, parallel-group multicentre study with masked endpoint adjudication, we recruited patients aged at least 18 years with acute ischaemic stroke or transient ischaemic attack without known atrial fibrillation in 38 certified stroke units in Germany. Patients were randomly assigned (1:1) to usual diagnostic procedures for atrial fibrillation detection (control group) or additional Holter-ECG recording for up to 7 days in hospital (intervention group). Patients were stratified by centre using a random permuted block design. The primary outcome was the proportion of patients on oral anticoagulants at 12 months after the index event in the intention-to-treat population. Secondary outcomes included the number of patients with newly diagnosed atrial fibrillation in hospital and the composite of recurrent stroke, major bleeding, myocardial infarction, or death after 6 months, 12 months, and 24 months. This trial was registered with ClinicalTrials.gov, NCT02204267, and is completed and closed for participants. FINDINGS: Between Dec 9, 2014, and Sept 11, 2017, 3465 patients were randomly assigned, 1735 (50·1%) to the intervention group and 1730 (49·9%) to the control group. Oral anticoagulation status was available in 2920 (84·3%) patients at 12 months (1484 [50·8%] in the intervention group and 1436 [49·2%] in the control group). For the primary outcome, at 12 months, 203 (13·7%) of 1484 patients in the intervention group versus 169 (11·8%) of 1436 in the control group were on oral anticoagulants (odds ratio [OR] 1·2 [95% CI 0·9-1·5]; p=0·13). Atrial fibrillation was newly detected in patients in hospital in 97 (5·8%) of 1714 in the intervention group versus 68 (4·0%) of 1717 in the control group (hazard ratio [HR] 1·4 [95% CI 1·0-2·0]; p=0·024). The composite of cardiovascular outcomes and death did not differ between patients randomly assigned to the intervention group versus the control group at 24 months (232 [13·5%] of 1714 vs 249 [14·5%] of 1717; HR 0·9 [0·8-1·1]; p=0·43). Skin reactions due to study ECG electrodes were reported in 56 (3·3%) patients in the intervention group. All-cause death occured in 73 (4·3%) patients in the intervention group and in 103 (6·0%) patients in the control group (OR 0·7 [0·5-0·9]). INTERPRETATION: Systematic core centrally reviewed ECG monitoring is feasible and increases the detection rate of atrial fibrillation in unselected patients hospitalised with acute ischaemic stroke or transient ischaemic attack, if added to usual diagnostic care in certified German stroke units. However, we found no effect of systematic ECG monitoring on the rate of oral anticoagulant use after 12 months and further efforts are needed to improve secondary stroke prevention. FUNDING: Bayer Vital. TRANSLATION: For the German translation of the abstract see Supplementary Materials section.


Assuntos
Fibrilação Atrial/fisiopatologia , Isquemia Encefálica/fisiopatologia , AVC Isquêmico/fisiopatologia , Monitorização Fisiológica/métodos , Idoso , Idoso de 80 Anos ou mais , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/epidemiologia , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/epidemiologia , Eletrocardiografia/métodos , Feminino , Humanos , AVC Isquêmico/diagnóstico , AVC Isquêmico/epidemiologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco
7.
Neurol Res ; 43(5): 396-405, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33478369

RESUMO

Objectives: Ischemic stroke (IS) is often associated with long-lasting physical deficits, linked to emotional symptoms (ES) and lowered quality of life (QoL). However, recent observations raised doubts regarding the traditional perspective of solely impairment-driven ES. In fact, anxiety and depression were also reported after transient ischemic attack (TIA) with a per definition absence of infarction and thus lacking physical deficits. This study follows the hypothesis that TIA patients might exhibit non-physical symptoms affecting individual QoL.Methods: In a prospective single-center observational study, IS patients (n = 73) were compared with TIA patients (n = 24) regarding their neurological deficit, ES and QoL, whereas the latter were evaluated by the Hospital Anxiety and Depression Scale (HADS) and the Short Form 36 Heath Survey (SF-36). Assessments were conducted six times within a one-year follow-up period.Results: Overall, anxiety and depression decreased over time, while anxiety decreased more substantially. TIA patients showed similar levels of anxiety and depression when compared to IS patients. ES were detectable very early after the event and remained throughout the follow-up period in both groups. ES were associated with an impaired QoL including non-functional dimensions, while the strongest interrelations were observed for TIA patients, emphasizing interrelations between QoL and anxiety.Discussion: This study indicates that ES after TIA are comparable to the emotional burden after IS. ES after TIA were associated with QoL, pointing out their crucial role for individual well-being. Although confirmation in larger studies is necessary, these data underpin the need for early clinical awareness regarding non-physical symptoms in TIA patients.

8.
Front Physiol ; 11: 575598, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33192578

RESUMO

Ischemic stroke causes cellular alterations in the "neurovascular unit" (NVU) comprising neurons, glia, and the vasculature, and affects the blood-brain barrier (BBB) with adjacent extracellular matrix (ECM). Limited data are available for the zone between the NVU and ECM that has not yet considered for neuroprotective approaches. This study describes ischemia-induced alterations for two main components of the neurovascular matrix adhesion zone (NMZ), i.e., collagen IV as basement membrane constituent and fibronectin as crucial part of the ECM, in conjunction with traditional NVU elements. For spatio-temporal characterization of these structures, multiple immunofluorescence labeling was applied to tissues affected by focal cerebral ischemia using a filament-based model in mice (4, 24, and 72 h of ischemia), a thromboembolic model in rats (24 h of ischemia), a coagulation-based model in sheep (2 weeks of ischemia), and human autoptic stroke tissue (3 weeks of ischemia). An increased fibronectin immunofluorescence signal demarcated ischemia-affected areas in mice, along with an increased collagen IV signal and BBB impairment indicated by serum albumin extravasation. Quantifications revealed a region-specific pattern with highest collagen IV and fibronectin intensities in most severely affected neocortical areas, followed by a gradual decline toward the border zone and non-affected regions. Comparing 4 and 24 h of ischemia, the subcortical fibronectin signal increased significantly over time, whereas neocortical areas displayed only a gradual increase. Qualitative analyses confirmed increased fibronectin and collagen IV signals in ischemic areas from all tissues and time points investigated. While the increased collagen IV signal was restricted to vessels, fibronectin appeared diffusely arranged in the parenchyma with focal accumulations associated to the vasculature. Integrin α5 appeared enriched in the vicinity of fibronectin and vascular elements, while most of the non-vascular NVU elements showed complementary staining patterns referring to fibronectin. This spatio-temporal characterization of ischemia-related alterations of collagen IV and fibronectin in various stroke models and human autoptic tissue shows that ischemic consequences are not limited to traditional NVU components and the ECM, but also involve the NMZ. Future research should explore more components and the pathophysiological properties of the NMZ as a possible target for novel neuroprotective approaches.

9.
Euro Surveill ; 25(46)2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33213686

RESUMO

Following a distinct summer heat wave, nine autochthonous cases of West Nile fever and West Nile neuroinvasive disease, including one fatality, were observed in Leipzig, Germany, in August and September 2020. Phylogenetic analysis demonstrated close relationships in viruses from humans, animals and mosquitos in eastern Germany, obtained during the preceding 2 years. The described large cluster of autochthonous West Nile virus infections in Germany indicates endemic seasonal circulation of lineage 2 viruses in the area.


Assuntos
Surtos de Doenças , Febre do Nilo Ocidental , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Alemanha/epidemiologia , Humanos , Pessoa de Meia-Idade , Filogenia , Febre do Nilo Ocidental/epidemiologia , Vírus do Nilo Ocidental/genética , Adulto Jovem
10.
Neurocrit Care ; 33(3): 708-717, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32198728

RESUMO

BACKGROUND/OBJECTIVE: Delirium is a common complication in critically ill patients with a negative impact on hospital length of stay, morbidity, and mortality. Little is known on how neurological deficits affect the outcome of commonly used delirium screening tools such as the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) and the Intensive Care Delirium Screening Checklist (ICDSC) in neurocritical care patients. METHODS: Over a period of 1 month, all patients admitted to a neurocritical care and stroke unit at a single academic center were prospectively screened for delirium using both CAM-ICU and ICDSC. Tool-based delirium screening was compared with delirium evaluation by the treating clinical team. Additionally, ICD-10 delirium criteria were assessed. RESULTS: One hundred twenty-three patients with a total of 644 daily screenings were included. Twenty-three patients (18.7%) were diagnosed with delirium according to the clinical evaluation. Delirium incidence amounted to 23.6% (CAM-ICU) and 26.8% (ICDSC). Sensitivity and specificity of both screening tools were 66.9% and 93.3% for CAM-ICU and 69.9% and 93.9% for ICDSC, respectively. Patients identified with delirium by either CAM-ICU or ICDSC presented a higher proportion of neurological deficits such as impaired consciousness, expressive aphasia, impaired language comprehension, and hemineglect. Subsequently, generalized estimating equations identified a significant association between impaired consciousness (as indexed by Richmond Agitation and Sedation Scale) and a positive delirium assessment with both CAM-ICU and ICDSC, while impaired language comprehension and hemineglect were only associated with a positive CAM-ICU result. CONCLUSIONS: A positive delirium screening with both CAM-ICU and ICDSC in neurocritical care and stroke unit patients was found to be significantly associated with the presence of neurological deficits. These findings underline the need for a more specific delirium screening tool in neurocritical care patients.

11.
JAMA ; 322(14): 1392-1403, 2019 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-31593272

RESUMO

Importance: The association of surgical hematoma evacuation with clinical outcomes in patients with cerebellar intracerebral hemorrhage (ICH) has not been established. Objective: To determine the association of surgical hematoma evacuation with clinical outcomes in cerebellar ICH. Design, Setting, and Participants: Individual participant data (IPD) meta-analysis of 4 observational ICH studies incorporating 6580 patients treated at 64 hospitals across the United States and Germany (2006-2015). Exposure: Surgical hematoma evacuation vs conservative treatment. Main Outcomes and Measures: The primary outcome was functional disability evaluated by the modified Rankin Scale ([mRS] score range: 0, no functional deficit to 6, death) at 3 months; favorable (mRS, 0-3) vs unfavorable (mRS, 4-6). Secondary outcomes included survival at 3 months and at 12 months. Analyses included propensity score matching and covariate adjustment, and predicted probabilities were used to identify treatment-related cutoff values for cerebellar ICH. Results: Among 578 patients with cerebellar ICH, propensity score-matched groups included 152 patients with surgical hematoma evacuation vs 152 patients with conservative treatment (age, 68.9 vs 69.2 years; men, 55.9% vs 51.3%; prior anticoagulation, 60.5% vs 63.8%; and median ICH volume, 20.5 cm3 vs 18.8 cm3). After adjustment, surgical hematoma evacuation vs conservative treatment was not significantly associated with likelihood of better functional disability at 3 months (30.9% vs 35.5%; adjusted odds ratio [AOR], 0.94 [95% CI, 0.81 to 1.09], P = .43; adjusted risk difference [ARD], -3.7% [95% CI, -8.7% to 1.2%]) but was significantly associated with greater probability of survival at 3 months (78.3% vs 61.2%; AOR, 1.25 [95% CI, 1.07 to 1.45], P = .005; ARD, 18.5% [95% CI, 13.8% to 23.2%]) and at 12 months (71.7% vs 57.2%; AOR, 1.21 [95% CI, 1.03 to 1.42], P = .02; ARD, 17.0% [95% CI, 11.5% to 22.6%]). A volume range of 12 to 15 cm3 was identified; below this level, surgical hematoma evacuation was associated with lower likelihood of favorable functional outcome (volume ≤12 cm3, 30.6% vs 62.3% [P = .003]; ARD, -34.7% [-38.8% to -30.6%]; P value for interaction, .01), and above, it was associated with greater likelihood of survival (volume ≥15 cm3, 74.5% vs 45.1% [P < .001]; ARD, 28.2% [95% CI, 24.6% to 31.8%]; P value for interaction, .02). Conclusions and Relevance: Among patients with cerebellar ICH, surgical hematoma evacuation, compared with conservative treatment, was not associated with improved functional outcome. Given the null primary outcome, investigation is necessary to establish whether there are differing associations based on hematoma volume.


Assuntos
Doenças Cerebelares/cirurgia , Hemorragia Cerebral/cirurgia , Tratamento Conservador , Hematoma/cirurgia , Idoso , Doenças Cerebelares/terapia , Cerebelo/cirurgia , Hemorragia Cerebral/terapia , Feminino , Hematoma/terapia , Humanos , Masculino , Estudos Observacionais como Assunto , Resultado do Tratamento
12.
Neurosci Lett ; 711: 134405, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31374325

RESUMO

Ischemic stroke not only affects neurons, but also glial and vascular elements. The development of novel neuroprotective strategies thus requires an improved pathophysiological understanding of ischemia-affected cell types that comprise the 'neurovascular unit' (NVU). To explore spatiotemporal alterations of oligodendrocytes, astrocytes and neurons after experimental ischemic stroke, we applied a permanent middle cerebral artery occlusion model in mice for 4 and 24 h. Using fluorescence microscopy, the oligodendrocyte marker 2',3'-cyclic nucleotide phosphodiesterase (CNP), the neuronal neurofilament light chain (NF-L) and the astroglial aquaporin-4 (AQP4) were analyzed in regional relation to one another. Immunofluorescence intensities of CNP and NF-L were simultaneously increased in the ischemic neocortex and striatum. AQP4 immunoreactivity was decreased in the ischemic striatum, which represents the initial and potentially strongest affected site of infarction. The more distant ischemic neocortex and infarct border zones exhibited areas with alternately increased or decreased AQP4 immunoreactivity, leading to an increase of fluorescence intensity in total. Further, deformed CNP-immunopositive processes were found around axonal spheroids, indicating a combined affection of oligodendrocytes and neurons due to ischemia. Importantly, altered AQP4 immunosignals were not limited to the ischemic core, but were also detectable in penumbral areas. This applies for CNP and NF-L also, since altered immunosignals of all three markers coincided regionally at both time points. In conclusion, the present study provides evidence for a simultaneous affection of oligodendrocytes, astrocytes and neurons after experimental focal cerebral ischemia. Consequently, CNP, AQP4 and NF-L immunofluorescence alterations can be utilized to identify ischemia-affected tissue. The simultaneity of the described alterations further strengthens the concept of interdependent NVU components and distinguishes NF-L, CNP and AQP4 as highly ischemia-sensitive elements. Consequently, future therapeutic approaches might influence stroke evolution via strategies simultaneously addressing both neuronal and glial functions.


Assuntos
2',3'-Nucleotídeo Cíclico 3'-Fosfodiesterase/metabolismo , Aquaporina 4/metabolismo , Astrócitos/metabolismo , Proteínas de Neurofilamentos/metabolismo , Oligodendroglia/metabolismo , Acidente Vascular Cerebral/metabolismo , Animais , Astrócitos/patologia , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oligodendroglia/patologia , Acidente Vascular Cerebral/patologia
13.
Front Neurol ; 10: 720, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31333571

RESUMO

Background: From the variety of factors underlying the ischemia-associated edema formation in large hemispheric stroke (LHS), an increased brain water content during the early phase seems to have a pivotal role for long-lasting tissue damage. However, the importance of the fluid management during the acute phase of LHS has so far not been adequately studied. Therefore, this study explored the association between the fluid balance and functional outcome in patients suffering from LHS. Methods: We analyzed hospital-based medical records of 39 consecutive patients with LHS and decompressive hemicraniectomy. Over the first 10 days after admission, the volumes of all administered fluids were assessed daily and corrected for daily urinary output and insensible loss. Functional outcome at 3 months was assessed with the modified Rankin Scale (mRS) and dichotomized into an acceptable (mRS ≤ 4) vs. a poor outcome (mRS ≥ 5). Results: Compared to patients with a poor functional outcome (n = 19), those with an acceptable outcome (n = 20) were characterized by a significantly lower cumulative net fluid balance at day 5 (1.6 ± 2.5 vs. 3.4 ± 4.4 l), day 7 (2.0 ± 2.9 vs. 4.6 ± 5.2 l), and day 10 (0 ± 2.5 vs. 5.6 ± 6.2 l). In addition to age, only the cumulative net fluid balance at day 10 served as an independent factor for poor functional outcome in multiple regression analyses. Conclusion: These data provide evidence for a critical role of the early phase net fluid balance with respect to the functional outcome after LHS. This observation leads to the hypothesis that patients with LHS might benefit from a more restrictive volume therapy. However, prospective studies are warranted to establish a causal relationship and recommendations for treatment strategies.

14.
Stroke ; 50(6): 1392-1402, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31092170

RESUMO

Background and Purpose- Given inconclusive studies, it is debated whether clinical and imaging characteristics, as well as functional outcome, differ among patients with intracerebral hemorrhage (ICH) related to vitamin K antagonists (VKA) versus non-vitamin K antagonist (NOAC)-related ICH. Notably, clinical characteristics according to different NOAC agents and dosages are not established. Methods- Multicenter observational cohort study integrating individual patient data of 1328 patients with oral anticoagulation-associated ICH, including 190 NOAC-related ICH patients, recruited from 2011 to 2015 at 19 tertiary centers across Germany. Imaging, clinical characteristics, and 3-months modified Rankin Scale (mRS) outcomes were compared in NOAC- versus VKA-related ICH patients. Propensity score matching was conducted to adjust for clinically relevant differences in baseline parameters. Subgroup analyses were performed regarding NOAC agent, dosing and present clinically relevant anticoagulatory activity (last intake <12h/24h or NOAC level >30 ng/mL). Results- Despite older age in NOAC patients, there were no relevant differences in clinical and hematoma characteristics between NOAC- and VKA-related ICH regarding baseline hematoma volume (median [interquartile range]: NOAC, 14.7 [5.1-42.3] mL versus VKA, 16.4 [5.8-40.6] mL; P=0.33), rate of hematoma expansion (NOAC, 49/146 [33.6%] versus VKA, 235/688 [34.2%]; P=0.89), and the proportion of patients with unfavorable outcome at 3 months (mRS, 4-6: NOAC 126/179 [70.4%] versus VKA 473/682 [69.4%]; P=0.79). Subgroup analyses revealed that NOAC patients with clinically relevant anticoagulatory effect had higher rates of intraventricular hemorrhage (n/N [%]: present 52/109 [47.7%] versus absent 9/35 [25.7%]; P=0.022) and hematoma expansion (present 35/90 [38.9%] versus absent 5/30 [16.7%]; P=0.040), whereas type of NOAC agent or different NOAC-dosing regimens did not result in relevant differences in imaging characteristics or outcome. Conclusions- If effectively anticoagulated, there are no differences in hematoma characteristics and functional outcome among patients with NOAC- or VKA-related ICH. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT03093233.


Assuntos
Anticoagulantes/administração & dosagem , Hemorragia Cerebral/tratamento farmacológico , Fibrinolíticos/administração & dosagem , Vitamina K/antagonistas & inibidores , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Hemorragia Cerebral/diagnóstico por imagem , Hemorragia Cerebral/epidemiologia , Feminino , Alemanha/epidemiologia , Humanos , Masculino , Estudos Retrospectivos
15.
Mol Neurobiol ; 56(11): 7631-7650, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31089963

RESUMO

Experimental stroke studies yielded insights into single reactions of the neurovascular unit (NVU) and associated extracellular matrix (ECM). However, the extent of simultaneous processes caused by ischemia and their underlying transcriptional changes are still poorly understood. Strictly following the NVU and ECM concept, this study explored transcriptional responses of cellular and non-cellular components as well as their morphological characteristics following ischemia. Mice were subjected to 4 or 24 h of unilateral middle cerebral artery occlusion. In the neocortex and the striatum, cytoskeletal and glial elements as well as blood-brain barrier and ECM components were analyzed using real-time PCR. Western blot analyses allowed characterization of protein levels and multiple immunofluorescence labeling enabled morphological assessment. Out of 37 genes analyzed, the majority exhibited decreased mRNA levels in ischemic areas, while changes occurred as early as 4 h after ischemia. Down-regulated mRNA levels were predominantly localized in the neocortex, such as the structural elements α-catenin 2, N-cadherin, ß-catenin 1, and ßIII-tubulin, consistently decreasing 4 and 24 h after ischemia. However, a few genes, e.g., claudin-5 and Pcam1, exhibited increased mRNA levels after ischemia. For several components such as ßIII-tubulin, N-cadherin, and ß-catenin 1, matching transcriptional and immunofluorescence signals were obtained, whereas a few markers including neurofilaments exhibited opposite directions. In conclusion, the variety in gene regulation emphasizes the complexity of interactions within the ischemia-affected NVU and ECM. These data might help to focus future research on a set of highly sensitive elements, which might prospectively facilitate neuroprotective strategies beyond the traditional single target perspective.


Assuntos
Encéfalo/irrigação sanguínea , Encéfalo/metabolismo , Matriz Extracelular/metabolismo , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/patologia , Transcrição Genética , Animais , Biomarcadores/metabolismo , Barreira Hematoencefálica/metabolismo , Isquemia Encefálica/genética , Isquemia Encefálica/patologia , Regulação da Expressão Gênica , Masculino , Camundongos Endogâmicos C57BL , Neocórtex/patologia , Proteínas de Neurofilamentos/metabolismo , Neuroglia/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
16.
J Neurol Neurosurg Psychiatry ; 90(7): 783-791, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30992334

RESUMO

OBJECTIVE: To determine the occurrence of intracranial haemorrhagic complications (IHC) on heparin prophylaxis (low-dose subcutaneous heparin, LDSH) in primary spontaneous intracerebral haemorrhage (ICH) (not oral anticoagulation-associated ICH, non-OAC-ICH), vitamin K antagonist (VKA)-associated ICH and non-vitamin K antagonist oral anticoagulant (NOAC)-associated ICH. METHODS: Retrospective cohort study (RETRACE) of 22 participating centres and prospective single-centre study with 1702 patients with VKA-associated or NOAC-associated ICH and 1022 patients with non-OAC-ICH with heparin prophylaxis between 2006 and 2015. Outcomes were defined as rates of IHC during hospital stay among patients with non-OAC-ICH, VKA-ICH and NOAC-ICH, mortality and functional outcome at 3 months between patients with ICH with and without IHC. RESULTS: IHC occurred in 1.7% (42/2416) of patients with ICH. There were no differences in crude incidence rates among patients with VKA-ICH, NOAC-ICH and non-OAC-ICH (log-rank p=0.645; VKA-ICH: 27/1406 (1.9%), NOAC-ICH 1/130 (0.8%), non-OAC-ICH 14/880 (1.6%); p=0.577). Detailed analysis according to treatment exposure (days with and without LDSH) revealed no differences in incidence rates of IHC per 1000 patient-days (LDSH: 1.43 (1.04-1.93) vs non-LDSH: 1.32 (0.33-3.58), conditional maximum likelihood incidence rate ratio: 1.09 (0.38-4.43); p=0.953). Secondary outcomes showed differences in functional outcome (modified Rankin Scale=4-6: IHC: 29/37 (78.4%) vs non-IHC: 1213/2048 (59.2%); p=0.019) and mortality (IHC: 14/37 (37.8%) vs non-IHC: 485/2048 (23.7%); p=0.045) in disfavour of patients with IHC. Small ICH volume (OR: volume <4.4 mL: 0.18 (0.04-0.78); p=0.022) and low National Institutes of Health Stroke Scale (NIHSS) score on admission (OR: NIHSS <4: 0.29 (0.11-0.78); p=0.014) were significantly associated with fewer IHC. CONCLUSIONS: Heparin administration for venous thromboembolism (VTE) prophylaxis in patients with ICH appears to be safe regarding IHC among non-OAC-ICH, VKA-ICH and NOAC-ICH in this observational cohort analysis. Randomised controlled trials are needed to verify the safety and efficacy of heparin compared with other methods for VTE prevention.


Assuntos
Hemorragia Cerebral/complicações , Heparina/uso terapêutico , Tromboembolia Venosa/prevenção & controle , Idoso , Idoso de 80 Anos ou mais , Hemorragia Cerebral/mortalidade , Feminino , Humanos , Masculino , Estudos Prospectivos , Estudos Retrospectivos , Tromboembolia Venosa/etiologia , Tromboembolia Venosa/mortalidade
17.
Acta Neuropathol Commun ; 7(1): 17, 2019 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-30744693

RESUMO

In the setting of stroke, ischemia-related blood-brain barrier (BBB) dysfunction aggravates the cerebral edema, which critically impacts on the clinical outcome. Further, an impaired vascular integrity is associated with the risk of intracranial bleeding, especially after therapeutic recanalization. Therefore, the present study was aimed to investigate early vascular alterations from 30 min to 4 h after experimental middle cerebral artery occlusion (MCAO) in mice. Here, an extravasation of the permeability marker FITC-albumin was detectable in animals 2 and 4 h after MCAO. Thereby, BBB breakdown correlated with alterations of the endothelial surface, indicated by a discontinuous isolectin-B4 staining, while tight junction strands remained detectable using electron and immunofluorescence microscopy. Noteworthy, already 30 min after MCAO, up to 60% of the ischemia-affected vessels showed an endothelial edema, paralleled by edematous astrocytic endfeet, clearly preceding FITC-albumin extravasation. With increasing ischemic periods, scores of vascular damage significantly increased with up to 60% of the striatal vessels showing loss of endothelial integrity. Remarkably, comparison of permanent and transient ischemia did not provide significant differences 4 h after ischemia induction. As these degenerations also involved penumbral areas of potentially salvageable tissue, adjuvant approaches of endothelial protection may help to reduce the vasogenic edema after ischemic stroke.


Assuntos
Barreira Hematoencefálica/patologia , Edema Encefálico/patologia , Isquemia Encefálica/patologia , Células Endoteliais/patologia , Animais , Aquaporina 4/metabolismo , Astrócitos/metabolismo , Astrócitos/patologia , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/ultraestrutura , Edema Encefálico/complicações , Isquemia Encefálica/complicações , Permeabilidade Capilar , Células Endoteliais/ultraestrutura , Masculino , Camundongos Endogâmicos C57BL
18.
Acta Vet Scand ; 61(1): 1, 2019 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-30602394

RESUMO

BACKGROUND: This case report describes a focal brain lesion in an alpaca (Vicugna pacos). Although this is a restricted study based on a single animal, neuropathological features are reported that are most likely attributed to a vascular event with either ischemic or hemorrhagic pathology. Concerning translational issues, these findings extend neurovascular unit concept to the alpacas' brain and qualify a larger panel of stroke tissue markers for further exploration of ischemic or hemorrhagic consequences beyond the usually used small animal models in stroke research. CASE PRESENTATION: A brain lesion indicative of a stroke was diagnosed in a 3-year-old female alpaca as an incidental finding during a post mortem examination. The rostral portion of the right frontal lobe contained a 1.0 × 1.5 × 1.7 cm lesion that extended immediately to the overlying leptomeninges. Microscopically, it was composed of liquefactive necrosis with cholesterol crystal deposition and associated granulomatous inflammation as well as vascularized fibrous connective tissue rimmed by proliferated astrocytes. Multiple fluorescence labeling of the affected brain regions revealed strong microgliosis as shown by immunostaining of the ionized calcium binding adapter molecule 1 and astrogliosis as demonstrated by enhanced immunoreactivity for glial fibrillary acidic protein. In parallel, a drastic neuronal loss was detected by considerably diminished immunolabeling of neuronal nuclei. Concomitantly, up-regulated immunoreactivities for collagen IV and neurofilament light chains were found in the affected tissues, indicating vascular and cytoskeletal reactions. CONCLUSIONS: Driven by these neuropathological features, the incidental brain lesion found in this alpaca strongly suggests an ischemic or hemorrhagic etiology. However, since typical hallmarks became verifiable as previously described for other species affected by focal cerebral ischemia, the lesion is more likely related to an ischemic event. Nevertheless, as such cellular alterations might be difficult to distinguish from other brain lesions as for instance caused by inflammatory processes, adjuvant observations and species-related features need to be considered for etiological interpretations. Indeed, the lack of neurological deficits is likely attributed to the location of the lesion within the rostral aspect of the right frontal lobe of the alpacas' brain. Further, fibroblast migration from the meninges likely caused the intralesional scar formation.


Assuntos
Camelídeos Americanos , Acidente Vascular Cerebral/veterinária , Animais , Encéfalo/patologia , Isquemia Encefálica/patologia , Isquemia Encefálica/veterinária , Feminino , Lobo Frontal/patologia , Necrose , Acidente Vascular Cerebral/patologia
19.
Eur Stroke J ; 4(3): 254-262, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31984233

RESUMO

Introduction: We assessed whether modest systemic cooling started within 6 hours of symptom onset improves functional outcome at three months in awake patients with acute ischaemic stroke. Patients and methods: In this European randomised open-label clinical trial with blinded outcome assessment, adult patients with acute ischaemic stroke were randomised to cooling to a target body temperature of 34.0-35.0°C, started within 6 h after stroke onset and maintained for 12 or 24 h , versus standard treatment. The primary outcome was the score on the modified Rankin Scale at 91 days, as analysed with ordinal logistic regression. Results: The trial was stopped after inclusion of 98 of the originally intended 1500 patients because of slow recruitment and cessation of funding. Forty-nine patients were randomised to hypothermia versus 49 to standard treatment. Four patients were lost to follow-up. Of patients randomised to hypothermia, 15 (31%) achieved the predefined cooling targets. The primary outcome did not differ between the groups (odds ratio for good outcome, 1.01; 95% confidence interval, 0.48-2.13; p = 0.97). The number of patients with one or more serious adverse events did not differ between groups (relative risk, 1.22; 95% confidence interval, 0.65-1.94; p = 0.52). Discussion: In this trial, cooling to a target of 34.0-35.0°C and maintaining this for 12 or 24 h was not feasible in the majority of patients. The final sample was underpowered to detect clinically relevant differences in outcomes. Conclusion: Before new trials are launched, the feasibility of cooling needs to be improved.

20.
Clin Neuroradiol ; 29(2): 303-309, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29297102

RESUMO

INTRODUCTION: Endovascular stroke therapy is mostly available in comprehensive stroke centers with state of the art bi-plane angiography suites. The aim of the present study was to analyze if it is justifiable to treat patients with alternative x­ray machines in the case of capacity constraints, or if it is mandatory to refer patients in such cases. Secondly, we wanted to draw conclusions for the feasibility of different logistic approaches in stroke treatment, such as a "helistroke" concept. METHODS: This was a retrospective dual center analysis of all patients treated on a single-plane angiography suite between 2009 and 2017. A propensity scored matching analysis at a 1:3 ratio was performed with patients treated on a bi-plane angiography suite to receive homogeneous groups. RESULTS: A total of 42 patients were treated on a single-plane angiography suite and were compared to 126 patients treated on a bi-plane angiography suite. No significant differences in technical parameters, procedure times, recanalization success and complications could be detected. Also, there was no difference in the clinical outcome between the two groups. The only significant difference was the higher amount of radiation dose used on the bi-plane angiography machines to achieve the final results (205,660 mGy × cm2 vs. 114,565 mGy × cm2; p < 0.001). DISCUSSION: In an era of an ever-changing stroke infrastructure and an increasing demand in thrombectomy procedures, it is feasible and safe for experienced neurointerventionalists to perform endovascular stroke procedures on single-plane angiography units.


Assuntos
Procedimentos Endovasculares/métodos , Acidente Vascular Cerebral/cirurgia , Idoso , Angiografia por Tomografia Computadorizada/métodos , Estudos de Viabilidade , Humanos , Doenças Arteriais Intracranianas/diagnóstico por imagem , Masculino , Encaminhamento e Consulta , Estudos Retrospectivos , Acidente Vascular Cerebral/diagnóstico por imagem , Resultado do Tratamento
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