Publications by authors named "Matthias Endres"

370 Publications

Influence of stroke infarct location on quality of life assessed in a multivariate lesion-symptom mapping study.

Sci Rep 2021 Jun 29;11(1):13490. Epub 2021 Jun 29.

Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.

Stroke has a deleterious impact on quality of life. However, it is less well known if stroke lesions in different brain regions are associated with reduced quality of life (QoL). We therefore investigated this association by multivariate lesion-symptom mapping. We analyzed magnetic resonance imaging and clinical data from the WAKE-UP trial. European Quality of Life 5 Dimensions (EQ-5D) 3 level questionnaires were completed 90 days after stroke. Lesion symptom mapping was performed using a multivariate machine learning algorithm (support vector regression) based on stroke lesions 22-36 h after stroke. Brain regions with significant associations were explored in reference to white matter tracts. Of 503 randomized patients, 329 were included in the analysis (mean age 65.4 years, SD 11.5; median NIHSS = 6, IQR 4-9; median EQ-5D score 90 days after stroke 1, IQR 0-4, median lesion volume 3.3 ml, IQR 1.1-16.9 ml). After controlling for lesion volume, significant associations between lesions and EQ-5D score were detected for the right putamen, and internal capsules of both hemispheres. Multivariate lesion inference analysis revealed an association between injuries of the cortico-spinal tracts with worse self-reported quality of life 90 days after stroke in comparably small stroke lesions, extending previous reports of the association of striato-capsular lesions with worse functional outcome. Our findings are of value to identify patients at risk of impaired QoL after stroke.
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http://dx.doi.org/10.1038/s41598-021-92865-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241844PMC
June 2021

Expert opinion paper on cardiac imaging after ischemic stroke.

Clin Res Cardiol 2021 Jul 18;110(7):938-958. Epub 2021 Jun 18.

Atrial Fibrillation NETwork (AFNET) e.V., Münster, Germany.

This expert opinion paper on cardiac imaging after acute ischemic stroke or transient ischemic attack (TIA) includes a statement of the "Heart and Brain" consortium of the German Cardiac Society and the German Stroke Society. The Stroke Unit-Commission of the German Stroke Society and the German Atrial Fibrillation NETwork (AFNET) endorsed this paper. Cardiac imaging is a key component of etiological work-up after stroke. Enhanced echocardiographic tools, constantly improving cardiac computer tomography (CT) as well as cardiac magnetic resonance imaging (MRI) offer comprehensive non- or less-invasive cardiac evaluation at the expense of increased costs and/or radiation exposure. Certain imaging findings usually lead to a change in medical secondary stroke prevention or may influence medical treatment. However, there is no proof from a randomized controlled trial (RCT) that the choice of the imaging method influences the prognosis of stroke patients. Summarizing present knowledge, the German Heart and Brain consortium proposes an interdisciplinary, staged standard diagnostic scheme for the detection of risk factors of cardio-embolic stroke. This expert opinion paper aims to give practical advice to physicians who are involved in stroke care. In line with the nature of an expert opinion paper, labeling of classes of recommendations is not provided, since many statements are based on expert opinion, reported case series, and clinical experience.
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http://dx.doi.org/10.1007/s00392-021-01834-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238761PMC
July 2021

[Lifestyle changes for stroke prevention].

Dtsch Med Wochenschr 2021 Jun 15;146(12):787-792. Epub 2021 Jun 15.

Changes of lifestyle have a substantial effect on stroke prevention, especially in high-risk patients. Maintaining a healthier lifestyle can have greater effects than most pharmacological therapies of cardiovascular prevention. For example, increasing the amount of physical activity, adopting a healthy diet, limiting alcohol consumption and quitting smoking are associated with a 70 % decrease in stroke risk. Despite the abundance of observational data and meta-analyses assessing the association of different lifestyle changes and stroke risk, the literature frequently lacks evidence from randomized controlled clinical trial. This article will provide an overview of various forms of lifestyle changes and summarize their potential to modify the risk of stroke.
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http://dx.doi.org/10.1055/a-1221-6985DOI Listing
June 2021

Frequency and phenotype of thalamic aphasia.

J Neurol 2021 Jun 8. Epub 2021 Jun 8.

Department of Neurology with Experimental Neurology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Campus Benjamin Franklin, Hindenburgdamm 30, 12203, Berlin, Germany.

Background: Aphasia is a recognized presenting symptom of thalamic lesions. Little is known regarding its frequency and phenotype. We examined the frequency of thalamic aphasia following Isolated Acute unilateral ischemic Lesions in the Thalamus (IALT) with respect to lesion location. Furthermore, we characterized thalamic aphasia according to affected language domains and severity.

Methods: Fifty-two patients with IALT were analyzed [44% female, median age: 73 years (IQR: 60-79)]. Lesion location was determined using 3-Tesla magnetic resonance imaging and categorized as anterior, posterior, paramedian or inferolateral. Standardized language assessment was performed using the validated Aphasia checklist (ACL) directly after symptom onset. Aphasia was defined as an ACL sum score of < 135 (range: 0-148).

Results: Of 52 patients, 23 (44%) fulfilled the ACL diagnostic criteria for aphasia, including nearly all lesion locations and both sides. The average ACL sum score was 132 ± 11 (range: 98-147). Aphasia was characterized by deficits within domains of complex understanding of speech and verbal fluency. Patients with left anterior IALT were most severely affected, having significantly lower ACL scores than all other patients (117 ± 13 vs. 135 ± 8; p < 0.001). In particular, aphasia in patients with left anterior IALT was characterized by significantly worse performance in the rating of verbal communication, verbal fluency, and naming (all p ≤ 0.001).

Conclusion: Aphasia occurs in almost half of patients with focal thalamic lesions. Thalamic aphasia is not confined to one predefined thalamic lesion location, but language deficits are particularly pronounced in patients with left anterior IALT presenting with a distinct pattern.
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http://dx.doi.org/10.1007/s00415-021-10640-4DOI Listing
June 2021

Systematic monitoring for detection of atrial fibrillation in patients with acute ischaemic stroke (MonDAFIS): a randomised, open-label, multicentre study.

Lancet Neurol 2021 06;20(6):426-436

Center for Stroke Research Berlin, Charité, Universitätsmedizin Berlin, Berlin, Germany; Klinik und Hochschulambulanz für Neurologie mit Abteilung für Experimentelle Neurologie, Charité, Universitätsmedizin Berlin, Berlin, Germany; German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany; German Center for Cardiovascular Research (DZHK), Berlin, Germany; Excellence Cluster NeuroCure, Berlin, Germany; Berlin Institute of Health (BIH), Berlin, Germany. Electronic address:

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.
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http://dx.doi.org/10.1016/S1474-4422(21)00067-3DOI Listing
June 2021

The smoking paradox in ischemic stroke patients treated with intra-arterial thrombolysis in combination with mechanical thrombectomy-VISTA-Endovascular.

PLoS One 2021 20;16(5):e0251888. Epub 2021 May 20.

Center for Stroke Research Berlin, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Background: The smoking-paradox of a better outcome in ischemic stroke patients who smoke may be due to increased efficacy of thrombolysis. We investigated the effect of smoking on outcome following endovascular therapy (EVT) with mechanical thrombectomy alone versus in combination with intra-arterial (IA-) thrombolysis.

Methods: The primary endpoint was defined by three-month modified Rankin Scale (mRS). We performed a generalized linear model and reported relative risks (RR) for smoking (adjustment for age, sex, hypertension, atrial fibrillation, stroke severity, time to EVT) in patient data stemming from the Virtual International Stroke Trials Archive-Endovascular database.

Results: Among 1,497 patients, 740(49.4%) were randomized to EVT; among EVT patients, 524(35.0%) received mechanical thrombectomy alone and 216(14.4%) received it in combination with IA-thrombolysis. Smokers (N = 396) had lower mRS scores (mean 2.9 vs. 3.2; p = 0.02) and mortality rates (10% vs. 17.3%; p<0.001) in univariate analysis. In all patients and in patients treated with mechanical thrombectomy alone, smoking had no effect on outcome in regression analyses. In patients who received IA-thrombolysis (N = 216;14%), smoking had an adjusted RR of 1.65 for an mRS≤1 (95%CI 0.77-3.55). Treatment with IA-thrombolysis itself led to reduced RR for favorable outcome (adjusted RR 0.30); interaction analysis of IA-thrombolysis and smoking revealed that non-smokers with IA-thrombolysis had mRS≤2 in 47 cases (30%, adjusted RR 0.53 [0.41-0.69]) while smokers with IA-thrombolysis had mRS≤2 in 23 cases (38%, adjusted RR 0.61 [0.42-0.87]).

Conclusions: Smokers had no clear clinical benefit from EVT that incorporates IA-thrombolysis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251888PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136663PMC
May 2021

Modeling chemotherapy induced neurotoxicity with human induced pluripotent stem cell (iPSC) -derived sensory neurons.

Neurobiol Dis 2021 Jul 11;155:105391. Epub 2021 May 11.

Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Klinik und Hochschulambulanz für Neurologie, Charitéplatz 1, 10117 Berlin, Germany; Berlin Institute of Health at Charité, Universitätsmedizin Berlin, Anna-Louisa-Karsch Straße 2, 10178 Berlin, Germany; Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, NeuroCure Cluster of Excellence, Charitéplatz 1, 10117 Berlin, Germany; Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Center for Stroke Research Berlin, Charitéplatz 1, 10117 Berlin, Germany; German Center for Neurodegenerative Diseases (DZNE), partner site Berlin, Germany; German Center for Cardiovascular Research (DZHK), partner site Berlin, Germany.

Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent, potentially irreversible adverse effect of cytotoxic chemotherapy often leading to a reduction or discontinuation of treatment which negatively impacts patients' prognosis. To date, however, neither predictive biomarkers nor preventive treatments for CIPN are available, which is partially due to a lack of suitable experimental models. We therefore aimed to evaluate whether sensory neurons derived from induced pluripotent stem cells (iPSC-DSN) can serve as human disease model system for CIPN. Treatment of iPSC-DSN for 24 h with the neurotoxic drugs paclitaxel, bortezomib, vincristine and cisplatin led to axonal blebbing and a dose dependent decline of cell viability in clinically relevant IC ranges, which was not observed for the non-neurotoxic compounds doxorubicin and 5-fluorouracil. Paclitaxel treatment effects were less pronounced after 24 h but prominent when treatment was applied for 72 h. Global transcriptome analyses performed at 24 h, i.e. before paclitaxel-induced cell death occurred, revealed the differential expression of genes of neuronal injury, cellular stress response, and sterol pathways. We further evaluated if known neuroprotective strategies can be reproduced in iPSC-DSN and observed protective effects of lithium replicating findings from rodent dorsal root ganglia cells. Comparing sensory neurons derived from two different healthy donors, we found preliminary evidence that these cell lines react differentially to neurotoxic drugs as expected from the variable presentation of CIPN in patients. In conclusion, iPSC-DSN are a promising platform to study the pathogenesis of CIPN and to evaluate neuroprotective treatment strategies. In the future, the application of patient-specific iPSC-DSN could open new avenues for personalized medicine with individual risk prediction, choice of chemotherapeutic compounds and preventive treatments.
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http://dx.doi.org/10.1016/j.nbd.2021.105391DOI Listing
July 2021

High-Sensitivity Cardiac Troponin T and Recurrent Vascular Events After First Ischemic Stroke.

J Am Heart Assoc 2021 May 13;10(10):e018326. Epub 2021 May 13.

Center for Stroke Research Berlin (CSB) Charité Universitätsmedizin Berlin Berlin Germany.

Background Recent evidence suggests cardiac troponin levels to be a marker of increased vascular risk. We aimed to assess whether levels of high-sensitivity cardiac troponin T (hs-cTnT) are associated with recurrent vascular events and death in patients with first-ever, mild to moderate ischemic stroke. Methods and Results We used data from the PROSCIS-B (Prospective Cohort With Incident Stroke Berlin) study. We computed Cox proportional hazards regression analyses to assess the association between hs-cTnT levels upon study entry (Roche Elecsys, upper reference limit, 14 ng/L) and the primary outcome (composite of recurrent stroke, myocardial infarction, and all-cause death). A total of 562 patients were analyzed (mean age, 67 years [SD 13]; 38.6% women; median National Institutes of Health Stroke Scale=2; hs-cTnT above upper reference limit, 39.2%). During a mean follow-up of 3 years, the primary outcome occurred in 89 patients (15.8%), including 40 (7.1%) recurrent strokes, 4 (0.7%) myocardial infarctions, and 51 (9.1%) events of all-cause death. The primary outcome occurred more often in patients with hs-cTnT above the upper reference limit (27.3% versus 10.2%; adjusted hazard ratio, 2.0; 95% CI, 1.3-3.3), with a dose-response relationship when the highest and lowest hs-cTnT quartiles were compared (15.2 versus 1.8 events per 100 person-years; adjusted hazard ratio, 4.8; 95% CI, 1.9-11.8). This association remained consistent in sensitivity analyses, which included age matching and stratification for sex. Conclusions Hs-cTnT is dose-dependently associated with an increased risk of recurrent vascular events and death within 3 years after first-ever, mild to moderate ischemic stroke. These findings support further studies of the utility of hs-cTnT for individualized risk stratification after stroke. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01363856.
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http://dx.doi.org/10.1161/JAHA.120.018326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200699PMC
May 2021

Preserved structural connectivity mediates the clinical effect of thrombolysis in patients with anterior-circulation stroke.

Nat Commun 2021 05 10;12(1):2590. Epub 2021 May 10.

Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Thrombolysis with recombinant tissue plasminogen activator in acute ischemic stroke aims to restore compromised blood flow and prevent further neuronal damage. Despite the proven clinical efficacy of this treatment, little is known about the short-term effects of systemic thrombolysis on structural brain connectivity. In this secondary analysis of the WAKE-UP trial, we used MRI-derived measures of infarct size and estimated structural network disruption to establish that thrombolysis is associated not only with less infarct growth, but also with reduced loss of large-scale connectivity between grey-matter areas after stroke. In a causal mediation analysis, infarct growth mediated a non-significant 8.3% (CI [-8.0, 32.6]%) of the clinical effect of thrombolysis on functional outcome. The proportion mediated jointly through infarct growth and change of structural connectivity, especially in the border zone around the infarct core, however, was as high as 33.4% (CI [8.8, 77.4]%). Preservation of structural connectivity is thus an important determinant of treatment success and favourable functional outcome in addition to lesion volume. It might, in the future, serve as an imaging endpoint in clinical trials or as a target for therapeutic interventions.
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http://dx.doi.org/10.1038/s41467-021-22786-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110812PMC
May 2021

Prognostication after intracerebral hemorrhage: a review.

Neurol Res Pract 2021 May 3;3(1):22. Epub 2021 May 3.

Department of Neurology, Universitätsklinikum Erlangen, Erlangen, Germany.

Background: Approximately half of patients with spontaneous intracerebral hemorrhage (ICH) die within 1 year. Prognostication in this context is of great importance, to guide goals of care discussions, clinical decision-making, and risk stratification. However, available prognostic scores are hardly used in clinical practice. The purpose of this review article is to identify existing outcome prediction scores for spontaneous intracerebral hemorrhage (ICH) discuss their shortcomings, and to suggest how to create and validate more useful scores.

Main Text: Through a literature review this article identifies existing ICH outcome prediction models. Using the Essen-ICH-score as an example, we demonstrate a complete score validation including discrimination, calibration and net benefit calculations. Score performance is illustrated in the Erlangen UKER-ICH-cohort (NCT03183167). We identified 19 prediction scores, half of which used mortality as endpoint, the remainder used disability, typically the dichotomized modified Rankin score assessed at variable time points after the index ICH. Complete score validation by our criteria was only available for the max-ICH score. Our validation of the Essen-ICH-score regarding prediction of unfavorable outcome showed good discrimination (area under the curve 0.87), fair calibration (calibration intercept 1.0, slope 0.84), and an overall net benefit of using the score as a decision tool. We discuss methodological pitfalls of prediction scores, e.g. the withdrawal of care (WOC) bias, physiological predictor variables that are often neglected by authors of clinical scores, and incomplete score validation. Future scores need to integrate new predictor variables, patient-reported outcome measures, and reduce the WOC bias. Validation needs to be standardized and thorough. Lastly, we discuss the integration of current ICH scoring systems in clinical practice with the awareness of their shortcomings.

Conclusion: Presently available prognostic scores for ICH do not fulfill essential quality standards. Novel prognostic scores need to be developed to inform the design of research studies and improve clinical care in patients with ICH.
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http://dx.doi.org/10.1186/s42466-021-00120-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8091769PMC
May 2021

Mechanical thrombectomy in patients with cervical artery dissection and stroke in the anterior or posterior circulation - a multicenter analysis from the German Stroke Registry.

Neurol Res Pract 2021 May 3;3(1):20. Epub 2021 May 3.

Klinik und Hochschulambulanz für Neurologie, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.

Background: Cervical artery dissection (CAD) is a rare cause of acute ischemic stroke (AIS) with large vessel occlusion (LVO) and may constitute a challenge for mechanical thrombectomy (MT). We compared procedural characteristics, reperfusion rates, and clinical outcome in AIS patients undergoing MT with and without CAD.

Methods: We performed a pre-specified analysis of patients registered within the German Stroke Registry, a prospectively maintained multicenter registry of consecutive patients with AIS patients treated by MT. Procedural characteristics included time periods and additional application of medication.

Results: Of 2589 patients, 62 (2.4%) were diagnosed with CAD. CAD patients were younger, had lower rates of known vascular risk factors and larger baseline stroke volumes. MT in CAD patients took significantly longer (median [IQR] groin-puncture-to-flow restoration time: 98 [67-136] versus 70 [45-100] minutes; p < 0.001) and more often required use of intra-arterial medication (34.4% versus 15.6%; p < 0.001). Reperfusion success (modified Treatment in Cerebral Infarction score 2b-3: 85.2% versus 83.3%, p = 0.690) and favorable functional outcome after 3 months (modified Rankin Scale score ≤ 2: 70.9% versus 36.4%, adjusted p = 0.086) did not differ significantly between patients with and without CAD. The latter findings held true for both CAD in the anterior and posterior circulation.

Conclusion: CAD in AIS requiring MT is rare. MT in patients with CAD constitutes a particular procedural challenge, but still achieves favorable radiological and functional outcomes in most patients. Our data provide indirect evidence that MT is of clinical benefit in patients with AIS due to LVO and CAD.
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http://dx.doi.org/10.1186/s42466-021-00119-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8091690PMC
May 2021

Magnetic resonance imaging-based changes in vascular morphology and cerebral perfusion in subacute ischemic stroke.

J Cereb Blood Flow Metab 2021 Apr 17:271678X211010071. Epub 2021 Apr 17.

Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Stroke Research Berlin, Berlin, Germany.

MRI-based vessel size imaging (VSI) allows for assessment of cerebral microvasculature and perfusion. This exploratory analysis of vessel size (VS) and density (Q; both assessed via VSI) in the subacute phase of ischemic stroke involved sixty-two patients from the BAPTISe cohort ('Biomarkers And Perfusion--Training-Induced changes after Stroke') nested within a randomized controlled trial (intervention: 4-week training relaxation). Relative VS, Q, cerebral blood volume (rCBV) and -flow (rCBF) were calculated for: ischemic lesion, perilesional tissue, and region corresponding to ischemic lesion on the contralateral side (mirrored lesion). Linear mixed-models detected significantly increased rVS and decreased rQ within the ischemic lesion compared to the mirrored lesion (coefficient[standard error]: 0.2[0.08] p = 0.03 and -1.0[0.3] p = 0.02, respectively); lesion rCBF and rCBV were also significantly reduced. Mixed-models did not identify time-to-MRI, nor training as modifying factors in terms of rVS or rQ up to two months post-stroke. Larger lesion VS was associated with larger lesion volumes (β 34, 95%CI 6.2-62; p = 0.02) and higher baseline NIHSS (β 3.0, 95%CI 0.49-5.3;p = 0.02), but was not predictive of six-month outcome. In summary, VSI can assess the cerebral microvasculature and tissue perfusion in the subacute phases of ischemic stroke, and may carry relevant prognostic value in terms of lesion volume and stroke severity.
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http://dx.doi.org/10.1177/0271678X211010071DOI Listing
April 2021

Spreading depression as an innate antiseizure mechanism.

Nat Commun 2021 04 13;12(1):2206. Epub 2021 Apr 13.

Neurovascular Research Unit, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Spreading depression (SD) is an intense and prolonged depolarization in the central nervous systems from insect to man. It is implicated in neurological disorders such as migraine and brain injury. Here, using an in vivo mouse model of focal neocortical seizures, we show that SD may be a fundamental defense against seizures. Seizures induced by topical 4-aminopyridine, penicillin or bicuculline, or systemic kainic acid, culminated in SDs at a variable rate. Greater seizure power and area of recruitment predicted SD. Once triggered, SD immediately suppressed the seizure. Optogenetic or KCl-induced SDs had similar antiseizure effect sustained for more than 30 min. Conversely, pharmacologically inhibiting SD occurrence during a focal seizure facilitated seizure generalization. Altogether, our data indicate that seizures trigger SD, which then terminates the seizure and prevents its generalization.
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http://dx.doi.org/10.1038/s41467-021-22464-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044138PMC
April 2021

Cost Effectiveness of Interhospital Transfer for Mechanical Thrombectomy of Acute Large Vessel Occlusion Stroke: Role of Predicted Recanalization Rates.

Circ Cardiovasc Qual Outcomes 2021 Apr 5;14(4):e007444. Epub 2021 Apr 5.

Klinik und Hochschulambulanz für Neurologie, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Germany (L.S., M.E., C.H.N.).

Background: Emergency interhospital transfer of patients with stroke with large vessel occlusion to a comprehensive stroke center for mechanical thrombectomy is resource-intensive and can be logistically challenging. Imaging markers may identify patients in whom intravenous thrombolysis (IVT) alone is likely to result in thrombus resolution, potentially rendering interhospital transfers unnecessary. Here, we investigate how predicted probabilities to achieve IVT-mediated recanalization affect cost-effectiveness estimates of interhospital transfer.

Methods: We performed a health economic analysis comparing emergency interhospital transfer of patients with acute large vessel occlusion stroke after administration of IVT with a scenario in which patients also receive IVT but remain at the primary hospital. Results were stratified by clinical parameters, treatment delays, and the predicted probability to achieve IVT-mediated recanalization. Estimated 3-month outcomes were combined with a long-term probabilistic model to yield quality-adjusted life years (QALYs) and costs. Uncertainty was quantified in probabilistic sensitivity analyses.

Results: Depending on input parameters, marginal costs of interhospital transfer ranged from USD -61 366 (cost saving) to USD +20 443 and additional QALYs gained from 0.1 to 3.0, yielding incremental cost-effectiveness ratios of
Conclusions: Predicted probabilities to achieve IVT-mediated recanalization significantly affect the cost-effectiveness of interhospital transfer for MT, in particular in elderly patients with moderate or severe stroke symptoms. However, high predicted recanalization rates alone do not generally imply that patients should not be considered for transfer.
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http://dx.doi.org/10.1161/CIRCOUTCOMES.120.007444DOI Listing
April 2021

Spinocerebellar ataxia type 14: refining clinicogenetic diagnosis in a rare adult-onset disorder.

Ann Clin Transl Neurol 2021 04 19;8(4):774-789. Epub 2021 Mar 19.

Institute of Neuroscience and Medicine (INM-1), Research Centre Juelich, Juelich, Germany.

Objectives: Genetic variant classification is a challenge in rare adult-onset disorders as in SCA-PRKCG (prior spinocerebellar ataxia type 14) with mostly private conventional mutations and nonspecific phenotype. We here propose a refined approach for clinicogenetic diagnosis by including protein modeling and provide for confirmed SCA-PRKCG a comprehensive phenotype description from a German multi-center cohort, including standardized 3D MR imaging.

Methods: This cross-sectional study prospectively obtained neurological, neuropsychological, and brain imaging data in 33 PRKCG variant carriers. Protein modeling was added as a classification criterion in variants of uncertain significance (VUS).

Results: Our sample included 25 cases confirmed as SCA-PRKCG (14 variants, thereof seven novel variants) and eight carriers of variants assigned as VUS (four variants) or benign/likely benign (two variants). Phenotype in SCA-PRKCG included slowly progressive ataxia (onset at 4-50 years), preceded in some by early-onset nonprogressive symptoms. Ataxia was often combined with action myoclonus, dystonia, or mild cognitive-affective disturbance. Inspection of brain MRI revealed nonprogressive cerebellar atrophy. As a novel finding, a previously not described T2 hyperintense dentate nucleus was seen in all SCA-PRKCG cases but in none of the controls.

Interpretation: In this largest cohort to date, SCA-PRKCG was characterized as a slowly progressive cerebellar syndrome with some clinical and imaging features suggestive of a developmental disorder. The observed non-ataxia movement disorders and cognitive-affective disturbance may well be attributed to cerebellar pathology. Protein modeling emerged as a valuable diagnostic tool for variant classification and the newly described T2 hyperintense dentate sign could serve as a supportive diagnostic marker of SCA-PRKCG.
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http://dx.doi.org/10.1002/acn3.51315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045942PMC
April 2021

Physical Fitness Training in Patients with Subacute Stroke (PHYS-STROKE): Safety analyses of a randomized clinical trial.

Int J Stroke 2021 Apr 7:17474930211006286. Epub 2021 Apr 7.

Center for Stroke Research Berlin (CSB), Charité - Universitätsmedizin Berlin, Berlin, Germany.

Background And Aim: To report the six-month safety analyses among patients enrolled in the "Physical Fitness Training in Subacute Stroke-PHYS-STROKE" trial and identify underlying risk factors associated with serious adverse events.

Methods: We performed a pre-specified safety analysis of a multicenter, randomized controlled, endpoint-blinded trial comprising 200 patients with moderate to severe subacute stroke (days 5-45 after stroke) that were randomly assigned (1:1) to receive either aerobic, bodyweight supported, treadmill-based training (n = 105), or relaxation sessions (n = 95, control group). Each intervention session lasted for 25 min, five times weekly for four weeks, in addition to standard rehabilitation therapy. Serious adverse events defined as cerebro- and cardiovascular events, readmission to hospital, and death were assessed during six months of follow-up. Incident rate ratios (IRR) were calculated, and Poisson regression analyses were conducted to identify risk factors for serious adverse events and to test the association with aerobic training.

Results: Six months after stroke, 50 serious adverse events occurred in the trial with a higher incidence rate (per 100 patient-months) in the training group compared to the relaxation group (6.31 vs. 3.22; IRR 1.70, 95% CI 0.96 to 3.12). The association of aerobic training with serious adverse events incidence rates were modified by diabetes mellitus (IRR for interaction: 7.10, 95% CI 1.56 to 51.24) and by atrial fibrillation (IRR for interaction: 4.37, 95% CI 0.97 to 31.81).

Conclusions: Safety analysis of the PHYS-STROKE trial found a higher rate of serious adverse events in patients randomized to aerobic training compared to control within six months after stroke. Exploratory analyses found an association between serious adverse events occurrence in the aerobic training group with pre-existing diabetes mellitus and atrial fibrillation which should be further investigated in future trials.

Data Access Statement: The raw data and analyses scripts are provided by the authors on a secure online repository for reproduction of reported findings.
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http://dx.doi.org/10.1177/17474930211006286DOI Listing
April 2021

Effect of intravenous alteplase on post-stroke depression in the WAKE UP trial.

Eur J Neurol 2021 Jun 22;28(6):2017-2025. Epub 2021 Mar 22.

Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.

Background And Purpose: The aim was to study the effect of intravenous alteplase on the development of post-stroke depression (PSD) in acute stroke patients, and to identify predictors of PSD.

Methods: This post hoc analysis included patients with unknown onset stroke randomized to treatment with alteplase or placebo in the WAKE-UP trial (ClinicalTrials.gov number, NCT01525290), in whom a composite end-point of PSD was defined as a Beck Depression Inventory ≥10, medication with an antidepressant, or depression recorded as an adverse event. Multiple logistic regression was used to identify predictors of PSD at 90 days. Structural equation modelling was applied to assess the indirect effect of thrombolysis on PSD mediated by the modified Rankin Scale.

Results: Information on the composite end-point was available for 438 of 503 randomized patients. PSD was present in 96 of 224 (42.9%) patients in the alteplase group and 115 of 214 (53.7%) in the placebo group (odds ratio 0.63; 95% confidence interval 0.43-0.94; p = 0.022; adjusted for age and National Institutes of Health Stroke Scale at baseline). Prognostic factors associated with PSD included baseline medication with antidepressants, higher lesion volume, history of depression and assignment to placebo. While 65% of the effect of thrombolysis on PSD were caused directly, 35% were mediated by an improvement of the mRS.

Conclusions: Treatment with alteplase in patients with acute stroke resulted in lower rates of depression at 90 days, which were only partially explained by reduced functional disability. Predictors of PSD including history and clinical characteristics may help in identifying patients at risk of PSD.
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http://dx.doi.org/10.1111/ene.14797DOI Listing
June 2021

BDNF serum concentrations in 2053 participants of the Berlin Aging Study II.

Neurobiol Aging 2021 05 2;101:221-223. Epub 2021 Feb 2.

Charité-Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Klinik und Poliklinik für Psychiatrie und Psychotherapie, Berlin, Germany.

Serum BDNF concentrations in 2053 participants of the Berlin Aging Study II (BASE-II; 1572 individuals from the older age group [60-85 years], 481 individuals from the younger-age reference group [22-37 years]) were studied. There was no effect of age, sex, body mass index, self-reported depression, or BDNF Val66Met variant on serum BDNF concentrations. Multiple linear regression analysis failed to detect significant relationships of Digit Symbol Substitution Test score and Consortium to Establish a Registry for Alzheimer's Disease memory score to BDNF levels. However, we detected a positive correlation between platelet counts and BDNF levels (r = 0.303, p < 0.001). Our findings do not support an effect of aging, self-reported depression, or the Val66Met variant on serum BDNF concentrations. The role of thrombocytes in the biology of serum BDNF merits further study.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.01.020DOI Listing
May 2021

Correction to: Neurological update: use of cardiac troponin in patients with stroke.

J Neurol 2021 Jun;268(6):2293

Klinik für Neurologie mit Experimenteller Neurologie, Charité-Universitätsmedizin Berlin, Berlin, Germany.

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http://dx.doi.org/10.1007/s00415-021-10434-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8179906PMC
June 2021

Extent of FLAIR Hyperintense Vessels May Modify Treatment Effect of Thrombolysis: A Analysis of the WAKE-UP Trial.

Front Neurol 2020 4;11:623881. Epub 2021 Feb 4.

Center for Stroke Research Berlin, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Fluid-attenuated inversion recovery (FLAIR) hyperintense vessels (FHVs) on MRI are a radiological marker of vessel occlusion and indirect sign of collateral circulation. However, the clinical relevance is uncertain. We explored whether the extent of FHVs is associated with outcome and how FHVs modify treatment effect of thrombolysis in a subgroup of patients with confirmed unilateral vessel occlusion from the randomized controlled WAKE-UP trial. One hundred sixty-five patients were analyzed. Two blinded raters independently assessed the presence and extent of FHVs (defined as the number of slices with visible FHV multiplied by FLAIR slice thickness). Patients were then separated into two groups to distinguish between few and extensive FHVs (dichotomization at the median <30 or ≥30). Here, 85% of all patients ( = 140) and 95% of middle cerebral artery (MCA) occlusion patients ( = 127) showed FHVs at baseline. Between MCA occlusion patients with few and extensive FHVs, no differences were identified in relative lesion growth ( = 0.971) and short-term [follow-up National Institutes of Health Stroke Scale (NIHSS) score; = 0.342] or long-term functional recovery [modified Rankin Scale (mRS) <2 at 90 days poststroke; = 0.607]. In linear regression analysis, baseline extent of FHV (defined as a continuous variable) was highly associated with volume of hypoperfused tissue (β = 2.161; 95% CI 0.96-3.36; = 0.001). In multivariable regression analysis adjusted for treatment group, stroke severity, lesion volume, occlusion site, and recanalization, FHV did not modify functional recovery. However, in patients with few FHVs, the odds for good functional outcome (mRS) were increased in recombinant tissue plasminogen activator (rtPA) patients compared to those who received placebo [odds ratio (OR) = 5.3; 95% CI 1.2-24.0], whereas no apparent benefit was observed in patients with extensive FHVs (OR = 1.1; 95% CI 0.3-3.8), -value for interaction was 0.11. While the extent of FHVs on baseline did not alter the evolution of stroke in terms of lesion progression or functional recovery, it may modify treatment effect and should therefore be considered relevant additional information in those patients who are eligible for intravenous thrombolysis. Main trial (WAKE-UP): ClinicalTrials.gov, NCT01525290; and EudraCT, 2011-005906-32. Registered February 2, 2012.
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http://dx.doi.org/10.3389/fneur.2020.623881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890254PMC
February 2021

Cardiomyocyte Injury Following Acute Ischemic Stroke: Protocol for a Prospective Observational Cohort Study.

JMIR Res Protoc 2021 Feb 5;10(2):e24186. Epub 2021 Feb 5.

Department of Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany.

Background: Elevated cardiac troponin, which indicates cardiomyocyte injury, is common after acute ischemic stroke and is associated with poor functional outcome. Myocardial injury is part of a broad spectrum of cardiac complications that may occur after acute ischemic stroke. Previous studies have shown that in most patients, the underlying mechanism of stroke-associated myocardial injury may not be a concomitant acute coronary syndrome. Evidence from animal research and clinical and neuroimaging studies suggest that functional and structural alterations in the central autonomic network leading to stress-mediated neurocardiogenic injury may be a key underlying mechanism (ie, stroke-heart syndrome). However, the exact pathophysiological cascade remains unclear, and the diagnostic and therapeutic implications are unknown.

Objective: The aim of this CORONA-IS (Cardiomyocyte injury following Acute Ischemic Stroke) study is to quantify autonomic dysfunction and to decipher downstream cardiac mechanisms leading to myocardial injury after acute ischemic stroke.

Methods: In this prospective, observational, single-center cohort study, 300 patients with acute ischemic stroke, confirmed via cerebral magnetic resonance imaging (MRI) and presenting within 48 hours of symptom onset, will be recruited during in-hospital stay. On the basis of high-sensitivity cardiac troponin levels and corresponding to the fourth universal definition of myocardial infarction, 3 groups are defined (ie, no myocardial injury [no cardiac troponin elevation], chronic myocardial injury [stable elevation], and acute myocardial injury [dynamic rise/fall pattern]). Each group will include approximately 100 patients. Study patients will receive routine diagnostic care. In addition, they will receive 3 Tesla cardiovascular MRI and transthoracic echocardiography within 5 days of symptom onset to provide myocardial tissue characterization and assess cardiac function, 20-min high-resolution electrocardiogram for analysis of cardiac autonomic function, and extensive biobanking. A follow-up for cardiovascular events will be conducted 3 and 12 months after inclusion.

Results: After a 4-month pilot phase, recruitment began in April 2019. We estimate a recruitment period of approximately 3 years to include 300 patients with a complete cardiovascular MRI protocol.

Conclusions: Stroke-associated myocardial injury is a common and relevant complication. Our study has the potential to provide a better mechanistic understanding of heart and brain interactions in the setting of acute stroke. Thus, it is essential to develop algorithms for recognizing patients at risk and to refine diagnostic and therapeutic procedures.

Trial Registration: Clinicaltrials.gov NCT03892226; https://www.clinicaltrials.gov/ct2/show/NCT03892226.

International Registered Report Identifier (irrid): DERR1-10.2196/24186.
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http://dx.doi.org/10.2196/24186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895641PMC
February 2021

Association Between Dispatch of Mobile Stroke Units and Functional Outcomes Among Patients With Acute Ischemic Stroke in Berlin.

JAMA 2021 02;325(5):454-466

Klinik für Neurologie, Klinikum Frankfurt (Oder), Germany.

Importance: Effects of thrombolysis in acute ischemic stroke are time-dependent. Ambulances that can administer thrombolysis (mobile stroke units [MSUs]) before arriving at the hospital have been shown to reduce time to treatment.

Objective: To determine whether dispatch of MSUs is associated with better clinical outcomes for patients with acute ischemic stroke.

Design, Setting, And Participants: This prospective, nonrandomized, controlled intervention study was conducted in Berlin, Germany, from February 1, 2017, to October 30, 2019. If an emergency call prompted suspicion of stroke, both a conventional ambulance and an MSU, when available, were dispatched. Functional outcomes of patients with final diagnosis of acute cerebral ischemia who were eligible for thrombolysis or thrombectomy were compared based on the initial dispatch (both MSU and conventional ambulance or conventional ambulance only).

Exposure: Simultaneous dispatch of an MSU (computed tomographic scanning with or without angiography, point-of-care laboratory testing, and thrombolysis capabilities on board) and a conventional ambulance (n = 749) vs conventional ambulance alone (n = 794).

Main Outcomes And Measures: The primary outcome was the distribution of modified Rankin Scale (mRS) scores (a disability score ranging from 0, no neurological deficits, to 6, death) at 3 months. The coprimary outcome was a 3-tier disability scale at 3 months (none to moderate disability; severe disability; death) with tier assignment based on mRS scores if available or place of residence if mRS scores were not available. Common odds ratios (ORs) were used to quantify the association between exposure and outcome; values less than 1.00 indicated a favorable shift in the mRS distribution and lower odds of higher levels of disability.

Results: Of the 1543 patients (mean age, 74 years; 723 women [47%]) included in the adjusted primary analysis, 1337 (87%) had available mRS scores (primary outcome) and 1506 patients (98%) had available the 3-tier disability scale assessment (coprimary outcome). Patients with an MSU dispatched had lower median mRS scores at month 3 (1; interquartile range [IQR], 0-3) than did patients without an MSU dispatched (2; IQR, 0-3; common OR for worse mRS, 0.71; 95% CI, 0.58-0.86; P < .001). Similarly, patients with an MSU dispatched had lower 3-month coprimary disability scores: 586 patients (80.3%) had none to moderate disability; 92 (12.6%) had severe disability; and 52 (7.1%) had died vs patients without an MSU dispatched: 605 (78.0%) had none to moderate disability; 103 (13.3%) had severe disability; and 68 (8.8%) had died (common OR for worse functional outcome, 0.73, 95% CI, 0.54-0.99; P = .04).

Conclusions And Relevance: In this prospective, nonrandomized, controlled intervention study of patients with acute ischemic stroke in Berlin, Germany, the dispatch of mobile stroke units, compared with conventional ambulances alone, was significantly associated with lower global disability at 3 months. Clinical trials in other regions are warranted.
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http://dx.doi.org/10.1001/jama.2020.26345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856548PMC
February 2021

Impact of Statins on Hematoma, Edema, Seizures, Vascular Events, and Functional Recovery After Intracerebral Hemorrhage.

Stroke 2021 Mar 1;52(3):975-984. Epub 2021 Feb 1.

Department of Neurology (M.I.S., J.B.K., B.V., J.I.S., J.A.S., S.T.G., S.B., H.M.H., H.B.H.), Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Germany.

Background And Purpose: The impact of statins on hematoma characteristics, perihemorrhagic edema (PHE), cardiovascular events, seizures, and functional recovery in patients with intracerebral hemorrhage (ICH) is insufficiently studied.

Methods: Patients with ICH of the prospective UKER-ICH (Universitätsklinikum Erlangen Cohort of Patients With Spontaneous Intracerebral Hemorrhage) study (URL: https://www.clinicaltrials.gov; Unique identifier: NCT03183167) were analyzed by multivariable regression modeling and propensity score matching, and PHE volumes were volumetrically assessed. Outcomes comprised hematoma characteristics, the impact of continuation, discontinuation, and initiation of statins on peak PHE extent, and the influence of statin treatment on the occurrence of seizures, cardiovascular adverse events, and functional recovery after ICH.

Results: A total of 1275 patients with ICH with information on statin treatment were analyzed. Statin treatment on hospital admission (21.7%) was associated with higher rates of lobar versus nonlobar ICH (odds ratio, 1.57 [1.03-2.40]; =0.038). Initiation of statins after ICH was associated with increased peak PHE (β=0.12, SE=0.06, =0.008), whereas continuation versus discontinuation of prior statin treatment was not significantly associated with edema formation (>0.10). There were no significant differences in the incidence of remote symptomatic seizures according to statin exposure during follow-up (statins: 11.5% versus no statins: 7.8%, subdistribution hazard ratio: 1.15 [0.80-1.66]; =0.512). Patients on statins revealed less cardiovascular adverse events and more frequently functional recovery after 12 months (functional recovery: 57.7% versus 45.0%, odds ratio 1.67 [1.09-2.56]; =0.019).

Conclusions: Among statin users, lobar ICH occurs more frequently as compared with nonstatin users. While continuation of prior statin treatment appears to be safe regarding PHE formation, the initiation of statins during the first days after ICH may increase PHE extent. However, statins should be initiated thereafter (eg, at hospital discharge) to prevent cardiovascular events and potentially improve functional recovery.
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http://dx.doi.org/10.1161/STROKEAHA.120.029345DOI Listing
March 2021

Stroke Admissions, Stroke Severity, and Treatment Rates in Urban and Rural Areas During the COVID-19 Pandemic.

Front Neurol 2020 6;11:607193. Epub 2021 Jan 6.

Klinik und Hochschulambulanz für Neurologie, Charité - Universitätsmedizin Berlin, Berlin, Germany.

Many regions worldwide reported a decline of stroke admissions during the early phase of the coronavirus disease 2019 (COVID-19) pandemic. It remains unclear whether urban and rural regions experienced similar declines and whether deviations from historical admission numbers were more pronounced among specific age, stroke severity or treatment groups. We used registry datasets from (a) nine acute stroke hospitals in Berlin, and (b) nine hospitals from a rural TeleNeurology network in Northeastern Germany for primary analysis of 3-week-rolling average of stroke/TIA admissions before and during the COVID-19 pandemic. We compared course of stroke admission numbers with regional cumulative severe acute respiratory syndrome coronavirus 2 (Sars-CoV-2) infections. In secondary analyses, we used emergency department logs of the Berlin Charité University hospital to investigate changes in age, stroke severity, and thrombolysis/thrombectomy frequencies during the early regional Sars-CoV-2 spread (March and April 2020) and compared them with preceding years. Compared to past years, stroke admissions decreased by 20% in urban and 20-25% in rural hospitals. Deviations from historical averages were observable starting in early March and peaked when numbers of regional Sars-CoV-2 infections were still low. At the same time, average admission stroke severity and proportions of moderate/severe strokes (NIHSS >5) were 20 and 20-40% higher, respectively. There were no relevant deviations observed in proportions of younger patients (<65 years), proportions of patients with thrombolysis, or number of thrombectomy procedures. Stroke admissions at Charité subsequently rebounded and reached near-normal levels after 4 weeks when the number of new Sars-CoV-2 infections started to decrease. During the early pandemic, deviations of stroke-related admissions from historical averages were observed in both urban and rural regions of Northeastern Germany and appear to have been mainly driven by avoidance of admissions of mildly affected stroke patients.
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http://dx.doi.org/10.3389/fneur.2020.607193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815522PMC
January 2021

Effect of early sleep apnoea treatment with adaptive servo-ventilation in acute stroke patients on cerebral lesion evolution and neurological outcomes: study protocol for a multicentre, randomized controlled, rater-blinded, clinical trial (eSATIS: early Sleep Apnoea Treatment in Stroke).

Trials 2021 Jan 22;22(1):83. Epub 2021 Jan 22.

Department of Neurology, Bern University Hospital (Inselspital) and University of Bern, Bern, Switzerland.

Background: Sleep-disordered breathing (SDB) is highly prevalent in acute ischaemic stroke and is associated with worse functional outcome and increased risk of recurrence. Recent meta-analyses suggest the possibility of beneficial effects of nocturnal ventilatory treatments (continuous positive airway pressure (CPAP) or adaptive servo-ventilation (ASV)) in stroke patients with SDB. The evidence for a favourable effect of early SDB treatment in acute stroke patients remains, however, uncertain.

Methods: eSATIS is an open-label, multicentre (6 centres in 4 countries), interventional, randomized controlled trial in patients with acute ischaemic stroke and significant SDB. Primary outcome of the study is the impact of immediate SDB treatment with non-invasive ASV on infarct progression measured with magnetic resonance imaging in the first 3 months after stroke. Secondary outcomes are the effects of immediate SDB treatment vs non-treatment on clinical outcome (independence in daily functioning, new cardio-/cerebrovascular events including death, cognition) and physiological parameters (blood pressure, endothelial functioning/arterial stiffness). After respiratory polygraphy in the first night after stroke, patients are classified as having significant SDB (apnoea-hypopnoea index (AHI) > 20/h) or no SDB (AHI < 5/h). Patients with significant SDB are randomized to treatment (ASV+ group) or no treatment (ASV- group) from the second night after stroke. In all patients, clinical, physiological and magnetic resonance imaging studies are performed between day 1 (visit 1) and days 4-7 (visit 4) and repeated at day 90 ± 7 (visit 6) after stroke.

Discussion: The trial will give information on the feasibility and efficacy of ASV treatment in patients with acute stroke and SDB and allows assessing the impact of SDB on stroke outcome. Diagnosing and treating SDB during the acute phase of stroke is not yet current medical practice. Evidence in favour of ASV treatment from a randomized multicentre trial may lead to a change in stroke care and to improved outcomes.

Trial Registration: ClinicalTrials.gov NCT02554487 , retrospectively registered on 16 September 2015 (actual study start date, 13 August 2015), and www.kofam.ch (SNCTP000001521).
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http://dx.doi.org/10.1186/s13063-020-04977-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820538PMC
January 2021

Intracerebral Hemorrhage with Intraventricular Extension Associated with Loss of Consciousness at Symptom Onset.

Neurocrit Care 2021 Jan 21. Epub 2021 Jan 21.

Department of Neurology, Yale School of Medicine, 15 York Street, LLCI 10th floor, Room 1003C, P.O. Box 208018, New Haven, CT, 06520, USA.

Background: In patients with spontaneous intracerebral hemorrhage (ICH), pre-hospital markers of disease severity might be useful to potentially triage patients to undergo early interventions.

Objective: Here, we tested whether loss of consciousness (LOC) at the onset of ICH is associated with intraventricular hemorrhage (IVH) on brain computed tomography (CT).

Methods: Among 3000 ICH cases from ERICH (Ethnic/Racial Variations of Intracerebral Hemorrhage study, NS069763), we included patients with complete ICH/IVH volumetric CT measurements and excluded those with seizures at ICH onset. Trained investigators extracted data from medical charts. Mental status at symptom onset (categorized as alert/oriented, alert/confused, drowsy/somnolent, coma/unresponsive/posturing) and 3-month disability (modified Rankin score, mRS) were assessed through standardized interviews of participants or dedicated proxies. We used logistic regression and mediation analysis to assess relationships between LOC, IVH, and unfavorable outcome (mRS 4-6).

Results: Two thousand seven hundred and twenty-four patients met inclusion criteria. Median admission Glasgow Coma Score was 15 (interquartile range 11-15). 46% had IVH on admission or follow-up CT. Patients with LOC (mental status: coma/unresponsive, n = 352) compared to those without LOC (all other mental status, n = 2372) were younger (60 vs. 62 years, p = 0.005) and had greater IVH frequency (77 vs. 41%, p < 0.001), greater peak ICH volumes (28 vs. 11 ml, p < 0.001), greater admission systolic blood pressure (200 vs. 184 mmHg, p < 0.001), and greater admission serum glucose (158 vs. 127 mg/dl, p < 0.001). LOC was independently associated with IVH presence (odds ratio, OR, 2.6, CI 1.9-3.5) and with unfavorable outcome (OR 3.05, CI 1.96-4.75). The association between LOC and outcome was significantly mediated by IVH (beta = 0.24, bootstrapped CI 0.17-0.32).

Conclusion: LOC at ICH onset may be a useful pre-hospital marker to identify patients at risk of having or developing IVH.
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http://dx.doi.org/10.1007/s12028-020-01180-2DOI Listing
January 2021

Neurological update: use of cardiac troponin in patients with stroke.

J Neurol 2021 Jun 29;268(6):2284-2292. Epub 2020 Dec 29.

Klinik für Neurologie mit Experimenteller Neurologie, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Cardiac troponin is a specific and sensitive biomarker to identify and quantify myocardial injury. Myocardial injury is frequently detected after acute ischemic stroke and strongly associated with unfavorable outcomes. Concomitant acute coronary syndrome is only one of several possible differential diagnoses that may cause elevation of cardiac troponin after stroke. As a result, there are uncertainties regarding the correct interpretation and optimal management of stroke patients with myocardial injury in clinical practice. Elevation of cardiac troponin may occur as part of a 'Stroke-Heart Syndrome'. The term 'Stroke-Heart Syndrome' subsumes a clinical spectrum of cardiac complications after stroke including cardiac injury, dysfunction, and arrhythmia which may relate to disturbances of autonomic function and the brain-heart axis. In this review, we provide an up-to-date overview about prognostic implications, mechanisms, and management of elevated cardiac troponin levels in patients with acute ischemic stroke.
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http://dx.doi.org/10.1007/s00415-020-10349-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8179917PMC
June 2021

High frequency of cerebrospinal fluid autoantibodies in COVID-19 patients with neurological symptoms.

Brain Behav Immun 2021 03 24;93:415-419. Epub 2020 Dec 24.

Department of Neurology and Experimental Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany; German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany.

Background: COVID-19 intensive care patients can present with neurological syndromes, usually in the absence of SARS-CoV-2 in cerebrospinal fluid (CSF). The recent finding of some virus-neutralizing antibodies cross-reacting with brain tissue suggests the possible involvement of specific autoimmunity.

Design: Blood and CSF samples from eleven critically ill COVID-19 patients presenting with unexplained neurological symptoms including myoclonus, oculomotor disturbance, delirium, dystonia and epileptic seizures, were analyzed for anti-neuronal and anti-glial autoantibodies.

Results: Using cell-based assays and indirect immunofluorescence on unfixed murine brain sections, all patients showed anti-neuronal autoantibodies in serum or CSF. Antigens included intracellular and neuronal surface proteins, such as Yo or NMDA receptor, but also various specific undetermined epitopes, reminiscent of the brain tissue binding observed with certain human monoclonal SARS-CoV-2 antibodies. These included vessel endothelium, astrocytic proteins and neuropil of basal ganglia, hippocampus or olfactory bulb.

Conclusion: The high frequency of autoantibodies targeting the brain in the absence of other explanations suggests a causal relationship to clinical symptoms, in particular to hyperexcitability (myoclonus, seizures). Several underlying autoantigens and their potential molecular mimicry with SARS-CoV-2 still await identification. However, autoantibodies may already now explain some aspects of multi-organ disease in COVID-19 and can guide immunotherapy in selected cases.
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http://dx.doi.org/10.1016/j.bbi.2020.12.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834471PMC
March 2021

Novichok nerve agent poisoning.

Lancet 2021 01 23;397(10270):249-252. Epub 2020 Dec 23.

Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany. Electronic address:

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http://dx.doi.org/10.1016/S0140-6736(20)32644-1DOI Listing
January 2021
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