Publications by authors named "Wolf-Dirk Niesen"

66 Publications

Temporal Expression Pattern of Hemoxygenase-1 Expression and Its Association with Vasospasm and Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage.

Neurocrit Care 2021 Jul 26. Epub 2021 Jul 26.

Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Background: Red blood cell-induced cerebral inflammation and toxicity has been shown to be attenuated by induction of the heme-catalyzing enzyme, hemoxygenase-1 (HO-1), in animal models of subarachnoid hemorrhage (SAH). Although inflammatory mechanisms leading to secondary neuronal injury in SAH are becoming increasingly well understood, markers of cerebral inflammation have so far not been implemented in clinical prediction models of SAH.

Methods: In this biomarker observational study, HO-1 messenger ribonucleic acid (mRNA) expression levels were determined in cerebrospinal fluid (CSF) and blood of 66 patients with aneurysmal SAH on days 1, 7, and 14 after the SAH event. HO-1 mRNA expression was determined via real time polymerase chain reaction (PCR), and relative expression changes were quantified in comparison with expression levels in nonhemorrhagic control CSF. Subarachnoid blood burden, as well as presence of vasospasm and delayed cerebral ischemia (DCI), were recorded. Short and long-term clinical outcomes were assessed using the Modified Rankin Scale at discharge and 1 year after the SAH event.

Results: CSF HO-1 expression levels showed a significant increase over the 14-day observation period (p < 0.001, F = 22.53) and correlated with intracranial hematoma burden (ρ = 0.349, p = 0.025). In multivariate analyses, CSF HO-1 expression levels did not reach significance as independent predictors of outcome. Vasospasm on computed tomographic angiography was associated with lower CSF HO-1 expression levels on day 7 after SAH (n = 53, p = 0.010), whereas patients with DCI showed higher CSF HO-1 expression levels on day 14 after SAH (n = 21, p = 0.009).

Conclusions: HO-1 expression in CSF in patients with SAH follows a distinct temporal induction pattern and is dependent on intracranial hematoma burden. CSF HO-1 expression was unable to predict functional outcome. Associations of early low HO-1 expression with vasospasm and late elevated HO-1 expression with DCI may point to detrimental effects of late HO-1 induction, warranting the need for further investigation in a larger study population.
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http://dx.doi.org/10.1007/s12028-021-01299-wDOI Listing
July 2021

Contralateral Stenosis and Echolucent Plaque Morphology are Associated with Elevated Stroke Risk in Patients Treated with Asymptomatic Carotid Artery Stenosis within a Controlled Clinical Trial (SPACE-2).

J Stroke Cerebrovasc Dis 2021 Sep 24;30(9):105940. Epub 2021 Jul 24.

Department of Neurology, University Hospital of Heidelberg, Heidelberg, Germany. Electronic address:

Background: Asymptomatic carotid artery stenosis (ACS) has a low risk of stroke. To achieve an advantage over noninterventional best medical treatment (BMT), carotid endarterectomy (CEA) or carotid artery stenting (CAS) must be performed with the lowest possible risk of stroke. Therefore, an analysis of risk-elevating factors is essential. Grade of ipsilateral and contralateral stenosis as well as plaque morphology are known risk factors in ACS.

Methods: The randomized, controlled, multicenter SPACE-2 trial had to be stopped prematurely after recruiting 513 patients. 203 patients were randomized to CEA, 197 to CAS, and 113 to BMT. Within one year, risk factors such as grade of stenosis and plaque morphology were analyzed.

Results: Grade of contralateral stenosis (GCS) was higher in patients with any stroke (50% vs. 20%; p=0.012). Echolucent plaque morphology was associated with any stroke on the day of intervention (OR 5.23; p=0.041). In the periprocedural period, any stroke was correlated with GCS in the CEA group (70% vs. 20%; p=0.026) and with echolucent plaque morphology in the CAS group (6% vs. 1%; p=0.048). In multivariate analysis, occlusion of the contralateral carotid artery (CCO) was associated with risk of any stroke (OR 7.00; p=0.006), without heterogeneity between CEA and CAS.

Conclusion: In patients with asymptomatic carotid artery stenosis, GCS, CCO, as well as echolucent plaque morphology were associated with a higher risk of cerebrovascular events. The risk of stroke in the periprocedural period was increased by GCS in CEA and by echolucent plaque in CAS. Due to small sample size, results must be interpreted carefully.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2021.105940DOI Listing
September 2021

Selective intra-carotid blood cooling in acute ischemic stroke: A safety and feasibility study in an ovine stroke model.

J Cereb Blood Flow Metab 2021 Jun 23:271678X211024952. Epub 2021 Jun 23.

Department of Neuroradiology, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Selective therapeutic hypothermia (TH) showed promising preclinical results as a neuroprotective strategy in acute ischemic stroke. We aimed to assess safety and feasibility of an intracarotid cooling catheter conceived for fast and selective brain cooling during endovascular thrombectomy in an ovine stroke model.Transient middle cerebral artery occlusion (MCAO, 3 h) was performed in 20 sheep. In the hypothermia group (n = 10), selective TH was initiated 20 minutes before recanalization, and was maintained for another 3 h. In the normothermia control group (n = 10), a standard 8 French catheter was used instead. Primary endpoints were intranasal cooling performance (feasibility) plus vessel patency assessed by digital subtraction angiography and carotid artery wall integrity (histopathology, both safety). Secondary endpoints were neurological outcome and infarct volumes.Computed tomography perfusion demonstrated MCA territory hypoperfusion during MCAO in both groups. Intranasal temperature decreased by 1.1 °C/3.1 °C after 10/60 minutes in the TH group and 0.3 °C/0.4 °C in the normothermia group (p < 0.001). Carotid artery and branching vessel patency as well as carotid wall integrity was indifferent between groups. Infarct volumes (p = 0.74) and neurological outcome (p = 0.82) were similar in both groups.Selective TH was feasible and safe. However, a larger number of subjects might be required to demonstrate efficacy.
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http://dx.doi.org/10.1177/0271678X211024952DOI Listing
June 2021

Stereotactic cisternal lavage in patients with aneurysmal subarachnoid hemorrhage with urokinase and nimodipine for the prevention of secondary brain injury (SPLASH): study protocol for a randomized controlled trial.

Trials 2021 Apr 15;22(1):285. Epub 2021 Apr 15.

Department of Stereotactic and Functional Neurosurgery, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.

Background: Delayed cerebral infarction (DCI) is a major cause of death and poor neurological outcome in patients with aneurysmal subarachnoid hemorrhage (aSAH). Direct intrathecal therapies with fibrinolytic and spasmolytic drugs have appeared promising in clinical trials. However, access to the subarachnoid space for intrathecal drug administration is an unsolved problem so far, especially in patients with endovascular aneurysm securing. We investigate a therapy protocol based on stereotactic catheter ventriculocisternostomy (STX-VCS), a new approach to overcome this problem. The primary objective of this study is to assess whether cisternal lavage with urokinase, nimodipine, and Ringer's solution administered via a stereotactically implanted catheter into the basal cisterns (= investigational treatment (IT)) is safe and improves neurological outcome in patients with aSAH.

Methods: This is a randomized, controlled, parallel-group, open-label phase II trial. Fifty-four patients with severe aSAH (WFNS grade ≥ 3) will be enrolled at one academic tertiary care center in Southern Germany. Patients will be randomized at a ratio of 1:1 to receive either standard of care only or standard of care plus the IT. The primary endpoint is the proportion of subjects with a favorable outcome on the Modified Rankin Scale (defined as mRS 0-3) at 6 months after aSAH. Further clinical and surrogate outcome parameters are defined as secondary endpoints.

Discussion: New approaches for the prevention and therapy of secondary brain injury in patients with aSAH are urgently needed. We propose this RCT to assess the clinical safety and efficacy of a novel therapy protocol for intrathecal administration of urokinase, nimodipine, and Ringer's solution.

Trial Registration: Deutsches Register Klinischer Studien (German Clinical Trials Register), DRKS00015645 . Registered on 8 May 2019.
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http://dx.doi.org/10.1186/s13063-021-05208-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048077PMC
April 2021

Intracerebral Hemorrhage in COVID-19 Patients with Pulmonary Failure: A Propensity Score-Matched Registry Study.

Neurocrit Care 2021 06 23;34(3):739-747. Epub 2021 Feb 23.

Department of Cardiology and Angiology I, Faculty of Medicine, Heart Center Freiburg University, University of Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany.

Background: Hypercoagulability in Coronavirus Disease 2019 (COVID-19) causes deep vein thrombosis and pulmonary embolism necessitating systemic anticoagulation. Case reports of intracerebral hemorrhages in ventilated COVID-19 patients warrant precaution. It is unclear, however, if COVID-19 patients with acute respiratory distress syndrome (ARDS) with or without veno-venous extracorporeal membrane oxygenation therapy (VV-ECMO) have more intracerebral hemorrhages (ICH) compared to other ARDS patients.

Methods: We conducted a retrospective observational single-center study enrolling all patients with ARDS from 01/2018 to 05/2020. PCR-positive SARS-CoV-2 patients with ARDS were allocated to the COVID-19 group. Propensity score matching was performed for age, VV-ECMO, and bleeding risk.

Results: A total of 163 patients with moderate or severe ARDS were identified, 47 (28.8%) in the COVID-19 group, and 116 (71.2%) in the non-COVID-19 group. In 63/163 cases (38.7%), VV-ECMO therapy was required. The ICU survival was 52.8%. COVID-19 patients were older, more often male, and exhibited a lower SOFA score, but the groups showed similar rates of VV-ECMO therapy. Treatments with antiplatelet agents (p = 0.043) and therapeutic anticoagulation (p = 0.028) were significantly more frequent in the COVID-19 patients. ICH was detected in 22 patients (13.5%) with no statistical difference between the groups (11.2 vs. 19.1% without and with SARS-CoV-2, respectively, p = 0.21). Propensity score matching confirmed similar rates of ICH in both groups (12.8 vs. 19.1% without and with SARS-CoV-2, respectively, p = 0.57), thus leveling out possible confounders.

Conclusions: Intracerebral hemorrhage was detected in every tenth patient with ARDS. Despite statistically higher rates of antiplatelet therapy and therapeutic anticoagulation in COVID-19 patients, we found a similar rate of ICH in patients with ARDS due to COVID-19 compared to other causes of ARDS.
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http://dx.doi.org/10.1007/s12028-021-01202-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899797PMC
June 2021

Triage and Allocation of Neurocritical Care Resources During the COVID 19 Pandemic - A National Survey.

Front Neurol 2020 6;11:609227. Epub 2021 Jan 6.

Department of Neurosurgery, University Hospital Bonn, Bonn, Germany.

In light of the ongoing COVID-19 pandemic and the associated hospitalization of an overwhelming number of ventilator-dependent patients, medical and/or ethical patient triage paradigms have become essential. While guidelines on the allocation of scarce resources do exist, such work within the subdisciplines of intensive care (e.g., neurocritical care) remains limited. A 16-item questionnaire was developed that sought to explore/quantify the expert opinions of German neurointensivists with regard to triage decisions. The anonymous survey was conducted via a web-based platform and in total, 96 members of the Initiative of German Neurointensive Trial Engagement (IGNITE)-study group were contacted via e-mail. The IGNITE consortium consists of an interdisciplinary panel of specialists with expertise in neuro-critical care (i.e., anesthetists, neurologists and neurosurgeons). Fifty members of the IGNITE consortium responded to the questionnaire; in total the respondents were in charge of more than 500 Neuro ICU beds throughout Germany. Common determinants reported which affected triage decisions included known patient wishes (98%), the state of health before admission (96%), SOFA-score (85%) and patient age (69%). Interestingly, other principles of allocation, such as a treatment of "youngest first" (61%) and members of the healthcare sector (50%) were also noted. While these were the most accepted parameters affecting the triage of patients, a "first-come, first-served" principle appeared to be more accepted than a lottery for the allocation of ICU beds which contradicts much of what has been reported within the literature. The respondents also felt that at least one neurointensivist should serve on any interdisciplinary triage team. The data gathered in the context of this survey reveal the estimation/perception of triage algorithms among neurointensive care specialists facing COVID-19. Further, it is apparent that German neurointensivists strongly feel that they should be involved in any triage decisions at an institutional level given the unique resources needed to treat patients within the Neuro ICU.
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http://dx.doi.org/10.3389/fneur.2020.609227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874200PMC
January 2021

Patients with Subarachnoid Hemorrhage Exhibit Disturbed Expression Patterns of the Circadian Rhythm Gene .

Life (Basel) 2021 Feb 5;11(2). Epub 2021 Feb 5.

Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.

Circadian rhythm gene expression in cerebral pacemaker regions is regulated by a transcriptional-translational feedback loop across the 24-h day-night cycle. In preclinical models of subarachnoid hemorrhage (SAH), cyclic gene expression is disrupted. Stabilization of circadian rhythm gene expression attenuates susceptibility to ischemic damage in both neuronal and myocardial tissues. In this clinical observational study, circadian rhythm gene () mRNA expression levels were determined from blood leukocytes and cerebrospinal fluid (CSF) cells via real-time PCR on days 1, 7 and 14 after aneurysm rupture in 49 patients with spontaneous SAH. CSF expression was markedly suppressed immediately after SAH and remained suppressed over the course of two weeks of ICU treatment. Short-term mortality as well as occurrence of delirium was associated with greater extent of suppression on day 1 after SAH. Patients that developed delayed cerebral ischemia exhibited comparatively lower expression levels on day 7 after SAH, while presence of vasospasm remained unaffected. However, expression did not differ in patient groups with favourable or non-favourable functional neurological outcome (modified Rankin Scales 1-3 vs. 4-6). While our findings suggest a potential protective effect of stable circadian rhythm gene expression on the extent of ischemic damage, this effect was confined to the early disease course and was not reflected in patients' functional neurological outcome.
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http://dx.doi.org/10.3390/life11020124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915417PMC
February 2021

Bedside Catheter Hematoma Evacuation in Vitamin K Antagonist-Related Intracerebral Hemorrhage: A Safe and Feasible Approach.

Front Neurol 2020 14;11:807. Epub 2020 Aug 14.

Department of Neurology, University of Freiburg, Freiburg im Breisgau, Germany.

Although outcome in intracerebral hemorrhage (ICH) patients is generally not improved by surgical intervention, the use of minimally invasive surgery (MIS) has shown promising results. However, vitamin K antagonist (VKA)-related ICH patients are underrepresented in surgical treatment trials. We therefore assessed the safety and efficacy of a bedside MIS approach including local application of urokinase in VKA-related ICH. Patients with a VKA-related ICH > 20 ml who received bedside hematoma evacuation treatment ( = 21) at the University Medical Center Freiburg were retrospectively included for analysis and compared to a historical control group ( = 35) selected from an institutional database (University Medical Center Erlangen) according to identical inclusion criteria. Propensity score matching was performed to obtain comparable cohorts. The evolution of hematoma and peri-hemorrhagic edema (PHE) volumes, midline shift, and the occurrence of adverse events were analyzed. Furthermore, we assessed the modified Rankin Scale and NIHSS scores recorded at discharge. Propensity score matching resulted in 16 patients per group with well-balanced characteristics. Median ICH volume at admission was 45.7 (IQR: 24.2-56.7) ml in the control group and 48.4 (IQR: 28.7-59.6) ml in the treatment group ( = 0.327). ICH volume at day 7 was less pronounced in the treatment group [MIS: 23.2 ml (IQR: 15.8-32.3) vs. control: 43.2 ml (IQR: 27.5-52.4); = 0.013], as was the increase in midline shift up to day 7 [MIS: -3.75 mM (IQR: -4.25 to -2) vs. control: 1 mM (IQR: 0-2); < 0.001]. No group differences were observed in PHE volume on day 7 [MIS: 42.4 ml (IQR: 25.0-72.3) vs. control: 31.0 ml (IQR: 18.8-53.8); = 0.274] or mRS at discharge [MIS: 5 (IQR: 4-5) and 5 (IQR: 4-5); = 0.949]. No hematoma expansion was observed. The catheter had to be replaced in 1 patient (6%). Bedside catheter-based hematoma evacuation followed by local thrombolysis with urokinase appears to be feasible and safe in cases of large VKA-related ICH. Further studies that assess the functional outcome associated with this technique are warranted. DRKS00007908 (German Clinical Trial Register; www.drks.de).
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http://dx.doi.org/10.3389/fneur.2020.00807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456824PMC
August 2020

Correction to: Endovascular stroke treatment's impact on malignant type of edema (ESTIMATE).

J Neurol 2020 08;267(8):2481

Department of Neurology, University Hospital Ulm, Oberer Eselsberg 45, 89081, Ulm, Germany.

The original keywords were not sufficiently precise in describing the article content. Therefore, the key words were amended to include hemicraniectomy and malignant edema.
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http://dx.doi.org/10.1007/s00415-020-09828-xDOI Listing
August 2020

Near-fatal primary manifestation of anti-aquaporin 4-positive neuromyelitis optica spectrum disorder survived without neurological sequelae: A case report.

J Neurol Sci 2020 05 21;412:116797. Epub 2020 Mar 21.

Clinic of Neurology and Neurophysiology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Breisacher Str. 64, D-79106 Freiburg, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.jns.2020.116797DOI Listing
May 2020

Twenty Years of Cerebral Ultrasound Perfusion Imaging-Is the Best yet to Come?

J Clin Med 2020 Mar 17;9(3). Epub 2020 Mar 17.

Department of Neurology, St. Josef-Hospital, Ruhr University Bochum, 44791 Bochum, Germany.

Over the past 20 years, ultrasonic cerebral perfusion imaging (UPI) has been introduced and validated applying different data acquisition and processing approaches. Clinical data were collected mainly in acute stroke patients. Some efforts were undertaken in order to compare different technical settings and validate results to gold standard perfusion imaging. This review illustrates the evolution of the method, explicating different technical aspects and milestones achieved over time. Up to date, advancements of ultrasound technology as well as data processing approaches enable semi-quantitative, gold standard proven identification of critically hypo-perfused tissue in acute stroke patients. The rapid distribution of CT perfusion over the past 10 years has limited the clinical need for UPI. However, the unexcelled advantage of mobile application raises reasonable expectations for future applications. Since the identification of intracerebral hematoma and large vessel occlusion can also be revealed by ultrasound exams, UPI is a supplementary multi-modal imaging technique with the potential of pre-hospital application. Some further applications are outlined to highlight the future potential of this underrated bedside method of microcirculatory perfusion assessment.
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http://dx.doi.org/10.3390/jcm9030816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141340PMC
March 2020

In Reply.

Authors:
Wolf-Dirk Niesen
January 2020

Cerebral amyloid angiopathy-related intracerebral hemorrhage: Feasibility and safety of bedside catheter hematoma evacuation with urokinase.

Clin Neurol Neurosurg 2020 03 30;190:105655. Epub 2019 Dec 30.

Neurological Department, University of Freiburg, Breisacher Strasse 64, 79106, Freiburg, Germany.

Objective: Cerebral amyloid angiopathy (CAA) is an important cause of intracerebral hemorrhage (ICH). However, data on surgical intervention in CAA-related ICH is very limited. In this retrospective study we assessed safety and efficacy of free-hand catheter aspiration followed by local thrombolysis in CAA-related large ICH.

Patients And Methods: Patients with CAA-related lobar ICH>30 ml that were treated with this catheter technique were identified from our prospective database. The catheter was inserted at the bedside in the core of the hematoma and urokinase (5000IE) was administered every 6 h for a maximum of 4 days. Evolution of hematoma volume, perihemorrhagic edema (PHE) and midline-shift (MLS) as well as adverse events and functional outcome were analyzed.

Results: Twenty-one patients (median age 79 years) were treated between 2013-2018. Hematoma volume decreased from 70 ml at admission (IQR 49-98 ml) to 52 ml (IQR 35-76 ml, p < 0.001) immediately after catheter aspiration, and to 23.5 ml (IQR 17-47 ml, p < 0.001) at the end of urokinase treatment. At day 4, PHE volume (from 45 ml [IQR 33-71 ml] to 36 ml [IQR 22-50 ml]; p = 0.001) and MLS (from 5 mm [IQR 3.5-7 mm] to 1 mm [IQR 0.5-3 mm]; p < 0.001) were reduced significantly. No infection was observed, rebleeding after administration of 4 × 5000IE urokinase occurred in one patient (5 %). At discharge, modified Rankin Scale was 3 in 33 %, 4 in 24 %, and 5 in 43 % of patients, and had further improved after rehabilitation to an mRS of 2 in 10 %, 3 in 38 %, 4 in 19 %, and 5 in 33 % (median 9 weeks after ictus). There were no patient deaths during this time.

Conclusions: Bedside catheter hematoma evacuation in large CAA-related ICH seemed feasible and safe and could immediately decrease mass effect. Further studies assessing functional outcome are warranted.
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http://dx.doi.org/10.1016/j.clineuro.2019.105655DOI Listing
March 2020

Long-term outcome changes after mechanical thrombectomy for anterior circulation acute ischemic stroke.

J Neurol 2020 Apr 13;267(4):1026-1034. Epub 2019 Dec 13.

Department of Neuroradiology, Medical Center, University Hospital Freiburg, Breisacher Straße 64, 79106, Freiburg, Germany.

Background And Purpose: Mechanical thrombectomy (MT) improves early clinical outcome in patients with acute ischemic stroke but insights on determinants of long-term outcome after MT treatment are scarce.

Methods: Data from stroke patients with anterior circulation large vessel occlusion of a prospective MT registry (01/2014-06/2017) of a large comprehensive stroke center were analyzed regarding clinical outcome between short- (3 months) and long-term (12 months) assessment reflected by a change of modified Rankin scores (∆mRS). Secondary endpoints included favorable long-term outcome (mRS 0-2). Multi-variable regression analysis was performed to identify determinants of outcome changes and favorable outcome at long term.

Results: Of 264 patients included, 42.0% showed a favorable long-term outcome. Longitudinal analysis found that some individuals still improved, but no overall mRS difference between short and long-term follow-up was detected [∆mRS - 0.004 (95% CI - 0.020; 0.013); p = 0.672]. Right hemispheric stroke [∆mRS 0.286 (0.011; 0.561); p = 0.043] and high NIHSS at discharge [∆mRS, 0.039 (0.004; 0.074); p = 0.029] were associated with a longitudinal mRS decline. Favorable long-term outcome was associated with successful recanalization (p < 0.0001).

Conclusions: A significant number of patients with MT experience a favorable long-term outcome. Outcomes remained stable between short- and long-term follow-up, but some individuals may still show improvement beyond short-term rehabilitation. Right hemispheric stroke and clinical stroke severity at hospital discharge may be frail predictors for delayed decline of functional status, whereas successful recanalization remains a positive outcome predictor. Death rarely occurs beyond 3 months after MT treatment.
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http://dx.doi.org/10.1007/s00415-019-09670-wDOI Listing
April 2020

Development of a Routinely Applicable Imaging Protocol for Fast and Precise Middle Cerebral Artery Occlusion Assessment and Perfusion Deficit Measure in an Ovine Stroke Model: A Case Study.

Front Neurol 2019 14;10:1113. Epub 2019 Nov 14.

Department of Neurosurgery, Faculty of Medicine, Medical Center - University of Freiburg, University of Freiburg, Freiburg, Germany.

Temporary middle cerebral artery occlusion (MCAO) in sheep allows modeling of acute large vessel occlusion stroke and subsequent vessel recanalization. However, rapid and precise imaging-based assessment of vessel occlusion and the resulting perfusion deficit during MCAO still represents an experimental challenge. Here, we tested feasibility and suitability of a strategy for MCAO verification and perfusion deficit assessment. We also compared the extent of the initial perfusion deficit and subsequent lesion size for different MCAO durations. The rete mirabile prevents reliable vascular imaging investigation of middle cerebral artery filling status. Hence, computed tomography perfusion imaging was chosen for indirect confirmation of MCAO. Follow-up infarct size evaluation by diffusion-weighted magnetic resonance imaging revealed fluctuating results, with no apparent relationship of lesion size with MCAO at occlusion times below 4 h, potentially related to the variable collateralization of the MCA territory. This underlines the need for intra-ischemic perfusion assessment and future studies focusing on the correlation between perfusion deficit, MCAO duration, and final infarct volume. Temporary MCAO and intra-ischemic perfusion imaging nevertheless has the potential to be applied for the simulation of novel recanalization therapies, particularly those that aim for a fast reperfusion effect in combination with mechanical thrombectomy in a clinically realistic scenario.
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http://dx.doi.org/10.3389/fneur.2019.01113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868089PMC
November 2019

Emergency Free-Hand Bedside Catheter Evacuation of Large Intracerebral Hematomas Following Thrombolysis for Ischemic Stroke: A Case Series.

Neurocrit Care 2020 08;33(1):207-217

Department of Neurology, University of Freiburg Medical School, Breisacher Str. 64, 79106, Freiburg, Germany.

Introduction: Symptomatic intracerebral hemorrhage (sICH) following systemic thrombolysis for ischemic stroke is often devastating, and open surgical evacuation is considered dangerous due to the increased risk of perioperative bleeding, and stereotactic placement of a catheter is too time-consuming. We therefore evaluated the feasibility of a free-hand bedside catheter technique for emergency hematoma evacuation.

Methods: Patients who had a supratentorial sICH after thrombolysis, a hematoma volume > 30 ml, and an ensuing reduction in vigilance were consecutively treated with acute minimally invasive catheter hematoma evacuation. Catheter insertion and trajectory were planned via 3D-reconstructed computed tomography (CT) scan, and free-hand insertion of an external ventricular catheter into the core of the hematoma was performed bedside, followed by careful blood aspiration. Cranial CT was used to verify catheter position and residual hematoma volume. In cases, where the residual volume exceeded 15 ml, urokinase (5000 IE) was administered into the clot every 6 h until the volume decreased to < 15 ml.

Results: In all six patients, catheter aspiration immediately reduced hematoma volume by 77%, from 73 ± 20 ml to 17 ± 16 ml (p = 0.028). In four patients, the hematoma was almost completely removed (< 10 ml) by singular aspiration. In the remaining two patients with a residual hematoma size > 15 ml, consecutive urokinase application resulted in a further reduction to 1 ml and 15 ml, respectively, after 30 h. The median National Institues of Health Stroke Scale/Score after sICH was 19.5 points, rapidly decreasing to 11 after catheter aspiration (p = 0.027), and further improving to 4 at discharge. No procedure-related complications were observed.

Conclusions: Emergency free-hand bedside catheter aspiration is a reasonable option for hematoma evacuation in large thrombolysis-associated sICH when performed by experienced neurosurgeons. Larger studies would help in determining the generalizability of our findings to other centers and assessing their impact on functional outcome.
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http://dx.doi.org/10.1007/s12028-019-00887-1DOI Listing
August 2020

Impact of Stereotactic Ventriculocisternostomy on Delayed Cerebral Infarction and Outcome After Subarachnoid Hemorrhage.

Stroke 2020 02 4;51(2):431-439. Epub 2019 Dec 4.

Department of Stereotactic and Functional Neurosurgery (B.S., V.A.C., P.C.R.), University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Germany.

Background and Purpose- Delayed cerebral infarction (DCI) is an important cause of morbidity and mortality in patients with aneurysmal subarachnoid hemorrhage (aSAH). Stereotactic catheter ventriculocisternostomy (STX-VCS) and fibrinolytic/spasmolytic lavage is a new method for DCI prevention. Here, we assess the effects of implementing STX-VCS in an unselected aSAH patient population of a tertiary referral center. Methods- Retrospective cohort study of all consecutive aSAH patients admitted to a neurosurgical referral center during a 7-year period (April 2012 to April 2019). Midterm STX-VCS was introduced and offered to patients at high risk for DCI. We compared the incidence and burden of DCI, neurological outcome, and the use of induced hypertension and endovascular rescue therapy in this consecutive aSAH population 3.5 years before versus 3.5 years after STX-VCS became available. Results- Four hundred thirty-six consecutive patients were included: 222 BEFORE and 214 AFTER. Fifty-seven of 214 (27%) patients received STX-VCS. Stereotactic procedures resulted in one (2%) subdural hematoma. Favorable neurological outcome at 6 months occurred in 118 (53%) patients BEFORE and 139 (65%) patients AFTER (relative risk, 0.79 [95% CI, 0.66-0.95]). DCI occurred in 40 (18.0%) patients BEFORE and 17 (7.9%) patients AFTER (relative risk, 0.68 [95% CI, 0.57-0.86]), and total DCI volumes were 8933 (100%) and 3329 mL (36%), respectively. Induced hypertension was used in 97 (44%) and 30 (15%) patients, respectively (relative risk, 0.55 [95% CI, 0.46-0.65]). Thirty (13.5%) patients BEFORE versus 5 (2.3%) patients AFTER underwent endovascular rescue therapies (relative risk, 0.17 [95% CI, 0.07-0.42]). Conclusions- Selecting high-risk patients for STX-VCS reduced the DCI incidence, burden, and related mortality in a consecutive aSAH patient population. This was associated with an improved neurological outcome.
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http://dx.doi.org/10.1161/STROKEAHA.119.027424DOI Listing
February 2020

Neuroprotection after Hemorrhagic Stroke Depends on Cerebral Heme Oxygenase-1.

Antioxidants (Basel) 2019 Oct 19;8(10). Epub 2019 Oct 19.

Department of Anesthesiology and Critical Care Medicine, Medical Center-University of Freiburg, 79106 Freiburg, Germany.

(1) Background: A detailed understanding of the pathophysiology of hemorrhagic stroke is still missing. We hypothesized that expression of heme oxygenase-1 (HO-1) in microglia functions as a protective signaling pathway. (2) Methods: Hippocampal HT22 neuronal cells were exposed to heme-containing blood components and cell death was determined. We evaluated HO-1-induction and cytokine release by wildtype compared to tissue-specific HO-1-deficient () primary microglia (PMG). In a study involving 46 patients with subarachnoid hemorrhage (SAH), relative HO-1 mRNA level in the cerebrospinal fluid were correlated with hematoma size and functional outcome. (3) Results: Neuronal cell death was induced by exposure to whole blood and hemoglobin. HO-1 was induced in microglia following blood exposure. Neuronal cells were protected from cell death by microglia cell medium conditioned with blood. This was associated with a HO-1-dependent increase in monocyte chemotactic protein-1 (MCP-1) production. HO-1 mRNA level in the cerebrospinal fluid of SAH-patients correlated positively with hematoma size. High HO-1 mRNA level in relation to hematoma size were associated with improved functional outcome at hospital discharge. (4) Conclusions: Microglial HO-1 induction with endogenous CO production functions as a crucial signaling pathway in blood-induced inflammation, determining microglial MCP-1 production and the extent of neuronal cell death. These results give further insight into the pathophysiology of neuronal damage after SAH and the function of HO-1 in humans.
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http://dx.doi.org/10.3390/antiox8100496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6827088PMC
October 2019

Central Pontine Myelinosis and Osmotic Demyelination Syndrome.

Dtsch Arztebl Int 2019 09;116(35-36):600-606

Department of Neurology and Neurophysiology, University Medical Center Freiburg, Germany.

Background: Osmotic demyelination syndrome (ODS), which embraces central pontine myelinolysis (CPM) and extrapontine myelinosis (EPM), is often underdiagnosed in clinical practice, but can be fatal. In this article, we review the etiology, patho- physiology, clinical features, diagnosis, treatment, and prognosis of ODS.

Methods: Pertinent publications from the years 1959 to 2018 were retrieved by a selective search in PubMed.

Results: The most common cause of ODS is hyponatremia; particular groups of patients, e.g., liver transplant recipients, are also at risk of developing ODS. The pathophysiology of ODS consists of cerebral apoptosis and loss of myelin due to osmotic stress. Accordingly, brain areas that are rich in oligodendrocytes and myelin tend to be the most frequently affected. Patients with ODS often have a biphasic course, the first phase reflecting the underlying predisposing illness and the second phase reflecting ODS itself, with pontine dysfunction, impaired vigilance, and movement disorders, among other neurological abnormalities. The diagnostic modality of choice is magnetic resonance imaging (MRI) of the brain, which can also be used to detect oligosymptomatic ODS. The current mainstay of management is prevention; treatment strategies for manifest ODS are still experimental. The prognosis has improved as a result of MRI-based diagnosis, but ODS can still be fatal (33% to 55% of patients either die or remain permanently dependent on nursing care).

Conclusion: ODS is a secondary neurological illness resulting from a foregoing primary disease. Though rare overall, it occurs with greater frequency in certain groups of patients. Clinicians of all specialties should therefore be familiar with the risk constellations, clinical presentation, and prevention of ODS. The treatment of ODS is still experimental at present, as no evidence-based treatment is yet available.
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http://dx.doi.org/10.3238/arztebl.2019.0600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804268PMC
September 2019

Correct Outcome Prognostication via Sonographic Volumetry in Supratentorial Intracerebral Hemorrhage.

Front Neurol 2019 8;10:492. Epub 2019 May 8.

Department of Neurology, Medical Center - University of Freiburg, Freiburg, Germany.

The intracerebral hemorrhage (ICH)-score is used for estimation of patients' prognosis. The hemorrhage volume calculated from computed tomography (CT) contributes as one main factor. Several studies have proven that dimensions of an ICH may be displayed sufficiently by transcranial sonography (TCS). Yet, the adequacy of ICH-volumetry via TCS in calculating the ICH-score and its use as prognostic tool has not been studied. Forty consecutive patients with supratentorial ICH diagnosed via CT were included in this prospective observational pilot study. 45 examination-series via CT and TCS were done in order to perform an ICH-volumetry and calculate the ICH-score. Volume was calculated using the ABC/2 estimation. Results of both imaging techniques were compared regarding quantification of ICH- volume and correct prognostication. A modified Rankin Scale (mRS)-score of 0-3 points was valued as good outcome. The imaging techniques did not show a difference in volumetry ( = 0.794) and TCS derived hemorrhage volume correlated significantly with ICH-volume measured on CT-scans. Calculated ICH-scores also did not differ ( = 0.323). Patients with an ICH-score larger than 2 points were predicted to experience a poor outcome at discharge with mRS 4-6 points, and the prognostication of the outcome was correct. Patients with a good outcome showed a smaller ICH-volume (11.2 ± 9.1ml) than patients with a poor outcome (38.2 ± 41.2 ml; = 0.002). Volumetry in supratentorial ICH via TCS is feasible and the prognostication with the ICH-score based on its results is comparable to CT-imaging and sufficient.
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http://dx.doi.org/10.3389/fneur.2019.00492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6517518PMC
May 2019

Meningitis Caused by after Professional Tooth Cleaning: First Case.

Case Rep Neurol 2019 Jan-Apr;11(1):1-3. Epub 2019 Jan 11.

Department of Neurology and Clinical Neurophysiology, Medical Center, University of Freiburg, Freiburg, Germany.

We report the first case of meningitis caused by (group B streptococcus; GBS) after professional tooth cleaning in a previously healthy patient. GBS is a common commensal of the human gastrointestinal and vaginal flora. Although occurrence in the oral flora is unusual, oral transmission and thus occurrence can be assumed.
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http://dx.doi.org/10.1159/000495747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6381919PMC
January 2019

Endovascular stroke treatment's impact on malignant type of edema (ESTIMATE).

J Neurol 2019 Jan 23;266(1):223-231. Epub 2018 Nov 23.

Department of Neurology, University Hospital Ulm, Oberer Eselsberg 45, 89081, Ulm, Germany.

Background And Purpose: In patients with acute ischemic stroke and large vessel occlusion, the prognosis has improved tremendously since the implementation of endovascular thrombectomy (EVT). The effect of EVT on the incidence of malignant middle cerebral artery infarctions (MMI) has not been studied before.

Methods: ESTIMATE, a multicenter retrospective study, evaluates data of ischemic stroke patients with occlusion in the anterior circulation in the years of 2007-2015 comparing three treatment options (no therapy; IV-TPA; IV-TPA plus EVT or EVT only). Primary endpoint of the study was the incidence of MMI on follow-up imaging and mortality rates. Secondary endpoints were functional outcome, further clinical and imaging data. Logistic and Cox-regression models with a propensity score weighting approach were applied to evaluate differences between treatment groups.

Results: In 2161 patients over 9 years, EVT reduced the MMI rates significantly: patients without acute stroke treatment had increased odds for MMI of 1.57 [95% confidence interval (CI) 1.49-1.65]. In contrast, after treatment with IV-TPA, only we observed an OR of 0.88 (95% CI 0.83-0.94, p < 0.001), and after EVT an OR of 0.80 (95% CI 0.76-0.85, p < 0.001). This was more pronounced in larger pretreatment infarctions (ASPECTS < 5, p < 0.01). IV-TPA also lowers the MMI rates but not to the same extent. EVT-treated patients had increased survival rates (p < 0.05) and the best functional outcome at discharge.

Conclusions: The findings of this study illustrate that occurrence of MMI and mortality rates was significantly reduced in patients treated with EVT.
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http://dx.doi.org/10.1007/s00415-018-9127-xDOI Listing
January 2019

Sonographic-Assisted Catheter-Positioning in Intracerebral Hemorrhage.

Front Neurol 2018 7;9:651. Epub 2018 Aug 7.

Department of Neurology, Medical Center-University of Freiburg, Freiburg, Germany.

Intracerebral structures and pathologies such as intracerebral hemorrhages (ICH) can be displayed sufficiently by transcranial sonography (TCS). In some patients with ICH clot evacuation via surgery or catheter drainage to reduce secondary parenchymal injuries may be necessary. We hypothesized that bedside-placement of drainage-catheters, which is a minimal invasive evacuation-technique complicated by a higher rate of catheter misplacement can be optimized via TCS. Eleven consecutive ICH-patients diagnosed via computertomography (CT) were included in this prospective observational pilot study. All patients were examined via TCS, firstly in order to illustrate the hematoma, secondly to optimize catheter placement. Catheter placement was primarily validated via CT. The TCS-depiction of ICH-extension was optimal in 10 patients; one patient showed a partially insufficient transtemporal bone window. Catheter positioning could be traced and adapted correctly via TCS-examination in all patients. Follow-up CT-scans confirmed TCS-description of catheter-positioning in all patients without any complications. Reduction of symptoms and ICH-volumes confirmed effectiveness of treatment. The illustration of ICH and the drainage-placement is possible via TCS in a cost- and time-efficient way.
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http://dx.doi.org/10.3389/fneur.2018.00651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6090040PMC
August 2018

Bedsided Transcranial Sonographic Monitoring for Expansion and Progression of Subdural Hematoma Compared to Computed Tomography.

Front Neurol 2018 28;9:374. Epub 2018 May 28.

Department of Neurology, University Medical Center, University of Freiburg, Freiburg, Germany.

Introduction: Transcranial high-resolution ultrasonography reliably allows diagnosis and monitoring of intracerebral hemorrhage in adults. Sonographic monitoring of subdural hematoma (SDH) has not been evaluated in adults so far. This study investigates the reliability of transcranial gray-scale sonography (TGS) in monitoring acute and chronic SDH in adults.

Methods: TGS was performed in 47 consecutive patients with either acute or chronic SDH confirmed by cerebral CT. Four patients were excluded due to insufficient bone window. After identification of SDH in TGS extent was measured and correlated with extent of SDH on cerebral computer tomography (CCT). If possible measurement was performed at least on 2 days to evaluate the possibility to monitor SDH with TGS.

Results: In 43 patients with SDH, 76 examinations were performed with 2 examinations in 23 patients and 3 examinations in 10 patients. Overall extent of SDH correlated significantly between TGS and CCT ( = 0.962). Accordingly correlation was high during each single examination time point. In patients in need for surgical evacuation sonographic measurement yielded a sensitivity of 90.9% and specificity of 93.8% in predicting surgical evacuation ( < 0.001).

Discussion: Imaging of SDH with TGS is possible in patients with SDH and extent of SDH correlates significantly between TGS and CCT during initial as well as during follow-up examination. Thus monitoring of SDH with TGS at patients' bedside is possible.
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http://dx.doi.org/10.3389/fneur.2018.00374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985297PMC
May 2018

Reversal of dabigatran using idarucizumab: single center experience in four acute stroke patients.

J Thromb Thrombolysis 2018 Jul;46(1):12-15

Department of Neurology and Clinical Neurophysiology, Medical Center, University of Freiburg, Breisacher Strasse 64, 79106, Freiburg, Germany.

Dabigatran is a direct thrombin inhibitor and a non-vitamin-K-antagonizing oral anticoagulant, approved for the prevention of stroke and systemic embolization in atrial fibrillation. Idarucizumab is a humanized monoclonal antibody that was recently approved for antagonizing the anticoagulant effects of dabigatran. Here, we report the use of idarucizumab in four acute stroke patients treated with dabigatran in order to enable intravenous thrombolysis in three patients and emergent trepanation in one patient with space occupying subdural hematoma. Since experience on the optimal management of acute stroke patients under medication with dabigatran and on the use of idarucizumab is currently limited, we propose an approach for laboratory testing and fast administration of intravenous thrombolysis and neurosurgery based on our experience.
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http://dx.doi.org/10.1007/s11239-018-1658-6DOI Listing
July 2018

Transcranial Sonography to Differentiate Primary Intracerebral Hemorrhage from Cerebral Infarction with Hemorrhagic Transformation.

J Neuroimaging 2018 07 25;28(4):370-373. Epub 2018 Mar 25.

Department of Neurology, University of Freiburg, Freiburg, Germany.

Background And Purpose: The differentiation of primary intracerebral hemorrhage (ICH) from parenchymal hemorrhagic transformation within an ischemic infarction (PHI) is crucial in order to adapt therapeutic measures. We hypothesized that a distinction of ICH and PHI can be made at bedside via transcranial gray-scale and perfusion sonography.

Methods: We prospectively included 14 patients with intracranial hemorrhage on admission imaging in this pilot study. Differentiation between ICH and PHI was made either by cerebral magnetic resonance imaging or follow-up computed tomography scan. All patients were examined via gray-scale and perfusion sonography.

Results: Eight patients were diagnosed with ICH, and 6 patients with PHI. Volumes of ICH did not differ between the two groups. However, PHI patients showed a significantly larger perfusion deficit compared to ICH patients (P < .01). At a cutoff value of 1.41 of the mismatch index of perfusion deficit and hyperechogenic lesion, the PHI diagnosis can be made with a 100%-sensitivity and 100%-specificity.

Conclusion: Differentiation of ICH and PHI via multimodal transcranial sonography with mismatch imaging is possible. Since sonographic imaging as a bedside-method is cost- as well as time-efficient, it may be a helpful tool for differentiation between these two entities particularly in critically ill patients with unclear ICH.
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http://dx.doi.org/10.1111/jon.12510DOI Listing
July 2018

Regional Differences in Thrombectomy Rates : Secondary use of Billing Codes in the MIRACUM (Medical Informatics for Research and Care in University Medicine) Consortium.

Clin Neuroradiol 2018 Jun 8;28(2):225-234. Epub 2018 Jan 8.

Department of Neuroradiology, Medical Center, University of Freiburg, Breisacher Str. 64, 79106, Freiburg, Germany.

Background And Purpose: Mechanical thrombectomy, in addition to intravenous (i.v.) thrombolysis is recommended for treatment of acute stroke in patients with large vessel occlusions (LVO) in the anterior circulation up to 6 h after symptom onset. We compared thrombectomy rates of eight university hospitals of the MIRACUM consortium to analyze the implementation of this guideline in clinical routine.

Methods: Anonymized billing data in a standardized format were loaded into a local i2b2 data warehouse by applying already existing extract, transform and load (ETL) routines. A locally executed uniform SQL (structured query language) query delivered aggregated site data for all inpatients with a discharge diagnosis of ischemic stroke (ICD-10 I63) containing counts for type of acute treatment, type of admission and age groups, which were centrally analyzed with R.

Results: From 2014 to 2016, the thrombectomy rate almost doubled from a mean of 4.7% to 9.6%, although significant differences between centers exist (range in 2016: 5.8-17%). The number of drip-and-ship procedures increased in 3 out of 8 centers. There was no evidence for a decrease in thrombectomy rates during weekends/holiday or among patients older than 80 years, but this age group is more likely to receive i.v. recombinant tissue plasminogen activator (rtPA).

Conclusion: The observed increase of thrombectomy rates and drip-and-ship procedures without a significant difference between weekdays and weekends or patients of different ages is substantiating a rapid implementation of stroke guidelines within the analyzed neurovascular centers. The prototype of the MIRACUM Data Integration Center already contributes to health services research in Germany.
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http://dx.doi.org/10.1007/s00062-017-0656-yDOI Listing
June 2018
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