Publications by authors named "Peter Ringleb"

196 Publications

Clinical Outcome After Endovascular Thrombectomy in 3 Triage Concepts: A Prospective, Observational Study (NEUROSQUAD).

Stroke 2021 Apr 29:STROKEAHA120030520. Epub 2021 Apr 29.

Neuroradiology, Heidelberg University Hospital, Germany. (F.S., M.A.M., C.H., M.B.).

Background And Purpose: NEUROSQUAD (Stroke Treatment: Quality and Efficacy in Different Referral Systems) is a prospective, observational, bicenter study comparing 3 triage pathways in endovascular stroke treatment: mothership, drip and ship (DS), and transferring a neurointerventionalist to a remote hospital for thrombectomy (drive the doctor [DD]).

Methods: Patients with anterior circulation stroke and premorbid modified Rankin Scale (mRS) score 0-3 who underwent thrombectomy within 24 hours after stroke onset were included. Primary outcome measure was good clinical outcome defined as 90-day mRS score 0-2 or clinical recovery to the status before stroke onset (ie, equal premorbid mRS and 90-day mRS). Secondary outcome measures were successful reperfusion, National Institutes of Health Stroke Scale at discharge, and mRS shift.

Results: In total, 360 patients were included in this study, of whom 111 patients (30.8%) were in the mothership group, 204 patients (56.7%) were in the DS group, and 45 patients (12.5%) were in the DD group. Good clinical outcome was achieved similarly in all three groups (mothership, 45.9%; DS, 43.1%; DD, 40.0%; =0.778). Likewise, frequency of successful reperfusion was similar in all three groups (mothership, 86.5%; DS, 85.3%; DD, 82.2%; =0.714). There was no significant difference among the groups regarding the National Institutes of Health Stroke Scale at discharge (=0.115) and mRS shift (=0.342). In the multivariate analysis, triage concept was not an independent predictor of good outcome (unadjusted odds ratio, 0.89 [CI, 0.64-1.23]; =0.479).

Conclusions: Our data suggest that clinical outcome after thrombectomy is similar in mothership, DS, and DD. Hence, DD can be a valuable triage option in acute stroke treatment.
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http://dx.doi.org/10.1161/STROKEAHA.120.030520DOI Listing
April 2021

Risk of Stroke before Revascularisation in Patients with Symptomatic Carotid Stenosis: A Pooled Analysis of Randomised Controlled Trials.

Eur J Vasc Endovasc Surg 2021 Apr 5. Epub 2021 Apr 5.

Department of Neurology and Stroke Centre, Department of Clinical Research, University Hospital, University of Basel, Basel, Switzerland; Stroke Research Centre, Department of Brain Repair and Rehabilitation, UCL Queen Square Institute of Neurology, University College London, London, UK. Electronic address:

Objective: Current guidelines recommending rapid revascularisation of symptomatic carotid stenosis are largely based on data from clinical trials performed at a time when best medical therapy was potentially less effective than today. The risk of stroke and its predictors among patients with symptomatic carotid stenosis awaiting revascularisation in recent randomised controlled trials (RCTs) and in medical arms of earlier RCTs was assessed.

Methods: The pooled data of individual patients with symptomatic carotid stenosis randomised to stenting (CAS) or endarterectomy (CEA) in four recent RCTs, and of patients randomised to medical therapy in three earlier RCTs comparing CEA vs. medical therapy, were compared. The primary outcome event was any stroke occurring between randomisation and treatment by CAS or CEA, or within 120 days after randomisation.

Results: A total of 4 754 patients from recent trials and 1 227 from earlier trials were included. In recent trials, patients were randomised a median of 18 (IQR 7, 50) days after the qualifying event (QE). Twenty-three suffered a stroke while waiting for revascularisation (cumulative 120 day risk 1.97%, 95% confidence interval [CI] 0.75 - 3.17). Shorter time from QE until randomisation increased stroke risk after randomisation (χ = 6.58, p = .011). Sixty-one patients had a stroke within 120 days of randomisation in the medical arms of earlier trials (cumulative risk 5%, 95% CI 3.8 - 6.2). Stroke risk was lower in recent than earlier trials when adjusted for time between QE and randomisation, age, severity of QE, and degree of carotid stenosis (HR 0.47, 95% CI 0.25 - 0.88, p = .019).

Conclusion: Patients with symptomatic carotid stenosis enrolled in recent large RCTs had a lower risk of stroke after randomisation than historical controls. The added benefit of carotid revascularisation to modern medical care needs to be revisited in future studies. Until then, adhering to current recommendations for early revascularisation of patients with symptomatic carotid stenosis considered to require invasive treatment is advisable.
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http://dx.doi.org/10.1016/j.ejvs.2021.02.024DOI Listing
April 2021

Trimethylamine-N-Oxide Levels Are Similar in Asymptomatic vs. Symptomatic Cerebrovascular Atherosclerosis.

Front Neurol 2021 19;12:617944. Epub 2021 Mar 19.

Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany.

Trimethylamine-N-oxide (TMAO) is correlated with atherosclerosis and vascular diseases such as coronary heart disease and ischemic stroke. The aim of the study was to investigate whether TMAO levels are different in symptomatic vs. asymptomatic cerebrovascular atherosclerosis. This was a prospective, case-control study, conducted at a tertiary care university hospital. Patients were included if they had large-artery atherosclerosis (TOAST criteria). Symptomatic patients with ischemic stroke were compared with asymptomatic patients. As primary endpoint, TMAO levels on admission were compared between symptomatic and asymptomatic patients. Univariable analysis was performed using Mann-Whitney test and multivariable analysis using binary logistic regression. TMAO values were adjusted for glomerular filtration rate (GFR), age, and smoking. Between 2018 and 2020, 82 symptomatic and asymptomatic patients were recruited. Median age was 70 years; 65% were male. Comparing symptomatic ( = 42) and asymptomatic ( = 40) patients, no significant differences were found in univariable analysis in TMAO [3.96 (IQR 2.30-6.73) vs. 5.36 (3.59-8.68) μmol/L; = 0.055], GFR [87 (72-97) vs. 82 (71-90) ml/min1.73 m; = 0.189] and age [71 (60-79) vs. 69 (67-75) years; = 0.756]. In multivariable analysis, TMAO was not a predictor of symptomatic cerebrovascular disease after adjusting for age and GFR [OR 1.003 (95% CI: 0.941-1.070); = 0.920]. In a sensitivity analysis, we only analyzed patients with symptomatic stenosis and excluded patients with occlusion of brain-supplying arteries. Again, TMAO was not a significant predictor of symptomatic stenosis [OR 1.039 (0.965-1.120), = 0.311]. TMAO levels could not be used to differentiate between symptomatic and asymptomatic cerebrovascular disease in our study.
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http://dx.doi.org/10.3389/fneur.2021.617944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017230PMC
March 2021

Global Impact of COVID-19 on Stroke Care and Intravenous Thrombolysis.

Neurology 2021 Mar 25. Epub 2021 Mar 25.

Department of Neurology, University of North Carolina at Chapel Hill, North Carolina, USA.

Objective: The objectives of this study were to measure the global impact of the pandemic on the volumes for intravenous thrombolysis (IVT), IVT transfers, and stroke hospitalizations over 4 months at the height of the pandemic (March 1 to June 30, 2020) compared with two control 4-month periods.

Methods: We conducted a cross-sectional, observational, retrospective study across 6 continents, 70 countries, and 457 stroke centers. Diagnoses were identified by their ICD-10 codes and/or classifications in stroke databases.

Results: There were 91,373 stroke admissions in the 4 months immediately before compared to 80,894 admissions during the pandemic months, representing an 11.5% (95%CI, -11.7 to - 11.3, p<0.0001) decline. There were 13,334 IVT therapies in the 4 months preceding compared to 11,570 procedures during the pandemic, representing a 13.2% (95%CI, -13.8 to -12.7, p<0.0001) drop. Interfacility IVT transfers decreased from 1,337 to 1,178, or an 11.9% decrease (95%CI, -13.7 to -10.3, p=0.001). Recovery of stroke hospitalization volume (9.5%, 95%CI 9.2-9.8, p<0.0001) was noted over the two later (May, June) versus the two earlier (March, April) pandemic months. There was a 1.48% stroke rate across 119,967 COVID-19 hospitalizations. SARS-CoV-2 infection was noted in 3.3% (1,722/52,026) of all stroke admissions.

Conclusions: The COVID-19 pandemic was associated with a global decline in the volume of stroke hospitalizations, IVT, and interfacility IVT transfers. Primary stroke centers and centers with higher COVID19 inpatient volumes experienced steeper declines. Recovery of stroke hospitalization was noted in the later pandemic months.
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http://dx.doi.org/10.1212/WNL.0000000000011885DOI Listing
March 2021

Dynamics of cerebral perfusion and oxygenation parameters following endovascular treatment of acute ischemic stroke.

J Neurointerv Surg 2021 Mar 24. Epub 2021 Mar 24.

Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Baden-Württemberg, Germany

Background: We studied the effects of endovascular treatment (EVT) and the impact of the extent of recanalization on cerebral perfusion and oxygenation parameters in patients with acute ischemic stroke (AIS) and large vessel occlusion (LVO).

Methods: Forty-seven patients with anterior LVO underwent computed tomography perfusion (CTP) before and immediately after EVT. The entire ischemic region (T >6 s) was segmented before intervention, and tissue perfusion (time-to-maximum (T), time-to-peak (TTP), mean transit time (MTT), cerebral blood volume (CBV), cerebral blood flow (CBF)) and oxygenation (coefficientof variation (COV), capillary transit time heterogeneity (CTH), metabolic rate of oxygen (CMRO), oxygen extraction fraction (OEF)) parameters were quantified from the segmented area at baseline and the corresponding area immediately after intervention, as well as within the ischemic core and penumbra. The impact of the extent of recanalization (modified Treatment in Cerebral Infarction (mTICI)) on CTP parameters was assessed with the Wilcoxon test and Pearson's correlation coefficients.

Results: The T, MTT, OEF and CTH values immediately after EVT were lower in patients with complete (as compared with incomplete) recanalization, whereas CBF and COV values were higher (P<0.05) and no differences were found in other parameters. The ischemic penumbra immediately after EVT was lower in patients with complete recanalization as compared with those with incomplete recanalization (P=0.002), whereas no difference was found for the ischemic core (P=0.12). Specifically, higher mTICI scores were associated with a greater reduction of ischemic penumbra volumes (R²=-0.48 (95% CI -0.67 to -0.22), P=0.001) but not of ischemic core volumes (P=0.098).

Conclusions: Our study demonstrates that the ischemic penumbra is the key target of successful EVT in patients with AIS and largely determines its efficacy on a tissue level. Furthermore, we confirm the validity of the mTICI score as a surrogate parameter of interventional success on a tissue perfusion level.
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http://dx.doi.org/10.1136/neurintsurg-2020-017163DOI Listing
March 2021

Predictors for Failure of Early Neurological Improvement After Successful Thrombectomy in the Anterior Circulation.

Stroke 2021 Apr 25;52(4):1291-1298. Epub 2021 Feb 25.

Department of Neurology (Y.M., S.S., P.A.R.), Heidelberg University Hospital, Germany.

Background And Purpose: Failure of early neurological improvement (fENI) despite successful mechanical thrombectomy in the anterior circulation is a clinically frequent occurrence. Purpose of this analysis was to define independent clinical, radiological, laboratory, or procedural predictors for fENI.

Methods: Retrospective single-center analysis of patients treated for acute ischemic stroke in the anterior circulation ensuing successful mechanical thrombectomy between January 2014 and April 2019. Patients were compared according to fENI (equal or higher National Institutes of Health Stroke Scale) and ENI (lower National Institutes of Health Stroke Scale at discharge). Thirty-eight variables were examined in multivariable analysis for association with fENI.

Results: Five hundred forty-nine out of 1146 patients experienced successful recanalization (modified Treatment in Cerebral Ischemia 2c-3). fENI occurred in 115/549 (20.9%) patients. Independent predictors of fENI were premorbid modified Rankin Scale (odds ratio [OR] per point [IC], 1.21 [1.00-1.46], =0.049), end-stage renal failure (OR [IC], 12.18 [2.01-73.63], =0.007), admission glucose (OR [IC], 1.018 [1.004-1.013] per mg/dL, =0.001), bridging IV lysis (OR [IC], 0.57 [0.35-0.93], : 0.024), time from groin puncture to final recanalization (OR [IC], 1.004 [1.001-1.007] per minute, =0.015), general anesthesia during mechanical thrombectomy (OR, 2.41 [1.43-4.08], <0.001), symptomatic intracranial hemorrhage (OR [CI], 6.81 [1.84-25.16], =0.004), and follow-up Alberta Stroke Program Early CT Score (OR [IC], 0.76 [0.69-0.84] per point, <0.001). In a secondary analysis, involvement of the regions internal capsule, M4 and M5 (motor cortex) were further independent predictors for fENI. Patients with ENI were more likely to experience a good outcome (modified Rankin Scale on day 90, 0-2: n=229/435 [52.8%] versus n=13/115 [11.3%]; <0.001).

Conclusions: The extent of infarction and the involvement of motor cortex and internal capsule as well as higher premorbid modified Rankin Scale, end-stage renal failure, high glucose level on admission, absence of bridging IV lysis, general anesthesia, and a longer therapy interval are presumably independent predictors for fENI in patients with successful mechanical thrombectomy.
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http://dx.doi.org/10.1161/STROKEAHA.120.030519DOI Listing
April 2021

The impact of the DWI-FLAIR-mismatch in the ECASS-4 trial - A post hoc analysis.

Eur Stroke J 2020 Dec 23;5(4):370-373. Epub 2020 Apr 23.

Heidelberg University Hospital, Department of Neurology, Heidelberg, Germany.

Introduction: To investigate the impact of a mismatch between diffusion-weighted imaging (DWI) and fluid attenuated inversion recovery (FLAIR) on functional outcome in patients with acute stroke in a prolonged time window or unknown time of symptom onset randomized to intravenous thrombolysis or placebo.

Patients And Methods: We performed a post-hoc analysis of the European Cooperative Acute Stroke Study-4 (ECASS-4) trial. ECASS-4 was an investigator driven, phase 3, multi-center, double-blind, placebo-controlled study which randomized ischemic stroke patients presenting within 4.5 and 9h of stroke onset or unknown time-window to either rt-PA or placebo after MR-imaging. Two subgroups "no mismatch" (nMM) and "any mismatch" (aMM) were created by applying a DWI-FLAIR-mismatch criterion. We calculated frequency of nMM and aMM and performed a univariate analysis (Fisher's Test) for excellent clinical outcome (mRS 0-1) and mortality (mRS=6).

Results: MR-Imaging of n=111/119 (93.2%) patients was suitable for this analysis. DWI-FLAIR mismatch was found in 49 patients (44.1%). Proportions of mismatch nMM and aMM were comparable in treatment-groups (aMM: Placebo 46.3%, Alteplase 42.1%; p=0.70). Patients with nMM showed no benefit of rt-PA-treatment (OR (95%CI) mRS 0-1: 0.95 (0.29-3.17)). Patients with aMM showed a point estimate of the odds ratio in favour of a treatment benefit of rt-PA (mRS 0-1: OR (95%CI) 2.62 (0.68-11.1)). Mortality within 90 days was not different in patients treated with rt-PA if nMM (15.2%) or aMM (12.5%) was present.

Discussion: In this analysis no significant evidence, but subtle indication towards patients treated with rt-PA in a prolonged time window reaching an excellent clinical outcome if a DWI-FLAIR-mismatch is present on initial stroke MR-imaging.

Conclusion: A DWI-FLAIR mismatch in the region of ischemia as imaging based surrogate parameter for patient selection for i.v. rt-PA should be strongly pursued.
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http://dx.doi.org/10.1177/2396987320920114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856579PMC
December 2020

Absence of Consistent Sex Differences in Outcomes From Symptomatic Carotid Endarterectomy and Stenting Randomized Trials.

Stroke 2021 Jan 25;52(2):416-423. Epub 2021 Jan 25.

Department of Neurology, Mayo Clinic, Jacksonville, FL (T.G.B.).

Background And Purpose: CREST (Carotid Revascularization Endarterectomy Versus Stenting Trial) reported a higher periprocedural risk for any stroke, death, or myocardial infarction for women randomized to carotid artery stenting (CAS) compared with women randomized to carotid endarterectomy (CEA). No difference in risk by treatment was detected for women relative to men in the 4-year primary outcome. We aimed to conduct a pooled analysis among symptomatic patients in large randomized trials to provide more precise estimates of sex differences in the CAS-to-CEA risk for any stroke or death during the 120-day periprocedural period and ipsilateral stroke thereafter.

Methods: Data from the Carotid Stenosis Trialists' Collaboration included outcomes from symptomatic patients in EVA-3S (Endarterectomy Versus Angioplasty in Patients With Symptomatic Severe Carotid Stenosis), SPACE (Stent-Protected Angioplasty Versus Carotid Endarterectomy in Symptomatic Patients), ICSS (International Carotid Stenting Study), and CREST. The primary outcome was any stroke or death within 120 days after randomization and ipsilateral stroke thereafter. Event rates and relative risks were estimated using Poisson regression; effect modification by sex was assessed with a sex-by-treatment-by-trial interaction term, with significant interaction defined a priori as ≤0.10.

Results: Over a median 2.7 years of follow-up, 433 outcomes occurred in 3317 men and 1437 women. The CAS-to-CEA relative risk of the primary outcome was significantly lower for women compared with men in 1 trial, nominally lower in another, and nominally higher in the other two. The sex-by-treatment-by-trial interaction term was significant (=0.065), indicating heterogeneity among trials. Contributors to this heterogeneity are primarily differences in periprocedural period. When the trials are nevertheless pooled, there were no significant sex differences in risk in any follow-up period.

Conclusions: There were significant differences between trials in the magnitude of sex differences in treatment effect (CAS-to-CEA relative risk), indicating pooling data from these trials to estimate sex differences might not be valid. Whether sex is acting as an effect modifier of the CAS-to-CEA treatment effect in symptomatic patients remains uncertain. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00190398 (EVA-3S) and NCT00004732 (CREST). URL: https://www.isrctn.com; Unique identifier: ISRCTN57874028 (SPACE) and ISRCTN25337470 (ICSS).
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http://dx.doi.org/10.1161/STROKEAHA.120.030184DOI Listing
January 2021

Optimal thresholds to predict long-term outcome after complete endovascular recanalization in acute anterior ischemic stroke.

J Neurointerv Surg 2021 Jan 21. Epub 2021 Jan 21.

Department of Neuroradiology, University Hospital Heidelberg, Heidelberg, Baden-Württemberg, Germany.

Background: Despite complete endovascular recanalization, a significant percentage of patients with acute anterior stroke do not achieve a good clinical outcome. We analyzed optimal thresholds of relevant parameters to discern functional independence after successful endovascular recanalization and test their predictive performance.

Methods: Patients with acute anterior ischemic stroke undergoing endovascular treatment between April 2015 and November 2019 were retrospectively analyzed. Only patients with premorbid modified Rankin Scale (mRS) score <3 and complete recanalization (modified Thrombolysis In Cerebral Infarction 2c/3) were included. Optimal thresholds of the most important variables predicting functional independence (mRS 0-2 after 90 days) were calculated using receiver operating characteristic curves and their predictive performance was tested in an independent dataset using machine learning algorithms.

Results: Overall, 371 patients met the inclusion criteria. Optimal thresholds for the overall most important variables to predict functional independence were (1) National Institutes of Health Stroke Scale (NIHSS) score ≤5 after 24 hours (area under the curve (AUC) 0.88 (95% CI 0.84 to 0.92)); (2) Alberta Stroke Program Early CT Score (ASPECTS) ≥7 on follow-up CT (AUC 0.72 (95% CI 0.68 to 0.77)); and (3) change in NIHSS score ≥8 after 24 hours (AUC 0.70 (95% CI 0.65 to 0.74)). The performance of these thresholds to predict a good outcome using machine learning in the independent dataset was evaluated for (1) NIHSS score ≤5 after 24 hours (AUC 0.76 (95% CI 0.71 to 0.81)); (2) follow-up ASPECTS ≥7 (AUC 0.64 (95% CI 0.58 to 0.70)); (3) change in NIHSS score ≥8 after 24 hours (AUC 0.61 (95% CI 0.55 to 0.67)); and (4) the combination of all three parameters (AUC 0.84 (95% CI 0.80 to 0.88)).

Conclusions: After complete recanalization in acute anterior circulation ischemic stroke, a good long-term outcome could be accurately predicted reaching NIHSS score ≤5 after 24 hours.
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http://dx.doi.org/10.1136/neurintsurg-2020-016997DOI Listing
January 2021

Combined Perfusion and Permeability Imaging Reveals Different Pathophysiologic Tissue Responses After Successful Thrombectomy.

Transl Stroke Res 2021 Jan 11. Epub 2021 Jan 11.

Department of Neuroradiology, Heidelberg University Hospital, INF 400, 69120, Heidelberg, Germany.

Despite successful recanalization of large-vessel occlusions in acute ischemic stroke, individual patients profit to a varying degree. Dynamic susceptibility-weighted perfusion and dynamic T1-weighted contrast-enhanced blood-brain barrier permeability imaging may help to determine secondary stroke injury and predict clinical outcome. We prospectively performed perfusion and permeability imaging in 38 patients within 24 h after successful mechanical thrombectomy of an occlusion of the middle cerebral artery M1 segment. Perfusion alterations were evaluated on cerebral blood flow maps, blood-brain barrier disruption (BBBD) visually and quantitatively on k maps and hemorrhagic transformation on susceptibility-weighted images. Visual BBBD within the DWI lesion corresponded to a median k elevation (IQR) of 0.77 (0.41-1.4) min and was found in all 7 cases of hypoperfusion (100%), in 10 of 16 cases of hyperperfusion (63%), and in only three of 13 cases with unaffected perfusion (23%). BBBD was significantly associated with hemorrhagic transformation (p < 0.001). While BBBD alone was not a predictor of clinical outcome at 3 months (positive predictive value (PPV) = 0.8 [0.56-0.94]), hypoperfusion occurred more often in patients with unfavorable clinical outcome (PPV = 0.43 [0.10-0.82]) compared to hyperperfusion (PPV = 0.93 [0.68-1.0]) or unaffected perfusion (PPV = 1.0 [0.75-1.0]). We show that combined perfusion and permeability imaging reveals distinct infarct signatures after recanalization, indicating the severity of prior ischemic damage. It assists in predicting clinical outcome and may identify patients at risk of stroke progression.
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http://dx.doi.org/10.1007/s12975-020-00885-yDOI Listing
January 2021

Differential effects of the SARS-CoV-2 pandemic on patients presenting to a neurological emergency room depending on their triage score in an area with low COVID-19 incidence.

Eur J Neurol 2020 Dec 29. Epub 2020 Dec 29.

Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany.

Background: We analyzed the effects of the SARS-CoV-2 pandemic on neurologic emergencies, depending on the patients' triage score in a setting with relatively few COVID-19 cases and without lack of resources.

Methods: Consecutive patients of a tertiary care center with a dedicated neurologic emergency room (nER) were analyzed. The time period of the first lockdown in Germany (calendar weeks 12-17, 2020) was retrospectively compared to the corresponding period in 2019 regarding the number of patients presenting to the nER, the number of patients with specific triage scores (Heidelberg Neurological Triage Score), the number of patients with stroke, and the quality of stroke care.

Results: A total of 4330 patients were included. Fewer patients presented themselves in 2020 compared to 2019 (median [interquartile range] per week: 134 [118-143] vs. 187 [182-192]; p = 0.015). The median numbers of patients per week with triage 1 (emergent) and 4 (non-urgent) were comparable (51 [43-58] vs. 59 [54-62]; p = 0.132, and 10 [4-16] vs. 16 [7-18]; p = 0.310, respectively).The median number of patients per week declined in categories 2 and 3 in 2020 (41 [37-45] vs. 57 [52-61]; p = 0.004, and 28 [23-35] vs. 61 [52-63]; p = 0.002, respectively. No change was observed in the absolute number of strokes (138 in 2019 and 141 in 2020). Quality metrics of stroke revascularization therapies (symptom-to-door time, door-to-needle time or relative number of therapies) and stroke severity remained constant.

Conclusion: During the lockdown period in 2020, the number of patients with emergent symptoms remained constant, while fewer patients with urgent symptoms presented to the nER. This may imply behavioral changes in care-seeking behavior.
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http://dx.doi.org/10.1111/ene.14709DOI Listing
December 2020

Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data.

Lancet 2020 11 8;396(10262):1574-1584. Epub 2020 Nov 8.

Department of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany.

Background: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers.

Methods: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0-1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0-2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4-6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903.

Findings: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10-2·03]; p=0·011), with low heterogeneity across studies (I=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05-1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06-2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4-6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52-1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03-4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [<1%], adjusted OR 5·58 [1·22-25·50]; p=0·024).

Interpretation: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death.

Funding: None.
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http://dx.doi.org/10.1016/S0140-6736(20)32163-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734592PMC
November 2020

Patient profiles contribute to differences in quality metrics of stroke centers.

Neurosciences (Riyadh) 2020 Aug;25(4):292-300

Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany.

Objective: To examine this association by comparing patient profiles in 2 closely affiliated hospitals and by examining their association with quality metrics.

Methods: We performed a retrospective cohort study comparing a university level comprehensive stroke centers (CSC) with its teaching hospital and local stroke unit (LSU) using routinely collected quality assurance data over a 2 year period. Both hospitals were closely affiliated, shared important resources and medical staff rotated amongst both hospitals. We compared patient profiles as well as internationally recognized quality metrics and examined the association of profiles with quality metrics.

Results: A total of 2,462 patients were treated in the CSC and 726 in the LSU. The LSU had a longer door-to-image and door-to-needle times. Rate of systemic thrombolysis was lower in the LSU. Patient profiles differed significantly and were associated with door-to-image and door-to-needle times as well as intravenous thrombolysis rates, even when adjusted for stroke service level. The diagnostic procedures for stroke work-up were similar. Discharge management differed strongly.

Conclusion: Although LSUs and CSCs are the primary care providers in their respective regions, differences in patient profiles may contribute to differences in performance parameters. Adjusting for patient profiles may improve the comparability of the quality of stroke care provided by hospitals belonging to different stroke service levels.
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http://dx.doi.org/10.17712/nsj.2020.4.20190100DOI Listing
August 2020

Only a Minority of Thrombectomy Candidates Are Admitted During Night Shift: A Rationale for Diurnal Stroke Care Planning.

Front Neurol 2020 30;11:573381. Epub 2020 Sep 30.

Department of Neurology, Heidelberg University, Heidelberg, Germany.

Widespread quick access to mechanical thrombectomy (MT) for acute ischemic stroke (AIS) is one of the main challenges in stroke care. It is unclear if newly established MT units are required 24 h/7 d. We explored the diurnal admission rate of patients with AIS potentially eligible for MT to provide a basis for discussion of daytime-adapted stroke care concepts. Data collected from the Baden-Württemberg Stroke Registry in Germany were assessed (2008-2012). We analyzed the admission rate of patients with AIS stratified by the National Institutes of Health Stroke Scale (NIHSS) score at admission in 3-h intervals. An NIHSS score ≥10 was considered a predictor of large vessel occlusion. The average annual admission number of patients with severe AIS were stratified by stroke service level and calculated for a three-shift model and working/non-working hours. Of 91,864, 22,527 (21%) presented with an NIHSS score ≥10. The average admission rates per year for a hospital without Stroke Unit (SU), with a local SU, with a regional SU and a stroke center were 8, 52, 90 and 178, respectively. Approximately 61% were admitted during working hours, 54% in the early shift, 36% in the late shift and 10% in the night shift. A two-shift model, excluding the night shift, would cover 90% of the patients with severe AIS. A model with coverage during working hours would miss ~40% of the patients with severe AIS. To achieve a quick and area-wide MT, it seems preferable for newly implemented MT-units to offer MT in a two-shift model at a minimum.
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http://dx.doi.org/10.3389/fneur.2020.573381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555607PMC
September 2020

Safety of Mechanical Thrombectomy with Combined Intravenous Thrombolysis in Stroke Treatment 4.5 to 9 Hours from Symptom Onset.

J Stroke Cerebrovasc Dis 2020 Nov 13;29(11):105204. Epub 2020 Aug 13.

Department of Neurology, University Hospital Heidelberg, Im Neuenheimer Feld 400, D-69120 Heidelberg, Germany. Electronic address:

Background: An extended time window for intravenous thrombolysis (IVT) for acute stroke patients up to 9 hours from symptom onset has been established in recent trials, excluding patients who received mechanical thrombectomy (MT). We therefore investigated whether combined therapy with IVT and MT (IVT+MT) is safe in patients with ischemic stroke and large vessel occlusion (LVO) in an extended time window.

Methods: We retrospectively analyzed patients with anterior circulation ischemic stroke and LVO who were treated within 4.5 to 9 hours after symptom onset using MT with or without IVT. Primary endpoint was the occurrence of any intracranial hemorrhage (ICH). Multivariable logistic regression was used to adjust for potential confounders.

Results: In total, 168 patients were included in the study, 44 (26%) were treated with IVT+ MT. 133 (79%) patients had a M1-/distal carotid artery occlusion. Median ASPECT-Score was 8 (IQR 7-10) and complete reperfusion (mTICI 2b-3) was achieved in 132 (79%) patients. 18 (41%) of the patients in the IVT+MT group developed any ICH vs. 45 (36%) patients in the direct MT group (p=0.587). Symptomatic ICH occurred in 5 (11%) patients with IVT+MT vs. 8 (6%) patients receiving direct MT (p=0.295). In multivariable analysis, IVT+MT was not an independent predictor of ICH (adjusted for NIHSS, degree of reperfusion, symptom-onset-to-treatment time and therapy with tirofiban; OR 0.95 [95% CI 0.43-2.08], p=0.896).

Conclusion: Mechanical thrombectomy in stroke patients seems to be safe with combined intravenous thrombolysis within 4.5 to 9 hours after onset as it did not significantly increase the risk for intracranial hemorrhage.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.105204DOI Listing
November 2020

Multimodal Predictive Modeling of Endovascular Treatment Outcome for Acute Ischemic Stroke Using Machine-Learning.

Stroke 2020 12 12;51(12):3541-3551. Epub 2020 Oct 12.

Department of Neuroradiology (G.B., U.N., M.A.M., M.F., Ch.H., S.H., C.U., M.B., M.A.M., J.A.R.P., P.V.), Heidelberg University Hospital, Germany.

Background And Purpose: This study assessed the predictive performance and relative importance of clinical, multimodal imaging, and angiographic characteristics for predicting the clinical outcome of endovascular treatment for acute ischemic stroke.

Methods: A consecutive series of 246 patients with acute ischemic stroke and large vessel occlusion in the anterior circulation who underwent endovascular treatment between April 2014 and January 2018 was analyzed. Clinical, conventional imaging (electronic Alberta Stroke Program Early CT Score, acute ischemic volume, site of vessel occlusion, and collateral score), and advanced imaging characteristics (CT-perfusion with quantification of ischemic penumbra and infarct core volumes) before treatment as well as angiographic (interval groin puncture-recanalization, modified Thrombolysis in Cerebral Infarction score) and postinterventional clinical (National Institutes of Health Stroke Scale score after 24 hours) and imaging characteristics (electronic Alberta Stroke Program Early CT Score, final infarction volume after 18-36 hours) were assessed. The modified Rankin Scale (mRS) score at 90 days (mRS-90) was used to measure patient outcome (favorable outcome: mRS-90 ≤2 versus unfavorable outcome: mRS-90 >2). Machine-learning with gradient boosting classifiers was used to assess the performance and relative importance of the extracted characteristics for predicting mRS-90.

Results: Baseline clinical and conventional imaging characteristics predicted mRS-90 with an area under the receiver operating characteristics curve of 0.740 (95% CI, 0.733-0.747) and an accuracy of 0.711 (95% CI, 0.705-0.717). Advanced imaging with CT-perfusion did not improved the predictive performance (area under the receiver operating characteristics curve, 0.747 [95% CI, 0.740-0.755]; accuracy, 0.720 [95% CI, 0.714-0.727]; =0.150). Further inclusion of angiographic and postinterventional characteristics significantly improved the predictive performance (area under the receiver operating characteristics curve, 0.856 [95% CI, 0.850-0.861]; accuracy, 0.804 [95% CI, 0.799-0.810]; <0.001). The most important parameters for predicting mRS 90 were National Institutes of Health Stroke Scale score after 24 hours (importance =100%), premorbid mRS score (importance =44%) and final infarction volume on postinterventional CT after 18 to 36 hours (importance =32%).

Conclusions: Integrative assessment of clinical, multimodal imaging, and angiographic characteristics with machine-learning allowed to accurately predict the clinical outcome following endovascular treatment for acute ischemic stroke. Thereby, premorbid mRS was the most important clinical predictor for mRS-90, and the final infarction volume was the most important imaging predictor, while the extent of hemodynamic impairment on CT-perfusion before treatment had limited importance.
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http://dx.doi.org/10.1161/STROKEAHA.120.030287DOI Listing
December 2020

Etiology of Ischemic Strokes of Patients with Atrial Fibrillation and Therapy with Anticoagulants.

J Clin Med 2020 Sep 11;9(9). Epub 2020 Sep 11.

Department of Neurology, Heidelberg University Hospital, 69120 Heidelberg, Germany.

Background: Reducing the number of ischemic strokes in patients with atrial fibrillation despite oral anticoagulation remains an important, yet largely unsolved challenge. Therefore, we assessed the etiology of ischemic strokes despite anticoagulation with vitamin K antagonists (VKA) or non-VKA oral anticoagulants (NOACs).

Methods: Patients with known atrial fibrillation (AF), treatment with VKA or NOAC, and acute ischemic stroke admitted between 2015 and 2018 (1st half) were identified from the hospital database. Brain imaging data were independently reviewed. An integrated etiologic classification according to the ASCOD system was made. Medication errors (admission INR <2.0 in the VKA- or NOAC-specific concentration <10 ng/mL) or dosage/dosing errors were also analyzed.

Results: Of 3610 patients screened, = 341 were included (VKA, = 127; NOAC, = 214). An overall increasing rate of OAC-associated stroke per year was observed. In 95.3% of patients with adequate diagnostic work-up ( = 321/337), at least one additional potential, uncertain, or unlikely non-cardiac cause of stroke was identified. More patients in the VKA than in the NOAC group had a medication error (81/127, 63.8% vs. 102/205, 49.8%; = 0.013).

Conclusions: Stroke risk factors despite atrial fibrillation were highly prevalent. Although less common with NOACs than VKAs, medication errors are still frequent.
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http://dx.doi.org/10.3390/jcm9092938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564370PMC
September 2020

Safety and early outcomes after intravenous thrombolysis in acute ischemic stroke patients with prestroke disability.

Int J Stroke 2020 Sep 2:1747493020954605. Epub 2020 Sep 2.

Department of Clinical Neurosciences, Karolinska Institutet, Stockholm, Sweden.

Background: There are limited data on intravenous thrombolysis treatment in ischemic stroke patients with prestroke disability.

Aim: We aimed to evaluate safety and outcomes of intravenous thrombolysis treatment in stroke patients with prestroke disability.

Methods: We analyzed 88,094 patients treated with intravenous thrombolysis, recorded in the Safe Implementation of Treatments in Stroke (SITS) International Thrombolysis Register between January 2003 and December 2017, with available NIHSS data at stroke-onset and after 24 h. Of them, 4566 patients (5.2%) had prestroke disability, defined as a modified Rankin Scale score of 3-5. Safety outcome measures included Symptomatic Intracerebral Hemorrhage, any type of parenchymal hematoma on 24 h imaging scans irrespective of clinical symptoms, and death within seven days. Early outcome measures were 24-h NIHSS improvement (≥4 from baseline to 24 h).

Results: Patients with prestroke disability were older, had more severe strokes, and more comorbidities than patients without prestroke disability. When comparing patients with prestroke disability with patients without prestroke disability, there was however no significant increase in adjusted odds for symptomatic intracerebral hemorrhage (adjusted odds ratio 0.83 (95% CI 0.60-1.15) (absolute difference in proportion 1.17% vs. 1.27%)) or for parenchymal hemorrhage (adjusted odds ratio 0.96 (0.83-1.11) (7.51% vs. 6.34%)). The prestroke disability group had a significantly lower-adjusted odds ratio for a 24-h NIHSS improvement (adjusted odds ratio 0.79 (0.73-0.85) (45.95% vs. 48.45%)) and a higher adjusted odds ratio for seven-day mortality (aOR 1.40 (1.21-1.61) (10.40% vs. 4.93%)).

Conclusions: Intravenous thrombolysis in acute ischemic stroke patients with prestroke disability was not associated with an increased risk of symptomatic intracerebral hemorrhage or parenchymal hemorrhage. Prestroke disability was however associated with a higher risk of early mortality compared to patients without prestroke disability.
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http://dx.doi.org/10.1177/1747493020954605DOI Listing
September 2020

Direct Transfer to Angio-Suite Versus Computed Tomography-Transit in Patients Receiving Mechanical Thrombectomy: A Randomized Trial.

Stroke 2020 09 10;51(9):2630-2638. Epub 2020 Aug 10.

Department of Neuroradiology (J.A.R.P., C.H., C.U., M.B., M.A.M.), Heidelberg University Hospital, Germany.

Background And Purpose: To quantify workflow metrics in patients receiving stroke imaging (noncontrast-enhanced computed tomography [CT] and CT-angiography) in either a computed-tomography scanner suite (CT-Transit [CTT]) or an angio-suite (direct transfer to angio-suite-[DTAS]-using flat-panel CT) before undergoing mechanical thrombectomy.

Methods: Prospective, single-center investigator initiated randomized controlled trial in a comprehensive stroke center focusing on time from imaging to groin puncture (primary end point) and time from hospital admission to final angiographic result (secondary end point) in patients receiving mechanical thrombectomy for anterior circulation large vessel occlusion after randomization to the CTT or DTAS pathway.

Results: The trial was stopped early after the enrollment of n=60 patients (CTT: n=34/60 [56.7 %]; DTAS: n=26/60 [43.3%]) of n=110 planned patients because of a preplanned interim analysis. Time from imaging to groin puncture was shorter in DTAS-patients (in minutes, median [interquartile range]: CTT: 26 [23-32]; DTAS: 19 [15-23]; value: 0.001). Time from hospital admission to stroke imaging was shorter in patients randomized to DTAS (CTT: 12 (7-18); DTAS: 21 (15-25), value: 0.007). Time from hospital admission to final angiographic reperfusion was comparable between patient groups (CTT: 78 [58-92], DTAS: 80 [66-118]; value: 0.067).

Conclusions: This trial showed a reduction in time from imaging to groin-puncture when patients are transferred directly to the angiosuite for advanced stroke-imaging compared with imaging in a CT scanner suite. This time saving was outweighed by a longer admission to imaging time and could not translate into a shorter time to final angiographic reperfusion in this trial.
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http://dx.doi.org/10.1161/STROKEAHA.120.029905DOI Listing
September 2020

Predictors of posttraumatic stress following transient ischemic attack: An observational cohort study.

J Psychosom Res 2020 Jul 29;137:110205. Epub 2020 Jul 29.

Department of Neurology, University of Heidelberg, Germany.

Objective: Transient ischemic attack (TIA) has been reported to be frequently followed by symptoms of post-TIA posttraumatic stress disorder (post-TIA PTSD). Risk factors for post-TIA PTSD remain largely unknown. We aimed to identify predictors of post-TIA PTSD development to enable post-TIA PTSD risk assessment and inform future development of treatment and prevention interventions.

Method: TIA patients were examined twice for this observational cohort study. Symptoms of post-TIA PTSD, depression and anxiety were assessed shortly after TIA during in-hospital stay (T) and three months after TIA (T). The impact of known general PTSD risk factors (psychiatric history, peritraumatic dissociation, social support), psychological resilience factors (sense of coherence, mindfulness, attachment style) and TIA characteristics (affected circulatory territory, symptom type and duration) at T on post-TIA PTSD symptom severity at T was tested using hierarchical multiple linear regression.

Results: Sixty-one patients (83.6%) completed the study at T. Fifteen patients (24.6%) were classified as post-TIA PTSD⊕ at T. In multiple linear regression analysis, age, sex, psychiatric history, peritraumatic dissociation and social support together explained 39.9% of variance of post-TIA posttraumatic stress symptom severity. Sense of coherence and mindfulness explained further 17.8% of variance. Clinical TIA characteristics were not associated with post-TIA PTSD.

Conclusions: Post-TIA PTSD is a common phenomenon. General PTSD risk factors can be applied for post-TIA PTSD risk assessment. Sense of coherence and mindfulness are promising target variables for post-TIA PTSD treatment and prevention interventions.
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http://dx.doi.org/10.1016/j.jpsychores.2020.110205DOI Listing
July 2020

Radiation exposure in endovascular stroke treatment of acute basilar artery occlusions-a matched-pair analysis.

Neuroradiology 2020 Dec 10;62(12):1701-1707. Epub 2020 Jul 10.

Department of Neuroradiology, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.

Purpose: To determine the radiation exposure in endovascular stroke treatment (EST) of acute basilar artery occlusions (BAO) and compare it with radiation exposure of EST for embolic middle cerebral artery occlusions (MCAO).

Methods: In this retrospective analysis of an institutional review board-approved prospective stroke database of a comprehensive stroke center, we focused on radiation exposure (as per dose area product in Gy × cm, median (IQR)), procedure time, and fluoroscopy time (in minutes, median [IQR]) in patients receiving EST for BAO. Patients who received EST for BAO were matched case by case with patients who received EST for MCAO according to number of thrombectomy attempts, target vessel reperfusion result, and thrombectomy technique.

Results: Overall 180 patients (n = 90 in each group) were included in this analysis. General anesthesia was conducted more often during EST of BAO (BAO: 75 (83.3%); MCAO: 18 (31.1%), p < 0.001). Procedure time (BAO: 31 (20-43); MCAO: 27 (18-38); p value 0.226) and fluoroscopy time (BAO: 29 (20-59); MCAO: 29 (17-49), p value 0.317) were comparable. Radiation exposure was significantly higher in patients receiving EST for BAO (BAO: 123.4 (78.7-204.2); MCAO: 94.3 (65.5-163.7), p value 0.046), which represents an increase by 23.7%.

Conclusion: Endovascular stroke treatment of basilar artery occlusions is associated with a higher radiation exposure compared with treatment of middle cerebral artery occlusions.
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http://dx.doi.org/10.1007/s00234-020-02490-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666669PMC
December 2020

Effect of haemoglobin levels on outcome in intravenous thrombolysis-treated stroke patients.

Eur Stroke J 2020 Jun 13;5(2):138-147. Epub 2019 Nov 13.

Stroke Center and Department of Neurology, University Hospital Basel and University of Basel, Basel, Switzerland.

Introduction: Alterations in haemoglobin levels are frequent in stroke patients. The prognostic meaning of anaemia and polyglobulia on outcomes in patients treated with intravenous thrombolysis is ambiguous.

Patients And Methods: In this prospective multicentre, intravenous thrombolysis register-based study, we compared haemoglobin levels on hospital admission with three-month poor outcome (modified Rankin Scale 3-6), mortality and symptomatic intracranial haemorrhage (European Cooperative Acute Stroke Study II-criteria (ECASS-II-criteria)). Haemoglobin level was used as continuous and categorical variable distinguishing anaemia (female: <12 g/dl; male: <13 g/dl) and polyglobulia (female: >15.5 g/dl; male: >17 g/dl). Anaemia was subdivided into mild and moderate/severe (female/male: <11 g/dl). Normal haemoglobin level (female: 12.0-15.5 g/dl, male: 13.0-17.0 g/dl) served as reference group. Unadjusted and adjusted odds ratios with 95% confidence intervals were calculated with logistic regression models.

Results: Among 6866 intravenous thrombolysis-treated stroke patients, 5448 (79.3%) had normal haemoglobin level, 1232 (17.9%) anaemia - of those 903 (13.2%) had mild and 329 (4.8%) moderate/severe anaemia - and 186 (2.7%) polyglobulia. Anaemia was associated with poor outcome (OR 1.25 (1.05-1.48)) and mortality (OR 1.58 (1.27-1.95)). In anaemia subgroups, both mild and moderate/severe anaemia independently predicted poor outcome (OR 1.29 (1.07-1.55) and 1.48 (1.09-2.02)) and mortality (OR 1.45 (1.15-1.84) and OR 2.00 (1.46-2.75)). Each haemoglobin level decrease by 1 g/dl independently increased the risk of poor outcome (OR 1.07 (1.02-1.11)) and mortality (OR 1.08 (1.02-1.15)). Anaemia was not associated with occurrence of symptomatic intracranial haemorrhage. Polyglobulia did not change any outcome.

Discussion: The more severe the anaemia, the higher the probability of poor outcome and death. Severe anaemia might be a target for interventions in hyperacute stroke.

Conclusion: Anaemia on admission, but not polyglobulia, is a strong and independent predictor of poor outcome and mortality in intravenous thrombolysis-treated stroke patients.
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http://dx.doi.org/10.1177/2396987319889468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7313367PMC
June 2020

Association of prestroke metformin use, stroke severity, and thrombolysis outcome.

Neurology 2020 07 29;95(4):e362-e373. Epub 2020 Jun 29.

From the Department of Neurology (L.P.W., R.W., A.R.L., S.W.), University Hospital Zurich; Epidemiology, Biostatistics and Prevention Institute, Department of Biostatistics (U.H., K.S.), University of Zurich, Switzerland; Department of Neurology (C.H., P.R.), University Hospital Heidelberg, Germany; Department of Neurology (S.C., N.M.-M., M.T.), University of Helsinki and Helsinki University Hospital, Finland; Department of Neurology and Center for Stroke Research (C.H.N., J.F.S., H.E.), Charité University Hospital, Berlin, Germany; Stroke Center and Neurology (A.A.P., C.T., H.G., S.T.E.), University Hospital Basel and University Basel; Department of Neurology (A.E., P.M.), University Hospital Lausanne; Department of Neurology (M.R.H., M.A.), Inselspital, Bern University Hospital, University of Bern, Switzerland; Department of Neurology and Stroke Center (A.Z.), IRCCS Istituto delle Scienze Neurologiche di Bologna, Maggiore Hospital; Stroke Unit (L.V.), Department of Neuroscience, S'Agostino-Estense Hospital, Modena University Hospital, Italy; Department of Neurology (J.M.C., A.E.G., P.N.), Amsterdam University Medical Centers (AUMC), Location AMC, University of Amsterdam, the Netherlands; Neurology Clinic Belgrade (V.P., D.R.J.), Clinical Centre of Serbia; Medical Faculty (D.R.J.), University of Belgrade, Serbia; Department of Neurology (Y.B., C.B.), University Hospital of Dijon, University of Burgundy; Department of Neurology (G.T., P.S.), Sainte-Anne Hospital, Paris, France; Department of Clinical and Experimental Sciences (A.P.), Neurology Clinic, University of Brescia; Stroke Unit (M.M.), ASST Spedali Civili, Brescia, Italy; Department of Neurology (D.L., S.G.), University Hospital of Lille, France; Department of Neurology (M.J.S., G.K.), St. Gallen Cantonal Hospital, Switzerland; Department of Neurology (T.T.), Sahlgrenska University Hospital; Department of Clinical Neurosciences (T.T.), Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Sweden; and Neurorehabilitation Unit (S.T.E.), University Center for Medicine of Aging and Rehabilitation Basel, Felix Platter Hospital, University of Basel, Switzerland.

Objective: To evaluate whether pretreatment with metformin (MET) is associated with less stroke severity and better outcome after IV thrombolysis (IVT), we analyzed a cohort of 1,919 patients with stroke with type 2 diabetes mellitus in a multicenter exploratory analysis.

Methods: Data from patients with diabetes and ischemic stroke treated with IVT were collected within the European Thrombolysis in Ischemic Stroke Patients (TRISP) collaboration. We applied propensity score matching (PSM) to obtain balanced baseline characteristics of patients treated with and without MET.

Results: Of 1,919 patients with stroke with type 2 diabetes who underwent IVT, 757 (39%) had received MET before stroke (MET+), whereas 1,162 (61%) had not (MET-). MET+ patients were younger with a male preponderance. Hypercholesterolemia and pretreatment with statins, antiplatelets, or antihypertensives were more common in the MET+ group. After PSM, the 2 groups were well balanced with respect to demographic and clinical aspects. Stroke severity on admission (NIH Stroke Scale 10.0 ± 6.7 vs 11.3 ± 6.5), 3-month degree of independence on modified Rankin Scale (2 [interquartile range (IQR) 1.0-4.0] vs 3 [IQR 1.0-4.0]), as well as mortality (12.5% vs 18%) were significantly lower in the MET+ group. The frequency of symptomatic intracerebral hemorrhages did not differ between groups. HbA1c levels were well-balanced between the groups.

Conclusions: Patients with stroke and diabetes on treatment with MET receiving IVT had less severe strokes on admission and a better functional outcome at 3 months. This suggests a protective effect of MET resulting in less severe strokes as well as beneficial thrombolysis outcome.
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http://dx.doi.org/10.1212/WNL.0000000000009951DOI Listing
July 2020

Distal arterial occlusions in patients with mild strokes - is endovascular therapy superior to thrombolysis alone?

J Stroke Cerebrovasc Dis 2020 Jul 13;29(7):104868. Epub 2020 May 13.

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

Background And Purpose: Safety and efficacy of endovascular thrombectomy (EVT) in patients with mild stroke syndromes is unclear, especially in distal vessel occlusions.

Methods: We analysed in our stroke database (HeiReKa) between 2002 and April 2019 safety and efficacy of EVT compared to intravenous thrombolysis (IVT) in patients with occlusions distal to the M1 segment of the middle cerebral artery and the top of the basilar artery who presented with a National Institute of Health Stroke Scale (NIHSS) below 6. Excellent (good) outcome was defined as modified rankin scale (mRS) 0-1 (0-2) or return to baseline mRS (good) after 3 months. Safety endpoints were mortality after 3 months and intracranial hemorrhage according to the Heidelberg Bleeding Classification (HBC).

Results: Of 4167 patients 94 met the inclusion criteria. Sixty-four patients were allocated to the IVT group and 30 to the EVT group of which 15 also received IVT; three patients (4.6%) in the IVT group received rescue EVT. Baseline characteristics did not differ but more M2 occlusions were found in the EVT group (93.3% vs. 64.1%, p = 0.02). Intracranial bleeding occurred more often in EVT patients (HBC class 2: 13.3% vs. 1.6%, p = 0.01). Excellent and good outcome were not significantly different (75% vs. 70%, p = 0.65 and 87.5% vs. 73.3%, p = 0.14). Mortality was significantly lower in IVT patients (1.6% vs. 13.3%, p = 0.04).

Conclusion: Rates of excellent and good outcome after IVT or EVT were almost similar, but safety parameters were increased after EVT. EVT may be considered in selected patients after careful risk/benefit analysis.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.104868DOI Listing
July 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

Radiation exposure per thrombectomy attempt in modern endovascular stroke treatment in the anterior circulation.

Eur Radiol 2020 Sep 24;30(9):5039-5047. Epub 2020 Apr 24.

Department of Neuroradiology, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.

Objective: To quantify radiation exposure (RE) of endovascular stroke treatment (EST) in the anterior circulation per thrombectomy attempt and determine causes for interventions associated with high RE.

Methods: A retrospective single-center study of an institutional review board-approved stroke database of patients receiving EST for large vessel occlusions in the anterior circulation between January 2013 and April 2018 to evaluate reference levels (RL) per thrombectomy attempt. ESTs with RE above the RL were analyzed to determine causes for high RE.

Results: Overall, n = 544 patients (occlusion location, M1 and M2 segments of the middle cerebral artery 53.5% and 27.2%, carotid artery 17.6%; successful recanalization rate 85.7%) were analyzed. In the overall population, DAP (in Gy cm, median (IQR)) was 113.7 (68.9-181.7) with a median fluoroscopy time of 31 min (IQR, 17-53) and a median of 2 (IQR, 1-4) thrombectomy attempts. RE increased significantly with every thrombectomy attempt (DAP, 68.7 (51.2-106.8); DAP, 106.4 (84.8-115.6); p value, < 0.001; DAP, 130.2 (89.1-183.6); p value, 0.044; DAP, 169.9 (128.4-224.1); p value, 0.001; and DAP, 227.6 (146.3-294.6); p value, 0.019). Procedures exceeding the 90th percentile of the attempt-dependent radiation exposure level were associated with procedural complications (n = 17/52, 29.8%) or a difficult vascular access (n = 8/52, 14%).

Conclusions: Radiation exposure in endovascular stroke treatment is depending on the number of thrombectomy attempts. Radiation exposure doubles when three attempts and triples when five attempts are necessary compared with single-maneuver interventions. Procedural complications and difficult vascular access were associated with a high radiation exposure in this collective.

Key Points: • Radiation exposure of endovascular stroke treatment (EST) is dependent on the number of thrombectomy attempts. • Reference levels as means for quality control in hospitals performing endovascular stroke treatment should be defined by the number of thrombectomy attempts-we suggest 107 Gy cm, 156 Gy cm, 184 Gy cm, 244 Gy cm, and 295 Gy cm for 1 to 5 maneuvers, respectively, for EST of the anterior circulation • Cases with high rates of radiation exposure are associated with periprocedural complications and difficult anatomical access as a probable cause for a high radiation exposure.
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http://dx.doi.org/10.1007/s00330-020-06837-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431433PMC
September 2020

Impact of slice thickness on clinical utility of automated Alberta Stroke Program Early Computed Tomography Scores.

Eur Radiol 2020 Jun 21;30(6):3137-3145. Epub 2020 Feb 21.

Department of Neuroradiology, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.

Objectives: The clinical utility of electronically derived ASPECTS (e-ASPECTS) to quantify signs of acute ischemic infarction could be demonstrated in multiple studies. Here, we aim to clinically validate the impact of CT slice thickness (ST) on the performance of e-ASPECTS software.

Methods: A consecutive series of n = 258 patients (06/2016 and 01/2019) with middle cerebral artery occlusion and subsequent treatment with mechanical thrombectomy was analyzed. The e-ASPECTS score and acute infarct volumes were calculated from baseline non-contrast CT with a software using 1-mm slice thickness (ST) (defined as ground truth) and axial reconstructions with 2-10-mm ST and correlated with baseline stroke severity (NIHSS) as well as clinical outcome (mRS) using logistic regressions.

Results: In comparison with the ground truth, significant differences were seen in e-ASPECTS scores with ST > 6 mm (p ≤ 0.031) and infarct volumes with ST > 4 mm (p ≤ 0.001). There was a significant correlation of lower e-ASPECTS and higher acute infarct volumes with increasing baseline NIHSS values for all ST (p ≤ 0.001, respectively), with values derived from 1 mm yielding the highest correlation for both parameters (rho, - 0.38 and 0.31, respectively). Similarly, lower e-ASPECTS and higher acute infarct volumes from all ST were significantly associated with poor outcome after 90 days (p ≤ 0.05, respectively) with values derived from 1-mm ST yielding the highest effects for both parameters (OR, 0.69 [95% CI 0.50-0.88] and 1.27 [95% CI 1.10-1.50], respectively).

Conclusions: The e-ASPECTS software generates robust values for e-ASPECTS and acute infarct volumes when using ST ≤ 4 mm with ST = 1 mm yielding the best performance for predicting baseline stroke severity and clinical outcome after 90 days.

Key Points: • Clinical utility of automatically derived ASPECTS from computed tomography scans was shown in patients with acute ischemic stroke and treatment with mechanical thrombectomy. • Thin slices (= 1 mm) had the highest clinical utility in comparison with thicker slices (2-10 mm) by having the strongest correlation with baseline stroke severity and independent effects on clinical outcome after 90 days. • Automatically calculated acute infarct volumes possess clinical utility beyond ASPECTS and should be considered in future studies.
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http://dx.doi.org/10.1007/s00330-019-06616-8DOI Listing
June 2020

Antagonizing dabigatran by idarucizumab in cases of ischemic stroke or intracranial hemorrhage in Germany-Updated series of 120 cases.

Int J Stroke 2020 Aug 19;15(6):609-618. Epub 2020 Jan 19.

Department of Neurology, University Hospital, Essen, Germany.

Background: Idarucizumab is a monoclonal antibody fragment with high affinity for dabigatran reversing its anticoagulant effects within minutes. Thereby, patients with acute ischemic stroke who are on dabigatran treatment may become eligible for thrombolysis with recombinant tissue-type plasminogen activator (rt-PA). In patients on dabigatran with intracerebral hemorrhage idarucizumab could prevent lesion growth.

Aims: To provide insights into the clinical use of idarucizumab in patients under effective dabigatran anticoagulation presenting with signs of acute ischemic stroke or intracranial hemorrhage.

Methods: Retrospective data collected from German neurological/neurosurgical departments administering idarucizumab following product launch from January 2016 to August 2018 were used.

Results: One-hundred and twenty stroke patients received idarucizumab in 61 stroke centers. Eighty patients treated with dabigatran presented with ischemic stroke and 40 patients suffered intracranial bleeding (intracerebral hemorrhage (ICH) in  = 27). In patients receiving intravenous thrombolysis with rt-PA following idarucizumab, 78% showed a median improvement of 7 points in National Institutes of Health Stroke Scale. No bleeding complications were reported. Hematoma growth was observed in 3 out of 27 patients with ICH. Outcome was favorable with a median National Institutes of Health Stroke Scale improvement of 4 points and modified Rankin score 0-3 in 61%. Six out of 40 individuals (15%) with intracranial bleeding died during hospital stay.

Conclusion: Administration of rt-PA after reversal of dabigatran activity with idarucizumab in case of acute ischemic stroke seems feasible, effective, and safe. In dabigatran-associated intracranial hemorrhage, idarucizumab appears to prevent hematoma growth and to improve outcome.
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http://dx.doi.org/10.1177/1747493019895654DOI Listing
August 2020