Unknown Time Of Symptom Onset Research Articles

Computed tomography hypoperfusion-hypodensity mismatch vs. automated perfusion mismatch to identify stroke patients eligible for thrombolysis.

Automated perfusion imaging can detect stroke patients with unknown time of symptom onset who are eligible for thrombolysis. However, the availability of this technique is limited. We, therefore, established the novel concept of computed tomography (CT) hypoperfusion-hypodensity mismatch, i.e., an ischemic core lesion visible on cerebral perfusion CT without visible hypodensity in the corresponding native cerebral CT. We compared both methods regarding their accuracy in identifying patients suitable for thrombolysis. In a retrospective analysis of the MissPerfeCT observational cohort study, patients were classified as suitable or not for thrombolysis based on established time window and imaging criteria. We calculated predictive values for hypoperfusion-hypodensity mismatch and automated perfusion imaging to compare accuracy in the identification of patients suitable for thrombolysis. Of 247 patients, 219 (88.7%) were eligible for thrombolysis and 28 (11.3%) were not eligible for thrombolysis. Of 197 patients who were within 4.5 h of symptom onset, 190 (96.4%) were identified by hypoperfusion-hypodensity mismatch and 88 (44.7%) by automated perfusion mismatch (p < 0.001). Of 22 patients who were beyond 4.5 h of symptom onset but were eligible for thrombolysis, 5 patients (22.7%) were identified by hypoperfusion-hypodensity mismatch. Predictive values for the hypoperfusion-hypodensity mismatch vs. automated perfusion mismatch were as follows: sensitivity, 89.0% vs. 50.2%; specificity, 71.4% vs. 100.0%; positive predictive value, 96.1% vs. 100.0%; and negative predictive value, 45.5% vs. 20.4%. The novel method of hypoperfusion-hypodensity mismatch can identify patients suitable for thrombolysis with higher sensitivity and lower specificity than established techniques. Using this simple method might therefore increase the proportion of patients treated with thrombolysis without the use of special automated software.The MissPerfeCT study is a retrospective observational multicenter cohort study and is registered with clinicaltrials.gov (NCT04277728).

Abstract WP115: DWI/FLAIR Mismatch Is Common In Late Window Patients With Target Perfusion Mismatch

Introduction: The presence of a DWI/FLAIR mismatch has been suggested as a method to identify patients within 4.5 hours from stroke symptom onset. We studied patients from DEFUSE 2 and 3 with the target perfusion mismatch profile to evaluate the rates of DWI/FLAIR mismatch in patients with who have favorable collaterals in early and late time windows. We hypothesize that the persistence of DWI/FLAIR mismatch in late window patients may reflect good collateral circulation. Methods: We identified 58 eligible patients in D2 and 30 patients from D3. Imaging was reviewed by two neuroradiologists and one neurologist who rated the presence of DWI-FLAIR mismatch. Results: The inter-rater agreement for the presence of DWI/FLAIR mismatch was 88.3%. There were 32 patients who were &lt; 6 hours from last known well (LKW) or symptom onset, 17 patients who were ≥ 6 hours from symptom onset, and 26 patients who were ≥ 6 hours from LKW with an unknown time of symptom onset. These are categorized as early, late, and suspected late window, respectively. The rate of DWI/FLAIR mismatch was 56% in the early window group, 41% in the late window group, and 35% in the suspected late window group. The overall rate of DWI/FLAIR mismatch did not differ significantly between these three groups (56% vs. 41% vs. 35%, p=0.239). Of the early window patients, the rate of DWI-FLAIR mismatch was higher in those with the target perfusion mismatch profile (67%) compared to those without (36%). All but one the known onset late window patients had the target perfusion mismatch profile, and the rate of DWI-FLAIR mismatch in this group was 35%. Forthcoming analyses will include predictors of DWI-FLAIR mismatch such as hypoperfusion intensity ratio, time from symptom onset, and NIHSS score. Conclusions: More than one-third of patients presenting &gt;6 hours from symptom onset with a target perfusion mismatch profile have DWI/FLAIR mismatch. This could reflect the presence of good collateral circulation that may delay the appearance of a FLAIR lesion. The rate of DWI/FLAIR mismatch did not differ among early, late, and expected late window patients. This suggests that, among patients with favorable collaterals, DWI/FLAIR mismatch does not reliably identify early window patients.

Multicentre registration of wake-up stroke in China (MCRWUSC): a protocol for a prospective, multicentre, registry-based cohort study

IntroductionWake-up stroke (WUS) is a type of acute ischaemic stroke (AIS) that occurs during sleep with unknown time of symptom onset. The best treatment is usually not suitable for WUS,...

Simplified Assessment of Lesion Water Uptake for Identification of Patients within 4.5 Hours of Stroke Onset: An Analysis of the MissPerfeCT Study.

Background and Purpose Many patients with stroke cannot receive intravenous thrombolysis because the time of symptom onset is unknown. We tested whether a simple method of computed tomography (CT)-based quantification of water uptake in the ischemic tissue can identify patients with stroke onset within 4.5 hours. Methods This retrospective analysis of the MissPerfeCT study (August 2009 to November 2017) includes consecutive patients with known onset of symptoms from seven tertiary stroke centers. We developed a simplified algorithm based on region of interest (ROI) measurements to quantify water uptake of the ischemic lesion and thereby quantify time of symptom onset within and beyond 4.5 hours. Perfusion CT was used to identify ischemic brain tissue, and its density was measured in non-contrast CT and related to the density of the corresponding area of the contralateral hemisphere to quantify lesion water uptake. Results Of 263 patients, 204 (77.6%) had CT within 4.5 hours. Water uptake was significantly lower in patients with stroke onset within (6.7%; 95% confidence interval [CI], 6.0% to 7.4%) compared to beyond 4.5 hours (12.7%; 95% CI, 10.7% to 14.7%). The area under the curve for distinguishing these patient groups according to percentage water uptake was 0.744 with an optimal cut-off value of 9.5%. According to this cut-off the positive predictive value was 88.8%, sensitivity was 73.5%, specificity 67.8%, negative predictive value was 42.6%. Conclusions Ischemic stroke patients with unknown time of symptom onset can be identified as being within a timeframe of 4.5 hours using a ROI-based method to assess water uptake on admission non-contrast head CT.

Editors' Note: Cerebral Microbleeds and Treatment Effect of Intravenous Thrombolysis in Acute Stroke: An Analysis of the WAKE-UP Randomized Clinical Trial

Dr. Schlemm et al. performed a prespecified analysis of the association of cerebral microbleeds (CMBs) with the treatment effect of IV alteplase vs placebo in the randomized controlled WAKE-UP (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke) trial of patients with acute ischemic stroke with unknown time of symptom onset and diffusion-weighted imaging–fluid-attenuated inversion recovery mismatch on MRI. Among 459 patients available for analysis, there was no evidence of reduced treatment effect of alteplase in the 98 (21.4%) patients who had at least 1 CMB on baseline imaging. However, CMBs were associated with a nonsignificant increased risk of symptomatic intracranial hemorrhage (ICH; 11.2% vs 4.2%; adjusted odds ratio 2.32, 95% CI 0.99–5.43). In response, Drs. Meinel and Seiffge highlight the importance of distinguishing patients with CMBs from cerebral amyloid angiopathy or other cerebral small vessel disease—who have an increased risk of postthrombolysis ICH—from those with other causes of CMBs and other such lesions on susceptibility-weighted imaging, like those seen after valve implantation, extracorporeal membrane oxygenation, or prolonged intensive care unit stay. They also recommend examining the interaction of CMBs and white matter hyperintensities to better elucidate the risk of postthrombolysis hemorrhage. Responding to these comments, the authors note that new CMBs in acute ischemic stroke patients after IV thrombolysis were associated with an increased risk of hemorrhagic complications in prior literature, whereas new CMBs after cardiac surgery were not associated with bleeding risk, suggesting different risk profiles for patients with different causes of acute CMBs—a topic meriting further investigation in histopathology and observational studies. This exchange highlights the challenges of disentangling cause-specific bleeding risks associated with CMBs when examining ICH outcomes in patients undergoing thrombolysis. Dr. Schlemm et al. performed a prespecified analysis of the association of cerebral microbleeds (CMBs) with the treatment effect of IV alteplase vs placebo in the randomized controlled WAKE-UP (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke) trial of patients with acute ischemic stroke with unknown time of symptom onset and diffusion-weighted imaging–fluid-attenuated inversion recovery mismatch on MRI. Among 459 patients available for analysis, there was no evidence of reduced treatment effect of alteplase in the 98 (21.4%) patients who had at least 1 CMB on baseline imaging. However, CMBs were associated with a nonsignificant increased risk of symptomatic intracranial hemorrhage (ICH; 11.2% vs 4.2%; adjusted odds ratio 2.32, 95% CI 0.99–5.43). In response, Drs. Meinel and Seiffge highlight the importance of distinguishing patients with CMBs from cerebral amyloid angiopathy or other cerebral small vessel disease—who have an increased risk of postthrombolysis ICH—from those with other causes of CMBs and other such lesions on susceptibility-weighted imaging, like those seen after valve implantation, extracorporeal membrane oxygenation, or prolonged intensive care unit stay. They also recommend examining the interaction of CMBs and white matter hyperintensities to better elucidate the risk of postthrombolysis hemorrhage. Responding to these comments, the authors note that new CMBs in acute ischemic stroke patients after IV thrombolysis were associated with an increased risk of hemorrhagic complications in prior literature, whereas new CMBs after cardiac surgery were not associated with bleeding risk, suggesting different risk profiles for patients with different causes of acute CMBs—a topic meriting further investigation in histopathology and observational studies. This exchange highlights the challenges of disentangling cause-specific bleeding risks associated with CMBs when examining ICH outcomes in patients undergoing thrombolysis.

Cerebral Microbleeds and Treatment Effect of Intravenous Thrombolysis in Acute Stroke: An Analysis of the WAKE-UP Randomized Clinical Trial.

Background and ObjectivesCerebral microbleeds (CMBs) are common in patients with acute ischemic stroke and are associated with increased risk of intracerebral hemorrhage (ICH) after intravenous thrombolysis. Whether CMBs modify the treatment effect of thrombolysis is unknown.MethodsWe performed a prespecified analysis of the prospective randomized controlled multicenter Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke (WAKE-UP) trial including patients with acute ischemic stroke with unknown time of symptom onset and diffusion-weighted imaging–fluid-attenuated inversion recovery mismatch on MRI receiving alteplase or placebo. Patients were screened and enrolled between September 2012 and June 2017 (with final follow-up in September 2017). Patients were randomized to treatment with IV thrombolysis with alteplase at 0.9 mg/kg body weight or placebo. CMB status (presence, number, and distribution) was assessed after study completion by 3 raters blinded to clinical information following a standardized protocol. Outcome measures were excellent functional outcome at 90 days, defined by modified Rankin Scale (mRS) score ≤1, and symptomatic ICH according to National Institutes of Neurological Disease and Stroke trial criteria 22 to 36 hours after treatment.ResultsOf 503 patients enrolled in the WAKE-UP trial, 459 (91.3%; 288 [63%] men) were available for analysis. Ninety-eight (21.4%) had at least 1 CMB on baseline imaging; 45 (9.8%) had exactly 1 CMB; 37 (8.1%) had 2 to 4 CMBs; and 16 (3.5%) had ≥5 CMBs. Presence of CMBs was associated with a nonsignificant increased risk of symptomatic ICH (11.2% vs 4.2%; adjusted odds ratio [OR] 2.32, 95% confidence interval [CI] 0.99–5.43, p = 0.052) but had no effect on functional outcome at 90 days (mRS score ≤1: 45.8% vs 50.7%; adjusted OR 0.99, 95% CI 0.59–1.64, p = 0.955). Patients receiving alteplase had better functional outcome (mRS score ≤1: 54.6% vs 44.6%, adjusted OR 1.61, 95% CI 1.07–2.43, p = 0.022) without evidence of heterogeneity in relation to CMB presence (p of the interactive term = 0.546). Results were similar for subpopulations with strictly lobar (presumed cerebral amyloid angiopathy related) or not strictly lobar CMB distribution.DiscussionIn the randomized-controlled WAKE-UP trial, we saw no evidence of reduced treatment effect of alteplase in patients with acute ischemic stroke with ≥1 CMBs. Additional studies are needed to determine the treatment effect of alteplase and its benefit-harm ratio in patients with a larger number of CMBs.Trial Registration InformationClinicalTrials.gov identifier NCT01525290; ClinicalTrialsRegister.EU identifier 2011-005906-32.Classification of EvidenceThis study provides Class II evidence that for patients with acute ischemic stroke with unknown time of onset and diffusion-weighted imaging–fluid-attenuated inversion recovery mismatch who received IV alteplase, CMBs are not significantly associated with functional outcome at 90 days.

Implementation of emergent MRI for wake-up stroke: a single-center experience.

Recent updates in national guidelines for management of acute ischemic stroke in patients of unknown time of symptom onset ("wake-up" strokes) incorporate, for the first time, use of emergent MRI. In this retrospective case series, we analyze our experience at a Comprehensive Stroke Center implementing a new workflow including MRI in this clinical setting. This study also describes "DWI-FLAIR" mismatch, a critical concept for the interpretation of emergent brain MRIs performed for wake-up strokes. Over a 14-month period, all brain MRIs for wake-up stroke were identified. The imaging was analyzed by two board-certified, fellowship-trained neuroradiologists, and a diagnosis of DWI-FLAIR mismatch was made by consensus. Process metrics assessed included interval between last known well time and brain imaging, interval between CT and MRI, and interval between brain MRI and interpretation. Sixteen patients with a history of "wake-up stroke" were identified. Thirteen of the 16 patients (81.3%) were found to have a DWI-FLAIR mismatch, suggesting infarct < 4.5h old. The mean time between last known well and MRI was 7.89h with mean interval between CT and MRI of 1.83h. Forty-six percent of patients with DWI-FLAIR mismatch received intravenous thrombolysis. In this "real world" assessment of incorporation of emergent MRI for wake-up strokes, there were several key factors to successful implementation of this new workflow, including effective and accurate description of MRI findings; close collaboration amongst stakeholders; 24/7 availability of MRI; and 24/7 onsite coverage by neurology and radiology physicians.

Challenges in managing ST elevation myocardial infarction during the COVID-19 pandemic.

BACKGROUNDCoronavirus disease 2019 (COVID-19) may contribute to delayed presentations of acute myocardial infarction. Delayed presentation with late reperfusion is often associated with an increased risk of mechanical complications and adverse outcomes. Inherent delays are possible as every patient who is acutely sick is being considered a potential case or a career of COVID-19. Also, standardized personal protective equipment precautions are established for all members of the team, regardless of pending COVID-19 testing which might further add to delays.AIMTo compare performance measures and clinical outcomes of all patients who presented to our facility with ST elevation myocardial infarction (STEMI) during the COVID-19 pandemic to same time cohort from 2019.METHODSAll patients who presented to our facility with STEMI during the pandemic were compared to a matched cohort during the same time period in 2019. STEMI with unknown time of symptom onset and inpatient STEMI patients were excluded. Primary outcome was major adverse cardiac events (MACE) in-hospital and up to 14 d after STEMI, including death, myocardial infarction, cardiac arrest, or stroke. Significant differences among groups for continuous variables were tested through ANOVA, using SYSTAT, version 13. Chi-square tests of association were used to compare patient characteristics among groups using SYSTAT. Relative risk scores and associated tests for significance were calculated for discrete variables using MedCalc (MedCalc Software, Ostend, Belgium).RESULTSThere was a significantly longer time interval from symptom onset to first medical contact (FMC) in the COVID-19 group (P < 0.02). Time to first electrocardiogram, door-to-balloon time, and FMC to balloon time were not significantly affected. The right coronary artery was the most common culprit for STEMI in both the cohorts. Over 60% of patients had one or more obstructive (> 50%) lesion(s) remote from the culprit site. In-hospital and 14 d MACE were more prevalent in the COVID-19 group (P < 0.01 and P < 0.001). CONCLUSIONThis single academic center study in the United States suggests that there is a delay in patients with STEMI seeking medical attention during the COVID-19 pandemic which could be translating into worse clinical outcomes.

Acute reperfusion therapies for acute ischemic stroke patients with unknown time of symptom onset or in extended time windows: an individualized approach.

Recent randomized controlled clinical trials (RCTs) have revolutionized acute ischemic stroke care by extending the use of intravenous thrombolysis and endovascular reperfusion therapies in time windows that have been originally considered futile or even unsafe. Both systemic and endovascular reperfusion therapies have been shown to improve outcome in patients with wake-up strokes or symptom onset beyond 4.5 h for intravenous thrombolysis and beyond 6 h for endovascular treatment; however, they require advanced neuroimaging to select stroke patients safely. Experts have proposed simpler imaging algorithms but high-quality data on safety and efficacy are currently missing. RCTs used diverse imaging and clinical inclusion criteria for patient selection during the dawn of this novel stroke treatment paradigm. After taking into consideration the dismal prognosis of nonrecanalized ischemic stroke patients and the substantial clinical benefit of reperfusion therapies in selected late presenters, we propose rescue reperfusion therapies for acute ischemic stroke patients not fulfilling all clinical and imaging inclusion criteria as an option in a subgroup of patients with clinical and radiological profiles suggesting low risk for complications, notably hemorrhagic transformation as well as local or remote parenchymal hemorrhage. Incorporating new data to treatment algorithms may seem perplexing to stroke physicians, since treatment and imaging capabilities of each stroke center may dictate diverse treatment pathways. This narrative review will summarize current data that will assist clinicians in the selection of those late presenters that will most likely benefit from acute reperfusion therapies. Different treatment algorithms are provided according to available neuroimaging and endovascular treatment capabilities.

PND46 Cost-Effectiveness of MRI-Guided Thrombolysis for Stroke Patients with Unknown Time of Onset

The aim of this study was to assess cost-effectiveness of MRI-guided thrombolysis with intravenous alteplase for acute ischemic stroke in patients with unknown time of onset compared to placebo. A Markov model was designed to predict cost-effectiveness over a 25 year time horizon. The data used in this analysis was extracted from the WAKE-UP trial, a European multi-center randomized controlled trial investigating the effects of intravenous thrombolysis with alteplase vs placebo based on a mismatch in MRI imaging in patients with unknown time of symptom onset. Incremental costs and effects over the patients’ lifetime were estimated. The model consisted of an in-patient acute care phase and a rest of life phase. Health states were defined by the modified Rankin Scale score. After the initial stroke, patients remained in their mRS score until death or recurrent stroke. Health state utilities were extracted from published literature. Cost data of acute care was taken from the University Medical Center Hamburg-Eppendorf, Germany. To establish cost of long-term care in the rest-of-life phase, mRS scores were matched to German degrees of care based on expert opinion. The analysis was conducted from a German societal perspective. Treatment with alteplase dominated placebo with incremental costs of 51,009€ ($40,807) and 1.30 gains in Quality-Adjusted Life Years (QALYs) at a discount rate of 5%. Univariate sensitivity analysis and probabilistic sensitivity analysis (Monet Carlo Simulation) was conducted to test robustness, both indicating robustness of our results across a wide range of parameters. MRI-guided thrombolysis with intravenous alteplase compared to placebo is cost-effective in ischemic stroke patients with unknown time of onset.

Wake-up stroke – diagnosis, management and treatment

Wake-up stroke is defined as ischaemic stroke with unknown time of symptom onset, when patients go to sleep normal and awaken with neurological symptoms. This type of stoke accounts for about 20% (14–24%) of all ischaemic strokes. The high incidence of wake-up stroke may be associated with diurnal variability of heart rate and blood pressure, coagulation processes, as well as episodes of atrial fibrillation, which are more common in the morning. The risk of wake-up stroke increases during REM sleep. Individuals with obstructive sleep apnoea account for the majority of patients with wake-up stroke. Until recently, wake-up stroke was considered a contraindication for reperfusion treatment due to the unknown time of onset and a potential risk of intracranial bleeding. The latest research has shown that wake-up stroke occurs shortly before awakening. Therefore, these patients could be qualified for reperfusion treatment, which would improve their clinical status.

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

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. 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). 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. 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. 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.

Time to Wake-Up: Extending the Window for Management of Unknown-Onset Strokes.

The term "Wake-Up Stroke" is applied to a patient who displays no symptoms before sleep, but wakes with neurologic deficits suggestive of stroke. The current guidelines for acute ischemic stroke limit intravenous tissue plasminogen activator use to stroke patients in whom symptom onset or last known well is less than 4.5 hours. Approximately one-third of acute ischemic stroke patients present with unknown time of symptom onset and are often not eligible for intravenous reperfusion therapy in clinical practice. This review provides an overview of several earlier trials that used advanced neuroimaging to determine eligibility for reperfusion therapy in patients with unknown stroke onset. The reassuring results of these earlier trials that led to recent thrombolysis trials specifically targeted at "wake-up stroke" patients are discussed in this review. Ongoing studies aim to expand our knowledge regarding the safety and efficacy of thrombolysis in these patients.

Should IV Thrombolysis be given in Patients with Suspected Ischemic Stroke but Unknown Symptom Onset and Without Diffusion-Weighted Imaging Lesion? – Results of a Case-Control Study

BackgroundMany acute ischemic stroke (AIS) patients present with unknown time of symptom onset (UTO). In these situations, wake-up MRI protocols can guide treatment decisions: patients with DWI (diffusion-weighted imaging) but no fluid-attenuated inversion recovery lesion were shown to benefit from IVT (intravenous thrombolysis). However, initial MRI of some stroke patients is DWI negative, leaving it unclear whether this subgroup profits from IVT. Therefore, we aimed to compare the safety and efficacy of IVT in wake-up AIS patients with or without a DWI lesion in initial imaging. MethodsWe performed a case-control study. All AIS patients with UTO who underwent wake-up MRI and were treated with IVT at a German University Hospital from 2013 to 2017 were included. Patients without (DWI-) were compared to patients with DWI lesion (DWI+) regarding clinico-radiological characteristics, adverse events, and outcome at discharge. Likely stroke mimics were excluded. ResultsEleven DWI- and 32 DWI+ patients were included. There were no statistically significant differences regarding functional scores, age, sex, door-to-needle time, bleeding complications, and death. DWI+ patients more frequently had anterior circulation stroke (P = .049) and higher modified Rankin Scale (mRS) scores at discharge (P = .048). Solely in the DWI+ group 3 bleeding complications (2 asymptomatic hemorrhagic transformations, 1 muscle hematoma) and 3 deaths occurred (P = .29). A favourable outcome (mRS≤ 2) was achieved in 82% of the DWI- and in 58% of the DWI+ group (p > .05). ConclusionsOur data suggest that IVT may be used in DWI- patients with UTO with acute neurological symptoms very likely to be related to AIS.

Current Smoking Does Not Modify the Treatment Effect of Intravenous Thrombolysis in Acute Ischemic Stroke Patients-A Post-hoc Analysis of the WAKE-UP Trial.

Background: The “smoking paradox” indicates that patients with acute ischemic stroke (AIS) who smoke at the time of their stroke may have a better prognosis after intravenous thrombolysis than non-smokers. However, findings are inconsistent and data analyzing the effect of smoking on treatment efficacy of intravenous thrombolysis are scarce.Methods: We performed a pre-specified post-hoc subgroup analysis of the Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke (WAKE-UP) trial that randomized AIS patients with unknown time of symptom onset who had diffusion-weighted imaging-fluid attenuation inversion recovery (DWI-FLAIR) mismatch to either alteplase or placebo. Patients were categorized as current smokers or non-smokers (including former smokers and never-smokers). Baseline demographic and clinical characteristics, as well as clinical and imaging follow-up data were analyzed according to smoking status.Results: Four hundred and eighty six patients were included in the analysis. Current smokers (133, 27.4%) were younger (60.1 ± 13.0 vs. 67.2 ± 10.3 years; p < 0.001) and less often had arterial hypertension (45.0% vs. 56.8%; p = 0.02) or atrial fibrillation (3.8% vs. 15.3%; p < 0.001). The acute stroke presentation was more often due to large vessel occlusion among current smokers (27.1 vs. 16.2%; p = 0.01), and smokers had a trend towards more severe strokes (National Institutes of Health Stroke Scale score>10 in 27.1% vs. 19.5%; p = 0.08). The treatment effect of alteplase, quantified as odds ratio for a favorable outcome (modified Rankin Scale [mRS] score at 90 days of 0 or 1), did not differ between current smokers and non-smokers (p-value for interaction: 0.59). After adjustment for age and stroke severity, neither the proportion of patients with favorable outcome, nor the median mRS score at 90 days differed between current smokers and non-smokers. When additional potential confounders were included in the model, the median mRS score was higher in current smokers than in non-smokers (cOR of better outcome for current smokers vs. non-smokers: 0.664 [0.451–0.978], p = 0.04).Conclusions: In patients with mild to moderate MRI-proven AIS and unknown time of symptom onset with DWI-FLAIR mismatch, current smokers had worse functional outcome as compared to non-smokers. Current smoking did not modify the treatment effect of alteplase.Clinical Trial registration: Main trial (WAKE-UP): ClinicalTrials.gov, NCT01525290; and EudraCT, 2011-005906-32. Registered 02 February 2012.

Homogeneous application of imaging criteria in a multicenter trial supported by investigator training: A report from the WAKE-UP study

Background and PurposeWAKE-UP is a randomized, placebo-controlled trial of thrombolysis in stroke with unknown time of symptom onset using magnetic resonance imaging criteria to determine patients’ eligibility. As it is a multicenter trial, homogeneous interpretation of criteria is an important contributor to the trial’s success. We describe the investigator image training as well as results of the quality control done by the central image reading board (CIRB). MethodsInvestigators at local centers were given an imaging manual and passed a software-based image training prior to being allowed to judge images in the trial. Throughout the trial, the CIRB gave feedback to recruiting centers in cases of disagreement regarding a patient’s randomization. We evaluated the investigators performance in the image training and analyzed results of this quality control from the first 1069 screened patients. Additionally, we obtained feedback from investigators regarding their experiences with the trial. ResultsFour-hundred-and-sixty physicians from eight European countries took part in the image training, of whom 436 (95%) successfully completed it. In the trial, agreement rates between the local investigators and members of the CIRB were high for the presence of an acute ischemic lesion (94%, κ = 0.87) as well as for the judgment of infarct extent (93%, κ = 0.87). Agreement for the criterion of DWI-FLAIR mismatch was 74%, κ = 0.60. The majority of investigators reported that the DWI-FLAIR mismatch was the hardest imaging criterion to evaluate. Ninety-one percent of investigators who responded to our survey stated that the image training specifically increased their confidence when assessing the DWI-FLAIR mismatch. ConclusionsDespite its multicenter design, the WAKE-UP study has demonstrated a high level of homogeneity amongst raters in interpreting the various imaging criteria for patient randomization, including the novel criterion of DWI-FLAIR mismatch. Systematic image training increased the confidence of investigators in applying imaging criteria.

Imaging assessment of acute ischaemic stroke: a review of radiological methods.

Acute ischaemic stroke is the second largest cause of death worldwide and a cause of major physical and psychological morbidity. Current evidence based treatment includes intravenous thrombolysis (IVT) and mechanical thrombectomy (MT), both requiring careful patient selection and to be administered as quickly as possible within a limited time window from symptom onset. Imaging plays a crucial role identifying patients who may benefit from MT or IVT whilst excluding those that may be harmed. For IVT, imaging must as a minimum exclude haemorrhage, stroke mimics and provide an estimate of non-viable brain. For MT, imaging must in addition detect and characterize intra-arterial thrombus and assess the intra and extracranial arterial architecture. More advanced imaging techniques may be used to assess more accurately the volume of non-viable and potentially salvageable brain tissue. It is highly likely that further research will identify patients who would benefit from treatment beyond currently accepted time windows for IVT (4.5 h) and MT (6 h) and patients with an unknown time of symptom onset. Current evidence indicates that best outcomes are achieved when treatment is instituted as soon as possible after symptom onset. A rapid, efficient imaging pathway including interpretation is fundamental to achieving the best outcomes. This review summarizes current techniques for imaging assessment of acute stroke, highlighting strengths and limitations of each. The optimum pathway is a balance between diagnostic information, local resources, specialization and the time taken to acquire, process and interpret the data. As new evidence emerges, it is likely that the minimum required imaging data will change.

Access to Thrombolysis for Non-Resident and Resident Stroke Patients-A Registry-Based Comparative Study from Berlin.

Stroke can happen to people away from home. It is unknown whether non-resident and resident stroke patients have equal access to thrombolysis. Consecutive patients cared for by the Stroke Emergency Mobile between 2011 and 2016 after prompting suspicion of acute stroke during the emergency call were included in our registry. Patients were categorized as residents or non-residents based on their main address. Clinical characteristics, thrombolysis rates, and time intervals from symptom onset/last seen well to alarm and to thrombolysis were compared between groups adjusting for age, pre-stroke modified Rankin Scale (mRS) score, and National Institutes of Health Stroke Scale (NIHSS) score. Of 4,254 patients for whom a stroke dispatch was activated, 2,451 had ischemic or hemorrhagic strokes, including 73 non-residents. Non-resident stroke patients were younger (median 69.4 vs. 76.6 years, p < 0.001), had less pre-stroke disability (mRS ≥ 2:17.8 vs. 47.5%, p < 0.001) and less severe strokes (median NIHSS 4 vs. 5, p = 0.02). Thrombolysis rates were higher in non-residents (30.9 vs. 22.0% of ischemic stroke patients, p = 0.04) and emergency calls were made faster (symptom onset/last-seen-well-to-alarm time 35 vs. 144 min, p = 0.04). A lower proportion of non-residents had unknown time of symptom onset (21.9 vs. 46.4%, p < 0.001). For patients with known time of symptom onset, thrombolysis rates, and prehospital delays were similar among non-residents and residents. In this study, non-resident stroke patients had higher rates of thrombolysis than residents. This may be explained by a lower proportion of patients with unknown time of symptom onset.

Clinical characteristics of unknown symptom onset stroke patients with and without diffusion-weighted imaging and fluid-attenuated inversion recovery mismatch.

Background Diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) mismatch was suggested to identify stroke patients with unknown time of symptom onset likely to be within the time window for thrombolysis. Aims We aimed to study clinical characteristics associated with DWI-FLAIR mismatch in patients with unknown onset stroke. Methods We analyzed baseline MRI and clinical data from patients with acute ischemic stroke proven by DWI from WAKE-UP, an investigator-initiated, randomized, placebo-controlled trial of MRI-based thrombolysis in stroke patients with unknown time of symptom onset. Clinical characteristics were compared between patients with and without DWI-FLAIR mismatch. Results Of 699 patients included, 418 (59.8%) presented with DWI-FLAIR mismatch. A shorter delay between last seen well and symptom recognition (p = 0.0063), a shorter delay between symptom recognition and arrival at hospital (p = 0.0025), and history of atrial fibrillation (p = 0.19) were predictors of DWI-FLAIR mismatch in multivariate analysis. All other characteristics were comparable between groups. Conclusions There are only minor differences in measured clinical characteristics between unknown symptom onset stroke patients with and without DWI-FLAIR mismatch. DWI-FLAIR mismatch as an indicator of stroke onset within 4.5 h shows no relevant association with commonly collected clinical characteristics of stroke patients. Clinical Trial Registration URL: http://www.clinicaltrials.gov . Unique identifier: NCT01525290; URL: https://www.clinicaltrialsregister.eu . Unique identifier: 2011-005906-32.

Stroke With Unknown Time of Symptom Onset: Baseline Clinical and Magnetic Resonance Imaging Data of the First Thousand Patients in WAKE-UP (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke: A Randomized, Doubleblind, Placebo-Controlled Trial).

We describe clinical and magnetic resonance imaging (MRI) characteristics of stroke patients with unknown time of symptom onset potentially eligible for thrombolysis from a large prospective cohort. We analyzed baseline data from WAKE-UP (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke: A Randomized, Doubleblind, Placebo-Controlled Trial), an investigator-initiated, randomized, placebo-controlled trial of MRI-based thrombolysis in stroke patients with unknown time of symptom onset. MRI judgment included assessment of the mismatch between visibility of the acute ischemic lesion on diffusion-weighted imaging and fluid-attenuated inversion recovery. Of 1005 patients included, diffusion-weighted imaging and fluid-attenuated inversion recovery mismatch was present in 479 patients (48.0%). Patients with daytime-unwitnessed stroke (n=138, 13.7%) had a shorter delay between symptom recognition and hospital arrival (1.5 versus 1.8 hours; P=0.002), a higher National Institutes of Stroke Scale score on admission (8 versus 6; P<0.001), and more often aphasia (72.5% versus 34.0%; P<0.001) when compared with stroke patients waking up from nighttime sleep. Frequency of diffusion-weighted imaging and fluid-attenuated inversion recovery mismatch was comparable between both groups (43.7% versus 48.7%; P=0.30). Almost half of the patients with unknown time of symptom onset stroke otherwise eligible for thrombolysis had MRI findings making them likely to be within a time window for safe and effective thrombolysis. Patients with daytime onset unwitnessed stroke differ from wake-up stroke patients with regards to clinical characteristics but are comparable in terms of MRI characteristics of lesion age. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01525290. URL: https://www.clinicaltrialsregister.eu. Unique identifier: 2011-005906-32.