Jens Fiehler

Effect of Intravenous Thrombolysis on MRI Parameters and Functional Outcome in Acute Stroke <6 Hours

Background and Purpose— The goals of this study were to examine MRI baseline characteristics of patients with acute ischemic stroke (AIS) and to study the influence of intravenous tissue plasminogen activator (tPA) on MR parameters and functional outcome using a multicenter approach. Methods— In this open-label, nonrandomized study of AIS patients with suspected anterior circulation stroke, subjects received a multiparametric stroke MRI protocol (diffusion- and perfusion-weighted imaging and MR angiography) within 6 hours after symptom onset and on follow-up. Patients were treated either with tPA (thrombolysis group) or conservatively (no thrombolysis group). Functional outcome was assessed on day 90 (modified Rankin Score; mRS). Results— We enrolled 139 AIS patients (no thrombolysis group, n=63; thrombolysis group, n=76). Patients treated with tPA were more severely affected (National Institutes of Health Stroke Scale score, 10 versus 13;P =0.002). Recanalization rates were higher in the thrombolysis group (Thrombolysis in Myocardial Infarction criteria 1 through 3 on day 1; 66.2% versus 32.7%;P <0.001). Proximal vessel occlusions resulted in larger infarct volumes and worse outcome (P =0.02). Thrombolysis was associated with a better outcome regardless of the time point of tPA treatment (≤3 hours or 3 to 6 hours) (univariate analysis: mRS ≤2, P =0.017; mRS ≤1, P =0.023). Age (P =0.003), thrombolytic therapy at 0 to 6 hours (P =0.01), recanalization (P =0.016), lesion volume on day 7 (P =0.001), and initial National Institutes of Health Stroke Scale score (P =0.001) affected functional outcome (mRS on day 90) positively (multivariate analysis). The time point of tPA therapy affected the recanalization rate (P =0.024) but not final infarct volume. Conclusions— In this pilot study, tPA therapy had a beneficial effect on vessel recanalization and functional outcome. Multiparametric MRI delineates tissue at risk of infarction in AIS patients, which may be helpful for the selection of patients for tPA therapy. tPA therapy appeared safe and effective beyond a 3-hour time window. This study delivers the rationale for a randomized, MR-based tPA trial.

MRI-Based and CT-Based Thrombolytic Therapy in Acute Stroke Within and Beyond Established Time Windows An Analysis of 1210 Patients

Background and Purpose— The use of intravenous thrombolysis is restricted to a minority of patients by the rigid 3-hour time window. This window may be extended by using modern imaging-based selection algorithms. We assessed safety and efficacy of MRI-based thrombolysis within and beyond 3 hours compared with standard CT-based thrombolysis. Methods— Five European stroke centers pooled the core data of their CT- and MRI-based prospective thrombolysis databases. Safety outcomes were predefined as symptomatic intracranial hemorrhage and mortality. Primary efficacy outcome was a favorable outcome (modified Rankin Scale 0 to 1). We performed univariate and multivariate analyses for all end points, including age, National Institutes of Health Stroke Scale, treatment group (CT <3 hours, MRI <3 hours and >3 hours), and onset to treatment time as variables. Results— A total of 1210 patients were included (CT <3 hours: N=714; MRI <3 hours: N=316; MRI >3 hours: N=180). Median age, National Institutes of Health Stroke Scale, and onset to treatment time were 69, 67, and 68.5 years (P=0.66); 12, 13, and 14 points (P=0.019); and 130, 135, and 240 minutes (P<0.001). Symptomatic intracranial hemorrhage rates were 5.3%, 2.8%, and 4.4% (P=0.213); mortality was 13.7%, 11.7%, and 13.3% (P=0.68). Favorable outcome occurred in 35.4%, 37.0%, and 40% (P=0.51). Age and National Institutes of Health Stroke Scale were independent predictors for all safety and efficacy outcomes. The overall use of MRI significantly reduced symptomatic intracranial hemorrhage (OR: 0.520, 95% CI: 0.270 to 0.999, P=0.05). Beyond 3 hours, the use of MRI significantly predicted a favorable outcome (OR: 1.467; 95% CI: 1.017 to 2.117, P=0.040). Within 3 hours and for all secondary end points, there was a trend in favor of MRI-based selection over standard <3-hour CT-based treatment. Conclusion— Despite significantly longer time windows and significantly higher baseline National Institutes of Health Stroke Scale scores, MRI-based thrombolysis is safer and potentially more efficacious than standard CT-based thrombolysis.

Outcome and Symptomatic Bleeding Complications of Intravenous Thrombolysis Within 6 Hours in MRI-Selected Stroke Patients: Comparison of a German Multicenter Study With the Pooled Data of ATLANTIS, ECASS, and NINDS tPA Trials

Background and Purpose— We compared outcome and symptomatic bleeding complications of intravenous tissue plasminogen activator (IV-tPA) within 6 hours of symptom onset in MRI-selected patients with acute middle cerebral artery infarction with the pooled data of the large stroke tPA trials. Methods— Patients were examined by perfusion-weighted and diffusion-weighted imaging ≤6 hours. Within 3 hours, patients were treated according to Second European-Australasian Acute Stroke Study (ECASS II) criteria. After 3 to 6 hours, treatment with IV-tPA was performed based on MRI findings. Favorable outcome was assessed after 90 days using a dichotomized modified Rankin scale score of 0 to 1. Intracerebral bleeding complications were assessed on follow-up MRI or computed tomography. Data were compared with the pooled placebo and pooled tPA patients of the ATLANTIS, ECASS, and National Institute of Neurological Disorders and Stroke (NINDS) tPA trials. Results— From 174 MRI-selected tPA patients, 62% (n=108) were treated in ≤3 hours and 38% (n=66) after 3 to 6 hours. Favorable outcome was more frequent in MRI-selected tPA patients (48% [95% CI, 39 to 54]) compared with pooled placebo (33% [95% CI, 31 to 36]; P<0.001) and pooled tPA patients (40% [95% CI, 37 to 42]; P=0.046). Odds ratios for favorable outcome in the MRI-selected tPA group were 1.82 (1.32 to 2.51) compared with the pooled placebo and 1.39 (1.01 to 1.92) compared with the pooled tPA group. The rate of symptomatic intracerebral hemorrhage in MRI-selected tPA patients (3% [95% CI, 0 to 5]) was lower than in the pooled tPA group (8% [95% CI, 7 to 10]; P=0.012) and comparable to the pooled placebo group (2% [95% CI, 1 to 3]; P=0.392). Conclusions— This study supports that it is safe and effective to expand the time window for IV-tPA up to 6 hours in patients with tissue at risk as defined by MRI.

Bleeding Risk Analysis in Stroke Imaging Before ThromboLysis (BRASIL): Pooled Analysis of T2*-Weighted Magnetic Resonance Imaging Data From 570 Patients

Background and Purpose— There has been speculation that the risk of secondary symptomatic intracranial hemorrhage (SICH) may be increased after thrombolytic therapy in ischemic stroke patients who have cerebral microbleeds (CMBs) on T2*-weighted magnetic resonance imaging. Because of this concern, some centers withhold potentially beneficial thrombolytic therapy from these patients. Methods— We analyzed magnetic resonance imaging data acquired within 6 hours after symptom onset from 570 ischemic stroke patients treated with intravenous tissue plasminogen activator in 13 centers in Europe, North America, and Asia. Baseline T2*-weighted magnetic resonance images were evaluated for the presence of CMBs. The primary end point was SICH, defined as clinical deterioration with an increase in the National Institutes of Health Stroke Scale score by ≥4 points, temporally related to a parenchymal hematoma on follow-up-imaging. Results— A total of 242 CMBs were detected in 86 of 570 patients (15.1%). The number of CMBs ranged from 1 to 77 in the individual patient, with ≥5 CMBs in 6 of 570 patients (1.1%). Proportions of patients with SICH were 5.8% (95% CI, 1.9 to 13.0) in the presence of CMBs and 2.7% (95% CI, 1.4 to 4.5) in patients without CMBs (P=0.170, Fishers exact test), resulting in no significant absolute increase in the risk of SICH of 3.1% (95% CI, −2.0 to 8.3). Conclusions— The data suggest that if there is any increased risk of SICH attributable to CMBs, it is likely to be small and unlikely to exceed the benefits of thrombolytic therapy. No reliable conclusion regarding risk in the rare patient with multiple CMBs can be reached.

Predictors of Apparent Diffusion Coefficient Normalization in Stroke Patients

Background and Purpose— We sought to describe the frequency of normalization of apparent diffusion coefficient (ADC) values that are decreased in hyperacute stroke and to identify characteristics of tissue demonstrating normalization. Methods— Sixty-eight acute ischemic stroke patients underwent MRI examination (including diffusion/perfusion imaging and MR angiography) within 6 hours (mean, 2.8 hours) after symptom onset, after 24 hours, and again 4 to 7 days later. Lesion volumes with decreased ADC and delayed time to peak in perfusion imaging were determined. In patients showing ADC normalization, volumes with ADC decrease graded as <50%, 50% to 60%, 60% to 70%, and 70% to 80% of the contralateral value were determined by thresholding. Patients were categorized as normalizers (demonstrating ADC normalization in >5 mL tissue with initially decreased ADC) or nonnormalizers (demonstrating ADC normalization in <5 mL tissue). Results— Fourteen patients (19.7%) were classified as normalizers. Eleven of 31 patients (35.5%) initially imaged <3 hours after stroke onset and 3 of 37 (7.5%) of those imaged 3 to 6 hours after onset were normalizers. ADC normalization occurred predominantly in the basal ganglia and white matter after thrombolytic therapy in patients with more distal vessel occlusions. All normalizers demonstrated at least partial tissue reperfusion. Tissue with more severe initial decrease in ADC was less likely to demonstrate normalization. Conclusions— ADC normalization is not a rare event in acute stroke after tissue reperfusion. Brain tissue with initially decreased ADC, especially within 3 hours after stroke onset, may include “tissue at risk.”

Leukoaraiosis Is a Risk Factor for Symptomatic Intracerebral Hemorrhage After Thrombolysis for Acute Stroke

Background and Purpose— The aim of the study was to evaluate whether leukoaraiosis (LA) is a risk factor for symptomatic intracerebral hemorrhage (sICH) in patients treated with thrombolysis for acute stroke. Methods— In this retrospective, multicenter analysis, we evaluated data from acute anterior circulation stroke patients (n=449; <6 hours after symptom onset) treated with thrombolysis. All patients had received standard magnetic resonance imaging evaluation before thrombolysis, including a high-quality T2-weighted sequence. For the analysis, LA in the deep white matter was dichotomized into absent or mild versus moderate or severe (corresponding to Fazekas scores of 0 to 1 versus 2 to 3). Results— The rate of sICH was significantly more frequent in patients with moderate to severe LA of the deep white matter (n=12 of 114; 10.5%) than in patients without relevant LA (n=13 of 335; 3.8%), corresponding to an odds ratio of 2.9 (95% CI, 1.29 to 6.59; P=0.015). In a logistic-regression analysis (including age, National Institutes of Health Stroke Scale score at presentation, and type of thrombolytic treatment), LA remained a significant independent risk factor (odds ratio, 2.9; P=0.03). Conclusions— LA of the deep white matter is an independent risk factor for sICH after thrombolytic treatment for acute stroke.

Prediction of Malignant Middle Cerebral Artery Infarction by Early Perfusion- and Diffusion-Weighted Magnetic Resonance Imaging

Background and Purpose— We tested the hypothesis that early diffusion- and perfusion-weighted MRI (DWI and PWI, respectively) allows the prediction of malignant middle cerebral artery (MCA) infarction (MMI). Methods— Thirty-seven patients with acute MCA infarction and proximal vessel occlusion (carotid-T, MCA main stem) were studied by DWI, PWI, and MR angiography within 6 hours of symptom onset. Eleven patients developed MMI, defined by decline of consciousness and radiological signs of space-occupying brain edema. Lesion volumes were retrospectively defined as apparent diffusion coefficient <80% (ADC<80%) and time to peak >+4 seconds (TTP>+4s) compared with the unaffected hemisphere. ADC decrease within the infarct core (ADCcore) and relative ADC within the ADC<80% lesion (rADClesion) were measured. Neurological deficit at admission was assessed with the National Institutes of Health Stroke Scale (NIHSS). Results— Patients with MMI showed larger ADC<80% (median, 157 versus 22 mL; P <0.001) and TTP>+4s (208 versus 125 mL; P <0.001) lesion volumes, smaller TTP/ADC mismatch ratio (1.5 versus 5.5; P <0.001), lower ADCcore values (290 versus 411 mm2/s; P <0.001), lower rADClesion (0.60 versus 0.66; P =0.001), higher frequency of carotid-T occlusion (64% versus 15%; P =0.006), and higher NIHSS score at admission (20 versus 15; P =0.001). Predictors of MMI were as follows for sensitivity and specificity, respectively: ADC<80% >82 mL, 87%, 91%; TTP>+4s >162 mL, 83%, 75%; TTP/ADC mismatch ratio <2.4, 80%, 79%; ADCcore <300 mm2/s, 83%, 85%; rADClesion <0.62, 79%, 74%; and NIHSS score at admission ≥19, 96%, 72%. Conclusions— Quantitative analysis of early DWI and PWI parameters allows the prediction of MMI and can help in the selection of patients for aggressive tissue-protective therapy.

Risk for symptomatic intracerebral hemorrhage after thrombolysis assessed by diffusion-weighted magnetic resonance imaging†

The risk for symptomatic intracerebral hemorrhage (sICH) associated with thrombolytic treatment has not been evaluated in large studies using diffusion‐weighted imaging (DWI). Here, we investigated the relation between pretreatment DWI lesion size and the risk for sICH after thrombolysis.

Mechanical thrombectomy in acute ischemic stroke: Consensus statement by ESO-Karolinska Stroke Update 2014/2015, supported by ESO, ESMINT, ESNR and EAN

The original version of this consensus statement on mechanical thrombectomy was approved at the European Stroke Organisation (ESO)-Karolinska Stroke Update conference in Stockholm, 16–18 November 2014. The statement has later, during 2015, been updated with new clinical trials data in accordance with a decision made at the conference. Revisions have been made at a face-to-face meeting during the ESO Winter School in Berne in February, through email exchanges and the final version has then been approved by each society. The recommendations are identical to the original version with evidence level upgraded by 20 February 2015 and confirmed by 15 May 2015. The purpose of the ESO-Karolinska Stroke Update meetings is to provide updates on recent stroke therapy research and to discuss how the results may be implemented into clinical routine. Selected topics are discussed at consensus sessions, for which a consensus statement is prepared and discussed by the participants at the meeting. The statements are advisory to the ESO guidelines committee. This consensus statement includes recommendations on mechanical thrombectomy after acute stroke. The statement is supported by ESO, European Society of Minimally Invasive Neurological Therapy (ESMINT), European Society of Neuroradiology (ESNR), and European Academy of Neurology (EAN).

Clinical and angiographic risk factors for stroke and death within 30 days after carotid endarterectomy and stent- protected angioplasty: a subanalysis of the SPACE study

BACKGROUND Carotid endarterectomy (CEA) and carotid artery stenting (CAS) are used to prevent ischaemic stroke in patients with stenosis of the internal carotid artery. Better knowledge of risk factors could improve assignment of patients to these procedures and reduce overall risk. We aimed to assess the risk of stroke or death associated with CEA and CAS in patients with different risk factors. METHODS We analysed data from 1196 patients randomised to CAS or CEA in the Stent-Protected Angioplasty versus Carotid Endarterectomy in Symptomatic Patients (SPACE) trial. The primary outcome event was death or ipsilateral stroke (ischaemic or haemorrhagic) with symptoms that lasted more than 24 h between randomisation and 30 days after therapy. Six predefined variables were assessed as potential risk factors for this outcome: age, sex, type of qualifying event, side of intervention, degree of stenosis, and presence of high-grade contralateral stenosis or occlusion. The SPACE trial is registered at Current Controlled Trials, with the international standard randomised controlled trial number ISRCTN57874028. FINDINGS Risk of ipsilateral stroke or death increased significantly with age in the CAS group (p=0.001) but not in the CEA group (p=0.534). Classification and regression tree analysis showed that the age that gave the greatest separation between high-risk and low-risk populations who had CAS was 68 years: the rate of primary outcome events was 2.7% (8/293) in patients who were 68 years old or younger and 10.8% (34/314) in older patients. Other variables did not differ between the CEA and CAS groups. INTERPRETATION Of the predefined covariates, only age was significantly associated with the risk of stroke and death. The lower risk after CAS versus CEA in patients up to 68 years of age was not detectable in older patients. This finding should be interpreted with caution because of the drawbacks of post-hoc analyses.