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Objective: Accurate identification of the ischemic penumbra, the therapeutic target in acute clinical stroke, is of critical importance to identify patients who might benefit from reperfusion therapies beyond the established time windows. Therefore, we aimed to validate magnetic resonance imaging (MRI) mismatch-based penumbra detection against full quantitative positron emission tomography ( 15 O-PET), the gold standard for penumbra detection in acute ischemic stroke., Methods: Ten patients (group A) with acute and subacute ischemic stroke underwent perfusion-weighted (PW)/diffusion-weighted MRI and consecutive full quantitative 15 O-PET within 48 hours of stroke onset. Penumbra as defined by 15 O-PET cerebral blood flow (CBF), oxygen extraction fraction, and oxygen metabolism was used to validate a wide range of established PW measures (eg, time-to-maximum [Tmax]) to optimize penumbral tissue detection. Validation was carried out using a voxel-based receiver-operating-characteristic curve analysis. The same validation based on penumbra as defined by quantitative 15 O-PET CBF was performed for comparative reasons in 23 patients measured within 48 hours of stroke onset (group B)., Results: The PW map Tmax (area-under-the-curve = 0.88) performed best in detecting penumbral tissue up to 48 hours after stroke onset. The optimal threshold to discriminate penumbra from oligemia was Tmax >5.6 seconds with a sensitivity and specificity of >80%., Interpretation: The performance of the best PW measure Tmax to detect the upper penumbral flow threshold in ischemic stroke is excellent. Tmax >5.6 seconds-based penumbra detection is reliable to guide treatment decisions up to 48 hours after stroke onset and might help to expand reperfusion treatment beyond the current time windows. ANN NEUROL 2019;85:875-886., (© 2019 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.)

Background: With regard to acute stroke, patients with unknown time from stroke onset are not eligible for thrombolysis. Quantitative diffusion weighted imaging (DWI) and fluid attenuated inversion recovery (FLAIR) MRI relative signal intensity (rSI) biomarkers have been introduced to predict eligibility for thrombolysis, but have shown heterogeneous results in the past. In the present work, we investigated whether the inclusion of easily obtainable clinical-radiological parameters would improve the prediction of the thrombolysis time window by rSIs and compared their performance to the visual DWI-FLAIR mismatch., Methods: In a retrospective study, patients from 2 centers with proven stroke with onset <12 h were included. The DWI lesion was segmented and overlaid on ADC and FLAIR images. rSI mean and SD, were calculated as follows: (mean ROI value/mean value of the unaffected hemisphere). Additionally, the visual DWI-FLAIR mismatch was evaluated. Prediction of the thrombolysis time window was evaluated by the area-under-the-curve (AUC) derived from receiver operating characteristic (ROC) curve analysis. Factors such as the association of age, National Institutes of Health Stroke Scale, MRI field strength, lesion size, vessel occlusion and Wahlund-Score with rSI were investigated and the models were adjusted and stratified accordingly., Results: In 82 patients, the unadjusted rSI measures DWI-mean and -SD showed the highest AUCs (AUC 0.86-0.87). Adjustment for clinical-radiological covariates significantly improved the performance of FLAIR-mean (0.91) and DWI-SD (0.91). The best prediction results based on the AUC were found for the final stratified and adjusted models of DWI-SD (0.94) and FLAIR-mean (0.96) and a multivariable DWI-FLAIR model (0.95). The adjusted visual DWI-FLAIR mismatch did not perform in a significantly worse manner (0.89). ADC-rSIs showed fair performance in all models., Conclusions: Quantitative DWI and FLAIR MRI biomarkers as well as the visual DWI-FLAIR mismatch provide excellent prediction of eligibility for thrombolysis in acute stroke, when easily obtainable clinical-radiological parameters are included in the prediction models., (© 2016 S. Karger AG, Basel.)

Background and Purpose: In acute stroke, the DWI-FLAIR mismatch allows for the allocation of patients to the thrombolysis window (<4.5 hours). FLAIR-lesions, however, may be challenging to assess. In comparison, DWI may be a useful bio-marker owing to high lesion contrast. We investigated the performance of a relative DWI signal intensity (rSI) threshold to predict the presence of FLAIR-lesions in acute stroke and analyzed its association with time-from-stroke-onset., Methods: In a retrospective, dual-center MR-imaging study we included patients with acute stroke and time-from-stroke-onset ≤12 hours (group A: n = 49, 1.5T; group B: n = 48, 3T). DW- and FLAIR-images were coregistered. The largest lesion extent in DWI defined the slice for further analysis. FLAIR-lesions were identified by 3 raters, delineated as regions-of-interest (ROIs) and copied on the DW-images. Circular ROIs were placed within the DWI-lesion and labeled according to the FLAIR-pattern (FLAIR+ or FLAIR-). ROI-values were normalized to the unaffected hemisphere. Adjusted and nonadjusted receiver-operating-characteristics (ROC) curve analysis on patient level was performed to analyze the ability of a DWI- and ADC-rSI threshold to predict the presence of FLAIR-lesions. Spearman correlation and adjusted linear regression analysis was performed to assess the relationship between DWI-intensity and time-from-stroke-onset., Results: DWI-rSI performed well in predicting lesions in FLAIR-imaging (mean area under the curve (AUC): group A: 0.84; group B: 0.85). An optimal mean DWI-rSI threshold was identified (A: 162%; B: 161%). ADC-maps performed worse (mean AUC: A: 0.58; B: 0.77). Adjusted regression models confirmed the superior performance of DWI-rSI. Correlation coefficents and linear regression showed a good association with time-from-stroke-onset for DWI-rSI, but not for ADC-rSI., Conclusion: An easily assessable DWI-rSI threshold identifies the presence of lesions in FLAIR-imaging with good accuracy and is associated with time-from-stroke-onset in acute stroke. This finding underlines the potential of a DWI-rSI threshold as a marker of lesion age.

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 < or =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 < or =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.

Background and Purpose: In ischemic stroke, diffusion-weighted (DW) and perfusion-weighted (PW) magnet resonance imaging (MRI) is used to define the mismatch as the therapeutic target. With positron emission tomography (PET), we characterized the metabolic patterns of tissue compartments identified by MRI and compared the volumes of mismatch to those of PET-defined penumbra., Methods: In 6 acute (median, 5.2 hours) and 7 chronic (median, 10 days) stroke patients in whom a mismatch was defined by PW/DW MRI, PET was performed (median, 120-minute delay). Cerebral blood flow (CBF), oxygen metabolism (CMRO2), and oxygen extraction fraction (OEF) was determined in the areas of DWI lesion, mismatch, and oligemia. Then, the mismatch volume was compared with the volume of penumbra., Results: DWI lesions showed impaired tissue integrity (low CMRO2 and low OEF). Mismatch areas were viable (normal CMRO2) but showed largely varying OEF. Oligemic areas had metabolic patterns comparable to normal tissue. A mismatch volume was found in all 13 patients. However, only 8 of 13 had a corresponding penumbra volume that covered only a part of the mismatch., Conclusions: Our comparative PET/MRI study confirmed the current pathophysiological hypothesis for the DWI lesion and for the oligemic areas. However, the mismatch area did not reliably detect elevated OEF and overestimated the penumbra defined by PET.