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In this study we explore the spatio-temporal trajectory and clinical relevance of microstructural white matter changes within and beyond subcortical stroke lesions detected by free-water imaging. Twenty-seven patients with subcortical infarct with mean age of 66.73 (SD 11.57) and median initial NIHSS score of 4 (IQR 3-7) received diffusion MRI 3-5 days, 1 month, 3 months, and 12 months after symptom-onset. Extracellular free-water and fractional anisotropy of the tissue (FA T ) were averaged within stroke lesions and the surrounding tissue. Linear models showed increased free-water and decreased FA T in the white matter of patients with subcortical stroke (lesion [free-water/FA T , mean relative difference in %, ipsilesional vs. contralesional hemisphere at 3-5 days, 1 month, 3 months, and 12 months after symptom-onset]: +41/-34, +111/-37, +208/-26, +251/-18; perilesional tissue [range in %]: +[5-24]/-[0.2-7], +[2-20]/-[3-16], +[5-43]/-[2-16], +[10-110]/-[2-12]). Microstructural changes were most prominent within the lesion and gradually became less pronounced with increasing distance from the lesion. While free-water elevations continuously increased over time and peaked after 12 months, FA T decreases were most evident 1 month post-stroke, gradually returning to baseline values thereafter. Higher perilesional free-water and higher lesional FA T at baseline were correlated with greater reductions in lesion size (rho = -0.51, p = .03) in unadjusted analyses only, while there were no associations with clinical measures. In summary, we find a characteristic spatio-temporal pattern of extracellular and cellular alterations beyond subcortical stroke lesions, indicating a dynamic parenchymal response to ischemia characterized by vasogenic edema, cellular damage, and white matter atrophy., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

Cerebral small vessel disease is a common finding in the elderly and associated with various clinical sequelae. Previous studies suggest disturbances in the integration capabilities of structural brain networks as a mediating link between imaging and clinical presentations. To what extent cerebral small vessel disease might interfere with other measures of global network topology is not well understood. Connectomes were reconstructed via diffusion weighted imaging in a sample of 930 participants from a population based epidemiologic study. Linear models were fitted testing for an association of graph-theoretical measures reflecting integration and segregation with both the Peak width of Skeletonized Mean Diffusivity (PSMD) and the load of white matter hyperintensities of presumed vascular origin (WMH). The latter were subdivided in periventricular and deep for an analysis of localisation-dependent correlations of cerebral small vessel disease. The median WMH volume was 0.6 mL (1.4) and the median PSMD 2.18 mm 2 /s x 10 -4 (0.5). The connectomes showed a median density of 0.880 (0.030), the median values for normalised global efficiency, normalised clustering coefficient, modularity Q and small-world propensity were 0.780 (0.045), 1.182 (0.034), 0.593 (0.026) and 0.876 (0.040) respectively. An increasing burden of cerebral small vessel disease was significantly associated with a decreased integration and increased segregation and thus decreased small-worldness of structural brain networks. Even in rather healthy subjects increased cerebral small vessel disease burden is accompanied by topological brain network disturbances. Segregation parameters and small-worldness might as well contribute to the understanding of the known clinical sequelae of cerebral small vessel disease., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Purpose: In acute ischemic stroke with unknown time of onset, magnetic resonance (MR)-based diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) estimates lesion age to guide intravenous thrombolysis. Computed tomography (CT)-based quantitative net water uptake (NWU) may be a potential alternative. The purpose of this study was to directly compare CT-based NWU to magnetic resonance imaging (MRI) at identifying patients with lesion age < 4.5 hours from symptom onset., Methods: Fifty patients with acute anterior circulation stroke were analyzed with both imaging modalities at admission between 0.5 and 8.0 hours after known symptom onset. DWI-FLAIR lesion mismatch was rated and NWU was measured in admission CT. An established NWU threshold (11.5%) was used to classify patients within and beyond 4.5 hours. Multiparametric MRI signal was compared with NWU using logistic regression analyses. The empirical distribution of NWU was analyzed in a consecutive cohort of patients with wake-up stroke., Results: The median time between CT and MRI was 35 minutes (interquartile range [IQR] = 24-50). The accuracy of DWI-FLAIR mismatch was 68.8% (95% confidence interval [CI] = 53.7-81.3%) with a sensitivity of 58% and specificity of 82%. The accuracy of NWU threshold was 86.0% (95% CI = 73.3-94.2%) with a sensitivity of 91% and specificity of 78%. The area under the curve (AUC) of multiparametric MRI signal to classify lesion age <4.5 hours was 0.86 (95% CI = 0.64-0.97), and the AUC of quantitative NWU was 0.91 (95% CI = 0.78-0.98). Among 87 patients with wake-up stroke, 46 patients (53%) showed low NWU (< 11.5%)., Conclusion: The predictive power of CT-based lesion water imaging to identify patients within the time window of thrombolysis was comparable to multiparametric DWI-FLAIR MRI. A significant proportion of patients with wake-up stroke exhibit low NWU and may therefore be potentially suitable for thrombolysis. ANN NEUROL 2020;88:1144-1152., (© 2020 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Purpose: Lacunar infarcts are thought to result from occlusion of small penetrating arteries due to microatheroma and lipohyalinosis, pathognomonic for cerebral small vessel disease (CSVD). Concurrent embolic ischemic lesions indicate a different stroke mechanism. The purpose of this study was to examine the clinical characteristics and outcome of patients with lacunar infarcts and concurrent embolic infarcts on diffusion-weighted imaging (DWI)., Methods: All patients screened for the WAKE-UP trial (ClinicalTrials.gov number, NCT01525290) were reviewed for acute lacunar infarcts and concurrent embolic lesions on baseline DWI. Clinical characteristics and outcome were compared between lacunar infarct patients with and without concurrent embolic lesions., Results: Of 244 patients with an acute lacunar infarct, 20 (8.2%) had concurrent acute embolic infarcts. Compared to patients with a lacunar infarct only, patients with concurrent embolic infarcts were older (mean age 69 years vs. 63 years; p = 0.031), more severely affected (median National Institutes of Health Stroke Scale [NIHSS] score 5 vs. 4; p = 0.046), and-among those randomized-had worse functional outcome at 90 days (median modified Rankin Scale [mRS] 3 vs. 1; p = 0.011)., Conclusion: Approximately 8% of lacunar infarct patients show concurrent embolic lesions suggesting a stroke etiology other than CSVD. These patients are more severely affected and have a worse functional outcome illustrating the need for a thorough diagnostic work-up of possible embolic sources even in patients with an imaging-defined diagnosis of lacunar infarcts.

Background and Aim: To analyze the incidence of peripheral emboli after successful mechanical thrombectomy (MT) of intracranial large vessel occlusions (LVO)., Methods: We performed a prospective analysis of patients with intracranial LVO who underwent successful MT and received a 1.5 T MRI including diffusion-weighted imaging (DWI) in standard- and high-resolution as well as susceptibility-weighted imaging (SWI) on the day following the intervention. Reperfusion grade was assessed on post-thrombectomy digital subtraction angiography (DSA) using the expanded thrombolysis in cerebral infarction (eTICI) scale. Punctuate DWI lesions distal to the DWI core lesion were classified as peripheral emboli. DWI lesions outside the primary affected vascular territory were classified as emboli into new territories. Additionally, SWI and post-thrombectomy DSA were analyzed and correlated to findings on DWI., Results: Twenty-eight patients undergoing successful MT met the inclusion criteria. In 26/28 patients (93%), a total of 324 embolic lesions were detected in DWI representing 2.1% of the cumulated ischemic core volume. 151 peripheral emboli were detected in standard-resolution DWI, 173 additional emboli were uncovered in high-resolution DWI. Eight out of nine patients with an eTICI 3 reperfusion had embolic lesions (29 DWI lesions). 9.6% (31/324) of peripheral emboli were observed in vascular territories not affected by the LVO. SWI lesions were observed in close proximity to 10.2% (33/324) of DWI lesions., Conclusions: Peripheral emboli are frequent after MT even after complete reperfusion. These emboli occur rather in the vascular territory of the occluded vessel than in other territories. A large proportion of peripheral emboli is only detected by high-resolution DWI.

Objectives: The aim of the present study was to assess the association between collateral status and DWI-FLAIR mismatch in patients with acute ischemic stroke within the 4.5 h time-window., Methods: We analysed DWI, FLAIR, and PWI data in patients within 4.5 h after symptom onset from the I-KNOW European database. Collateral flow maps were graded by analyzing contrast 'staining' extent over the early, mid and late perfusion phases. ADC values, DWI lesion volume, and normalised perfusion parameters (CBV,Tmax) within DWI lesions were determined. Visibility of parenchymal hyperintensivty on FLAIR was evaluated ("FLAIR positive"), and DWI-FLAIR mismatch was assessed. Spontaneously reperfused regions were defined as voxels with Tmax <6 s within the DWI lesion. Final infarct size was assessed on day-30 FLAIR images., Results: Of the 168 patients included in I-KNOW database, 87 were eligible for this study. DWI-FLAIR mismatch was present in 69 patients. There was no difference between poor and good collaterals status according to age, sex, baseline NIHSS score, time to MRI and DWI lesion volume. Collateral status was significantly better in the FLAIR positive group (p = .001). Patients with poor collaterals had significantly increased Tmax (p = .005). Baseline DWI lesion volume and final lesion volume were significantly smaller in patients with good collateral status (p < .001 and 0.01, respectively)., Conclusions: We found that patients with early FLAIR lesion visibility have a better collateral status. This finding has implications for the management of stroke patients with unknown time-of-onset, and more widely should be considered in the current context of extending the therapeutic window., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: To develop an automated model based on diffusion-weighted imaging (DWI) to detect patients within 4.5 hours after stroke onset and compare this method to the visual DWI-FLAIR (fluid-attenuated inversion recovery) mismatch., Methods: We performed a subanalysis of the "DWI-FLAIR mismatch for the identification of patients with acute ischemic stroke within 4.5 hours of symptom onset" (PRE-FLAIR) and the "AX200 for ischemic stroke" (AXIS 2) trials. We developed a prediction model with data from the PRE-FLAIR study by backward logistic regression with the 4.5-hour time window as dependent variable and the following explanatory variables: age and median relative DWI (rDWI) signal intensity, interquartile range (IQR) rDWI signal intensity, and volume of the core. We obtained the accuracy of the model to predict the 4.5-hour time window and validated our findings in an independent cohort from the AXIS 2 trial. We compared the receiver operating characteristic curve to the visual DWI-FLAIR mismatch., Results: In the derivation cohort of 118 patients, we retained the IQR rDWI as explanatory variable. A threshold of 0.39 was most optimal in selecting patients within 4.5 hours after stroke onset resulting in a sensitivity of 76% and specificity of 63%. The accuracy was validated in an independent cohort of 200 patients. The predictive value of the area under the curve of 0.72 (95% confidence interval 0.64-0.80) was similar to the visual DWI-FLAIR mismatch (area under the curve = 0.65; 95% confidence interval 0.58-0.72; p for difference = 0.18)., Conclusions: An automated analysis of DWI performs at least as good as the visual DWI-FLAIR mismatch in selecting patients within the 4.5-hour time window., (© 2018 American Academy of Neurology.)

Background and Purpose: Acute stroke patients with unknown time of symptom onset are ineligible for thrombolysis. The diffusion-weighted imaging and fluid-attenuated inversion recovery (FLAIR) mismatch is a reasonable predictor of stroke within 4.5 hours of symptom onset, and its clinical usefulness in selecting patients for thrombolysis is currently being investigated. The accuracy of the visual mismatch rating is moderate, and we hypothesized that the predictive value of stroke onset within 4.5 hours could be improved by including various clinical and imaging parameters., Methods: In this study, 141 patients in whom magnetic resonance imaging was obtained within 9 hours after symptom onset were included. Relative FLAIR signal intensity was calculated in the region of nonreperfused core. Mean Tmax was calculated in the total region with Tmax >6 s. Mean relative FLAIR, mean Tmax, lesion volume with Tmax >6 s, age, site of arterial stenosis, core volume, and location of infarct were analyzed by logistic regression to predict stroke onset time before or after 4.5 hours., Results: Receiver-operating characteristic curve analysis revealed an area under the curve of 0.68 (95% confidence interval 0.59-0.78) for the visual diffusion-weighted imaging/FLAIR mismatch, thereby correctly classifying 69% of patients with an onset time before or after 4.5 hours. Age, relative FLAIR, and Tmax increased the accuracy significantly (P<0.01) to an area under the curve of 0.82 (95% confidence interval 0.74-0.89). This new predictive model correctly categorized 77% of patients according to stroke onset before versus after 4.5 hours., Conclusions: In patients with unknown stroke onset, the accuracy of predicting time from symptom onset within 4.5 hours is improved by obtaining relative FLAIR and perfusion imaging., (© 2016 American Heart Association, Inc.)

Background and Purpose: Our aim was to explore whether the mismatch in lesion visibility between b1000 and b0 images is an alternative to mismatch between diffusion-weighted imaging and fluid-attenuated inversion recovery imaging as a surrogate marker of stroke age., Methods: We analyzed patients from the European multicenter I-KNOW database. Independent readers assessed the visibility of ischemic lesions of the anterior circulation on b0 and fluid-attenuated inversion recovery imaging images. The signal-intensity ratio for b0 and fluid-attenuated inversion recovery imaging images was also measured from the segmented stroke lesion volume on b1000 images., Results: This study included 112 patients (68 men; mean age, 67.4 years) with stroke onset within (n=85) or longer than (n=27) 4.5 hours. b1000-b0 mismatch identified patients within 4.5 hours of stroke onset with moderate sensitivity (72.9%; 95% confidence interval [CI], 63.5-82.4) and specificity (70.4%; 95% CI, 53.2-87.6), high positive predictive value (88.6%; 95% CI, 81.1-96.0), and low negative predictive value (45.2%; 95% CI, 30.2-60.3). Global comparison of b1000-b0 mismatch with diffusion-weighted imaging-fluid-attenuated inversion recovery imaging mismatch (considered the imaging gold standard) indicated high sensitivity (85.9%; 95% CI, 78.2-93.6), specificity (91.2%; 95% CI, 76.3-98.1), and positive predictive value (96.7%; 95% CI, 88.0-99.1) and moderate negative predictive value (73.8%; 95% CI, 60.5-87.1) of this new approach. b0 signal-intensity ratio (r=0.251; 95% CI, 0.069-0.417; P=0.008) was significantly although weakly correlated with delay between stroke onset and magnetic resonance imaging., Conclusions: b1000-b0 mismatch may identify patients with ischemic stroke of the within 4.5 hours of onset with high positive predictive value, perhaps constituting an alternative imaging tissue clock., (© 2016 American Heart Association, Inc.)

Background: In acute ischemic stroke (AIS), gray matter (GM) and white matter (WM) have different vulnerabilities to ischemia. Thus, we compared the evolution of ischemic lesions within WM and GM using MRI., Methods: From a European multicenter prospective database (I-KNOW), available T1-weighted images were identified for 50 patients presenting with an anterior AIS and a perfusion weighted imaging (PWI)/diffusion weighted imaging (DWI) mismatch ratio of 1.2 or more. Six lesion compartments were outlined: initial DWI (b = 1,000 s/mm2) lesion, initial PWI-DWI mismatch (Tmax >4 s and DWI-negative), final infarct mapped on 1-month fluid-attenuated inversion recovery (FLAIR) imaging, lesion growth between acute DWI and 1-month FLAIR, DWI lesion reversal at 1 month and salvaged mismatch. The WM and GM were segmented on T1-weighted images, and all images were co-registered within subjects to the baseline MRI. WM and GM proportions were calculated for each compartment., Results: Fifty patients were eligible for the study. Median delay between symptom onset and baseline MRI was 140 min. The percentage of WM was significantly greater in the following compartments: initial mismatch (52.5 vs. 47.5%, p = 0.003), final infarct (56.7 vs. 43.3%, p < 0.001) and lesion growth (58.9 vs. 41.2%, p < 0.001). No significant difference was found between GM and WM percentages within the initial DWI lesion, DWI reversal and salvaged mismatch compartments., Conclusions: Ischemic lesions may extend preferentially within the WM. Specific therapeutic strategies targeting WM ischemic processes may deserve further investigation., (© 2016 S. Karger AG, Basel.)

The perfusion-/diffusion-weighted imaging (PWI/DWI) mismatch and the diffusion/fluid attenuated inversion recovery (DWI/FLAIR) mismatch are magnetic resonance imaging (MRI) markers of evolving brain ischemia. We examined whether the DWI/FLAIR mismatch was independently associated with the PWI/DWI mismatch. Furthermore, we determined whether the presence of the DWI/FLAIR mismatch in patients with the PWI/DWI mismatch would provide additional information regarding last seen normal time (LTM). We used data from the 'AX200 for ischemic stroke' trial (AXIS 2 study NCT00927836). We studied the association between the presence of the DWI/FLAIR and PWI/DWI mismatch, baseline National Institute of Health Stroke Scale (NIHSS), age, ischemic-core volume, gender, intravenous (IV) tissue plasminogen activator (tPA), and perfusion-mismatch volume in univariate analysis. Significant variables (P<0.05) were added into the final multivariate model. We analyzed 197 patients. Seventy-two (37%) had both the PWI/DWI and the DWI/FLAIR mismatch. Patients with the double mismatch pattern had a shorter LTM than patients with the PWI/DWI mismatch alone (Median difference 90 minutes, P<0.01). Multivariate analysis confirmed the independent association between the two mismatch patterns (odds ratio (OR) 2.6, 95% confidence interval (CI) 1.2 to 5.4). Our study implies that the DWI/FLAIR mismatch and PWI/DWI mismatch are strongly associated, independent from LTM. Furthermore, in the presence of the PWI/DWI mismatch, the DWI/FLAIR pattern indicates a shorter LTM. This could have implications in selecting patients for reperfusion therapy.

Background and Purpose: Alberta Stroke Program Early Computed Tomographic Score (ASPECTS) has been used to estimate diffusion-weighted imaging (DWI) lesion volume in acute stroke. We aimed to assess correlations of DWI-ASPECTS with lesion volume in different middle cerebral artery (MCA) subregions and reproduce existing ASPECTS thresholds of a malignant profile defined by lesion volume ≥100 mL., Methods: We analyzed data of patients with MCA stroke from a prospective observational study of DWI and fluid-attenuated inversion recovery in acute stroke. DWI-ASPECTS and lesion volume were calculated. The population was divided into subgroups based on lesion localization (superficial MCA territory, deep MCA territory, or both). Correlation of ASPECTS and infarct volume was calculated, and receiver-operating characteristics curve analysis was performed to identify the optimal ASPECTS threshold for ≥100-mL lesion volume., Results: A total of 496 patients were included. There was a significant negative correlation between ASPECTS and DWI lesion volume (r=-0.78; P<0.0001). With regards to lesion localization, correlation was weaker in deep MCA region (r=-0.19; P=0.038) when compared with superficial (r=-0.72; P<0.001) or combined superficial and deep MCA lesions (r=-0.72; P<0.001). Receiver-operating characteristics analysis revealed ASPECTS≤6 as best cutoff to identify ≥100-mL DWI lesion volume; however, positive predictive value was low (0.35)., Conclusions: ASPECTS has limitations when lesion location is not considered. Identification of patients with malignant profile by DWI-ASPECTS may be unreliable. ASPECTS may be a useful tool for the evaluation of noncontrast computed tomography. However, if MRI is used, ASPECTS seems dispensable because lesion volume can easily be quantified on DWI maps., (© 2014 American Heart Association, Inc.)

In patients with malignant middle cerebral artery infarction (MMI) decompressive surgery within 48 h improves functional outcome. In this respect, early identification of patients at risk of developing MMI is crucial. While the acute diffusion weighted imaging (DWI) lesion volume was found to predict MMI with high predictive values, the potential impact of preexisting brain atrophy on the course of space-occupying middle cerebral artery (MCA) infarction and the development of MMI remains unclear. We tested the hypothesis that the combination of the acute DWI lesion volume with simple measures of brain atrophy improves the early prediction of MMI. Data from a prospective, multicenter, observational study, which included patients with acute middle cerebral artery main stem occlusion studied by MRI within 6 h of symptom onset, was analyzed retrospectively. The development of MMI was defined according to the European randomized controlled trials of decompressive surgery. Acute DWI lesion volume, as well as brain and cerebrospinal fluid volume (CSF) were delineated. The intercaudate distance (ICD) was assessed as a linear brain atrophy marker by measuring the hemi-ICD of the intact hemisphere to account for local brain swelling. Binary logistic regression analysis was used to identify significant predictors of MMI. Cut-off values were determined by Classification and Regression Trees analysis. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the resulting models were calculated. Twenty-one (18 %) of 116 patients developed a MMI. Malignant middle cerebral artery infarctions patients had higher National Institutes of Health Stroke Scale scores on admission and presented more often with combined occlusion of the internal carotid artery and MCA. There were no differences in brain and CSF volume between the two groups. Diffusion weighted imaging lesion volume was larger (p < 0.001), while hemi-ICD was smaller (p = 0.029) in MMI patients. Inclusion of hemi-ICD improved the prediction of MMI. Best cut-off values to predict the development of MMI were DWI lesion volume > 87 ml and hemi-ICD ≤ 9.4 mm. The addition of hemi-ICD to the decision tree strongly increased PPV (0.93 vs. 0.70) resulting in a reduction of false positive findings from 7/23 (30 %) to 1/15 (7 %), while there were only slight changes in specificity, sensitivity and NPV. The absolute number of correct classifications increased by 4 (3.4 %). The integration of hemi-ICD as a linear marker of brain atrophy, that can easily be assessed in an emergency setting, may improve the prediction of MMI by lesion volume based predictive models.

The aim of this study is to investigate whether different spatial perfusion-deficit patterns, which indicate differing compensatory mechanisms, can be recognized and used to predict recanalization success of intravenous fibrinolytic therapy in acute stroke patients. Twenty-seven acute stroke data sets acquired within 6 hours from symptom onset including diffusion- (DWI) and perfusion-weighted magnetic resonance (MR) imaging (PWI) were analyzed and dichotomized regarding recanalization outcome using time-of-flight follow-up data sets. The DWI data sets were used for calculation of apparent diffusion coefficient (ADC) maps and subsequent infarct core segmentation. A patient-individual three-dimensional (3D) shell model was generated based on the segmentation and used for spatial analysis of the ADC as well as cerebral blood volume (CBV), cerebral blood flow, time to peak (TTP), and mean transit time (MTT) parameters derived from PWI. Skewness, kurtosis, area under the curve, and slope were calculated for each parameter curve and used for classification (recanalized/nonrecanalized) using a LogitBoost Alternating Decision Tree (LAD Tree). The LAD tree optimization revealed that only ADC skewness, CBV kurtosis, and MTT kurtosis are required for best possible prediction of recanalization success with a precision of 85%. Our results suggest that the propensity for macrovascular recanalization after intravenous fibrinolytic therapy depends not only on clot properties but also on distal microvascular bed perfusion. The 3D approach for characterization of perfusion parameters seems promising for further research.

Background and Purpose: WAKE-UP is a randomized, placebo-controlled MRI-based trial of thrombolysis in wake-up stroke using the mismatch between a lesion's visibility in diffusion-weighted imaging and fluid-attenuated inversion recovery (FLAIR) sequences as its main imaging inclusion criterion. Visual judgment of lesion conspicuity on FLAIR is however methodically limited by moderate inter-rater agreement. We therefore sought to improve rating homogeneity by incorporating quantitative signal intensity measurements., Methods: One hundred forty-three data sets of patients with acute ischemic stroke were visually rated by 8 raters with respect to WAKE-UP study inclusion and exclusion criteria, and inter-rater agreement was calculated. A subanalysis was performed on 45 cases to determine a threshold value of relative signal intensity (rSI) between the ischemic lesion and contralateral healthy tissue which best corresponded to a visually established verdict of FLAIR positivity. The usefulness of this threshold in improving inter-rater agreement was evaluated in an additional sample of 50 patients., Results: Inter-rater agreement for inclusion into the WAKE-UP trial was 73% with a free-marginal κ of 0.46. A threshold of rSI which best correlated with the visual rating of lesions as FLAIR positive was 1.20. The addition of rSI measurements to visual evaluation did not change the inter-rater agreement., Conclusions: Introducing a semiquantitative measure for FLAIR rSI did not improve the agreement between individual raters. However, enhancing visual assessment with rSI measurements can provide reassurance to local investigators in cases of uncertainty.

Background and Purpose: The mismatch between lesions identified in perfusion- and diffusion-weighted MR imaging is typically used to identify tissue at risk of infarction in acute stroke. The purpose of this study was to analyze the variability of mismatch volumes resulting from different time-to-peak or time-to-maximum estimation techniques used for hypoperfused tissue definition., Materials and Methods: Data of 50 patients with middle cerebral artery stroke and intracranial vessel occlusion imaged within 6 hours of symptom onset were analyzed. Therefore, 10 different TTP/Tmax techniques and delay thresholds between +2 and +12 seconds were used for calculation of perfusion lesions. Diffusion lesions were semiautomatically segmented and used for mismatch quantification after registration., Results: Mean volumetric differences up to 40 and 100 mL in individual patients were found between the mismatch volumes calculated by the 10 TTP/Tmax estimation techniques for typically used delay thresholds. The application of typical criteria for the identification of patients with a clinically relevant mismatch volume resulted in different mismatch classifications in ≤24% of all cases, depending on the TTP/Tmax estimation method used., Conclusions: High variations of tissue-at-risk volumes have to be expected when using different TTP/Tmax estimation techniques. An adaption of different techniques by using correction formulas may enable more comparable study results until a standard has been established by agreement.

In acute stroke magnetic resonance imaging, a 'mismatch' between visibility of an ischemic lesion on diffusion-weighted imaging (DWI) and missing corresponding parenchymal hyperintensities on fluid-attenuated inversion recovery (FLAIR) data sets was shown to identify patients with time from symptom onset ≤4.5 hours with high specificity. However, moderate sensitivity and suboptimal interpreter agreement are limitations of a visual rating of FLAIR lesion visibility. We tested refined image analysis methods in patients included in the previously published PREFLAIR study using refined visual analysis and quantitative measurements of relative FLAIR signal intensity (rSI) from a three-dimensional, segmented stroke lesion volume. A total of 399 patients were included. The rSI of FLAIR lesions showed a moderate correlation with time from symptom onset (r=0.382, P<0.001). A FLAIR rSI threshold of <1.0721 predicted symptom onset ≤4.5 hours with slightly increased specificity (0.85 versus 0.78) but also slightly decreased sensitivity (0.47 versus 0.58) as compared with visual analysis. Refined visual analysis differentiating between 'subtle' and 'obvious' FLAIR hyperintensities and classification and regression tree algorithms combining information from visual and quantitative analysis also did not improve diagnostic accuracy. Our results raise doubts whether the prediction of stroke onset time by visual image judgment can be improved by quantitative rSI measurements.

Purpose: Few magnetic resonance imaging (MRI) studies of stroke have evaluated the value of visual assessment of perfusion/diffusion mismatch, which is crucial for routine application. In this study an attempt was made to visually assess perfusion lesions resembling the acute clinical situation and identify parameters with the highest interobserver reliability when used to define a perfusion/diffusion mismatch and the highest accuracy for prediction of infarct growth., Methods: Magnetic resonance imaging was performed within 6 h of symptom onset and again 1-11 days thereafter in 86 consecutive stroke patients who received intravenous thrombolytic therapy. The MRI protocol included diffusion-weighted imaging apparent diffusion coefficient (DWI/ADC), fluid-attenuated inversion recovery (FLAIR) and perfusion imaging (PI). Maps for different perfusion parameters, e.g. cerebral blood volume (CBV), cerebral blood flow (CBF), mean transit time (MTT) and time to peak (TTP) were calculated. Areas of perfusion deficits of all perfusion parameters were visually compared to corresponding ADCs and final infarct size by two independent observers., Results: The final infarct size was overestimated by TTP (in 81/83 patients by raters 1 and 2, respectively), MTT (82/83) and CBF (65/74) lesions. The ADC lesions were rated smaller than the final infarct size in 43/38 cases by raters 1 and 2 and the CBV decrease was rated to underestimate final infarct size in 40/31 cases. The only significantly increased OR of 3.883 (95 % CI 1.466-10.819, p = 0.004, rater 1)/5.142 (95 % CI 1.828-15.142, p = 0.001, rater 2) for predicting infarct growth was observed for the presence of a CBV > ADC mismatch, which also showed the highest kappa value of 0.407., Conclusions: All mismatch patterns were prone to high interrater variability when assessed under conditions resembling the clinical setting. Of all tested mismatch patterns the CBV > ADC mismatch was the strongest predictor of lesion growth while visual assessment of TTP and CBF generally resulted in an overestimation of infarct sizes and the presence of a TTP > ADC or CBF > ADC mismatch was not significantly predictive for lesion growth. Visual inspection of these most commonly used mismatch patterns has a low value for the prediction of infarct growth and thus the estimation of the penumbra in ischemic stroke patients.

Patients waking up with stroke symptoms are generally excluded from intravenous thrombolysis. It was shown that magnetic resonance imaging (MRI) can identify patients within the time window for thrombolysis (≤  4.5 h from symptom onset) by a mismatch between the acute ischemic lesion visible on diffusion-weighted imaging (DWI) but not visible on fluid-attenuated inversion recovery (FLAIR) imaging. The WAKE-UP trial is an investigator initiated, European, randomized, double-blind, placebo-controlled trial designed to test efficacy and safety of MRI-based thrombolysis with alteplase (tPA) in stroke patients with unknown time of symptom onset, e.g. due to symptom recognition on awakening. A total of 800 patients showing MRI findings of a DWI-FLAIR-mismatch will be randomized to either tPA or placebo. The primary efficacy endpoint will be favourable outcome defined by a modified Rankin scale score 0-1 at day 90. The primary safety outcome measures will be mortality and death or dependency defined by modified Rankin scale score 4-6 at 90 days. If positive the WAKE-UP trial is expected to change clinical practice and to make effective and safe treatment available for a large group of acute stroke patients currently excluded from specific acute treatment.

Background: Many patients with stroke are precluded from thrombolysis treatment because the time from onset of their symptoms is unknown. We aimed to test whether a mismatch in visibility of an acute ischaemic lesion between diffusion-weighted MRI (DWI) and fluid-attenuated inversion recovery (FLAIR) MRI (DWI-FLAIR mismatch) can be used to detect patients within the recommended time window for thrombolysis., Methods: In this multicentre observational study, we analysed clinical and MRI data from patients presenting between Jan 1, 2001, and May 31, 2009, with acute stroke for whom DWI and FLAIR were done within 12 h of observed symptom onset. Two neurologists masked to clinical data judged the visibility of acute ischaemic lesions on DWI and FLAIR imaging, and DWI-FLAIR mismatch was diagnosed by consensus. We calculated predictive values of DWI-FLAIR mismatch for the identification of patients with symptom onset within 4·5 h and within 6 h and did multivariate regression analysis to identify potential confounding covariates. This study is registered with ClinicalTrials.gov, number NCT01021319., Findings: The final analysis included 543 patients. Mean age was 66·0 years (95% CI 64·7-67·3) and median National Institutes of Health Stroke Scale score was 8 (IQR 4-15). Acute ischaemic lesions were identified on DWI in 516 patients (95%) and on FLAIR in 271 patients (50%). Interobserver agreement for acute ischaemic lesion visibility on FLAIR imaging was moderate (κ=0·569, 95% CI 0·504-0·634). DWI-FLAIR mismatch identified patients within 4·5 h of symptom onset with 62% (95% CI 57-67) sensitivity, 78% (72-84) specificity, 83% (79-88) positive predictive value, and 54% (48-60) negative predictive value. Multivariate regression analysis identified a longer time to MRI (p<0·0001), a lower age (p=0·0009), and a larger DWI lesion volume (p=0·0226) as independent predictors of lesion visibility on FLAIR imaging., Interpretation: Patients with an acute ischaemic lesion detected with DWI but not with FLAIR imaging are likely to be within a time window for which thrombolysis is safe and effective. These findings lend support to the use of DWI-FLAIR mismatch for selection of patients in a future randomised trial of thrombolysis in patients with unknown time of symptom onset., Funding: Else Kröner-Fresenius-Stiftung, National Institutes of Health., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background and Purpose: Stroke magnetic resonance imaging with perfusion and diffusion weighting has shown its potential to select patients likely to benefit from intravenous thrombolysis with tissue-type plasminogen activator (IV-tPA). We aimed to determine the predictors of favorable outcome in magnetic resonance imaging-selected, acute stroke patients treated with IV-tPA., Methods: We analyzed the data of acute ischemic stroke patients from a prospective, multicenter, observational study of magnetic resonance imaging-based IV-tPA treatment initiated ≤6 hours from symptom onset. Neurologic deficit on admission was assessed by the National Institutes of Health Stroke Scale. Clinical outcome was assessed after 90 days according to the modified Rankin Scale. Favorable outcome was defined as a modified Rankin Scale score of 0 to 1. Patients were compared regarding baseline parameters. Multivariate regression analysis was used to identify predictors of favorable outcome., Results: Of 174 patients, 83 (48%) reached a favorable outcome. They were younger (median age, 62 versus 67 years; P=0.001), had a lower National Institutes of Health Stroke Scale score on admission (median, 11 versus 15; P<0.001), and had smaller diffusion-weighted imaging lesions (median, 12.9 versus 20 mL; P=0.001). Perfusion-weighted imaging lesion volumes and onset-to-treatment time were comparable between the groups. Age (P=0.017), National Institutes of Health Stroke Scale score on admission (P<0.001), and diffusion-weighted imaging lesion volume (P=0.047) were identified as independent predictors of favorable outcome., Conclusions: A lower age, lower National Institutes of Health Stroke Scale score on admission, and smaller pretreatment diffusion-weighted imaging lesion volume were found to be associated with a favorable outcome after treatment with IV-tPA. Pretreatment perfusion lesion volume and onset-to-treatment time were not associated with outcome when patients were selected for IV-tPA by magnetic resonance imaging within 6 hours of symptom onset.

Objective: Early identification of patients at risk of space-occupying "malignant" middle cerebral artery (MCA) infarction (MMI) is needed to enable timely decision for potentially life-saving treatment such as decompressive hemicraniectomy. We tested the hypothesis that acute stroke magnetic resonance imaging (MRI) predicts MMI within 6 hours of stroke onset., Methods: In a prospective, multicenter, observational cohort study patients with acute ischemic stroke and MCA main stem occlusion were studied by MRI including diffusion-weighted imaging (DWI), perfusion imaging (PI), and MR-angiography within 6 hours of symptom onset. Multivariate regression analysis was used to identify clinical and imaging predictors of MMI., Results: Of 140 patients included, 27 (19.3%) developed MMI. The following parameters were identified as independent predictors of MMI: larger acute DWI lesion volume (per 1 ml odds ratio [OR] 1.04, 95% confidence interval [CI] 1.02-1.06; p < 0.001), combined MCA + internal carotid artery occlusion (5.38, 1.55-18.68; p = 0.008), and severity of neurological deficit on admission assessed by the National Institutes of Health Stroke Scale score (per 1 point 1.16, 1.00-1.35; p = 0.053). The prespecified threshold of a DWI lesion volume >82 ml predicted MMI with high specificity (0.98, 95% CI 0.94-1.00), negative predictive value (0.90, 0.83-0.94), and positive predictive value (0.88, 0.62-0.98), but sensitivity was low (0.52, 0.32-0.71)., Interpretation: Stroke MRI on admission predicts malignant course in severe MCA stroke with high positive and negative predictive value and may help in guiding treatment decisions, such as decompressive surgery. In a subset of patients with small initial DWI lesion volumes, repeated diagnostic tests are required.

Background and Purpose: Pretreatment lesion size on diffusion-weighted imaging (DWI) is a risk factor for symptomatic intracerebral hemorrhage (sICH) associated with thrombolytic treatment. Here, we investigated whether the Alberta Stroke Programme Early CT Score (ASPECTS) applied to DWI images (DWI-ASPECTS) predicts sICH risk accurately., Methods: In this retrospective multicenter study, prospectively collected data of 217 patients with anterior circulation stroke treated with intravenous or intraarterial thrombolysis within 6 hours after symptom onset were analyzed. Pretreatment DWI-ASPECTS scores were assessed by 2 independent investigators. For bleeding risk analysis, DWI-ASPECTS scores were either categorized into 0 to 7 (n=105) or 8 to 10 (n=112) or in 3 groups of similar sample size (DWI-ASPECTS 0 to 5 [n=69], 6 to 7 [n=70], and 8 to 10 [n=78])., Results: DWI-ASPECTS scores correlated well with the DWI lesion volume (r=0.77, P<0.001, Spearman Rank test). Interobserver reliability for the assessment of DWI-ASPECTS was moderate (weighted kappa 0.441 [95% CI 0.373 to 0.509]). Twenty-three (10.6%) patients developed sICH. The sICH rate was significantly higher in patients with DWI-ASPECTS scores 0 to 7 (n=21, 15.1%) as compared to patients with DWI-ASPECTS scores 8 to 10 (n=2, 2.6%, P=0.004). sICH risk was 20.3%, 10%, and 2.6% in the 0 to 5, 6 to 7, and 8 to 10 DWI-ASPECTS groups, respectively. DWI-ASPECTS remained an independent prognostic factor for sICH after adjustment for clinical baseline variables (age, NIHSS, time to thrombolysis)., Conclusions: DWI-ASPECTS predicts sICH risk after thrombolysis and may be helpful to contributing to quick sICH risk assessment before thrombolytic therapy.

Objective: To evaluate the use of fluid-attenuated inversion recovery (FLAIR) imaging as surrogate marker of lesion age within the first 6 hours of ischemic stroke., Methods: e analyzed FLAIR and diffusion-weighted imaging (DWI) sequences performed within 6 hours of symptom onset in 120 consecutive patients with ischemic stroke with known symptom onset. The visibility of acute ischemic lesions on FLAIR images was judged in two steps (on FLAIR alone and with knowledge of DWI) and compared with DWI., Results: egative FLAIR in the case of positive DWI allocated ischemic lesions to a time window 3 hours or less with a high specificity (0.93) and a high positive predictive value (0.94), whereas sensitivity (0.48) and negative predictive value (0.43) were low. Lesion visibility on FLAIR images alone (35.6%) and with knowledge of DWI (62.5%) was lower than on DWI (97.1%). The sensitivity of FLAIR increased with increasing time from symptom onset from 27.0/50.0%

Multiparametric MRI including diffusion and perfusion imaging provides information on the extent of irreversibly damaged ischemic and/or critically hypoperfused tissue. Magnetic resonance angiography provides additional information on vessel status. The concept of perfusion-diffusion mismatch allows the estimation of tissue at risk of infarction which might be salvaged by timely reperfusion. In large case series and nonrandomized cohort studies, perfusion-diffusion mismatch-based thrombolysis was performed not less than 3 h after symptom onset with excellent safety and signs of good efficacy. However no randomised controlled trial has confirmed this to date. Recent studies improved the understanding of the mismatch concept and identified reperfusion unequivocally as an important predictor of the clinical response to thrombolysis. At the moment MRI-based thrombolysis can be performed after 3 h based on individual benefit:risk assessment in experienced stroke centers.

Purpose: To show that measurement of the transverse relaxation time that characterizes signal loss caused by local susceptibilities (T2') is sensitive to an increased deoxyhemoglobin concentration in the brain, indicating tissue at risk for infarction., Materials and Methods: The study was approved by the local institutional review board; patients or their guardians provided informed consent. Magnetic resonance (MR) imaging was performed within 6 hours of symptom onset and again 1-11 days thereafter in 100 consecutive stroke patients, all of whom received intravenous thrombolytic therapy (mean age, 67 years). The MR imaging protocol included diffusion- and perfusion-weighted imaging for determination of apparent diffusion coefficient (ADC) and time to peak (TTP), along with quantitative T2 and T2* imaging. T2' maps were calculated and visually compared with ADC and TTP lesions by two independent observers., Results: A T2'>ADC mismatch was observed by reader 1 in 73 (73%) of 100 patients, and by reader 2 in 65 (65%) patients. Respective sensitivities of T2'>ADC and of TTP>ADC mismatches for later infarct growth were 0.87 and 0.98 for reader 1 and 0.78 and 0.98 for reader 2, with respective specificities of 0.42 and 0.04 for reader 1 and 0.46 and 0.04 for reader 2. The odds ratios for infarct growth in the presence of a T2'>ADC mismatch were 4.59 (reader 1 P = .002) and 3.10 (reader 2 P = .012), while the odds ratios for TTP>ADC mismatch were 2.22 (reader 1 P = .606) and 1.73 (reader 2 P > .999)., Conclusion: The presence of a T2'>ADC mismatch is a more specific predictor of infarct growth than is TTP>ADC mismatch and hence may be of clinical value in patient selection for acute stroke therapies in the future., (RSNA, 2008)

Purpose: Delineation of brain tissue that is at risk but not yet infarcted (penumbra) continues to be a major challenge for stroke imaging. Metabolic characterization of the penumbra might be able to be achieved using blood-oxygen-level-dependent (BOLD) imaging., Materials and Methods: We analyzed MRI data from 20 patients within the first 6 hours after stroke onset and after 5-8 days. Among other sequences, the MRI protocol consisted of diffusion-weighted (DWI/ADC = apparent diffusion coefficient) and quantitative T2 and T2* imaging (qT2, qT2*). BOLD images (T2') were calculated using 1/T2' = 1/qT2* - 1/qT2. BOLD lesions were rated by two blinded observers., Results: Based on the primary blinded reading of the BOLD images, the lesion side was rated correctly by observers 1 and 2 in 80/50 % of the cases, incorrectly in 5/40 % of the cases, and rated as not visible in 15/10 % of the cases. After unblinding the observers, the visibility was rated in 45/45 % of the cases as good, in 35/40 % of the cases as reasonable, and in 20/15 % of the cases as insufficient for diagnostic purposes. The sensitivity for subsequent infarct growth was 0.88 (95 % confidence interval, CI 0.47 to 0.99), the specificity was 0.33 (95 % CI 0.07 to 0.70), the positive predictive value (PPV) was 0.54 (95 % CI 0.25 to 0.81), and the negative predictive value (NPV) was 0.75 (95 % CI 0.19 to 0.99). The odds ratio for subsequent infarct growth was 3.5 (95 % CI 0.20 to 115.53)., Conclusion: Hypo-intense lesions in BOLD imaging were visible and exceeded the lesion in diffusion-weighted imaging in most of the stroke patients. The encouraging results justify further testing of the hypothesis that BOLD lesions, when larger than DWI lesions, are associated with infarct growth from initial DWI to final infarct.

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: Occlusion of major cerebral arteries is the primary source of tissue damage in ischemic stroke and the target of thrombolytic therapy. We hypothesized that large infarcts in more proximal vascular occlusions correspond with substantially increased ischemic lesions shown on initial apparent diffusion coefficient (ADC) maps., Methods: Initial ADC lesions in 120 patients with acute ischemic stroke were analyzed within 6 hours of stroke onset. Patients were categorized on the basis of vascular occlusion, as shown on MR angiography. Lesion volumes were determined by using manual delineation (ADC(man)) and a threshold method for ADC values (<550 x 10(-9) mm(2)/s(-1), ADC(<550)). Infarct volumes were analyzed by using T2-weighted (n = 109) or CT (n = 11) images obtained on days 5-8., Results: Median lesion volumes for ADC(<550), ADC(man), and infarcts, respectively, were as follows: proximal internal carotid artery (ICA)/middle cerebral artery (MCA) occlusions, 10, 23, and 32 cm(3); carotid-T occlusions, 11, 37, and 138 cm(3); MCA trunk occlusions, 11, 27, and 44 cm(3)); and MCA branch occlusions 8, 27, and 21 cm(3). Initial ADC lesion volumes were different only between the carotid T and the MCA branch (P < .05). On days 5-8, infarct volumes decreased from proximal to distal sites (P < .05), with the exception of MCA trunk versus proximal ICA/MCA occlusions. Recanalization rate in carotid-T occlusion was significantly lower than those of all other occlusion types., Conclusion: Initial ADC lesions can be small, even in patients with proximal vascular occlusions. These patients develop considerably large infarctions, suggesting a high potential for infarct growth. This growth might be averted with improved early recanalization of proximal vascular occlusions.

We used diffusion tensor imaging (DTI) to assess Wallerian degeneration of the pyramidal tract within the first 2 weeks after ischemic stroke, and correlated the extent of Wallerian degeneration with the motor deficit. Nine patients with middle cerebral artery stroke were examined 2-16 days after stroke by DTI and T2-weighted MRI. We measured fractional anisotropy (FA), averaged diffusivity (Dav), eigenvalues of the diffusion tensor and T2-weighted signal in the cerebral peduncle and compared these values between the affected and the unaffected side and between patients and six controls. FA was significantly reduced on the affected side compared to the unaffected side and compared to the control group. The largest eigenvalue was reduced, whereas the smallest eigenvalue was elevated on the affected side. There was no significant difference in T2-weighted signal and Dav. The decrease of anisotropy correlated positively with the motor deficit at the time of DTI study and 90 days after stroke. The reduction of anisotropy mirrors the disintegration of axonal structures, as it occurs in the early phase of Wallerian degeneration. DTI detects changes of water diffusion related to beginning pyramidal tract degeneration within the first 2 weeks after stroke that are not yet visible in conventional T2-weighted or orientationally averaged diffusion weighted MRI. We demonstrated for the first time a correlation of early DTI findings of pyramidal tract damage with the motor deficit. DTI can help prognosing recovery of motor function after stroke within the early subacute phase.