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IntroductionCerebrovascular disease is a major public health challenge. An important biomarker is cerebral hemodynamics. To measure cerebral hemodynamics, however, only invasive, potentially harmful or time-to-treatment prolonging methods are available. We present a simulation-based alternative which allows calculation of cerebral hemodynamics based on the individual vessel con figuration of a patient derived from structural vessel imaging.MethodsWe implemented a framework allowing annotation of extracted brain vessels from structural imaging followed by 0-dimensional lumped modelling of cerebral hemodynamics. For annotation, a 3D-graphical user interface (GUI) was implemented. For 0D-simulation, we used a modified nodal analysis (MNA), which was adapted for easy implementation by code. The code was written in-house in java. The simulation GUI allows inspection of simulation results, identification of vulnerable areas, simulation of changes due to different systemic blood pressures. Moreover, sensitivity analysis was implemented allowing the live simulation of changes of variables such as vessel lumen to simulate procedures and disease courses. In two exemplary patients, simulation results were compared to dynamic-susceptibility-weighted-contrast-enhanced magnetic- resonance(DSC-MR) perfusion imaging.ResultsThe successful implementation of the framework allowing individualized annotation and simulation of patients is presented. In two exemplary patients, both the simulation as well as DSC- MRI showed the same results pertaining to the identification of areas vulnerable to ischemia. Sensitivity analysis allows the individualized simulation of changes in vessel lumen and the effect on hemodynamics.DiscussionWe present the first precision medicine pipeline for cerebrovascular disease which allows annotation of the arterial vasculature derived from structural vessel imaging followed by personalized simulation of brain hemodynamics. This paves the way for further development of precision medicine in stroke using novel biomarkers and might make the application of harmful and complex perfusion methods obsolete for certain use cases in the future.

Stroke is a major cause for death or disability. As imaging based patient stratification improves acute stroke therapy, dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) is is of major interest to image brain perfusion. However, expert-level perfusion maps require a manual or semi-manual post-processing by a medical expert making the procedure time-consuming and less standardized. Modern machine learning methods such as generative adversarial networks (GANs) have the potential to automate the perfusion map generation on an expert-level without manual validation. We propose a modified pix2pix GAN with a temporal component (temp-pix2pix-GAN) that generates perfusion maps in an end-to-end fashion. We train our model on perfusion maps infused with expert knowledge to encode it into the GANs. The performance was trained and evaluated using the structural similarity index measure (SSIM) on two datasets including acute stroke patients and patients with steno-occlusive disease. Our temp-pix2pix architecture showed high performance on the acute stroke dataset for all perfusion maps (mean SSIM 0.92-0.99) and good performance on data including patients with steno-occlusive disease (mean SSIM 0.84-0.99). While clinical validation is still necessary in future studies, our results mark an important step towards automated expert-level perfusion maps and thus, fast patient stratification.

International audience; BACKGROUND: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers. METHODS: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0-1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0-2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4-6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903. FINDINGS: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10-2·03]; p=0·011), with low heterogeneity across studies (I(2)=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05-1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06-2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4-6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52-1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03-4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [\textless1%], adjusted OR 5·58 [1·22-25·50]; p=0·024). INTERPRETATION: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death. FUNDING: None.

ObjectiveTo determine the occurrence of intracranial haemorrhagic complications (IHC) on heparin prophylaxis (low-dose subcutaneous heparin, LDSH) in primary spontaneous intracerebral haemorrhage (ICH) (not oral anticoagulation-associated ICH, non-OAC-ICH), vitamin K antagonist (VKA)-associated ICH and non-vitamin K antagonist oral anticoagulant (NOAC)-associated ICH.MethodsRetrospective cohort study (RETRACE) of 22 participating centres and prospective single-centre study with 1702 patients with VKA-associated or NOAC-associated ICH and 1022 patients with non-OAC-ICH with heparin prophylaxis between 2006 and 2015. Outcomes were defined as rates of IHC during hospital stay among patients with non-OAC-ICH, VKA-ICH and NOAC-ICH, mortality and functional outcome at 3 months between patients with ICH with and without IHC.ResultsIHC occurred in 1.7% (42/2416) of patients with ICH. There were no differences in crude incidence rates among patients with VKA-ICH, NOAC-ICH and non-OAC-ICH (log-rank p=0.645; VKA-ICH: 27/1406 (1.9%), NOAC-ICH 1/130 (0.8%), non-OAC-ICH 14/880 (1.6%); p=0.577). Detailed analysis according to treatment exposure (days with and without LDSH) revealed no differences in incidence rates of IHC per 1000 patient-days (LDSH: 1.43 (1.04–1.93) vs non-LDSH: 1.32 (0.33–3.58), conditional maximum likelihood incidence rate ratio: 1.09 (0.38–4.43); p=0.953). Secondary outcomes showed differences in functional outcome (modified Rankin Scale=4–6: IHC: 29/37 (78.4%) vs non-IHC: 1213/2048 (59.2%); p=0.019) and mortality (IHC: 14/37 (37.8%) vs non-IHC: 485/2048 (23.7%); p=0.045) in disfavour of patients with IHC. Small ICH volume (OR: volume ConclusionsHeparin administration for venous thromboembolism (VTE) prophylaxis in patients with ICH appears to be safe regarding IHC among non-OAC-ICH, VKA-ICH and NOAC-ICH in this observational cohort analysis. Randomised controlled trials are needed to verify the safety and efficacy of heparin compared with other methods for VTE prevention.

Public education campaigns are recommended to increase awareness for stroke. The effect of a public advertising and education campaign in an urban region in Germany was assessed and compared with a control region. We hypothesized that such a campaign would increase the number of patients being admitted by emergency medical services (EMS). A multimedia campaign and targeted education of health care professionals and the public was employed in Berlin during six consecutive months to disseminate knowledge about stroke symptoms and appropriate actions to take. Data on time to hospital admission and details on transport were retrieved from registries for the episode before, during, and after the campaign. To test the effect of the campaign, it was compared with another urban region in Germany (Ruhr-Area), where no campaign had been conducted. Between January 2010 and February 2011, 9,166 patients with stroke or transient ischemic attack (TIA) were documented in Berlin and 9,994 in the Ruhr-Area. In both regions, following the campaign period, patients were more often admitted to hospital within the first 2 hr after onset (Berlin: odds ratio [OR] = 1.16, 95% confidence interval [CI] = [1.02, 1.32]; Ruhr-Area: OR = 1.18, 95% CI = [1.05, 1.34]). Patients were more likely being admitted via EMS after the campaign (Berlin: OR = 1.71, 95% CI = [1.50, 1.94]; Ruhr-Area: OR = 1.34, 95% CI = [1.17, 1.53]). The results suggest that an increased uptake of EMS triggered shorter time to hospital admission. A reduction in delay to hospitalization and an increased uptake of EMS were observed over the study period for both regions. No effect of the campaign was identified.

Anonymization and data sharing are crucial for privacy protection and acquisition of large datasets for medical image analysis. This is a big challenge, especially for neuroimaging. Here, the brain's unique structure allows for re-identification and thus requires non-conventional anonymization. Generative adversarial networks (GANs) have the potential to provide anonymous images while preserving predictive properties. Analyzing brain vessel segmentation, we trained 3 GANs on time-of-flight (TOF) magnetic resonance angiography (MRA) patches for image-label generation: 1) Deep convolutional GAN, 2) Wasserstein-GAN with gradient penalty (WGAN-GP) and 3) WGAN-GP with spectral normalization (WGAN-GP-SN). The generated image-labels from each GAN were used to train a U-net for segmentation and tested on real data. Moreover, we applied our synthetic patches using transfer learning on a second dataset. For an increasing number of up to 15 patients we evaluated the model performance on real data with and without pre-training. The performance for all models was assessed by the Dice Similarity Coefficient (DSC) and the 95th percentile of the Hausdorff Distance (95HD). Comparing the 3 GANs, the U-net trained on synthetic data generated by the WGAN-GP-SN showed the highest performance to predict vessels (DSC/95HD 0.85/30.00) benchmarked by the U-net trained on real data (0.89/26.57). The transfer learning approach showed superior performance for the same GAN compared to no pre-training, especially for one patient only (0.91/24.66 vs. 0.84/27.36). In this work, synthetic image-label pairs retained generalizable information and showed good performance for vessel segmentation. Besides, we showed that synthetic patches can be used in a transfer learning approach with independent data. This paves the way to overcome the challenges of scarce data and anonymization in medical imaging.

IntroductionArterial brain vessel assessment is crucial for the diagnostic process in patients with cerebrovascular disease. Noninvasive neuroimaging techniques such as time-of-flight (TOF) magnetic resonance angiography (MRA) imaging are applied in the clinical routine to depict arteries. They are, however, only visually assessed. Fully automated vessel segmentation integrated into the clinical routine could facilitate the time-critical diagnosis of vessel abnormalities and might facilitate the identification of valuable biomarkers for cerebrovascular events. In the present work, we developed and validated a new deep learning model for vessel segmentation, coined BRAVE-NET, on a large aggregated dataset of patients with cerebrovascular diseases.MethodsBRAVE-NET is a multiscale 3-D convolutional neural network (CNN) model developed on a dataset of 264 patients from 3 different studies enrolling patients with cerebrovascular diseases. A context path, dually capturing high- and low-resolution volumes, and deep supervision were implemented. The BRAVE-NET model was compared to a baseline Unet model and variants with only context paths and deep supervision, respectively. The models were developed and validated using high-quality manual labels as ground truth. Next to precision and recall, the performance was assessed quantitatively by Dice coefficient (DSC); average Hausdorff distance (AVD); 95- percentile Hausdorff distance (95HD) and via visual qualitative rating.ResultsThe BRAVE-NET performance surpassed the other models for arterial brain vessel segmentation with a DSC = 0.931, AVD = 0.165 and 95HD = 29.153. The BRAVE-NET model was also the most resistant towards false labelings as revealed by the visual analysis. The performance improvement is primarily attributed to the integration of the multiscaling context path into the 3-D Unet and to a lesser extent to the deep supervision architectural component.DiscussionWe present a new state-of-the-art of arterial brain vessel segmentation tailored to cerebrovascular pathology. We provide an extensive experimental validation of the model using a large aggregated dataset encompassing a large variability of cerebrovascular disease. The framework provides the technological foundation for improving the clinical workflow and can serve as a biomarker extraction tool in cerebrovascular diseases.

Background and Purpose— Stroke imaging is pivotal for diagnosis and stratification of patients with acute ischemic stroke to treatment. The potential of combining multimodal information into reliable estimates of outcome learning calls for robust machine learning techniques with high flexibility and accuracy. We applied the novel extreme gradient boosting algorithm for multimodal magnetic resonance imaging–based infarct prediction. Methods— In a retrospective analysis of 195 patients with acute ischemic stroke, fluid-attenuated inversion recovery, diffusion-weighted imaging, and 10 perfusion parameters were derived from acute magnetic resonance imaging scans. They were integrated to predict final infarct as seen on follow-up T2-fluid-attenuated inversion recovery using the extreme gradient boosting and compared with a standard generalized linear model approach using cross-validation. Submodels for recanalization and persistent occlusion were calculated and were used to identify the important imaging markers. Performance in infarct prediction was analyzed with receiver operating characteristics. Resulting areas under the curve and accuracy rates were compared using Wilcoxon signed-rank test. Results— The extreme gradient boosting model demonstrated significantly higher performance in infarct prediction compared with generalized linear model in both cross-validation approaches: 5-folds ( P P Conclusions— We demonstrate extreme gradient boosting as a state-of-the-art method for clinically applicable multimodal magnetic resonance imaging infarct prediction in acute ischemic stroke. Our findings emphasize the role of perfusion parameters as important biomarkers for infarct prediction. The effect of cross-validation techniques on performance indicates that the intrapatient variability is expressed in nonlinear dynamics of the imaging modalities.

Background: In acute stroke, the magnetic resonance (MR) imaging-based mismatch concept is used to select patients with tissue at risk of infarction for reperfusion therapies. There is however a controversy if non-deconvolved or deconvolved perfusion weighted (PW) parameter maps perform better in tissue at risk prediction and which parameters and thresholds should be used to guide treatment decisions. Methods: In a group of 22 acute stroke patients with consecutive MR and quantitative positron emission tomography (PET) imaging, non-deconvolved parameters were validated with the gold standard for penumbral-flow (PF) detection 15O-water PET. Performance of PW parameters was assessed by a receiver operating characteristic curve analysis to identify the accuracy of each PWI map to detect the ­upper PF threshold as defined by PET cerebral blood flow Results: Among normalized non-deconvolved parameters, PW-first moment without delay correction (FM without DC) > 3.6 s (area under the curve [AUC] = 0.89, interquartile range [IQR] 0.85–0.94), PW-maximum of the concentration curve (Cmax) < 0.66 (AUC = 0.92, IQR 0.84–0.96) and PW-time to peak (TTP) > 4.0 s (AUC = 0.92, IQR 0.87–0.94) perform significantly better than other non-deconvolved parameters to detect the PF threshold as defined by PET. Conclusions: Non-deconvolved parameters FM without DC, Cmax and TTP are an observer-independent alternative to established deconvolved parameters (e.g., Tmax) to guide treatment decisions in acute stroke.

Background and Purpose— Identification of salvageable penumbra tissue by dynamic susceptibility contrast magnetic resonance imaging is a valuable tool for acute stroke patient stratification for treatment. However, prior studies have not attempted to combine the different perfusion maps into a predictive model. In this study, we established a multiparametric perfusion imaging model and cross-validated it using positron emission tomography perfusion for detection of penumbral flow. Methods— In a retrospective analysis of 17 subacute stroke patients with consecutive magnetic resonance imaging and H2O15 positron emission tomography scans, perfusion maps of cerebral blood flow, cerebral blood volume, mean transit time, time-to-maximum, and time-to-peak were constructed and combined using a generalized linear model (GLM). Both the GLM maps and the single perfusion maps alone were cross-validated with positron emission tomography-cerebral blood flow scans to predict penumbral flow on a voxel-wise level. Performance was tested by receiver-operating characteristics curve analysis, that is, the area under the curve, and the models’ fits were compared using the likelihood ratio test. Results— The GLM demonstrated significantly improved model fit compared with each of the single perfusion maps ( P Conclusions— Our results support a dynamic susceptibility contrast magnetic resonance imaging–based GLM as an improved model for penumbral flow prediction in stroke patients. With given perfusion maps, this model is a straightforward and observer-independent alternative for therapy stratification.

BACKGROUND AND PURPOSE In acute stroke, arterial-input-function (AIF) determination is essential for obtaining perfusion estimates with dynamic susceptibility-weighted contrast-enhanced magnetic resonance imaging (DSC-MRI). Standard DSC-MRI postprocessing applies single AIF selection, ie, global AIF. Physiological considerations, however, suggest that a multiple AIFs selection method would improve perfusion estimates to detect penumbral flow. In this study, we developed a framework based on comparable DSC-MRI and positron emission tomography (PET) images to compare the two AIF selection approaches and assess their performance in penumbral flow detection in acute stroke. METHODS In a retrospective analysis of 17 sub(acute) stroke patients with consecutive MRI and PET scans, voxel-wise optimized AIFs were calculated based on the kinetic model as derived from both imaging modalities. Perfusion maps were calculated based on the optimized-AIF using two methodologies: (1) Global AIF and (2) multiple AIFs as identified by cluster analysis. Performance of penumbral-flow detection was tested by receiver–operating characteristics (ROC) curve analysis, ie, the area under the curve (AUC). RESULTS Large variation of optimized AIFs across brain voxels demonstrated that there is no optimal single AIF. Subsequently, the multiple-AIF method (AUC range over all maps: .82-.90) outperformed the global AIF methodology (AUC .72-.85) significantly. CONCLUSIONS We provide PET imaging-based evidence that a multiple AIF methodology is beneficial for penumbral flow detection in comparison with the standard global AIF methodology in acute stroke.

Stroke thrombolysis with alteplase is currently recommended 0-4·5 h after stroke onset. We aimed to determine whether perfusion imaging can identify patients with salvageable brain tissue with symptoms 4·5 h or more from stroke onset or with symptoms on waking who might benefit from thrombolysis.In this systematic review and meta-analysis of individual patient data, we searched PubMed for randomised trials published in English between Jan 1, 2006, and March 1, 2019. We also reviewed the reference list of a previous systematic review of thrombolysis and searched ClinicalTrials.gov for interventional studies of ischaemic stroke. Studies of alteplase versus placebo in patients (aged ≥18 years) with ischaemic stroke treated more than 4·5 h after onset, or with wake-up stroke, who were imaged with perfusion-diffusion MRI or CT perfusion were eligible for inclusion. The primary outcome was excellent functional outcome (modified Rankin Scale [mRS] score 0-1) at 3 months, adjusted for baseline age and clinical severity. Safety outcomes were death and symptomatic intracerebral haemorrhage. We calculated odds ratios, adjusted for baseline age and National Institutes of Health Stroke Scale score, using mixed-effects logistic regression models. This study is registered with PROSPERO, number CRD42019128036.We identified three trials that met eligibility criteria: EXTEND, ECASS4-EXTEND, and EPITHET. Of the 414 patients included in the three trials, 213 (51%) were assigned to receive alteplase and 201 (49%) were assigned to receive placebo. Overall, 211 patients in the alteplase group and 199 patients in the placebo group had mRS assessment data at 3 months and thus were included in the analysis of the primary outcome. 76 (36%) of 211 patients in the alteplase group and 58 (29%) of 199 patients in the placebo group had achieved excellent functional outcome at 3 months (adjusted odds ratio [OR] 1·86, 95% CI 1·15-2·99, p=0·011). Symptomatic intracerebral haemorrhage was more common in the alteplase group than the placebo group (ten [5%] of 213 patients vs one [1%] of 201 patients in the placebo group; adjusted OR 9·7, 95% CI 1·23-76·55, p=0·031). 29 (14%) of 213 patients in the alteplase group and 18 (9%) of 201 patients in the placebo group died (adjusted OR 1·55, 0·81-2·96, p=0·66).Patients with ischaemic stroke 4·5-9 h from stroke onset or wake-up stroke with salvageable brain tissue who were treated with alteplase achieved better functional outcomes than did patients given placebo. The rate of symptomatic intracerebral haemorrhage was higher with alteplase, but this increase did not negate the overall net benefit of thrombolysis.None.

Background and Purpose— Given inconclusive studies, it is debated whether clinical and imaging characteristics, as well as functional outcome, differ among patients with intracerebral hemorrhage (ICH) related to vitamin K antagonists (VKA) versus non–vitamin K antagonist (NOAC)-related ICH. Notably, clinical characteristics according to different NOAC agents and dosages are not established. Methods— Multicenter observational cohort study integrating individual patient data of 1328 patients with oral anticoagulation–associated ICH, including 190 NOAC-related ICH patients, recruited from 2011 to 2015 at 19 tertiary centers across Germany. Imaging, clinical characteristics, and 3-months modified Rankin Scale (mRS) outcomes were compared in NOAC- versus VKA-related ICH patients. Propensity score matching was conducted to adjust for clinically relevant differences in baseline parameters. Subgroup analyses were performed regarding NOAC agent, dosing and present clinically relevant anticoagulatory activity (last intake 30 ng/mL). Results— Despite older age in NOAC patients, there were no relevant differences in clinical and hematoma characteristics between NOAC- and VKA-related ICH regarding baseline hematoma volume (median [interquartile range]: NOAC, 14.7 [5.1–42.3] mL versus VKA, 16.4 [5.8–40.6] mL; P =0.33), rate of hematoma expansion (NOAC, 49/146 [33.6%] versus VKA, 235/688 [34.2%]; P =0.89), and the proportion of patients with unfavorable outcome at 3 months (mRS, 4–6: NOAC 126/179 [70.4%] versus VKA 473/682 [69.4%]; P =0.79). Subgroup analyses revealed that NOAC patients with clinically relevant anticoagulatory effect had higher rates of intraventricular hemorrhage (n/N [%]: present 52/109 [47.7%] versus absent 9/35 [25.7%]; P =0.022) and hematoma expansion (present 35/90 [38.9%] versus absent 5/30 [16.7%]; P =0.040), whereas type of NOAC agent or different NOAC-dosing regimens did not result in relevant differences in imaging characteristics or outcome. Conclusions— If effectively anticoagulated, there are no differences in hematoma characteristics and functional outcome among patients with NOAC- or VKA-related ICH. Clinical Trial Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT03093233.

IMPORTANCE: The association of surgical hematoma evacuation with clinical outcomes in patients with cerebellar intracerebral hemorrhage (ICH) has not been established. OBJECTIVE: To determine the association of surgical hematoma evacuation with clinical outcomes in cerebellar ICH. DESIGN, SETTING, AND PARTICIPANTS: Individual participant data (IPD) meta-analysis of 4 observational ICH studies incorporating 6580 patients treated at 64 hospitals across the United States and Germany (2006-2015). EXPOSURE: Surgical hematoma evacuation vs conservative treatment. MAIN OUTCOMES AND MEASURES: The primary outcome was functional disability evaluated by the modified Rankin Scale ([mRS] score range: 0, no functional deficit to 6, death) at 3 months; favorable (mRS, 0-3) vs unfavorable (mRS, 4-6). Secondary outcomes included survival at 3 months and at 12 months. Analyses included propensity score matching and covariate adjustment, and predicted probabilities were used to identify treatment-related cutoff values for cerebellar ICH. RESULTS: Among 578 patients with cerebellar ICH, propensity score–matched groups included 152 patients with surgical hematoma evacuation vs 152 patients with conservative treatment (age, 68.9 vs 69.2 years; men, 55.9% vs 51.3%; prior anticoagulation, 60.5% vs 63.8%; and median ICH volume, 20.5 cm(3) vs 18.8 cm(3)). After adjustment, surgical hematoma evacuation vs conservative treatment was not significantly associated with likelihood of better functional disability at 3 months (30.9% vs 35.5%; adjusted odds ratio [AOR], 0.94 [95% CI, 0.81 to 1.09], P = .43; adjusted risk difference [ARD], −3.7% [95% CI, −8.7% to 1.2%]) but was significantly associated with greater probability of survival at 3 months (78.3% vs 61.2%; AOR, 1.25 [95% CI, 1.07 to 1.45], P = .005; ARD, 18.5% [95% CI, 13.8% to 23.2%]) and at 12 months (71.7% vs 57.2%; AOR, 1.21 [95% CI, 1.03 to 1.42], P = .02; ARD, 17.0% [95% CI, 11.5% to 22.6%]). A volume range of 12 to 15 cm(3) was identified; below this level, surgical hematoma evacuation was associated with lower likelihood of favorable functional outcome (volume ≤12 cm(3), 30.6% vs 62.3% [P = .003]; ARD, −34.7% [−38.8% to −30.6%]; P value for interaction, .01), and above, it was associated with greater likelihood of survival (volume ≥15 cm(3), 74.5% vs 45.1% [P

PURPOSE: The quality and precision of post‐mortem MRI microscopy may vary depending on the embedding medium used. To investigate this, our study evaluated the impact of 5 widely used media on: (1) image quality, (2) contrast of high spatial resolution gradient-echo (T(1) and T(2)*-weighted) MR images, (3) effective transverse relaxation rate (R(2)*), and (4) quantitative susceptibility measurements (QSM) of post-mortem brain specimens. METHODS: Five formaldehyde-fixed brain slices were scanned using 7.0T MRI in: (1) formaldehyde solution (formalin), (2) phosphate-buffered saline (PBS), (3) deuterium oxide (D(2)O), (4) perfluoropolyether (Galden), and (5) agarose gel. SNR and contrast-to-noise ratii (SNR/CNR) were calculated for cortex/white matter (WM) and basal ganglia/WM regions. In addition, median R(2)* and QSM values were extracted from caudate nucleus, putamen, globus pallidus, WM, and cortical regions. RESULTS: PBS, Galden, and agarose returned higher SNR/CNR compared to formalin and D(2)O. Formalin fixation, and its use as embedding medium for scanning, increased tissue R(2)*. Imaging with agarose, D(2)O, and Galden returned lower R(2)* values than PBS (and formalin). No major QSM offsets were observed, although spatial variance was increased (with respect to R(2)* behaviors) for formalin and agarose. CONCLUSIONS: Embedding media affect gradient-echo image quality, R(2)*, and QSM in differing ways. In this study, PBS embedding was identified as the most stable experimental setup, although by a small margin. Agarose and Galden were preferred to formalin or D(2)O embedding. Formalin significantly increased R(2)* causing noisier data and increased QSM variance.

Importance Moderate hypothermia in addition to early decompressive hemicraniectomy has been suggested to further reduce mortality and improve functional outcome in patients with malignant middle cerebral artery (MCA) stroke. Objective To investigate whether moderate hypothermia vs standard treatment after early hemicraniectomy reduces mortality at day 14 in patients with malignant MCA stroke. Design, Setting, and Participants This randomized clinical trial recruited patients from August 2011 through September 2015 at 6 German university hospitals with dedicated neurointensive care units. Of the patients treated with hemicraniectomy and assessed for eligibility, patients were randomly assigned to either standard care or moderate hypothermia. Data analysis was completed from December 2016 to June 2018. Interventions Moderate hypothermia (temperature, 33.0 ± 1.0°C) was maintained for at least 72 hours immediately after hemicraniectomy. Main Outcomes and Measures The primary outcome was mortality rate at day 14 compared with the Fisher exact test and expressed as odds ratio (ORs) with 95% CIs. Rates of patients with serious adverse events were estimated for the period of the first 14 days after hemicraniectomy and 12 months of follow-up. Secondary outcome measures included functional outcome at 12 months. Results Of the 50 study participants, 24 were assigned to standard care and 26 to moderate hypothermia. Twenty-eight were male (56%); the mean (SD) patient age was 51.3 (6.6) years. Recruitment was suspended for safety concerns: 12 of 26 patients (46%) in the hypothermia group and 7 of 24 patients (29%) receiving standard care had at least 1 serious adverse event within 14 days (OR, 2.05 [95% CI, 0.56-8.00];P = .26); after 12 months, rates of serious adverse events were 80% (n = 20 of 25) in the hypothermia group and 43% (n = 10 of 23) in the standard care group (hazard ratio, 2.54 [95% CI, 1.29-5.00];P = .005). The mortality rate at day 14 was 19% (5 of 26 patients) in the hypothermia group and 13% (3 of 24 patients) in the group receiving standard care (OR, 1.65 [95% CI, 0.28-12.01];P = .70). There was no significant difference regarding functional outcome after 12 months of follow-up. Interpretation In patients with malignant MCA stroke, moderate hypothermia early after hemicraniectomy did not improve mortality and functional outcome compared with standard care, but may cause serious harm in this specific setting. Trial Registration http://www.drks.de, identifierDRKS00000623

Brain vessel status is a promising biomarker for better prevention and treatment in cerebrovascular disease. However, classic rule-based vessel segmentation algorithms need to be hand-crafted and are insufficiently validated. A specialized deep learning method-the U-net -is a promising alternative. Using labeled data from 66 patients with cerebrovascular disease, the U-net framework was optimized and evaluated with three metrics: Dice coefficient, 95% Hausdorff distance (95HD) and average Hausdorff distance (AVD). The model performance was compared with the traditional segmentation method of graph-cuts. Training and reconstruction was performed using 2D patches. A full and a reduced architecture with less parameters were trained. We performed both quantitative and qualitative analyses. The U-net models yielded high performance for both the full and the reduced architecture: A Dice value of similar to 0.88, a 95HD of similar to 47 voxels and an AVD of similar to 0.4 voxels. The visual analysis revealed excellent performance in large vessels and sufficient performance in small vessels. Pathologies like cortical laminar necrosis and a rete mirabile led to limited segmentation performance in few patients. The U-net outperfomed the traditional graph-cuts method (Dice similar to 0.76, 95HD similar to 59, AVD similar to 1.97). Our work highly encourages the development of clinically applicable segmentation tools based on deep learning. Future works should focus on improved segmentation of small vessels and methodologies to deal with specific pathologies.

Perfusion-weighted (PW) magnetic resonance imaging (MRI) is used to detect penumbral tissue in acute stroke, but the selection of optimal PW-maps and thresholds for tissue at risk detection remains a matter of debate. We validated the performance of PW-maps with 15O-water-positron emission tomography (PET) in a large comparative PET-MR cohort of acute stroke patients. In acute and subacute stroke patients with back-to-back MRI and PET imaging, PW-maps were validated with 15O-water-PET. We pooled two different cerebral blood flow (CBF) PET-maps to define the critical flow (CF) threshold, (i) quantitative (q)CBF-PET with the CF threshold 6.1 s (AUC = 0.94) and non-deconvolved PW-time-to-peak (TTP) >4.8 s (AUC = 0.93) showed the best performance to detect the CF threshold as defined by PET. PW-Tmax with a threshold >6.1 s and TTP with a threshold >4.8 s are the most predictive in detecting the CF threshold for MR-based mismatch definition.

Aims: In Wilson disease (WD), T2/T2*-weighted (T2*w) MRI frequently shows hypointensity in the basal ganglia that is suggestive of paramagnetic deposits. It is currently unknown whether this hypointensity is related to copper or iron deposition. We examined the neuropathological correlate of this MRI pattern, particularly in relation to iron and copper concentrations. Methods: Brain slices from nine WD and six control cases were investigated using a 7T-MRI system. High resolution T2*w images were acquired and R2* parametric maps were reconstructed using a multi-gradient recalled echo sequence. R2* was measured in the globus pallidus (GP) and the putamen. Corresponding histopathological sections containing the lentiform nucleus were examined using Turnbull iron staining, and double staining combining Turnbull with immunohistochemistry for macrophages or astrocytes. Quantitative densitometry of the iron staining as well as copper and iron concentrations were measured in the GP and putamen and correlated to R2* values. Results: T2*w hypointensity in the GP and/or putamen was apparent in WD cases and R2* values correlated with quantitative densitometry of iron staining. In WD, iron and copper concentrations were increased in the putamen compared to controls. R2* was correlated with the iron concentration in the GP and putamen whereas no correlation was observed for the copper concentration. Patients with more pronounced pathological severity in the putamen displayed increased iron concentration, which correlated with an elevated number of iron-containing macrophages. Conclusions: T2/T2*w hypointensity observed in vivo in the basal ganglia of WD patients is related to iron rather than copper deposits.

BACKGROUND AND PURPOSE Arterial spin labeling (ASL) is an MRI technique to measure cerebral blood flow (CBF) without the need of exogenous contrast agents and is thus a promising alternative to the clinical standard dynamic susceptibility-weighted contrast-enhanced (DSC) perfusion imaging. Latest international guidelines encourage its application in the clinical setting. However, susceptibility-induced image distortions impair ASL with fast readout modules (eg Echo Planar Imaging, EPI; gradient and spin echo, GRASE). In the present study, we investigated the benefit of a distortion correction for ASL compared to DSC. METHODS A pulsed ASL (PASL) sequence combined with a 3D-GRASE readout at multiple inflow times (multi-TI) was used and was corrected for susceptibility distortions using a FMRIB Software Library (FSL) implemented tool TOPUP. We performed qualitative (three expert raters) and quantitative (volume of interest [VOI]-based) comparisons of ASL and DSC imaging in 13 patients with chronic steno-occlusive disease. RESULTS In the qualitative analysis, distortion correction of the images led to a strong increase in diagnostic precision of ASL compared to DSC in the anterior cerebral artery (ACA) perfusion territory, where the susceptibility artifact was most pronounced (specificity 8% vs. 75%). In the quantitative analysis, the correlation between ASL and DSC values increased for all perfusion territories with the best improvement for the ACA territory (for anterior, middle and posterior cerebral artery: ACA: rho −0.22 vs. 0.71; MCA: rho 0.58 vs. 0.76; PCA: rho 0.58 vs. 0.63). CONCLUSIONS We showed that susceptibility distortion correction strongly improves the comparability of multi-TI ASL 3D-GRASE to DSC in steno-occlusive disease. We suggest it to be implemented in ASL postprocessing routines.

The quality and precision of post-mortem MRI microscopy may vary depending on the embedding medium used. To investigate this, our study evaluated the impact of 5 widely used media on: (1) image quality, (2) contrast of high spatial resolution gradient-echo (TFive formaldehyde-fixed brain slices were scanned using 7.0T MRI in: (1) formaldehyde solution (formalin), (2) phosphate-buffered saline (PBS), (3) deuterium oxide (DPBS, Galden, and agarose returned higher SNR/CNR compared to formalin and DEmbedding media affect gradient-echo image quality, R

In acute stroke, the magnetic resonance (MR) imaging-based mismatch concept is used to select patients with tissue at risk of infarction for reperfusion therapies. There is however a controversy if non-deconvolved or deconvolved perfusion weighted (PW) parameter maps perform better in tissue at risk prediction and which parameters and thresholds should be used to guide treatment decisions.In a group of 22 acute stroke patients with consecutive MR and quantitative positron emission tomography (PET) imaging, non-deconvolved parameters were validated with the gold standard for penumbral-flow (PF) detection 15O-water PET. Performance of PW parameters was assessed by a receiver operating characteristic curve analysis to identify the accuracy of each PWI map to detect the -upper PF threshold as defined by PET cerebral blood flow20 mL/100 g/min.Among normalized non-deconvolved parameters, PW-first moment without delay correction (FM without DC)3.6 s (area under the curve [AUC] = 0.89, interquartile range [IQR] 0.85-0.94), PW-maximum of the concentration curve (Cmax)0.66 (AUC = 0.92, IQR 0.84-0.96) and PW-time to peak (TTP)4.0 s (AUC = 0.92, IQR 0.87-0.94) perform significantly better than other non-deconvolved parameters to detect the PF threshold as defined by PET.Non-deconvolved parameters FM without DC, Cmax and TTP are an observer-independent alternative to established deconvolved parameters (e.g., Tmax) to guide treatment decisions in acute stroke.

Aims Evidence is lacking regarding acute anticoagulation management in patients after intracerebral haemorrhage (ICH) with implanted mechanical heart valves (MHVs). Our objective was to investigate anticoagulation reversal and resumption strategies by evaluating incidences of haemorrhagic and thromboembolic complications, thereby defining an optimal time-window when to restart therapeutic anticoagulation (TA) in patients with MHV and ICH. Methods and results We pooled individual patient-data (n = 2504) from a nationwide multicentre cohort-study (RETRACE, conducted at 22 German centres) and eventually identified MHV-patients (n = 137) with anticoagulation-associated ICH for outcome analyses. The primary outcome consisted of major haemorrhagic complications analysed during hospital stay according to treatment exposure (restarted TA vs. no-TA). Secondary outcomes comprised thromboembolic complications, the composite outcome (haemorrhagic and thromboembolic complications), timing of TA, and mortality. Adjusted analyses involved propensity-score matching and multivariable cox-regressions to identify optimal timing of TA. In 66/137 (48%) of patients TA was restarted, being associated with increased haemorrhagic (TA = 17/66 (26%) vs. no-TA = 4/71 (6%); P

Purpose Walsh ordering of Hadamard encoding-matrices and an additional averaging strategy are proposed for Hadamard-encoded pseudocontinuous arterial spin labeling (H-pCASL). In contrast to conventional H-pCASL the proposed method generates more perfusion-weighted images which are accessible already during a running experiment and even from incomplete sets of encoded images. Theory Walsh-ordered Hadamard matrices consist of fully decodable Hadamard submatrices. At any time during a measurement these submatrices may yield perfusion-weighted images, even at runtime and with incomplete datasets. The usage of an additional so-called mirrored matrix for averaging leads to more decodable subboli. Methods Perfusion-weighted images (five healthy volunteers) are generated using both a Walsh-ordered and a corresponding mirrored Hadamard matrix. To test their correctness they are compared with equivalent images from conventional multi postlabeling-delay (PLD) pCASL-measurements. Results All predicted perfusion-weighted images could be generated and correlated very well with multi-PLD images. Already small subsets of encoded images, acquired early during the measurement, yielded perfusion-weighted images. The mirrored matrix generates more perfusion-weighted images without time penalty. Conclusion Early access to perfusion-weighted images despite incomplete datasets allows dynamic adaptation of parameters and increases robustness against artifacts. Thus, the approach may be well suited for clinical applications, where pathologies demand rapid parameter adaptation and increase the chance of artifacts. Magn Reson Med 76:1814-1824, 2016. © 2015 International Society for Magnetic Resonance in Medicine.

Objectives Time-of-flight (TOF) magnetic-resonance-angiography (MRA) identifies vessel pathology in cerebrovascular disease. At 7.0 T, the clinical performance of TOF-MRA is constrained owing to radio frequency power deposition. We studied the diagnostic value of whole-brain MPRAGE-based MRA as an alternative imaging technique in comparison to the clinical standard 3.0 T TOF-MRA. Methods Patients with stroke and/or moya-moya disease were included. TOF-MRA was performed at 3.0 T and MPRAGE-MRA at 7.0 T. Two radiologists rated the MRAs independently for overall quality and local arterial segment visualization. The identification of steno-occlusive pathology was reported for each protocol. Results In 18 patients (9 females; 6 patients with moya-moya) 7.0 T MPRAGE-MRA provided better overall image quality and better distinction of small structures compared to 3.0 T TOF-MRA. These findings were pronounced in the proximal segments of the anterior cerebral artery (A1), middle cerebral artery (M1, M2), posterior cerebral artery (P1) and the posterior communicating artery. Seven steno-occlusive findings were identified by both imaging protocols. Conclusions For clinical studies using ultrahigh field MRI, 7.0 T MPRAGE-MRA provides a suitable alternative to TOF-MRA imaging to identify brain vessel pathology and yields simultaneous structural brain imaging within clinically feasible acquisition times.

Objective The improvement in Arterial Spin Labeling (ASL) perfusion quantification, especially for delayed bolus arrival times (BAT), with an acquisition redistribution scheme mitigating the T1 decay of the label in multi-TI ASL measurements is investigated. A multi inflow time (TI) 3D-GRASE sequence is presented which adapts the distribution of acquisitions accordingly, by keeping the scan time constant. Material and Methods The MR sequence increases the number of averages at long TIs and decreases their number at short TIs and thus compensating the T1 decay of the label. The improvement of perfusion quantification is evaluated in simulations as well as in-vivo in healthy volunteers and patients with prolonged BATs due to age or steno-occlusive disease. Results The improvement in perfusion quantification depends on BAT. At healthy BATs the differences are small, but become larger for longer BATs typically found in certain diseases. The relative error of perfusion is improved up to 30% at BATs > 1500 ms in comparison to the standard acquisition scheme. Conclusion This adapted acquisition scheme improves the perfusion measurement in comparison to standard multi-TI ASL implementations. It provides relevant benefit in clinical conditions that cause prolonged BATs and is therefore of high clinical relevance for neuroimaging of steno-occlusive diseases.

Pulsed arterial spin labeling (PASL) at multiple inflow times (multi-TIs) is advantageous for the measurement of brain perfusion in patients with long arterial transit times (ATTs) as in steno-occlusive disease, because bolus-arrival-time can be measured and blood flow measurements can be corrected accordingly. Owing to its increased signal-to-noise ratio, a combination with a three-dimensional gradient and spin echo (GRASE) readout allows acquiring a sufficient number of multi-TIs within a clinically feasible acquisition time of 5 minutes. We compared this technique with the clinical standard dynamic susceptibility-weighted contrast-enhanced imaging—magnetic resonance imaging in patients with unilateral stenosis >70% of the internal carotid or middle cerebral artery (MCA) at 3 Tesla. We performed qualitative (assessment by three expert raters) and quantitative (region of interest (ROI)/volume of interest (VOI) based) comparisons. In 43 patients, multi-TI PASL-GRASE showed perfusion alterations with moderate accuracy in the qualitative analysis. Quantitatively, moderate correlation coefficients were found for the MCA territory (ROI based: r=0.52, VOI based: r=0.48). In the anterior cerebral artery (ACA) territory, a readout related right-sided susceptibility artifact impaired correlation (ROI based: r=0.29, VOI based: r=0.34). Arterial transit delay artifacts were found only in 12% of patients. In conclusion, multi-TI PASL-GRASE can correct for arterial transit delay in patients with long ATTs. These results are promising for the transfer of ASL to the clinical practice.

Introduction: Perfusion imaging by DSC-MRI (dynamic susceptibility contrast MRI) is the clinical method of choice for identification of penumbral flow (PF) in acute stroke. To date, the tissue at risk is estimated by a single predefined perfusion map. However, integration of various perfusion parameters may amplify the pathophysiological information and yield better estimation of PF. We therefore combined the common perfusion maps in a generalized linear model (GLM) to predict PF as defined by positron emission tomography (PET). Methods: In 18 patients with (sub)acute stroke, consecutive DSC-MRI and O15-water PET was performed (median age/NIHSS: 58 y , 12). PF was defined as cerebral-blood-flow (CBF) < 20 mL/100g/min on PET. MRI perfusion maps included: CBF, CBV, MTT, Tmax, TTP (cerebral-blood-volume, mean-transit-time, time-to-maximum and time-to-peak respectively). Probability maps for PF prediction were generated by a) single maps and b) multi-parametric maps (GLM) and underwent cross validation. ROC analysis assessed performance for PF prediction as area-under the curve (AUC). Results: Single maps showed AUC values between 0.57 and 0.72 (Tmax and CFB showing best performance). The GLM approach yielded an AUC of 0.75. Comparison by the Wilcoxon signed rank test showed that while the absolute difference was moderate, it was significant (p Conclusions: Our results suggest that a multi-parameter perfusion model yields the highest accuracy for PF prediction. This finding, while preliminary, suggest a straight-forward model that can be easily integrated in clinical routine for improved stroke stratification based on the mismatch paradigm. Figure 1: Performance in penumbral flow prediction The graph shows performance in PF prediction for perfusion parameters and GLM. The error-bars represent standard-error. (*) marks significance for p value

Background and Purpose— On the basis of phase II trials, we considered that transcranial laser therapy could have neuroprotective effects in patients with acute ischemic stroke. Methods— We studied transcranial laser therapy in a double-blind, sham-controlled randomized clinical trial intended to enroll 1000 patients with acute ischemic stroke treated ≤24 hours after stroke onset and who did not undergo thrombolytic therapy. The primary efficacy measure was the 90-day functional outcome as assessed by the modified Rankin Scale, with hierarchical Bayesian analysis incorporating relevant previous data. Interim analyses were planned after 300 and 600 patients included. Results— The study was terminated on recommendation by the Data Monitoring Committee after a futility analysis of 566 completed patients found no difference in the primary end point (transcranial laser therapy 140/282 [49.6%] versus sham 140/284 [49.3%] for good functional outcome; modified Rankin Scale, 0–2). The results remained stable after inclusion of all 630 randomized patients (adjusted odds ratio, 1.024; 95% confidence interval, 0.705–1.488). Conclusions— Once the results of the interim futility analysis became available, all study support was immediately withdrawn by the capital firms behind PhotoThera, and the company was dissolved. Proper termination of the trial was difficult but was finally achieved through special efforts by former employees of PhotoThera, the CRO Parexel and members of the steering and the safety committees. We conclude that transcranial laser therapy does not have a measurable neuroprotective effect in patients with acute ischemic stroke when applied within 24 hours after stroke onset. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01120301.

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 (p0.001), 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 volume87 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.