MRI in the Evaluation of Cryptogenic Stroke and Embolic Stroke of Undetermined Source.

Cryptogenic stroke refers to a stroke of undetermined etiology. It accounts for approximately one-fifth of ischemic strokes and has a higher prevalence in younger patients. Embolic stroke of undetermined source (ESUS) refers to a subgroup of patients with nonlacunar cryptogenic strokes in whom embolism is the suspected stroke mechanism. Under the classifications of cryptogenic stroke or ESUS, there is wide heterogeneity in possible stroke mechanisms. In the absence of a confirmed stroke etiology, there is no established treatment for secondary prevention of stroke in patients experiencing cryptogenic stroke or ESUS, despite several clinical trials, leaving physicians with a clinical dilemma. Both conventional and advanced MRI techniques are available in clinical practice to identify differentiating features and stroke patterns and to determine or infer the underlying etiologic cause, such as atherosclerotic plaques and cardiogenic or paradoxical embolism due to occult pelvic venous thrombi. The aim of this review is to highlight the diagnostic utility of various MRI techniques in patients with cryptogenic stroke or ESUS. Future trends in technological advancement for promoting the adoption of MRI in such a special clinical application are also discussed.

MR Multitasking-based multi-dimensional assessment of cardiovascular system (MT-MACS) with extended spatial coverage and water-fat separation.

PURPOSE: To extend the MR MultiTasking-based Multidimensional Assessment of Cardiovascular System (MT-MACS) technique with larger spatial coverage and water-fat separation for comprehensive aortocardiac assessment. METHODS: MT-MACS adopts a low-rank tensor image model for 7D imaging, with three spatial dimensions for volumetric imaging, one cardiac motion dimension for cine imaging, one respiratory motion dimension for free-breathing imaging, one T2-prepared inversion recovery time dimension for multi-contrast assessment, and one T2*-decay time dimension for water-fat separation. Nine healthy subjects were recruited for the 3T study. Overall image quality was scored on bright-blood (BB), dark-blood (DB), and gray-blood (GB) contrasts using a 4-point scale (0-poor to 3-excellent) by two independent readers, and their interreader agreement was evaluated. Myocardial wall thickness and left ventricular ejection fraction (LVEF) were quantified on DB and BB contrasts, respectively. The agreement in these metrics between MT-MACS and conventional breath-held, electrocardiography-triggered 2D sequences were evaluated. RESULTS: MT-MACS provides both water-only and fat-only images with excellent image quality (average score = 3.725/3.780/3.835/3.890 for BB/DB/GB/fat-only images) and moderate to high interreader agreement (weighted Cohen's kappa value = 0.727/0.668/1.000/1.000 for BB/DB/GB/fat-only images). There were good to excellent agreements in myocardial wall thickness measurements (intraclass correlation coefficients [ICC] = 0.781/0.929/0.680/0.878 for left atria/left ventricle/right atria/right ventricle) and LVEF quantification (ICC = 0.716) between MT-MACS and 2D references. All measurements were within the literature range of healthy subjects. CONCLUSION: The refined MT-MACS technique provides multi-contrast, phase-resolved, and water-fat imaging of the aortocardiac systems and allows evaluation of anatomy and function. Clinical validation is warranted.

Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data.

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 (I2=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 [<1%], 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.

Plaque Morphologic Quantification Reliability of 3D Whole-Brain Vessel Wall Imaging in Patients With Intracranial Atherosclerotic Disease: A Comparison With Conventional 3D Targeted Vessel Wall Imaging.

BACKGROUND: Three-dimensional (3D) whole-brain vessel wall imaging (VWI) has demonstrated exquisite image quality for delineating intracranial atherosclerotic disease (ICAD) and reliability for quantifying normal vessel dimensions. However, its reliability in quantifying plaque morphology remains unknown. PURPOSE: To evaluate the plaque morphologic quantification reliability of 3D whole-brain VWI in patients via comparison with 3D targeted VWI and 2D turbo spin-echo (TSE). STUDY TYPE: Prospective. POPULATION: Thirty-three patients with symptomatic ICAD. FIELD STRENGTH/SEQUENCE: A 3D and 2D TSE acquired at 3.0 T. ASSESSMENT: Each participant underwent two VWI sessions with an interval of 7-10 days. Three readers identified in consensus all the plaques on both whole-brain and targeted 3D VWI. Their lumen and vessel wall area and volume, plaque burden, percent stenosis, and vessel wall remodeling were measured for by two independent readers. At each culprit plaque determined by a radiologist, the lumen and vessel wall area, plaque burden, plaque-to-wall contrast ratio (CR), and plaque enhancement ratio (ER) were measured for 2D and 3D VWI methods. STATISTICAL TESTS: Intra-class correlation coefficient (ICC) was used to evaluate for 3D VWI's interobserver/intraobserver agreement, interscan repeatability, and agreement with 2D TSE in each plaque morphologic measurements. Paired t test was performed for detecting the differences in plaque-to-wall CR and plaque ER between the two 3D methods. RESULTS: Eighty-four plaques were detected by both 3D VWI methods. Whole-brain VWI provided excellent interobserver/intraobserver agreement (ICCs: 0.79-0.99/0.95-0.99), interscan repeatability (ICCs: 0.85-0.99), agreement with 2D TSE (ICC: 0.80-0.94) in all morphologic measurements. ICCs of whole-brain VWI (0.79-0.99) were higher or equal to those of targeted VWI (0.76-0.99). The plaque-to-wall CR and plaque ER were significantly higher on whole-brain VWI than on targeted VWI. DATA CONCLUSION: The 3D whole-brain VWI provides excellent interobserver/intraobserver agreement, interscan repeatability, and agreement with 2D TSE in plaque morphologic quantification of ICAD and outperforms 3D targeted VWI. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 2.

COVID-19 Impact on Acute Ischemic Stroke Treatment at 9 Comprehensive Stroke Centers across Los Angeles.

OBJECTIVE: To describe the impact of COVID-19 on acute cerebrovascular disease care across 9 comprehensive stroke centers throughout Los Angeles County (LAC). METHODS: Volume of emergency stroke code activations, patient characteristics, stroke severity, reperfusion rates, treatment times, and outcomes from February 1 to April 30, 2020, were compared against the same time period in 2019. Demographic data were provided by each participating institution. RESULTS: There was a 17.3% decrease in stroke code activations across LAC in 2020 compared to 2019 (1,786 vs. 2,159, respectively, χ2 goodness of fit test p < 0.0001) across 9 participating comprehensive stroke centers. Patients who did not receive any reperfusion therapy decreased by 16.6% in 2020 (1,527) compared to 2019 (1,832). Patients who received only intravenous thrombolytic (IVT) therapy decreased by 31.8% (107 vs. 157). Patients who received only mechanical thrombectomy (MT) increased by 3% (102 vs. 99). Patients who received both IVT and MT decreased by 31.8% (45 vs. 66). Recanalization treatment times in 2020 were comparable to 2019. CSCs serving a higher proportion of Latinx populations in the eastern parts of LAC experienced a higher incidence of MT in 2020 compared to 2019. Mild increase in stroke severity was seen in 2020 compared to 2019 (8.95 vs. 8.23, p = 0.046). A higher percentage of patients were discharged home in 2020 compared to 2019 (59.5 vs. 56.1%, p = 0.034), a lower percentage of patients were discharged to skilled nursing facility (16.1 vs. 20.7%, p = 0.0004), and a higher percentage of patients expired (8.6 vs. 6.3%, p = 0.008). CONCLUSION: LAC saw a decrease in overall stroke code activations in 2020 compared to 2019. Reperfusion treatment times remained comparable to prepandemic metrics. There has been an increase in severe stroke incidence and higher volume of thrombectomy treatments in Latinx communities within LAC during the pandemic of 2020. More patients were discharged home, less patients discharged to skilled nursing facilities, and more patients expired in 2020, compared to the same time frame in 2019.

Magnetic resonance multitasking for multidimensional assessment of cardiovascular system: Development and feasibility study on the thoracic aorta.

PURPOSE: To develop an MR multitasking-based multidimensional assessment of cardiovascular system (MT-MACS) with electrocardiography-free and navigator-free data acquisition for a comprehensive evaluation of thoracic aortic diseases. METHODS: The MT-MACS technique adopts a low-rank tensor image model with a cardiac time dimension for phase-resolved cine imaging and a T2 -prepared inversion-recovery dimension for multicontrast assessment. Twelve healthy subjects and 2 patients with thoracic aortic diseases were recruited for the study at 3 T, and both qualitative (image quality score) and quantitative (contrast-to-noise ratio between lumen and wall, lumen and wall area, and aortic strain index) analyses were performed in all healthy subjects. The overall image quality was scored based on a 4-point scale: 3, excellent; 2, good; 1, fair; and 0, poor. Statistical analysis was used to test the measurement agreement between MT-MACS and its corresponding 2D references. RESULTS: The MT-MACS images reconstructed from acquisitions as short as 6 minutes demonstrated good or excellent image quality for bright-blood (2.58 ± 0.46), dark-blood (2.58 ± 0.50), and gray-blood (2.17 ± 0.53) contrast weightings, respectively. The contrast-to-noise ratios for the three weightings were 49.2 ± 12.8, 20.0 ± 5.8 and 2.8 ± 1.8, respectively. There were good agreements in the lumen and wall area (intraclass correlation coefficient = 0.993, P < .001 for lumen; intraclass correlation coefficient = 0.969, P < .001 for wall area) and strain (intraclass correlation coefficient = 0.947, P < .001) between MT-MACS and conventional 2D sequences. CONCLUSION: The MT-MACS technique provides high-quality, multidimensional images for a comprehensive assessment of the thoracic aorta. Technical feasibility was demonstrated in healthy subjects and patients with thoracic aortic diseases. Further clinical validation is warranted.

WEAVE Trial: Final Results in 152 On-Label Patients.

Background and Purpose- The WEAVE trial (Wingspan Stent System Post Market Surveillance) is a postmarket surveillance trial mandated by the Food and Drug Administration to assess the periprocedural safety of the Wingspan Stent system in the treatment of symptomatic intracranial atherosclerotic disease. Methods- A total of 152 consecutive patients who met the Food and Drug Administration on-label usage criteria were enrolled at 24 hospitals and underwent angioplasty and stenting with the Wingspan stent. On-label criteria included age 22 to 80 years, symptomatic intracranial atherosclerotic stenosis of 70% to 99%, baseline modified Rankin Scale score ≤3, ≥2 strokes in the vascular territory of the stenotic lesion with at least 1 stroke while on medical therapy, and stenting of the lesion ≥8 days after the last stroke. The primary analysis assessed the periprocedural stroke, bleed, and death rate within 72 hours of the procedure with adjudication by a core study Stroke Neurologist. Results- The trial was stopped early after interim analysis of 152 consecutive patients demonstrated a lower than expected 2.6% (4/152 patients) periprocedural stroke, bleed, and death rate. This was lower than the 4% periprocedural primary event safety benchmark set for the interim analysis in the study. A total of 97.4% (148/152) patients were event-free at 72 hours, 1.3% (2/152) had nonfatal strokes, and 1.3% (2/152) of patients died. Conclusions- With experienced interventionalists, and proper patient selection following the on-label usage guidelines, the use of the Wingspan stent for intracranial atherosclerotic disease demonstrated a low periprocedural complication rate and excellent safety profile. This is the largest on-label, multicenter, prospective trial of the Wingspan stent system to date with the lowest reported complication rate. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT02034058.

Intravenous thrombolysis in unwitnessed stroke onset: MR WITNESS trial results.

OBJECTIVE: Most acute ischemic stroke (AIS) patients with unwitnessed symptom onset are ineligible for intravenous thrombolysis due to timing alone. Lesion evolution on fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) correlates with stroke duration, and quantitative mismatch of diffusion-weighted MRI with FLAIR (qDFM) might indicate stroke duration within guideline-recommended thrombolysis. We tested whether intravenous thrombolysis ≤4.5 hours from the time of symptom discovery is safe in patients with qDFM in an open-label, phase 2a, prospective study (NCT01282242). METHODS: Patients aged 18 to 85 years with AIS of unwitnessed onset at 4.5 to 24 hours since they were last known to be well, treatable within 4.5 hours of symptom discovery with intravenous alteplase (0.9mg/kg), and presenting with qDFM were screened across 14 hospitals. The primary outcome was the risk of symptomatic intracranial hemorrhage (sICH) with preplanned stopping rules. Secondary outcomes included symptomatic brain edema risk, and functional outcomes of 90-day modified Rankin Scale (mRS). RESULTS: Eighty subjects were enrolled between January 31, 2011 and October 4, 2015 and treated with alteplase at median 11.2 hours (IQR = 9.5-13.3) from when they were last known to be well. There was 1 sICH (1.3%) and 3 cases of symptomatic edema (3.8%). At 90 days, 39% of subjects achieved mRS = 0-1, as did 48% of subjects who had vessel imaging and were without large vessel occlusions. INTERPRETATION: Intravenous thrombolysis within 4.5 hours of symptom discovery in patients with unwitnessed stroke selected by qDFM, who are beyond the recommended time windows, is safe. A randomized trial testing efficacy using qDFM appears feasible and is warranted in patients without large vessel occlusions. Ann Neurol 2018;83:980-993.

Differential Expression of Vascular Endothelial Growth Factor-A165 Isoforms Between Intracranial Atherosclerosis and Moyamoya Disease.

BACKGROUND: Vascular endothelial growth factor-A165 (VEGF-A165) has been identified as a combination of 2 alternative splice variants: proangiogenic VEGF-A165a and antiangiogenic VEGF-A165b. Intracranial atherosclerotic disease (ICAD) and moyamoya disease (MMD) are 2 main types of intracranial arterial steno-occlusive disorders with distinct capacities for collateral formation. Recent studies indicate that VEGF-A165 regulates collateral growth in ischemia. Therefore, we investigated if there is a distinctive composition of VEGF-A165 isoforms in ICAD and MMD. METHODS: Sixty-six ICAD patients, 6 MMD patients, and 5 controls were enrolled in this prospective study. ICAD and MMD patients received intensive medical management upon enrollment. Surgery was offered to 9 ICAD patients who had recurrent ischemic events, 6 MMD patients, and 5 surgical controls without ICAD. VEGF-A165a and VEGF-A165b plasma levels were measured at baseline, within 1 week after patients having surgery, and at 1, 3, and 6 months after treatment. RESULTS: A significantly higher baseline VEGF-A165a/b ratio was observed in MMD compared to ICAD (P = .016). The VEGF-A165a/b ratio increased significantly and rapidly after surgical treatment in ICAD (P = .026) more so than in MMD and surgical controls. In patients with ICAD receiving intensive medical management, there was also an elevation of the VEGF-A165a/b ratio, but at a slower rate, reaching the peak at 3 months after initiation of treatment (baseline versus 3 months VEGF-A165a/b ratio, P = .028). CONCLUSIONS: Our study shows an increased VEGF-A165a/b ratio in MMD compared to ICAD, and suggests that both intensive medical management and surgical revascularization elevate the VEGF-A165a/b ratio in ICAD patients.

3D whole-brain vessel wall cardiovascular magnetic resonance imaging: a study on the reliability in the quantification of intracranial vessel dimensions.

BACKGROUND: One of the potentially important applications of three-dimensional (3D) intracranial vessel wall (IVW) cardiovascular magnetic resonance (CMR) is to monitor disease progression and regression via quantitative measurement of IVW morphology during medical management or drug development. However, a prerequisite for this application is to validate that IVW morphologic measurements based on the modality are reliable. In this study we performed comprehensive reliability analysis for the recently proposed whole-brain IVW CMR technique. METHODS: Thirty-four healthy subjects and 10 patients with known intracranial atherosclerotic disease underwent repeat whole-brain IVW CMR scans. In 19 of the 34 subjects, two-dimensional (2D) turbo spin-echo (TSE) scan was performed to serve as a reference for the assessment of vessel dimensions. Lumen and wall volume, normalized wall index, mean and maximum wall thickness were measured in both 3D and 2D IVW CMR images. Scan-rescan, intra-observer, and inter-observer reproducibility of 3D IVW CMR in the quantification of IVW or plaque dimensions were respectively assessed in volunteers and patients as well as for different healthy subjectsub-groups (i.e. < 50 and ≥ 50 years). The agreement in vessel wall and lumen measurements between the 3D technique and the 2D TSE method was also investigated. In addition, the sample size required for future longitudinal clinical studies was calculated. RESULTS: The intra-class correlation coefficient (ICC) and Bland-Altman plots indicated excellent reproducibility and inter-method agreement for all morphologic measurements (All ICCs > 0.75). In addition, all ICCs of patients were equal to or higher than that of healthy subjects except maximum wall thickness. In volunteers, all ICCs of the age group of ≥50 years were equal to or higher than that of the age group of < 50 years. Normalized wall index and mean and maximum wall thickness were significantly larger in the age group of ≥50 years. To detect 5% - 20% difference between placebo and treatment groups, normalized wall index requires the smallest sample size while lumen volume requires the highest sample size. CONCLUSIONS: Whole-brain 3D IVW CMR is a reliable imaging method for the quantification of intracranial vessel dimensions and could potentially be useful for monitoring plaque progression and regression.

Management of Factor Xa inhibitor-associated life-threatening major hemorrhage: A retrospective multi-center analysis.

BACKGROUND: Factor Xa (FXa) inhibitors, used for stroke prevention in atrial fibrillation and venous thromboembolism treatment and prevention, are the dominant non-Vitamin K oral anticoagulants on the market. While major bleeding may be less common with these agents compared to warfarin, it is always a risk, and little has been published on the most serious bleeding scenarios. This study describes a cohort of patients with FXa inhibitor-associated life-threatening bleeding events, their clinical characteristics, interventions and outcomes. METHODS: We performed a retrospective, 5-center review of FXa inhibitor-treated major bleeding patients. Investigators identified potential cases by cross-referencing ICD-9/10 codes for hemorrhage with medication lists. Investigators selected cases they deemed to require immediate reversal of coagulopathy, and reviewed charts for characteristics, reversal strategies and other interventions, and outcomes. RESULTS: A total of 56 charts met the inclusion criteria for the retrospective cohort, including 29 (52%) gastrointestinal bleeds (GIB), 19 (34%) intracranial hemorrhages (ICH) and 8 (14%) others. Twenty-four (43%) patients received various factor or plasma products, and the remainder received supportive care. Thirty-day mortality was 21% (n=12). Re-anticoagulation within 30-days occurred in 23 (41%) patients. Thromboembolic events (TEEs) occurred in 6 (11%) patients. No differences were observed in outcomes by treatment strategy. CONCLUSIONS: This cohort of FXa inhibitor-associated major bleeding scenarios deemed appropriate for acute anticoagulant reversal illustrates the variable approaches in the absence of a specific reversal agent.

Whole-brain vessel wall MRI: A parameter tune-up solution to improve the scan efficiency of three-dimensional variable flip-angle turbo spin-echo.

PURPOSE: To propose and evaluate a parameter tune-up solution to expedite a three-dimensional (3D) variable-flip-angle turbo spin-echo (TSE) sequence for whole-brain intracranial vessel wall (IVW) imaging. MATERIALS AND METHODS: Elliptical k-space sampling and prolonged echo train length (ETL), were used to expedite a 3D variable-flip-angle TSE-based sequence. To compensate for the potential loss in vessel wall signal, optimal combination of prescribed T2 and ETL was experimentally investigated on 22 healthy volunteers at 3 Tesla. The optimized protocol (7-8 min) was then compared with a previous protocol (reference protocol, 11-12 min) in terms of signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), vessel wall sharpness, and wall delineation quality on a 4-point scale (0:poor; 3:excellent) in 10 healthy volunteers. A pilot study of five patients was performed and lesion delineation score was used to demonstrate the diagnostic quality. RESULTS: A protocol with ETL = 52 and prescribed T2 = 170 ms was deemed an optimized one, which, compared with the reference protocol, provided significantly improved wall SNR (12.0 ± 1.3 versus 10.0 ± 1.1; P = 0.002), wall-lumen CNR (9.7 ± 1.2 versus 8.0 ± 0.9; P = 0.002), wall-CSF CNR (2.8 ± 1.0 versus 1.7 ± 1.0; P = 0.026), similar vessel wall sharpness at both inner (1.59 ± 0.18 versus 1.58 ± 0.14, P = 0.87) and outer (1.71 ± 0.25 versus 1.83 ± 0.30; P = 0.18) boundaries, and comparable vessel wall delineation score for individual segments (1.95-3; P > 0.06). In all patients, atherosclerotic plaques (10) or wall dissection (5) were identified with a delineation score of 3 or 2. CONCLUSION: A parameter tune-up solution can accelerate 3D variable-flip-angle TSE acquisitions, particularly allowed for expedited whole-brain IVW imaging with preserved wall delineation quality. LEVEL OF EVIDENCE: 2. Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2017;46:751-757.

Negative diffusion-weighted imaging after intravenous tissue-type plasminogen activator is rare and unlikely to indicate averted infarction.

BACKGROUND AND PURPOSE: Some patients treated with intravenous (IV) tissue-type plasminogen activator (tPA) have negative diffusion-weighted imaging (DWI) on follow-up imaging. Without a visible infarct, there may be uncertainty as to whether the patient was having a stroke that was averted by tPA or whether the symptoms had not been cerebrovascular in origin. We evaluated patients presenting with suspected acute stroke with a positive DWI lesion before IV tPA to determine the probability of finding a negative DWI up to 48 hours after treatment. METHODS: We included patients from the Lesion Evolution in Stroke and Ischemia On Neuroimaging (LESION) project who had acute MRI screening with a positive DWI lesion before IV tPA treatment and had follow-up MRI up to 48 hours later. Experienced readers interpreted all acute and follow-up MRIs looking for ischemic lesions on DWI. RESULTS: There were 231 patients who met study inclusion criteria, of which 225 patients (97.4%) had a persistent positive DWI corresponding to the acute stroke lesion on all follow-up imaging. Four patients (1.7%) had transient DWI lesion reversal with positive DWI on subsequent follow-up imaging. There were only 2 cases (0.9%) of complete DWI lesion reversal on all follow-up imaging. CONCLUSIONS: Averted infarction after IV tPA is rare, occurring in 0.9% of patients with pretreatment positive DWI evidence of acute ischemia. For IV tPA-treated patients who have a negative DWI on follow-up imaging, a cause other than acute stroke should be explored.

Advanced imaging in acute ischemic stroke.

Advances in stroke neuroimaging have evolved from excluding acute intracranial hemorrhage on computed tomography (CT) to now using perfusion studies (PWI) and magnetic resonance imaging (MRI) to possibly expand thrombolytic treatment to patients most likely to benefit from reperfusion therapy. Advanced imaging has also helped identify those at high risk for hemorrhage and poor outcome so appropriate treatment can occur with fewer complications. Identifying those who can benefit from endovascular recanalization using advanced neuroimaging techniques is particularly useful because endovascular treatment is often initiated much later than intravenous thrombolytic treatment due to logistical constraints. Using imaging markers of tissue injury may eventually lead to a paradigm shift from time-based treatment eligibility in acute stroke reperfusion treatment as the sensitivity and specificity to identify ischemic penumbra improves and correlation with clinical outcomes becomes clearer.

Symptomatic Intracranial Hemorrhage With Tenecteplase vs Alteplase in Patients With Acute Ischemic Stroke: The Comparative Effectiveness of Routine Tenecteplase vs Alteplase in Acute Ischemic Stroke (CERTAIN) Collaboration.

Importance: Symptomatic intracranial hemorrhage (sICH) is a serious complication of stroke thrombolytic therapy. Many stroke centers have adopted 0.25-mg/kg tenecteplase instead of alteplase for stroke thrombolysis based on evidence from randomized comparisons to alteplase as well as for its practical advantages. There have been no significant differences in symptomatic intracranial hemorrhage (sICH) reported from randomized clinical trials or published case series for the 0.25-mg/Kg dose. Objective: To assess the risk of sICH following ischemic stroke in patients treated with tenecteplase compared to those treated with alteplase. Design, Setting, and Participants: This was a retrospective observational study using data from the large multicenter international Comparative Effectiveness of Routine Tenecteplase vs Alteplase in Acute Ischemic Stroke (CERTAIN) collaboration comprising deidentified data on patients with ischemic stroke treated with intravenous thrombolysis. Data from more than 100 hospitals in New Zealand, Australia, and the US that used alteplase or tenecteplase for patients treated between July 1, 2018, and June 30, 2021, were included for analysis. Participating centers included a mix of nonthrombectomy- and thrombectomy-capacity comprehensive stroke centers. Standardized data were abstracted and harmonized from local or regional clinical registries. Consecutive patients with acute ischemic stroke who were considered eligible and received thrombolysis at the participating stroke registries during the study period were included. All 9238 patients who received thrombolysis were included in this retrospective analysis. Main Outcomes and Measures: sICH was defined as clinical worsening of at least 4 points on the National Institutes of Health Stroke Scale (NIHSS), attributed to parenchymal hematoma, subarachnoid, or intraventricular hemorrhage. Differences between tenecteplase and alteplase in the risk of sICH were assessed using logistic regression, adjusted for age, sex, NIHSS score, and thrombectomy. Results: Of the 9238 patients included in the analysis, the median (IQR) age was 71 (59-80) years, and 4449 patients (48%) were female. Tenecteplase was administered to 1925 patients. The tenecteplase group was older (median [IQR], 73 [61-81] years vs 70 [58-80] years; P < .001), more likely to be male (1034 of 7313 [54%] vs 3755 of 1925 [51%]; P < .01), had higher NIHSS scores (median [IQR], 9 [5-17] vs 7 [4-14]; P < .001), and more frequently underwent endovascular thrombectomy (38% vs 20%; P < .001). The proportion of patients with sICH was 1.8% for tenecteplase and 3.6% for alteplase (P < .001), with an adjusted odds ratio (aOR) of 0.42 (95% CI, 0.30-0.58; P < .01). Similar results were observed in both thrombectomy and nonthrombectomy subgroups. Conclusions and Relevance: In this large study, ischemic stroke treatment with 0.25-mg/kg tenecteplase was associated with lower odds of sICH than treatment with alteplase. The results provide evidence supporting the safety of tenecteplase for stroke thrombolysis in real-world clinical practice.

A pragmatic approach using magnetic resonance imaging to treat ischemic strokes of unknown onset time in a thrombolytic trial.

BACKGROUND AND PURPOSE: Toward the goal of designing a clinical trial using imaging parameters to treat stroke patients with unknown onset time, we investigated the timing of changes on MRI in patients with well-defined stroke onset. METHODS: Hypothesis-generating (n=85) and confirmatory (n=111) samples were scored by blinded readers for fluid-attenuated inversion recovery (FLAIR) hyperintensity in diffusion-positive regions. Reader-measured signal intensity ratio (SIR) of the lesion to contralateral tissue was compared with SIR measured by coregistration. RESULTS: Lesion conspicuity increased with time on FLAIR (P=0.006). Qualitative assessment of FLAIR-negative vs FLAIR hyperintensity (k=0.7091; 95% CI, 0.61-0.81) showed good interrater agreement. Subtle hyperintensity was less reliably categorized (k=0.59; 95% CI, 0.47-0.71). Reader-measured SIR <1.15 can identify patients within the treatable time window of 4.5 hours (positive predictive value=0.90). The SIR was greater for right hemisphere lesions (P=0.04) for a given reported time from stroke symptom onset. CONCLUSIONS: The SIR on FLAIR provides a quantitative tool to identify early ischemic strokes. In developing SIR thresholds, right hemisphere lesions may confound the accurate estimate of stroke onset time. Image coregistration for thrombolytic trial enrollment is not necessary. A SIR <1.15 on FLAIR yields a practical estimate of stroke onset within 4.5 hours.

Sex Differences in Intracranial Atherosclerosis in Patients With Hypertension With Acute Ischemic Stroke.

Background Studies suggest the presence of sex differences in hypertension prevalence and its associated outcomes in atherosclerosis and stroke. We hypothesized a higher intracranial atherosclerosis burden among men with hypertension and acute ischemic stroke compared with women. Methods and Results A multicenter retrospective study was performed from a prospective database identifying patients with hypertension presenting with intracranial atherosclerosis-related acute ischemic stroke and imaged with intracranial vessel wall magnetic resonance imaging. Proximal and distal plaques on vessel wall magnetic resonance imaging were scored. Negative binomial models assessed the associations between plaque-count and sex and the interaction between sex and treatment. Covariates were selected by a least absolute shrinkage and selection operator procedure. Sixty-one patients (n=42 men) were included. There were no significant differences in demographic or cardiovascular risk factors except for smoking history (P=0.002). Adjusted total and proximal plaque counts for men were 1.6 (95% CI, 1.2-2.1; P<0.01) and 1.4 (95% CI, 1.0-1.9; P=0.03) times as high as women, respectively. Female sex was more protective for proximal plaque if treated for hypertension. The risk ratio of men versus women was 1.5 (95% CI, 1.0-2.1) for treated patients. The risk ratio of men versus women was 0.7 (95% CI, 0.4-1.3) for untreated patients. The relative difference between these 2 risk ratios was 2.0 (95% CI, 1.1-3.9), which was statistically significant from the interaction test, P=0.04. Conclusions Men with hypertension with acute ischemic stroke have significantly higher total and proximal plaque burdens than women. Women with hypertension on anti-hypertensive medication showed a greater reduction in proximal plaque burden than men. Further confirmation with a longitudinal cohort study is needed and may help evaluate whether different treatment guidelines for managing hypertension by sex can help reduce intracranial atherosclerosis burden and ultimately acute ischemic stroke risk.

Disparate trends of atherosclerotic plaque evolution in stroke patients under 18-month follow-up: a 3D whole-brain magnetic resonance vessel wall imaging study.

PURPOSE: The trend of atherosclerotic plaque feature evolution is unclear in stroke patients with and without recurrence. We aimed to use three-dimensional whole-brain magnetic resonance vessel wall imaging to quantify the morphological changes of causative lesions during medical therapy in patients with symptomatic intracranial atherosclerotic disease. METHODS: Patients with acute ischemic stroke attributed to intracranial atherosclerotic disease were retrospectively enrolled if they underwent both baseline and follow-up magnetic resonance vessel wall imaging. The morphological features of the causative plaque, including plaque volume, peak normalized wall index, maximum wall thickness, degree of stenosis, pre-contrast plaque-wall contrast ratio, and post-contrast plaque enhancement ratio, were quantified and compared between the non-recurrent and recurrent groups (defined as the recurrence of a vascular event within 18 months of stroke). RESULTS: Twenty-nine patients were included in the final analysis. No significant differences were found in plaque features in the baseline scan between the non-recurrent (n = 22) and recurrent groups (n = 7). The changes in maximum wall thickness (-13.32% vs. 8.93%, P = 0.026), plaque-wall contrast ratio (-0.82% vs. 3.42%, P = 0.005) and plaque enhancement ratio (-11.03% vs. 9.75%, P = 0.019) were significantly different between the non-recurrent and recurrent groups. Univariable logistic regression showed that the increase in plaque-wall contrast ratio (odds ratio 3.22, 95% confidence interval 1.55-9.98, P = 0.003) was related to stroke recurrence. CONCLUSION: Morphological changes of plaque features on magnetic resonance vessel wall imaging demonstrated distinct trends in symptomatic intracranial atherosclerotic disease patients with and without stroke recurrence.