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Patients with atrial fibrillation (AF) and ischemic stroke are at high risk for stroke recurrence. Early anticoagulation may reduce the risk of recurrent events but is usually avoided due to the risk of hemorrhagic transformation (HT). Current guidelines are based on empiric expert opinion. The assumed risk of HT is based on historical data from an older generation of anticoagulants. The direct oral anticoagulants (DOACs) have demonstrated lower risk of intracranial hemorrhage compared to older anticoagulants. However, the optimal timing of DOAC initiation after AF-related ischemic stroke has remained an area of clinical equipoise, as the pivotal phase III trials did not include patients in the early period after ischemic stroke. Multiple prospective studies and a few smaller randomized controlled trials evaluating the safety and efficacy of early versus delayed DOAC initiation have been completed. These studies have reported promising results of early DOAC initiation after acute ischemic stroke. However, a standardized documentation of HT rates on follow-up imaging with objective assessment criteria is missing from most of these studies. Larger randomized trials of early versus delayed DOAC are ongoing. A literature review was performed using keywords and Medical Subject Headings in MEDLINE/PubMed and Google Scholar databases. For each relevant paper, the bibliography was scrutinized for other relevant articles and journals. In this article, we review the risk of recurrent ischemic stroke and HT in patients with AF, pathophysiology, classification, predictors, natural history, and outcomes of HT and discuss the studies of early anticoagulation after AF-related ischemic stroke.

Background: Definitive diagnosis of acute ischemic stroke is challenging, particularly in telestroke settings. Although the prognostic utility of CT perfusion (CTP) has been questioned, its diagnostic value remains under-appreciated, especially in cases without an easily visible intracranial occlusion. We assessed the diagnostic accuracy of routine CTP in the acute telestroke setting., Methods: Acute and follow-up data collected prospectively from consecutive suspected patients with stroke assessed by a state-wide telestroke service between March 2020 and August 2021 at 12 sites in Australia were analyzed. All patients in the final analysis had been assessed with multimodal CT, including CTP, which was post-processed with automated volumetric software. Diagnostic sensitivity and specificity were calculated for multimodal CT and each individual component (noncontrast CT [NCCT], CT angiogram [CTA], and CTP). Final diagnosis determined by consensus review of follow-up imaging and clinical data was used as the reference standard., Results: During the study period, complete multimodal CT examination was obtained in 831 patients, 457 of whom were diagnosed with stroke. Diagnostic sensitivity for ischemic stroke increased by 19.5 percentage points when CTP was included with NCCT and CTA compared with NCCT and CTA alone (73.1% positive with NCCT+CTA+CTP [95% CI, 68.8-77.1] versus 53.6% positive with NCCT+CTA alone [95% CI, 48.9-58.3], P <0.001). No difference was observed between specificities of NCCT+CTA and NCCT+CTA+CTP (98.7% [95% CI, 98.5-100] versus 98.7% [95% CI, 96.9-99.6], P =0.13). Multimodal CT, including CTP, demonstrated the highest negative predictive value (75.0% [95% CI, 72.1-77.7]). Patients with stroke not evident on CTP had small volume infarcts on follow-up (1.2 mL, interquartile range 0.5-2.7mL)., Conclusions: Acquisition of CTP as part of a telestroke imaging protocol permits definitive diagnosis of cerebral ischemia in 1 in 5 patients with normal NCCT and CTA.

Objective: The objective of this study was to evaluate functional and safety outcomes of endovascular thrombectomy (EVT) versus medical management (MM) in patients with M2 occlusion and examine their association with perfusion imaging mismatch and stroke severity., Methods: In a pooled, patient-level analysis of 3 randomized controlled trials (EXTEND-IA, EXTEND-and IA-TNK parts 1 and 2) and 2 prospective nonrandomized studies (INSPIRE and SELECT), we evaluated EVT association with 90-day functional independence (modified Rankin Scale [mRS] = 0-2) in isolated M2 occlusions as compared to medical management overall and in subgroups by mismatch profile status and stroke severity., Results: We included 517 patients (EVT = 195 and MM = 322), baseline median (interquartile range [IQR]) National Institutes of Health Stroke Scale (NIHSS) was 13 (8-19) in EVT versus 10 (6-15) in MM, p < 0.001. Pretreatment ischemic core did not differ (EVT = 10 [0-24] ml vs MM = 9 [3-21] ml, p = 0.59). Compared to MM, EVT was more frequently associated with functional independence (68.3 vs 61.6%, adjusted odds ratio [aOR] = 2.42, 95% confidence interval [CI] = 1.25-4.67, p = 0.008, inverse probability of treatment weights [IPTW]-OR = 1.75, 95% CI = 1.00-3.75, p = 0.05) with a shift toward better mRS outcomes (adjusted cOR = 2.02, 95% CI:1.23-3.29, p = 0.005), and lower mortality (5 vs 10%, aOR = 0.32, 95% CI = 0.12-0.87, p = 0.025). EVT was associated with higher functional independence in patients with a perfusion mismatch profile (EVT = 70.7% vs MM = 61.3%, aOR = 2.29, 95% CI = 1.09-4.79, p = 0.029, IPTW-OR = 2.02, 1.08-3.78, p = 0.029), whereas no difference was found in those without mismatch (EVT = 43.8% vs MM = 62.7%, p = 0.17, IPTW-OR: 0.71, 95% CI = 0.18-2.78, p = 0.62). Functional independence was more frequent with EVT in patients with moderate or severe strokes, as defined by baseline NIHSS above any thresholds from 6 to 10, whereas there was no difference between groups with milder strokes below these thresholds., Interpretation: In patients with M2 occlusion, EVT was associated with improved clinical outcomes when compared to MM. This association was primarily observed in patients with a mismatch profile and those with higher stroke severity. ANN NEUROL 2022;91:629-639., (© 2022 American Neurological Association.)

Background: The optimal timing of anticoagulation after stroke in patients with atrial fibrillation (AF) is unknown. We aimed to objectively assess the rate of radiological hemorrhagic transformation (HT) associated with early anticoagulation., Patients and Methods: A prospective, open label study (NCT04435418) of patients with AF treated with apixaban within 14 days of ischemic stroke/TIA onset was conducted. Baseline and follow-up CT scans were assessed for HT and graded using European Cooperative Acute Stroke Study (ECASS) criteria. The primary endpoint was symptomatic HT. Incident HT rates were assessed as Objective Performance Criteria., Results: One-hundred AF stroke patients, with a mean age of 79 ± 11 years were enrolled. Median infarct volume was 4 (0.5-10.75) ml. Median time from index event onset to apixaban initiation was 2 (1-6) days, and median baseline NIHSS was 4 (1-9). Asymptomatic HT on baseline imaging was present in 15 patients. Infarct volume (OR = 1.1, [1.02-1.12], p < 0.0001) and NIHSS (OR = 1.11, [1.03-1.20], p = 0.007) were both associated with baseline HT. No patients developed symptomatic HT or systemic hemorrhage. Incident asymptomatic HT was seen on follow-up CT scan in 3 patients. Patients with incident HT were functionally independent (mRS = 0-2) at 90 days. Recurrent ischemic events occurred within 90 days in 13 patients, 4 of which were associated with severe disability (mRS 3-5) and 4 with death., Discussion: Early apixaban treatment did not precipitate symptomatic HT after stroke. All HT was asymptomatic identified on imaging. Recurrent ischemic events were common and clinically symptomatic., Conclusions: Symptomatic HT rates are likely to be low in randomized trials of DOAC initiation post-stroke. Recurrent ischemic stroke may be the major clinical outcome. These data may be used as expected event rates when calculating sample size requirements for future safety/efficacy trials of early versus late DOAC initiation after AF-related stroke.

Background and Purpose- Patients with transient ischemic attack (TIA) and minor ischemic stroke are at risk for early recurrent cerebral ischemia. Anticoagulants are associated with reduced recurrence but also increased hemorrhagic transformation (HT). The safety of the novel oral anticoagulant dabigatran in acute stroke has not been evaluated. Methods- DATAS II (Dabigatran Treatment of Acute Stroke II) was a phase II prospective, randomized open label, blinded end point trial. Patients with noncardioembolic stroke/transient ischemic attack (National Institutes of Health Stroke Scale score, ≤9; infarct volume, ≤25 mL) were randomized to dabigatran or aspirin. Magnetic resonance imaging was performed before randomization and repeated at day 30. Imaging end points were ascertained centrally by readers blinded to treatment. The primary end point was symptomatic HT within 37 days of randomization. Results- A total of 305 patients, mean age 66.59±13.21 years, were randomized to dabigatran or aspirin a mean of 42.00±17.31 hours after symptom onset. The qualifying event was a transient ischemic attack in 21%, and ischemic stroke in 79% of patients. Median National Institutes of Health Stroke Scale (interquartile range) was 1 (0-2), and mean infarct volume 3.2±6.5 mL. No symptomatic HT occurred. Asymptomatic petechial HT developed in 11/142 (7.8%) of dabigatran-assigned patients and 5/142 (3.5%) of aspirin-assigned patients (relative risk, 2.301 [95% CI, 0.778-6.802]). Baseline infarct volume predicted incident HT (odds ratio, 1.07 [95% CI, 1.03-1.12]; P =0.0026). Incident covert infarcts on day 30 imaging occurred in 9/142 (6.3%) of dabigatran-assigned and 14/142 (9.8%) of aspirin-assigned patients (relative risk, 0.62 [95% CI, 0.26, 1.48]). Conclusions- Dabigatran was associated with a risk of HT similar to aspirin in acute minor noncardioembolic ischemic stroke/transient ischemic attack. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT02295826.

Background: 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., Methods: 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., Findings: 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)., Interpretation: 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., Funding: None., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: We assessed patient clinical outcomes based on occlusion location, focusing on distal occlusions to understand if occlusion location was an independent predictor of outcome, and tested the relationship between occlusion location and baseline ischemic core, a known predictor of modified Rankin Scale (mRS) score at 90 days., Methods: We analyzed a prospectively collected cohort of thrombolysis-eligible ischemic stroke patients from the International Stroke Perfusion Imaging Registry who underwent multimodal CT pretreatment. For the primary analysis, logistic regression was used to predict the effect of occlusion location and ischemic core on the likelihood of excellent (mRS 0-1) and favorable (mRS 0-2) 90-day outcomes., Results: This study included 945 patients. The rates of excellent and favorable outcome in patients with distal occlusion (M2, M3 segment of middle cerebral artery, anterior cerebral artery, and posterior cerebral artery) were higher than M1 occlusions (mRS 0%-1%, 55% vs 37%; mRS 0%-2%, 73% vs 50%, p < 0.001). Vessel occlusion location was not a strong predictor of outcomes compared to baseline ischemic core (area under the curve, mRS 0-1, 0.64 vs 0.83; mRS 0-2, 0.70 vs 0.86, p < 0.001). There was no interaction between occlusion location and ischemic core (interaction coefficient 1.00, p = 0.798)., Conclusions: Ischemic stroke patients with a distal occlusion have higher rate of excellent and favorable outcome than patients with an M1 occlusion. The baseline ischemic core was shown to be a more powerful predictor of functional outcome than the occlusion location, but the relationship between ischemic core and outcome does not different by occlusion locations., (© 2019 American Academy of Neurology.)

Background: CT perfusion (CTP) and diffusion or perfusion MRI might assist patient selection for endovascular thrombectomy. We aimed to establish whether imaging assessments of irreversibly injured ischaemic core and potentially salvageable penumbra volumes were associated with functional outcome and whether they interacted with the treatment effect of endovascular thrombectomy on functional outcome., Methods: In this systematic review and meta-analysis, the HERMES collaboration pooled patient-level data from all randomised controlled trials that compared endovascular thrombectomy (predominantly using stent retrievers) with standard medical therapy in patients with anterior circulation ischaemic stroke, published in PubMed from Jan 1, 2010, to May 31, 2017. The primary endpoint was functional outcome, assessed by the modified Rankin Scale (mRS) at 90 days after stroke. Ischaemic core was estimated, before treatment with either endovascular thrombectomy or standard medical therapy, by CTP as relative cerebral blood flow less than 30% of normal brain blood flow or by MRI as an apparent diffusion coefficient less than 620 μm 2 /s. Critically hypoperfused tissue was estimated as the volume of tissue with a CTP time to maximum longer than 6 s. Mismatch volume (ie, the estimated penumbral volume) was calculated as critically hypoperfused tissue volume minus ischaemic core volume. The association of ischaemic core and penumbral volumes with 90-day mRS score was analysed with multivariable logistic regression (functional independence, defined as mRS score 0-2) and ordinal logistic regression (functional improvement by at least one mRS category) in all patients and in a subset of those with more than 50% endovascular reperfusion, adjusted for baseline prognostic variables. The meta-analysis was prospectively designed by the HERMES executive committee, but not registered., Findings: We identified seven studies with 1764 patients, all of which were included in the meta-analysis. CTP was available and assessable for 591 (34%) patients and diffusion MRI for 309 (18%) patients. Functional independence was worse in patients who had CTP versus those who had diffusion MRI, after adjustment for ischaemic core volume (odds ratio [OR] 0·47 [95% CI 0·30-0·72], p=0·0007), so the imaging modalities were not pooled. Increasing ischaemic core volume was associated with reduced likelihood of functional independence (CTP OR 0·77 [0·69-0·86] per 10 mL, p interaction =0·29; diffusion MRI OR 0·87 [0·81-0·94] per 10 mL, p interaction =0·94). Mismatch volume, examined only in the CTP group because of the small numbers of patients who had perfusion MRI, was not associated with either functional independence or functional improvement. In patients with CTP with more than 50% endovascular reperfusion (n=186), age, ischaemic core volume, and imaging-to-reperfusion time were independently associated with functional improvement. Risk of bias between studies was generally low., Interpretation: Estimated ischaemic core volume was independently associated with functional independence and functional improvement but did not modify the treatment benefit of endovascular thrombectomy over standard medical therapy for improved functional outcome. Combining ischaemic core volume with age and expected imaging-to-reperfusion time will improve assessment of prognosis and might inform endovascular thrombectomy treatment decisions., Funding: Medtronic., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background and Purpose: In alteplase-treated patients with acute ischemic stroke, we investigated the relationship between penumbral reperfusion at 24 hours and clinical outcomes, with and without adjustment for baseline ischemic core volume., Methods: Data were collected from consecutive acute ischemic stroke patients with baseline and follow-up perfusion imaging presenting to hospital within 4.5 hours of symptom onset at 7 hospitals. Logistic regression models were used for predicting the effect of the reperfused penumbral volume on the dichotomized modified Rankin Scale (mRS) at 90 days and improvement of National Institutes of Health Stroke Scale at 24 hours, both adjusted for baseline ischemic core volume., Results: This study included 1507 patients. Reperfused penumbral volume had moderate ability to predict 90-day mRS 0 to 1 (area under the curve, 0.77; R 2 , 0.28; P <0.0001). However, after adjusting for baseline ischemic core volume, the reperfused penumbral volume was a strong predictor of good functional outcome (area under the curve, 0.946; R 2 , 0.55; P <0.0001). For every 1% increase in penumbral reperfusion, the odds of achieving mRS 0 to 1 at day 90 increased by 7.4%. Improvement in acute 24-hour National Institutes of Health Stroke Scale was also significantly related to the degree of reperfused penumbra ( R 2 , 0.31; P<0.0001). This association was again stronger after adjustment for baseline ischemic core volume ( R 2 , 0.41; P <0.0001). For each 1% of penumbra that was reperfused, the 24-hour National Institutes of Health Stroke Scale decreased by 0.069 compared with baseline., Conclusions: In patients treated with alteplase, the extent of the penumbra that is reperfused is a powerful predictor of early and late clinical outcomes, particularly when baseline ischemic core is taken into account., (© 2017 American Heart Association, Inc.)

Background: Chronic low bone mineral density is associated with an increased risk of stroke. However, little is known about the influence of bone mineral density at the time of stroke on clinical outcome. We investigated the association between bone mineral density and functional disability at three-months in patients with acute ischemic stroke., Methods: We retrospectively examined consecutive acute ischemic stroke patients who underwent bone densitometry tests within seven-days of stroke symptom onset. Patient demographics, risk factors, and initial National Institute of Health Stroke Scale scores were assessed. Bone mineral density was measured at the lumbar spine and bilateral femoral necks. Osteoporosis was defined as bone mineral density ≤-2·5 T-scores at each site. The primary outcome was modified Rankin Scale at 90 days poststroke. A favorable outcome was defined as modified Rankin Scale 0-1 and poor outcome as modified Rankin Scale 2-6., Results: Of the 191 patients included, 61 (31·9%) were men. Mean age (±standard deviation) was 69·8 ± 11·1 years. Patients with osteoporosis of the right femoral neck were more likely to have poor outcome (25/82; 30·5%) than those without (12/109; 11·0%, P = 0·001). After adjustment for age, sex, and initial National Institute of Health Stroke Scale score, osteoporosis of the right femoral neck was significantly associated with poor outcome (odds ratio, 2·97; 95% confidence interval 1·21 to 7·32, P = 0·018)., Conclusions: Low bone mineral density of the right femur in the acute poststroke period is associated with poor outcome at three-months. Assessment of bone mineral density in acute stroke patients may be a useful prognosticator and facilitate early intervention., (© 2011 The Authors. International Journal of Stroke © 2011 World Stroke Organization.)

Background: Warfarin-associated intracerebral hemorrhage (WAICH) is a devastating disease with increasing incidence. In this setting, treatment with prothrombin complex concentrates (PCC) is essential to correct coagulopathy. Yet despite the availability of coagulopathy correction strategies, significant treatment delays can occur in emergency departments (EDs), which may be overcome using stroke prenotification strategies. To explore this, we compared arrival-to-treatment times with PCC for WAICH between two different stroke response systems that used the same international normalized ratio (INR) correction protocol., Methods: We established a registry of consecutive patients presenting with WAICH and treated with PCC presenting to two Canadian tertiary-care academic stroke centers: one with a stroke prenotification system, and one with a traditional ED assessment, treatment and referral system. In this comparative cohort design, we defined the WAICH diagnosis time as the earliest time point where both INR and CT were available. We compared median times from arrival to treatment, as well as arrival to diagnosis, and diagnosis to treatment., Results: Between 2008 and 2010, we collected data from 123 consecutive patients with intracranial hemorrhage who received PCC for INR correction (79 from ED referral, and 44 prenotification). Onset-to-arrival times, demographics, Glasgow Coma Scale scores, and baseline INR were similar between the two systems. Arrival-to-treatment times were significantly shorter in the prenotification system as compared to the traditional ED referral system (135 vs. 267 min; p = 0.001), which was driven by both decreased arrival-to-diagnosis time (49 vs. 117 min; p = 0.006), as well as decreased diagnosis-to-treatment time (56 vs. 112 min; p < 0.001). Arrival-to-scan times and arrival-to-INR times were similarly shorter in the prenotification system (68 vs. 118 min and 20.5 vs. 47 min, respectively)., Conclusion: Stroke prenotification was associated with shorter arrival-to-treatment times for emergent INR correction in patients with WAICH, which was driven by both faster diagnosis and treatment. Our results are consistent with those seen in ischemic stroke, suggesting that prenotification systems present an opportunity to optimize acute intracerebral hemorrhage therapy.

Purpose: To assess the relationship between sodium signal intensity changes and oligemia, measured with perfusion-weighted imaging (PWI), in ischemic stroke patients., Materials and Methods: Nine ischemic stroke patients (55 ± 13 years), four with follow-up scans, underwent sodium and proton imaging 4-32 hours after symptom onset. Relative sodium intensity was calculated as the ratio of signal intensities in core (identified as hypertintense lesions on diffusion-weighted imaging [DWI]) or putative penumbra (PWI-DWI mismatch) to contralateral homologous regions., Results: Sodium intensity increases in the core were not correlated with the severity of hypoperfusion, measured with either cerebral blood flow (rho = 0.157; P = 0.61) or cerebral blood volume (rho = -0.234; P = 0.44). In contrast, relative sodium intensity was not elevated (4-7 hours 0.96 ± 0.07; 17-32 hours 1.00 ± 0.07) in PWI-DWI mismatch regions., Conclusion: Sodium signal intensity cannot be predicted by the degree of hypoperfusion acutely. Sodium intensity also remains unchanged in PWI-DWI mismatch tissue, indicating preservation of ionic homeostasis. Sodium magnetic resonance imaging (MRI), in conjunction with PWI and DWI, may permit identification of patients with viable tissue, despite an unknown symptom onset time., (Copyright © 2010 Wiley-Liss, Inc.)

Background and Purpose: In ischemic stroke, the site of arterial obstruction has been shown to influence recanalization and clinical outcomes. However, this has not been studied in randomized controlled trials, nor has the impact of arterial obstruction site on reperfusion and infarct growth been assessed. We studied the influence of site and degree of arterial obstruction patients enrolled in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET)., Methods: EPITHET was a prospective, randomized, placebo-controlled trial of intravenous tissue plasminogen activator (tPA) in the 3- to 6-hour time window. Arterial obstruction site and degree were rated on magnetic resonance angiography blinded to treatment allocation and outcomes., Results: In 101 EPITHET patients, 87 had adequate quality magnetic resonance angiography, of whom 54 had baseline arterial obstruction. Infarct growth attenuation was greater in those with tPA treatment compared to placebo among patients with middle cerebral artery (MCA) obstruction (P=0.037). The treatment benefit of tPA over placebo in attenuating infarct growth was greater for MCA than internal carotid artery (ICA) obstruction (P=0.060). With tPA treatment, good clinical outcome was more likely with MCA than with ICA obstruction (P=0.005). Most patients with ICA obstruction did not achieve good clinical outcome, whether treated with tPA (100%) or placebo (77%). The study was underpowered to prove any treatment benefit of tPA among patients with any or severe degree of arterial obstruction., Conclusions: Arterial obstruction site strongly predicts outcomes. ICA obstruction carries a uniformly poor prognosis, whereas good outcomes with MCA obstruction are associated with tPA therapy.

Background and Purpose: Currently, diffusion-weighted imaging (DWI) lesion volume is the most useful magnetic resonance imaging predictor of hemorrhagic transformation (HT). Preliminary studies have suggested that very low cerebral blood volume (VLCBV) predicts HT. We compared HT prediction by VLCBV and DWI using data from the EPITHET study., Methods: Normal-percentile CBV values were calculated from the nonstroke hemisphere. Whole-brain masks with CBV thresholds of the <0, 2.5, 5, and 10th percentiles were created. The volume of tissue with VLCBV was calculated within the acute DWI ischemic lesion. HT was graded as per ECASS criteria., Results: HT occurred in 44 of 91 patients. Parenchymal hematoma (PH) occurred in 13 (4 symptomatic) and asymptomatic hemorrhagic infarction (HI) in 31. The median volume of VLCBV was significantly higher in cases with PH. VLCBV predicted HT better than DWI lesion volume and thresholded apparent diffusion coefficient lesion volume in receiver operating characteristic analysis and logistic regression. A cutpoint at 2 mL VLCBV with the <2.5th percentile had 100% sensitivity for PH and, in patients treated with tissue plasminogen activator, defined a population with a 43% risk of PH (95% CI, 23% to 66%, likelihood ratio=16). VLCBV remained an independent predictor of PH in multivariate analysis with traditional clinical risk factors for HT., Conclusions: VLCBV predicted HT after thrombolysis better than did DWI or apparent diffusion coefficient volume in this large patient cohort. The advantage was greatest in patients with smaller DWI volumes. Prediction was better in patients who recanalized. If validated in an independent cohort, the addition of VLCBV to prethrombolysis decision making may reduce the incidence of HT.

Objective: Establishing time of onset is important in acute stroke management. Current imaging modalities do not allow determination of stroke onset time. Although correlations between sodium magnetic resonance imaging signal intensity within ischemic lesions and time of onset have been shown in animal models, the relation to onset time has not been established in human stroke. Utilizing high-quality sodium images, we tested the hypothesis that sodium signal intensity increases with time from symptom onset in human ischemic stroke., Methods: Twenty-one stroke patients (63 +/- 15 years old) were scanned 4 to 104 hours after symptom onset. Follow-up images were obtained in 10 patients at 23 to 161 hours after onset, yielding a total of 32 time points. A standard stroke imaging protocol was acquired at 1.5 Tesla, followed by sodium magnetic resonance imaging at 4.7 Tesla. Relative sodium signal intensity within each lesion was measured with respect to the contralateral side., Results: The sodium image quality was sufficient to visualize each acute lesion (lesion volume range, 1.7-217cm(3)). Relative sodium signal intensity increased nonlinearly over time after stroke onset. Sodium images acquired within 7 hours (n = 5) demonstrated a relative increase in lesion intensity of 10% or less, whereas the majority beyond 9 hours demonstrated increases of 23% or more, with an eventual leveling at 69 +/- 18%., Interpretation: Increases of sodium signal intensity within the ischemic lesion are related to time after stroke onset. Thus, noninvasive imaging of sodium may be a novel metabolic biomarker related to stroke progression. Ann Neurol 2009;66:55-62.

Background and Purpose: Before Phase III trials of acute stroke therapies, proof-of-concept MRI trials are increasingly used to gauge the likelihood of success. Given that animal models use infarct volume as the end point, Phase II trials have aimed to translate the findings using infarct growth. These trials could be expedited if subacute diffusion-weighted imaging lesion volume replaced late T2-weighted lesion volume as the primary end point., Methods: In the Echoplanar Imaging Thrombolytic Evaluation Trial, patients with acute ischemic stroke presenting within 3 to 6 hours were randomized to tissue plasminogen activator or placebo. We assessed correlations between acute (Day 1), subacute (Day 3 to 5) as well as late (Day 90) lesion volumes and clinical outcome (National Institutes of Health Stroke Scale). We compared lesion growth between placebo- and tissue plasminogen activator-treated patients., Results: All 3 scans were performed in 72 of 101 patients (32 tissue plasminogen activator, 40 placebo). Median time to subacute imaging was 3 days (interquartile range, 2 to 4) and 90 days (interquartile range, 90 to 95) for the late scan. Increase in lesion volume from acute to subacute scans was smaller in the tissue plasminogen activator group compared with the placebo group (6.77 mL; interquartile range, 2.30 to 49.10; versus 30.00 mL; interquartile range, 7.19 to 85.93; P=0.03). Subsequent shrinkage did not reveal significant treatment effects. Correlation coefficient between acute and late lesion volumes was 0.81 (P<0.01). Subacute and late lesion volumes were strongly correlated (rho=0.94, P<0.01). Correlation coefficient for acute, subacute, and late lesion volume and late National Institutes of Health Stroke Scale score was 0.64 (P<0.01), 0.81 (P<0.01), and 0.77 (P<0.01), respectively., Conclusions: These findings suggest that subacute imaging at Day 3 after thrombolysis is an appropriate imaging end point for proof-of-concept MRI-based stroke treatment trials and can replace later MRI measurements.

Diffusion tensor imaging (DTI) studies of human ischemic stroke within 24 h of symptom onset have reported variable findings of changes in diffusion anisotropy. Serial DTI within 24 h may clarify these heterogeneous results. We characterized longitudinal changes of diffusion anisotropy by analyzing discrete ischemic white matter (WM) and gray matter (GM) regions during the hyperacute (2.5-7 h) and acute (21.5-29 h) scanning phases of ischemic stroke onset in 13 patients. Mean diffusivity (MD), fractional anisotropy (FA) and T2-weighted signal intensity were measured for deep and subcortical WM and deep and cortical GM areas in lesions outlined by a > or =30% decrease in MD. Average reductions of approximately 40% in relative (r) MD were observed in all four brain regions during both the hyperacute and acute phases post stroke. Overall, 9 of 13 patients within 7 h post symptom onset showed elevated FA in at least one of the four tissues, and within the same cohort, 11 of 13 patients showed reduced FA in at least one of the ischemic WM and GM regions at 21.5-29 h after stroke. The fractional anisotropy in the lesion relative to the contralateral side (rFA, mean+/-S.D.) was significantly elevated in some patients in the deep WM (1.10+/-0.11, n=4), subcortical WM (1.13+/-0.14, n=4), deep GM (1.07+/-0.06, n=1) and cortical GM (1.22+/-0.13, n=5) hyperacutely (< or =7 h); however, reductions of rFA at approximately 24 h post stroke were more consistent (rFA= 0.85+/-0.12).

Background and Purpose: Apparent diffusion coefficient (ADC) thresholds for tissue infarction have been identified in acute stroke. IV tissue plasminogen activator (tPA) is associated with tissue salvage. We hypothesized that tPA would lower the ADC threshold for infarction., Methods: ADC and mean transit time (MTT) maps were generated for 26 patients imaged within 6 hours of stroke onset (12 tPA and 14 conservatively managed controls). MTT maps and day-90 T2-weighted images were coregistered to ADC maps. Relative ADC (rADC) values were calculated for initial diffusion-weighted imaging (DWI) lesions, infarct growth regions (final infarct volume-the acute DWI lesion volume), and hypoperfused salvaged regions (HS; MTT map abnormality-the final infarct volume). When relevant, the DWI lesion was subdivided into DWI reversal and DWI infarct regions., Results: Mean DWI lesion rADC was 0.79 in tPA and 0.74 in untreated patients (P=0.097). Mean rADC in HS and infarct growth regions were similar in tPA patients (0.950 and 0.946) and untreated patients (0.957, P=0.76; 0.970, P=0.08, respectively). The rADC in HS tissue was directly correlated with the time to treatment with tPA (r=0.685; P=0.029). DWI reversal was seen in 67% of tPA-treated patients and in 36% of those conservatively managed (Fisher exact test; P=0.238). In the 13 patients with DWI reversal, the mean rADC in these regions (0.81+/-0.07) was significantly higher than in the acute DWI region that infarcted (0.74+/-0.07; P=0.02), although no absolute thresholds could be identified., Conclusions: The peri-DWI lesion region contains tissue with intermediate ADC values. The fate of this tissue is variable and cannot be predicted based on the ADC alone. DWI expansion occurs in bioenergetically normal tissue, and this is attenuated by tPA in a time-dependent fashion.

Background: Elevated hematocrit (Hct) contributes to blood viscosity and has an adverse effect in acute stroke. The authors investigated the influence of Hct on tissue fate using serial MRI in acute stroke patients., Methods: The effects of Hct on reperfusion, penumbral salvage, and infarct expansion in 64 patients presenting within 24 hours of stroke onset were measured. MRI was performed at baseline (< 24 hours), days 3 to 5, and 90 days from stroke onset., Results: Median Hct was 42% with a bimodal distribution. There was a strong inverse relationship between Hct and reperfusion (Spearman rho = -0.74, p < 0.0001). The odds of major reperfusion (> 50% resolution of the baseline perfusion-weighted imaging deficit) were significantly lower with increasing Hct (odds ratio [OR] = 0.53; 95% CI = 0.97 to 1.00), independent of age, perfusion, and diffusion lesion volumes and recombinant tissue plasminogen activator (rtPA) administration. There was a trend toward reduced penumbral salvage at days 3 to 5 with increasing Hct (p = 0.06, 95% CI = -4.76 to 0.14). An increasing Hct was a significant predictor of infarct growth (OR = 1.26, 95% CI = 1.00 to 1.59), independent of baseline perfusion and diffusion volumes and glucose. The effect of Hct on reperfusion and infarct expansion was similar irrespective of rtPA administration (p = 0.31) and independent of smoking status., Conclusions: Higher hematocrit (Hct) values have a significant independent association with reduced reperfusion and greater infarct size after ischemic stroke. An elevated Hct may also be a potential physiologic determinant of reduced penumbral salvage.

Background and Purpose: Acute poststroke hyperglycemia has been associated with larger infarct volumes and a cortical location, regardless of diabetes status. Stress hyperglycemia has been attributed to activation of the hypothalamic-pituitary-adrenal axis but never a specific cortical location. We tested the hypothesis that damage to the insular cortex, a site with autonomic connectivity, results in hyperglycemia reflecting sympathoadrenal dysregulation., Methods: Diffusion-weighted MRI, glycosylated hemoglobin (HbA1c), and blood glucose measurements were obtained in 31 patients within 24 hours of ischemic stroke onset. Acute diffusion-weighted imaging (DWI) lesion volumes were measured, and involvement of the insular cortex was assessed on T2-weighted images., Results: Median admission glucose was significantly higher in patients with insular cortical ischemia (8.6 mmol/L; n=14) compared with those without (6.5 mmol/L; n=17; P=0.006). Multivariate linear regression demonstrated that insular cortical ischemia was a significant independent predictor of glucose level (P=0.001), as was pre-existing diabetes mellitus (P=0.008). After controlling for the effect of insular cortical ischemia, DWI lesion volume was not associated with higher glucose levels (P=0.849). There was no association between HbA1c and glucose level (P=0.737)., Conclusions: Despite the small sample size, insular cortical ischemia appeared to be associated with the production of poststroke hyperglycemia. This relationship is independent of pre-existing glycemic status and infarct volume. Neuroendocrine dysregulation after insular ischemia may be 1 aspect of a more generalized acute stress response. Future studies of poststroke hyperglycemia should account for the effect of insular cortical ischemia.

Background and Purpose: Hyperglycemia at the time of ischemic stroke is associated with increased mortality and morbidity. Animal studies suggest that infarct expansion may be responsible. The influence of persisting hyperglycemia after stroke has not previously been examined. We measured the blood glucose profile after acute ischemic stroke and correlated it with infarct volume changes using T2- and diffusion-weighted MRI., Methods: We recruited 25 subjects within 24 hours of ischemic stroke symptoms. Continuous glucose monitoring was performed with a glucose monitoring device (CGMS), and 4-hour capillary glucose levels (BGL) were measured for 72 hours after admission. MRI and clinical assessments were performed at acute (median, 15 hours), subacute (median, 5 days), and outcome (median, 85 days) time points., Results: Mean CGMS glucose and mean BGL glucose correlated with infarct volume change between acute and subacute diffusion-weighted MRI (r>or=0.60, P<0.01), acute and outcome MRI (r=0.56, P=0.01), outcome National Institutes of Health Stroke Scale (NIHSS; r>or=0.53, P<0.02), and outcome modified Rankin Scale (mRS; r>or=0.53, P=0.02). Acute and final infarct volume change and outcome NIHSS and mRS were significantly higher in patients with mean CGMS or mean BGL glucose >or=7 mmol/L. Multiple regression analysis indicated that both mean CGMS and BGL glucose levels >or=7 mmol/L were independently associated with increased final infarct volume change., Conclusions: Persistent hyperglycemia on serial glucose monitoring is an independent determinant of infarct expansion and is associated with worse functional outcome. There is an urgent need to study normalization of blood glucose after stroke.