Summary Background Whether intravenous tissue plasminogen activator (alteplase) is effective beyond 3 h after onset of acute ischaemic stroke is unclear. We aimed to test whether alteplase given 3–6 ...h after stroke onset promotes reperfusion and attenuates infarct growth in patients who have a mismatch in perfusion-weighted MRI (PWI) and diffusion-weighted MRI (DWI). Methods We prospectively and randomly assigned 101 patients to receive alteplase or placebo 3–6 h after onset of ischaemic stroke. PWI and DWI were done before and 3–5 days after therapy, with T2-weighted MRI at around day 90. The primary endpoint was infarct growth between baseline DWI and the day 90 T2 lesion in mismatch patients. Major secondary endpoints were reperfusion, good neurological outcome, and good functional outcome. Patients, caregivers, and investigators were unaware of treatment allocations. Primary analysis was per protocol. This study is registered with ClinicalTrials.gov , number NCT00238537. Findings We randomly assigned 52 patients to alteplase and 49 patients to placebo. Mean age was 71·6 years, and median score on the National Institutes of Health stroke scale was 13. 85 of 99 (86%) patients had mismatch of PWI and DWI. The geometric mean infarct growth (exponential of the mean log of relative growth) was 1·24 with alteplase and 1·78 with placebo (ratio 0·69, 95% CI 0·38–1·28; Student's t test p=0·239); the median relative infarct growth was 1·18 with alteplase and 1·79 with placebo (ratio 0·66, 0·36–0·92; Wilcoxon's test p=0·054). Reperfusion was more common with alteplase than with placebo and was associated with less infarct growth (p=0·001), better neurological outcome (p<0·0001), and better functional outcome (p=0·010) than was no reperfusion. Interpretation Alteplase was non-significantly associated with lower infarct growth and significantly associated with increased reperfusion in patients who had mismatch. Because reperfusion was associated with improved clinical outcomes, phase III trials beyond 3 h after treatment are warranted. Funding National Health and Medical Research Council, Australia; National Stroke Foundation, Australia; Heart Foundation of Australia.
Intracerebral hemorrhage (ICH) growth predicts mortality and functional outcome. We hypothesized that irregular hematoma shape and density heterogeneity, reflecting active, multifocal bleeding or a ...variable bleeding time course, would predict ICH growth.
Three raters examined baseline sub-3-hour CT brain scans of 90 patients in the placebo arm of a Phase IIb trial of recombinant activated Factor VII in ICH. Each rater, blinded to growth data, independently applied novel 5-point categorical scales of density and shape to randomly presented baseline CT images of ICH. Density and shape were defined as either homogeneous/regular (Category 1 to 2) or heterogeneous/irregular (Category 3 to 5). Within- and between-rater reliability was determined for these scales. Growth was assessed as a continuous variable and using 3 binary definitions: (1) any ICH growth; (2) >or=33% or >or=12.5 mL ICH growth; and (3) radial growth >1 mm between baseline and 24-hour CT scan. Patients were divided into tertiles of baseline ICH volume: "small" (0 to 10 mL), "medium" (10 to 25 mL), and "large" (25 to 106 mL).
Inter- and intrarater agreements for the novel scales exceeded 85% (+/-1 category). Median growth was significantly higher in the large-volume group compared with the small group (P<0.001) and in heterogeneous compared with homogeneous ICH (P=0.008). Median growth trended higher in irregular ICHs compared with regular ICHs (P=0.084). Small ICHs were more regularly shaped (43%) than medium (17%) and large (3%) ICHs (P<0.001). Small ICHs were more homogeneous (73%) compared with medium (37%) and large (17%) ICHs (P<0.001). Adjusting for baseline ICH volume and time to scan, density heterogeneity, but not shape irregularity, independently predicted ICH growth (P=0.046) on a continuous growth scale.
Large ICHs were significantly more irregular in shape, heterogeneous in density, and had greater growth. Density heterogeneity independently predicted ICH growth using some definitions.
Changes in collateral blood flow, which sustains brain viability distal to arterial occlusion, may impact infarct evolution but have not previously been demonstrated in humans. We correlated ...leptomeningeal collateral flow, assessed using novel perfusion magnetic resonance imaging (MRI) processing at baseline and 3 to 5 days, with simultaneous assessment of perfusion parameters. Perfusion raw data were averaged across three consecutive slices to increase leptomeningeal collateral vessel continuity after subtraction of baseline signal analogous to digital subtraction angiography. Changes in collateral quality, Tmax hypoperfusion severity, and infarct growth were assessed between baseline and days 3 to 5 perfusion-diffusion MRI. Acute MRI was analysed for 88 patients imaged 3 to 6 hours after ischemic stroke onset. Better collateral flow at baseline was associated with larger perfusion-diffusion mismatch (Spearman's Rho 0.51, P < 0.001) and smaller baseline diffusion lesion volume (Rho − 0.70, P < 0.001). In 30 patients without reperfusion at day 3 to 5, deterioration in collateral quality between baseline and subacute imaging was strongly associated with absolute (P = 0.02) and relative (P < 0.001) infarct growth. The deterioration in collateral grade correlated with increased mean Tmax hypoperfusion severity (Rho − 0.68, P < 0.001). Deterioration in Tmax hypoperfusion severity was also significantly associated with absolute (P = 0.003) and relative (P = 0.002) infarct growth. Collateral flow is dynamic and failure is associated with infarct growth.
Controversy exists whether acute hyperglycemia is causally associated with worse stroke outcome or simply reflects a more severe stroke. In reversible ischemia models, hyperglycemia is associated ...with lactic acidosis and conversion of penumbral tissue to infarction. However, the relationship between hyperglycemia, lactic acidosis, and stroke outcome has not been explored in humans. Sixty‐three acute stroke patients were prospectively evaluated with serial diffusion‐weighted and perfusion‐weighted magnetic resonance imaging and acute blood glucose measurements. Patients with hypoperfused at‐risk tissue were identified by acute perfusion‐diffusion lesion mismatch. As a substudy, acute and subacute magnetic resonance spectroscopy was performed in the 33 most recent patients to assess the relationship between acute blood glucose and lactate production in the ischemic region. In 40 of 63 patients with acute perfusion‐diffusion mismatch, acute hyperglycemia was correlated with reduced salvage of mismatch tissue from infarction, greater final infarct size, and worse functional outcome. These correlations were independent of baseline stroke severity, lesion size, and diabetic status. Furthermore, higher acute blood glucose in patients with perfusion‐diffusion mismatch was associated with greater acute‐subacute lactate production, which, in turn, was independently associated with reduced salvage of mismatch tissue. In contrast, acute blood glucose levels in nonmismatch patients did not independently correlate with outcome measures, nor was there any acute‐subacute increase in lactate in this group. Acute hyperglycemia increases brain lactate production and facilitates conversion of hypoperfused at‐risk tissue into infarction, which may adversely affect stroke outcome. These findings support the need for randomized controlled trials of aggressive glycemic control in acute stroke.
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≥0.60, P<0.01), acute and outcome MRI (r=0.56, P=0.01), outcome National Institutes of Health Stroke Scale (NIHSS; r≥0.53, P<0.02), and outcome modified Rankin Scale (mRS; r≥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 ≥7 mmol/L. Multiple regression analysis indicated that both mean CGMS and BGL glucose levels ≥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.
Diffusion‐ and perfusion‐weighted magnetic resonance imaging provides important pathophysiological information in acute brain ischemia. We performed a prospective study in 19 sub‐6‐hour stroke ...patients using serial diffusion‐ and perfusion‐weighted imaging before intravenous thrombolysis, with repeat studies, both subacutely and at outcome. For comparison of ischemic lesion evolution and clinical outcome, we used a historical control group of 21 sub‐6‐hour ischemic stroke patients studied serially with diffusion‐ and perfusion‐weighted imaging. The two groups were well matched for the baseline National Institutes of Health Stroke Scale and magnetic resonance parameters. Perfusion‐weighted imaging–diffusion‐weighted imaging mismatch was present in 16 of 19 patients treated with tissue plasminogen activator, and 16 of 21 controls. Perfusion‐weighted imaging–diffusion‐weighted imaging mismatch patients treated with tissue plaminogen activator had higher recanalization rates and enhanced reperfusion at day 3 (81% vs 47% in controls), and a greater proportion of severely hypoperfused acute mismatch tissue not progressing to infarction (82% vs −25% in controls). Despite similar baseline diffusion‐weighted imaging lesions, infarct expansion was less in the recombinant tissue plaminogen activator group (14cm3 vs 56cm3 in controls). The positive effect of thrombolysis on lesion growth in mismatch patients translated into a greater improvement in baseline to outcome National Institutes of Health Stroke Scale in the group treated with recombinant tissue plaminogen activator, and a significantly larger proportion of patients treated with recombinant tissue plaminogen activator having a clinically meaningful improvement in National Institutes of Health Stroke Scale of ≥7 points. The natural evolution of acute perfusion‐weighted imaging–diffusion‐weighted imaging mismatch tissue may be altered by thrombolysis, with improved stroke outcome. This has implications for the use of diffusion‐ and perfusion‐weighted imaging in selecting and monitoring patients for thrombolytic therapy.
the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) was a prospective, randomized, double-blinded, placebo-controlled, phase II trial of alteplase between 3 and 6 hours after stroke onset. ...The primary outcome of infarct growth attenuation on MRI with alteplase in mismatch patients was negative when mismatch volumes were assessed volumetrically, without coregistration, which underestimates mismatch volumes. We hypothesized that assessing the extent of mismatch by coregistration of perfusion and diffusion MRI maps may more accurately allow the effects of alteplase vs placebo to be evaluated.
patients were classified as having mismatch if perfusion-weighted imaging divided by coregistered diffusion-weighted imaging volume ratio was >1.2 and total coregistered mismatch volume was ≥ 10 mL. The primary outcome was a comparison of infarct growth in alteplase vs placebo patients with coregistered mismatch.
of 99 patients with baseline diffusion-weighted imaging and perfusion-weighted imaging, coregistration of both images was possible in 95 patients. Coregistered mismatch was present in 93% (88/95) compared to 85% (81/95) with standard volumetric mismatch. In the coregistered mismatch patients, of whom 45 received alteplase and 43 received placebo, the primary outcome measure of geometric mean infarct growth was significantly attenuated by a ratio of 0.58 with alteplase compared to placebo (1.02 vs 1.77; 95% CI, 0.33-0.99; P=0.0459).
when using coregistration techniques to determine the presence of mismatch at study entry, alteplase significantly attenuated infarct growth. This highlights the necessity for a randomized, placebo-controlled, phase III clinical trial of alteplase using penumbral selection beyond 3 hours.
Introduction
Protoplasmic astrocytomas are a poorly recognized and uncommon subtype of astrocytoma. While usually categorized with other low-grade gliomas, there is literature to suggest that ...protoplasmic astrocytomas have differences in biology compared to other gliomas in this group. This paper presents the MR imaging characteristics of a series of eight protoplasmic astrocytomas.
Methods
We retrospectively reviewed MR images and histopathology of eight consecutive cases of histologically proven protoplasmic astrocytomas.
Results
Patients ranged from 17 to 51 years of age with a 5:3 male to female ratio. The tumors were located in the frontal or temporal lobes and tended to be large, well defined, and had a very high signal on T2 (close to cerebrospinal fluid). Generally, a large proportion of the tumor showed substantial signal suppression on T2 fluid-attenuated inversion recovery (FLAIR). Six of the eight lesions also demonstrated a partial or complete rim of reduced apparent diffusion coefficient (ADC) around the T2 FLAIR suppressing portion.
Conclusions
The possibility that a primary cerebral neoplasm represents a protoplasmic astrocytoma should be considered in a patient with a large frontal or temporal tumor that has a very high signal on T2 with a large proportion of the tumor showing substantial T2 FLAIR suppression. A further clue is a partial or complete rim of reduced ADC.
We sought to characterize the evolution of apparent diffusion coefficient (ADC) and apparent diffusion anisotropy (ADA) in acute stroke and to evaluate their roles in predicting stroke evolution and ...outcome.
We studied 26 stroke patients acutely (<24 hours), subacutely (3 to 5 days), and at outcome (3 months). Ratios of the ADC and ADA within a region of infarction and the normal contralateral region were evaluated and compared with the Canadian Neurological Scale, Barthel Index, and Rankin Scale.
Heterogeneity in ADC and ADA evolution was observed not only between patients but also within individual lesions. Three patterns of ADA evolution were observed: (1) elevated ADA acutely and subacutely; (2) elevated ADA acutely and reduced ADA subacutely; and (3) reduced ADA acutely and subacutely. At outcome, reduced ADA with elevated ADC was observed generally. We identified 3 phases of diffusion abnormalities: (1) reduced ADC and elevated ADA; (2) reduced ADC and reduced ADA; and (3) elevated ADC and reduced ADA. The ADA ratios within 12 hours correlated with the acute Canadian Neurological Scale (r=0.46, P=0.06), subacute Canadian Neurological Scale (r=0.55, P=0.02), outcome Barthel Index (r=0.62, P=0.01), and Rankin Scale (r=-0.77, P<0.0005) scores.
Combined ADC and ADA provide differential patterns of stroke evolution. Early ADA changes reflect cellular alterations in acute ischemia and may provide a potential marker to predict stroke outcome.
In ischemic stroke, perfusion-weighted imaging (PWI) and diffusion-weighted imaging (DWI) provide important pathophysiological information. A PWI>DWI mismatch pattern suggests the presence of ...salvageable tissue. However, improved methods for distinguishing PWI>DWI mismatch tissue that is critically hypoperfused from benign oligemia are required.
We investigated the usefulness of maps of relative cerebral blood flow (rCBF), volume (rCBV), and mean transit time (rMTT) to predict transition to infarction in hyperacute (<6 hours) stroke patients with PWI>DWI mismatch patterns. Semiquantitative color-thresholded analysis was used to measure hypoperfusion volumes, including increasing color signal intensity thresholds of rMTT delay, which were compared with infarct expansion, outcome infarct size, and clinical status.
Acute rCBF lesion volume had the strongest correlation with final infarct size (r=0.91, P<0.001) and clinical outcome (r=0.67, P<0.01). There was a trend for acute rCBF>DWI mismatch volume to overestimate infarct expansion between the acute and outcome study (P=0.06). Infarct expansion was underestimated by acute rCBV>DWI mismatch (P<0.001). When rMTT lesions included tissue with moderately prolonged transit times (mean delay 4.3 seconds, signal intensity values 50% to 70%), infarct expansion was overestimated. In contrast, when rMTT lesions were restricted to more severely prolonged transit times (mean delay 6.1 seconds, signal intensity >70%), these regions progressed to infarction in all except 1 patient, but infarct expansion was underestimated (P<0.001).
The acute rCBF lesion most accurately identified tissue in the PWI>DWI mismatch region at risk of infarction. Color-thresholded PWI maps show potential for use in an acute clinical setting to prospectively predict tissue outcome.
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