Marie Luby

Magnetic resonance imaging and computed tomography in emergency assessment of patients with suspected acute stroke: a prospective comparison

BACKGROUND Although the use of magnetic resonance imaging (MRI) for the diagnosis of acute stroke is increasing, this method has not proved more effective than computed tomography (CT) in the emergency setting. We aimed to prospectively compare CT and MRI for emergency diagnosis of acute stroke. METHODS We did a single-centre, prospective, blind comparison of non-contrast CT and MRI (with diffusion-weighted and susceptibility weighted images) in a consecutive series of patients referred for emergency assessment of suspected acute stroke. Scans were independently interpreted by four experts, who were unaware of clinical information, MRI-CT pairings, and follow-up imaging. RESULTS 356 patients, 217 of whom had a final clinical diagnosis of acute stroke, were assessed. MRI detected acute stroke (ischaemic or haemorrhagic), acute ischaemic stroke, and chronic haemorrhage more frequently than did CT (p<0.0001, for all comparisons). MRI was similar to CT for the detection of acute intracranial haemorrhage. MRI detected acute ischaemic stroke in 164 of 356 patients (46%; 95% CI 41-51%), compared with CT in 35 of 356 patients (10%; 7-14%). In the subset of patients scanned within 3 h of symptom onset, MRI detected acute ischaemic stroke in 41 of 90 patients (46%; 35-56%); CT in 6 of 90 (7%; 3-14%). Relative to the final clinical diagnosis, MRI had a sensitivity of 83% (181 of 217; 78-88%) and CT of 26% (56 of 217; 20-32%) for the diagnosis of any acute stroke. INTERPRETATION MRI is better than CT for detection of acute ischaemia, and can detect acute and chronic haemorrhage; therefore it should be the preferred test for accurate diagnosis of patients with suspected acute stroke. Because our patient sample encompassed the range of disease that is likely to be encountered in emergency cases of suspected stroke, our results are directly applicable to clinical practice.

Comparison of MRI and CT for Detection of Acute Intracerebral Hemorrhage

CONTEXT Noncontrast computed tomography (CT) is the standard brain imaging study for the initial evaluation of patients with acute stroke symptoms. Multimodal magnetic resonance imaging (MRI) has been proposed as an alternative to CT in the emergency stroke setting. However, the accuracy of MRI relative to CT for the detection of hyperacute intracerebral hemorrhage has not been demonstrated. OBJECTIVE To compare the accuracy of MRI and CT for detection of acute intracerebral hemorrhage in patients presenting with acute focal stroke symptoms. DESIGN, SETTING, AND PATIENTS A prospective, multicenter study was performed at 2 stroke centers (UCLA Medical Center and Suburban Hospital, Bethesda, Md), between October 2000 and February 2003. Patients presenting with focal stroke symptoms within 6 hours of onset underwent brain MRI followed by noncontrast CT. MAIN OUTCOME MEASURES Acute intracerebral hemorrhage and any intracerebral hemorrhage diagnosed on gradient recalled echo (GRE) MRI and CT scans by a consensus of 4 blinded readers. RESULTS The study was stopped early, after 200 patients were enrolled, when it became apparent at the time of an unplanned interim analysis that MRI was detecting cases of hemorrhagic transformation not detected by CT. For the diagnosis of any hemorrhage, MRI was positive in 71 patients with CT positive in 29 (P<.001). For the diagnosis of acute hemorrhage, MRI and CT were equivalent (96% concordance). Acute hemorrhage was diagnosed in 25 patients on both MRI and CT. In 4 other patients, acute hemorrhage was present on MRI but not on the corresponding CT--each of these 4 cases was interpreted as hemorrhagic transformation of an ischemic infarct. In 3 patients, regions interpreted as acute hemorrhage on CT were interpreted as chronic hemorrhage on MRI. In 1 patient, subarachnoid hemorrhage was diagnosed on CT but not on MRI. In 49 patients, chronic hemorrhage, most often microbleeds, was visualized on MRI but not on CT. CONCLUSION MRI may be as accurate as CT for the detection of acute hemorrhage in patients presenting with acute focal stroke symptoms and is more accurate than CT for the detection of chronic intracerebral hemorrhage.

Early magnetic resonance imaging findings in patients receiving tissue plasminogen activator predict outcome: Insights into the pathophysiology of acute stroke in the thrombolysis era†

We measured ischemic brain changes with diffusion and perfusion MRI in 42 ischemic stroke patients before and 2 hours (range approximately 1.5 to 4.5 hours) after standard intravenous tissue plasminogen activator (tPA) therapy. The median time from stroke onset to tPA was 131 minutes. Clinical and MRI variables (change in perfusion and/or diffusion weighted lesion volume) were compared between those with excellent outcome defined as 3‐month modified Rankin score (mRS) of 0 to 1 and those with incomplete recovery (mRS >1). In multivariate logististic regression analysis, the most powerful independent predictor for excellent outcome was improved brain perfusion: hypoperfusion volume on mean transit time (MTT) map decrease >30% from baseline to 2‐hour post tPA scan (p=0.009; odds ratio [95% confidence interval], 20.7 [2.1‐203.9]). Except for age < 70 years, no other baseline clinical or imaging variable was an independent predictor of outcome. We propose MTT lesion volume decrease more than 30% 2 hours after tPA as an early marker of long‐term clinical benefit of thrombolytic therapy.

Blood–Brain Barrier Disruption in Humans Is Independently Associated With Increased Matrix Metalloproteinase-9

Background and Purpose— Matrix metalloproteinases (MMP) may play a role in blood–brain barrier (BBB) disruption after ischemic stroke. We hypothesized that plasma concentrations of MMP-9 are associated with a marker of BBB disruption in patients evaluated for acute stroke. Methods— Patients underwent MRI on presentation and ≈24 hours later. The MRI marker, termed hyperintense acute reperfusion injury marker (HARM), is gadolinium enhancement of cerebrospinal fluid on fluid-attenuated inversion recovery MRI. Plasma MMP-9 and tissue inhibitor of matrix metalloproteinase-1 were measured by enzyme-linked immunosorbent assay. Logistic regression models tested for predictors of HARM on 24-hour follow-up scans separately for MMP-9 and the ratio of MMP-9 to TIMP-1. Results— For the 41 patients enrolled, diagnoses were: acute ischemic cerebrovascular syndrome, 33 (80.6%); intracerebral hemorrhage, 6 (14.6%); stroke mimic, 1 (2.4%); and no stroke, 1 (2.4%). HARM was present in 17 (41.5%) patients. In model 1, HARM was associated with baseline plasma MMP-9 concentration (odds ratio [OR], 1.01; 95% confidence interval [CI], 1.001–1.019; P=0.033). In model 2, HARM was associated with the ratio of MMP-9 to tissue inhibitor of matrix metalloproteinase-1 (OR, 4.94; 95% CI, 1.27–19.14; P=0.021). Conclusions— Baseline MMP-9 was a significant predictor of HARM at 24-hour follow-up, supporting the hypothesis that MMP-9 is associated with BBB disruption. If the association between MMP-9 and BBB disruption is confirmed in future studies, HARM may be a useful imaging marker to evaluate MMP-9 inhibition in ischemic stroke and other populations with BBB disruption.

Distal hyperintense vessels on FLAIR: An MRI marker for collateral circulation in acute stroke?

Background: Hyperintense vessels (HV) on fluid-attenuated inversion recovery imaging are frequently observed in acute ischemic stroke patients. However, the exact mechanism and clinical implications of this sign have not yet been clearly defined. The features of HV and its relevance to other imaging factors are presented here. Methods: Prominence and location of HV were documented in 52 consecutive patients with middle cerebral artery (MCA) territory infarction, before treatment with IV recombinant tissue plasminogen activator. Pretreatment ischemic lesion volume, perfusion lesion volume, and vessel occlusion were determined in addition to recanalization status and ischemic lesion volume on follow-up imaging. NIH Stroke Scale (NIHSS) was used as a measure of clinical severity. Results: HV distal to arterial occlusion was observed in 73% of patients; more frequent in proximal than distal MCA occlusion patients. Among the 38 patients with proximal MCA occlusion, initial perfusion lesion volume was comparable among patients with different grade distal HV. However, patients with more prominent distal HV had smaller initial, 24-hour, and subacute ischemic lesion volumes and lower initial NIHSS scores. Conclusions: The presence of distal hyperintense vessels before thrombolytic treatment is associated with large diffusion–perfusion mismatch and smaller subacute ischemic lesion volumes in patients with proximal middle cerebral artery occlusion. DWI = diffusion-weighted imaging; FLAIR = fluid-attenuated inversion recovery; GRE = gradient recalled echo; HV = hyperintense vessels; MCA = middle cerebral artery; MRA = magnetic resonance angiography; MTT = mean transit time; NIHSS = NIH Stroke Scale; PWI = perfusion-weighted imaging; rt-PA = recombinant tissue plasminogen activator; TE = echo time; TI = inversion time; TIMI = thrombolysis in myocardial infarction; TR = repetition time.

Intra- and Interrater Reliability of Ischemic Lesion Volume Measurements on Diffusion-Weighted, Mean Transit Time and Fluid-Attenuated Inversion Recovery MRI

Background and Purpose— We investigated the intra- and interrater reliability of ischemic lesion volumes measurements assessed by different MRI sequences at various times from onset. Methods— Ischemic lesion volumes were measured for intrarater reliability using diffusion-weighted (DWI), mean transit time (MTT) perfusion and fluid-attenuated inversion recovery (FLAIR) MRI at chronic (>3 days from stroke onset) time points. A single intrarater reader, blind to clinical information and time point, repeated the volume measurements on two occasions separated by at least 1 week. Interrater reliability was also obtained in the second set of patients using acute DWI, MTT and chronic FLAIR MRI. Four blinded readers performed these volume measurements. Average deviations across repeat measurements per lesion and differences between sample means between the two measurements were calculated globally, ie, across all sequences and time points, and per reader type for each sequence at each time point. Results— There was good concordance of the mean sample volumes of the 2 intrarater readings (deviations were <4% and 2 mL globally, <2% and 2 mL for DWI, <6% and 7 mL for MTT, and <2% and 1 mL for FLAIR). There was also good concordance of the interrater readings (<5% and 2 mL globally). Conclusions— Repeat measurements of stroke lesion volumes show excellent intra- and interrater concordance for DWI, MTT and FLAIR at acute through chronic time points.

Establishing Final Infarct Volume Stroke Lesion Evolution Past 30 Days Is Insignificant

Background and Purpose— Lesion volume measured on MRI has been used as an objective surrogate marker for outcome in clinical trials. However, lesion volumes vary over time because of edema and tissue loss. This study aims to determine if lesion volumes measured at 30 and 90 days after ictus significantly differ. Methods— We performed a retrospective study of 18 patients who had acute (<24 hours) DWI and follow-up fluid-attenuated inversion recovery imaging at 5, 30, and 90 days. Two expert readers segmented lesions and the mean volumes of both reads were used in all statistical analyses. Results— Patient age was 65.8 (SD, 13.7) years and median NIHSS at baseline was 11.5. Inter-rater variability for lesion volume measurements was 3.7 (5.8) mL. Acute DWI volume was 19.3 (17.3) mL. Fluid-attenuated inversion recovery volumes for 5, 30, and 90 days were 34.3 (23.5), 18.6 (14.0), and 15.9 (13.8) mL, respectively. These volumes differed significantly (P<0.001). Linear regression revealed a strong correlation (r=0.96; P<0.001) between lesion volumes at 30 and 90 days with a slope that did not vary significantly from 1.0 (P=0.448). Conclusions— Lesions continue to evolve between 5 and 90 days, but by 30 days lesion volume approaches final infarct volume. While clinical response is the most meaningful outcome measure, our findings suggest that lesion volumes measured at 30 days may provide a sufficient approximation for final infarct volume for use in early phase clinical trials.

Effect of the Glycine Antagonist Gavestinel on Cerebral Infarcts in Acute Stroke Patients, a Randomized Placebo-Controlled Trial: The GAIN MRI Substudy

Background and Purpose: Gavestinel, GV150526, is a selective antagonist at the glycine site of the N-methyl-D-aspartate receptor. The safety and efficacy of GV150526 were studied in two phase III randomized placebo-controlled clinical trials of acute ischemic stroke patients within 6 h from onset [The Glycine Antagonist in Neuroprotection (GAIN) International and GAIN Americas Trials]. A planned MRI substudy within these trials investigated the effect of gavestinel on infarct volume. Methods: Patients enrolled in the GAIN trials at designated MRI substudy sites were eligible if they had a pretreatment acute cortical lesion on diffusion-weighted MRI of at least 1.5 cm diameter or 5 cm3. Final lesion assessment was performed on T2-weighted MRI at month 3. Blinded image analysis was performed centrally. The primary hypothesis was that gavestinel would attenuate lesion growth from baseline relative to placebo. Results: A total of 106 patients were eligible, 75 (34 gavestinel, 41 placebo) of whom had month 3 scans (primary analysis population). No effects of gavestinel on infarct volume were observed in the primary or other analyses. However, significant associations of lesion volume to clinical severity and outcomes were observed. Ischemic lesion volume decrease was predictive of substantial clinical improvement. Conclusion: Consistent with the clinical outcomes in the GAIN trials, no effects of gavestinel on ischemic infarction was observed. Concordance of results of the clinical outcome trials with those of this infarct volume substudy as well the associations of infarct volume to clinical outcomes further support the potential role of infarct volume as a marker of outcome in dose finding and proof of principle acute stroke trials.

Endothelial progenitor cells correlate with lesion volume and growth in acute stroke

Objectives: Circulating endothelial progenitor cells (EPC) are markers of vascular injury and their numbers decrease in acute stroke. However, the relation of EPC levels to stroke severity has not been quantified. MRI measurements of lesion volume provide an objective method for stroke severity assessment and outcome prediction. This cross-sectional study aims to determine whether EPC are correlated with lesion volume at baseline, lesion growth, and final lesion volume. Methods: Seventeen patients (median age 63 years, NIH Stroke Scale score 7) were selected from 175 patients with imaging-confirmed acute ischemic stroke. EPC were quantified by flow cytometry using CD34, CD133, and VEGFR2 surface markers. Brain MRI was performed at baseline and at days 1 and 5 after the stroke onset. Stroke lesion volumes were quantified. Results: Larger lesion volumes measured on diffusion-weighted images (DWI) at baseline were associated with low EPC levels, while smaller lesion volumes and less lesion growth were linked with high levels of EPC subsets (CD34+CD133+, CD133+VEGFR2+, and CD34+ CD133+VEGFR2+). Similar results were observed with DWI lesion volumes and EPC (CD34+CD133+) on day 1. Lesion growth volume, represented as a difference between final lesion volume and baseline DWI, was larger in patients with lower day 1 EPC (CD133+VEGFR2+). After adjustments for age and admission glucose (model 1), mean arterial pressure and white blood cells (model 2), INR and hematocrit (model 3), the CD34+CD133+ subset remained predictive of baseline and day 1 lesion volumes, while CD133+VEGFR2+ predicted baseline lesion volume and growth of lesion volume. Conclusions: Higher EPC levels were indicative of smaller volumes of acute lesion, final lesion, and lesion growth, and may serve as markers of acute phase stroke severity. However, a larger prospective study is needed to confirm our findings.

Stromal-Derived Factor-1α Correlates With Circulating Endothelial Progenitor Cells and With Acute Lesion Volume in Stroke Patients

Background and Purpose— Endothelial progenitor cells (EPC) are important participants of neovascularization and are mobilized through signaling with stromal-derived factor (SDF-1&agr;), vascular endothelial growth factor (VEGF), granulocyte colony-stimulating factor, and stem cell factor. The association between EPC levels and these growth factors (GF) in acute stroke has not been previously established. We aimed to determine the association between EPC and these GF, and to elucidate a relationship between these GF and stroke severity in acute stroke patients. Methods— Seventeen patients were selected from 175 patients with imaging-confirmed acute ischemic stroke. EPC were quantified using CD34, CD133, and VEGF-R2 markers. Plasma VEGF, SDF-1&agr;, granulocyte colony-stimulating factor, and stem cell factor were determined by enzyme-linked immunosorbent assay on days 1 and 3, and brain MRI was performed at baseline and on days 1 and 5 after the stroke onset. Results— Levels of SDF-1&agr; strongly (r=0.6) correlated with the numbers of EPC subsets CD133+VEFG-R2+ (P<0.004), CD34+VEGF-R2+ (P<0.01), and CD34+CD133+VEGF-R2+ (P<0.01) on day 1. Stem cell factor strongly (r=0.5) correlated with CD133+VEGF-R2+ (P<0.05). SDF-1&agr; moderately inversely (r=−0.49) correlated with baseline diffusion-weighted imaging lesion volumes (P<0.04). Median levels of SDF-1&agr; (1561 pg/mL) increased (P<0.04) on day 3 compared to day 1 (1379 pg/mL). Similarly, VEGF at day 3 (95 pg/mL) increased (P<0.03) compared to day 1 (64 pg/mL). Conclusions— These results indicate that SDF-1&agr; and stem cell factor correlate with an increase in EPC early in ischemic stroke patients.