Salvador Pedraza

Perfusion-CT Assessment of Infarct Core and Penumbra: Receiver Operating Characteristic Curve Analysis in 130 Patients Suspected of Acute Hemispheric Stroke

Background and Purpose— Different definitions have been proposed to define the ischemic penumbra from perfusion-CT (PCT) data, based on parameters and thresholds tested only in small pilot studies. The purpose of this study was to perform a systematic evaluation of all PCT parameters (cerebral blood flow, volume [CBV], mean transit time [MTT], time-to-peak) in a large series of acute stroke patients, to determine which (combination of) parameters most accurately predicts infarct and penumbra. Methods— One hundred and thirty patients with symptoms suggesting hemispheric stroke ≤12 hours from onset were enrolled in a prospective multicenter trial. They all underwent admission PCT and follow-up diffusion-weighted imaging/fluid-attenuated inversion recovery (DWI/FLAIR); 25 patients also underwent admission DWI/FLAIR. PCT maps were assessed for absolute and relative reduced CBV, reduced cerebral blood flow, increased MTT, and increased time-to-peak. Receiver-operating characteristic curve analysis was performed to determine the most accurate PCT parameter, and the optimal threshold for each parameter, using DWI/FLAIR as the gold standard. Results— The PCT parameter that most accurately describes the tissue at risk of infarction in case of persistent arterial occlusion is the relative MTT (area under the curve=0.962), with an optimal threshold of 145%. The PCT parameter that most accurately describes the infarct core on admission is the absolute CBV (area under the curve=0.927), with an optimal threshold at 2.0 ml×100 g−1. Conclusion— In a large series of 130 patients, the optimal approach to define the infarct and the penumbra is a combined approach using 2 PCT parameters: relative MTT and absolute CBV, with dedicated thresholds.

Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion-diffusion weighted imaging or perfusion CT (DIAS-2): a prospective, randomised, double-blind, placebo-controlled study.

BACKGROUND Previous studies have suggested that desmoteplase, a novel plasminogen activator, has clinical benefit when given 3-9 h after the onset of the symptoms of stroke in patients with presumptive tissue at risk that is identified by magnetic resonance perfusion imaging (PI) and diffusion-weighted imaging (DWI). METHODS In this randomised, placebo-controlled, double-blind, dose-ranging study, patients with acute ischaemic stroke and tissue at risk seen on either MRI or CT imaging were randomly assigned (1:1:1) to 90 microg/kg desmoteplase, 125 microg/kg desmoteplase, or placebo within 3-9 h after the onset of symptoms of stroke. The primary endpoint was clinical response rates at day 90, defined as a composite of improvement in National Institutes of Health stroke scale (NIHSS) score of 8 points or more or an NIHSS score of 1 point or less, a modified Rankin scale score of 0-2 points, and a Barthel index of 75-100. Secondary endpoints included change in lesion volume between baseline and day 30, rates of symptomatic intracranial haemorrhage, and mortality rates. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, NCT00111852. FINDINGS Between June, 2005, and March, 2007, 193 patients were randomised, and 186 patients received treatment: 57 received 90 microg/kg desmoteplase; 66 received 125 microg/kg desmoteplase; and 63 received placebo. 158 patients completed the study. The median baseline NIHSS score was 9 (IQR 6-14) points, and 30% (53 of 179) of the patients had a visible occlusion of a vessel at presentation. The core lesion and the mismatch volumes were small (median volumes were 10.6 cm(3) and 52.5 cm(3), respectively). The clinical response rates at day 90 were 47% (27 of 57) for 90 microg/kg desmoteplase, 36% (24 of 66) for 125 microg/kg desmoteplase, and 46% (29 of 63) for placebo. The median changes in lesion volume were: 90 microg/kg desmoteplase 14.0% (0.5 cm(3)); 125 microg/kg desmoteplase 10.8% (0.3 cm(3)); placebo -10.0% (-0.9 cm(3)). The rates of symptomatic intracranial haemorrhage were 3.5% (2 of 57) for 90 microg/kg desmoteplase, 4.5% (3 of 66) for 125 microg/kg desmoteplase, and 0% for placebo. The overall mortality rate was 11% (5% [3 of 57] for 90 microg/kg desmoteplase; 21% [14 of 66] for 125 microg/kg desmoteplase; and 6% [4 of 63] for placebo). INTERPRETATION The DIAS-2 study did not show a benefit of desmoteplase given 3-9 h after the onset of stroke. The high response rate in the placebo group could be explained by the mild strokes recorded (low baseline NIHSS scores, small core lesions, and small mismatch volumes that were associated with no vessel occlusions), which possibly reduced the potential to detect any effect of desmoteplase. FUNDING PAION Deutschland GmbH; Forest Laboratories.

Comparative Overview of Brain Perfusion Imaging Techniques

Background and Purpose— Numerous imaging techniques have been developed and applied to evaluate brain hemodynamics. Among these are positron emission tomography, single photon emission computed tomography, Xenon-enhanced computed tomography, dynamic perfusion computed tomography, MRI dynamic susceptibility contrast, arterial spin labeling, and Doppler ultrasound. These techniques give similar information about brain hemodynamics in the form of parameters such as cerebral blood flow or cerebral blood volume. All of them are used to characterize the same types of pathological conditions. However, each technique has its own advantages and drawbacks. Summary of Review— This article addresses the main imaging techniques dedicated to brain hemodynamics. It represents a comparative overview established by consensus among specialists of the various techniques. Conclusions— For clinicians, this article should offer a clearer picture of the pros and cons of currently available brain perfusion imaging techniques and assist them in choosing the proper method for every specific clinical setting.

Bleeding Risk Analysis in Stroke Imaging Before ThromboLysis (BRASIL): Pooled Analysis of T2*-Weighted Magnetic Resonance Imaging Data From 570 Patients

Background and Purpose— There has been speculation that the risk of secondary symptomatic intracranial hemorrhage (SICH) may be increased after thrombolytic therapy in ischemic stroke patients who have cerebral microbleeds (CMBs) on T2*-weighted magnetic resonance imaging. Because of this concern, some centers withhold potentially beneficial thrombolytic therapy from these patients. Methods— We analyzed magnetic resonance imaging data acquired within 6 hours after symptom onset from 570 ischemic stroke patients treated with intravenous tissue plasminogen activator in 13 centers in Europe, North America, and Asia. Baseline T2*-weighted magnetic resonance images were evaluated for the presence of CMBs. The primary end point was SICH, defined as clinical deterioration with an increase in the National Institutes of Health Stroke Scale score by ≥4 points, temporally related to a parenchymal hematoma on follow-up-imaging. Results— A total of 242 CMBs were detected in 86 of 570 patients (15.1%). The number of CMBs ranged from 1 to 77 in the individual patient, with ≥5 CMBs in 6 of 570 patients (1.1%). Proportions of patients with SICH were 5.8% (95% CI, 1.9 to 13.0) in the presence of CMBs and 2.7% (95% CI, 1.4 to 4.5) in patients without CMBs (P=0.170, Fishers exact test), resulting in no significant absolute increase in the risk of SICH of 3.1% (95% CI, −2.0 to 8.3). Conclusions— The data suggest that if there is any increased risk of SICH attributable to CMBs, it is likely to be small and unlikely to exceed the benefits of thrombolytic therapy. No reliable conclusion regarding risk in the rare patient with multiple CMBs can be reached.

The clinical-DWI mismatch: a new diagnostic approach to the brain tissue at risk of infarction.

Objective: To evaluate the usefulness of a mismatch between the severity of acute clinical manifestations and the diffusion-weighted imaging (DWI) lesion in predicting early stroke outcome and infarct volume. Methods: One hundred sixty-six patients with a hemispheric ischemic stroke of <12 hours’ duration were studied. The NIH Stroke Scale (NIHSS) score and the volume of DWI lesion were measured on admission and at 72 ± 12 hours. Infarct volume was measured on T2-weighted or fluid-attenuated inversion recovery images at day 30. Early neurologic deterioration (END) was defined as an increase of ≥4 points between the two NIHSS evaluations. Thirty-eight patients received IV thrombolysis or abciximab. Clinical–DWI mismatch (CDM) was defined as NIHSS score of ≥8 and ischemic volume on DWI of ≤25 mL on admission. The adjusted influence of CDM on END, DWI lesion enlargement at 72 hours, and infarct growth at day 30 was evaluated by logistic regression analysis and generalized linear models. Results: CDM was found in 87 patients (52.4%). Patients with CDM had a higher risk of END than patients without CDM because NIHSS < 8 (odds ratio [OR], 9.0; 95% CI,1.9 to 42) or DWI lesion > 25 mL (OR, 2.0; 95% CI, 0.8 to 4.9). CDM was associated with an increase of 46 to 68 mL in the mean volume of DWI lesion enlargement and infarct growth in comparison with non-CDM. All the effects were even greater and significant in patients not treated with reperfusion therapies. Conclusions: Acute stroke patients with an NIHSS score of ≥8 and DWI volume of ≤25 mL have a higher probability of infarct growth and early neurologic deterioration. The new concept of CDM may identify patients with tissue at risk of infarction for thrombolytic or neuroprotective drugs.

Plasma Cellular-Fibronectin Concentration Predicts Hemorrhagic Transformation After Thrombolytic Therapy in Acute Ischemic Stroke

Background and Purpose— Elevated plasma levels of cellular fibronectin (c-Fn) reflect vascular damage, so c-Fn might be a marker of secondary bleeding risk in cerebral ischemia. We investigated whether high plasma levels of c-Fn were associated with hemorrhagic transformation (HT) after treatment with tissue plasminogen activator (tPA) in patients with acute stroke. Methods— Eighty-seven patients (mean age: 67±12) received tPA after the ECASS II criteria (mean time to infusion: 160±46 minutes; median NIHSS: 12). HT and hypodensity volume were studied on computed tomography (CT) performed 24 to 36 hours after treatment. HT was classified according to the ECASS II definitions. c-Fn and matrix metalloproteinase 9 (MMP-9) levels were determined by ELISA in blood samples obtained before treatment and in 30 healthy subjects. Results— HT was found in 26 patients (30%); 15 patients had hemorrhagic infarction type 1 (HI-1), 7 had HI-2, and 4 had parenchymal hemorrhage (PH). Median c-Fn concentrations were 1.3, 1.7, 4.2, 5.4, and 7.3 μg/mL in controls, non-HT, HI-1, HI-2, and PH groups, respectively (P <0.001); median MMP-9 values were 54, 87, 154, 176, and 225 ng/mL (P <0.001). Logistic regression analysis showed that only c-Fn plasma levels remained independently associated with HT after adjusting for potential confounders (OR, 2.1; 95% CI, 1.3 to 3.4; P =0.002). Similar results were obtained in the 71 patients treated within 3 hours. Conclusions— High plasma c-Fn levels are significantly associated with subsequent HT in stroke patients treated with tPA, so plasma c-Fn determinations might be useful in clinical practice to improve the risk/benefit ratio of thrombolytic treatment.

Wallerian Degeneration in the Corticospinal Tract Evaluated by Diffusion Tensor Imaging Correlates with Motor Deficit 30 Days after Middle Cerebral Artery Ischemic Stroke

BACKGROUND AND PURPOSE: The quantification and clinical significance of WD in CSTs following supratentorial stroke are not well understood. We evaluated the anisotropy by using DTI and signal-intensity changes on conventional MR imaging in the CST to determine whether these findings are correlated with limb motor deficit in patients with MCA ischemic stroke. MATERIALS AND METHODS: We studied 60 patients within 12 hours of stroke onset. At admission, day 3, and day 30 of evolution, patients underwent multimodal MR imaging, including DTI sequences. We assessed the severity of limb weakness by using the motor subindex scores (5a, 5b, 6a, 6b) of the m-NIHSS and established 3 groups: I (m-NIHSS scores of 0), II (m-NIHSS, 1–4), and III (m-NIHSS, 5–8). FA values and rFAs were measured on the affected and the unaffected CSTs in the pons. RESULTS: FA values for the CST were significantly lower on the affected side compared with the unaffected side only at day 30 (P < .001), and the rFA was significantly correlated with the motor deficit at day 30 (P < .001; r = −0.793). The sensitivity, specificity, and positive and negative predictive values for motor deficit by rFA < 0.925 were 95.2%, 94.9%, 90.9%, and 97.4%, respectively. CONCLUSIONS: WD in the CST revealed by DTI correlates with motor deficit 30 days after MCA ischemic stroke. This study highlights the utility of imaging follow-up at 30 days and the potential of DTI as a surrogate marker in clinical trials.

A multicenter, randomized, double-blind, placebo-controlled trial to test efficacy and safety of magnetic resonance imaging-based thrombolysis in wake-up stroke (WAKE-UP).

Rationale In about 20% of acute ischemic stroke patients stroke occurs during sleep. These patients are generally excluded from intravenous thrombolysis. MRI can identify patients within the time-window for thrombolysis (≤4·5 h from symptom onset) by a mismatch between the acute ischemic lesion visible on diffusion weighted imaging (DWI) but not visible on fluid-attenuated inversion recovery (FLAIR) imaging. Aims and hypothesis The study aims to test the efficacy and safety of MRI-guided thrombolysis with tissue plasminogen activator (rtPA) in ischemic stroke patients with unknown time of symptom onset, e.g., waking up with stroke symptoms. We hypothesize that stroke patients with unknown time of symptom onset with a DWI-FLAIR-mismatch pattern on MRI will have improved outcome when treated with rtPA compared to placebo. Design WAKE-UP is an investigator initiated, European, multicentre, randomized, double-blind, placebo-controlled clinical trial. Patients with unknown time of symptom onset who fulfil clinical inclusion criteria (disabling neurological deficit, no contraindications against thrombolysis) will be studied by MRI. Patients with MRI findings of a DWI-FLAIR-mismatch will be randomised to either treatment with rtPA or placebo. Study outcome The primary efficacy endpoint will be favourable outcome defined by modified Rankin Scale 0–1 at day 90. The primary safety outcome measures will be mortality and death or dependency defined by modified Rankin Scale 4–6 at 90 days. Discussion If positive, WAKE-UP is expected to change clinical practice making effective and safe treatment available for a large group of acute stroke patients currently excluded from specific acute therapy.

Comparative overview of brain perfusion imaging techniques

Numerous imaging techniques have been developed and applied to evaluate brain hemodynamics. Among these are: Positron Emission Tomography (PET), Single Photon Emission Computed Tomography (SPECT), Xenon-enhanced Computed Tomography (XeCT), Dynamic Perfusion-computed Tomography (PCT), Magnetic Resonance Imaging Dynamic Susceptibility Contrast (DSC), Arterial Spin-Labeling (ASL), and Doppler Ultrasound. These techniques give similar information about brain hemodynamics in the form of parameters such as cerebral blood flow (CBF) or volume (CBV). All of them are used to characterize the same types of pathological conditions. However, each technique has its own advantages and drawbacks. This article addresses the main imaging techniques dedicated to brain hemodynamics. It represents a comparative overview, established by consensus among specialists of the various techniques. For clinicians, this paper should offers a clearer picture of the pros and cons of currently available brain perfusion imaging techniques, and assist them in choosing the proper method in every specific clinical setting.

Acute damage to the posterior limb of the internal capsule on diffusion tensor tractography as an early imaging predictor of motor outcome after stroke.

Practical applications of diffusion tensor imaging are few, but this seems to be an interesting and a potentially important one: can it be used to predict motor outcome after stroke? Sixty patients within 12 hours of stroke were assessed with tractography at 5 different locations in the corticospinal tracts at admission, and at days 3 and 30. Patients with acute damage to the posterior limb of the internal capsule had the worst outcome and clinical severity at presentation. Conclusions: In the acute setting, tractography is promising for stroke mapping to predict motor outcome. Acute corticospinal tract damage at the level of the posterior limb of the internal capsule is a significant predictor of unfavorable motor outcome. BACKGROUND AND PURPOSE: Early prediction of motor outcome is of interest in stroke management. We aimed to determine whether lesion location at DTT is predictive of motor outcome after acute stroke and whether this information improves the predictive accuracy of the clinical scores. MATERIALS AND METHODS: We evaluated 60 consecutive patients within 12 hours of middle cerebral artery stroke onset. We used DTT to evaluate CST involvement in the motor cortex and premotor cortex, centrum semiovale, corona radiata, and PLIC and in combinations of these regions at admission, at day 3, and at day 30. Severity of limb weakness was assessed by using the motor subindex scores of the National Institutes of Health Stroke Scale (5a, 5b, 6a, 6b). We calculated volumes of infarct and fractional anisotropy values in the CST of the pons. RESULTS: Acute damage to the PLIC was the best predictor associated with poor motor outcome, axonal damage, and clinical severity at admission (P < .001). There was no significant correlation between acute infarct volume and motor outcome at day 90 (P = .176, r = 0.485). The sensitivity, specificity, and positive and negative predictive values of acute CST involvement at the level of the PLIC for motor outcome at day 90 were 73.7%, 100%, 100%, and 89.1%, respectively. In the acute stage, DTT predicted motor outcome at day 90 better than the clinical scores (R2 = 75.50, F = 80.09, P < .001). CONCLUSIONS: In the acute setting, DTT is promising for stroke mapping to predict motor outcome. Acute CST damage at the level of the PLIC is a significant predictor of unfavorable motor outcome.