Acute Lesion Volume Research Articles

Metabolomics Predicts Neuroimaging Characteristics of Transient Ischemic Attack Patients

BackgroundNeuroimaging is essential for the diagnosis and prognosis of transient ischemic attack (TIA). The discovery of a plasmatic biomarker related to neuroimaging findings is of enormous interest because, despite its relevance, magnetic resonance diffusion weighted imaging (DWI) is not always available in all hospitals that attend to TIA patients. MethodsMetabolomic analyses were performed by liquid chromatography coupled to mass spectrometry in order to establish the metabolomic patterns of positive DWI, DWI patterns and acute ischemic lesion volumes. We used these methods with an initial TIA cohort of 129 patients and validated them with a 2nd independent cohort of 152 patients. FindingsPositive DWI was observed in 115 (40.9%) subjects and scattered pearls in one arterial territory was the most frequent lesion pattern (35.7%). The median acute ischemic lesion volume was 0.33 (0.15–1.90)cm3. We detected a specific metabolomic profile common to both cohorts for positive DWI (11 molecules including creatinine, threoninyl-threonine, N-acetyl-glucosamine, lyso phosphatidic acid and cholesterol-related molecules) and ischemic lesion volume (10 molecules including lysophosphatidylcholine, hypoxanthine/threonate, and leucines). Moreover lysophospholipids and creatinine clearly differed the subcortical DWI pattern from other patterns. InterpretationThere are specific metabolomic profiles associated with representative neuroimaging features in TIA patients. Our findings could allow the development of serum biomarkers related to acute ischemic lesions and specific acute ischemic patterns.

Acute Ischemic Stroke Infarct Topology: Association with Lesion Volume and Severity of Symptoms at Admission and Discharge.

Acute stroke presentation and outcome depend on both ischemic infarct volume and location. We aimed to determine the association between acute ischemic infarct topology and lesion volume and stroke severity at presentation and discharge. Patients with acute ischemic stroke who underwent MR imaging within 24 hours of symptom onset or last seen well were included. Infarcts were segmented and coregistered on the Montreal Neurological Institute-152 brain map. Voxel-based analyses were performed to determine the distribution of infarct lesions associated with larger volumes, higher NIHSS scores at admission and discharge, and greater NIHSS/volume ratios. A total of 238 patients were included. Ischemic infarcts involving the bilateral lentiform nuclei, insular ribbons, middle corona radiata, and right precentral gyrus were associated with larger infarct volumes (average, 76.7 ± 125.6 mL versus 16.4 ± 24.0 mL, P < .001) and higher admission NIHSS scores. Meanwhile, brain stem and thalami infarctions were associated with higher admission NIHSS/volume ratios. The discharge NIHSS scores were available in 218 patients, in whom voxel-based analysis demonstrated that ischemic infarcts of the bilateral posterior insular ribbons, middle corona radiata, and right precentral gyrus were associated with more severe symptoms at discharge, whereas ischemic lesions of the brain stem, bilateral thalami, and, to a lesser extent, the middle corona radiata were associated with higher ratios of discharge NIHSS score/infarct volume. Acute ischemic infarcts of the insulae, lentiform nuclei, and middle corona radiata tend to have larger volumes, more severe presentations, and worse outcomes, whereas brain stem and thalamic infarcts have greater symptom severity relative to smaller lesion volumes.

Multi-site laser Doppler flowmetry for assessing collateral flow in experimental ischemic stroke: Validation of outcome prediction with acute MRI

High variability in infarct size is common in experimental stroke models and affects statistical power and validity of neuroprotection trials. The aim of this study was to explore cerebral collateral flow as a stratification factor for the prediction of ischemic outcome. Transient intraluminal occlusion of the middle cerebral artery was induced for 90 min in 18 Wistar rats. Cerebral collateral flow was assessed intra-procedurally using multi-site laser Doppler flowmetry monitoring in both the lateral middle cerebral artery territory and the borderzone territory between middle cerebral artery and anterior cerebral artery. Multi-modal magnetic resonance imaging was used to assess acute ischemic lesion (diffusion-weighted imaging, DWI), acute perfusion deficit (time-to-peak, TTP), and final ischemic lesion at 24 h. Infarct volumes and typology at 24 h (large hemispheric versus basal ganglia infarcts) were predicted by both intra-ischemic collateral perfusion and acute DWI lesion volume. Collateral flow assessed by multi-site laser Doppler flowmetry correlated with the corresponding acute perfusion deficit using TTP maps. Multi-site laser Doppler flowmetry monitoring was able to predict ischemic outcome and perfusion deficit in good agreement with acute MRI. Our results support the additional value of cerebral collateral flow monitoring for outcome prediction in experimental ischemic stroke, especially when acute MRI facilities are not available.

The influence of gender on ‘tissue at risk’ in acute stroke: A diffusion-weighted magnetic resonance imaging study in a rat model of focal cerebral ischaemia

This is the first study to assess the influence of sex on the evolution of ischaemic injury and penumbra. Permanent middle cerebral artery occlusion was induced in male (n = 9) and female (n = 10) Sprague-Dawley rats. Diffusion-weighted imaging was acquired over 4 h and infarct determined from T2 images at 24 h post-permanent middle cerebral artery occlusion. Penumbra was determined retrospectively from serial apparent diffusion coefficient lesions and T2-defined infarct. Apparent diffusion coefficient lesion volume was significantly smaller in females from 0.5 to 4 h post permanent middle cerebral artery occlusion as was infarct volume. Penumbral volume, and its loss over time, was not significantly different despite the sex difference in acute and final lesion volumes.

Distance to thrombus on MR angiography predicts outcome of middle cerebral artery occlusion treated with IV thrombolysis.

The distance to thrombus (DT) on CT angiography was recently proposed as a predictor of outcome in patients treated by intravenous thrombolysis (IVT) for stroke due to occlusion of the middle cerebral artery (MCA). The purpose of the present study was to validate its inter-rater reliability and its prognostic value on contrast-enhanced magnetic resonance angiography (CE-MRA). Furthermore, we investigated the relation between DT and FLAIR-vascular hyperintensities (FVH) as a surrogate of collateral circulation and hypoperfusion. Patients with acute MCA occlusions treated by IVT and diagnosed with magnetic resonance imaging (MRI) were included. Two readers measured DT. FVH and acute DWI lesion volumes were quantified. Clinical status was determined using the initial NIH stroke scale (NIHSS) and 90-day modified Rankin Scale (90d mRS). Sixty-one patients showed a lesion on diffusion-weighted magnetic resonance images and an occlusion of the MCA on CE-MRA. We found significant inverse correlations between DT and NIHSS scores at admission (ρ = -0.29; P = 0.02), DT and mRS at 90 days (ρ = -0.29; P = 0.04), and between DT and FVH (ρ = -0.32; P = 0.01). For a DT <22 mm, the likelihood of an unfavorable outcome (90d mRS 3-6 or NIHSS score improvement of ≤10 points at discharge) was >50 %. Initial DWI lesion volumes showed no correlation with the outcome. Excellent inter-rater agreement for DT was observed (Cronbach's α = 0.98; P < 0.001). DT on CE-MRA is reliably measurable, correlates inversely with FLAIR-vascular hyperintensities, and predicts outcome in patients with acute MCA occlusion treated with IVT.

The Role of Matrix Metalloproteinase 3 and 9 in the Pathogenesis of Acute Neuroinflammation. Implications for Disease Modifying Therapy.

Matrix metalloproteinases (MMPs) are proteolytic enzymes that are involved in a variety of physiological and pathological processes, including those in CNS. In this study, plasma values of MMP-3 and MMP-9 have been compared in clinically isolated syndrome (CIS) and relapsing-remitting multiple sclerosis (RRMS) patients during their acute attacks, in relation to the biological activity of disease. Therefore, we compared the MMPs plasma values regarding Expanded Disability Status Scale (EDSS), progression index of disease (PID), acute brain lesion volume seen on magnetic resonance imaging (MRI) and index of blood-brain barrier (BBB) permeability destruction. The obtained results demonstrated higher plasma values of MMPs in both study groups than control values (p < 0.05). No statistical significances have been detected comparing the obtained values of both enzymes between CIS and RRMS group (p > 0.05). In both CIS and RRMS groups, the patients with higher EDSS showed higher MMPs plasma values (p < 0.05). The MMPs values were also significantly higher in both study patients with higher total number comparing to those with lower number of MRI brain lesion (p < 0.05) (beyond MMP-3 in RRMS). All obtained correlations, between MMPs and EDSS, PID, volume of MRI Gd-enhancement brain lesions, and index of BBB permeability, were positive (p < 0.05.) This study demonstrates alterations of both tested MMPs with closed correlation with the disease biological activity. Although MMPs are being implicated in the pathogenesis of acute neuroinflammation, the MMPs modulation might be useful in the future design of disease modifying therapy with the specific target profile.

Validity of acute stroke lesion volume estimation by diffusion-weighted imaging-Alberta Stroke Program Early Computed Tomographic Score depends on lesion location in 496 patients with middle cerebral artery stroke.

Alberta Stroke Program Early Computed Tomographic Score (ASPECTS) has been used to estimate diffusion-weighted imaging (DWI) lesion volume in acute stroke. We aimed to assess correlations of DWI-ASPECTS with lesion volume in different middle cerebral artery (MCA) subregions and reproduce existing ASPECTS thresholds of a malignant profile defined by lesion volume ≥100 mL. We analyzed data of patients with MCA stroke from a prospective observational study of DWI and fluid-attenuated inversion recovery in acute stroke. DWI-ASPECTS and lesion volume were calculated. The population was divided into subgroups based on lesion localization (superficial MCA territory, deep MCA territory, or both). Correlation of ASPECTS and infarct volume was calculated, and receiver-operating characteristics curve analysis was performed to identify the optimal ASPECTS threshold for ≥100-mL lesion volume. A total of 496 patients were included. There was a significant negative correlation between ASPECTS and DWI lesion volume (r=-0.78; P<0.0001). With regards to lesion localization, correlation was weaker in deep MCA region (r=-0.19; P=0.038) when compared with superficial (r=-0.72; P<0.001) or combined superficial and deep MCA lesions (r=-0.72; P<0.001). Receiver-operating characteristics analysis revealed ASPECTS≤6 as best cutoff to identify ≥100-mL DWI lesion volume; however, positive predictive value was low (0.35). ASPECTS has limitations when lesion location is not considered. Identification of patients with malignant profile by DWI-ASPECTS may be unreliable. ASPECTS may be a useful tool for the evaluation of noncontrast computed tomography. However, if MRI is used, ASPECTS seems dispensable because lesion volume can easily be quantified on DWI maps.

Corticospinal Tract Diffusion Abnormalities Early After Stroke Predict Motor Outcome

Background. Prognosis of long-term motor outcome of acute stroke patients with severe motor impairment is difficult to determine. Objective. Our primary goal was to evaluate the prognostic value of corticospinal tract (CST) injury on motor outcome of the upper limb compared with motor impairment level and lesion volume. Methods. In all, 10 acute stroke patients with moderately severe to severe motor impairment of the upper limb underwent diffusion tensor imaging (DTI) and testing of upper limb strength and dexterity at acute, subacute, and chronic poststroke time points. A density-weighted CST atlas was constructed using DTI tractography data from normal participants. This CST atlas was applied, using a largely automated process, to DTI data from patients to quantify CST injury at each time point. Differences in axial diffusivity (AD), radial diffusivity (RD), and fractional anisotropy (FA) of the ipsilesional CST relative to the contralesional CST were measured. Results. Acute loss in CST AD correlated most strongly and significantly with subacute and chronic strength and dexterity and remained significant after adjusting for acute motor impairment or lesion volume. Subacute loss in CST FA correlated most strongly with chronic dexterity, whereas subacute behavioral measures of limb strength correlated most strongly with chronic strength measures. Conclusions. Loss in acute CST AD and subacute CST FA are strong prognostic indicators of future motor functions of the upper limb for stroke patients with substantial initial motor impairment. DTI-derived measure of CST injury early after stroke may have utility in health care planning and in design of acute stroke clinical trials.

Predictors of Acute and Persisting Ischemic Brain Lesions in Patients Randomized to Carotid Stenting or Endarterectomy

We investigated predictors for acute and persisting periprocedural ischemic brain lesions among patients with symptomatic carotid stenosis randomized to stenting or endarterectomy in the International Carotid Stenting Study. We assessed acute lesions on diffusion-weighted imaging 1 to 3 days after treatment in 124 stenting and 107 endarterectomy patients and lesions persisting on fluid-attenuated inversion recovery after 1 month in 86 and 75 patients, respectively. Stenting patients had more acute (relative risk, 8.8; 95% confidence interval, 4.4-17.5; P<0.001) and persisting lesions (relative risk, 4.2; 95% confidence interval, 1.6-11.1; P=0.005) than endarterectomy patients. Acute lesion count was associated with age (by trend), male sex, and stroke as the qualifying event in stenting; high systolic blood pressure in endarterectomy; and white matter disease in both groups. The rate of conversion from acute to persisting lesions was lower in the stenting group (relative risk, 0.4; 95% confidence interval, 0.2-0.8; P=0.007), and was only predicted by acute lesion volume. Stenting caused more acute and persisting ischemic brain lesions than endarterectomy. However, the rate of conversion from acute to persisting lesions was lower in the stenting group, most likely attributable to lower acute lesion volumes. Clinical Trial Registration -URL: www.isrctn.org. Unique identifier: ISRCTN25337470.

Apparent Diffusion Coefficient Thresholds and Diffusion Lesion Volume in Acute Stroke

Apparent diffusion coefficient (ADC) thresholds are used to determine acute stroke lesion volume, but the reliability of this approach and comparability to the volume of the magnetic resonance diffusion-weighted imaging (MR-DWI) hyperintense lesion is unclear. We prospectively recruited and clinically assessed patients who had experienced acute ischemic stroke and performed DWI less than 24 hours and at 3 to 7 days after stroke. We compared the volume of the manually outlined DW hyperintense lesion (reference standard) with lesion volumes derived from 3 commonly used ADC thresholds: .55 × 10(-3)/mm(2)/second(-1), .65 × 10(-3)/mm(2)/second(-1), and .75 × 10(-3)/mm(2)/second(-1), with and without "editing" of erroneous tissue. We compared the volumes obtained by reference standard, "raw," and "edited" thresholds. Among 33 representative patients, the acute DWI lesion volume was 15,284 mm(3); the median unedited/edited ADC volumes were 52,972/2786 mm(3), 92,707/6,987 mm(3), and 227,681/unmeasureable mm(3) (.55 × 10(-3)/mm(2)/second(-1), .65 × 10(-3)/mm(2)/second(-1), and .75 × 10(-3)/mm(2)/second(-1) thresholds, respectively). Subacute lesions gave similar differences. These differences between edited and unedited diffusion-weighted imaging and ADC volumes were statistically significant. Threshold-derived ADC volumes require substantial manual editing to avoid over- or underestimating the visible DWI lesion and should be used with caution.

Outcome of MRI-based intravenous thrombolysis in carotid-T occlusion

Low recanalization rates and poor clinical outcome have been reported after intravenous thrombolysis (IV-tPA) in carotid-T occlusion (CTO). We studied clinical outcome and imaging findings of MRI-based intravenous thrombolysis in CTO. Data of patients with acute ischemic stroke and CTO treated with IV-tPA within 6 h of symptom onset based on MRI criteria were retrospectively analyzed. Vessel occlusion was defined based on MR angiography. Acute diffusion and perfusion lesion volumes and final infarct volumes after 3-7 days were delineated. The National Institutes of Health Stroke Scale (NIHSS) was used to assess the neurological deficit on admission. Recanalization was evaluated after 24 h. Clinical outcome was assessed using the modified Rankin Scale (mRS) after 90 days. Clinical and imaging data were compared to patients with middle cerebral artery main stem occlusion (MCAO). A total of 20 patients with CTO and 51 patients with MCAO were studied. Onset to treatment time, NIHSS on admission, initial diffusion and perfusion lesion volumes, and recanalization rates after 24 h were similar between groups. Final infarct volume was larger for CTO (82 vs. 30 ml, p = 0.006). Although overall outcome was not significantly different between groups (p = 0.251), independent outcome (mRS 0-2) tended to be less frequent in CTO (17 vs. 39 %), while poor outcome (mRS 4-6) appeared more common (72 vs. 43 %). The proportion of patients with good clinical outcome after intravenous thrombolysis in CTO is small. Moreover, final infarct volume is larger and clinical outcome appears to be worse compared to MCAO.

Abstract 3319: Prediction Of Lesion Expansion In Stroke Patients Using Acute MRI

Background: We investigated whether MRI-based algorithms combining acute DWI &amp; PWI can be used to identify patients likely to experience lesion expansion. Methods: We analyzed MRI from 181 unilateral stroke patients who underwent DWI &amp; PWI ≤ 12h from last seen well and had follow-up imaging (F/u) ≥4 days with lesions ≥ 1 cm 3 . Apparent diffusion coefficient, T2, DWI, CBF, CBV, MTT and Tmax (time of peak of deconvolved residue function) maps were co-registered, normalized and used as covariates in a model that produced infarction risk maps. Coefficients were calculated from 111 non-lysed patients and applied to 70 patients who received mechanical or drug lysis. Area under generated receiver operating characteristic curves (AUC) were calculated. Regional analyses were performed comparing mean risk values in Core (acute DWI), Growth (F/u - Core), Reverse (Core - F/u) and Normal (ipsilesional hemisphere - F/u) regions. Predicted lesion volumes (PLV) using a 50% risk threshold and post-hoc artifact removal for classifying infarcted tissue were correlated with the measured lesion volumes (MLV) on F/u. Values are median [IQR] or mean±SD. Results: The thrombolysis-treated group differed significantly from the non-lysis group in admission NIH Stroke Scale scores (12 [9-16] vs 6 [3-13]; P&lt;0.001), time-to-MRI (4.8±1.9 h vs 5.9±2.8 h; P=0.005), acute DWI lesion volumes (21 [7-56] vs 11 [3-36] cm 3 ; P=0.02) and F/u lesion volumes (39 [12-72] vs 17 [6-56] cm 3 ; P=0.02). No significant difference was found between age (67±15 vs 65±17 years old), male sex (59% vs 67%) and time to F/u (15 [6-47] vs 10 [6-46] days). Significant differences in predicted risk between the 4 regions were found for both lysed (Core: 0.72±0.15; Growth: 0.41±0.13; Reverse: 0.64±0.16; Normal: 0.25±0.06; P&lt;0.0001) and non-lysed groups (Core: 0.72±0. 15; Growth:0.42±0.12; Reverse: 0.64±0.15; Normal: 0.22±0.05; P&lt;0.0001). AUCs of the prediction for the non-lysed group were higher than for the lysed group (0.86±0.09 vs 0.81±0.11; P&lt;0.001). Correlations between PLV and MLV were significant for both lysed (R=0.57, P&lt;0.001) and non-lysed groups (R=0.85, P&lt;0.001). Mismatch between PLV and Core volumes (i.e. predicted lesion growth) was significantly correlated with actual lesion growth for the non-lysed group (R=0.49, P&lt;0.001) but not for the lysed group (R=0.04, P=0.72). Conclusion: Mismatch in PLV and core can be used to identify patients most likely to experience lesion expansion if not given reperfusion therapy. The performance of the models was reduced in thrombolysed patients, which we propose is due to salvage of tissue that would have otherwise infarcted. MRI-based algorithms may identify patients who are not candidates for thrombolysis, yet have tissue to salvage. This may be useful as imaging selection criteria for future investigational trials of reperfusion therapy in extended time windows or for patients with unclear onsets.

Circulating CD133+CD34+ progenitor cells inversely correlate with soluble ICAM-1 in early ischemic stroke patients

Background and PurposeBoth endothelial progenitor cells (EPC) and markers of neuroinflammation are candidate biomarkers for stroke severity and outcome prediction. A relationship between EPC and neuroinflammatory markers in early stroke is not fully elucidated. The objectives were to investigate correlations between EPC and neuroinflammation markers (adhesion molecules ICAM-1, VCAM-1, E-selectin, tumor necrosis factor (TNF)-α, interleukin (IL)-6, endothelin (ET)-1, markers of tissue injury (matrix metalloproteinases (MMP)-9 and tissue inhibitor of matrix metalloproteinases (TIMP)-1) in early stroke patients.MethodsWe prospectively recruited symptomatic patients with ischemic cerebrovascular disease. We assessed stroke severity by using of acute (diffusion-weighted imaging (DWI) and final lesion volumes (fluid attenuated inversion recovery (FLAIR). We measured serum soluble ICAM-1, VCAM-1, E-selectin, MMP-9, TIMP-1 and plasma TNF-α, IL-6, ET-1 by ELISA, and quantified EPC in mononuclear fraction of peripheral blood on days 1 and 3 in 17 patients (mean(SD) age 62(14), with admission National Institutes of Health Stroke Scale (NIHSS) 10(8)) selected from 175 patients with imaging confirmed ischemic stroke. Non-parametric statistics, univariate and multivariate analysis were used.ResultsOnly ICAM-1 inversely correlated with EPC subset CD133+CD34+ on day 1 (Spearman r = -0.6, p < 0.01) and on day 3 (r = -0.967, p < 0.001). This correlation remained significant after adjustment for age and NIHSS (beta -0.992, p < 0.004), for glucose and systolic blood pressure (beta -0.86, p < 0.005), and for white blood cells and hematocrit (beta -1.057, p < 0.0001) on day 3. MMP-9 (r = 0.509, p < 0.04) and MMP-9/TIMP-1 (r = 0.59, p < 0.013) on day 1 correlated with acute lesion volume. Both IL-6 (r = 0.624, p < 0.01) and MMP-9/TIMP-1 (r = 0.56, p < 0.02) correlated with admission NIHSS.ConclusionOur study showed that high ICAM-1 is associated with low CD133+CD34+subset of EPC. Biomarkers of neuroinflammation may predict tissue injury and stroke severity in early ischemia.

Noninvasive Brain Stimulation May Improve Stroke-Related Dysphagia

Treatment options for stroke-related dysphagia are currently limited. In this study, we investigated whether noninvasive brain stimulation in combination with swallowing maneuvers facilitates swallowing recovery in dysphagic stroke patients during early stroke convalescence. Fourteen patients with subacute unilateral hemispheric infarction were randomized to anodal transcranial direct current stimulation (tDCS) versus sham stimulation to the sensorimotor cortical representation of swallowing in the unaffected hemisphere over the course of 5 consecutive days with concurrent standardized swallowing maneuvers. Severity of dysphagia was measured using a validated swallowing scale, Dysphagia Outcome and Severity scale, before the first and after the last session of tDCS or sham. The effect of tDCS was analyzed in a multivariate linear regression model using changes in Dysphagia Outcome and Severity Scale as the outcome variable after adjusting for the effects of other potential confounding variables such as the National Institutes of Health Stroke Scale and Dysphagia Outcome and Severity scale scores at baseline, acute ischemic lesion volumes, patient age, and time from stroke onset to stimulation. Patients who received anodal tDCS gained 2.60 points of improvement in Dysphagia Outcome and Severity scale scores compared to patients in the sham stimulation group who showed an improvement of 1.25 points (P=0.019) after controlling for the effects of other aforementioned variables. Six out 7 (86%) patients in tDCS stimulation group gained at least 2 points of improvement compared with 3 out 7 (43%) patients in the sham group (P=0.107). Because brain stem swallowing centers have bilateral cortical innervations, measures that enhance cortical input and sensorimotor control of brain stem swallowing may be beneficial for dysphagia recovery.

Visual Perfusion–Diffusion Mismatch Is Equivalent to Quantitative Mismatch

The concept of stroke MRI mismatch based on qualitative evaluation of diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) has been applied in clinical practice for several years. The benefit of MRI in providing pathological evidence of ischemia before thrombolytic treatment has been demonstrated. The purpose of this study is to determine the reliability of the qualitative method and compare it with quantitative mismatch measurement in thrombolytic-treated patients. Patients (n=70) were selected from the Lesion Evolution of Stroke and Ischemic On Neuroimaging (LESION) database if they: (1) were treated with intravenous recombinant tissue plasminogen activator; (2) had a pretreatment MRI with evaluable DWI and PWI; and (3) had acute ischemic lesion volume >10 mL on DWI as determined by core imaging laboratory measurements. Quantitative mismatch was defined as a difference of >50 mL between abnormal mean transit time and DWI volumes. Sample characteristics and postdischarge modified Rankin Scale for the positive mismatch patients were compared between the subgroups identified by qualitative versus quantitative methods. Patient characteristics and thrombolytic outcomes (sex, age, National Institutes of Health Stroke Scale, mismatch volume, and modified Rankin Scale) did not differ for mismatch patients identified by qualitative versus quantitative methods. Qualitative mismatch selection among neurologists had a high sensitivity (0.82), specificity (0.80), accuracy (0.81), and positive predictive value (0.88) compared with quantitative measurements. We observed that qualitative evaluation of mismatch identified the same thrombolytic-treated patients compared with retrospective quantitative mismatch measurements.

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

Endothelial progenitor cells (EPC) are important participants of neovascularization and are mobilized through signaling with stromal-derived factor (SDF-1α), 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. 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-1α, 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. Levels of SDF-1α 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-1α moderately inversely (r=-0.49) correlated with baseline diffusion-weighted imaging lesion volumes (P<0.04). Median levels of SDF-1α (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). These results indicate that SDF-1α and stem cell factor correlate with an increase in EPC early in ischemic stroke patients.

Predictors of Percutaneous Endoscopic Gastrostomy Tube Placement in Patients With Severe Dysphagia From an Acute-Subacute Hemispheric Infarction

This study investigated the influence of age, National Institutes of Health Stroke Scale (NIHSS) score, time from stroke onset, infarct location and volume in predicting placement of a percutaneous endoscopic gastrostomy (PEG) tube in patients with severe dysphagia from an acute-subacute hemispheric infarction. We performed a retrospective analysis of a hospital-based patient cohort to analyze the effect of the aforementioned variables on the decision of whether or not to place a PEG tube. Consecutive patients were identified using International Classification of Diseases, Ninth Revision (ICD-9) codes for acute ischemic stroke, Current Procedural Terminology (CPT)-4 codes for a formal swallowing evaluation by a speech pathologist, and procedure codes for PEG placement over a 5-year period from existing medical records at our institution. Only patients with severe dysphagia were enrolled. A total of 77 patients met inclusion criteria; 20 of them underwent PEG placement. The relationship between age (dichotomized; < and ≥75 years), time from stroke onset (days), NIHSS score, acute infarct lesion volume (dichotomized; < and ≥100 cc), and infarct location (ie, insula, anterior insula, periventricular white matter, inferior frontal gyrus, motor cortex, or bilateral hemispheres) with PEG tube placement were analyzed using logistic regression analysis. In univariate analysis, NIHSS score (P = .005), lesion volume (P = .022), and presence of bihemispheric infarction (P = .005) were found to be the main predictors of interest. After multivariate adjustment, only NIHSS score (odds ratio [OR], 1.15; 90% confidence interval [CI], 1.02-1.29; P = .04) and presence of bihemispheric infarcts (OR, 4.67; 90% CI, 1.58-13.75; P = .018) remained significant. Our data indicates that baseline NIHSS score and the presence of bihemispheric infarcts predict PEG placement during hospitalization from an acute-subacute hemispheric infarction in patients with severe dysphagia. These results require further validation in future studies.

Combination Treatment with Normobaric Hyperoxia and Cilostazol Protects Mice against Focal Cerebral Ischemia-Induced Neuronal Damage Better Than Each Treatment Alone

Normobaric hyperoxia (NBO) and cilostazol (6-[4-(1-cyclohexy-1H-tetrazol-5-yl)butoxyl]-3,4-dihydro-2-(1H)-quinolinone) (a selective inhibitor of phosphodiesterase 3) have each been reported to exert neuroprotective effects against acute brain injury after cerebral ischemia in rodents. Here, we evaluated the potential neuroprotective effects of combination treatment with NBO and cilostazol against acute and subacute brain injuries after simulated stroke. Mice subjected to 2-h filamental middle cerebral artery (MCA) occlusion were treated with NBO (95% O(2), during the ischemia) alone, with cilostazol (3 mg/kg i.p. after the ischemia) alone, with both of these treatments (combination), or with vehicle. The histological and neurobehavioral outcomes were assessed at acute (1 day) or subacute (7 days) stages after reperfusion. We measured regional cerebral blood flow (rCBF) during and after ischemia by laser-Doppler flowmetry and recovery (versus vehicle) in the combination therapy group just after reperfusion. Mean acute and subacute lesion volumes were significantly reduced in the combination group but not in the two monotherapy groups. The combination therapy increased endothelial nitric-oxide synthase (eNOS) activity in the lesion area after ischemia versus vehicle. Combination therapy with NBO plus cilostazol protected mice subjected to focal cerebral ischemia by improvement of rCBF after reperfusion, in part in association with eNOS activity.

Relationships Between Cerebral Perfusion and Reversibility of Acute Diffusion Lesions in DEFUSE

Acute ischemic lesions with restricted diffusion can resolve after early recanalization. The impact of superimposed perfusion abnormalities on the fate of acute diffusion lesions is unclear. Data were obtained from DEFUSE, a prospective multicenter study of patients treated with IV tPA 3 to 6 hours after stroke onset. Thirty-two patients with baseline diffusion and perfusion lesions and 30 day FLAIR scans were coregistered. The acute diffusion lesion was divided into 3 regions according to the Tmax delay of the superimposed perfusion lesion: normal baseline perfusion; mild-moderately hypoperfused (2 s<Tmax<or=8 s) and severely hypoperfused (Tmax >8 s). The reversal rate was calculated as the percentage of the acute diffusion lesion that did not overlap with the final infarct on 30-day FLAIR. Diffusion reversal rates were compared based on whether a favorable clinical response occurred and whether early recanalization was achieved. On average, 54% of the acute diffusion lesion volume had normal perfusion. Diffusion reversal rates were significantly increased among cases with favorable clinical response and in patients with early recanalization, especially in regions with normal baseline perfusion. The portion of the diffusion lesion with normal perfusion had significantly higher mean apparent diffusion coefficient values and reversal rates. Acute ischemic lesions with restricted diffusion are most likely to recover if reperfusion occurs within 6 hours of symptom onset, and reversibility is associated with early recanalization and favorable clinical outcome. We propose the term RADAR (Reversible Acute Diffusion lesion Already Reperfused) to describe regions of acute restricted diffusion with normal perfusion.

Expediting MRI-Based Proof-of-Concept Stroke Trials Using an Earlier Imaging End Point

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. 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. 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. 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.