Diffusional kurtosis imaging as a possible prognostic marker of cervical incomplete spinal cord injury outcome: a prospective pilot study.

BACKGROUND: Spinal cord injury (SCI) is associated with substantial chronic morbidity and mortality. Routine imaging techniques such as T1- and T2-weighted magnetic resonance imaging (MRI) are not effective in predicting neurological deficiency grade or outcome. Diffusional kurtosis imaging (DKI) is an MR imaging technique that provides microstructural information about biological tissue. There are no longitudinal prospective studies assessing DKI metrics in acute traumatic SCI. Therefore, the purpose of this study was to establish a DKI protocol for acute SCI and correlate the DKI metrics to the functional neurological outcome of the patients. METHODS: Eight consecutive SCI patients referred to our institution with cervical SCI were included in the study. An acute diagnostic MRI scan was supplemented with a novel fast, mean kurtosis DKI protocol, which describes the average deviation from Gaussian diffusional along nine different directions. Mean kurtosis values were measured at the injury site and normalized to the mean kurtosis values of a non-injured site. At discharge form specialized rehabilitation, patients were evaluated using the Spinal Cord Independence Measure-III (SCIM-III). The DKI metrics and SCIM-III were analysed using Spearman's rank correlation. RESULTS: This pilot study found a significant correlation between decreasing mean kurtosis values at the injury site of the spinal cord and higher grade of disability measured by the SCIM-III (p = 0.002). CONCLUSION: This pilot study found that DKI may be a valuable tool as a prognostic marker in the acute phase of SCI.

Theophylline as an Add-On to Thrombolytic Therapy in Acute Ischemic Stroke: A Randomized Placebo-Controlled Trial.

BACKGROUND AND PURPOSE: Delayed recanalization increases the risk of infarct growth and poor clinical outcome in acute ischemic stroke. The vasoactive agent theophylline has shown neuroprotective effects in animal stroke models but inconclusive results in case series and randomized clinical trials. The primary objective of this study was to evaluate whether theophylline, as an add-on to thrombolytic therapy, is safe and effective in acute ischemic stroke patients. METHODS: The TEA-Stroke trial (The Theophylline in Acute Ischemic Stroke) was an investigator-initiated 2-center, proof-of-concept, phase II clinical study with a randomized, double-blinded, placebo-controlled design. The main inclusion criteria were magnetic resonance imaging-verified acute ischemic stroke, moderate to severe neurological deficit (National Institutes of Health Stroke Scale score of ≥4), and treatment with thrombolysis within 4.5 hours of onset. Participants were randomly assigned in the ratio 1:1 to either 220 mg of intravenous theophylline or placebo. The co-primary outcomes were early clinical improvement on the National Institutes of Health Stroke Scale score and infarct growth on magnetic resonance imaging at 24-hour follow-up. RESULTS: Theophylline as an add-on to thrombolytic therapy improved the National Institutes of Health Stroke Scale score at 24 hours by mean 4.7 points (SD, 5.6) compared with an improvement of 1.3 points (SD, 7.5) in the control group (P=0.044). Mean infarct growth was 141.6% (SD, 126.5) and 104.1% (SD, 62.5) in the theophylline and control groups, respectively (P=0.146). Functional independence at 90 days was 61% in the theophylline group and 58% in the control group (P=0.802). CONCLUSIONS: This proof-of-concept trial investigated theophylline administration as an add-on to thrombolytic therapy in acute ischemic stroke. The co-primary end points early clinical improvement and infarct growth at 24-hour follow-up were not significantly different after post hoc correction for multiplicity (Bonferroni technique). The small study size precludes a conclusion as to whether theophylline has a neuroprotective effect but provides a promising clinical signal that may support a future clinical trial. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: EudraCT number 2013-001989-42.

Individualized quantification of the benefit from reperfusion therapy using stroke predictive models.

PURPOSE: Recent imaging developments have shown the potential of voxel-based models in assessing infarct growth after stroke. Many models have been proposed but their relevance in predicting the benefit of a reperfusion therapy remains unclear. We searched for a predictive model whose volumetric predictions would identify stroke patients who are to benefit from tissue plasminogen activator (t-PA)-induced reperfusion. MATERIAL AND METHODS: Forty-five cases were used to study retrospectively stroke progression from admission to end of follow-up. Predictive approaches based on various statistical models, predictive variables and spatial filtering methods were compared. The optimal approach was chosen according to the area under the precision-recall curve (AUPRC). The final lesion volume was then predicted assuming that the patient would or would not reperfuse. Patients, with an acute lesion of ≤50 ml and a predicted reduction in the presence of reperfusion >6 ml and >25% of the acute lesion, were classified as responders. RESULTS: The optimal model was a logistic regression using the voxel distance to the acute lesion, the volume of the acute lesion and Gaussian-filtered MRI contrast parameters as predictive variables. The predictions gave a median AUPRC of 0.655, a median AUC of 0.976 and a median volumetric error of 8.29 ml. Nineteen patients matched the responder profile. A non-significant trend of improved reduction in NIHSS score (-42.8%, p = .09) and in lesion volume (-78.1%, p = 0.21) following reperfusion was observed for responder patients. CONCLUSION: Despite limited volumetric accuracy, predictive stroke models can be used to quantify the benefit of reperfusion therapies.

Comparison of classification methods for tissue outcome after ischaemic stroke.

In acute ischaemic stroke, identifying brain tissue at high risk of infarction is important for clinical decision-making. This tissue may be identified with suitable classification methods from magnetic resonance imaging data. The aim of the present study was to assess and compare the performance of five popular classification methods (adaptive boosting, logistic regression, artificial neural networks, random forest and support vector machine) in identifying tissue at high risk of infarction on human voxel-based brain imaging data. The classification methods were used with eight MRI parameters, including diffusion-weighted imaging and perfusion-weighted imaging obtained in 55 patients. The five criteria used to assess the performance of the methods were the area under the receiver operating curve (AUCroc ), the area under the precision-recall curve (AUCpr ), sensitivity, specificity and the Dice coefficient. The methods performed equally in terms of sensitivity and specificity, while the results of AUCroc and the Dice coefficient were significantly better for adaptive boosting, logistic regression, artificial neural networks and random forest. However, there was no statistically significant difference between the performances of these five classification methods regarding AUCpr , which was the main comparison metric. Machine learning methods can provide valuable prognostic information using multimodal imaging data in acute ischaemic stroke, which in turn can assist in developing personalized treatment decision for clinicians after a thorough validation of methods with an independent data set.

Transit time homogenization in ischemic stroke - A novel biomarker of penumbral microvascular failure?

Cerebral ischemia causes widespread capillary no-flow in animal studies. The extent of microvascular impairment in human stroke, however, is unclear. We examined how acute intra-voxel transit time characteristics and subsequent recanalization affect tissue outcome on follow-up MRI in a historic cohort of 126 acute ischemic stroke patients. Based on perfusion-weighted MRI data, we characterized voxel-wise transit times in terms of their mean transit time (MTT), standard deviation (capillary transit time heterogeneity - CTH), and the CTH:MTT ratio (relative transit time heterogeneity), which is expected to remain constant during changes in perfusion pressure in a microvasculature consisting of passive, compliant vessels. To aid data interpretation, we also developed a computational model that relates graded microvascular failure to changes in these parameters. In perfusion-diffusion mismatch tissue, prolonged mean transit time (>5 seconds) and very low cerebral blood flow (≤6 mL/100 mL/min) was associated with high risk of infarction, largely independent of recanalization status. In the remaining mismatch region, low relative transit time heterogeneity predicted subsequent infarction if recanalization was not achieved. Our model suggested that transit time homogenization represents capillary no-flow. Consistent with this notion, low relative transit time heterogeneity values were associated with lower cerebral blood volume. We speculate that low RTH may represent a novel biomarker of penumbral microvascular failure.

The effects of hypercapnia on cortical capillary transit time heterogeneity (CTH) in anesthetized mice.

Capillary flow patterns are highly heterogeneous in the resting brain. During hyperemia, capillary transit-time heterogeneity (CTH) decreases, in proportion to blood's mean transit time (MTT) in passive, compliant microvascular networks. Previously, we found that functional activation reduces the CTH:MTT ratio, suggesting that additional homogenization takes place through active neurocapillary coupling mechanisms. Here, we examine changes in the CTH:MTT ratio during hypercapnic hyperemia in anesthetized mice (C57Bl/6NTac), expecting that homogenization is smaller than during functional hyperemia. We used an indicator-dilution technique and multiple capillary scans by two-photon microscopy to estimate CTH and MTT. During hypercapnia, MTT and CTH decreased as derived from indicator-dilution between artery and vein, as well as between arterioles and venules. The CTH:MTT ratio, however, increased. The same tendency was observed in the estimates from capillary scans. The parallel reductions of MTT and CTH are consistent with previous data. We speculate that the relative increase in CTH compared to MTT during hypercapnia represents either or both capillary constrictions and blood passage through functional thoroughfare channels. Intriguingly, hemodynamic responses to hypercapnia declined with cortical depth, opposite previous reports of hemodynamic responses to functional activation. Our findings support the role of CTH in cerebral flow-metabolism coupling during hyperemia.

Effect of electrical forepaw stimulation on capillary transit-time heterogeneity (CTH).

Functional hyperemia reduces oxygen extraction efficacy unless counteracted by a reduction of capillary transit-time heterogeneity of blood. We adapted a bolus tracking approach to capillary transit-time heterogeneity estimation for two-photon microscopy and then quantified changes in plasma mean transit time and capillary transit-time heterogeneity during forepaw stimulation in anesthetized mice (C57BL/6NTac). In addition, we analyzed transit time coefficient of variance = capillary transit-time heterogeneity/mean transit time, which we expect to remain constant in passive, compliant microvascular networks. Electrical forepaw stimulation reduced, both mean transit time (11.3% ± 1.3%) and capillary transit-time heterogeneity (24.1% ± 3.3%), consistent with earlier literature and model predictions. We observed a coefficient of variance reduction (14.3% ± 3.5%) during functional activation, especially for the arteriolar-to-venular passage. Such coefficient of variance reduction during functional activation suggests homogenization of capillary flows beyond that expected as a passive response to increased blood flow by other stimuli. This finding is consistent with an active neurocapillary coupling mechanism, for example via pericyte dilation. Mean transit time and capillary transit-time heterogeneity reductions were consistent with the relative change inferred from capillary hemodynamics (cell velocity and flux). Our findings support the important role of capillary transit-time heterogeneity in flow-metabolism coupling during functional activation.

Evaluation of Early Reperfusion Criteria in Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Though still debated, early reperfusion is increasingly used as a biomarker for clinical outcome. However, the lack of a standard definition hinders the assessment of reperfusion therapies and study comparisons. The objective was to determine the optimal early reperfusion criteria that predicts clinical outcome in ischemic stroke. METHODS: Early reperfusion was assessed voxel-wise in 57 patients within 6 hours of symptom onset. The performance of the time to peak (TTP), the mean transit time (MTT), and the time to maximum of residue function (Tmax ) at various delays thresholds in predicting the neurological response (based on the National Institutes of Health Stroke Scale) and the functional outcome (modified Rankin scale ≤1) at 1 month were compared. A receiver operating characteristics (ROC) analysis determined the optimal extent of reperfusion. A novel unsupervised classification of reperfusion using group-based trajectory modeling (GBTM) was evaluated. RESULTS: MTT had a lower performance than TTP and Tmax in predicting the neurological response (P = .008 vs. TTP and P = .006 vs. Tmax ) or the functional outcome (P = .0006 vs. TTP; P = .002 vs. Tmax ). No delay threshold had a significantly higher predictive value than another. The optimal percentage of reperfusion was dependent on the outcome scale (P < .001). The GBTM-based classification of reperfusion was closely associated with the clinical outcome and had a similar accuracy compared to ROC-based classification. CONCLUSIONS: TTP and Tmax should be preferred to MTT in defining early reperfusion. GBTM provided a clinically relevant reperfusion classification that does not require prespecified delay thresholds or clinical outcomes.

Reperfusion within 6 hours outperforms recanalization in predicting penumbra salvage, lesion growth, final infarct, and clinical outcome.

BACKGROUND AND PURPOSE: The relative merits of reperfusion versus recanalization to predict tissue and clinical outcomes in anterior circulation stroke have been previously assessed using data acquired >12 hours postonset. To avoid late-occurring confounders such as non-nutritional reperfusion, futile recanalization and no-reflow phenomenon, we performed ultraearly assessment of reperfusion and recanalization. METHODS: From a multicenter prospective database, 46 patients with acute magnetic resonance angiography-visible occlusion and in whom both reperfusion and recanalization were assessed on follow-up magnetic resonance imaging ≤6 hours of symptom onset were identified. Multiple linear regressions modeled salvaged penumbra, diffusion-weighted imaging lesion growth, and final infarct at 1 month using baseline clinical and imaging parameters and acute reperfusion or recanalization. Best predictors were determined with the Akaike information criterion. Univariate and multivariate logistic regressions identified the clinical and imaging predictors of clinical outcome. RESULTS: Admission magnetic resonance imaging showed M1 occlusion in 15 (33%) patients; median penumbra volume was 13.4 mL. Acute reperfusion was observed in 27 (59%) patients; 42% of nonrecanalized patients demonstrated reperfusion. The dichotomized classification of reperfusion and recanalization was discordant (P=0.0002). Reperfusion≤6 hours was a significant (P<0.05) predictor of increased penumbra salvage, reduced lesion growth, and final infarct size. Recanalization did not improve model accuracy. Reperfusion, but not recanalization, was significantly associated with good clinical outcome in logistic regressions. CONCLUSIONS: Reperfusion≤6 hours was consistently superior to recanalization in predicting tissue and clinical outcome. Reperfusion without recanalization was frequent and probably related to retrograde reperfusion through leptomeningeal collaterals. Acute reperfusion was the strongest predictor of, and may therefore, represent a reliable surrogate for, clinical outcome.

Biased visualization of hypoperfused tissue by computed tomography due to short imaging duration: improved classification by image down-sampling and vascular models.

OBJECTIVES: Lesion detection in acute stroke by computed-tomography perfusion (CTP) can be affected by incomplete bolus coverage in veins and hypoperfused tissue, so-called bolus truncation (BT), and low contrast-to-noise ratio (CNR). We examined the BT-frequency and hypothesized that image down-sampling and a vascular model (VM) for perfusion calculation would improve normo- and hypoperfused tissue classification. METHODS: CTP datasets from 40 acute stroke patients were retrospectively analysed for BT. In 16 patients with hypoperfused tissue but no BT, repeated 2-by-2 image down-sampling and uniform filtering was performed, comparing CNR to perfusion-MRI levels and tissue classification to that of unprocessed data. By simulating reduced scan duration, the minimum scan-duration at which estimated lesion volumes came within 10% of their true volume was compared for VM and state-of-the-art algorithms. RESULTS: BT in veins and hypoperfused tissue was observed in 9/40 (22.5%) and 17/40 patients (42.5%), respectively. Down-sampling to 128 × 128 resolution yielded CNR comparable to MR data and improved tissue classification (p = 0.0069). VM reduced minimum scan duration, providing reliable maps of cerebral blood flow and mean transit time: 5 s (p = 0.03) and 7 s (p < 0.0001), respectively). CONCLUSIONS: BT is not uncommon in stroke CTP with 40-s scan duration. Applying image down-sampling and VM improve tissue classification. KEY POINTS: • Too-short imaging duration is common in clinical acute stroke CTP imaging. • The consequence is impaired identification of hypoperfused tissue in acute stroke patients. • The vascular model is less sensitive than current algorithms to imaging duration. • Noise reduction by image down-sampling improves identification of hypoperfused tissue by CTP.

The impact of reliable prebolus T 1 measurements or a fixed T 1 value in the assessment of glioma patients with dynamic contrast enhancing MRI.

INTRODUCTION: Accurate quantification of hemodynamic parameters using dynamic contrast enhanced (DCE) MRI requires a measurement of tissue T 1 prior to contrast injection (T 1). We evaluate (i) T 1 estimation using the variable flip angle (VFA) and the saturation recovery (SR) techniques and (ii) investigate if accurate estimation of DCE parameters outperform a time-saving approach with a predefined T 1 value when differentiating high- from low-grade gliomas. METHODS: The accuracy and precision of T 1 measurements, acquired by VFA and SR, were investigated by computer simulations and in glioma patients using an equivalence test (p > 0.05 showing significant difference). The permeability measure, K trans, cerebral blood flow (CBF), and - volume, V p, were calculated in 42 glioma patients, using fixed T 1 of 1500 ms or an individual T 1 measurement, using SR. The areas under the receiver operating characteristic curves (AUCs) were used as measures for accuracy to differentiate tumor grade. RESULTS: The T 1 values obtained by VFA showed larger variation compared to those obtained using SR both in the digital phantom and the human data (p > 0.05). Although a fixed T 1 introduced a bias into the DCE calculation, this had only minor impact on the accuracy differentiating high-grade from low-grade gliomas, (AUCfix = 0.906 and AUCind = 0.884 for K trans; AUCfix = 0.863 and AUCind = 0.856 for V p; p for AUC comparison > 0.05). CONCLUSION: T 1 measurements by VFA were less precise, and the SR method is preferable, when accurate parameter estimation is required. Semiquantitative DCE values, based on predefined T 1 values, were sufficient to perform tumor grading in our study.

Assessment of ischemic penumbra in patients with hyperacute stroke using amide proton transfer (APT) chemical exchange saturation transfer (CEST) MRI.

Chemical exchange saturation transfer (CEST)-derived, pH-weighted, amide proton transfer (APT) MRI has shown promise in animal studies for the prediction of infarction risk in ischemic tissue. Here, APT MRI was translated to patients with acute stroke (1-24 h post-symptom onset), and assessments of APT contrast, perfusion, diffusion, disability and final infarct volume (23-92 days post-stroke) are reported. Healthy volunteers (n = 5) and patients (n = 10) with acute onset of symptoms (0-4 h, n = 7; uncertain onset <24 h, n = 3) were scanned with diffusion- and perfusion-weighted MRI, fluid-attenuated inversion recovery (FLAIR) and CEST. Traditional asymmetry and a Lorentzian-based APT index were calculated in the infarct core, at-risk tissue (time-to-peak, TTP; lengthening) and final infarct volume. On average (mean ± standard deviation), control white matter APT values (asymmetry, 0.019 ± 0.005; Lorentzian, 0.045 ± 0.006) were not significantly different (p > 0.05) from APT values in normal-appearing white matter (NAWM) of patients (asymmetry, 0.022 ± 0.003; Lorentzian, 0.048 ± 0.003); however, ischemic regions in patients showed reduced (p = 0.03) APT effects compared with NAWM. Representative cases are presented, whereby the APT contrast is compared quantitatively with contrast from other imaging modalities. The findings vary between patients; in some patients, a trend for a reduction in the APT signal in the final infarct region compared with at-risk tissue was observed, consistent with tissue acidosis. However, in other patients, no relationship was observed in the infarct core and final infarct volume. Larger clinical studies, in combination with focused efforts on sequence development at clinically available field strengths (e.g. 3.0 T), are necessary to fully understand the potential of APT imaging for guiding the hyperacute management of patients.

The role of the microcirculation in delayed cerebral ischemia and chronic degenerative changes after subarachnoid hemorrhage.

The mortality after aneurysmal subarachnoid hemorrhage (SAH) is 50%, and most survivors suffer severe functional and cognitive deficits. Half of SAH patients deteriorate 5 to 14 days after the initial bleeding, so-called delayed cerebral ischemia (DCI). Although often attributed to vasospasms, DCI may develop in the absence of angiographic vasospasms, and therapeutic reversal of angiographic vasospasms fails to improve patient outcome. The etiology of chronic neurodegenerative changes after SAH remains poorly understood. Brain oxygenation depends on both cerebral blood flow (CBF) and its microscopic distribution, the so-called capillary transit time heterogeneity (CTH). In theory, increased CTH can therefore lead to tissue hypoxia in the absence of severe CBF reductions, whereas reductions in CBF, paradoxically, improve brain oxygenation if CTH is critically elevated. We review potential sources of elevated CTH after SAH. Pericyte constrictions in relation to the initial ischemic episode and subsequent oxidative stress, nitric oxide depletion during the pericapillary clearance of oxyhemoglobin, vasogenic edema, leukocytosis, and astrocytic endfeet swelling are identified as potential sources of elevated CTH, and hence of metabolic derangement, after SAH. Irreversible changes in capillary morphology and function are predicted to contribute to long-term relative tissue hypoxia, inflammation, and neurodegeneration. We discuss diagnostic and therapeutic implications of these predictions.

Very low cerebral blood volume predicts parenchymal hematoma in acute ischemic stroke.

BACKGROUND AND PURPOSE: Parenchymal hematoma (PH) may worsen the outcome of patients with stroke. The aim of our study was to confirm the relationship between the volume of very low cerebral blood volume (CBV) and PH using a European multicenter database (I-KNOW). A secondary objective was to explore the impact of early reperfusion and recanalization. METHODS: The volume of cerebral tissue with CBV≤2.5th percentile of the normal hemisphere was calculated within the acute diffusion-weighted imaging lesion. Hemorrhagic transformation was assessed on day 2 MRI according to the European Cooperative Acute Stroke Study II criteria. Recanalization and reperfusion were assessed on 3-hour follow-up MRI. RESULTS: Of the 110 patients, hemorrhagic transformation occurred in 59 patients, including 7 PH. In univariate analysis, the acute National Institutes of Health Stroke Scale score (P=0.002), acute diffusion-weighted imaging lesion volume (P=0.02), and thrombolysis (P=0.03), but not very low CBV (P=0.52), were associated with hemorrhagic transformation. The volume of very low CBV was the only predictor of PH (P=0.007). Early reperfusion and recanalization had no influence on either hemorrhagic transformation or PH. CONCLUSION: Very low CBV was the only independent predictor of PH in patients with acute stroke.

The role of the cerebral capillaries in acute ischemic stroke: the extended penumbra model.

The pathophysiology of cerebral ischemia is traditionally understood in relation to reductions in cerebral blood flow (CBF). However, a recent reanalysis of the flow-diffusion equation shows that increased capillary transit time heterogeneity (CTTH) can reduce the oxygen extraction efficacy in brain tissue for a given CBF. Changes in capillary morphology are typical of conditions predisposing to stroke and of experimental ischemia. Changes in capillary flow patterns have been observed by direct microscopy in animal models of ischemia and by indirect methods in humans stroke, but their metabolic significance remain unclear. We modeled the effects of progressive increases in CTTH on the way in which brain tissue can secure sufficient oxygen to meet its metabolic needs. Our analysis predicts that as CTTH increases, CBF responses to functional activation and to vasodilators must be suppressed to maintain sufficient tissue oxygenation. Reductions in CBF, increases in CTTH, and combinations thereof can seemingly trigger a critical lack of oxygen in brain tissue, and the restoration of capillary perfusion patterns therefore appears to be crucial for the restoration of the tissue oxygenation after ischemic episodes. In this review, we discuss the possible implications of these findings for the prevention, diagnosis, and treatment of acute stroke.

Infarction of 'non-core-non-penumbral' tissue after stroke: multivariate modelling of clinical impact.

There is considerable intersubject variability in early neurological course after anterior circulation stroke, yet the pathophysiology underlying this variability is not fully understood. Here, we hypothesize that, although not predicted by current pathophysiological models, infarction of 'non-core-non-penumbral' (i.e. clinically silent) brain tissue may nevertheless occur, and negatively influence clinical course over and above the established positive impact of penumbral salvage. In order to test this hypothesis, non-core-non-penumbral tissue was identified in two independent prospectively recruited cohorts, using computed tomography perfusion, and magnetic resonance perfusion- and diffusion-weighted imaging, respectively. Follow-up structural magnetic resonance imaging was obtained about 1 month later in all patients to map the final infarct. The volumes of both the acutely silent but eventually infarcted tissue, and the eventually non-infarcted penumbra, were determined by performing voxel-wise analysis of the acute and follow-up image sets, using previously validated perfusion thresholds. Early neurological course was expressed as change in National Institutes of Health Stroke Scale scores between the acute and 1-month assessments, relative to the acute score. The relationship between the acutely silent but eventually infarcted tissue volume and early neurological course was tested using a multivariate regression model that included the volume of non-infarcted penumbra. Thirty-four and 58 patients were recruited in the computed tomography perfusion and magnetic resonance perfusion cohorts, respectively (mean onset-to-imaging time: 136 and 156 min; 27 and 42 patients received intravenous thrombolysis, respectively). Infarction of acutely silent tissue was identified in most patients in both cohorts. Although its volume (median 0.2 and 2 ml, respectively) was much smaller than that of salvaged penumbra (59.3 and 93 ml, respectively), it was substantial in ∼10% of patients. As expected, salvaged penumbra strongly positively influenced early neurological course. Even after correcting for the latter effect in the multivariate model, infarction of acutely silent tissue independently negatively influenced early neurological course in both cohorts (P=0.018 and 0.031, respectively). This is the first systematic study to document infarction of acutely silent tissue after anterior circulation stroke, and to show that it affects a sizeable fraction of patients and has the predicted negative impact on clinical course. These findings were replicated in two independent cohorts, regardless of the perfusion imaging modality used. Preventing infarction of the tissue not initially at risk should have direct clinical benefit.