Salvageable Penumbra Research Articles

Abstract 61: Reperfusion Beyond 4.5 Hours Reduces Infarct Growth And Improves Clinical Outcome

Background and purpose: The ECASS 3 study demonstrated efficacy of intravenous thrombolysis up to 4.5h after stroke onset. It has been hypothesized that some patients have tissue at risk and an acceptably low hemorrhage risk beyond 4.5h. Imaging based selection may help identify these patients for late reperfusion therapies. No randomized data have shown efficacy of tPA or reperfusion later than 4.5h after onset. We analysed the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) data to assess the effect of treatment and reperfusion on attenuation of infarct growth in the 4.5 to 6 hour time window. Methods: Patients were randomized to placebo or tissue plasminogen activator (tPA) between 4.5-6h from stroke onset (without using imaging selection criteria). Pre-treatment DWI and day 90 T2-weighted lesion volumes (average of manually outlined lesions by 2 independent raters) were compared to assess the influence of tPA and reperfusion on absolute and relative infarct growth. Day 3 volume was used when day 90 data was missing. The effect of tPA on reperfusion was also assessed. Good clinical outcome was defined as a National Institute of Health Stroke Scale (NIHSS) at day 90 0-1 or improvement ≥ 8 from baseline. Good functional outcome was defined as modified Rankin Scale (mRS) 0-2. Results: Of 69 patients treated 4.5-6hrs hours after stroke onset, infarct growth could be assessed in 63. The median relative growth was significantly lower in the tPA group compared to placebo (0.94 vs 1.68, p=0.025). There was a nonsignificant trend towards lower absolute growth (-0.17mL vs 9.56mL, p=0.069). Reperfusion markedly reduced relative (0.80 vs 1.89, p<0.001) and absolute infarct growth (-2.49mL vs 39.50mL, p<0.001). Reperfusion was more likely in the tPA group (57.7 vs 25.0% p=0.026) and was associated with better clinical and functional outcomes (86.4% vs 28.1% p<0.001 and 72.7 vs 34.4% p=0.012). Conclusion: Thrombolysis after 4.5 hours reduced infarct growth and increased the rate of reperfusion. The strong positive effect of reperfusion on clinical and functional outcomes in this later time window is evidence of persisting salvageable ischemic penumbra. This supports continuing efforts to extend the treatment window for reperfusion therapies.

Abstract 2451: Arterial Spin Labelling Provides Usual Clinical Information In Acute Stroke

Introduction Arterial Spin Labelling (ASL) is a readily available MR scanning technique and may provide similar information to conventional bolus-tracking dynamic susceptibility MR sequences. However, there is little comparative data in acute stroke. Methods: Patients with an acute ischemic stroke were imaged within 6 hours of ischeamic stroke onset with perfusion CT (CTP) and at 24 hours with MRI, including diffusion weighted MR (DWI),ASL and Perfusion Weighted Magnetic Resonance Imaging (PWI). Patient neurological status was determined using the National institutes of stroke score acutely and at 24 hours, as well as a modified Rankin score at 90 days. The ASL baseline perfusion value was defined as the mean value of the healthy, non ischeamic stroke hemisphere of the patient. Values 20% higher or lower than the mean healthy hemisphere were considered abnormal. A pixel based analysis was also undertaken to compare the perfusion lesion on ASL to the perfusion lesion on the baseline CTP and concurrent PWI maps of CBV, CBF, MTT and Tmax. Results Of the 80 patients in this study there were 32 patients with hyperperfusion in the ischaemic region and 48 with persistent hypoperfusion on follow-up ASL imaging. Hyperperfusion was linked to greater penumbral salvage (defined by the acute CTP and 24 hour DWI) and an improved early clinical outcome (mean improvement in between acute and 24 hour NIHSS = 9) as well as better 3 month outcome (mRS mean = 2, p=0.15). Patients with persistent ASL hypoperfusion showed less improvement in NIHSS (mean improvement 3) and had a poorer 90 day outcome (mean mRS 4). Interestingly, The ASL hypoperfusion lesion was closest to the Tmax PWI map (AUC=0.85) rather than CBF(AUC=0.66) or MTT(AUC=0.73). Discussion. At 24 hours, hyper- or hypo-perfusion on ASL was strongly correlated to clinical outcome. ASL may have clinical utility in the prediction of stroke prognosis based on the difference in clinical outcome (mRS) between the patient groups with hyper- or hypo- perfusion.

Abstract 2716: Patients with Leukoaraiosis Have Poor Recruitment of Collaterals After Middle Cerebral Artery Occlusion

Background: Previous studies have shown reduced penumbral salvage in ischemic stroke patients with higher leukoaraisosis (LA) volume. Although unproven, decreased cerebral vessel density and diminished capacity of cerebral vessels to dilate in response to reduced blood flow in severe LA, are considered among the factors that might explain the association between LA burden and infarct growth in ischemic stroke. Both of these factors, in theory, might negatively affect the extent of collateral blood flow, an important predictor of tissue and clinical outcome in patients with acute ischemic stroke. In this study, we therefore analyzed whether extent of LA adversely affected the degree of collateral circulation in a cohort of patients presenting with middle cerebral artery occlusion. Methods: We retrospectively analyzed a consecutive series of patients admitted with a diagnosis of middle cerebral artery occlusion. Computed tomography angiography source images (CTA-SI) were used to assess the degree of collateral circulation, based on a previously validated scoring system which grades collateral vessels in the sylvian fissure and leptomeningeal convexity separately on a scale from 1 to 5, with 1 being the worst and 5 the best. The extent of LA was determined on FLAIR images by using the Fazekas scale. Multivariate analysis was used to explore the relationship between extent of LA and degree of collateral circulation, adjusted for other covariates like age, gender, vascular risk factors and time from symptom onset to CTA imaging. Results: A total of 51 patients (31 female, 20 male) were included into the study. LA severity was significantly and negatively correlated with the degree of collateral supply (r=-0.31, p=0.03). LA severity (OR 5.9, 95%CI 1.5-24.0) and history of prior stroke (OR 7.8, 95%CI 1.0-59.3) were the only significant variables associated with insufficient collaterals (defined as a combined sylvian and lepotmeningeal collateral score of 5 or less) in the multivariate logistic regression analysis. Conclusion: Patients with higher LA burden have a poor recruitment of collateral vessels after middle cerebral artery occlusion. This association might contribute to reduced penumbral salvage and increased susceptibility to infarct growth observed in patients with severe LA.

Circulation: Clinical Summaries

<i>Circulation:</i> Clinical Summaries

Imaging-Based Endovascular Therapy for Acute Ischemic Stroke due to Proximal Intracranial Anterior Circulation Occlusion Treated Beyond 8 Hours From Time Last Seen Well

Current selection criteria for intra-arterial therapies in the anterior circulation use time windows of 8 hours. Modern neuroimaging techniques have identified individuals with salvageable penumbra who present beyond this timeframe. We sought to assess safety, procedural, and clinical outcomes of MRI or CT perfusion imaging-based endovascular therapy in patients with anterior circulation stroke treated beyond 8 hours from time last seen well. We conducted a multicenter retrospective review of consecutive patients meeting the following criteria: (1) acute proximal intracranial anterior circulation occlusion; (2) endovascular treatment initiated >8 hours from time last seen well; and (3) treatment selection based on MRI or CT perfusion imaging. Two hundred thirty-seven patients were identified (mean age, 63.8 ± 16 years; mean baseline National Institutes of Health Stroke Scale, 15 ± 5.5; mean time last seen well to treatment, 15 ± 11.2 hours; male gender, 46%). Successful revascularization was achieved in 175 of 237 (73.84%) patients. Parenchymal hematoma occurred in 21 of 237 (8.86%) patients. The 90-day mortality rate was 21.5% (51 of 237). The rate of good outcomes was 45% (100 of 223) in the 223 patients with available modified Rankin Scale data at 90 days or time of hospital discharge. In multivariate analyses, age (OR, 0.96; 95% CI, 0.94 to 0.98; P=0.002), admission National Institutes of Health Stroke Scale (OR, 0.93; 0.87 to 0.98; P=0.016), and successful revascularization (OR, 4.32; 1.99 to 9.39; P<0.0001) were identified as independent predictors of good outcomes. Endovascular therapy can be instituted with acceptable safety beyond 8 hours from time last seen well when selection is based on advanced neuroimaging. Successful revascularization is significantly associated with higher rates of good outcomes. The benefit of this approach compared with standard medical therapy should be assessed in a prospective randomized trial.

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.

Establishing a Rodent Stroke Perfusion Computed Tomography Model

Brain computed tomography perfusion imaging in acute stroke may help guide therapy. However, the perfusion thresholds defining potentially salvageable (penumbra) and irreversibly injured (infarct core) tissue require further validation. The aim of this study was to validate infarct core and penumbra perfusion thresholds in a rodent stroke model by developing and optimising perfusion computed tomography imaging, performing serial scanning and correlating scans with final histology. Stroke was induced in male Wistar rats (n=17) using the middle cerebral artery thread-occlusion method. Perfusion computed tomography scans were obtained immediately pre- and postocclusion, and every 30 min for 2.5 h. Histological changes of infarction were assessed after 24 h. High-quality maps of cerebral blood flow and cerebral blood volume were generated at multiple coronal planes after optimisation of contrast injection and scanning parameters. The prestroke absolute cerebral blood flow and cerebral blood volume values (mean ± SD) were 158.2 ± 49.94 ml/min per 100 g and 5.6 ± 1.13 ml per 100 g, respectively. Cerebral blood flow was significantly lower in the infarct region of interest than the contralateral hemisphere region of interest at all time points, except the 0.5 h postocclusion time point. However, cerebral blood volume was only significantly lower in the infarct region of interest than the contralateral hemisphere region of interest at the 1 h and the 1.5 h time points (postocclusion). This study has demonstrated for the first time the feasibility of performing perfusion computed tomography in the most commonly used animal model of stroke. The model will allow definitive studies to determine optimal thresholds and the reliability of perfusion computed tomography measures for infarct core and penumbra.

Susceptibility weighted imaging: does it give information similar to perfusion weighted imaging in acute stroke?

In a patient presenting with acute stroke it is essential to make a quick decision on thrombolysis based on history, clinical findings and the information obtained on an urgent CT or MRI. Though CT is considered the imaging technique of choice to rule out intracerebral haemorrhage, MRI using a gradient T2*/SWI sequence has been found to be equally good [1]. If the presentation is beyond the first 3 h, there is a need to image the salvageable penumbra. MRI gives information about the penumbra by using the diffusion–perfusion imaging. The role of susceptibility weighted imaging (SWI) in patients with stroke has already been documented [2]. We report two interesting cases of acute stroke where the findings in SWI helped in early diagnosis and management. A 43-year-old male presented with wake up stroke and was rushed to our hospital. The patient could not move the right sided limbs and had aphasia. Magnetic resonance imaging done at 7.30 a.m, soon after his arrival in the hospital, revealed a left middle cerebral territory infarct involving the frontal operculum, insular and lateral frontal cortex. The diffusion restriction was minimal. Prominent veins were noted in the SWI posterior to the area of infarct. The same area showed reduced regional cerebral blood flow and increased mean transit time (Fig. 1). The diffusion restricted areas showed normal cerebral blood flow and mean transmit time. The second patient was a 44-year-old male who presented with sudden onset of weakness of right sided limbs and complete inability to speak at 8.30 a.m. The patient was immediately taken to a local hospital from where a CT scan was done and this was reported to be showing a doubtable dense MCA sign. At around 10.30 a.m his weakness started improving, and by 11 a.m his speaking difficulty also improved. In view of complete improvement, thrombolysis was deferred. He was referred to our hospital for further evaluation. An MRI done on the same day in the afternoon revealed no areas of restricted diffusion. The SWI showed MCA susceptibility vessel sign [3] and prominent veins in the left MCA territory. Hyperintense vessel sign [3] was noted in the FLAIR sequence. The MR angiography showed thrombus close to the MCA bifurcation (Fig. 2a–j). Since the patient improved and thrombolysis was not being planned, a perfusion MRI was not done. As part of workup for the transient ischemic attack, an MR angiography of neck vessels, FLAIR and diffusion weighted imaging of brain was repeated after 3 days. This revealed diffusion restriction in the left caudoputaminal region (Fig. 2k, l). In the first patient, the findings in SWI were corresponding to the areas showing change in the cerebral blood flow and mean transit time. Prominence of veins following stroke has been described earlier [4–6]. The prominence is thought to be due to increased deoxyhemoglobin in the veins. This may be secondary to increased oxygen extraction fraction due to reduced blood flow [7]. The findings in the second patient show that the SWI changes can be seen even without changes in diffusion imaging. In this patient, the clinical picture was that of transient ischemic attack. A reduction in cerebral blood flow due to C. Kesavadas (&) B. Thomas H. Pendharakar Department of Imaging Sciences and Interventional Radiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, India e-mail: chandkesav@yahoo.com

Sclérose en plaques de début d’emblée progressif

This review paper summarises the yield of the different imaging modalities in the evaluation of patients for IV thrombolysis. Non-contrast CT and CTA or brain MRI combined with MRA are the recommended sequences for the evaluation of patients within the 4.5 hours time window. Multimodal MRI (DWI/PWI), and more recently, CT perfusion, offer reliable surrogate of salvageable penumbra, the target mismatch, which is now currently used as selection criteria for revascularisation treatment in an extended time window. Those sequences may also help the physician for the management of other limited cases when the diagnosis of acute ischemic stroke is difficult. Another approach the DWI/FLAIR mismatch has been proposed to identify among wake-up stroke patients those who have been experiencing an acute ischemic stroke evolving from less than 4.5 hrs. Other biomarkers, such as the clot imaging on MRI and CT, help to predict the recanalisation rate after IVT, while the impact of the presence microbleeds on MRI remains to be determined.

Evaluation of CT Perfusion in the Setting of Cerebral Ischemia: Patterns and Pitfalls

CTP has a growing role in evaluating stroke. It can be performed immediately following NCCT and has advantages of accessibility and speed. Differentiation of salvageable ischemic penumbra from unsalvageable core infarct may help identify patients most likely to benefit from thrombectomy or thrombolysis. Still, CTP interpretation can be complex. We review normal and ischemic perfusion patterns followed by an illustrative series of technical/diagnostic challenges of CTP interpretation in the setting of acute stroke syndromes.

Pharmacologic Interventions for Stroke

The majority of pharmacological agents for stroke were developed based on the assumption that neurological deficits will be reduced upon the successful interruption of biochemical mechanisms leading to neuronal death. Despite significant evidence of preclinical efficacy, none of these agents succeeded. They either failed to demonstrate efficacy in the clinic or their development was halted for safety, strategic, or commercial reasons. This "neuroprotection strategy" has focused primarily on targets in the neurotoxic environment that occurs under ischemic conditions. In many cases, these agents were designed to tackle events that are known to start almost immediately after onset of ischemia, which is far before a realistic therapeutic time window opens for most, if not all, patients with stroke. In other instances, they were evaluated beyond a realistic timeframe in which one could expect significant salvageable tissue or penumbra to exist. Surprisingly, most of these agents were not evaluated in conjunction with strategies for improving perfusion to the affected tissue, indicating an overoptimistic assumption that neuroprotection alone could be sufficient to halt injury caused by an abrupt interruption of brain blood flow. We provide a constructive translational medicine perspective about how one could improve the drug development process with the hope that the probability for success can increase in our quest to establish a novel therapy for stroke.

Emerging impact of CTA/perfusion CT on acute stroke thrombolysis in a community hospital

Our objective was to retrospectively review the emerging role of CT, CTA, and perfusion CT (pCT) in the hyperacute stroke population of a community hospital. We reviewed 50 consecutive patients'...

Hyperthermia Exacerbates Ischaemic Brain Injury

Hyperthermia frequently occurs in stroke patients. Hyperthermia negatively correlates with clinical outcome and adversely effects treatment regiments otherwise successful under normothermic conditions. Preclinical studies also demonstrate that hyperthermia converts salvageable penumbra to ischaemic infarct. The present article reviews the knowledge accumulated from both clinical and preclinical studies about hyperthermia and ischaemic brain injury, examines current treatment strategies and discusses future research directions.

MR Mismatch Is Useful for Patient Selection for Thrombolysis

The clinical constellation of a large MCA stroke with a substantial mismatch between DWI and PWI in the 3- to 6-hour time window is for many stroke neurologists an indication for the off-label use of intravenous t-PA. Clinical practice, however, frequently shows that a significant mismatch can persist for days and that such patients typically improve without any recanalizing therapy. Mismatch imaging may thus not only identify patients with a salvageable penumbra eligible for thrombolysis but also those who may simply recover on their own. To equate the mismatch in a stroke patient with a treatment indication may therefore not be inappropriate. The mismatch or the penumbra imaging concept was developed by experimental studies and translated into human stroke almost a decade ago. Until today several hundred patients were investigated mainly in smaller unblinded and nonrandomized studies. These …

MR Mismatch Is Useful for Patient Selection for Thrombolysis

Geoffrey A. Donnan MD, FRACP Stephen M. Davis MD, FRACP Section Editors: The MR perfusion diffusion (PI/DWI) mismatch concept for the selection of patients for intravenous thrombolysis (IVT) was introduced with several smaller case series in the late 1990s and early 2000s,1 followed by larger series by many international groups over the last 8 years. A potentially salvageable penumbra was operationally defined as a PI/DWI-(volume) mismatch where PI indicates the hypoperfused tissue and DWI shows the more or less severe ischemic core.2 A mismatch volume of 20% (PI>DWI) has been widely accepted as indicator of a penumbral MRI setting. In an ideal world perfusion postprocessing would provide absolute values for cerebral blood flow (CBF). Perfusion maps could then indicate penumbra based on different thresholds for gray and white matter and thus …

Optimal Tmax Threshold for Predicting Penumbral Tissue in Acute Stroke

We sought to assess whether the volume of the ischemic penumbra can be estimated more accurately by altering the threshold selected for defining perfusion-weighting imaging (PWI) lesions. DEFUSE is a multicenter study in which consecutive acute stroke patients were treated with intravenous tissue-type plasminogen activator 3 to 6 hours after stroke onset. Magnetic resonance imaging scans were obtained before, 3 to 6 hours after, and 30 days after treatment. Baseline and posttreatment PWI volumes were defined according to increasing Tmax delay thresholds (>2, >4, >6, and >8 seconds). Penumbra salvage was defined as the difference between the baseline PWI lesion and the final infarct volume (30-day fluid-attenuated inversion recovery sequence). We hypothesized that the optimal PWI threshold would provide the strongest correlations between penumbra salvage volumes and various clinical and imaging-based outcomes. Thirty-three patients met the inclusion criteria. The correlation between infarct growth and penumbra salvage volume was significantly better for PWI lesions defined by Tmax >6 seconds versus Tmax >2 seconds, as was the difference in median penumbra salvage volume in patients with a favorable versus an unfavorable clinical response. Among patients who did not experience early reperfusion, the Tmax >4 seconds threshold provided a more accurate prediction of final infarct volume than the >2 seconds threshold. Defining PWI lesions based on a stricter Tmax threshold than the standard >2 seconds delay appears to provide more a reliable estimate of the volume of the ischemic penumbra in stroke patients imaged between 3 and 6 hours after symptom onset. A threshold between 4 and 6 seconds appears optimal for early identification of critically hypoperfused tissue.

MR and CT Monitoring of Recanalization, Reperfusion, and Penumbra Salvage

Revascularization therapies for acute stroke patients aim to rescue the ischemic penumbra by restoring the patency of the occluded artery ("recanalization") and the downstream capillary blood flow ("reperfusion"). This article reviews the definition of recanalization and reperfusion used in stroke clinical trials and their limitations and proposes a study design to determine the relative importance of recanalization, reperfusion, and collateral flow in evaluating the efficacy of revascularization therapies for acute ischemic stroke.

PATHOPHYSIOLOGY OF ACUTE ISCHEMIC STROKE

ABSTRACT In acute ischemic stroke, abrupt vessel occlusion results in a drop in regional CBF, leading to time-dependent compartmentalization of the ischemic brain into tissue that is irreversibly damaged (ischemic core), tissue that is functionally impaired but structurally intact and thus potentially salvageable (penumbra), and tissue that is hypoperfused but not threatened under normal circumstances (oligemic brain). At a cellular level, neuronal damage occurs through a complex interaction of mechanisms (necrosis, apoptosis, excitotoxicity, inflammation, peri-infarct depolarization, acidosis, and free radical formation) that are characteristic for each compartment. All these mechanisms are potential targets for neuroprotective therapy, which, combined with flow restoration strategies, is likely to improve outcome significantly in human stroke.

Use of MRI to Estimate the Therapeutic Window in Acute Stroke

Marc Fisher MD Kennedy Lees MD Section Editors: The fundamental goal of many acute stroke therapies is rapid arterial recanalization leading to reperfusion of critically hypoperfused brain tissue. Clinical benefits of this therapeutic approach require the presence of a salvageable penumbra. It is estimated that salvageable tissue is present in up to 80% of patients with stroke who present rapidly, but these capricious zones of potentially recoverable parenchyma typically disappear within the first 6 to 12 hours after symptom onset.1 The rate of disappearance of the penumbral tissue appears to vary considerably between individuals based on a variety of physiological factors, predominantly the availability of adequate collateral circulation. How to quickly and reliably identify these fortunate patients who may have a prolonged therapeutic window has been the ultimate quest of a large volume of modern cerebrovascular neuroimaging research. A leading approach to this challenge has been to estimate the ischemic penumbra based on the difference between the volume of tissue that exhibits a disturbance in cerebral blood flow, as assessed by perfusion-weighted MRI (PWI), and the volume of tissue that has already developed evidence of advanced ischemic injury reflected by cytotoxic edema on diffusion-weighted MRI (DWI).2 The “mismatch” regions (areas of PWI abnormality that do not have corresponding DWI lesions) have been considered likely to benefit from reperfusion therapies. This hypothesis has been assessed in a variety of recent clinical trials, including DIAS, DEDAS, DIAS II, DEFUSE, and now, most recently, EPITHET.3–7 EPITHET was a randomized, double-blind, placebo-controlled trial designed to determine whether intravenous tissue plasminogen activator, administered 3 to 6 hours after stroke onset, would reduce infarct growth in patients with PWI/DWI mismatch.7 Because technology to rapidly and accurately determine which patients have a PWI/DWI mismatch was not available, both mismatch and nonmismatch patients were …

Response to Letter by Liebeskind

Response: We thank Dr Liebeskind for his interest in our study and appreciate his comments underscoring the complexity of enhancing perfusion to improve outcome in metastable ischemic brain tissue. We see merit in most of his comments and recognize the contributions he has made to collateral therapeutics in acutely ischemic brain. We would like to take this opportunity to clarify what may have been lost in translation. Dr Liebeskind observes that ischemic core was situated only microns away from the penumbra in our model, and considers this a marked discrepancy with human stroke. The calculation he makes underestimates considerably the values we obtained. To estimate salvageable penumbra in our model, we …