A. Dávalos

Thrombectomy within 8 Hours after Symptom Onset in Ischemic Stroke

BACKGROUND We aimed to assess the safety and efficacy of thrombectomy for the treatment of stroke in a trial embedded within a population-based stroke reperfusion registry. METHODS During a 2-year period at four centers in Catalonia, Spain, we randomly assigned 206 patients who could be treated within 8 hours after the onset of symptoms of acute ischemic stroke to receive either medical therapy (including intravenous alteplase when eligible) and endovascular therapy with the Solitaire stent retriever (thrombectomy group) or medical therapy alone (control group). All patients had confirmed proximal anterior circulation occlusion and the absence of a large infarct on neuroimaging. In all study patients, the use of alteplase either did not achieve revascularization or was contraindicated. The primary outcome was the severity of global disability at 90 days, as measured on the modified Rankin scale (ranging from 0 [no symptoms] to 6 [death]). Although the maximum planned sample size was 690, enrollment was halted early because of loss of equipoise after positive results for thrombectomy were reported from other similar trials. RESULTS Thrombectomy reduced the severity of disability over the range of the modified Rankin scale (adjusted odds ratio for improvement of 1 point, 1.7; 95% confidence interval [CI], 1.05 to 2.8) and led to higher rates of functional independence (a score of 0 to 2) at 90 days (43.7% vs. 28.2%; adjusted odds ratio, 2.1; 95% CI, 1.1 to 4.0). At 90 days, the rates of symptomatic intracranial hemorrhage were 1.9% in both the thrombectomy group and the control group (P=1.00), and rates of death were 18.4% and 15.5%, respectively (P=0.60). Registry data indicated that only eight patients who met the eligibility criteria were treated outside the trial at participating hospitals. CONCLUSIONS Among patients with anterior circulation stroke who could be treated within 8 hours after symptom onset, stent retriever thrombectomy reduced the severity of post-stroke disability and increased the rate of functional independence. (Funded by Fundació Ictus Malaltia Vascular through an unrestricted grant from Covidien and others; REVASCAT ClinicalTrials.gov number, NCT01692379.).

The Desmoteplase in Acute Ischemic Stroke Trial (DIAS) A Phase II MRI-Based 9-Hour Window Acute Stroke Thrombolysis Trial With Intravenous Desmoteplase

Background and Purpose— Most acute ischemic stroke patients arrive after the 3-hour time window for recombinant tissue plasminogen activator (rtPA) administration. The Desmoteplase In Acute Ischemic Stroke trial (DIAS) was a dose-finding randomized trial designed to evaluate the safety and efficacy of intravenous desmoteplase, a highly fibrin-specific and nonneurotoxic thrombolytic agent, administered within 3 to 9 hours of ischemic stroke onset in patients with perfusion/diffusion mismatch on MRI. Methods— DIAS was a placebo-controlled, double-blind, randomized, dose-finding phase II trial. Patients with National Institute of Health Stroke Scale (NIHSS) scores of 4 to 20 and MRI evidence of perfusion/diffusion mismatch were eligible. Of 104 patients, the first 47 (referred to as Part 1) were randomized to fixed doses of desmoteplase (25 mg, 37.5 mg, or 50 mg) or placebo. Because of an excessive rate of symptomatic intracranial hemorrhage (sICH), lower weight-adjusted doses escalating through 62.5 &mgr;g/kg, 90 &mgr;g/kg, and 125 &mgr;g/kg were subsequently investigated in 57 patients (referred to as Part 2). The safety endpoint was the rate of sICH. Efficacy endpoints were the rate of reperfusion on MRI after 4 to 8 hours and clinical outcome as assessed by NIHSS, modified Rankin scale, and Barthel Index at 90 days. Results— Part 1 was terminated prematurely because of high rates of sICH with desmoteplase (26.7%). In Part 2, the sICH rate was 2.2%. No sICH occurred with placebo in either part. Reperfusion rates up to 71.4% (P=0.0012) were observed with desmoteplase (125 &mgr;g/kg) compared with 19.2% with placebo. Favorable 90-day clinical outcome was found in 22.2% of placebo-treated patients and between 13.3% (62.5 &mgr;g/kg; P=0.757) and 60.0% (125 &mgr;g/kg; P=0.0090) of desmoteplase-treated patients. Early reperfusion correlated favorably with clinical outcome (P=0.0028). Favorable outcome occurred in 52.5% of patients experiencing reperfusion versus 24.6% of patients without reperfusion. Conclusions— Intravenous desmoteplase administered 3 to 9 hours after acute ischemic stroke in patients selected with perfusion/diffusion mismatch is associated with a higher rate of reperfusion and better clinical outcome compared with placebo. The sICH rate with desmoteplase was low, using doses up to 125 &mgr;g/kg.

Proinflammatory Cytokines and Early Neurological Worsening in Ischemic Stroke

Background and Purpose The mechanisms for clinical deterioration in patients with ischemic stroke are not completely understood. Several proinflammatory cytokines are released early after the onset of brain ischemia, but it is unknown whether inflammation predisposes to neurological deterioration. We assessed the implication of interleukin (IL)-6 and tumor necrosis factor (TNF)-&agr; in early neurological worsening in ischemic stroke. Methods Two hundred thirty-one patients consecutively admitted with first-ever ischemic cerebral infarction within the first 24 hours from onset were included. Neurological worsening was defined when the Canadian Stroke Scale (CSS) score fell at least 1 point during the first 48 hours after admission. IL-6 and TNF-&agr; were determined in plasma and cerebrospinal fluid (CSF; n=81) obtained on admission. Results Eighty-three patients (35.9%) deteriorated within the first 48 hours. IL-6 in plasma (>21.5 pg/mL; OR 37.7, CI 11.9 to 118.8) or in CSF (>6.3 pg/mL; OR 13.1, CI 2.2 to 77.3) were independent factors for early clinical worsening, with multiple logistic regression. The association was statistically significant in all ischemic stroke subtypes as well as in subjects with cortical or subcortical infarctions. IL-6 in plasma was highly correlated with body temperature, glucose, fibrinogen, and infarct volume. CSF and plasma concentrations of TNF-&agr; were also higher in patients who deteriorated, but the differences observed did not remain significant on multivariate analysis. Conclusions In addition to participating in the acute-phase response that follows focal cerebral ischemia, IL-6 levels on admission are associated with early clinical deterioration. The association between IL-6 and early neurological worsening prevails without regard to the initial size, topography, or mechanism of the ischemic infarction.

Early neurologic deterioration in intracerebral hemorrhage Predictors and associated factors

Objective: To identify potential predictors of and factors associated with early neurologic deterioration (END) in primary intracerebral hemorrhage (ICH). Methods: Two hundred sixty-six patients with spontaneous supratentorial ICH admitted within 12 hours of stroke onset were investigated in a multicenter, prospective study. Sixty-one clinical, biochemical, and neuroimaging variables were registered on admission, and 37 clinical and neuroimaging variables were registered at 48 hours. The volumes of the ICH and peripheral edema on admission and at 48 hours were measured on CT scan. Stroke severity and functional outcome were evaluated with the Canadian Stroke Scale (CSS) and modified Rankin Scale. END was diagnosed when the CSS score decreased ≥1 points between admission and 48 hours. With use of logistic regression analyses, baseline variables that predicted END and factors measured after the early acute phase and associated with END were investigated. Results: END occurred in 61 (22.9%) patients. Body temperature of >37.5 °C (odds ratio [OR] 24.5; 95% CI 4.8 to 125), neutrophil count (by 1,000-unit increase; OR 2.1; 95% CI 1.6 to 2.6), and serum fibrinogen levels of >523 mg/dL (OR 5.6; 95% CI 1.9 to 16.2) on admission were independent predictors of END. Among the factors recorded at 48 hours, early ICH growth (OR 4.3; 95% CI 1.3 to 14.5), intraventricular bleeding (OR 2.6; 95% CI 1.4 to 5.0), and highest systolic blood pressure (by 10-unit increase; OR 1.17; 95% CI 1.02 to 1.32) were associated with END in multivariate analyses. Conclusions: Clinical and biologic markers of the inflammatory reaction on admission are predictors of subsequent END, whereas early ICH growth, intraventricular bleeding, and high systolic blood pressure within 48 hours are factors associated with END in patients with spontaneous ICH.

Statin treatment withdrawal in ischemic stroke A controlled randomized study

Background: Pretreatment with statins has been shown to reduce brain injury in cerebral ischemia. In this controlled randomized study, we investigated the influence of statin pretreatment and its withdrawal on the outcome of acute ischemic stroke patients. Methods: From 215 patients admitted within 24 hours of a hemispheric ischemic stroke, 89 patients on chronic statin treatment were randomly assigned either to statin withdrawal for the first 3 days after admission (n = 46) or to immediately receive atorvastatin 20 mg/day (n = 43). The primary outcome event was death or dependency (modified Rankin Scale [mRS] score > 2) at 3 months. Early neurologic deterioration (END) and infarct volume at days 4 to 7 were secondary outcome variables. In a secondary analysis, outcome variables were compared with the nonrandomized patients without previous statin therapy (n = 126). Results: Patients with statin withdrawal showed a higher frequency of mRS score > 2 at the end of follow-up (60.0% vs 39.0%; p = 0.043), END (65.2% vs 20.9%; p < 0.0001), and greater infarct volume (74 [45, 126] vs 26 [12, 70] mL; p = 0.002) compared with the non–statin-withdrawal group. Statin withdrawal was associated with a 4.66 (1.46 to 14.91)–fold increase in the risk of death or dependency, a 8.67 (3.05 to 24.63)–fold increase in the risk of END, and an increase in mean infarct volume of 37.63 mL (SE 10.01; p < 0.001) after adjusting for age and baseline stroke severity. Compared with patients without previous treatment with statins, statin withdrawal was associated with a 19.01 (1.96 to 184.09)–fold increase in the risk of END and an increase in mean infarct volume of 43.51 mL (SE 21.91; p = 0.048). Conclusion: Statin withdrawal is associated with increased risk of death or dependency at 90 days. Hence, this treatment should be continued in the acute phase of ischemic stroke.

Neurological Deterioration in Acute Ischemic Stroke Potential Predictors and Associated Factors in the European Cooperative Acute Stroke Study (ECASS) I

BACKGROUND AND PURPOSE The present study was undertaken to identify potential predictors of and factors associated with early and late progression in acute stroke. We performed secondary analysis of the clinical, biochemical, and radiological data recorded in the acute phase of stroke patients enrolled in the European Cooperative Acute Stroke Study (ECASS) I. METHODS Early progressing stroke (EPS) was diagnosed when there was a decrease of > or = 2 points in consciousness or motor power or a decrease of > or = 3 points in speech scores in the Scandinavian Neurological Stroke Scale from baseline to the 24-hour evaluation, and late progressing stroke (LPS) was diagnosed when 1 of these decreases occurred between the 24-hour evaluation and the evaluation at day 7. Using logistic regression analyses, we looked for baseline variables that predicted EPS and LPS and for factors measured after the early or late acute phase and associated with the 2 clinical courses. RESULTS Of the 615 patients studied, 231 (37.5%) worsened during the first 24 hours after inclusion. The overall incidence of EPS was 37% in the placebo group and 38% in the recombinant tissue plasminogen activator group (P=0.68, Fishers Exact Test). Focal hypodensity (odds ratio [OR], 1.9; 95% confidence interval [CI], 1.3 to 2.9) and hyperdensity of the middle cerebral artery sign (OR, 1.8; 95% CI, 1.1 to 3.1) on baseline computed tomography, longer delay until treatment (OR, 1.2; 95% CI, 1.1 to 1. 4) and history of coronary heart disease (OR, 1.7; 95% CI, 1.1 to 2. 8) and diabetes (OR, 1.8; 95% CI, 1.0 to 3.1) were independent prognostic factors for EPS. Extent of hypodensity >33% in the middle cerebral artery territory (OR, 2.5; 95% CI, 1.6 to 4.0) and brain swelling (OR, 1.8; 95% CI, 1.1 to 3.2) on CT at 24 hours but not hemorrhagic transformation of cerebral infarct nor decrease in systolic blood pressure within the first 24 hours after treatment were associated with EPS in multivariate analyses. LPS was observed in 20.3% of patients. Older age, a low neurological score, and brain swelling at admission independently predicted late worsening. CONCLUSION In the setting of a multicenter trial, EPS and LPS are mainly related to computed tomographic signs of cerebral edema. Treatment with recombinant tissue plasminogen activator, hemorrhagic transformation, and moderate changes in systolic blood pressure did not influence the early clinical course.

Molecular signatures of brain injury after intracerebral hemorrhage.

BackgroundThe mechanisms of cellular death in the tissue surrounding an intracerebral hemorrhage (ICH) are not defined. ObjectiveTo investigate the relationship of markers of excitotoxicity and inflammation to brain injury after ICH. MethodsA total of 124 consecutive patients with spontaneous ICH admitted within 24 hours of stroke onset were prospectively investigated. The volumes of the initial ICH, peripheral edema on days 3 to 4, and the residual cavity at 3 months were measured on CT scan. Glutamate, cytokines, and adhesion molecules were measured in blood samples obtained on admission. Stroke severity and neurologic outcome were evaluated with the Canadian Stroke Scale. ResultsPoor neurologic outcome at 3 months (Canadian Stroke Scale < 7) was observed in 53 patients (43%). Stroke severity and glutamate concentrations (by each increment of 10 &mgr;mol/L, odds ratio 1.23; 95% CI 1.09 to 1.41), but not the initial volume of ICH, were independent predictors of poor outcome. In the multiple linear regression analyses, tumor necrosis factor-&agr; concentration was correlated (r = 0.83, p < 0.0001) with the volume of perihematoma edema, and glutamate concentrations were correlated (r = 0.78, p < 0.0001) with the volume of the residual cavity. These same results were observed when lobar (n = 58) and deep (n = 66) ICH were analyzed separately. ConclusionsHigh plasma levels of proinflammatory molecules within 24 hours of intracerebral hemorrhage onset are correlated with the magnitude of the subsequent perihematoma brain edema, whereas poor neurologic outcome and the volume of the residual cavity are related to increased plasma glutamate concentrations.

Levels of Anti-Inflammatory Cytokines and Neurological Worsening in Acute Ischemic Stroke

Background— Mechanisms involved in stroke progression are incompletely understood. Ischemic brain injury is characterized by acute local inflammatory response mediated by cytokines. Anti-inflammatory cytokines act in a feedback loop to inhibit continued proinflammatory cytokine production. We assessed the implication of interleukin (IL)-10 and IL-4 in deteriorating ischemic stroke. Methods— Two hundred thirty-one patients with ischemic stroke within the first 24 hours from onset were included. Neurological worsening was defined when the Canadian Stroke Scale score fell at least 1 point during the first 48 hours after admission. Anti-inflammatory cytokines were determined in plasma obtained on admission. Results— Eighty-three patients (35.9%) worsened within the first 48 hours after stroke onset. Significantly lower concentrations of IL-10 were found in patients with neurological worsening (P <0.05), but IL-4 levels were similar in patients with or without deterioration. Lower plasma concentrations of IL-10 (<6 pg/mL) were associated with clinical worsening on multivariate analysis (odds ratio=3.1, 95% CI=1.1 to 8.9) independently of hyperthermia, hyperglycemia, or neurological condition on admission. Further analysis disclosed that early worsening was independently associated with lower IL-10 plasma levels in patients with subcortical infarcts or lacunar stroke but not in patients with cortical lesions. Conclusions— Anti-inflammatory cytokine IL-10 is associated with the early clinical course of patients with acute ischemic stroke, especially in patients with small vessel disease or subcortical infarctions.

The Increase of Circulating Endothelial Progenitor Cells After Acute Ischemic Stroke Is Associated With Good Outcome

Background and Purpose— Increased circulating endothelial progenitor cells (EPC) have been associated with a low cardiovascular risk and may be involved in endothelial cell regeneration. The present study was designed to evaluate the prognostic value of EPC in acute ischemic stroke. Methods— Forty-eight patients with a first-ever nonlacunar ischemic stroke were prospectively included in the study within 12 hours of symptoms onset. Stroke severity was evaluated by the National Institutes of Health Stroke Scale, and functional outcome was assessed at 3 months by the modified Rankin Scale (mRS). Infarct volume growth between admission and days 4 to 7 was measured on multiparametric MRI. EPC colonies were defined as early outgrowth colony-forming unit-endothelial cell (CFU-EC). The increment of CFU-EC was quantified during the first week and defined as the absolute difference between the number of CFU-EC at day 7 and admission. The influence of CFU-EC increase on good functional outcome (mRS ≤2) and infarct growth was analyzed by logistic regression and linear models. Results— Patients with good outcome (n=25) showed a higher CFU-EC increment during the first week (median [quartiles], 23 [11, 36] versus −3 [−7, 1], P<0.0001) compared with patients with poor outcome. CFU-EC increment ≥4 during the first week was associated with good functional outcome at 3 months (odds ratio, 30.7; 95% CI, 2.4 to 375.7; P=0.004) after adjustment for baseline stroke severity, ischemic volume and thrombolytic treatment. For each unit increase in the CFU-EC the mean reduction in the growth of infarct volume was 0.39 (0.03 to 0.76) mL (P=0.033). Conclusions— The increase of circulating EPC after acute ischemic stroke is associated with good functional outcome and reduced infarct growth. These findings suggest that EPC might participate in neurorepair after ischemic stroke.

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

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