Gregory J. del Zoppo

Guidelines for the Early Management of Patients With Ischemic Stroke: A Scientific Statement From the Stroke Council of the American Stroke Association

In 1994, a panel appointed by the Stroke Council of the American Heart Association authored guidelines for the management of patients with acute ischemic stroke.1 After the approval of the use of intravenous recombinant tissue plasminogen activator (rtPA) for treatment of acute ischemic stroke by the Food and Drug Administration, the guidelines were supplemented by a series of recommendations 2 years later.2 Several promising interventions for the treatment of acute ischemic stroke have subsequently been tested in clinical trials, and other components of acute management have been evaluated since the previous guidelines were published. These new data have prompted the present revision of the prior guideline statement. The goal of these guidelines is to provide updated recommendations that can be used by primary care physicians, emergency medicine physicians, neurologists, and other physicians who provide acute stroke care from admission to an emergency department through the first 24 to 48 hours of hospitalization by addressing the diagnosis and emergent treatment of the acute ischemic stroke in addition to the management of its acute and subacute neurological and medical complications. Several groups have now written statements about management of stroke.3–7 These statements also include recommendations about public educational programs, the organization of stroke resources, and other aspects of patient management. For example, the Brain Attack Coalition published recommendations for organizing stroke services in a community, and the recommendations of the American Heart Association Emergency Cardiovascular Care Committee provide an outline for emergency medical services.6 The current panel elected not to duplicate these recent efforts. Therapies to prevent recurrent stroke, also a component of acute management, are similar to prophylactic medical or surgical therapies used for patients with transient ischemic attacks and other high-risk patients. The reader is referred to relevant recent statements for additional information.8,9 In developing …

PROACT: A Phase II Randomized Trial of Recombinant Pro-Urokinase by Direct Arterial Delivery in Acute Middle Cerebral Artery Stroke

BACKGROUND AND PURPOSE To test the safety and recanalization efficacy of intra-arterial local delivery of plasminogen activators in acute ischemic stroke, a randomized trial of recombinant pro-urokinase (rpro-UK) versus placebo was undertaken in patients with angiographically documented proximal middle cerebral artery occlusion. METHODS After exclusion of intracranial hemorrhage by CT scan, patients with abrupt onset of symptoms of focal ischemia likely to receive treatment within 6 hours who satisfied all clinical eligibility criteria underwent carotid angiography. Patients displaying Thrombolysis in Acute Myocardial Infarction grade 0 or 1 occlusion of the M1 or M2 middle cerebral artery were randomized 2:1 to receive rpro-UK (6 mg) or placebo over 120 minutes into the proximal thrombus face. All patients received intravenous heparin. Recanalization efficacy was assessed at the end of the 2-hour infusion, and intracerebral hemorrhage causing neurological deterioration was assessed at 24 hours. RESULTS Of 105 patients who underwent angiography, 59 were excluded from randomization. Among the 46 patients randomized, 40 were treated with rpro-UK (n=26) or placebo (n=14) a median of 5.5 hours from symptom onset. Recanalization was significantly associated with rpro-UK (2P=.017). Hemorrhagic transformation causing neurological deterioration within 24 hours of treatment occurred in 15.4% of the rpro-UK-treated patients and 7.1% of the placebo-treated patients (2P=.64). Both recanalization and hemorrhage frequencies were influenced by heparin dose. CONCLUSIONS Intra-arterial local rpro-UK infusion was associated with superior recanalization in acute thrombotic/ thromboembolic stroke compared with placebo. In this regimen, heparin dose influenced hemorrhage frequency and recanalization. Although symptomatic hemorrhage remains a concern, this study suggests that recanalization is enhanced with rpro-UK and heparin.

Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator: a science advisory from the American Heart Association/American Stroke Association.

Current guidelines for the management of patients with acute ischemic stroke published by the American Heart Association Stroke Council include specific recommendations for the administration of intravenous recombinant tissue plasminogen activator (rtPA).1 Despite its effectiveness in improving neurological outcomes, the majority of patients with ischemic stroke are not treated with rtPA, largely because they arrive after the currently approved 3-hour time limit for administration of the medication. One of the potential approaches to increase treatment opportunities has been the designation of a longer time window for treatment.2–4 A recent prospective study, the European Cooperative Acute Stroke Study (ECASS)-3, has provided new data on rtPA (alteplase) treatment in the 3-to-4.5–hour window.5 The circumstances surrounding this study are important. In 2002, the European Medicines Evaluation Agency granted license for the use of rtPA for the treatment of ischemic stroke patients within 3 hours of symptom onset on condition of (1) the completion of a prospective registry of patient treatment experience with rtPA given within the 3-hour window from symptom onset (Safe Implementation of Thrombolysis in Stroke–Monitoring Study, or SITS-MOST)6 and (2) the completion of a prospective, randomized, placebo-controlled trial of rtPA administered between 3 and 4.5 hours after stroke onset, ECASS-3.5 SITS-MOST, which used a specified protocol, reported that the frequency of symptomatic intracerebral hemorrhage (per the SITS-MOST definition) at 24 hours after rtPA was 1.7% (95% confidence interval [CI] 1.4% to 2.0%; Figure 3 in Wahlgren et al6). The frequency of symptomatic intracerebral hemorrhage per the Cochrane/National Institute of Neurological Disorders and Stroke (NINDS) definition at 24 hours after rtPA was 7.3% (95% CI 6.7% to 7.9%). By comparison, this frequency was slightly less than 8.6% in data taken from a pool of randomized, controlled trials (Figure 2 in Wahlgren et al6). For efficacy, …

Inflammation and Stroke: Putative Role for Cytokines, Adhesion Molecules and iNOS in Brain Response to Ischemia

Ischemic stroke is a leading cause of death and disability in developed countries. Yet, in spite of substantial research and development efforts, no specific therapy for stroke is available. Several mechnism for neuroprotection have been explored including ionchannels, excitatory amino acids and oxygen raicals yet none has culminated in an effective therapeutic effect. The review article on “inflammation and stroke” summarizes key data in support for the possibility that inflammatory cells and mediators are important contributing and confounding factors in ischemic brain injury. In particular, the role of cytokines, endothelial cells and leukocyte adhesion molecules, nitric oxide and cyclooxygenase (COX‐2) products are discussed. Furthermore, the potential role for certain cytokines in modulation of brain vulnerability to ischemia is also reviewed.The data suggest that novel therapeutic strategies may evolve from detailed research on some specific inflammatory factors that act in spatial and temporal relationships with traditionally recognized neurotoxic factors. The dual nature of some mediators in reformatting of brain cells for resistance or sensitivity to injury demonstrate the delicate balance needed in interventions based on anti‐inflammatory strategies.

Role for Matrix Metalloproteinase 9 after Focal Cerebral Ischemia: Effects of Gene Knockout and Enzyme Inhibition with BB-94

It has been shown recently that matrix metalloproteinases (MMPs) are elevated after cerebral ischemia. In the current study, we investigated the pathophysiologic role for MMP-9 (gelatinase B, EC.3.4.24.35) in a mouse model of permanent focal cerebral ischemia, using a combination of genetic and pharmacologic approaches, Zymography and Western blot analysis demonstrated that MMP-9 protein levels were rapidly up-regulated in brain after ischemic onset. Reverse transcription polymerase chain reaction showed increased transcription of MMP-9. There were no differences in systemic hemodynamic parameters and gross cerebrovascular anatomy between wild type mice and mutant mice with a targeted knockout of the MMP-9 gene. After induction of focal ischemia, similar reductions in cerebral blood flow were obtained. In the MMP-9 knockout mice, ischemic lesion volumes were significantly reduced compared with wild type littermates in male and female mice. In normal wild type mice, the broad spectrum MMP inhibitor BB-94 (batimastat) also significantly reduced ischemic lesion size, However, BB-94 had no detectable protective effect when administered to MMP-9 knockout mice subjected to focal cerebral ischemia. These data demonstrate that MMP-9 plays a deleterious role in the development of brain injury after focal ischemia.

Matrix Metalloproteinases Increase Very Early during Experimental Focal Cerebral Ischemia

Microvascular integrity is lost during focal cerebral ischemia. The degradation of the basal lamina and extracellular matrix are, in part, responsible for the loss of vascular integrity. Matrix metalloproteinases (MMPs) may play a primary role in basal lamina degradation. By using a sensitive modification of gelatin zymography, the authors investigated the activity of MMP-2 and MMP-9 in frozen 10-µm sections of ischemic and nonischemic basal ganglia and plasma samples of 27 non-human primates after middle cerebral artery occlusion/reperfusion (MCAO/R) for various periods. The gelatinolytic activities were compared with parallel cell dUTP incorporation in the ischemic zones of adjacent sections. In the brain, the integrated density of MMP-2 increased significantly by 1 hour after MCAO and was persistently elevated thereafter. Matrix metalloproteinase-2 expression was highly correlated with the extent of neuron injury and the number of injured neurons (r = 0.9763, SE = 0.004, 2P < 0.0008). Matrix metalloproteinase-9 expression only was significantly increased in subjects with hemorrhagic transformation. In plasma, only MMP-9 increased transiently at 2 hours of MCAO. These findings highlight the early potential role of MMP-2 in the degradation of basal lamina leading to neuronal injury, and an association of MMP-9 with hemorrhagic transformation after focal cerebral ischemia.

Cerebral Microvessel Responses to Focal Ischemia

Cerebral microvessels have a unique ultrastructure form, which allows for the close relationship of the endothelium and blood elements to the neurons they serve, via intervening astrocytes. To focal ischemia, the cerebral microvasculature rapidly displays multiple dynamic responses. Immediate events include breakdown of the primary endothelial cell permeability barrier, with transudation of plasma, expression of endothelial cell-leukocyte adhesion receptors, loss of endothelial cell and astrocyte integrin receptors, loss of their matrix ligands, expression of members of several matrix-degrading protease families, and the appearance of receptors associated with angiogenesis and neovascularization. These events occur pari passu with neuron injury. Alterations in the microvessel matrix after the onset of ischemia also suggest links to changes in nonvascular cell viability. Microvascular obstruction within the ischemic territory occurs after occlusion and reperfusion of the feeding arteries (“focal no-reflow” phenomenon). This can result from extrinsic compression and intravascular events, including leukocyte(-platelet) adhesion, platelet-fibrin interactions, and activation of coagulation. All of these events occur in microvessels heterogeneously distributed within the ischemic core. The panorama of acute microvessel responses to focal cerebral ischemia provide opportunities to understand interrelationships between neurons and their microvascular supply and changes that underlie a number of central nervous system neurodegenerative disorders.

Hemorrhagic Transformation in Acute Ischemic Stroke Potential Contributing Factors in the European Cooperative Acute Stroke Study

BACKGROUND AND PURPOSE Recent studies suggest that thrombolytic therapy may be of benefit to patients with acute ischemic stroke. However, the treatment also carries a significant risk of hemorrhagic transformation (HT). The purpose of this study was to select potential contributors to HT. METHODS We provide an explanatory analysis of the European Cooperative Acute Stroke Study (ECASS) data. ECASS was a multicenter, placebo-controlled, randomized trial of recombinant tissue plasminogen activator in ischemic stroke, within 6 hours of symptom onset, which enrolled 620 patients. HTs were classified into either hemorrhagic infarction or parenchymal hemorrhage according to their CT scan appearance. We used logistic regression analysis to select potential contributing factors to each type of HT. RESULTS The severity of initial clinical deficit (odds ratio [OR], 2.5; 95% confidence interval [CI], 1.6 to 4.0) and the presence of early ischemic changes on CT scan (OR, 3.5; 95% CI, 2.3 to 5.3) were associated with increased risk of hemorrhagic infarction. Increasing age (in decades; OR, 1.3; 95% CI, 1.0 to 1.7) and treatment with recombinant tissue plasminogen activator (OR, 3.6; 95% CI, 2.1 to 6.1) were related to the risk of parenchymal hemorrhage. CONCLUSIONS Since all potential contributing factors are readily discernible upon hospital admission, they should be used to improve selection of patients into future studies.

Hemorrhagic Transformation Within 36 Hours of a Cerebral Infarct Relationships With Early Clinical Deterioration and 3-Month Outcome in the European Cooperative Acute Stroke Study I (ECASS I) Cohort

BACKGROUND AND PURPOSE The clinical correlates of the varying degrees of early hemorrhagic transformation of a cerebral infarct are unclear. We investigated the cohort of a randomized trial of thrombolysis to assess the early and late clinical course associated with different subtypes of hemorrhagic infarction (HI) and parenchymal hematoma (PH) detected within the first 36 hours of an ischemic stroke. METHODS We exploited the database of the European Cooperative Acute Stroke Study I (ECASS I), a randomized, placebo-controlled, phase III trial of intravenous recombinant tissue plasminogen activator in acute ischemic stroke. Findings on 24- to 36- hour CT were classified into 5 categories: no hemorrhagic transformation, HI types 1 and 2, and PH types 1 and 2. We assessed the risk of concomitant neurological deterioration and of 3-month death and disability associated with subtypes of hemorrhagic transformation, as opposed to no bleeding. Risks were adjusted for age and extent of ischemic damage on baseline CT. RESULTS Compared with absence of hemorrhagic transformation, HI1, HI2, and PH1 did not modify the risk of early neurological deterioration, death, and disability, whereas, in both the placebo and the recombinant tissue plasminogen activator groups, PH2 had a devastating impact on early neurological course (odds ratio for deterioration, 32.3; 95% CI, 13. 4 to 77.7), and on 3-month death (odds ratio, 18.0; 95% CI, 8.05 to 40.1). Risk of disability was also higher, but not significantly, after PH2. CONCLUSIONS Risk of early neurological deterioration and of 3-month death was severely increased after PH2, indicating that large hematoma is the only type of hemorrhagic transformation that may alter the clinical course of ischemic stroke.

Peak plasma interleukin-6 and other peripheral markers of inflammation in the first week of ischaemic stroke correlate with brain infarct volume, stroke severity and long-term outcome

BackgroundCerebral ischaemia initiates an inflammatory response in the brain and periphery. We assessed the relationship between peak values of plasma interleukin-6 (IL-6) in the first week after ischaemic stroke, with measures of stroke severity and outcome.MethodsThirty-seven patients with ischaemic stroke were prospectively recruited. Plasma IL-6, and other markers of peripheral inflammation, were measured at pre-determined timepoints in the first week after stroke onset. Primary analyses were the association between peak plasma IL-6 concentration with both modified Rankin score (mRS) at 3 months and computed tomography (CT) brain infarct volume.ResultsPeak plasma IL-6 concentration correlated significantly (p < 0.001) with CT brain infarct volume (r = 0.75) and mRS at 3 months (r = 0.72). It correlated similarly with clinical outcome at 12 months or stroke severity. Strong associations were also noted between either peak plasma C-reactive protein (CRP) concentration or white blood cell (WBC) count, and all outcome measures.ConclusionsThese data provide evidence that the magnitude of the peripheral inflammatory response is related to the severity of acute ischaemic stroke, and clinical outcome.