Jeffrey A. Switzer

Pathophysiology and treatment of stroke in sickle-cell disease: present and future

Sickle-cell anaemia is the most common cause of stroke in children, and stroke is one of the most devastating complications of sickle-cell disease. Overt strokes are typically due to large-artery vasculopathy affecting the intracranial internal carotid arteries and proximal middle cerebral arteries, whereas silent strokes typically occur in the territory of penetrating arteries. The sickled red blood cell can contribute to the pathogenesis of stroke via abnormal adherence to the vascular endothelium and by haemolysis, which results in endothelial cell activation, a hypercoaguable state, and alterations in vasomotor tone. Red-blood-cell transfusion, the most common preventive measure for stroke in sickle-cell disease, is associated with iron overload in chronic disease. Therefore, interventions directed towards the potential mechanisms that promote vasculopathy and occlusion in sickle-cell anaemia should be investigated. Here we review the epidemiology, clinical spectrum, and pathophysiology of stroke in sickle-cell disease to identify potential therapeutic targets.

Minocycline to Improve Neurologic Outcome in Stroke (MINOS): A dose-finding study

Background and Purpose— Minocycline is a promising anti-inflammatory and protease inhibitor that is effective in multiple preclinical stroke models. We conducted an early phase trial of intravenous minocycline in acute ischemic stroke. Methods— Following an open-label, dose-escalation design, minocycline was administered intravenously within 6 hours of stroke symptom onset in preset dose tiers of 3, 4.5, 6, or 10 mg/kg daily over 72 hours. Minocycline concentrations for pharmacokinetic analysis were measured in a subset of patients. Subjects were followed for 90 days. Results— Sixty patients were enrolled, 41 at the highest dose tier of 10 mg/kg. Overall age (65±13.7 years), race (83% white), and sex (47% female) were consistent across the doses. The mean baseline National Institutes of Health Stroke Scale score was 8.5±5.8 and 60% received tissue plasminogen activator. Minocycline infusion was well tolerated with only 1 dose limiting toxicity at the 10-mg/kg dose. No severe hemorrhages occurred in tissue plasminogen activator-treated patients. Pharmacokinetic analysis (n=22) revealed a half-life of approximately 24 hours and linearity of parameters over doses. Conclusions— Minocycline is safe and well tolerated up to doses of 10 mg/kg intravenously alone and in combination with tissue plasminogen activator. The half-life of minocycline is approximately 24 hours, allowing every 24-hour dosing. Minocycline may be an ideal agent to use with tissue plasminogen activator.

Increased hemorrhagic transformation and altered infarct size and localization after experimental stroke in a rat model type 2 diabetes

BackgroundInterruption of flow through of cerebral blood vessels results in acute ischemic stroke. Subsequent breakdown of the blood brain barrier increases cerebral injury by the development of vasogenic edema and secondary hemorrhage known as hemorrhagic transformation (HT). Diabetes is a risk factor for stroke as well as poor outcome of stroke. The current study tested the hypothesis that diabetes-induced changes in the cerebral vasculature increase the risk of HT and augment ischemic injury.MethodsDiabetic Goto-Kakizaki (GK) or control rats underwent 3 hours of middle cerebral artery occlusion and 21 h reperfusion followed by evaluation of infarct size, hemorrhage and neurological outcome.ResultsInfarct size was significantly smaller in GK rats (10 ± 2 vs 30 ± 4%, p < 0.001). There was significantly more frequent hematoma formation in the ischemic hemisphere in GK rats as opposed to controls. Cerebrovascular tortuosity index was increased in the GK model (1.13 ± 0.01 vs 1.34 ± 0.06, P < 0.001) indicative of changes in vessel architecture.ConclusionThese findings provide evidence that there is cerebrovascular remodeling in diabetes. While diabetes-induced remodeling appears to prevent infarct expansion, these changes in blood vessels increase the risk for HT possibly exacerbating neurovascular damage due to cerebral ischemia/reperfusion in diabetes.

Matrix Metalloproteinase-9 in an Exploratory Trial of Intravenous Minocycline for Acute Ischemic Stroke

Background and Purpose— Plasma matrix metalloproteinase-9 levels predict posttissue plasminogen activator (tPA) hemorrhage. Methods— The authors investigated the effect of minocycline on plasma matrix metalloproteinase-9 in acute ischemic stroke in the Minocycline to Improve Neurological Outcome in Stroke (MINOS) trial and a comparison group. Results— Matrix metalloproteinase-9 level decreased at 72 hours compared with baseline in MINOS (tPA, P=0.0022; non-tPA, P=0.0066) and was lower than in the non-MINOS comparison group at 24 hours (tPA, P<0.0001; non-tPA, P=0.0019). Conclusions— Lower plasma matrix metalloproteinase-9 was seen among tPA-treated subjects in the MINOS trial. Combining minocycline with tPA may prevent the adverse consequences of thrombolytic therapy through suppression of matrix metalloproteinase-9 activity.

Cost-Effectiveness of Hub-and-Spoke Telestroke Networks for the Management of Acute Ischemic Stroke From the Hospitals’ Perspectives

Background— A hub-and-spoke telestroke network is an effective way to extend quality acute stroke care to remote hospitals and to improve patient outcomes. This study assessed the cost-effectiveness of a telestroke network in the management of acute ischemic stroke from the perspectives of a network, a hub hospital, and a spoke hospital. Methods and Results— A model was developed to compare costs and effectiveness with and without a telestroke network over a 5-year time horizon. The model considered differences in rates of teleconsultations, intravenous thrombolysis, endovascular stroke therapies, and spoke-to-hub transfers. These inputs were estimated through the use of data from Georgia Health Sciences University and Mayo Clinic telestroke networks. A network model with 1 hub and 7 spokes predicted that 45 more patients would be treated with intravenous thrombolysis and 20 more with endovascular stroke therapies per year compared with no network, leading to an estimate of 6.11 more home discharges. Each year, a telestroke network was associated with

A web-based telestroke system facilitates rapid treatment of acute ischemic stroke patients in rural emergency departments.

358 435 in cost savings; each spoke had

Improving Modified Rankin Scale Assessment With a Simplified Questionnaire

109 080 in cost savings, whereas the hub had positive costs of

A double-blind placebo-controlled clinical evaluation of MultiStem for the treatment of ischemic stroke.

405 121. However, cost sharing can be arranged so that each hospital could achieve an equal amount of cost savings (

A Telestroke Network Enhances Recruitment into Acute Stroke Clinical Trials

44 804/y). Results were sensitive to the number of spokes, marginal treatment costs in spokes and rates of transfer, and endovascular stroke therapies. Conclusions— The results of this study suggest that a telestroke network may increase the number of patients discharged home and reduce the costs borne by the network hospitals. Hospitals should consider their available resources and the network features when deciding whether to join or set up a network.

Telemedicine Quality and Outcomes in Stroke: A Scientific Statement for Healthcare Professionals From the American Heart Association/American Stroke Association

Patients in rural communities lack access to acute stroke therapies. Rapid administration of thrombolytic therapy increases the likelihood of a favorable outcome in ischemic stroke. We aimed to detail the safety, feasibility, and treatment times of thrombolytic therapy with a web-based telestroke system. At the Medical College of Georgia, we have developed a telestroke system (Remote Evaluation of Acute IsCHemic Stroke; REACH) in which emergency physicians in surrounding counties may consult stroke specialists at our institution. The web-based system allows the stroke consultant to obtain history, examine the patient with live video, and review computed tomography. A recommendation is made regarding the administration of tissue plasminogen activator (tPA) before patient transport to the tertiary medical center. A systematic review of the literature was conducted regarding the use of tPA in academic and community hospitals. Symptomatic hemorrhagic transformation and stroke onset-to-treatment times were compared between the REACH network and other stroke care delivery systems. Between February 2003 and March 2006, 50 patients were treated with intravenous tPA using the REACH telestroke system. There was one (2%) symptomatic hemorrhage. The mean onset-to-treatment time was 127.6 min (95% confidence interval 117.1-138.0) using REACH compared with 145.9 min (95% confidence interval 126.9-164.9) in our Emergency Department and 147.8 min in other published systems. REACH, a web-based telestroke system, facilitates the safe administration of thrombolytic therapy to patients within rural communities suffering an acute ischemic stroke.