Intravenous ancrod for treatment of acute ischemic stroke: the STAT study: a randomized controlled trial. Stroke Treatment with Ancrod Trial.

CONTEXT: Approved treatment options for acute ischemic stroke in the United States and Canada are limited at present to intravenous tissue-type plasminogen activator, but bleeding complications, including intracranial hemorrhage, are a recognized complication. OBJECTIVE: To evaluate the efficacy and safety of the defibrinogenating agent ancrod in patients with acute ischemic stroke. DESIGN: The Stroke Treatment with Ancrod Trial (STAT), a randomized, parallel-group, double-blind, placebo-controlled trial conducted between August 1993 and January 1998. SETTING: Forty-eight centers, primarily community hospitals, in the United States and Canada. PATIENTS: A total of 500 patients with an acute or progressing ischemic neurological deficit were enrolled and included in the intent-to-treat analysis. INTERVENTIONS: Patients were randomly assigned to receive ancrod (n=248) or placebo (n =252) as a continuous 72-hour intravenous infusion beginning within 3 hours of stroke onset, followed by infusions lasting approximately 1 hour at 96 and 120 hours. The ancrod regimen was designed to decrease plasma fibrinogen levels to 1.18 to 2.03 micromol/L. MAIN OUTCOME MEASURES: The primary efficacy end point was functional status, with favorable functional status defined as survival to day 90 with a Barthel Index of 95 or more or at least the prestroke value, compared by treatment group. Primary safety variables included symptomatic intracranial hemorrhage and mortality. RESULTS: Favorable functional status was achieved by more patients in the ancrod group (42.2%) than in the placebo group (34.4%; P=.04) by the prespecified covariate-adjusted analysis. Mortality was not different between treatment groups (at 90 days, 25.4% for the ancrod group and 23% for the placebo group; P=.62), and the proportion of severely disabled patients was less in the ancrod group than in the placebo group (11.8% vs 19.8%; P=.01). The favorable functional status observed with ancrod vs placebo was consistent in all subgroups defined for age, stroke severity, sex, prestroke disability, and time to treatment (< or = 3 or > 3 hours after stroke onset). There was a trend toward more symptomatic intracranial hemorrhages in the ancrod group vs placebo (5.2% vs 2.0%; P=.06), as well as a significant increase in asymptomatic intracranial hemorrhages (19.0% vs 10.7%; P=.01). CONCLUSION: In this study, ancrod had a favorable benefit-risk profile for patients with acute ischemic stroke.

Gene expression of IL-10 in relationship to TNF-alpha, IL-1beta and IL-2 in the rat brain following middle cerebral artery occlusion.

To systematically elucidate the gene expression of inflammatory and immune modulators following middle cerebral artery occlusion (MCAO) in the rat, we studied interleukin-10 (IL-10) along with tumor necrosis factor alpha (TNF-alpha), interleukin-1 beta (IL-1beta) and interleukin-2 (IL-2). Gene expression of these cytokines was studied ipsilateral and contralateral to the MCAO, with mRNA expression levels evaluated 2, 4, 6, 8 and 12 h following permanent MCAO by reverse transcriptase polymerase chain reaction (RT-PCR). In the ischemic hemisphere TNF-alpha and IL-1beta mRNA increased at 2 h following MCAO and peaked at 6 h, with IL-10 mRNA detected only at 6 h. Contralaterally, both TNF-alpha and IL-1beta mRNAs were expressed with a similar pattern to that in the ischemic hemisphere, but at lower levels, with no contralateral IL-10 expression. There was no difference in IL-2 gene expression between control and experimental animals in either hemisphere. These results demonstrate that IL-10 and TNF-alpha, IL-1beta gene expression is induced early following MCAO. The temporal profile of these cytokines is similar to that seen in sepsis, where TNF-alpha induces IL-10; subsequently IL-10 inhibits TNF-alpha expression. The similarity of the temporal profile of cytokine expression in sepsis and cerebral ischemia suggests that IL-10 should be studied as a potential inhibitor of TNF-alpha production in ischemic brain tissue. The factors inducing contralateral expression of the inflammatory cytokines, TNF-alpha and IL-1beta, along with the potential clinical significance of this remote cytokine gene expression, merit further study.

Stroke is an emergency.

Stroke is an emergency. Ischemic stroke is similar to myocardial infarction in that the pathogenesis is loss of blood supply to the tissue, which can result in irreversible damage if blood flow is not restored quickly. Public education is needed to emphasize the warning signs of stroke. Patients should seek medical help immediately, using emergency transport systems. Therapy geared toward minimizing the damage from an acute stroke should be started without delay in the emergency room. This includes measures to protect brain tissue, support perfusion pressure, and minimize cerebral edema. Strategies for improving recovery should also begin immediately. All major medical centers need stroke teams and stroke units. Stroke prevention should be given high priority as a public health strategy. Risk factor management should be part of general health care and should begin in childhood, with emphasis on nutrition, exercise, weight control, and avoidance of tobacco. Health screening and early treatment of hypertension and hypercholesterolemia has decreased the incidence of stroke and heart disease, but these efforts need to be expanded to reach all segments of the population. Basic research has opened the door to new therapies aimed at re-establishing blood flow and limiting tissue damage. Clinical trials have already led to changes in stroke prevention, including studies of carotid endarterectomy and ticlopidine and warfarin therapy (for patients with atrial fibrillation). Trials in progress are testing the usefulness of ancrod, neuroprotective agents, antioxidant agents, anti-inflammatory agents, low-molecular-weight heparin, thrombolytic drugs, and angioplasty. Any delay starting therapy after an acute stroke will result in progressive, irreversible loss of brain tissue. Clinicians should remember that for a stroke patient, time is brain tissue.

Gender influences the magnitude of the inflammatory response within embolic cerebral infarcts in young rats.

BACKGROUND AND PURPOSE: The inflammatory response within cerebral infarcts may have an influence on tissue damage. Since old animals with an impaired immune response have decreased inflammation after experimental cerebral infarction, we postulated that female animals with an increased immune response will have an increased inflammatory response after cerebral infarction. METHODS: Embolic cerebral infarcts were produced by photochemical irradiation of the right carotid artery in 12 female Fischer rats. The inflammatory response within 4-day-old infarcts was quantitated by histology with the use of computer-assisted image analysis and compared with that in 12 male rats from a previous series. RESULTS: Severe infarcts had the most pronounced inflammatory response. Female rats had an increased inflammatory response in infarcts of all severity, which was statistically significant in severe cerebral infarcts even after adjustment for infarct size. Severe infarcts in males were significantly larger than those in females. CONCLUSIONS: Gender influences the outcome of embolic cerebral infarcts after photochemical damage to the carotid artery, both in terms of the magnitude of the inflammatory response and infarct size. There are numerous gender-related differences in neurochemicals, cytokine production, and drug metabolism that may influence tissue damage after stroke and responsiveness to therapeutic intervention. The preponderance of male animals in stroke research may produce results not applicable to female stroke patients. The use of female animals will be required to provide adequate models for the study of stroke in women.

A reproducible model of middle cerebral infarcts, compatible with long-term survival, in aged rats.

BACKGROUND AND PURPOSE: Stroke is a disease associated with aging, but experimental stroke studies are generally done in young male animals. Because there are numerous differences associated with aging, such as an altered immune system and altered neurochemistry, that could affect the outcome of these experiments, a model of reproducible cerebral infarction in aged rats is needed. METHODS: We attempted to produce middle cerebral artery (MCA) infarcts in aged (22 months of age) rats using two standard methods. A nylon suture with a heat-induced bulb was passed through the external carotid artery in seven animals, with an attempt to place the tip at the origin of the MCA. The MCA was ligated through a craniotomy just proximal to the internal cerebral vein in 14 rats. Survival potential was tested by attempting 2-week survival in four rats and 2-month survival in one rat. RESULTS: The suture model failed to produce MCA infarcts, even when the bulb of the suture was properly placed in the MCA. The intracranial MCA occlusion resulted in reproducible MCA infarcts. There were no deaths, including the animals allowed to survive 2 weeks and 2 months. CONCLUSIONS: We conclude that reproducible MCA infarcts can be produced in aged rats by craniotomy and that these lesions may be compatible with long-term survival. This should be a useful technique for studying therapeutic interventions and rehabilitation strategies in an animal model that immunologically and neurochemically more closely resembles humans at risk for stroke.

Anticoagulation for prevention of cerebral infarcts following subarachnoid hemorrhage.

BACKGROUND: Late neurologic deterioration following subarachnoid hemorrhage is often due to vasospasm and rebleeding. Although the sudden onset of a focal neurologic deficit can actually be the result of thromboembolism, anticoagulation has rarely been used in such cases. METHODS: We report a case of a 55-year-old woman who developed recurrent transient focal neurologic deficits 13 days after having a subarachnoid hemorrhage, with multiple cerebral infarcts by CT. Two cerebral angiograms showed no aneurysm. Her symptoms and clinical temporal profile were consistent with thromboembolic phenomenon. We elected to treat her with systemic anticoagulation. RESULTS: The patient had no recurrent events after systemic anticoagulation, but had episodic sensory changes and a new infarct on MRI once the anticoagulation was discontinued. CONCLUSIONS: Anticoagulant was safely administered after subarachnoid hemorrhage (SAH) in this patient and may have been effective in preventing further cerebral ischemic infarction following her SAH. Our patient's clinical profile of sudden (rather than gradual) onset of a transient focal neurologic deficit and resolution of blood on CT indicates one setting in which the use of heparin may be considered.

Inflammatory vascular disorders: diagnosis and treatment in ischemic stroke.

Recent advances in understanding the role of inflammatory vascular disorders in the production of ischemic stroke have resulted in improved diagnosis and treatment of this subset of stroke patients. These disorders include collagen vascular diseases, the primary anti-phospholipid antibody syndrome and vasculitic diseases. However, the interest generated in this area has led to an overdiagnosis of vasculitis in stroke patients, some overuse of steroids, and the routine ordering of expensive laboratory tests which do not contribute to the evaluation and treatment of most cases of stroke. Inflammatory vascular disorders are reviewed in relation to the potential mechanisms of ischemic stroke, along with specific diagnostic and therapeutic considerations. The appropriate use of specialized laboratory tests and diagnostic pitfalls are also reviewed.

Fibrin content of carotid thrombi alters the production of embolic stroke in the rat.

BACKGROUND AND PURPOSE: Mechanical denudation of the endothelium of the carotid artery in animals produces a nonocclusive thrombus, but the brains of these animals have not been examined for the presence of embolic stroke. METHODS: The endothelium of the right carotid artery of 16 Wistar rats was denuded using a balloon catheter. Phosphotungstic acid hematoxylin (PTAH) staining and scanning electron micrographs of the nonocclusive thrombi in the carotid arteries were compared with those produced by photochemical methods, and brains were examined for infarcts. RESULTS: Although nonocclusive thrombi were present in the carotid arteries of 4 of 4 rats killed at 4 hours and in 8 of 12 killed at 24 hours, neither cerebral infarcts nor emboli were seen in the 14 brains evaluated by light microscopy. PTAH demonstrated a high fibrin content in the thrombus produced by the endothelial denudation, with almost no fibrin seen in photochemically induced thrombi. Scanning electron microscopy confirmed dense networks of fibrin in the thrombi produced by balloon denudation. CONCLUSIONS: The composition of a nonocclusive thrombus may determine the embolic potential of this thrombus. A low fibrin content in a nonocclusive platelet thrombus may enhance the embolic potential. This suggests that platelet inhibition may also be indicated in patients with carotid artery disease who are being treated with anticoagulant.

Neurologic disorders of pregnancy. Connective tissue disorders.

Although neurological manifestations are well described in patients with connective tissue diseases, there is no evidence of increased frequency during pregnancy. Treatment varies with the neurological disorder and the nature of pathogenetic process, with modifications of usual therapies sometimes required during pregnancy. Termination of pregnancy is a consideration only with the more serious vasculitic diseases (i.e., PAN or WG), in patients with cardiac or renal failure, or in patients with severe exacerbations of their systemic disease that is refractory to therapy.

Connective tissue disease and sarcoidosis of the central nervous system.

The mechanism for central nervous system (CNS) involvement in connective tissue diseases is variable. Although CNS vasculitis does occur in some connective tissue diseases, it is rare in many others, including systemic lupus erythematosus. Overall, the most common pathogenetic mechanism for CNS dysfunction in patients with connective tissue disease is probably secondary CNS involvement, due either to multiple systemic organ dysfunction (including hypercoagulable or hypofibrinolytic states) or due to CNS and systemic infections. The pathogenetic role of antineuronal antibodies is yet to be defined. Generally, nervous system complications of those collagen diseases that classically produce necrotizing vasculitis should be treated with cytotoxic agents. The less severe vasculitides, particularly temporal arteritis, respond well to steroids, as does sarcoidosis. There are a variety of mechanisms for nervous system disorders in complex multiple system diseases. The etiology is often outside of the nervous system, and results of therapy are highly variable.

The ultrastructure of photochemically induced thrombi with embolization in a rat model.

BACKGROUND AND PURPOSE: Photochemical techniques, currently used in stroke and cancer research, produce endothelial damage and thrombosis. To further characterize these thrombi and to determine whether they embolize, we studied the ultrastructure of photochemically damaged carotid arteries and small vessels distal to the irradiated carotid. METHODS: The right carotid artery of 9 Wistar rats was irradiated with a laser (632 nm, 200 mW/cm2, 15 minutes) after the injection of the photosensitizing dye Photofrin II, 12.5 mg/kg. There were 6 additional control rats: laser only, 2 rats; dye only, 2; carrier only (5% dextrose), 1; and normal, 1. The carotid artery and cerebral arterioles were studied using scanning and transmission electron microscopy. RESULTS: Endothelial damage was present in all irradiated carotid arteries, and consisted of exposure of the subendothelium and the formation of a nonocclusive thrombus. Although most cerebral arterioles were normal, 32 of these vessels contained peripheral blood elements, with platelet or red blood cell aggregates present in 15. The endothelium adjacent to the aggregates was intact. A few scattered endothelial cells had been lost in the carotid artery of control animals (compatible with normal cell turnover), with a few platelets adhering to the exposed subendothelium. CONCLUSIONS: Aggregates of blood cells and platelets in cerebral vessels in the absence of endothelial denudation verifies embolism as the mechanism for cerebral vascular occlusion in this experimental model. The possibility of embolization distal to the site of photochemical irradiation has implications for potential applications of photochemistry for cancer treatment and the ablation of vascular malformations and/or aneurysms.

Embolic infarcts of carotid origin differ in size and site with contralateral carotid patency.

Carotid emboli cause small infarcts in the ipsilateral hemisphere in rats when the contralateral carotid artery is fully patent. With contralateral carotid occlusion, embolic infarcts, both large and small, occur with equal proportions in both hemispheres. To determine if emboli also cross to the territory of a stenotic carotid artery, we combined high grade (78-96%) stenosis of the left common carotid artery with photochemically-induced (laser irradiation 632 nm, 200 mW/cm2, 15 min; intravenous Photofrin II, 12.5 mg/kg) embolism from the right common carotid artery in 12 rats. Ninety-eight cerebral infarcts occurred in 9 experimental animals, with eight infarcts being large (> 2.5 mm). The mean proportions of infarcts and emboli on the left were 25% and 19%, respectively. These results suggest that contralateral carotid artery stenosis, like occlusion, will influence the site and size of embolic infarcts and that the "symptomatic" carotid artery cannot always be determined by the side of the cerebral infarct.

Central nervous system disease in patients with systemic lupus erythematosus.

Central nervous system (CNS) dysfunction in patients with systemic lupus erythematosus (SLE) is highly variable, although it is often described under a single heading of "neuropsychiatric" or "CNS" SLE. To clarify these CNS abnormalities, we studied 91 lupus patients, 63 of whom had CNS symptoms or signs, over 599 patient years. By placing patients in relatively homogeneous clinical groups (stroke, seizure, suicide attempt, hallucination, confusion, decreased alertness) we detected significant (but variable among groups) correlations with other manifestations of SLE, suggesting separate mechanisms for each CNS disorder. These correlations were lost if all "CNS-SLE" was considered as a single group. Patients with decreased alertness often had undetected systemic infections and had a high death rate from infection, rather than from CNS-SLE. The understanding of the pathogenesis and potential treatment of CNS disorders in lupus will depend on classifying the patients into homogeneous groups.