Cervene (Nalmefene) in acute ischemic stroke : final results of a phase III efficacy study. The Cervene Stroke Study Investigators.

BACKGROUND AND PURPOSE: The goals of the present study were to assess the efficacy and safety of nalmefene (Cervene) in patients with acute (< or =6 hours) ischemic stroke and to investigate the safety of combined recombinant tissue plasminogen activator and nalmefene in a separate subset of patients. Nalmefene, an opioid antagonist with relative kappa receptor selectivity, has shown neuroprotective effects in multiple experimental central nervous system injury and ischemic models. Results from an earlier phase II study in patients with acute ischemic stroke suggested that nalmefene was safe and tolerable and may be effective for patients <70 years old. METHODS: This investigation was a phase III, placebo-controlled, double-blind, randomized study of a 24-hour infusion of nalmefene. Patients with acute ischemic stroke who had an onset of symptoms within 6 hours and a baseline score of > or =4 on the NIH Stroke Scale were randomized to receive either 60 mg nalmefene administered as a 10-mg bolus over 15 minutes and then a 50-mg infusion over 23.75 hours or placebo. The primary efficacy outcome was the proportion of patients achieving a score of > or =60 on the Barthel Index and a rating of "moderate disability" or better on the Glasgow Outcome Scale at 12 weeks. Assessments were performed at baseline (predose), hours 12 and 24, days 2 and 7, and week 12. RESULTS: A total of 368 patients were randomized at 42 centers, including 32 patients treated with recombinant tissue plasminogen activator and study drug. Nalmefene was well tolerated. Overall, there was no significant difference in 3-month functional outcome for nalmefene treatment compared with placebo on any of the planned analyses. A prospective secondary analysis also failed to find a treatment effect in patients <70 years old. CONCLUSIONS: Although nalmefene appears to be safe and well tolerated, this study failed to find any treatment benefit in stroke patients treated within 6 hours.

Scleromyxedema: successful treatment of cutaneous and neurologic symptoms.

Scleromyxedema is a rare systemic disorder characterized by cutaneous sclerosis and papulosis, accompanied by deposition of mucin in the skin and other organs. We describe a case of scleromyxedema in a 62-year-old man. The cutaneous symptoms of the disorder were preceded by episodes of acute central nervous system dysfunction that included mental confusion, hemiparesis, tremor, and migraine. As the cutaneous symptoms progressed, the patient experienced persistent confusion and difficulty concentrating. Therapy with melphalan and plasmapheresis led to complete resolution of the cutaneous symptoms as well as near-resolution of the neurologic symptoms. This is the first report to describe the successful treatment of the cutaneous symptoms of scleromyxedema accompanied by reversal of chronic neurologic dysfunction.

Effect of hypervolemic therapy on cerebral blood flow after subarachnoid hemorrhage : a randomized controlled trial.

BACKGROUND AND PURPOSE: Cerebral blood flow (CBF) is reduced after subarachnoid hemorrhage (SAH), and symptomatic vasospasm is a major cause of morbidity and mortality. Volume expansion has been reported to increase CBF after SAH, but CBF values in hypervolemic (HV) and normovolemic (NV) subjects have never been directly compared. METHODS: On the day after aneurysm clipping, we randomly assigned 82 patients to receive HV or NV fluid management until SAH day 14. In addition to 80 mL/h of isotonic crystalloid, 250 mL of 5% albumin solution was given every 2 hours to maintain normal (NV group, n=41) or elevated (HV group, n=41) cardiac filling pressures. CBF ((133)xenon clearance) was measured before randomization and approximately every 3 days thereafter (mean, 4.5 studies per patient). RESULTS: HV patients received significantly more fluid and had higher pulmonary artery diastolic and central venous pressures than NV patients, but there was no effect on net fluid balance or on blood volume measured on the third postoperative day. There was no difference in mean global CBF during the treatment period between HV and NV patients (P=0.55, random-effects model). Symptomatic vasospasm occurred in 20% of patients in each group and was associated with reduced minimum regional CBF values (P=0.04). However, there was also no difference in minimum regional CBF between the 2 treatment groups. CONCLUSIONS: HV therapy resulted in increased cardiac filling pressures and fluid intake but did not increase CBF or blood volume compared with NV therapy. Although careful fluid management to avoid hypovolemia may reduce the risk of delayed cerebral ischemia after SAH, prophylactic HV therapy is unlikely to confer an additional benefit.

Statins and cerebrovascular disease: plaque attack to prevent brain attack.

Stroke is the third leading cause of death in the USA and in the developed world. The beneficial role of cholesterol reduction in decreasing stroke has been uncertain. However, recent data indicate that statin treatment in patients with a history of myocardial infarction not only reduces the risk of a second myocardial infarction, coronary heart disease, revascularization procedures and death, but also significantly reduces the risk of stroke. However, the mechanism(s) by which statins reduce stroke remain uncertain. Thus, the therapeutic armamentarium for the reduction of stroke in secondary prevention now includes cholesterol reduction with statins.

Noninvasive magnetic resonance imaging evaluation of cerebral blood flow with acetazolamide challenge in patients with cerebrovascular stenosis.

To evaluate the utility of using magnetic resonance imaging (MRI) of cerebral blood flow (CBF) in conjunction with pharmacologic flow augmentation, the authors imaged 14 patients with ischemic symptoms referable to large artery cerebrovascular stenosis of the anterior circulation. CBF was measured by using continuous arterial spin labeling (CASL) both at rest and 10 minutes after 1 g intravenous acetazolamide on a commercial 1.5 Tesla scanner. Quantitative CBF images were calculated along with augmentation images showing the effects of acetazolamide. Interpretable studies were obtained from all patients. Based on the image data as well as a region of interest analysis of CBF changes in middle cerebral artery distributions, varying patterns of augmentation were observed that suggested differing mechanisms of ischemic symptomatology. The ability to obtain this information in conjunction with a structural MRI examination extends the diagnostic potential for MRI in cerebrovascular disease and allows the value of augmentation testing in clinical management to be assessed more widely. J. Magn. Reson. Imaging 1999;10:870-875.

Antiplatelet therapy in the prevention of ischemic vascular events: literature review and evidence-based guidelines for drug selection.

BACKGROUND: New antiplatelet drugs are being developed and many clinical trials evaluating the benefits of antiplatelet drugs for the secondary prevention of ischemic events in patients with atherosclerotic vascular disease have been performed. HYPOTHESIS: An updated systematic review and evidence-based guidelines for the appropriate selection of antiplatelet drugs may be beneficial to physicians and healthcare organizations attempting to create or update current clinical practice guidelines or clinical pathways aimed at caring for these patients. METHODS: (1) A systematic review of the recent literature on the relative efficacy and safety of aspirin, ticlopidine, and clopidogrel was undertaken; (2) an evidence-based, expert panel approach using a modified Delphi technique to create explicit guidelines for prescribing antiplatelet therapy was instituted; and (3) the recommendations of an expert panel were summarized. RESULTS: Consensus guidelines were developed for the utilization of aspirin, ticlopidine, or clopidogrel for the prevention of ischemic events in patients with manifestations of atherosclerotic vascular disease (prior myocardial infarction, prior ischemic stroke, or established peripheral arterial disease) who are at increased risk for recurrent ischemic events. Based on efficacy and safety, clopidogrel was recommended as the drug of choice for patients with established peripheral arterial disease; aspirin or clopidogrel should be considered in patients with prior myocardial infarction (with clopidogrel favored for patients who have had a recurrent event while on aspirin or in whom aspirin is contraindicated); aspirin or clopidogrel should be considered as first-line treatment in patients with prior ischemic (nonhemorrhagic) stroke--however, clopidogrel is the favored drug in patients in whom other antiplatelet drugs are either contraindicated or who have had recurrent events while on therapy. CONCLUSIONS: Myocardial infarction, ischemic stroke, and peripheral arterial disease are all clinical manifestations of the same underlying disease process (atherosclerosis), with thrombus formation on the disrupted atherosclerotic plaque (atherothrombosis) being a common precipitating factor of ischemic events in patients suffering from these disorders. An evidence-based approach was used to develop a practice guideline, based on available published evidence, for the appropriate utilization of antiplatelet agents (aspirin, ticlopidine, or clopidogrel). These guidelines may be of use to multidisciplinary teams wishing to create or update clinical guidelines or clinical pathways which address the care of patients with atherosclerotic vascular disease. New antiplatelet agents such as clopidogrel may be more effective and associated with lower risk of selected adverse effects (such as gastrointestinal distress, gastrointestinal hemorrhage, and neutropenia) than those previously used to prevent thrombus formation in the setting of atherosclerotic arterial disease. Combination antiplatelet therapy is being evaluated as an option for those patients who experience recurrent events on a single antiplatelet agent.

Reliability and validity of estimating the NIH stroke scale score from medical records.

BACKGROUND AND PURPOSE: The aim of our study was to determine whether the National Institutes of Health Stroke Scale (NIHSS) can be estimated retrospectively from medical records. The NIHSS is a quantitative measure of stroke-related neurological deficit with established reliability and validity for use in prospective clinical research. Recently, retrospective observational studies have estimated NIHSS scores from medical records for quantitative outcome analysis. The reliability and validity of estimation based on chart review has not been determined. METHODS: Thirty-nine patients were selected because their NIHSS scores were formally measured at admission and discharge. Handwritten notes from medical records were abstracted and NIHSS scores were estimated by 6 raters who were blinded to the actual scores. Estimated scores were compared among raters and with the actual measured scores. RESULTS: Interrater reliability was excellent, with an intraclass correlation coefficient of 0.82. Scores were well calibrated among the 6 raters. Estimated NIHSS scores closely approximated the actual scores, with a probability of 0.86 of correctly ranking a set of patients according to 5-point interval categories (as determined by the area under the receiver-operator characteristic curve). Patients with excellent outcomes (NIHSS score of

Endovascular thrombolysis for symptomatic cerebral venous thrombosis.

OBJECT: The authors sought to treat potentially catastrophic intracranial dural and deep cerebral venous thrombosis by using a multimodality endovascular approach. METHODS: Six patients aged 14 to 75 years presented with progressive symptoms of thrombotic intracranial venous occlusion. Five presented with neurological deficits, and one patient had a progressive and intractable headache. All six had known risk factors for venous thrombosis: inflammatory bowel disease (two patients), nephrotic syndrome (one), cancer (one), use of oral contraceptive pills (one), and puerperium (one). Four had combined dural and deep venous thrombosis, whereas clot formation was limited to the dural venous sinuses in two patients. All patients underwent diagnostic cerebral arteriograms followed by transvenous catheterization and selective sinus and deep venous microcatheterization. Urokinase was delivered at the proximal aspect of the thrombus in dosages of 200,000 to 1,000,000 IU. In two patients with thrombus refractory to pharmacological thrombolytic treatment, mechanical wire microsnare maceration of the thrombus resulted in sinus patency. Radiological studies obtained 24 hours after thrombolysis reconfirmed sinus/vein patency in all patients. All patients' symptoms and neurological deficits improved, and no procedural complications ensued. Follow-up periods ranged from 12 to 35 months, and all six patients remain free of any symptomatic venous reocclusion. Factors including patients' age, preexisting medical conditions, and duration of symptoms had no statistical bearing on the outcome. CONCLUSIONS: Patients with both dural and deep cerebral venous thrombosis often have a variable clinical course and an unpredictable neurological outcome. With recent improvements in interventional techniques, endovascular therapy is warranted in symptomatic patients early in the disease course, prior to morbid and potentially fatal neurological deterioration.

Prevention of a first stroke: a review of guidelines and a multidisciplinary consensus statement from the National Stroke Association.

OBJECTIVE: To establish, in a single resource, up-to-date recommendations for primary care physicians regarding prevention strategies for a first stroke. PARTICIPANTS: Members of the National Stroke Association's (NSA's) Stroke Prevention Advisory Board and Cedars-Sinai Health System Department of Health Services Research convened on April 9, 1998, in an open meeting. The conference attendees, selected to participate by the NSA, were recognized experts in neurology (9), cardiology (2), family practice (1), nursing (1), physician assistant practices (1), and health services research (2). EVIDENCE: A literature review was carried out by the Department of Health Services Research, Cedars-Sinai Health System, Los Angeles, Calif, using the MEDLINE database search for 1990 through April 1998 and updated in November 1998. English-language guidelines, statements, meta-analyses, and overviews on prevention of a first stroke were reviewed. CONSENSUS PROCESS: At the meeting, members of the advisory board identified 6 important stroke risk factors (hypertension, myocardial infarction [MI], atrial fibrillation, diabetes mellitus, blood lipids, asymptomatic carotid artery stenosis), and 4 lifestyle factors (cigarette smoking, alcohol use, physical activity, diet). CONCLUSIONS: Several interventions that modify well-documented and treatable cardiovascular and cerebrovascular risk factors can reduce the risk of a first stroke. Good evidence for direct stroke reduction exists for hypertension treatment; using warfarin for patients after MI who have atrial fibrillation, decreased left ventricular ejection fraction, or left ventricular thrombus; using 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors for patients after MI; using warfarin for patients with atrial fibrillation and specific risk factors; and performing carotid endarterectomy for patients with stenosis of at least 60%. Observational studies support the role of modifying lifestyle-related risk factors (eg, smoking, alcohol use, physical activity, diet) in stroke prevention. Measures to help patients improve adherence are an important component of a stroke prevention plan.

Cervene in acute ischemic stroke: results of a double-blind, placebo-controlled, dose-comparison study.

UNLABELLED: Cervene (nalmefene), an opioid antagonist with relative kappa receptor selectivity, has shown neuroprotective effects in multiple experimental central nervous system injury and ischemic models. The agent already has a well-established safety profile in various clinical indications. Results from an earlier pilot study in 44 acute stroke patients suggest that Cervene administered by 24-hour maintenance infusion was safe and tolerable. The primary and secondary objectives of the current study were to assess the dose-related safety and preliminary efficacy of Cervene in patients with acute ischemic stroke. METHODS: The present investigation was a Phase II, placebo-controlled, double-blind, randomized, dose-comparison, parallel-group study of a 24-hour administration of Cervene injection. Patients with acute ischemic stroke, onset of symptoms within 6 hours, and baseline score > or =4 on the National Institute of Health Stroke Scale (NIHSS) were randomized to 1 of 4 treatment groups: Cervene 6 mg, 20 mg, 60 mg or placebo. The primary efficacy outcome was the proportion of patients achieving a score of > or =60 on the Barthel Index and a rating of "moderate disability" or better on the Glasgow Outcome Scale at 12 weeks. RESULTS: A total of 312 patients were randomized at 28 centers. All doses of Cervene were well tolerated. Overall, there was no significant difference in 3-month functional outcome for any dose of Cervene treatment compared with placebo. However, a prospective secondary analysis showed that both male and female patients less than age 70 years may have had an improved 3-month outcome. CONCLUSIONS: The results of this study indicate that the competitive kappa receptor opiate antagonist Cervene can be given safely to acute stroke patients at doses up to 60 mg/24 hr. Although overall there was no significant difference in the 3-month outcome, Cervene treatment may be associated with improved outcomes for patients younger than age 70.

Disseminated intravascular coagulation and stroke associated with cervical cancer.

Stroke in patients with cancer is second only to metastasis as a cause of focal neurological deficit. Stroke in this setting is usually linked to mucinous tumors or hematologic malignancies. We describe 2 patients with cervical cancer who developed disseminated intravascular coagulation (DIC)-mediated cerebral infarctions. The protean manifestations of DIC in cancer patients with stroke are emphasized.

Acute stroke teams: results of a national survey. National Acute Stroke Team Group.

BACKGROUND AND PURPOSE: The sensitivity of the brain to brief periods of profound ischemia or prolonged periods of modest ischemia mandates an aggressive approach to acute stroke care. Past studies have shown that many stroke patients do not receive acute care in an urgent and timely fashion. The formation of acute stroke teams (AST) is one approach that can be used to accelerate the delivery of acute stroke care. METHODS: We conducted a survey of major stroke program directors and neurovascular experts throughout the United States. The survey focused on issues related to the presence of AST, their staffing, operational features, and utilization at the surveyed programs and hospitals. RESULTS: Surveys were returned from 45 of 60 centers. Ninety-one percent of the respondents indicated that they currently had an AST, with 66% formed between 1995 and 1997. Staffing of ASTs consisted of attending physicians (95%), nurses or study coordinators (73%), fellows (49%), and residents (46%). In almost all cases (98%), the AST was led by a neurologist or neurosurgeon, and 98% of the ASTs operated on a 24-hours-per-day, 7-days-per-week basis. The most common call frequency was 2 to 3 times per week (41%), followed by >5 calls per week (29%). In 59% of the cases, the teams cost

Dementia resulting from dural arteriovenous fistulas: the pathologic findings of venous hypertensive encephalopathy.

PURPOSE: Dural arteriovenous fistulas (DAVFs) are acquired arteriovenous shunts located within the dura. The highly variable natural history and symptomatology of DAVFs range from subjective bruit to intracranial hemorrhage and are related to the lesion's pattern of venous drainage and its effect on the drainage of adjacent brain. We examined the prevalence and features of DAVFs in patients with progressive dementia or encephalopathy. METHODS: The records and radiologic studies of 40 consecutive patients with DAVFs treated at our institution were reviewed. RESULTS: Five (12.5%) of 40 consecutive patients with DAVFs had encephalopathy or dementia. In each patient, high flow through the arteriovenous shunt combined with venous outflow obstruction caused impairment of cerebral venous drainage. Hemodynamically, the result was widespread venous hypertension causing diffuse ischemia and progressive dysfunction of brain parenchyma. Results of CT or MR imaging revealed abnormalities in each patient, reflecting the impaired parenchymal venous drainage. Pathologic findings in one patient confirmed the mechanism of cerebral dysfunction as venous hypertension. The hemodynamic mechanism and resulting abnormality appeared identical to that seen in progressive chronic myelopathy resulting from a spinal DAVF (Foix-Alajouanine syndrome). Remission of cognitive symptoms occurred in each patient after embolization. CONCLUSION: Venous hypertensive encephalopathy resulting from a DAVF should be considered a potentially reversible cause of vascular dementia in patients with progressive cognitive deficits.

Treatment of refractory status epilepticus with propofol: clinical and pharmacokinetic findings.

PURPOSE: We compared propofol with high-dose barbiturates in the treatment of refractory status epilepticus (RSE) and propose a protocol for the administration of propofol in RSE in adults, correlating propofol's effect with plasma levels. METHODS: Sixteen patients with RSE were included; 8 were treated primarily with high-dose barbiturates and 8 were treated primarily with propofol. RESULTS: Both groups of patients had multiple medical problems and a subsequent high mortality. A smaller but not statistically significant fraction of patients had their seizures controlled with propofol (63%) than with high-dose barbiturate therapy (82%). The time from initiation of high-dose barbiturate therapy to attainment of control of RSE was longer (123 min) than the time to attainment of seizure control in the group receiving propofol (2.6 min, p = 0.002). Plasma concentrations of propofol associated with control of SE were 14 microM +/- 4 (2.5 microg/ml). Recurrent seizures were common when propofol infusions were suddenly discontinued but not when the infusions were gradually tapered. CONCLUSIONS: If used appropriately, propofol infusions can effectively and quickly terminate many but not all episodes of RSE. Propofol is a promising agent for use in treating RSE, but more studies are required to determine its true value in comparison with other agents.

Noninvasive MRI evaluation of cerebral blood flow in cerebrovascular disease.

Previous studies have demonstrated that cerebral blood flow (CBF) can be assessed noninvasively by MRI using magnetic labeling of arterial water as a diffusible flow tracer. The purpose of this study was to assess the quality of CBF images obtained from patients with cerebrovascular disease using this method, and to begin to evaluate the potential clinical role for this technique. We recruited 14 patients who presented with stroke, TIA, or severe carotid stenosis and were likely to have altered CBF based on clinical assessment. In many of these patients, CBF imaging disclosed both focal and hemispheric hypoperfusion, either in vascular territories or in watershed regions. In 11 patients with significant proximal arterial stenosis, hemispheric CBF abnormalities localized to the side of most significant stenosis for the anterior circulation distribution. In several patients watershed hypoperfusion was even more pronounced. Our results suggest that good-quality MR CBF images can be obtained reliably from patients with cerebrovascular disease. CBF imaging can be combined with standard structural imaging within a single MRI examination, and provides clinically meaningful information. The capability of measuring CBF easily provides a potentially useful tool for clinical assessment and further investigation of stroke pathophysiology.

Neurologic complications of transplantation.

Organ transplantation is a marvel of 20th century medicine. However, it is not without costs. Complications of transplant procedures, particularly neurologic complications, are a significant cause of morbidity and mortality. Neurologic complications in the transplant population may be divided into three groups: those occurring prior to transplantation, those in the perioperative period, and those arising weeks to months after the procedure. This review discusses neurologic complications associated with organ failure and transplantation in the perioperative period.