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.

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.

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.

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.

Dural arteriovenous fistulas involving the superior sagittal sinus: acute presentation with intracranial hemorrhage.

BACKGROUND: Intracranial dural arteriovenous fistulas (DAVF) usually drain directly into large dural venous sinuses. Intracranial hemorrhage is therefore unusual with these lesions. Certain subgroups of DAVF may drain into cortical veins causing engorgement, venous hypertension, and hemorrhage. The region of the superior sagittal sinus (SSS), while an unusual location for DAVF, is one in which drainage typically occurs directly into cortical veins. METHODS: We report on three patients with dural arteriovenous malformations of the superior sagittal sinus, all of whom presented with intracranial hemorrhage. Intraparenchymal hemorrhage in two of the cases was surrounded by excessive edema, suggesting the presence of underlying venous hypertension. RESULTS: Interventional treatment of all three of the lesions was accomplished at the time of diagnostic angiography. CONCLUSIONS: SSS DAVF is an uncommon lesion whose presentation is usually with intracranial hemorrhage. Large amounts of edema surrounding an acute hemorrhage may suggest the diagnosis, which usually requires confirmation with angiography. Treatment of SSS DAVF can often be accomplished at the time of diagnostic angiography by embolization using interventional neuroradiologic techniques. When endovascular obliteration of the fistula is not feasible or is incomplete, surgical resection of the DAVF site may be achieved without difficulty.

Clinical evaluation and management of aneurysmal subarachnoid hemorrhage.

As neuroradiologic techniques become more critical to the care of patients suffering from aneurysmal subarachnoid hemorrhage, a thorough understanding of the natural history and medical management of this disorder by neuroradiologists is required to insure appropriate diagnosis and therapy. This article addresses the medical and perioperative management of subarachnoid hemorrhage, with an emphasis on features relevant to neuroradiologic diagnosis and treatment.

Cigarette smoking-induced increase in the risk of symptomatic vasospasm after aneurysmal subarachnoid hemorrhage.

Vasospasm following aneurysmal subarachnoid hemorrhage (SAH) is correlated with the thickness of blood within the basal cisterns on the initial computerized tomography (CT) scan. To identify additional risk factors for symptomatic vasospasm, the authors performed a prospective analysis of 75 consecutively admitted patients who were treated for aneurysmal SAH. Five patients who died before treatment or were comatose postoperatively were excluded from the study. Of the remaining 70 patients, demographic (age, gender, and race) and clinical (hypertension, diabetes, coronary artery disease, smoking, alcohol abuse, illicit drug use, sentinel headache, Fisher grade, Hunt and Hess grade, World Federation of Neurological Surgeons grade, and ruptured aneurysm location) parameters were evaluated using multivariate logistic regression to determine factors independently associated with cerebral vasospasm. All patients were treated with hypervolemic therapy and administration of nimodipine as prophylaxis for vasospasm. Cerebral vasospasm was suspected in cases that exhibited (by elevation of transcranial Doppler velocities) neurological deterioration 3 to 14 days after SAH with no other explanation and was confirmed either by clinical improvement in response to induced hypertension or by cerebral angiography. The mean age of the patients was 50 years. Sixty-three percent of the patients were women, 74% were white, 64% were cigarette smokers, and 46% were hypertensive. Ten percent of the patients suffered from alcohol abuse, 19% from sentinel bleed, and 49% had a Fisher Grade 3 SAH. Twenty-nine percent of the patients developed symptomatic vasospasm. Multivariate analysis demonstrated that cigarette smoking (p = 0.033; odds ratio 4.7, 95% confidence interval [CI] 2.4-8.9) and Fisher Grade 3, that is, thick subarachnoid clot (p = 0.008; odds ratio 5.1, 95% CI 2-13.1), were independent predictors of symptomatic vasospasm. The authors make the novel observation that cigarette smoking increases the risk of symptomatic vasospasm after aneurysmal SAH, independent of Fisher grade.

Carotid and vertebral artery dissections.

Dissections of the carotid and vertebral arteries are a common cause of stroke in young adults. The diagnosis may be missed because the typical signs and symptoms are often delayed in onset, or easily confused with other more commonly encountered entities. Dissections of the carotid and vertebral arteries may occur spontaneously or may accompany mild to severe trauma. They present with a variety of findings including headache, neck and face pain, Horner's syndrome, or stroke.

Direct muscle stimulation in acute quadriplegic myopathy.

We have previously found that muscle is electrically inexcitable in severe acute quadriplegic myopathy (AQM). In contrast, muscle retains normal electrical excitability in peripheral neuropathy. To study the relationship between muscle electrical excitability and all types of flaccid weakness occurring in the intensive care unit, we identified 14 critically ill, weak patients and measured the amplitude of compound muscle action potentials (CMAPs) obtained with direct muscle stimulation (dmCMAP) and with nerve stimulation (neCMAP). In 11 of 14 patients dmCMAP amplitudes were reduced and the ratio of the neCMAP amplitude to the dmCMAP amplitude (nerve/muscle ratio) was indicative of loss of muscle electrical excitability. In 2 other patients, the nerve/muscle ratio indicated neuropathy. Direct muscle stimulation may allow differentiation of AQM from neuropathy even in comatose or encephalopathic critically ill patients. AQM may be more common than has previously been appreciated.