William D. Freeman

Treatment of warfarin-associated intracerebral hemorrhage: literature review and expert opinion.

Wider use of oral anticoagulants has led to an increasing frequency of warfarin-related intracerebral hemorrhage (ICH). The high early mortality of approximately 50% has remained stable in recent decades. In contrast to spontaneous ICH, the duration of bleeding is 12 to 24 hours in many patients, offering a longer opportunity for intervention. Treatment varies widely, and optimal therapy has yet to be defined. An OVID search was conducted from January 1996 to January 2006, combining the terms warfarin or anticoagulation with intracranial hemorrhage or intracerebral hemorrhage. Seven experts on clinical stroke, neurologic intensive care, and hematology were provided with the available information and were asked to independently address 3 clinical scenarios about acute reversal and resumption of anticoagulation in the setting of warfarin-associated ICH. No randomized trials assessing clinical outcomes were found on management of warfarin-associated ICH. All experts agreed that anticoagulation should be urgently reversed, but how to achieve it varied from use of prothrombin complex concentrates only (3 experts) to recombinant factor VIIa only (2 experts) to recombinant factor VIIa along with fresh frozen plasma (1 expert) and prothrombin complex concentrates or fresh frozen plasma (1 expert). All experts favored resumption of warfarin therapy within 3 to 10 days of ICH in stable patients in whom subsequent anticoagulation is mandatory. No general agreement occurred regarding subsequent anticoagulation of patients with atrial fibrillation who survived warfarin-associated ICH. For warfarin-associated ICH, discontinuing warfarin therapy with administration of vitamin K does not reverse the hemostatic defect for many hours and is inadequate. Reasonable management based on expert opinion includes a wide range of additional measures to reverse anticoagulation in the absence of solid evidence.

Recombinant Factor VIIa for Rapid Reversal of Warfarin Anticoagulation in Acute Intracranial Hemorrhage

OBJECTIVE To assess the effects of recombinant factor VIIa (rFVIIa) on hemorrhage volume and functional outcomes in warfarin-related acute intracranial hemorrhage (ICH), which has a 30-day mortality of more than 50%. PATIENTS AND METHODS We reviewed the clinical, laboratory, and radiographic features of a consecutive series of 7 patients (median age, 87 years; 5 women) with symptomatic, nontraumatic warfarin-related acute ICH treated with intravenous rFVIIa at St. Lukes Hospital in Jacksonville, Fla, between December 2002 and September 2003. Prestroke baseline functional status was assessed with the modified Rankin Scale. Outcome was assessed with the Glasgow Outcome Scale. RESULTS The international normalized ratio decreased from a mean of 2.7 before administration of rFVIIa to 1.08 after administration of rFVIIa. The median prestroke score on the modified Rankin Scale was zero. The median presenting score on the Glasgow Coma Scale was 14 (range, 4-15). The mean time from onset to treatment was 6.2 hours. The mean initial dose of rFVIIa was 62.1 microg/kg. One patient underwent placement of an external ventricular drain, and another underwent craniotomy and hematoma evacuation. Five of the 7 patients survived and were dismissed from the hospital with severe disability (Glasgow Outcome Scale, 3); 2 patients died during hospitalization. CONCLUSIONS Intravenous bolus administration of rFVIIa can rapidly lower the international normalized ratio and appears to be safe for patients with warfarin-related ICH. Prospective controlled studies are needed to determine whether rFVIIa can prevent hematoma expansion and improve neurologic outcomes in patients with warfarin-related ICH.

Validation of frontal near-infrared spectroscopy as noninvasive bedside monitoring for regional cerebral blood flow in brain-injured patients

OBJECT Near-infrared spectroscopy (NIRS) offers noninvasive bedside measurement of direct regional cerebral arteriovenous (mixed) brain oxygenation. To validate the accuracy of this monitoring technique, the authors analyzed the statistical correlation of NIRS and CT perfusion with respect to regional cerebral blood flow (CBF) measurements. METHODS The authors retrospectively reviewed all cases in which NIRS measurements were obtained at a single, academic neurointensive care unit from February 2008 to June 2011 in which CT perfusion was performed at the same time as NIRS data was collected. Regions of interest were obtained 2.5 cm below the NIRS bifrontal scalp probe on CT perfusion with an average volume between 2 and 4 ml, with mean CBF values used for purposes of analysis. Linear regression analysis was performed for NIRS and CBF values. RESULTS The study included 8 patients (2 men, 6 women), 6 of whom suffered subarachnoid hemorrhage, 1 ischemic stroke, and 1 intracerebral hemorrhage and brain edema. Mean CBF measured by CT perfusion was 61 ml/100 g/min for the left side and 60 ml/100 g/min for the right side, while mean NIRS values were 75 on the right and 74 on the left. Linear regression analysis demonstrated a statistically significant probability value (p<0.0001) comparing NIRS frontal oximetry and CT perfusion-obtained CBF values. CONCLUSIONS The authors demonstrated a linear correlation for frontal NIRS cerebral oxygenation measurements compared with regional CBF on CT perfusion imaging. Thus, frontal NIRS cerebral oxygenation measurement may serve as a useful, noninvasive, bedside intensive care unit monitoring tool to assess brain oxygenation in a direct manner.

Therapeutic Hypothermia for Neuroprotection: History, Mechanisms, Risks, and Clinical Applications

The earliest recorded application of therapeutic hypothermia in medicine spans about 5000 years; however, its use has become widespread since 2002, following the demonstration of both safety and efficacy of regimens requiring only a mild (32°C-35°C) degree of cooling after cardiac arrest. We review the mechanisms by which hypothermia confers neuroprotection as well as its physiological effects by body system and its associated risks. With regard to clinical applications, we present evidence on the role of hypothermia in traumatic brain injury, intracranial pressure elevation, stroke, subarachnoid hemorrhage, spinal cord injury, hepatic encephalopathy, and neonatal peripartum encephalopathy. Based on the current knowledge and areas undergoing or in need of further exploration, we feel that therapeutic hypothermia holds promise in the treatment of patients with various forms of neurologic injury; however, additional quality studies are needed before its true role is fully known.

Leflunomide-Associated Progressive Multifocal Leukoencephalopathy

A 68-YEAR-OLD MAN had a subacute progressive decline in speech and rightsided weakness after his rheumatoidarthritis regimenwas changedfromazathioprinetoleflunomide. His primary care physician diagnosedastroke.Threemonths later, in our neurology clinic, the patient soughttreatmentfortranscorticalmotor aphasia and mild right hemiparesis, and magnetic resonance imaging (MRI) was performed (Figure 1). Results showed bilateral subcortical, asymmetrical hyperintensities, without notable mass effect, in the frontal lobes, greater on the left than the right, and in the left parietal lobe. Gadolinium images (not shown) revealed no abnormal enhancement. Cerebrospinal fluid analysis revealed 3 white blood cells, no red blood cells, a glucose level within the reference range, an elevated protein level (48 mg/dL), and no organisms. Results of a polymerase chain reaction analysis for John Cunningham (JC) virus were negative. Analysis of a brain biopsy specimen confirmed the presence of progressive multifocal leukoencephalopathy (PML) (Figure 2). The patient’s condition improved with discontinuation of leflunomide and treatment with cytosine arabinoside (2 mg/kg intravenously each day for 5 days). The patient subsequently developed focal motor seizures with secondarily generalized seizures from the left frontal hemisphere (seen on an electroencephalogram that corresponded to the site of his PML and the biopsy), which required treatment with both oral phenytoin sodium and levetiracetam for adequateprophylaxis.Fourmonthsafter a brain biopsy was performed, the patient was hospitalized for focal motor status epilepticus, worsened aphasia, and right hemiparesis requiring adjustments in his anticonvulsant medications. Results of an MRI were essentially unchanged, showing persistent left frontal white matter abnormalities and postbiopsy changes withnogadoliniumenhancement. Six months after the biopsy, he had no further seizures, and examination showed improved speech from global aphasia to transcortical motor aphasia, residual right lower facial weakness, improved right arm and leg weakness, andspastichemipareticgait requiring a cane. One year later, the patient’s strengthhad improvednearly to normal, but he still had a mild spastic hemiparesis and gait. Unfortunately, because of his severe aphasia and gait instability, he was unable to return to his previous independent level of functioning. A follow-up MRI at 1 year appeared to have identical results to those of the MRI from the 6-month follow-up visit.

The Workforce Task Force Report: clinical implications for neurology.

The American Academy of Neurology Workforce Task Force (WFTF) report predicts a future shortfall of neurologists in the United States. The WFTF data also suggest that for most states, the current demand for neurologist services already exceeds the supply, and by 2025 the demand for neurologists will be even higher. This future demand is fueled by the aging of the US population, the higher health care utilization rates of neurologic services, and by a greater number of patients gaining access to the health care system due to the Patient Protection and Affordable Care Act. Uncertainties in health care delivery and patient access exist due to looming concerns about further Medicare reimbursement cuts. This uncertainty is set against a backdrop of Congressional volatility on a variety of issues, including the repeal of the sustainable growth rate for physician reimbursement. The impact of these US health care changes on the neurology workforce, future increasing demands, reimbursement, and alternative health care delivery models including accountable care organizations, nonphysician providers such as nurse practitioners and physician assistants, and teleneurology for both stroke and general neurology are discussed. The data lead to the conclusion that neurologists will need to play an even larger role in caring for the aging US population by 2025. We propose solutions to increase the availability of neurologic services in the future and provide other ways of meeting the anticipated increased demand for neurologic care.

Outcomes of Intravenous Tissue Plasminogen Activator for Acute Ischemic Stroke in Patients Aged 90 Years or Older

Although age is a major risk factor for stroke, physicians are often reluctant to use thrombolytic agents in those who are very old. No published study provides detailed information on the use of intravenous tissue plasminogen activator (tPA) in patients aged 90 years or older. We retrospectively reviewed the use of intravenous tPA for patients 90 years or older who were admitted with acute ischemic stroke to the hospital at 4 academic centers from March 1, 1999, to March 1, 2008. We reviewed the clinical features of the patients at presentation, complications, and outcomes. Twenty-two patients (11 women; median age, 93 years; range, 90-101 years) were identified who had received intravenous tPA for symptoms of acute ischemic stroke (average time to treatment, 143 minutes; range, 90-180 minutes; no tPA protocol violations; mean National Institutes of Health Stroke Scale score, 15; range, 5-28). Nearly all patients were highly functional at baseline (median modified Rankin Scale [mRS] score, 1; median Barthel Index score, 95), and all but one performed the activities of daily living with little or no assistance before stroke. By the 30-day follow-up, 2 patients (9%) had a favorable outcome (mRS score, 0-2) and 2 (9%) had moderate disability (mRS score, 3). Most patients died (n=10) or experienced severe disability, defined as an mRS score of 4 or 5 (n=5). Asymptomatic intracerebral hemorrhage occurred in 3 patients (14%) and was nonfatal. Most patients aged 90 years or older who received intravenous tPA for acute ischemic stroke had poor 30-day functional outcomes or died. Intravenous tPA treatment in this age group does not improve the outcome of ischemic stroke.

Safety of Recombinant Activated Factor VII in Patients With Warfarin-Associated Hemorrhages of the Central Nervous System

Background and Purpose— Recombinant Factor VIIa decreases hematoma growth after spontaneous intracerebral hemorrhage (ICH) and rapidly decreases international normalized ratios in patients on warfarin but is also associated with an increased risk for thromboembolic complications. In this study, we assessed the risk of thromboembolic events in patients receiving recombinant Factor VIIa after ICH associated with warfarin treatment. Methods— We reviewed the medical charts, laboratory data, and radiological findings of consecutive patients with anticoagulation-related hemorrhages of the central nervous system who received recombinant Factor VIIa at Mayo Clinic Rochester and Mayo Clinic Florida between 2002 and 2009. The primary end point was the frequency of new thromboembolic events, including myocardial infarction, deep vein thrombosis, ischemic stroke, and pulmonary embolism. Results— We identified 101 patients; 54% had ICH and 30% subdural hematomas. The most common indications for anticoagulation were atrial fibrillation, deep vein thrombosis, and prosthetic valve. Thirteen patients (12.8%) had new thromboembolic events (10 deep vein thromboses and 3 ischemic strokes) within 90 days after recombinant Factor VIIa administration. Eight of these adverse events occurred within 2 weeks of treatment. In patients with ICH, the rate of thromboembolic complications was 5% and all events were venous. Conclusion— The risk of thromboembolic events in patients who received recombinant Factor VIIa for anticoagulation-associated ICH was not higher than that seen in patients treated for spontaneous ICH in the Factor Seven for Acute Hemorrhagic Stroke (FAST) trial. Spontaneous deep vein thrombosis was the most common complication in our series.

Brain Injury After Cardiopulmonary Arrest and Its Assessment With Diffusion-Weighted Magnetic Resonance Imaging

OBJECTIVE To characterize the frequency and pattern of diffusion-weighted imaging (DWI) abnormalities detected as part of brain magnetic resonance imaging (MRI) and their association with short-term neurologic outcomes in patients successfully resuscitated after cardiopulmonary arrest (CPA). PATIENTS AND METHODS We retrospectively analyzed a case series of patients who experienced CPA between May 1, 2000, and April 29, 2004, at St Lukes Hospital in Jacksonville, Fla. Eligible patients required treatment by the Code Blue team and had 1 DWI study before discharge or death. Two neuroradiologists jointly classified DWI abnormalities by anatomic location. Outcome was measured by Cerebral Performance Category score. RESULTS Resuscitation was performed 628 times during the 48-month study period. Of 514 CPA survivors, 18 (3.5%) had MRI studies. The median age was 62 years (interquartile range [IQR], 49-73), and 10 were men. Median code duration was 16 minutes (IQR, 11-19 minutes), and median code-to-scan time was 72 hours (IQR, 28-229 hours). A DWI abnormality was noted in 9 (50%) of 18 patients. Cortical areas (global and regional) were the most common sites of restricted diffusion. Diffusion-weighted imaging abnormalities were present in 7 (70%) of 10 patients with a poor neurologic outcome at discharge. CONCLUSION Magnetic resonance imaging is performed rarely after survival of CPA. In this study with limited sample size, a greater proportion of patients with normal DWI findings had a good neurologic outcome at the time of hospital discharge vs those with abnormal findings. Prospective studies of early and serial MRI (with DWI) are needed to confirm this association and to clarify the prognostic usefulness of such studies.

Invited Article: Is it time for neurohospitalists?

Background: Explosive growth of hospital-based medicine specialists, termed hospitalists, has occurred in the past decade. This was fueled by pressures within the American health care system for timely, cost-effective, and high-quality care and by the growing chasm between inpatient and outpatient care. In this article, we sought to answer five questions: 1) What is a neurohospitalist? 2) How many neurohospitalists practice in the United States? 3) What are potential advantages of neurohospitalists? 4) What are the challenges of implementing a neurohospitalist practice? 5) What effect does a neurohospitalist have on clinical outcomes? Methods: We queried biomedical databases (e.g., PubMed) by using the search terms “hospitalist,” “neurohospitalist,” and “neurology hospitalist.” We also searched the Society of Hospital Medicine and the American Academy of Neurology Dendrite classified advertisement Web sites for hospitalist and neurology hospitalist growth by using the same search terms. Results: We defined neurology hospitalists (neurohospitalists) as neurologists who devote at least one-quarter of their time managing inpatients with neurologic disease. Although the number of hospitalists has grown considerably over the past decade, limited data on neurohospitalists exist. Advertisements for neurohospitalist positions have increased from 2003 through 2007, but accurate assessment of growth is limited by the lack of a central organizational affiliation and unifying terminology. Conclusion: Health care pressures spawned the growth of medicine and pediatric hospitalists, who provide efficient, cost-effective care by reducing the length of hospitalization. Because neurologists experience the same pressures, we expect neurohospitalists to increase in number, especially within areas that have sufficient inpatient volume and resources.