Kevin M. Barrett

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.

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.

Enhancing Recovery After Acute Ischemic Stroke with Donepezil as an Adjuvant Therapy to Standard Medical Care: Results of a Phase IIa Clinical Trial

BACKGROUND Our aim was to assess the safety, tolerability, and efficacy signal of early donepezil administration with regard to enhancing recovery in a diverse acute ischemic stroke population. METHODS This was a multicenter, single-arm, National Institute of Neurological Disorders and Stroke Recombinant Tissue Plasminogen Activator trial-controlled, modified 2-stage adaptive clinical trial set in 2 tertiary care hospitals in the United States. Adults with ischemic stroke treated within 24 hours after onset of symptoms were included. The intervention studied was donepezil 5 mg/day for 30 days, followed by an increase to 10 mg/day for 60 days. Our main outcome measures included treatment-related adverse events and side effects. The primary favorable outcome was a 90-day National Institutes of Health Stroke Scale (NIHSS) score ≤1. Neurologic, cognitive, functional, and psychological outcomes were assessed longitudinally. RESULTS Thirty-three adults (median age 66 years; 59% female; 39% received tissue plasminogen activator) initiated treatment with donepezil. There were no treatment-related serious adverse events. Three participants (9%) discontinued donepezil because of side effects and 3 participants (9%) required a reduction to 5 mg/day after titration to 10 mg/day. Fifteen participants (45%) had a favorable outcome (NIHSS score ≤1 at day 90), and the study met prespecified criteria for continuing to a randomized trial (P < .10). Statistically significant improvements from baseline were observed with several secondary cognitive measures, including the Trail Making Tests and Mini-Mental State Exam (P < .01 for both). CONCLUSIONS Adjuvant donepezil therapy initiated within 24 hours of acute ischemic stroke was safe and tolerated at 5 mg/day to 10 mg/day. The study met a priori criteria to move forward with a randomized clinical trial.

Emerging Subspecialties in Neurology: Neurohospitalist

Career opportunities available to graduates of neurology residency programs continue to grow. In contrast to traditional neurology subspecialty practice that is outpatient-centered and disease specific, neurology hospitalists or “neurohospitalists” specialize in the care of patients admitted to the hospital with a wide array of nervous system disorders. This subspecialty has emerged in parallel with mounting pressures on office-based neurologists to see larger outpatient volumes and the increasing complexity of inpatient neurologic care.1,2 Neurohospitalists are uniquely positioned to provide high-quality care at a time when many neurologists have limited or abandoned emergency coverage because of reduced reimbursement and increased litigation risk.3–5 The purpose of this article is to define what neurohospitalists do as professionals, discuss training and employment trends, and provide a future outlook on neurohospitalist practice. Neurohospitalists are best defined as “site-based” subspecialists dedicated to providing and improving inpatient neurologic care. In contrast to the traditional model of an office-based neurologist concurrently delivering inpatient care, the neurohospitalist is free of outpatient responsibility and provides on-site availability for urgent evaluations and administration of time-sensitive therapies.1 Neurohospitalists evaluate and treat a multitude of conditions including altered mental status, acute stroke, seizure disorders, …

Asymptomatic carotid stenosis: What we can learn from the next generation of randomized clinical trials

Stroke remains an exceedingly incident and prevalent public health burden across the globe, with an estimated 16 million new strokes per annum and prevalence over 60 million, and extracranial internal carotid artery atherosclerotic disease is an important risk factor for stroke. Randomized trials of surgical treatment were conducted (North American Symptomatic Carotid Endarterectomy Trial, European Carotid Surgery Trial) and demonstrated efficacy of carotid endarterectomy for secondary prevention of stroke in patients with cerebrovascular events (e.g. ipsilateral stroke, transient ischemic attack, and/or amaurosis fugax) attributable to a diseased artery with 50–99% stenosis. Therapeutic clarity, however, proved elusive with asymptomatic carotid artery disease. Asymptomatic Carotid Atherosclerosis Study (ACAS), Asymptomatic Carotid Surgery Trial, and Veterans Affairs Cooperative Study (VACS) suggested only modest benefit from surgical intervention for primary stroke prevention and the best medical therapy at the time of these trials is not comparable to modern medical therapy. ACT-1, Asymptomatic Carotid Surgery Trial-2, Stent-Protected Angioplasty in asymptomatic Carotid artery stenosis versus Endarterectomy Trial-2, European Carotid Surgery Trial-2, Carotid Revascularization Endarterectomy Versus Stenting Trial-2 are trials that are recent, ongoing, or in development that include diverse populations across Europe and North America, complementary trial designs, and a collaborative spirit that should provide clinicians with evidence that informs best clinical practice for asymptomatic carotid artery disease.

Carotid revascularization and medical management for asymptomatic carotid stenosis: Protocol of the CREST-2 clinical trials

Rationale Trials conducted decades ago demonstrated that carotid endarterectomy by skilled surgeons reduced stroke risk in asymptomatic patients. Developments in carotid stenting and improvements in medical prevention of stroke caused by atherothrombotic disease challenge understanding of the benefits of revascularization. Aim Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial (CREST-2) will test whether carotid endarterectomy or carotid stenting plus contemporary intensive medical therapy is superior to intensive medical therapy alone in the primary prevention of stroke in patients with high-grade asymptomatic carotid stenosis. Methods and design CREST-2 is two multicenter randomized trials of revascularization plus intensive medical therapy versus intensive medical therapy alone. One trial randomizes patients to carotid endarterectomy plus intensive medical therapy versus intensive medical therapy alone; the other, to carotid stenting plus intensive medical therapy versus intensive medical therapy alone. The risk factor targets of centrally directed intensive medical therapy are LDL cholesterol <70 mg/dl and systolic blood pressure <140 mmHg. Study outcomes The primary outcome is the composite of stroke and death within 44 days following randomization and stroke ipsilateral to the target vessel thereafter, up to four years. Change in cognition and differences in major and minor stroke are secondary outcomes. Sample size Enrollment of 1240 patients in each trial provides 85% power to detect a treatment difference if the event rate in the intensive medical therapy alone arm is 4.8% higher or 2.8% lower than an anticipated 3.6% rate in the revascularization arm. Discussion Management of asymptomatic carotid stenosis requires contemporary randomized trials to address whether carotid endarterectomy or carotid stenting plus intensive medical therapy is superior in preventing stroke beyond intensive medical therapy alone. Whether carotid endarterectomy or carotid stenting has favorable effects on cognition will also be tested. Trial registration United States National Institutes of Health Clinicaltrials.gov NCT02089217

Optical Coherence Tomography in a Case of Bilateral Neuroretinitis

A 42-year-old man had fever, chills, and bilateral visual loss. Visual acuity was markedly subnormal OU and ophthalmoscopy disclosed optic disc swelling with retinal thickening extending into the macula OU, findings consistent with neuroretinitis. Fluorescein angiography revealed optic disc leakage and submacular accumulation of dye OU without retinal vascular leakage. Optical coherence tomography (OCT) showed outer plexiform layer retinal edema and subfoveal detachments. There was evidence of active human immune deficiency virus and cytomegalovirus infections. Several weeks after multidrug therapy, sequential OCT scans documented resolution of the outer plexiform edema and submacular detachments in parallel with improved visual acuity. The OCT findings support the theory that submacular detachments in neuroretinitis result from diffusion of fluid from the optic disc to the outer plexiform layer and through the outer limiting membrane to the subretinal space.

Future Neurohospitalist Teleneurohospitalist

Despite the growing demand for emergency neurological evaluations and neurohospitalists, the supply of neurologists remains relatively fixed over time. Telemedicine is a unique tool that has the ability to put a medical specialist like a neurologist in 2 places in a relatively short period of time, expanding expertise in many rural and in some underserved urban facilities that would ordinarily be devoid of such expertise. Teleneurology is a branch of telemedicine that consults and practices through remote neurological evaluation. Telestroke is defined as remote stroke evaluation. The demand for timely neurological evaluation, especially acute stroke evaluation and treatment with intravenous recombinant tissue plasminogen activator (IV rtPA), continues to fuel the growth of neurohospitalists, telestroke, and teleneurology services. Remote, rural, or underserved urban emergency departments and hospitals which are unable to successfully recruit a neurologist or neurohospitalist to provide this service are uniquely suited to a teleneurology option. The number of private practices and academic centers providing telestroke services has grown significantly in the past decade with continued growth expected. We describe the benefits and drawbacks of teleneurology/telestroke, as well as other practical aspects for the teleneurohospitalist.

What to do With Wake-Up Stroke.

Wake-up stroke, defined as the situation where a patient awakens with stroke symptoms that were not present prior to falling asleep, represents roughly 1 in 5 acute ischemic strokes and remains a therapeutic dilemma. Patients with wake-up stroke were excluded from most ischemic stroke treatment trials and are often not eligible for acute reperfusion therapy in clinical practice, leading to poor outcomes. Studies of neuroimaging with standard noncontrast computed tomography (CT), magnetic resonance imaging (MRI), and multimodal perfusion-based CT and MRI suggest wake-up stroke may occur shortly before awakening and may assist in selecting patients for acute reperfusion therapies. Pilot studies of wake-up stroke treatment based on these neuroimaging features are promising but have limited generalizability. Ongoing randomized treatment trials using neuroimaging-based patient selection may identify a subset of patients with wake-up stroke that can safely benefit from acute reperfusion therapies.

Hypoxic-ischemic brain injury and prognosis after cardiac arrest.

Purpose of Review: Cardiac death is the leading cause of death in the United States, and patients who have out-of-hospital cardiac arrest have only a 1% to 10% survival rate, despite improvements in advanced life support. The neurologic sequelae of hypoxic-ischemic brain injury after cardiac arrest vary from subtle cognitive impairment to coma, persistent vegetative state, and brain death. Neurologists are commonly asked to prognosticate neurologic outcome after cardiac arrest. Recent Findings: In 2002, two randomized controlled trials demonstrated that therapeutic hypothermia (32°C to 34°C [89.6°F to 93.2°F]) increases the odds of improved neurologic outcome and reduces the risk of death compared with normothermia when applied for the initial 12 to 24 hours after ventricular fibrillation or tachycardia cardiac arrest. Considerable research continues into neurologic prognostication after hypoxic-ischemic brain injury, especially with the advent of therapeutic hypothermia and its effects on the clinical examination, neurophysiologic studies, and serum biomarkers of brain injury. Recent reports indicate that poor motor response 72 hours after cardiac arrest, absent cortical responses on median nerve somatosensory-evoked potentials, and elevated neuron-specific enolase may not necessarily indicate poor prognosis in patients treated with therapeutic hypothermia compared with historical populations not treated with hypothermia, perhaps because of sedation and neuromuscular blockade. Summary: Neurologic prognostication after cardiac arrest remains challenging because of the sedation and neuromuscular blocking agents given to patients who undergo therapeutic hypothermia. A multimodal algorithmic approach (clinical, electrophysiologic, and possibly serum biomarker testing) is suggested for cardiac arrest patients treated with hypothermia, but further research is needed to determine more accurate prognostic predictors.