Scott Silverman

Cerebrovascular Events in 21 105 Patients With Atrial Fibrillation Randomized to Edoxaban Versus Warfarin Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48

Background and Purpose— The once-daily oral factor Xa inhibitor, edoxaban, is as effective as warfarin in preventing stroke and systemic embolism while decreasing bleeding in a phase III trial of patients with atrial fibrillation at moderate–high stroke risk. Limited data regarding cerebrovascular events with edoxaban were reported previously. Methods— We analyzed the subtypes of cerebrovascular events in 21 105 patients participating in Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) comparing outcomes among patients randomized to warfarin versus 2 edoxaban regimens (high dose, low dose). The primary end point for this prespecified analysis of cerebrovascular events was all stroke (ischemic plus hemorrhagic), defined as an abrupt onset of focal neurological deficit because of infarction or bleeding with symptoms lasting ≥24 hours or fatal in <24 hours. Independent stroke neurologists unaware of treatment adjudicated all cerebrovascular events. Results— Patients randomized to high-dose edoxaban had fewer strokes on-treatment (hazard ratio, 0.80; 95% confidence interval, 0.65–0.98) than warfarin (median time-in-therapeutic range, 68.4%); patients in the low-dose edoxaban group had similar rates (hazard ratio, 1.10 versus warfarin; 95% confidence interval, 0.91–1.32). Rates of ischemic stroke or transient ischemic attack were similar with high-dose edoxaban (1.76% per year) and warfarin (1.73% per year; P=0.81), but more frequent with low-dose edoxaban (2.48% per year; P<0.001). Both edoxaban regimens significantly reduced hemorrhagic stroke and other subtypes of intracranial bleeds. Conclusions— In patients with atrial fibrillation, once-daily edoxaban was as effective as warfarin in preventing all strokes, with significant reductions in various subtypes of intracranial bleeding. Ischemic cerebrovascular event rates were similar with high-dose edoxaban and warfarin, whereas low-dose edoxaban was less effective than warfarin. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00781391.

Outcomes With Edoxaban Versus Warfarin in Patients With Previous Cerebrovascular Events: Findings From ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48).

Background and Purpose— Patients with atrial fibrillation and previous ischemic stroke (IS)/transient ischemic attack (TIA) are at high risk of recurrent cerebrovascular events despite anticoagulation. In this prespecified subgroup analysis, we compared warfarin with edoxaban in patients with versus without previous IS/TIA. Methods— ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) was a double-blind trial of 21 105 patients with atrial fibrillation randomized to warfarin (international normalized ratio, 2.0–3.0; median time-in-therapeutic range, 68.4%) versus once-daily edoxaban (higher-dose edoxaban regimen [HDER], 60/30 mg; lower-dose edoxaban regimen, 30/15 mg) with 2.8-year median follow-up. Primary end points included all stroke/systemic embolic events (efficacy) and major bleeding (safety). Because only HDER is approved, we focused on the comparison of HDER versus warfarin. Results— Of 5973 (28.3%) patients with previous IS/TIA, 67% had CHADS2 (congestive heart failure, hypertension, age, diabetes, prior stroke/transient ischemic attack) >3 and 36% were ≥75 years. Compared with 15 132 without previous IS/TIA, patients with previous IS/TIA were at higher risk of both thromboembolism and bleeding (stroke/systemic embolic events 2.83% versus 1.42% per year; P<0.001; major bleeding 3.03% versus 2.64% per year; P<0.001; intracranial hemorrhage, 0.70% versus 0.40% per year; P<0.001). Among patients with previous IS/TIA, annualized intracranial hemorrhage rates were lower with HDER than with warfarin (0.62% versus 1.09%; absolute risk difference, 47 [8–85] per 10 000 patient-years; hazard ratio, 0.57; 95% confidence interval, 0.36–0.92; P=0.02). No treatment subgroup interactions were found for primary efficacy (P=0.86) or for intracranial hemorrhage (P=0.28). Conclusions— Patients with atrial fibrillation with previous IS/TIA are at high risk of recurrent thromboembolism and bleeding. HDER is at least as effective and is safer than warfarin, regardless of the presence or the absence of previous IS or TIA. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00781391.

Cortical superficial siderosis predicts early recurrent lobar hemorrhage

Objective: To identify predictors of early lobar intracerebral hemorrhage (ICH) recurrence, defined as a new ICH within 6 months of the index event, in patients with cerebral amyloid angiopathy (CAA). Methods: Participants were consecutive survivors (age ≥55 years) of spontaneous symptomatic probable or possible CAA-related lobar ICH according to the Boston criteria, drawn from an ongoing single-center cohort study. Neuroimaging markers ascertained in CT or MRI included focal (≤3 sulci) or disseminated (>3 sulci) cortical superficial siderosis (cSS), acute convexity subarachnoid hemorrhage (cSAH), cerebral microbleeds, white matter hyperintensities burden and location, and baseline ICH volume. Participants were followed prospectively for recurrent symptomatic ICH. Cox proportional hazards models were used to identify predictors of early recurrent ICH adjusting for potential confounders. Results: A total of 292 patients were enrolled. Twenty-one patients (7%) had early recurrent ICH. Of these, 24% had disseminated cSS on MRI and 19% had cSAH on CT scan. In univariable analysis, the presence of disseminated cSS, cSAH, and history of previous ICH were predictors of early recurrent ICH (p < 0.05 for all comparisons). After adjusting for age and history of previous ICH, disseminated cSS on MRI and cSAH on CT were independent predictors of early recurrent ICH (hazard ratio [HR] 3.92, 95% confidence interval [CI] 1.38–11.17, p = 0.011, and HR 3.48, 95% CI 1.13–10.73, p = 0.030, respectively). Conclusions: Disseminated cSS on MRI and cSAH on CT are independent imaging markers of increased risk for early recurrent ICH. These markers may provide additional insights into the mechanisms of ICH recurrence in patients with CAA.

Recrudescence of Deficits After Stroke: Clinical and Imaging Phenotype, Triggers, and Risk Factors

Importance Reemergence of previous stroke-related deficits (or poststroke recrudescence [PSR]) is an underrecognized and inadequately characterized phenomenon. Objective To investigate the clinical features, triggers, and risk factors for PSR. Design, Setting, and Participants This retrospective study incorporated a crossover cohort study to identify triggers and a case-control study to identify risk factors. The study used the Massachusetts General Hospital Research Patient Data Repository to identify patients for the period January 1, 2000, to November 30, 2015, who had a primary or secondary diagnosis of cerebrovascular disease, who underwent magnetic resonance imaging of the brain at least once, and whose inpatient or outpatient clinician note or discharge summary stated the term recrudescence. In all, 153 patients met the preliminary diagnostic criteria for PSR: transient worsening of residual poststroke focal neurologic deficits or transient recurrence of prior stroke-related focal deficits, admission magnetic resonance imaging showing a chronic stroke but no acute infarct or hemorrhage, no evidence of transient ischemic attack or seizure, no acute lesion on diffusion-weighted imaging, and no clinical or electroencephalographic evidence of seizure around the time of the event. Main Outcomes and Measures Clinical and imaging features of PSR; triggers (identified by comparing PSR admissions with adjacent admissions without PSR); and risk factors (identified by comparing PSR cases with control cases from the Massachusetts General Hospital Stroke Registry). Results Of the 153 patients, 145 had prior infarct, 8 had hypertensive brain hemorrhage, and 164 admissions for PSR were identified. The patients’ mean (SD) age was 67 (16) years, and 92 (60%) were women. Recrudescence occurred a mean (SD) of 3.9 (0.6) years after the stroke, lasted 18.4 (20.4) hours, and was resolved on day 1 for 91 of the 131 episodes with documented resolution time (69%). Deficits were typically abrupt and mild and affected motor-sensory or language function. No patient had isolated gaze paresis, hemianopia, or neglect. During PSR, the National Institutes of Health Stroke Scale (NIHSS) score worsened by a mean (SD) 2.5 (1.9) points, and deficits were limited to a single NIHSS item in 62 episodes (38%). The underlying chronic strokes were variably sized, predominantly affected white matter tracts, and involved the middle cerebral artery territory for 112 patients (73%). Infection, hypotension, hyponatremia, insomnia or stress, and benzodiazepine use were higher during PSR admissions. Compared with the control group (patients who did not experience recrudescence), the PSR group (patients who were hospitalized for recrudescence) had more women, African American individuals, and those who self-identified as being from “other” race. The PSR group also had more diabetes, dyslipidemia, smoking, infarcts from small-vessel disease, and “other definite” causes and worse onset NIHSS scores. Six patients (4%) received intravenous tissue plasminogen activator without complications. Conclusions and Relevance The PSR features identified in the study should enable prompt diagnosis and distinguish recrudescence from mimics, such as transient ischemic attacks, migraine, Todd paralysis, and Uhthoff phenomenon. Prospective studies are required to validate the proposed diagnostic criteria and to decipher underlying mechanisms.

Baseline Predictors of Poor Outcome in Patients Too Good to Treat With Intravenous Thrombolysis

Background and Purpose— Several studies have reported poor outcomes in patients too good to treat with intravenous thrombolysis because of mild or rapidly improving symptoms. We sought to determine baseline clinical and imaging predictors of poor outcome in these patients. Methods— Among 3950 consecutive stroke admissions (2009–2015) in our local Get With the Guidelines–Stroke database, 632 patients presented ⩽4.5 hours and did not receive tissue-type plasminogen activator, with 380 of 632 (60.1%) being too good to treat. Univariate and multivariable analyses explored the clinical and imaging features associated with poor outcome (defined as not being discharged to home) in these 380 cases. Results— Among these 380 cases, only 68% were discharged home; the other 25% to inpatient rehabilitation, 4% to a skilled nursing facility, and 3% expired or were discharged to hospice. Patients with poor outcome were older, were more often Hispanic, had more vascular risk factors, and had higher median National Institutes of Health Stroke Scale. Imaging characteristics associated with poor outcomes included large or multifocal infarction and poor collaterals. In multivariable analysis, only age, initial National Institutes of Health Stroke Scale, and infarct location were independently associated with poor outcome. Conclusions— Approximately one third of patients deemed too good for intravenous tissue-type plasminogen activator are unable to be discharged directly to home. Given the current safety profile of intravenous tissue-type plasminogen activator, our results suggest that the concept of being too good to treat should be re-examined with an emphasis on the features associated with poor outcome identified in our study. If replicated, these findings could be incorporated into tissue-type plasminogen activator decision-making algorithms.

Dynamic Angiographic Nature of Cerebral Mycotic Aneurysms in Patients With Infective Endocarditis.

A 41-year-old male with nonischemic cardiomyopathy and left ventricular assist device on coumadin presented with constitutional symptoms for 1 week. Blood cultures were drawn. The next day, he developed severe headache (Hunt–Hess grade II), and noncontrast head computed tomography (CT) showed Fisher grade II subarachnoid hemorrhage over bilateral frontal convexities. International Normalized Ratio was 9. The blood cultures grew methicillin-resistant Staphylococcus aureus within a day. He was diagnosed with an infected left ventricular assist device and started on intravenous vancomycin. Brain CT angiography was negative for any vessel abnormality. Cerebral angiography on post bleed day 1 showed areas of subocclusive emboli in the left M3 segment of the middle cerebral artery (MCA) and left pericallosal artery, but did not reveal any identifiable source for subarachnoid hemorrhage. On post bleed day 2, the patient developed left frontal seizures that eventually progressed to status epilepticus. Repeat CT head showed a new intraparenchymal hemorrhage within the left frontal operculum, measuring 1.8 cm in diameter. Repeat cerebral angiography on post bleed day 2 revealed a new left M3 fusiform mycotic aneurysm (MA) in the exact location of the previously seen left M3 segment embolus. The pericallosal branch embolus had progressed to near vessel occlusion rather than aneurysm formation. The patient’s family withdrew care because of his poor cardiac and neurological status (Figure 1). Figure 1. Initial cerebral angiogram ( A ) showing subocclusive filling defects in the left pericallosal (black arrows) and M3 middle cerebral artery branch (white arrow) arteries. Follow-up angiography shows near occlusion of the left pericallosal branch ( B ), and fusiform mycotic aneurysmal dilatation of the previous left M3 lesion ( C and D ). A 31-year-old female with history of Tetrology of Fallot that had been repaired when she was a child, and previous infective endocarditis secondary to intravenous drug abuse requiring aortic valve replacement, …

Carotid-Cavernous Fistula: A Rare but Treatable Cause of Rapidly Progressive Vision Loss.

An 89-year-old woman with hypertension, hyperlipidemia, stroke, deep venous thrombosis, and atrial fibrillation presented with 4 days of right eye (OD) redness and swelling and intermittent diplopia. An ophthalmologic evaluation revealed visual acuity 20/50 OD. There was limited abduction OD, right upper and lower lid erythema and edema, and conjunctival injection. Funduscopic examination was unremarkable. Erythrocyte sedimentation rate and C-reactive protein were normal. Follow-up ophthalmologic examination 2 weeks later showed visual acuity decreased to 20/70 OD with increased right orbital congestion, exophthalmos (25 mm OD and 21 mm OS [left eye]), and worsening limitation of ductions OD. A magnetic resonance imaging/magnetic resonance angiography of her head demonstrated fusiform dilatation of the cavernous segment of the right internal carotid artery (ICA) with asymmetrical enhancement of the right cavernous sinus and an enlarged right superior ophthalmic vein (SOV) consistent with arterialized flow from a carotid-cavernous fistula (CCF). The patient was urgently referred to neuro-interventional radiology for diagnostic angiography and embolization of the CCF. The cerebral angiogram showed a right direct (Barrow type A) CCF, with rapid enhancement of the right cavernous sinus and right SOV. A 7-mm fusiform aneurysm of the right cavernous ICA was found to be the likely cause of the CCF (Figure 1A). Transarterial access of the fistula for coil embolization was unsuccessful. Figure 1. A , Pretreatment digital subtraction angiography, lateral magnified view, right common carotid artery injection, showing early, rapid opacification of the right cavernous sinus (black arrow) and right superior ophthalmic vein (white arrows) consistent with a direct carotid-cavernous fistula. There is also fusiform dilatation of the cavernous right internal carotid artery representing dysplasia with an aneurysm. B , Photograph showing the direct access provided to the right superior ophthalmic vein for coil embolization. C , …

Paroxysmal Atrial Fibrillation: Novel Strategies for Monitoring and Implications for Treatment in Stroke

Opinion statementIn cryptogenic stroke, prolonged cardiac monitoring is often employed to search for and diagnose atrial fibrillation (AF). Multiple monitoring modalities with multiple durations of monitoring exist. Finding atrial fibrillation after an ischemic stroke is extremely important as anticoagulation is the standard of care and results in the lowest stroke recurrence rate. The protocol at our institution is to carry out 30-day mobile cardiac outpatient telemetry (MCOT) in all patients with cryptogenic stroke. If this MCOT fails to reveal AF, yet the suspicion is high based on the presence of clinical, biochemical, electrocardiographic, and echocardiographic factors, we may proceed to use an implantable cardiac monitor. When AF is diagnosed after cryptogenic stroke, regardless of its duration and assuming no contraindications exist, anticoagulation is recommended with either warfarin or one of the DOACs (direct oral anticoagulants).

Implementation of a Rapid, Protocol-based TIA Management Pathway

Introduction Our goal was to assess whether use of a standardized clinical protocol improves efficiency for patients who present to the emergency department (ED) with symptoms of transient ischemic attack (TIA). Methods We performed a structured, retrospective, cohort study at a large, urban, tertiary care academic center. In July 2012 this hospital implemented a standardized protocol for patients with suspected TIA. The protocol selected high-risk patients for admission and low/intermediate-risk patients to an ED observation unit for workup. Recommended workup included brain imaging, vascular imaging, cardiac monitoring, and observation. Patients were included if clinical providers determined the need for workup for TIA. We included consecutive patients presenting during a six-month period prior to protocol implementation, and those presenting between 6–12 months after implementation. Outcomes included ED length of stay (LOS), hospital LOS, use of neuroimaging, and 90-day risk of stroke or TIA. Results From 01/2012 to 06/2012, 130 patients were evaluated for TIA symptoms in the ED, and from 01/2013 to 06/2013, 150 patients. The final diagnosis was TIA or stroke in 45% before vs. 41% after (p=0.18). Following the intervention, the inpatient admission rate decreased from 62% to 24% (p<0.001), median ED LOS decreased by 1.2 hours (5.7 to 4.9 hours, p=0.027), and median total hospital LOS from 29.4 hours to 23.1 hours (p=0.019). The proportion of patients receiving head computed tomography (CT) went from 68% to 58% (p=0.087); brain magnetic resonance (MR) imaging from 83% to 88%, (p=0.44) neck CT angiography from 32% to 22% (p=0.039); and neck MR angiography from 61% to 72% (p=0.046). Ninety-day stroke or recurrent TIA among those with final diagnosis of TIA was 3% for both periods. Conclusion Implementation of a TIA protocol significantly reduced ED LOS and total hospital LOS.

Aneurysmal Subarachnoid and Spinal Hemorrhage Associated With Systemic Lupus Erythematosus

A 42-year-old woman with systemic lupus erythematosis (SLE), positive lupus anticoagulant, elevated titers of IgG and IgM anticardiolipin antibody and β2 glycoprotein antibodies, idiopathic thrombocytopenia, and hemolytic anemia presented with menorrhagia and anemia. She received both platelet and red cell transfusions and had an unrevealing endometrial biopsy. She was treated with intravenous immunoglobulin therapy for autoimmune-mediated thrombocytopenia and was taking hydroxychloroquine 200 mg twice daily that was a home medication. She was started on prednisone 60 mg daily. During her hospitalization, she developed a sudden, severe, sharp, and pounding occipital and nuchal headache with sharp shooting pains radiating down the back of the neck. She was alert and oriented with normal cranial nerve function, motor strength, and sensation. Her headache was unsuccessfully treated with fioricet and acetaminophen. The day after headache onset, a noncontrast head computed tomography revealed a subarachnoid hemorrhage (SAH) extending from the interpeduncular fossa caudally to the cervicomedullary junction (Figure 1). Computed tomographic angiogram of the head and neck revealed a focal left vertebral artery stenosis with poststenotic aneurysmal dilation of the intradural (V4) segment. There were additional multifocal areas of beading and long tapered vessel narrowing involving the M2 division of the left middle cerebral artery and anterior cerebral arteries and M3 division of the right middle cerebral artery (Figure 1). Magnetic resonance brain demonstrated multifocal but posteriorly predominant T2 hyperintense lesions that resembled posterior reversible leukoencephalopathy syndrome (Figure 2). Conventional angiogram confirmed the global small and medium vessel vasculopathy with a left V4 vertebral artery fusiform aneurysm measuring 10.6 mm×5.5 mm distal to the origin of the left posterior inferior cerebellar artery (Figure 2). Figure 1. Lupus-associated central nervous system vasculitis and subarachnoid hemorrhage (SAH). A , Computed tomographic (CT) head demonstrating perimedullary SAH (black arrow). B , CT angiogram demonstrating focal stenosis of the intracranial …