Results from the long-term extension of PRIME: A randomized Phase 1b trial of aducanumab.

INTRODUCTION: Aducanumab selectively targets aggregated forms of amyloid beta (Aß), a neuropathological hallmark of Alzheimer's disease (AD). METHODS: PRIME was a Phase 1b, double-blind, randomized clinical trial of aducanumab. During the 12-month placebo-controlled period, participants with prodromal AD or mild AD dementia were randomized to receive aducanumab or placebo. At week 56, participants could enroll in a long-term extension (LTE), in which all participants received aducanumab. The primary endpoint was safety and tolerability. RESULTS: Amyloid-related imaging abnormalities-edema (ARIA-E) were the most common adverse event. Dose titration was associated with a decrease in the incidence of ARIA-E. Over 48 months, aducanumab decreased brain amyloid levels in a dose- and time-dependent manner. Exploratory endpoints suggested a continued benefit in the reduction of clinical decline over 48 months. DISCUSSION: The safety profile of aducanumab remained unchanged in the LTE of PRIME. Amyloid plaque levels continued to decrease in participants treated with aducanumab. HIGHLIGHTS: PRIME was a Phase 1b, double-blind, randomized clinical trial of aducanumab. We report cumulative safety and 48-month efficacy results from PRIME. Amyloid-related imaging abnormalities-edema (ARIA-E) were the most common adverse event (AE); 61% of participants with ARIA-E were asymptomatic. Dose titration was associated with a decrease in the incidence of ARIA-E. Aducanumab decreased levels of amyloid beta (Aß) in a dose- and time-dependent manner.

Artificial Intelligence Assistive Software Tool for Automated Detection and Quantification of Amyloid-Related Imaging Abnormalities.

Importance: Amyloid-related imaging abnormalities (ARIA) are brain magnetic resonance imaging (MRI) findings associated with the use of amyloid-ß-directed monoclonal antibody therapies in Alzheimer disease (AD). ARIA monitoring is important to inform treatment dosing decisions and might be improved through assistive software. Objective: To assess the clinical performance of an artificial intelligence (AI)-based software tool for assisting radiological interpretation of brain MRI scans in patients monitored for ARIA. Design, Setting, and Participants: This diagnostic study used a multiple-reader multiple-case design to evaluate the diagnostic performance of radiologists assisted by the software vs unassisted. The study enrolled 16 US Board of Radiology-certified radiologists to perform radiological reading with (assisted) and without the software (unassisted). The study encompassed 199 retrospective cases, where each case consisted of a predosing baseline and a postdosing follow-up MRI of patients from aducanumab clinical trials PRIME, EMERGE, and ENGAGE. Statistical analysis was performed from April to July 2023. Exposures: Use of icobrain aria, an AI-based assistive software for ARIA detection and quantification. Main Outcomes and Measures: Coprimary end points were the difference in diagnostic accuracy between assisted and unassisted detection of ARIA-E (edema and/or sulcal effusion) and ARIA-H (microhemorrhage and/or superficial siderosis) independently, assessed with the area under the receiver operating characteristic curve (AUC). Results: Among the 199 participants included in this study of radiological reading performance, mean (SD) age was 70.4 (7.2) years; 105 (52.8%) were female; 23 (11.6%) were Asian, 1 (0.5%) was Black, 157 (78.9%) were White, and 18 (9.0%) were other or unreported race and ethnicity. Among the 16 radiological readers included, 2 were specialized neuroradiologists (12.5%), 11 were male individuals (68.8%), 7 were individuals working in academic hospitals (43.8%), and they had a mean (SD) of 9.5 (5.1) years of experience. Radiologists assisted by the software were significantly superior in detecting ARIA than unassisted radiologists, with a mean assisted AUC of 0.87 (95% CI, 0.84-0.91) for ARIA-E detection (AUC improvement of 0.05 [95% CI, 0.02-0.08]; P = .001]) and 0.83 (95% CI, 0.78-0.87) for ARIA-H detection (AUC improvement of 0.04 [95% CI, 0.02-0.07]; P = .001). Sensitivity was significantly higher in assisted reading compared with unassisted reading (87% vs 71% for ARIA-E detection; 79% vs 69% for ARIA-H detection), while specificity remained above 80% for the detection of both ARIA types. Conclusions and Relevance: This diagnostic study found that radiological reading performance for ARIA detection and diagnosis was significantly better when using the AI-based assistive software. Hence, the software has the potential to be a clinically important tool to improve safety monitoring and management of patients with AD treated with amyloid-ß-directed monoclonal antibody therapies.

Acute occlusion of the fetal posterior cerebral artery: diagnosis and management paradigms.

BACKGROUND AND PURPOSE: The diagnosis and management of acute fetal posterior cerebral artery occlusion are challenging. While endovascular treatment is established for anterior circulation large vessel occlusion stroke, little is known about the course of acute fetal posterior cerebral artery occlusions. We report the clinical course, radiological findings and management considerations of acute fetal posterior cerebral artery occlusion stroke. METHODS: We performed a retrospective review of consecutive patients presenting with acute large vessel occlusion who underwent cerebral angiogram and/or mechanical thrombectomy between January 2015 and January 2021. Patients diagnosed with fetal posterior cerebral artery occlusion were included. Demographic data, clinical presentation, imaging findings and management strategies were reviewed. RESULTS: Between January 2015 and January 2021, three patients with fetal posterior cerebral artery occlusion were identified from 400 patients who underwent angiogram and/or mechanical thrombectomy for acute stroke (0.75%). The first patient presented with concomitant fetal posterior cerebral artery and middle cerebral artery occlusions. Thrombectomy was performed with recanalisation of the fetal posterior cerebral artery but the patient died from malignant oedema. The second patient presented with isolated fetal posterior cerebral artery occlusion. No endovascular intervention was performed and the patient was disabled from malignant posterior cerebral artery infarct. The third patient presented with carotid occlusion and was found to have fetal posterior cerebral artery occlusion after internal carotid artery recanalisation. No further intervention was performed. The patient was left with residual contralateral homonymous hemianopia and mild left sided weakness. CONCLUSION: Fetal posterior cerebral artery occlusion is a rare, but potentially disabling, cause of ischaemic stroke. Endovascular treatment is feasible. Further investigation is needed to compare the efficacy of medical versus endovascular management strategies.

Cerebrovascular events and outcomes in hospitalized patients with COVID-19: The SVIN COVID-19 Multinational Registry.

BACKGROUND: Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has been associated with a significant risk of thrombotic events in critically ill patients. AIM: To summarize the findings of a multinational observational cohort of patients with SARS-CoV-2 and cerebrovascular disease. METHODS: Retrospective observational cohort of consecutive adults evaluated in the emergency department and/or admitted with coronavirus disease 2019 (COVID-19) across 31 hospitals in four countries (1 February 2020-16 June 2020). The primary outcome was the incidence rate of cerebrovascular events, inclusive of acute ischemic stroke, intracranial hemorrhages (ICH), and cortical vein and/or sinus thrombosis (CVST). RESULTS: Of the 14,483 patients with laboratory-confirmed SARS-CoV-2, 172 were diagnosed with an acute cerebrovascular event (1.13% of cohort; 1130/100,000 patients, 95%CI 970-1320/100,000), 68/171 (40.5%) were female and 96/172 (55.8%) were between the ages 60 and 79 years. Of these, 156 had acute ischemic stroke (1.08%; 1080/100,000 95%CI 920-1260/100,000), 28 ICH (0.19%; 190/100,000 95%CI 130-280/100,000), and 3 with CVST (0.02%; 20/100,000, 95%CI 4-60/100,000). The in-hospital mortality rate for SARS-CoV-2-associated stroke was 38.1% and for ICH 58.3%. After adjusting for clustering by site and age, baseline stroke severity, and all predictors of in-hospital mortality found in univariate regression (p < 0.1: male sex, tobacco use, arrival by emergency medical services, lower platelet and lymphocyte counts, and intracranial occlusion), cryptogenic stroke mechanism (aOR 5.01, 95%CI 1.63-15.44, p < 0.01), older age (aOR 1.78, 95%CI 1.07-2.94, p = 0.03), and lower lymphocyte count on admission (aOR 0.58, 95%CI 0.34-0.98, p = 0.04) were the only independent predictors of mortality among patients with stroke and COVID-19. CONCLUSIONS: COVID-19 is associated with a small but significant risk of clinically relevant cerebrovascular events, particularly ischemic stroke. The mortality rate is high for COVID-19-associated cerebrovascular complications; therefore, aggressive monitoring and early intervention should be pursued to mitigate poor outcomes.

Cerebral Venous Sinus Thromboses in Patients with SARS-CoV-2 Infection: Three Cases and a Review of the Literature.

INTRODUCTION: Early studies suggest that acute cerebrovascular events may be common in patients with coronavirus disease 2019 (COVID-19) and may be associated with a high mortality rate. Most cerebrovascular events described have been ischemic strokes, but both intracerebral hemorrhage and rarely cerebral venous sinus thrombosis (CVST) have also been reported. The diagnosis of CVST can be elusive, with wide-ranging and nonspecific presenting symptoms that can include headache or altered sensorium alone. OBJECTIVE: To describe the presentation, barriers to diagnosis, treatment, and outcome of CVST in patients with COVID-19. METHODS: We abstracted data on all patients diagnosed with CVST and COVID-19 from March 1 to August 9, 2020 at Boston Medical Center. Subsequently, we reviewed the literature and extracted all published cases of CVST in patients with COVID-19 from January 1, 2020 through August 9, 2020 and included all studies with case descriptions. RESULTS: We describe the clinical features and management of CVST in 3 women with COVID-19 who developed CVST days to months after initial COVID-19 symptoms. Two patients presented with encephalopathy and without focal neurologic deficits, while one presented with visual symptoms. All patients were treated with intravenous hydration and anticoagulation. None suffered hemorrhagic complications, and all were discharged home. We identified 12 other patients with CVST in the setting of COVID-19 via literature search. There was a female predominance (54.5%), most patients presented with altered sensorium (54.5%), and there was a high mortality rate (36.4%). CONCLUSIONS: During this pandemic, clinicians should maintain a high index of suspicion for CVST in patients with a recent history of COVID-19 presenting with non-specific neurological symptoms such as headache to provide expedient management and prevent complications. The limited data suggests that CVST in COVID-19 is more prevalent in females and may be associated with high mortality.

Intravenous tPA for Acute Ischemic Stroke in Patients with COVID-19.

BACKGROUND/PURPOSE: Coronavirus disease 2019 (COVID-19) is associated with increased risk of acute ischemic stroke (AIS), however, there is a paucity of data regarding outcomes after administration of intravenous tissue plasminogen activator (IV tPA) for stroke in patients with COVID-19. METHODS: We present a multicenter case series from 9 centers in the United States of patients with acute neurological deficits consistent with AIS and COVID-19 who were treated with IV tPA. RESULTS: We identified 13 patients (mean age 62 (±9.8) years, 9 (69.2%) male). All received IV tPA and 3 cases also underwent mechanical thrombectomy. All patients had systemic symptoms consistent with COVID-19 at the time of admission: fever (5 patients), cough (7 patients), and dyspnea (8 patients). The median admission NIH stroke scale (NIHSS) score was 14.5 (range 3-26) and most patients (61.5%) improved at follow up (median NIHSS score 7.5, range 0-25). No systemic or symptomatic intracranial hemorrhages were seen. Stroke mechanisms included cardioembolic (3 patients), large artery atherosclerosis (2 patients), small vessel disease (1 patient), embolic stroke of undetermined source (3 patients), and cryptogenic with incomplete investigation (1 patient). Three patients were determined to have transient ischemic attacks or aborted strokes. Two out of 12 (16.6%) patients had elevated fibrinogen levels on admission (mean 262.2 ± 87.5 mg/dl), and 7 out of 11 (63.6%) patients had an elevated D-dimer level (mean 4284.6 ±3368.9 ng/ml). CONCLUSIONS: IV tPA may be safe and efficacious in COVID-19, but larger studies are needed to validate these results.

Optimization of resources and modifications in acute ischemic stroke care in response to the global COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic has presented unprecedented challenges to healthcare organizations worldwide. A steadily rising number of patients requiring intensive care, a large proportion from racial and ethnic minorities, demands creative solutions to provide high-quality care while ensuring healthcare worker safety in the face of limited resources. Boston Medical Center has been particularly affected due to the underserved patient population we care for and the increased risk of ischemic stroke in patients with COVID-19 infection. METHODS: We present protocol modifications developed to manage patients with acute ischemic stroke in a safe and effective manner while prioritizing judicious use of personal protective equipment and intensive care unit resources. CONCLUSION: We feel this information will benefit other organizations facing similar obstacles in caring for the most vulnerable patient populations during this ongoing public health crisis.

End-of-life and brain death in acute coma and disorders of consciousness.

Consulting neurologists are often asked to evaluate patients in acute nontraumatic coma. The authors review prognostication of functional outcomes, determining brain death, and managing end-of-life care. Prognostication of outcome after cardiac arrest in comatose patients is a frequently encountered scenario with high-stakes implications. However, current guidelines are limited by a failure to address the use of therapeutic hypothermia and thus may lead to overly pessimistic outcome prediction. Pupillary light responses and corneal reflexes remain highly predictive clinical signs of a poor prognosis. Motor responses have a high false-positive rate for predicting a poor outcome, especially in patients treated with therapeutic hypothermia. Ancillary testing with electroencephalography, somatosensory evoked potentials, serum neuron-specific enolase, and neuroimaging is often useful in predicting outcomes. Brain death is a clinical condition of irreversible coma of known cause with absent brainstem reflexes and apnea. An understanding of the value of confirmatory testing and the potential for confounding factors is essential in making a correct diagnosis. As coma carries a high mortality rate, neurologists must be capable of guiding goals of care, discussing end-of-life issues, and understanding organ-procurement procedures.

Plantar flexion with noxious dorsal foot stimulation in brain death.

BACKGROUND: Plantar flexion with plantar stimulation has been well described in brain death, and is compatible with brain death. However, plantar flexion with stimulation to the dorsal surface of the foot has not been reported previously in brain dead patients. METHODS: Case report with Technetium-99 m hexamethylpropyleneamine oxime brain scan and video. RESULTS: A 46-year-old woman suffered severe anoxic brain injury following massive pulmonary embolism 5 days after arthroscopic knee surgery. Neurologic examination was consistent with brain death, with the exception of plantar flexion when noxious stimulation was applied to the dorsal surface of the great toe on each side. Ancillary testing with a technetium-99 m nuclear scan demonstrated absence of cerebral perfusion, supporting the diagnosis of brain death. CONCLUSIONS: Noxious stimulation to the dorsal surface of the foot may trigger spinally mediated plantar flexion in patients with brain death.