Search

Background: Prior systematic reviews have compared the efficacy of intravenous tenecteplase and alteplase in acute ischemic stroke, assigning their relative complications as a secondary objective. The objective of the present study is to determine whether the risk of treatment complications differs between patients treated with either agent. Methods: We performed a systematic review including interventional studies and prospective and retrospective, observational studies enrolling adult patients treated with intravenous tenecteplase for ischemic stroke (both comparative and noncomparative with alteplase). We searched MEDLINE, Embase, the Cochrane Library, Web of Science, and the www.ClinicalTrials.gov registry from inception through June 3, 2022. The primary outcome was symptomatic intracranial hemorrhage, and secondary outcomes included any intracranial hemorrhage, angioedema, gastrointestinal hemorrhage, other extracranial hemorrhage, and mortality. We performed random effects meta-analyses where appropriate. Evidence was synthesized as relative risks, comparing risks in patients exposed to tenecteplase versus alteplase and absolute risks in patients treated with tenecteplase. Results: Of 2226 records identified, 25 full-text articles (reporting 26 studies of 7913 patients) were included. Sixteen studies included alteplase as a comparator, and 10 were noncomparative. The relative risk of symptomatic intracranial hemorrhage in patients treated with tenecteplase compared with alteplase in the 16 comparative studies was 0.89 ([95% CI, 0.65–1.23]; I 2 =0%). Among patients treated with low dose (2 =0%), 0.77 ([95% CI, 0.53–1.14]; I 2 =0%), and 2.31 ([95% CI, 0.69–7.75]; I 2 =40%), respectively. The pooled risk of symptomatic intracranial hemorrhage in tenecteplase-treated patients, including comparative and noncomparative studies, was 0.99% ([95% CI, 0%–3.49%]; I 2 =0%, 7 studies), 1.69% ([95% CI, 1.14%–2.32%]; I 2 =1%, 23 studies), and 4.19% ([95% CI, 1.92%–7.11%]; I 2 =52%, 5 studies) within the low-, medium-, and high-dose groups. The risks of any intracranial hemorrhage, mortality, and other studied outcomes were comparable between the 2 agents. Conclusions: Across medium- and low-dose tiers, the risks of complications were generally comparable between those treated with tenecteplase versus alteplase for acute ischemic stroke.

Background: Carotid stenosis is thought to be the primary risk factor for central retinal artery occlusion (CRAO); however, it is not known whether atrial fibrillation (AF)—a cardiac arrhythmia that underlies over 25% of cerebral ischemic strokes—predisposes patients to CRAO. Methods: A retrospective, observational, cohort study was performed using data from the State Inpatient Databases and State Emergency Department Databases from New York (2006–2015), California (2003–2011), and Florida (2005–2015) to determine the association between AF and CRAO. The primary exposure was hospital-documented AF. The primary end point was hospital-documented CRAO, defined as having an International Classification of Diseases, Ninth Revision, Clinical Modification , code 362.31 in the primary diagnosis position. Cause-specific hazard models were used to model CRAO-free survival among patients according to hospital-documented AF status. Results: Of 39 834 885 patients included in the study, 2 723 842 (median age, 72.7 years; 48.5% women) had AF documented during the exposure window. The median follow-up duration was 6 years and 1 month. Patients with AF were older, more likely to be of non-Hispanic White race/ethnicity, and had a higher burden of cardiovascular comorbidities compared with patients without AF. The cumulative incidence of CRAO determined prospectively after exclusions was 8.69 per 100 000 at risk in those with AF and 2.39 per 100 000 at risk in those without AF over the study period. Before adjustment, AF was associated with higher risk of CRAO (hazard ratio, 2.55 [95% CI, 2.15–3.03]). However, after adjustment for demographics, state, and cardiovascular comorbidities, there was an inverse association between AF and risk of CRAO (adjusted hazard ratio, 0.72 [95% CI, 0.60–0.87]). These findings were robust in our prespecified sensitivity analyses. By contrast, positive control outcomes of embolic and ischemic stroke showed an expected strong relationship between AF and risk of stroke. Conclusions: We found an inverse association between AF and CRAO in a large, representative study of hospitalized patients; however, this cohort did not ascertain AF or CRAO occurring outside of hospital or emergency department settings.

We report the case of a 79-year-old woman in good general health aside from early-stage Alzheimer’s disease who was enrolled in a randomized controlled trial of the novel therapeutic monoclonal antibody lecanemab where she was treated with the placebo, and subsequently in the open label extension study where she received lecanemab infusions every two weeks. After the third infusion, she suffered a seizure followed by aphasia and progressively worsening encephalopathy. Magnetic resonance imaging revealed multifocal cerebral edema and an increased burden of cerebral microhemorrhages compared to pre-trial imaging, consistent with Amyloid Related Imaging Abnormality (ARIA). She was treated with an antiepileptic regimen and high-dose intravenous corticosteroids but continued to worsen and expired after five days in the hospital. The family requested an autopsy and consented to evaluation of her brain for research. Post-mortem MRI confirmed extensive microhemorrhagic changes in the temporal, parietal and occipital lobes, some of which were visible on gross inspection of the brain. Autopsy confirmed APOE genotype of E4/E4 and the presence of typical neuropathological features of Alzheimer’s disease along with severe cerebral amyloid angiopathy with inflammatory features, including perivascular lymphocytic infiltrates, reactive macrophages and fibrinoid degeneration of vessel walls. There were deposits of β-amyloid in meningeal vessels and penetrating arterioles with numerous microaneurysms. Cerebral microhemorrhages were associated with arterioles harboring β-amyloid deposits and having degenerative morphologies. We conclude from these results that the patient likely died as a result of severe cerebral amyloid angiopathy with marked microvascular degeneration and meningoencephalitis. Further study of the mechanism of ARIA and the neuropathological changes associated with plaque clearance are needed.

Examination of healthy and diseased human brain is essential to translational neuroscience. Protein-protein interactions play a pivotal role in physiological and pathological processes, but their detection is difficult, especially in aged and fixed human brain tissue. We used the proximity ligation assay (PLA) to broaden the range of molecular interactions assessable in-situ in human neuropathology. We adapted fluorescent in-situ PLA to detect ubiquitin-modified proteins in human brains with Alzheimer’s disease (AD), including approaches for the management of autofluorescence and quantification using a high-content image analysis system. We confirmed that hyperphosphorylated microtubule-associated protein tau (Serine202, Threonine205) aggregates were modified by ubiquitin and that phospho-tau-ubiquitin complexes were increased in hippocampal and frontal cortex regions in AD compared to non-AD brains. Overall, we refined PLA for use in human neuropathology, which has revealed a profound change in the distribution of ubiquitin in AD brain and its association with characteristic tau pathologies.

Introduction: Prior systematic reviews have focused on a comparison of efficacy endpoints between tenecteplase (TNK) and alteplase. The objectives of this study are to determine whether the rate of treatment complications differs between patients treated with the two agents. Methods: This systematic review (CRD42022303835) was performed according to PRISMA guidelines. We included prospective, interventional studies and prospective and retrospective observational studies. We searched MEDLINE, the Cochrane Central Register of Controlled Trials, Embase, Web of Science and the ClinicalTrials.gov registry from inception through June 3 rd 2022. The primary endpoint was symptomatic intracranial hemorrhage (sICH) and secondary endpoints included any ICH, mortality, angioedema, gastrointestinal hemorrhage and other extracranial hemorrhage. We performed separate random effects meta analyses for each endpoint. Evidence was synthesized as relative risks, comparing subjects exposed to TNK versus alteplase as well as absolute risks in those treated with TNK. Results: Of 2,226 records identified, 26 were eligible for inclusion including 7,921 patients. Seventeen studies included alteplase as a comparator group and 10 were non-comparative. The relative risk of sICH in patients treated with TNK compared with alteplase was 0.93 (95% CI: 0.68-1.28). Across those treated with low, medium and high doses of TNK, the relative risks were 0.78 (95% CI: 0.22-2.82), 0.84 (95% CI: 0.58-1.20) and 2.31 (0.69-7.75) respectively. The unadjusted rate of sICH, including comparative and non-comparative studies, was 1%, 2% and 4% within the low, medium and high dose groups. Discussion: To-date, this is the most comprehensive systematic review examining relative complications of TNK and alteplase. The rate of treatment harms is broadly comparable between those treated with the two agents. We present evidence that the rate of sICH may be increased in those treated with higher doses of TNK.

BackgroundIntracerebral hemorrhage (ICH) occurs in ~20%–30% of stroke patients undergoing endovascular therapy (EVT). However, there is conflicting evidence regarding the effect of asymptomatic ICH (aICH) on post-EVT outcomes. We sought to evaluate the effect of aICH on immediate and 90-day post-EVT neurological outcomes.MethodsIn this post-hoc analysis of the multicenter, prospective Blood Pressure after Endovascular Therapy (BEST) study we identified subjects with ICH following EVT. This population was divided into no ICH, aICH, and symptomatic ICH (sICH). Associations with 90-day modified Rankin Scale (mRS) dichotomized by functional independence (0–2 vs 3–6) and early neurological recovery (ENR) were determined using univariate/multivariate logistic regression models.ResultsOf 485 patients enrolled in BEST, 446 had 90-day follow-up data available. 92 (20.6%) developed aICH, and 18 (4%) developed sICH. Compared with those without ICH, aICH was not associated with worse 90-day outcome or lower ENR (OR 0.84 [0.53–1.35], P=0.55, aOR 0.84 [0.48–1.44], P=0.53 for 90-day mRS 0–2; OR 0.77 [0.48–1.23], P=0.34, aOR 0.72 [0.43–1.22] for ENR). aICH was not associated with 90-day outcome or ENR in patients with mTICI ≥2 b (OR 0.78 [0.48–1.26], P=0.33 for 90-day mRS 0–2; OR 0.89 [0.69–1.12], P=0.15 for ENR). A higher proportion of patients with aICH had mTICI ≥2 b than those without ICH (97%vs 87%, P=0.01).ConclusionsaICH was not associated with worse outcomes in patients with large-vessel stroke treated with EVT. aICH was more frequent in patients with successful recanalization. Further validation of our findings in large cohort studies of EVT-treated patients is warranted.

BACKGROUND: Anticoagulation increases the risk of intracerebral hemorrhage (ICH) in patients with cerebral amyloid angiopathy (CAA), so the management of stroke-risk in patients with both atrial fibrillation (AF) and CAA is controversial. Advances in left atrial appendage closure (LAAC) techniques provide a stroke-risk-reduction option which avoids long-term oral anticoagulation (OAC). We aimed to evaluate the safety of this intervention in patients with CAA. METHODS: This is an observational cohort study of patients with severe CAA (with or without ICH) and AF who were treated with LAA closure. The Watchman™ and Amulet® LAAC devices, Lariat procedure or open surgical closure of the LAA were all considered acceptable means of closure. Patients with symptomatic ICH and those naive to anticoagulation were placed on clopidogrel and/or aspirin for 6 weeks after the procedure; patients who previously tolerated anticoagulation remained on warfarin or a DOAC for 6 weeks post-procedure. All antiplatelet and anticoagulation therapy was discontinued after confirmation of LAAC. All patients had aggressively optimized blood pressure and fall precautions in addition to surgical intervention. Safety, tolerability, stroke and hemorrhage rates were documented. OUTCOME: Twenty-six patients with a mean CHA(2)DS(2)-VASc score of 4.6 were treated, 13 with a history of symptomatic lobar hemorrhage and 13 without. All patients who completed LAAC tolerated device implantation. There were no documented ischemic strokes or symptomatic ICH during the 30 days after device implantation. Patients were followed for an average of 25 months. One patient who underwent LARIAT LAAC had an ischemic stroke in follow-up, but recovered well; there were no other thromboemboli in this cohort. CONCLUSIONS: This cohort study provides evidence that LAAC appears to be a safe and tolerable treatment to reduce stroke risk in patients with CAA. Because of the small size of the cohort and relatively short follow-up, the efficacy for stroke and ICH prevention is not conclusive, but the preliminary results are encouraging. LAA closure may be a good alternative to anticoagulation in patients with CAA and atrial fibrillation.

Highlights •ICH, although less common than ischemic stroke, is the major cause of stroke mortality and there is not yet a definitive therapy beyond supportive care. •Early stabilization of acute ICH involves identifying and treating the cause(s) of decreased alertness, aggressively correcting blood pressure, and reversing any coagulopathy. •Long-term management of ICH requires correctly identifying the underlying etiology and, when possible, correcting it. •Initial clinical trials of minimally invasive hemorrhage evacuation were promising and ongoing trials are evaluating new hemorrhage evacuation technologies.

BACKGROUND AND PURPOSE: The increased severity of white matter disease is associated with worse outcomes and an increased rate of intracerebral hemorrhage in patients with ischemic stroke undergoing thrombolytic treatment. However, whether white matter disease is associated with outcomes in patients undergoing endovascular treatment remains unclear. MATERIALS AND METHODS: In this prespecified exploratory analysis of our prospective multi-institutional study that enrolled consecutive adult patients with anterior circulation ischemic stroke undergoing endovascular treatment from November 2017 to September 2018, we compared the following outcomes between patients with none-to-minimal (van Swieten score, 0–2) and moderate-to-severe (van Swieten score, 3–4) white matter disease using logistic regression: 90-day mRS 3–6, death, intracerebral hemorrhage, successful recanalization, and early neurologic recovery. RESULTS: Of the 485 patients enrolled in the Blood Pressure after Endovascular Stroke Therapy (BEST) study, 389 had white matter disease graded (50% women; median age, 68 years; range, 58–79 years). A van Swieten score of 3–4 (n = 74/389, 19%) was associated with a higher rate of 90-day mRS of 3–6 (45% versus 18%; adjusted OR, 2.73; 95% CI, 1.34–5.93; P = .008). Although the death rate was higher in patients with van Swieten scores of 3–4 (26% versus 15%), the adjusted likelihood was not significantly different (adjusted OR, 1.14; 95% CI, 0.56–2.26; P = .710). Ordered regression revealed a shift toward worse mRS scores with increasing van Swieten scores (adjusted common OR, 3.04; 95% CI, 1.93–4.84; P

PURPOSE OF REVIEW Intracerebral hemorrhage (ICH) represents about 15% of all strokes in the USA, but almost 50% of fatal strokes. There are many causes of ICH, but the most common are hypertension and cerebral amyloid angiopathy. This review will discuss new advances in the treatment of intracerebral hemorrhage. RECENT FINDINGS The treatment of ICH focuses on management of edema, aggressive blood pressure reduction, and correction of coagulopathy. Early initiation of supportive medical therapies, including blood pressure management, in a neurological intensive care unit reduces mortality, but at present there is no definitive, curative therapy analogous to mechanical thrombectomy for ischemic stroke. Nonetheless, new medical and surgical approaches promise more successful management of ICH patients, especially new approaches to surgical management. In this review, we focus on the current standard of care of acute ICH and discuss emerging therapies that may alter the landscape of this devastating disease.

Introduction The carotid web is a compelling potential mechanism of embolic ischemic stroke. In this study, we aim to determine the prevalence of ipsilateral carotid web in a cohort of ischemic stroke patients and to perform a systematic review and meta-analysis of similar cohorts. Patients & methods We performed a retrospective, observational, cohort study of acute ischemic stroke patients admitted to a comprehensive stroke center from June 2012 to September 2017. Carotid web was defined on computed tomography angiography (CTA) as a thin shelf of non-calcified tissue immediately distal to the carotid bifurcation. We described the prevalence of carotid artery webs in our cohort, then performed a systematic review and meta-analysis of similar cohorts in the published literature. Results We identified 1,435 potentially eligible patients of whom 879 met criteria for inclusion in our analysis. An ipsilateral carotid web was detected in 4 out of 879 (0.45%) patients, of which 4/4 (1.6%) were in 244 patients with cryptogenic stroke and 3/4 were in 66 (4.5%) patients 2 = 66.1%). The relative risk (RR) of ipsilateral versus contralateral carotid web in all patients was 2.5 (95% CI 1.5–4.2, p = 0.0009) whereas in patients less than 60 with cryptogenic stroke it was 3.0 (95% CI 1.6–5.8, p = 0.0011). Discussion Carotid webs are more common in young patients with cryptogenic stroke than in other stroke subtypes. Future studies concerning the diagnosis and secondary prevention of stroke associated with carotid web should focus on this population.

Background: Central retinal artery occlusion (CRAO) causes sudden, irreversible blindness and is a form of acute ischemic stroke. In this study, we sought to determine the proportion of patients in whom atrial fibrillation (AF) is detected by extended cardiac monitoring after CRAO. Methods: We performed a retrospective, observational cohort study using data from the Optum deidentified electronic health record of 30.8 million people cross-referenced with the Medtronic CareLink database of 2.7 million people with cardiac monitoring devices in situ. We enrolled patients in 3 groups: (1) CRAO, (2) cerebral ischemic stroke, and (3) age-, sex-, and comorbidity-matched controls. The primary end point was the detection of new AF (defined as ≥2 minutes of AF detected on a cardiac monitoring device). Results: We reviewed 884 431 patient records in common between the two databases to identify 100 patients with CRAO, 6559 with ischemic stroke, and 1000 matched controls. After CRAO, the cumulative incidence of new AF at 2 years was 49.6% (95% CI, 37.4%–61.7%). Patients with CRAO had a higher rate of AF than controls (hazard ratio, 1.64 [95% CI, 1.17–2.31]) and a comparable rate to patients with stroke (hazard ratio, 1.01 [95% CI, 0.75–1.36]). CRAO was associated with a higher incidence of new stroke compared with matched controls (hazard ratio, 2.85 [95% CI, 1.29–6.29]). Conclusions: The rate of AF detection after CRAO is higher than that seen in age-, sex-, and comorbidity-matched controls and comparable to that seen after ischemic cerebral stroke. Paroxysmal AF should be considered as part of the differential etiology of CRAO, and those patients may benefit from long-term cardiac monitoring.

Perivascular spaces (PVS) are fluid filled compartments that are part of the cerebral blood vessel wall and represent the conduit for fluid transport in and out of the brain. PVS are considered pathologic when sufficiently enlarged to be visible on magnetic resonance imaging. Recent studies have demonstrated that enlarged PVS (ePVS) may have clinical consequences related to cognition. Emerging literature points to arterial stiffening and abnormal protein aggregation in vessel walls as two possible mechanisms that drive ePVS formation. In this review, we describe the clinical consequences, anatomy, fluid dynamics, physiology, risk factors, and in vivo quantification methods of ePVS. Given competing views of PVS physiology, we detail the two most prominent theoretical views and review ePVS associations with other common small vessel disease markers. As ePVS are a marker of small vessel disease and ePVS burden is higher in Alzheimer’s disease, a comprehensive understanding about ePVS is essential in developing prevention and treatment strategies.

Purpose: Central retinal artery occlusion (CRAO) is a form of acute ischemic stroke that causes severe visual loss and is a harbinger of further cerebrovascular and cardiovascular events. There is a paucity of scientific information on the appropriate management of CRAO, with most strategies based on observational literature and expert opinion. In this scientific statement, we critically appraise the literature on CRAO and provide a framework within which to consider acute treatment and secondary prevention. Methods: We performed a literature review of randomized controlled clinical trials, prospective and retrospective cohort studies, case-control studies, case reports, clinical guidelines, review articles, basic science articles, and editorials concerning the management of CRAO. We assembled a panel comprising experts in the fields of vascular neurology, neuro-ophthalmology, vitreo-retinal surgery, immunology, endovascular neurosurgery, and cardiology, and document sections were divided among the writing group members. Each member received an assignment to perform a literature review, synthesize the data, and offer considerations for practice. Multiple drafts were circulated among the group until consensus was achieved. Results: Acute CRAO is a medical emergency. Systems of care should evolve to prioritize early recognition and triage of CRAO to emergency medical attention. There is considerable variability in management patterns among practitioners, institutions, and subspecialty groups. The current literature suggests that treatment with intravenous tissue plasminogen activator may be effective. Patients should undergo urgent screening and treatment of vascular risk factors. There is a need for high-quality, randomized clinical trials in this field.

Background and purpose According to evidence-based clinical practice guidelines, patients presenting with disabling stroke symptoms should be treated with intravenous tissue plasminogen activator (IV tPA) within 4.5 h of time last known well. However, 25% of strokes are detected upon awakening (i.e., wake-up stroke [WUS]), which renders patients ineligible for IV tPA administered via time-based treatment algorithms, because it is impossible to establish a reliable time of symptom onset. We performed a systematic review and meta-analysis of the efficacy and safety of IV tPA compared with normal saline, placebo, or no treatment in patients with WUS using imaging-based treatment algorithms. Methods We searched MEDLINE, Web of Science, and Scopus between January 1, 2006 and April 30, 2020. We included controlled trials (randomized or nonrandomized), observational cohort studies (prospective or retrospective), and single-arm studies in which adults with WUS were administered IV tPA after magnetic resonance imaging (MRI)- or computed tomography (CT)-based imaging. Our primary outcome was recovery at 90 days (defined as a modified Rankin Scale [mRS] score of 0-2), and our secondary outcomes were symptomatic intracranial hemorrhage (sICH) within 36 h, mortality, and other adverse effects. Results We included 16 studies that enrolled a total of 14,017 patients. Most studies were conducted in Europe (37.5%) or North America (37.5%), and 1757 patients (12.5%) received IV tPA. All studies used MRI-based (five studies) or CT-based (10 studies) imaging selection, and one study used a combination of modalities. Sixty-one percent of patients receiving IV tPA achieved an mRS score of 0 to 2 at 90 days (95% confidence interval [CI]: 51%-70%, 12 studies), with a relative risk (RR) of 1.21 compared with patients not receiving IV tPA (95% CI: 1.01-1.46, four studies). Three percent of patients receiving IV tPA experienced sICH within 36 h (95% CI: 2.5%-4.1%; 16 studies), which is an RR of 4.00 compared with patients not receiving IV tPA (95% CI: 2.85-5.61, seven studies). Conclusions This systematic review and meta-analysis suggests that IV tPA is associated with a better functional outcome at 90 days despite the increased but acceptable risk of sICH. Based on these results, IV tPA should be offered as a treatment for WUS patients with favorable neuroimaging findings.

Introduction: Hyperglycemia is associated with increased lesion volume and worse functional outcome after acute ischemic stroke, however, it is not known whether it is associated with further cerebrovascular events. The aim of this study was to examine the association between admission hyperglycemia and subsequent ischemic stroke. Methods: This was an exploratory analysis of the Platelet Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial, which compared combined clopidogrel/aspirin with aspirin alone with respect to the primary outcome of subsequent ischemic stroke, myocardial infarction, or vascular death. We dichotomized patients based on a serum glucose threshold of 180mg/dl (chosen a priori based on the upper boundary of the active control arm of SHINE). We calculated hazard ratios (HR) for subsequent ischemic stroke at 90 days via a Cox proportional hazards model adjusting for age, sex, study treatment assignment and vascular risk factors. We performed sensitivity analyses excluding patients with a known history of diabetes and in patients whose index event was a TIA vs. minor stroke. Results: Of 4,878 patients in this analysis (mean age 64.6 years), 594 (12.2%) were hyperglycemic on presentation and 267 (5.5%) had a subsequent ischemic stroke within 90 days. Admission hyperglycemia was associated with subsequent ischemic stroke (HR 1.88; 95% CI:1.39-2.53, p Conclusions: Hyperglycemia portends a higher risk of subsequent ischemic stroke after adjusting for known predictors of stroke recurrence. This study may provide further support to pursuing aggressive secondary prevention strategies in this population.

Central retinal artery occlusion (CRAO) is a form of acute ischemic stroke which affects the retina. Intravenous thrombolysis is emerging as a compelling therapeutic approach. However, it is not known which patients may benefit from this therapy because there are no imaging modalities that adequately distinguish viable retina from irreversibly infarcted retina. The inner retina receives arterial supply from the central retinal artery and there is robust collateralization between this circulation and the outer retinal circulation, provided by the posterior ciliary circulation. Fundus photography can show canonical changes associated with CRAO including a cherry-red spot, arteriolar boxcarring and retinal pallor. Fluorescein angiography provides 2-dimensional imaging of the retinal circulation and can distinguish a complete from a partial CRAO as well as central versus peripheral retinal non-perfusion. Transorbital ultrasonography may assay flow through the central retinal artery and is useful in the exclusion of other orbital pathology that can mimic CRAO. Optical coherence tomography provides structural information on the different layers of the retina and exploratory work has described its utility in determining the time since onset of ischemia. Two experimental techniques are discussed. 1) Retinal functional imaging permits generation of capillary perfusion maps and can assay retinal oxygenation and blood flow velocity. 2) Photoacoustic imaging combines the principles of optical excitation and ultrasonic detection and - in animal studies - has been used to determine the retinal oxygen metabolic rate. Future techniques to determine retinal viability in clinical practice will require rapid, easily used, and reproducible methods that can be deployed in the emergency setting.

Introduction: The carotid web is a compelling potential mechanism of embolic ischemic stroke. In this study, we perform a systematic review and meta-analysis to determine the prevalence of ipsilesional carotid webs in patients with acute ischemic stroke. Methods: We performed a systematic review of prospective and retrospective observational studies enrolling consecutive patients with acute ischemic stroke. We included only studies in which high quality imaging of the cervical vessels was performed and in which the presence or absence of carotid web was adjudicated based on established criteria. The prevalence of carotid web was calculated in each study and pooled prevalence calculated via a random effects model. We also calculated relative risks of carotid web ipsilateral versus contralateral to stroke in the same pool of patients and performed sensitivity analyses including patients with cryptogenic stroke, patients less than 60 and patients with cryptogenic stroke Results: A systematic review yielded 3,814 patients from 11 studies of whom 1,127 had cryptogenic stroke. We identified 4 studies in which we could derive data on patients Figure A-C ). The pooled prevalence of ipsilateral carotid web in patients 2 = 66.1%) ( Figure D ). Discussion: Carotid webs are more common in young patients with ESUS than in other stroke subtypes. Future studies concerning the diagnosis and secondary prevention of stroke associated with carotid web should focus on this population.

Introduction: Twenty-five percent of strokes are detected upon awakening (‘wake-up strokes’; WUS) and are not amenable to thrombolytic therapy via existing time-based treatment approaches. We performed a systematic review and meta-analysis of the efficacy and safety of thrombolysis in patients with WUS using imaging-based selection algorithms. Methods: This systematic review was registered through PROSPERO (CRD42020151552). We searched PubMed, Web of Science, and Scopus between January 1, 2006 and April 30, 2020 for controlled trials and observational cohort studies (prospective or retrospective), in which adults with WUS were administered thrombolysis after MR- or CT-based imaging. Our primary outcome was recovery (mRS 0-2) at 90 days and our secondary outcome was symptomatic intracranial hemorrhage (sICH). We assessed risk of bias using the Cochrane Risk of Bias 2.0 and ROBINS-I tools. Results: We included 16 studies that enrolled a total of 14,017 patients. Sixty-one percent of patients receiving tPA achieved a functional recovery at 90 days (95% CI: 51% to 70%; 12 studies), with a relative risk (RR) of recovery of 1.21 compared with patients not receiving tPA (95% CI 1.01 to 1.46; 4 comparative studies). As shown in Figure 1, 3% of patients receiving tPA in the treated WUS stroke group experienced sICH, an RR of 4.0 (95% CI 2.85-5.61) compared with patients not receiving tPA. On meta-regression, advancing age was negatively associated with the RR of recovery (p Conclusions: In patients with WUS, thrombolysis is associated with functional recovery and with a low risk of sICH. This risk is comparable to the sICH rate from tPA-treatment of stroke utilizing the standard protocol timeframe (2.4% in ECASS III). Thrombolysis should be considered in the treatment of WUS in patients with favorable neuroimaging.

Phospholipase D3 (PLD3) is a protein of unclear function that structurally resembles other members of the phospholipase D superfamily. A coding variant in this gene confers increased risk for the development of Alzheimer’s disease (AD), although the magnitude of this effect has been controversial. Because of the potential significance of this obscure protein, we undertook a study to determine whether PLD3 is relevant to memory and cognition in sporadic AD, to observe its distribution in normal human brain and AD-affected brain, to describe its subcellular localization, and to evaluate its molecular function. PLD3 mRNA levels in the human pre-frontal cortex inversely correlated with β-amyloid pathology severity and rate of cognitive decline in 531 participants enrolled in the Religious Orders Study and Rush Memory and Aging Project. PLD3 levels across genetically diverse BXD mouse strains and strains crossed with 5xFAD mice correlated strongly with learning and memory performance in a fear conditioning task. In human neuropathological samples, PLD3 was primarily found within neurons and colocalized with lysosome markers (LAMP2, progranulin, and cathepsins D and B). This colocalization was also present in AD brain with prominent enrichment on lysosomal accumulations within dystrophic neurites surrounding β-amyloid plaques. This pattern of protein distribution was conserved in mouse brain in wild type and the 5xFAD mouse model of cerebral β-amyloidosis. We discovered PLD3 has phospholipase D activity in lysosomes. A coding variant in PLD3 reported to confer AD risk significantly reduced enzymatic activity compared to wild-type PLD3. In summary, this study identified a new functional mammalian phospholipase D isoform which is lysosomal and closely associated with both β-amyloid pathology and cognition.

A 45-year-old right-handed hypertensive man presented with a 6-month history of worsening neuropsychiatric symptoms, abnormal movements, and weight loss. He was hallucinating, apathetic, and having severe insomnia (total sleep duration of 1–2 hours/night). During sleep, his wife noted labored and sonorous breathing. Six months before admission, he led a healthy and active lifestyle.

Background and Purpose: Central retinal artery occlusion results in sudden, painless, usually permanent loss of vision in the affected eye. There is no proven, effective treatment to salvage visual acuity and a clear, unmet need for an effective therapy. In this work, we evaluated the efficacy of intravenous tissue-type plasminogen activator (IV alteplase) in a prospective cohort study and an updated systematic review and meta-analysis. Methods: We enrolled consecutive patients with acute central retinal artery occlusion within 48 hours of symptoms onset and with a visual acuity of Results: We enrolled 112 patients, of whom 25 (22.3% of the cohort) were treated with IV alteplase. One patient had an asymptomatic intracerebral hemorrhage after IV alteplase treatment. Forty-four percent of alteplase-treated patients had recovery of visual acuity when treated within 4.5 hours versus 13.1% of those not treated with alteplase ( P =0.003) and 11.6% of those presenting within 4 hours who did not receive alteplase ( P =0.03). Our updated patient-level meta-analysis of 238 patients included 67 patients treated with alteplase within 4.5 hours since time last known well with a recovery rate of 37.3%. This favorably compares with a 17.7% recovery rate in those without treatment. In linear regression, earlier treatment correlated with a higher rate of visual recovery ( P =0.01). Conclusions: This study showed that the administration of intravenous alteplase within 4.5 hours of symptom onset is associated with a higher likelihood of a favorable visual outcome for acute central retinal artery occlusion. Our results strongly support proceeding to a randomized, placebo-controlled clinical trial.

IMPORTANCE: Genetic studies of Alzheimer disease have focused on the clinical or pathologic diagnosis as the primary outcome, but little is known about the genetic basis of the preclinical phase of the disease. OBJECTIVE: To examine the underlying genetic basis for brain amyloidosis in the preclinical phase of Alzheimer disease. DESIGN, SETTING, AND PARTICIPANTS: In the first stage of this genetic association study, a meta-analysis was conducted using genetic and imaging data acquired from 6 multicenter cohort studies of healthy older individuals between 1994 and 2019: the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease Study, the Berkeley Aging Cohort Study, the Wisconsin Registry for Alzheimer’s Prevention, the Biomarkers of Cognitive Decline Among Normal Individuals cohort, the Baltimore Longitudinal Study of Aging, and the Alzheimer Disease Neuroimaging Initiative, which included Alzheimer disease and mild cognitive impairment. The second stage was designed to validate genetic observations using pathologic and clinical data from the Religious Orders Study and Rush Memory and Aging Project. Participants older than 50 years with amyloid positron emission tomographic (PET) imaging data and DNA from the 6 cohorts were included. The largest cohort, the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease Study (n = 3154), was the PET screening cohort used for a secondary prevention trial designed to slow cognitive decline associated with brain amyloidosis. Six smaller, longitudinal cohort studies (n = 1160) provided additional amyloid PET imaging data with existing genetic data. The present study was conducted from March 29, 2019, to February 19, 2020. MAIN OUTCOMES AND MEASURES: A genome-wide association study of PET imaging amyloid levels. RESULTS: From the 4314 analyzed participants (age, 52-96 years; 2478 participants [57%] were women), a novel locus for amyloidosis was noted within RBFOX1 (β = 0.61, P = 3 × 10(−9)) in addition to APOE. The RBFOX1 protein localized around plaques, and reduced expression of RBFOX1 was correlated with higher amyloid-β burden (β = −0.008, P = .002) and worse cognition (β = 0.007, P = .006) during life in the Religious Orders Study and Rush Memory and Aging Project cohort. CONCLUSIONS AND RELEVANCE: RBFOX1 encodes a neuronal RNA-binding protein known to be expressed in neuronal tissues and may play a role in neuronal development. The findings of this study suggest that RBFOX1 is a novel locus that may be involved in the pathogenesis of Alzheimer disease.

Hypertension is a known risk factor for intracerebral hemorrhage (ICH), but it is unclear whether blood pressure (BP) at hospital arrival can be used to distinguish hypertensive ICH from non-hypertensive etiologies.We performed a single-center cohort study using data from consecutive ICH patients over 12 months. ICH characteristics including etiology were prospectively adjudicated by two attending neurologists. Using adjusted linear regression models, we compared first recorded systolic BPs (SBP) and mean arterial pressures (MAP) in patients with hypertensive vs. other ICH etiologies. We then used area under the ROC curve (AUC) analysis to determine the accuracy of admission BP in differentiating between hypertensive and non-hypertensive ICH.Of 311 patients in our cohort (mean age 70.6 ± 15.6, 50% male, 83% white), the most frequent ICH etiologies were hypertension (50%) and cerebral amyloid angiopathy (CAA; 22%). Mean SBP and MAP for patients with hypertensive ICH was 175.1 ± 32.9 mmHg and 120.4 ± 22.9 mmHg, respectively, compared to 156.4 ± 28.0 mmHg and 109.6 ± 20.3 mmHg in non-hypertensive ICH (p .001). Adjusted models showed that hypertensive ICH patients had higher BPs than those with CAA (mean SBP difference 10.7 mmHg [95% CI 0.8-20.5]; mean MAP difference 8.1 mmHg [1.1-15.0]) and especially patients with other non-CAA causes (mean SBP difference 23.9 mmHg [15.3-32.4]; mean MAP difference 14.5 mmHg [8.5-20.6]). However, on a patient-level, arrival BP did not reliably discriminate between hypertensive and non-hypertensive etiologies (AUC 0.660 [0.599-0.720]).Arrival BP differs between hypertensive and non-hypertensive ICH but should not be used as a primary determinant of etiology, as hypertension may be implicated in various subtypes of ICH.

Background and Purpose— We aimed to compare functional and procedural outcomes of patients with acute ischemic stroke with none-to-minimal (modified Rankin Scale [mRS] score, 0–1) and moderate (mRS score, 2–3) prestroke disability treated with mechanical thrombectomy. Methods— Consecutive adult patients undergoing mechanical thrombectomy for an anterior circulation stroke were prospectively identified at 2 comprehensive stroke centers from 2012 to 2018. Procedural and 90-day functional outcomes were compared among patients with prestroke mRS scores 0 to 1 and 2 to 3 using χ 2 , logistic, and linear regression tests. Primary outcome and significant differences in secondary outcomes were adjusted for prespecified covariates. Results— Of 919 patients treated with mechanical thrombectomy, 761 were included and 259 (34%) patients had moderate prestroke disability. Ninety-day mRS score 0 to 1 or no worsening of prestroke mRS was observed in 36.7% and 26.7% of patients with no-to-minimal and moderate prestroke disability, respectively (odds ratio, 0.63 [0.45–0.88], P =0.008; adjusted odds ratio, 0.90 [0.60–1.35], P =0.6). No increase in the disability at 90 days was observed in 22.4% and 26.7%, respectively. Rate of symptomatic intracerebral hemorrhage (7.3% versus 6.2%, P =0.65), successful recanalization (86.7% versus 83.8%, P =0.33), and median length of hospital stay (5 versus 5 days, P =0.06) were not significantly different. Death by 90 days was higher in patients with moderate prestroke disability (14.3% versus 40.3%; odds ratio, 4.06 [2.82–5.86], P P Conclusions— One-third of patients undergoing mechanical thrombectomy had a moderate prestroke disability. There was insufficient evidence that functional and procedural outcomes were different between patients with no-to-minimal and moderate prestroke disability. Patients with prestroke disability were more likely to die by 90 days.

Frequency and outcomes of mechanical thrombectomy (MT) in clinical practice for patients with severe pre-stroke disability are largely unknown. In this case series, we aim to describe the disability make-up and outcomes of 33 patients with severe pre-stroke disability undergoing MT. Patients with a permanent, severe, pre-stroke disability (modified Rankin Score, mRS, 4-5) were identified from a prospectively-maintained database of consecutive, MT-treated, anterior circulation acute ischemic stroke patients at two comprehensive stroke centers in the United States. We present details on the cause of disability and socio-demographic status as well as procedural and functional outcomes. This study, despite the lack of inferential testing due to limited sample size, provides insight into demographics and outcomes of MT-treated patients with severe pre-stroke disability. Rate of return to functional baseline as well as rates of procedural success and complications were comparable to that reported in the literature for patients without any pre-existing disability.

Introduction: Carotid web is a putative mechanism of cryptogenic ischemic stroke. We aimed to determine the prevalence of carotid web based on assigned stroke mechanism, and hypothesized that carotid webs would be found more frequently in younger cryptogenic stroke patients. Methods: We performed a single-center retrospective cohort study using institutional registry data from consecutive patients with confirmed anterior circulation ischemic stroke between July 2015-September 2017. We reviewed all available computed tomography angiogram (CTA) studies of the neck, and excluded patients who did not have a high-quality CTA of the neck performed. Carotid web was defined as a thin shelf of non-calcified tissue protruding into the lumen of the internal carotid artery immediately distal to the bifurcation, best visualized on sagittal oblique imaging and evident as a small septum on axial imaging. Stroke subtype was adjudicated a priori using validated methods, and we compared relevant risk factors in patients with cryptogenic stroke with and without carotid web. Results: We identified 882 patients with anterior circulation stroke who had a CTA neck available for review (49.3% male, 30% cryptogenic). A total of 7 patients (0.8%) were found to have carotid webs, of which 4 were ipsilateral to a patient’s stroke; all patients with ipsilateral carotid webs were adjudicated to have cryptogenic stroke. Patients with carotid web were younger than other patients in our cohort (age 49.0±14.6 vs. 72.2±14.9 years, p=0.003), and none of them had a history of hypertension (0% vs. 72%, p=0.04). In patients with cryptogenic stroke, overall prevalence of carotid webs was 1.5%, but the prevalence was significantly higher in younger cryptogenic stroke patients (age Discussion: Carotid web may represent an under-recognized occult mechanism of cryptogenic stroke, particularly amongst younger patients.

Background: The current AHA/ASA guidelines recommend only offering mechanical thrombectomy (MT) to patients without pre-stroke disability. We aimed to compare outcomes of acute ischemic stroke patients with none-to-minimal (modified Rankin score, mRS, 0-1) and moderate (mRS 2-3) pre-stroke disability treated with MT. Methods: Consecutive adult patients undergoing MT for an anterior circulation stroke were prospectively identified at two comprehensive stroke centers from 2012-2018. Procedural and 90-day functional outcomes were compared among patients with pre-stroke mRS 0-1 and 2-3 using Chi-squared, logistic, and linear regression tests and were adjusted for prespecified covariates. Results: A total of 881 patients were included (mean age 70±16 years; 45% female) and 259 (29.4%) had moderate pre-stroke disability. Primary outcome of no accumulation of additional disability at 90 days was observed in 22.4% and 26.7% of patients with no-to-minimal and moderate pre-stroke disability, respectively (OR 1.27[0.88-1.81], p=0.2; adjusted OR 1.90[1.24, 2.94], p=0.004, Figure). Rate of symptomatic intracerebral hemorrhage (7.3% vs 6.2%, p=0.65), successful recanalization (86.7% vs 83.8%, p=0.33), and median length of hospital stay (5 vs 5 days, p=0.06) were not significantly different. Mean change in utility weighted mRS from baseline to 90 days was 0.35±0.35 in pre-stroke mRS 0-1 vs -0.38 ±0.32 in pre-stroke mRS 2-3, p=0.17. Death by 90-days was higher in patients with moderate pre-stroke disability (14.3% vs 40.3%, OR 4.06[2.82-5.86], p Interpretation: One-third of patients undergoing MT had a moderate pre-stroke disability. The odds of maintaining pre-stroke functional status at 90-days and procedural success rates were not different between patients with no-to-minimal and moderate pre-stroke disability. However, patients with pre-stroke disability were more likely to die by 90 days.

Introduction: Central retinal artery occlusion (CRAO) is a form of ischemic stroke and necessitates a comprehensive workup, including for cardioembolic sources such as atrial fibrillation (AF). However, the incidence of new AF diagnosed after CRAO is unknown. We aimed to examine the incidence of new, cardiac device-detected AF after CRAO in a large population-based cohort. Methods: Using patient-level data from the Optum® de-identified EHR dataset (2007-2017) linked with Medtronic implantable cardiac device data, we identified patients that had a diagnosis-code corresponding to CRAO and no known history of AF, and who also had either a device in-situ at the time of CRAO or implanted ≤1 year post-CRAO with continuous AF monitoring data available. AF incidence was defined as ≥2 minutes of device-detected AF in a day. Results: Of 467,167 patients screened, 246/433 (56.8%) with CRAO had no history of AF, of whom 39 had an eligible implantable cardiac device (mean age 66.7±14.8, 41.0% female). Prevalence of vascular risk factors was high (hypertension, 71.8%; hyperlipidemia, 61.5%; coronary artery disease, 46.2%). Within 3 months, 7.7% of these patients (n=3) had device-detected AF. At 36 months, 33.3% of patients (n=13). The maximum daily AF burden post CRAO ranged from 2 minutes to 24 hours with a mean of 390±530 minutes. Of the patients with device-detected AF, 9 were found by an implantable cardiac monitor and 4 by pacemaker or defibrillator. Discussion: The rate of long-term AF detection after CRAO was high in patients with implanted cardiac devices, and appears comparable with rates seen after cryptogenic ischemic stroke and in other high-risk populations. Our findings warrant future prospective studies not limited by selection bias.

Introduction: Spontaneous intracerebral hemorrhage (ICH) most commonly arises due to primary etiologies such as hypertensive or cerebral amyloid angiopathy (CAA), but may also occur due to underlying secondary causes such as vascular malformations or intracranial neoplasms. However, focal mass effect may potentially obscure underlying lesions on neuroimaging performed during the acute phase of ICH, and follow-up imaging is often recommended. We sought to determine the yield of interval magnetic resonance imaging (MRI) in identifying cryptogenic ICH etiologies. Methods: We performed a single-center descriptive cohort study of consecutive patients enrolled in an institutional ICH registry over 12 months. ICH features including etiology and acute neuroimaging were prospectively adjudicated, while planned interval follow-up imaging was retrospectively reviewed. We determined the frequency of newly-discovered findings on interval MRI, and classified new findings according to whether or not they contributed meaningfully to patient management. Results: There were 241 ICH patients in our cohort who survived to discharge and did not have MRI-incompatible devices; 44 had planned follow-up imaging and 33 ultimately completed a follow-up MRI. Mean interval between initial and follow-up MRI was 61 (±34) days. New findings were identified in 33% of follow-up cases (11/33), with changes in patient management occurring in 12% (4/33). Age (59.4 vs. 61.5, p=0.74), sex (45% vs. 45% male, p>0.99), and secondary ICH score (median 3 [IQR 2-3] vs. 3 [1-4], p=0.87) were not significantly different between patients who had new findings and those who did not. New findings included cavernoma (n=4; 1 underwent resection), CAA-related changes (n=3), intracranial malignancy (n=2; 1 transitioned to hospice care, 1 led to cancer workup), new embolic stroke (n=1, underwent extended cardiac monitoring), and demyelination (n=1). Conclusions: Interval MRI aided in diagnosing ICH etiology in one-third of patients who received one, though few cases led to direct actionable changes in patient management.

ObjectiveTo determine the impact of delirium on withdrawal of life-sustaining treatment (WLST) after intracerebral hemorrhage (ICH) in the context of established predictors of poor outcome, using data from an institutional ICH registry.MethodsWe performed a single-center cohort study on consecutive patients with ICH admitted over 12 months. ICH features were prospectively adjudicated, and WLST and corresponding hospital day were recorded retrospectively. Patients were categorized using DSM-5 criteria as never delirious, ever delirious (either on admission or later during hospitalization), or persistently comatose. We determined the impact of delirium on WLST using Cox regression models adjusted for demographics and ICH predictors (including Glasgow Coma Scale score), then used logistic regression with receiver operating characteristic curve analysis to compare the accuracy of ICH score–based models with and without delirium category in predicting WLST.ResultsOf 311 patients (mean age 70.6 ± 15.6, median ICH score 1 [interquartile range 1–2]), 50% had delirium. WLST occurred in 26%, and median time to WLST was 1 day (0–6). WLST was more frequent in patients who developed delirium (adjusted hazard ratio 8.9 [95% confidence interval (CI) 2.1–37.6]), with high rates of WLST in both early (occurring ≤24 hours from admission) and later delirium groups. An ICH score-based model was strongly predictive of WLST (area under the curve [AUC] 0.902 [95% CI 0.863–0.941]), and the addition of delirium category further improved the model's accuracy (AUC 0.936 [95% CI 0.909–0.962], p = 0.004).ConclusionDelirium is associated with WLST after ICH regardless of when it occurs. Further study on the impact of delirium on clinician and surrogate decision-making is warranted.

Oxidative stress and decreased cellular responsiveness to oxidative stress are thought to influence brain aging and Alzheimer's disease, but the specific patterns of oxidative damage and the underlying mechanism leading to this damage are not definitively known. The objective of this study was to define the pattern of changes in oxidative-stress related markers by brain region in human Alzheimer's disease and mild cognitive impairment brain tissue. Observational case-control studies were identified from systematic queries of PubMed, ISI Web of Science and Scopus databases and studies were evaluated with appropriate quality measures. The data was used to construct a region-by-region meta-analysis of malondialdehyde, 4-hydroxynonenal, protein carbonylation, 8-hydroxyguanine levels and superoxide dismutase, glutathione peroxidase, glutathione reductase and catalase activities. We also evaluated ascorbic acid, tocopherol, uric acid and glutathione levels. The analysis was complicated in several cases by publication bias and/or outlier data. We found that malondialdehyde levels were slightly increased in the temporal and occipital lobes and hippocampus, but this analysis was significantly impacted by publication bias. 4-hydroxynonenal levels were unchanged in every brain region. There was no change in 8-hydroxyguanine level in any brain region and protein carbonylation levels were unchanged except for a slight increase in the occipital lobe. Superoxide dismutase, glutathione peroxidase and reductase and catalase activities were not decreased in any brain region. There was limited data reporting non-enzymatic antioxidant levels in Alzheimer's disease brain, although glutathione and tocopherol levels appear to be unchanged. Minimal quantitative data is available from brain tissue from patients with mild cognitive impairment. While there is modest evidence supporting minor regional changes in markers of oxidative damage, this analysis fails to identify a consistent pattern of pro-oxidative changes and accumulation of oxidative damage in bulk tissue analysis in the setting of Alzheimer's disease, as has been widely reported.

Intracerebral hemorrhage (ICH) accounts for a disproportionate amount of stroke-related morbidity and mortality. Although chronic hypertension and cerebral amyloid angiopathy are the underlying cerebral vasculopathies accounting for the majority of ICH, there are a broad range of potential causes, and effective management requires accurate identification and treatment of the underlying mechanism of hemorrhage. Magnetic resonance imaging and vascular imaging techniques play a critical role in identifying disease mechanisms. Modern treatment of ICH focuses on rapid stabilization, often requiring urgent treatment of mass effect, aggressive blood pressure reduction and correction of contributing coagulopathies to achieve hemostasis. We discuss management of patients with ICH who continue to require long-term anticoagulation, the interaction of ICH with neurodegenerative diseases, and our approach to prognostication after ICH. We close this review with a discussion of novel medical and surgical approaches to ICH treatment that are being tested in clinical trials.