Utilization of FDA approved treatments for neuromyelitis optica spectrum disorder in clinical practice: A survey study of academic neuroimmunologists.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune condition for which three treatments have been approved since 2019: eculizumab, inebilizumab, and satralizumab. We conducted a survey of U.S. academic neuroimmunologists to assess adoption of these therapies and barriers to use. Thirty-three neuroimmunologists from 18 states completed the survey. Nearly all (88 %) reported using the novel NMOSD treatments (NNTs). They uncommonly switched clinically stable patients to NNTs (69 % switched none, 22 % switched 1-25 % of their patients). For newly diagnosed patients, NNT initiation rates varied. Following relapse, respondents were dichotomized, either switching 75-100 % of patients (60 %) or 0-25 % (40 %). Insurance and cost-related barriers were common.

Real-World Outcomes for Basilar Artery Occlusion Thrombectomy With Mild Deficits: The National Inpatient Sample.

BACKGROUND: Thrombectomy for basilar artery occlusion (BAO) has proven efficacy in patients with moderate-to-severe deficits, but has unclear benefits for those with mild symptoms. METHODS: Using an observational cohort design, the US National Inpatient Sample (2018-2020) was queried for adult patients with basilar artery occlusion and National Institutes of Health Stroke Scale (NIHSS) <10 for patients treated with thrombectomy versus medical management. The primary outcome of routine discharge (to home or self-care) was evaluated using multivariable logistic regression and propensity score matching, adjusted for baseline characteristics, stroke severity, and treatment with thrombolysis. RESULTS: Of 17 019 with basilar artery occlusion, 5795 patients met the criteria for inclusion criteria for our study, and 880 (15.4%) were treated with endovascular thrombectomy. In the propensity score-matched cohort, 880 patients were treated with medical management and endovascular thrombectomy, respectively. In multivariable regression, endovascular thrombectomy was associated with both an increased odds of routine discharge (odds ratio, 1.95 [95% CI, 1.31-2.90]; P=0.001) and a decreased length of hospital stay (B, -0.74 [95% CI, -1.36 to -0.11]; P=0.02) compared with medical management. In the propensity score matched cohort, endovascular thrombectomy remained associated with greater odds of routine discharge (2.01 [95% CI, 1.21-3.34]; P=0.007) but no difference in length of hospital stay (B, -0.22 [95% CI, -0.90 to 0.46]; P=0.53). CONCLUSIONS: Routine discharge was more common in this representative US cohort of patients with basilar artery occlusion and National Institutes of Health Stroke Scale <10 who underwent thrombectomy compared to conventional medical management. These findings suggest thrombectomy may be associated with better functional outcomes despite lower National Institutes of Health Stroke Scale and should be validated in a clinical trial setting.

Neuroimaging mimics of anoxic brain injury: A review.

Diffuse cortical diffusion changes on magnetic resonance imaging (MRI) are characteristically ascribed to global cerebral anoxia, typically after cardiac arrest. Far from being pathognomonic, however, this neuroimaging finding is relatively nonspecific, and can manifest in a myriad of disease states including hypoxia, metabolic derangements, infections, seizure, toxic exposures, and neuroinflammation. While these various conditions can all produce a neuroimaging pattern of widespread cortical diffusion restriction, many of these underlying causes do have subtly unique imaging features that are appreciable on MRI and can be of clinical and diagnostic utility. Specific populations of neurons are variably sensitive to certain types of injury, whether due to differences in perfusion, receptor type density, or the unique tropisms of infectious organisms. In this narrative review, we discuss a number of distinct etiologies of diffuse cortical diffusion restriction on MRI, the unique pathophysiologies responsible for tissue injury, and the resulting neuroimaging characteristics that can be of assistance in differentiating them. As widespread cortical injury from any cause often presents with altered mental status or coma, the differential diagnosis can be enhanced with rapid acquisition of MRI when clinical history or detailed physical examination is limited. In such settings, the distinct imaging features discussed in this article are of interest to both the clinician and the radiologist.

Eptifibatide use in ischemic stroke patients undergoing endovascular thrombectomy: A matched cohort analysis.

Introduction: Small studies have suggested that eptifibatide (EPT) may be safe in acute ischemic stroke (AIS) following intravenous thrombolysis or during endovascular therapy (EVT) for large vessel occlusion (LVO). However, studies are called upon to better delineate the safety of EPT use during EVT. Methods: A comprehensive stroke center registry (09/2015-12/2020) of consecutive adults who had undergone EVT for anterior LVO was queried. Patients treated with EPT were matched with 2 control groups based on known factors associated with intracranial hemorrhage (ICH) risk - age, Alberta Stroke Program Early Computed Tomography Score (ASPECTS), and number of thrombectomy passes. Safety outcomes (intracranial hemorrhage [ICH], parenchymal hematoma [PH-2] grade hemorrhagic transformation, symptomatic ICH [sICH]) and efficacy outcomes (TICI 2B/3 recanalization, 24-h National Institutes of Health Stroke Scale [NIHSS] score), were compared between matched groups using descriptive statistics. In addition, multivariable logistic regression was used to assess for an association between EPT and PH-1/PH-2 grade hemorrhages. Results: A total of 162 patients were included, 54 of whom (33%) received EPT. The rate of ICH was similar between groups (p = 0.62), while PH-2 was significantly more frequent with EPT (16.7% EPT vs. 3.7 vs. 1.9%; p = 0.009), but without significant differences in sICH (5.6% EPT vs. 7.4 vs. 3.7%; p = 0.72). Rates of TICI Score ≥ 2B were nominally higher with EPT use (83.3 vs. 77.8 vs. 77.8%, p = 0.70). Between the EPT and control groups, there were no differences in 24-h NIHSS (p = 0.09) or 90-day mortality (p = 0.58). Our adjusted multivariate analysis identified that the number of passes (p < 0.01), EPT use (p < 0.01), and tandem occlusion (p = 0.03) were independent predictors of PH1/PH2 grade hemorrhage. Additionally, every unit increase in number of passes resulted in a 1.5 times greater odds of a high-grade hemorrhagic transformation in EPT-treated patients (adjusted OR = 1.594). Conclusion: In this single-center analysis, EPT use during EVT was associated with a significantly higher rate of PH1/PH2 grade hemorrhages, but not with differences in sICH, 24-h NIHSS, or 90-day mortality. Randomized prospective trials are needed to determine the safety and efficacy of EPT in this population.

Clinical and radiographic phenotypes of patients with multifocal subcortical versus cortical cerebral infarcts.

BACKGROUND AND PURPOSE: Infarct topology is a key determinant in classification of a stroke as potentially embolic, with cortical and multifocal lesions being presumed embolic. Whether isolated subcortical multifocal infarcts are likely embolic has not been well studied. METHODS: A prospective, single-center cohort study of consecutive patients with acute multifocal strokes confirmed on diffusion-weighting imaging (DWI) was queried, and patients compared according to the presence of isolated subcortical infarct topology versus cortical ± subcortical topology. Descriptive statistics and multivariable logistic regression were used to determine independent predictors of cryptogenic, subcortical infarcts. RESULTS: Of 1739 patients screened, 743 had complete diagnostic testing with DWI evidence of acute infarction, 183 (24.6%) of whom had a multifocal stroke pattern. Isolated subcortical involvement was disproportionate among patients with ESUS (64.9%) when compared to patients with cardioembolic (24.3%) or large vessel disease (10.8%, p<0.01). Following multivariable adjustment, independent predictors of isolated subcortical multifocal infarction were milder strokes (OR 0.94, 95%CI 0.89-0.98) and higher grade Fazekas score (OR 2.32, 95%CI 1.02-5.29), while cardioembolism (OR 0.30, 95%CI 0.08-1.13) and large vessel disease (OR 0.27, 95%CI 0.08-0.91) remained inversely associated (as compared to ESUS). CONCLUSIONS: These data suggest that multifocal subcortical infarctions are less likely to have an associated proximal embolic source than multifocal infarctions with cortical involvement. The strong association with chronic microvascular disease suggests this topology is more consistent with acute-on-chronic microvascular injury rather than an occult embolic source.

Severe Wernicke's Encephalopathy Associated with Cortical Ribboning and Intracranial Hemorrhage.

Wernicke's encephalopathy (WE) is a neurological emergency that results from thiamine deficiency. It is most commonly associated with chronic alcohol consumption but can result from any cause of impaired thiamine absorption or dietary intake. The classic triad of ophthalmoparesis, ataxia, and altered sensorium is rarely seen in toto, and while certain radiographic findings strongly correlate with the disease, one should have a low threshold to suspect (and promptly treat) patients in order to mitigate the risk of morbidity and mortality. However, atypical presentations can result in delayed or missed diagnoses. In this report, we describe a case of severe non-alcoholic WE associated with atypical brain Magnetic resonance imaging (MRI) manifestations of both cortical diffusion restriction and intracranial hemorrhage, which have previously been associated with poor outcomes. Early treatment with high-dose parenteral thiamine resulted in rapid improvement in ocular motility and reversal of MRI abnormalities, and on long-term follow up, the patient had made a marked functional improvement. This case highlights the importance of recognizing these unusual imaging features of WE in a patient with a compatible clinical syndrome in order to make a timely diagnosis and initiate treatment, as there is potential for a good clinical outcome despite these imaging findings.

Resident-Driven Dysphagia Screening Protocol for Expedited Antithrombotic Delivery in Acute Ischemic Stroke.

Background: We implemented a multi-disciplinary process improvement intervention at our Comprehensive Stroke Center with speech/language pathologists to expedite oral medication delivery in stroke patients. Following a failed nursing dysphagia screen, trained neurology physicians screened dysphagia further to approve use of oral medications. We analyzed the safety and efficacy of this intervention. Methods: We analyzed retrospectively collected data for hospital course, timing of first screen, first oral medication use, and complications (e.g., aspiration pneumonia) in consecutive ischemic stroke patients (9/2019-07/2021). Patients were included if they passed a dysphagia assessment by physicians (Ph), nurses (RN), or speech/language pathologists (SLP). Arrival-to-dysphagia screen and arrival-to-antithrombotic were assessed using restricted mean survival time (RMST). Results: Of the 789 included patients, 673 were passed by RN, 104 by SLP, and 12 by Ph. Compared to patients passed by SLP, those passed by Ph were younger and had less severe deficits (P < .01 for both). Patients were screened more quickly by Ph than RN or SLP (median 38 vs 182 vs 1330-min post-arrival, P = .0001; 299-min RMST difference vs RN [95%CI 22-575, P = .03]; 470-min RMST difference vs SLP [95%CI 175-765, P = .002]). This translated to faster oral antithrombotic use for Ph-passed patients (138-min RMST difference vs RN [95%CI 59-216]; 332-min RMST difference vs SLP [95%CI 253-411]). No patients passed by Ph experienced aspiration pneumonia (0%). Conclusions: We safely conducted a physician-driven dysphagia screening paradigm which led to faster oral antithrombotic delivery without signal of patient harm. Physician availability to complete dysphagia screens in acute stroke patients was a limitation.

Functional Recovery in Patients with Acute Stroke and Pre-Existing Disability: A Natural History Study.

OBJECTIVES: We aimed to determine which factors influence recovery in stroke patients with pre-existing disability, as these patients are often excluded from acute treatment trials. MATERIALS AND METHODS: A prospective stroke center registry of admitted patients from 2019-2021 with acute stroke was queried for patients with pre-stroke modified Rankin Scale (mRS) of 0-4. Multivariable logistic regression was used to estimate odds of functional recovery at 90 days (mRS 0-2, or return to pre-stroke mRS). RESULTS: Of 1228 patients, 856 (70%) included patients had pre-stroke mRS 0-4 and 90-day follow-up mRS. The median age was 68y (IQR 59-78), with a median National Institutes of Health Stroke Scale (NIHSS) of 5 (IQR 2-17). Compared to those with mRS 0-1 (n = 596), patients with pre-stroke mRS of 2 (n = 126), 3 (n = 96), or 4 (n = 38) were less likely to achieve functional recovery in univariate analysis. After multivariable adjustment, odds of functional recovery were significantly lower for patients with pre-stroke mRS of 2 (adjusted odds ratio [ORadj] 0.45, 95% confidence interval [CI] 0.28-0.72), but not those with pre-stroke mRS of 3 (ORadj 1.14, 95%CI 0.66-1.97) or 4 (ORadj 0.50, 95%CI 0.21-1.19). Older age (ORadj per year 0.97, 95%CI 0.95-0.97) and higher NIHSS (ORadj per point 0.89, 95%CI 0.88-0.91) were associated with lower odds of functional recovery, while thrombolysis (ORadj 2.43, 95%CI 1.42-4.15) and a cryptogenic stroke mechanism (ORadj 1.57, 95%CI 1.07-2.31) were protective. CONCLUSIONS: Recovery of patients with pre-existing disability was driven by age and stroke severity. Thrombolysis remained predictive of recovery irrespective of age, stroke severity, and pre-stroke disability.

Age Alters Prevalence of Left Atrial Enlargement and Nonstenotic Carotid Plaque in Embolic Stroke of Undetermined Source.

BACKGROUND: Nonstenotic carotid plaque and undetected atrial fibrillation are potential mechanisms of embolic stroke of undetermined source (ESUS), but it is unclear which is more likely to be the contributing stroke mechanism. We explored the relationship between left atrial enlargement (LAE) and nonstenotic carotid plaque across age ranges in an ESUS population. METHODS: A retrospective multicenter cohort of consecutive patients with unilateral, anterior circulation ESUS was queried (2015 to 2021). LAE and plaque thickness were determined by transthoracic echocardiography and computed tomography angiography, respectively. Descriptive statistics were used to compare plaque features in relation to age and left atrial dimensions. RESULTS: Among the 4155 patients screened, 273 (7%) met the inclusion criteria. The median age was 65 years (interquartile range [IQR] 54-74), 133 (48.7%) were female, and the median left atrial diameter was 3.5 cm (IQR 3.1-4.1). Patients with any LAE more frequently had hypertension (85.9% versus 67.2%, P<0.01), diabetes (41.0% versus 25.6%, P=0.01), dyslipidemia (56.4% versus 40.0%, P=0.01), and coronary artery disease (22.8% versus 11.3%, P=0.02). Carotid plaque thickness was greater ipsilateral versus contralateral to the stroke hemisphere in the overall cohort (median 1.9 mm [IQR 0-3] versus 1.5 mm [IQR 0-2.6], P<0.01); however, this was largely driven by the subgroup of patients without any LAE (median 1.8 mm [IQR 0-2.9] versus 1.5 mm [IQR 0-2.5], P<0.01). Compared with patients ≥70 years, younger patients had more carotid plaque ipsilateral versus contralateral (mean difference 0.42 mm±1.24 versus 0.08 mm±1.54, P=0.047) and less moderate-to-severe LAE (6.3% versus 15.3%, P=0.02). CONCLUSIONS: Younger patients with ESUS had greater prevalence of ipsilateral nonstenotic plaque, while the elderly had more LAE. The differential effect of age on the probability of specific mechanisms underlying ESUS should be considered in future studies.

Unique Clinicopathologic Subclassifiers of Cryptogenic Cerebral Emboli.

INTRODUCTION: Ipsilateral nonstenotic (<50%) internal carotid artery (ICA) plaque, cardiac atriopathy, and patent foramen ovale (PFO) may account for a substantial proportion of embolic stroke of undetermined source (ESUS). METHODS: Consecutive stroke patients at our center (2019-2021) with unilateral, anterior circulation ESUS were categorized into the following mutually exclusive etiologies: (1) nonstenotic ipsilateral ICA plaque (NSP, ≥3mm in maximal axial diameter), (2) sex-adjusted mod-to-severe left atrial enlargement (LAE), (3) PFO, and (4) "occult ESUS" (patients who failed to meet criteria for these 3 groups). Descriptive statistics and multivariable logistic regression were used to model group characteristics. RESULTS: Of 132 included patients, the median age was 65 (IQR 56-73), 74 (56%) of whom were White, and 54 (41%) were female. Twenty-one patients (16%) had NSP proximal to the infarct territory, 17 (13%) had LAE, 9 (7%) had a PFO, and 85 (64%) had no other mechanism. Patients with LAE were older (p=0.004), and had more frequent intracranial occlusions of the internal carotid and proximal middle cerebral artery (p=0.048), while tobacco use was most commonly found among patients with NSP (75%) when compared to other ESUS groups (p=0.02). Five of 9 patients with LAE who underwent outpatient telemetry had paroxysmal atrial fibrillation (56%), while zero patients with PFO or NSP had paroxysmal atrial fibrillation (p=0.005). Older age (adjusted OR [aOR] 1.05, 95%CI 1.03-1.07), coronary artery disease (aOR 3.22, 95%CI 1.61-6.44) and hypertension (aOR 2.16, 95%CI 1.14-4.06) were independently associated with LAE, while only tobacco use was associated with NSP when compared to other ESUS subclassifiers (OR 3.18, 95%CI 1.08-0.42). Age and tobacco use were both inversely associated with PFO (aOR 0.93, 95%CI 0.88-0.98, and aOR 0.10, 95%CI 0.02-0.90, respectively). CONCLUSIONS: Certain clinical and radiographic features may be useful in predicting the proximal source of occult cerebral emboli, and can be used for cost-effective outpatient diagnostic testing.

Endovascular thrombectomy time metrics in the era of COVID-19: observations from the Society of Vascular and Interventional Neurology Multicenter Collaboration.

BACKGROUND: Unprecedented workflow shifts during the coronavirus disease 2019 (COVID-19) pandemic have contributed to delays in acute care delivery, but whether it adversely affected endovascular thrombectomy metrics in acute large vessel occlusion (LVO) is unknown. METHODS: We performed a retrospective review of observational data from 14 comprehensive stroke centers in nine US states with acute LVO. EVT metrics were compared between March to July 2019 against March to July 2020 (primary analysis), and between state-specific pre-peak and peak COVID-19 months (secondary analysis), with multivariable adjustment. RESULTS: Of the 1364 patients included in the primary analysis (51% female, median NIHSS 14 [IQR 7-21], and 74% of whom underwent EVT), there was no difference in the primary outcome of door-to-puncture (DTP) time between the 2019 control period and the COVID-19 period (median 71 vs 67 min, P=0.10). After adjustment for variables associated with faster DTP, and clustering by site, there remained a trend toward shorter DTP during the pandemic (ßadj=-73.2, 95% CI -153.8-7.4, Pp=0.07). There was no difference in DTP times according to local COVID-19 peaks vs pre-peak months in unadjusted or adjusted multivariable regression (ßadj=-3.85, 95% CI -36.9-29.2, P=0.80). In this final multivariable model (secondary analysis), faster DTP times were significantly associated with transfer from an outside institution (ßadj=-46.44, 95% CI -62.8 to - -30.0, P<0.01) and higher NIHSS (ßadj=-2.15, 95% CI -4.2to - -0.1, P=0.05). CONCLUSIONS: In this multi-center study, there was no delay in EVT among patients treated for intracranial occlusion during the COVID-19 era compared with the pre-COVID era.

Utility of transesophageal echocardiography in the identification and treatment of occult mechanisms of cerebral infarction.

Cryptogenic stroke comprises approximately 25% of all cases of ischemic stroke. The diagnostic evaluation of these patients remains a challenge in clinical practice. Transesophageal echocardiography (TEE) has been shown to have superior diagnostic accuracy in identifying potential cardioembolic sources of ischemic stroke when compared to transthoracic echocardiography (TTE). However, there has been inconsistent data on the management implications of these new cardiac findings. The addition of TEE to the comprehensive stroke evaluation will better identify potential cardiac sources of embolism (CSE) and will result in significant management changes. A prospective registry of consecutively admitted patients with acute ischemic stroke (1/1/2015-8/10/2020) was retrospectively queried. Patients 18 to 60 years of age with stroke due to mechanisms other than large or small vessel disease, or atrial fibrillation were eligible for inclusion. The primary outcome was any high-risk CSE identified on TEE following unrevealing TTE. Of the 2,404 consecutive stroke patients evaluated during the study period, 263 (11%) met inclusion criteria and the median age was 53 (IQR 46-57). TEE was performed in 108 patients (41%). A high-risk CSE was identified in 36 patients (33%), the majority of which were PFOs (n = 29). TEE led to a clinical management change in 14 patients (39%) after identification of a high-risk CSE; 6 underwent PFO closure and 8 had adjustment to their antithrombotic therapy. The addition of TEE to the comprehensive stroke evaluation led to the identification of a high-risk CSE in one in three patients resulting in significant management changes.

Outcomes associated with antithrombotic strategies in heart failure with reduced ejection fraction and sinus rhythm following acute ischemic stroke.

Purpose: Insufficient data exist regarding the benefit of long-term antiplatelet vs. anticoagulant therapy in the prevention of recurrent ischemic stroke in patients with ischemic stroke and heart failure with reduced ejection fraction (HFrEF). Therefore, this study aimed to compare longitudinal outcomes associated with antiplatelet vs. anticoagulant use in a cohort of patients with stroke and with an ejection fraction of ≤40%. Methods: We retrospectively analyzed single-center registry data (2015-2021) of patients with ischemic stroke, HFrEF, and sinus rhythm. Time to the primary outcome of recurrent ischemic stroke, major bleeding, or death was assessed using the adjusted Cox proportional hazards model and was compared between patients treated using anticoagulation (±antiplatelet) vs. antiplatelet therapy alone after propensity score matching using an intention-to-treat (ITT) approach, with adjustment for residual measurable confounders. Sensitivity analyses included the multivariable Cox proportional hazards model using ITT and as-treated approaches without propensity score matching. Results: Of 2,974 screened patients, 217 were included in the secondary analyses, with 130 patients matched according to the propensity score for receiving anticoagulation treatment for the primary analysis, spanning 143 patient-years of follow-up. After propensity score matching, there was no significant association between anticoagulation and the primary outcome [hazard ratio (HR) 1.10, 95% confidence interval (CI): 0.56-2.17]. Non-White race (HR 2.26, 95% CI: 1.16-4.41) and the presence of intracranial occlusion (HR 2.86, 95% CI: 1.40-5.83) were independently associated with the primary outcome, while hypertension was inversely associated (HR 0.42, 95% CI: 0.21-0.84). There remained no significant association between anticoagulation and the primary outcome in sensitivity analyses. Conclusion: In HFrEF patients with an acute stroke, there was no difference in outcomes of antithrombotic strategies. While this study was limited by non-randomized treatment allocation, the results support future trials of stroke patients with HFrEF which may randomize patients to anticoagulation or antiplatelet.

Imaging as a Selection Tool for Thrombectomy in Acute Ischemic Stroke: Pathophysiologic Considerations.

Large vessel occlusion (LVO) stroke represents a stroke subset associated with the highest morbidity and mortality. Multiple prospective randomized trials have shown that thrombectomy, alone or in conjunction with IV thrombolysis, is highly effective in reestablishing cerebral perfusion and improving clinical outcomes. In unselected patients and especially in patients with poor collaterals, the benefit of reperfusion therapy is exquisitely time sensitive; the earlier thrombectomy is started, the lower the likelihood of disability or death. Understanding both the pathophysiologic underpinnings and the modifying factors of this strong time-to-treatment effect demonstrated in numerous randomized clinical trials is important for implementation of intrahospital workflow measures to maximize time efficiency of thrombectomy. Reducing delays in reperfusion therapy initiation has become a priority in acute stroke care, and therefore a thorough understanding of the main systems-based factors responsible for these delays is critical. Because the time spent evaluating the patient in the emergency department, which typically includes neuroimaging studies performed in scanners remote from the angiography suite, represents the main source of delays in thrombectomy initiation, the direct to angiography (DTA) model has emerged as a means to substantially reduce treatment times and is being instituted at an increasing number of thrombectomy centers across the world. The aim of this report is to introduce DTA as an emerging stroke care paradigm for patients with suspicion of LVO stroke, review results from studies evaluating its feasibility and impact on outcomes, describe current barriers to its more widespread adoption, and propose potential solutions to overcoming these barriers.

Enhanced Virus Detection and Metagenomic Sequencing in Patients with Meningitis and Encephalitis.

Meningitis and encephalitis are leading causes of central nervous system (CNS) disease and often result in severe neurological compromise or death. Traditional diagnostic workflows largely rely on pathogen-specific tests, sometimes over days to weeks, whereas metagenomic next-generation sequencing (mNGS) profiles all nucleic acid in a sample. In this single-center, prospective study, 68 hospitalized patients with known (n = 44) or suspected (n = 24) CNS infections underwent mNGS from RNA and DNA to identify potential pathogens and also targeted sequencing of viruses using hybrid capture. Using a computational metagenomic classification pipeline based on KrakenUniq and BLAST, we detected pathogen nucleic acid in cerebrospinal fluid (CSF) from 22 subjects, 3 of whom had no clinical diagnosis by routine workup. Among subjects diagnosed with infection by serology and/or peripheral samples, we demonstrated the utility of mNGS to detect pathogen nucleic acid in CSF, importantly for the Ixodes scapularis tick-borne pathogens Powassan virus, Borrelia burgdorferi, and Anaplasma phagocytophilum. We also evaluated two methods to enhance the detection of viral nucleic acid, hybrid capture and methylated DNA depletion. Hybrid capture nearly universally increased viral read recovery. Although results for methylated DNA depletion were mixed, it allowed the detection of varicella-zoster virus DNA in two samples that were negative by standard mNGS. Overall, mNGS is a promising approach that can test for multiple pathogens simultaneously, with efficacy similar to that of pathogen-specific tests, and can uncover geographically relevant infectious CNS disease, such as tick-borne infections in New England. With further laboratory and computational enhancements, mNGS may become a mainstay of workup for encephalitis and meningitis. IMPORTANCE Meningitis and encephalitis are leading global causes of central nervous system (CNS) disability and mortality. Current diagnostic workflows remain inefficient, requiring costly pathogen-specific assays and sometimes invasive surgical procedures. Despite intensive diagnostic efforts, 40 to 60% of people with meningitis or encephalitis have no clear cause of CNS disease identified. As diagnostic uncertainty often leads to costly inappropriate therapies, the need for novel pathogen detection methods is paramount. Metagenomic next-generation sequencing (mNGS) offers the unique opportunity to circumvent these challenges using unbiased laboratory and computational methods. Here, we performed comprehensive mNGS from 68 prospectively enrolled patients with known (n = 44) or suspected (n = 24) CNS viral infection from a single center in New England and evaluated enhanced methods to improve the detection of CNS pathogens, including those not traditionally identified in the CNS by nucleic acid detection. Overall, our work helps elucidate how mNGS can become integrated into the diagnostic toolkit for CNS infections.

Decline in Rehab Transfers Among Rehab-Eligible Stroke Patients During the COVID-19 Pandemic.

OBJECTIVE: To characterize differences in disposition arrangement among rehab-eligible stroke patients at a Comprehensive Stroke Center before and during the COVID-19 pandemic. MATERIALS AND METHODS: We retrospectively analyzed a prospective registry for demographics, hospital course, and discharge dispositions of rehab-eligible acute stroke survivors admitted 6 months prior to (10/2019-03/2020) and during (04/2020-09/2020) the COVID-19 pandemic. The primary outcome was discharge to an inpatient rehabilitation facility (IRF) as opposed to other facilities using descriptive statistics, and IRF versus home using unadjusted and adjusted backward stepwise logistic regression. RESULTS: Of the 507 rehab-eligible stroke survivors, there was no difference in age, premorbid disability, or stroke severity between study periods (p>0.05). There was a 9% absolute decrease in discharges to an IRF during the pandemic (32.1% vs. 41.1%, p=0.04), which translated to 38% lower odds of being discharged to IRF versus home in unadjusted regression (OR 0.62, 95%CI 0.42-0.92, p=0.016). The lower odds of discharge to IRF persisted in the multivariable model (aOR 0.16, 95%CI 0.09-0.31, p<0.001) despite a significant increase in discharge disability (median discharge mRS 4 [IQR 2-4] vs. 2 [IQR 1-3], p<0.001) during the pandemic. CONCLUSIONS: Admission for stroke during the COVID-19 pandemic was associated with a significantly lower probability of being discharged to an IRF. This effect persisted despite adjustment for predictors of IRF disposition, including functional disability at discharge. Potential reasons for this disparity are explored.

Sex Differences in Carotid Plaque Composition in Patients With Embolic Stroke of Undetermined Source.

Background We examined sex differences in nonstenotic carotid plaque composition in patients with embolic stroke of undetermined source (ESUS). Methods and Results Patients with anterior circulation ischemic stroke imaged with neck computed tomographic angiography who met criteria for ESUS or had atrial fibrillation were identified. Patients with atrial fibrillation were included as a negative control. Semiautomated plaque quantification software analyzed carotid artery bifurcations. Plaque subcomponent (calcium, intraplaque hemorrhage [IPH], and lipid rich necrotic core) volumes were compared by sex and in paired analyses of plaque ipsilateral versus contralateral to stroke. Multivariate linear regressions tested for associations. Ninety-four patients with ESUS (55% women) and 95 patients with atrial fibrillation (47% women) were identified. Men with ESUS showed significantly higher volumes of calcified plaque (63.9 versus 19.6 mm3, P<0.001), IPH (9.4 versus 3.3 mm3, P=0.008) and a IPH/lipid rich necrotic core ratio (0.17 versus 0.07, P=0.03) in carotid plaque ipsilateral to stroke side than women. The atrial fibrillation cohort showed no significant sex differences in plaque volumes ipsilateral to stroke. Multivariate analyses of the ESUS cohort showed male sex was associated with IPHipsi (ß=0.49; 95% CI, 0.11-0.87) and calciumipsi (ß=0.78; 95% CI, 0.33-1.23). Paired plaque analyses in men with ESUS showed significantly higher calcified plaque (63.9 versus 34.1 mm3, P=0.03) and a trend of higher IPHipsi (9.4 versus 7.5 mm3, P=0.73) and lipid rich necrotic coreipsi (59.0 versus 48.4 mm3, P=0.94) volumes. Conclusions Sex differences in carotid plaque composition in ESUS suggest the possibility of a differential contribution of nonstenosing carotid plaque as a stroke mechanism in men versus women.