Atherosclerotic burden and cerebral small vessel disease: exploring the link through microvascular aging and cerebral microhemorrhages.

Cerebral microhemorrhages (CMHs, also known as cerebral microbleeds) are a critical but frequently underestimated aspect of cerebral small vessel disease (CSVD), bearing substantial clinical consequences. Detectable through sensitive neuroimaging techniques, CMHs reveal an extensive pathological landscape. They are prevalent in the aging population, with multiple CMHs often being observed in a given individual. CMHs are closely associated with accelerated cognitive decline and are increasingly recognized as key contributors to the pathogenesis of vascular cognitive impairment and dementia (VCID) and Alzheimer's disease (AD). This review paper delves into the hypothesis that atherosclerosis, a prevalent age-related large vessel disease, extends its pathological influence into the cerebral microcirculation, thereby contributing to the development and progression of CSVD, with a specific focus on CMHs. We explore the concept of vascular aging as a continuum, bridging macrovascular pathologies like atherosclerosis with microvascular abnormalities characteristic of CSVD. We posit that the same risk factors precipitating accelerated aging in large vessels (i.e., atherogenesis), primarily through oxidative stress and inflammatory pathways, similarly instigate accelerated microvascular aging. Accelerated microvascular aging leads to increased microvascular fragility, which in turn predisposes to the formation of CMHs. The presence of hypertension and amyloid pathology further intensifies this process. We comprehensively overview the current body of evidence supporting this interconnected vascular hypothesis. Our review includes an examination of epidemiological data, which provides insights into the prevalence and impact of CMHs in the context of atherosclerosis and CSVD. Furthermore, we explore the shared mechanisms between large vessel aging, atherogenesis, microvascular aging, and CSVD, particularly focusing on how these intertwined processes contribute to the genesis of CMHs. By highlighting the role of vascular aging in the pathophysiology of CMHs, this review seeks to enhance the understanding of CSVD and its links to systemic vascular disorders. Our aim is to provide insights that could inform future therapeutic approaches and research directions in the realm of neurovascular health.

Magnesium and Hematoma Expansion in Intracerebral Hemorrhage: A FAST-MAG Randomized Trial Analysis.

BACKGROUND: Observational studies suggest that magnesium may have hemostatic effects. FAST-MAG (Field Administration of Stroke Therapy-Magnesium) was a pragmatic clinical trial of magnesium sulfate administered prehospital for acute clinical stroke syndromes and included patients with intracerebral hemorrhage. Exploratory secondary analysis by the treatment group found no reduction in hematoma expansion (HE) associated with magnesium treatment in intracerebral hemorrhage but did not consider serum magnesium levels achieved. We analyzed FAST-MAG intracerebral hemorrhage data for associations between serum magnesium level, HE, and early neurological deterioration, accounting for groupwise biases. METHODS: HE was defined as hematoma volume increase ≥3 mL within 24 hours and early neurological deterioration as ≥1-point Glasgow Coma Scale decline from arrival to hospital day 4. Comparing treatment and placebo groups confirmed biased availability of neuroimaging data. Therefore, HE and neurological deterioration were analyzed and stratified by treatment and placebo groups using univariate tests and adjusted logistic regression. RESULTS: Spontaneous intracerebral hemorrhage was present in 381 patients. Placebo patients had fewer serial neuroimaging studies available (123 [65.4%] versus 145 [75.1%]; P=0.038). Necessary data were available in 104 magnesium- and 85 placebo-treated patients (age, 64.9 [13.0] years; 67.7% male). In the magnesium group, higher magnesium level was associated with less HE (adjusted odds ratio, 0.64 per mg/dL [95% CI, 0.42-0.93]) and less neurological deterioration (adjusted odds ratio, 0.54 per mg/dL [95% CI, 0.33-0.82]). In the placebo group, magnesium level was not associated with either HE or neurological deterioration. CONCLUSIONS: Magnesium may exhibit a hemostatic effect that was only observable in the FAST-MAG magnesium treatment group. Equipoise should be maintained, and specific trials are needed. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00059332.

Corrigendum: Neuro-PASC is characterized by enhanced CD4+ and diminished CD8+ T cell responses to SARSCoV-2 Nucleocapsid protein.

[This corrects the article DOI: 10.3389/fimmu.2023.1155770.].

Plasma proteomics show altered inflammatory and mitochondrial proteins in patients with neurologic symptoms of post-acute sequelae of SARS-CoV-2 infection.

Persistent symptoms of COVID-19 survivors constitute long COVID syndrome, also called post-acute sequelae of SARS-CoV-2 infection (PASC). Neurologic manifestations of PASC (Neuro-PASC) are particularly debilitating, long lasting, and poorly understood. To gain insight into the pathogenesis of PASC, we leveraged a well-characterized group of Neuro-PASC (NP) patients seen at our Neuro-COVID-19 clinic who had mild acute COVID-19 and never required hospitalization to investigate their plasma proteome. Using the SomaLogic platform, SomaScan, the plasma concentration of >7000 proteins was measured from 92 unvaccinated individuals, including 48 NP patients, 20 COVID-19 convalescents (CC) without lingering symptoms, and 24 unexposed healthy controls (HC) to interrogate underlying pathobiology and potential biomarkers of PASC. We analyzed the plasma proteome based on post-COVID-19 status, neurologic and non-neurologic symptoms, as well as subjective and objective standardized tests for changes in quality-of-life (QoL) and cognition associated with Neuro-PASC. The plasma proteome of NP patients differed from CC and HC subjects more substantially than post-COVID-19 groups (NP and CC combined) differed from HC. Proteomic differences in NP patients 3-9 months following acute COVID-19 showed alterations in inflammatory proteins and pathways relative to CC and HC subjects. Proteomic associations with Neuro-PASC symptoms of brain fog and fatigue included changes in markers of DNA repair, oxidative stress, and neutrophil degranulation. Furthermore, we discovered a correlation between NP patients lower subjective impression of recovery to pre-COVID-19 baseline with an increase in the concentration of the oxidative phosphorylation protein COX7A1, which was also associated with neurologic symptoms and fatigue, as well as impairment in QoL and cognitive dysfunction. Finally, we identified other oxidative phosphorylation-associated proteins correlating with central nervous system symptoms. Our results suggest ongoing inflammatory changes and mitochondrial involvement in Neuro-PASC and pave the way for biomarker validation for use in monitoring and development of therapeutic intervention for this debilitating condition.

Neuro-PASC is characterized by enhanced CD4+ and diminished CD8+ T cell responses to SARS-CoV-2 Nucleocapsid protein.

Introduction: Many people with long COVID symptoms suffer from debilitating neurologic post-acute sequelae of SARS-CoV-2 infection (Neuro-PASC). Although symptoms of Neuro-PASC are widely documented, it is still unclear whether PASC symptoms impact virus-specific immune responses. Therefore, we examined T cell and antibody responses to SARS-CoV-2 Nucleocapsid protein to identify activation signatures distinguishing Neuro-PASC patients from healthy COVID convalescents. Results: We report that Neuro-PASC patients exhibit distinct immunological signatures composed of elevated CD4+ T cell responses and diminished CD8+ memory T cell activation toward the C-terminal region of SARS-CoV-2 Nucleocapsid protein when examined both functionally and using TCR sequencing. CD8+ T cell production of IL-6 correlated with increased plasma IL-6 levels as well as heightened severity of neurologic symptoms, including pain. Elevated plasma immunoregulatory and reduced pro-inflammatory and antiviral response signatures were evident in Neuro-PASC patients compared with COVID convalescent controls without lasting symptoms, correlating with worse neurocognitive dysfunction. Discussion: We conclude that these data provide new insight into the impact of virus-specific cellular immunity on the pathogenesis of long COVID and pave the way for the rational design of predictive biomarkers and therapeutic interventions.

Multidisciplinary Center Care for Long COVID Syndrome-A Retrospective Cohort Study.

BACKGROUND: Persistent multi-organ symptoms after coronavirus disease 2019 (COVID-19) have been termed "long COVID" or "post-acute sequelae of SARS-CoV-2 infection." The complexity of these clinical manifestations posed challenges early in the pandemic as different ambulatory models formed out of necessity to manage the influx of patients. Little is known about the characteristics and outcomes of patients seeking care at multidisciplinary post-COVID centers. METHODS: We performed a retrospective cohort study of patients evaluated at our multidisciplinary comprehensive COVID-19 center in Chicago, Ill, between May 2020 and February 2022. We analyzed specialty clinic utilization and clinical test results according to severity of acute COVID-19. RESULTS: We evaluated 1802 patients a median of 8 months from acute COVID-19 onset, including 350 post-hospitalization and 1452 non-hospitalized patients. Patients were seen in 2361 initial visits in 12 specialty clinics, with 1151 (48.8%) in neurology, 591 (25%) in pulmonology, and 284 (12%) in cardiology. Among the patients tested, 742/878 (85%) reported decreased quality of life, 284/553 (51%) had cognitive impairment, 195/434 (44.9%) had alteration of lung function, 249/299 (83.3%) had abnormal computed tomography chest scans, and 14/116 (12.1%) had elevated heart rate on rhythm monitoring. Frequency of cognitive impairment and pulmonary dysfunction was associated with severity of acute COVID-19. Non-hospitalized patients with positive SARS-CoV-2 testing had findings similar to those with negative or no test results. CONCLUSIONS: The experience at our multidisciplinary comprehensive COVID-19 center shows common utilization of multiple specialists by long COVID patients, who harbor frequent neurologic, pulmonary, and cardiologic abnormalities. Differences in post-hospitalization and non-hospitalized groups suggest distinct pathogenic mechanisms of long COVID in these populations.

Neurologic Manifestations of Long COVID Differ Based on Acute COVID-19 Severity.

OBJECTIVE: To characterize neurologic manifestations in post-hospitalization Neuro-PASC (PNP) and non-hospitalized Neuro-PASC (NNP) patients. METHODS: Prospective study of the first 100 consecutive PNP and 500 NNP patients evaluated at a Neuro-COVID-19 clinic between 5/2020 and 8/2021. RESULTS: PNP were older than NNP patients (mean 53.9 vs 44.9 y; p < 0.0001) with a higher prevalence of pre-existing comorbidities. An average 6.8 months from onset, the main neurologic symptoms were "brain fog" (81.2%), headache (70.3%), and dizziness (49.5%) with only anosmia, dysgeusia and myalgias being more frequent in the NNP compared to the PNP group (59 vs 39%, 57.6 vs 39% and 50.4 vs 33%, all p < 0.003). Moreover, 85.8% of patients experienced fatigue. PNP more frequently had an abnormal neurologic exam than NNP patients (62.2 vs 37%, p < 0.0001). Both groups had impaired quality of life in cognitive, fatigue, sleep, anxiety, and depression domains. PNP patients performed worse on processing speed, attention, and working memory tasks than NNP patients (T-score 41.5 vs 55, 42.5 vs 47 and 45.5 vs 49, all p < 0.001) and a US normative population. NNP patients had lower results in attention task only. Subjective impression of cognitive ability correlated with cognitive test results in NNP but not in PNP patients. INTERPRETATION: PNP and NNP patients both experience persistent neurologic symptoms affecting their quality of life. However, they harbor significant differences in demographics, comorbidities, neurologic symptoms and findings, as well as pattern of cognitive dysfunction. Such differences suggest distinct etiologies of Neuro-PASC in these populations warranting targeted interventions. ANN NEUROL 2023;94:146-159.

Household income is associated with functional outcomes in a multi-institutional cohort of patients with ischemic stroke and COVID-19.

OBJECTIVES: The COVID-19 pandemic has heightened awareness of health disparities associated with socioeconomic status (SES) across the United States. We examined whether household income is associated with functional outcomes after stroke and COVID-19. MATERIALS AND METHODS: This was a multi-institutional, retrospective cohort study of consecutively hospitalized patients with SARS-CoV-2 and radiographically confirmed stroke presenting from March through November 2020 to any of five comprehensive stroke centers in metropolitan Chicago, Illinois, USA. Zip-code-derived household income was dichotomized at the Chicago median. Logistic regression was used to examine the relationship between household income and good functional outcome (modified Rankin Scale 0-3 at discharge, after ischemic stroke). RESULTS: Across five hospitals, 159 patients were included. Black patients comprised 48.1%, White patients 38.6%, and Hispanic patients 27.7%. Median household income was $46,938 [IQR: $32,460-63,219]. Ischemic stroke occurred in 115 (72.3%) patients (median NIHSS 7, IQR: 0.5-18.5) and hemorrhagic stroke in 37 (23.7%). When controlling for age, sex, severe COVID-19, and NIHSS, patients with ischemic stroke and household income above the Chicago median were more likely to have a good functional outcome at discharge (OR 7.53, 95% CI 1.61 - 45.73; P=0.016). Race/ethnicity were not included in final adjusted models given collinearity with income. CONCLUSIONS: In this multi-institutional study of hospitalized patients with stroke, those residing in higher SES zip codes were more likely to have better functional outcomes, despite controlling for stroke severity and COVID-19 severity. This suggests that area-based SES factors may play a role in outcomes from stroke and COVID-19.

Clinical Reasoning: A Young Adult Man With Cognitive Changes, Gait Difficulty, and Renal Insufficiency.

A 22-year-old right-handed man with recently diagnosed gout and renal insufficiency presented with 3 months of progressive gait instability and cognitive changes. He initially presented to an outside institution and underwent a broad workup, but an etiology for his symptoms was not found. On subsequent presentation to our institution, his examination revealed multidomain cognitive dysfunction, spasticity, hyperreflexia, and clonus. A broad workup was again pursued and was notable for an MRI of the brain, revealing cortical atrophy advanced for his age, bland CSF, and a weakly positive serum acetylcholine receptor ganglionic neuronal antibody of unclear significance. The history of gout and inadequately explained renal insufficiency led to a workup for inborn errors of metabolism, including urine amino acid analysis, which revealed a homocysteine peak. This finding prompted further evaluation, revealing markedly elevated serum homocysteine and methylmalonic acid and low methionine. He ultimately developed superficial venous thromboses, a segmental pulmonary embolism, and clinical and electrographic seizures. He was initiated on appropriate treatment, and his symptoms markedly improved. The case serves as a reminder to include late-onset inborn errors of metabolism in the differential for young adult patients with onset of neurologic, psychiatric, renal, and thromboembolic symptoms.

Patient Income Does Not Predict Disability or Mortality in Hospitalized COVID-19 Patients in a Large Health Care System in the Chicago Metropolitan Area.

Race, income, and their role in COVID-19 infection in the community have been extensively reported, but their impact on outcomes in hospitalized patients is less well defined. We retrospectively analyzed the first 509 COVID-19 patients in our hospital network, examining associations between median household income, 30-day mortality, and ambulatory state at discharge (using the modified Rankin scale (mRS)), adjusting for hospitalization at the academic medical center (AMC) and other variables. Income did not predict mortality. Higher income was associated with slightly increased odds of ability to ambulate at discharge only when accounting for hospital type. At the AMC, income and mortality were lower and functional outcomes more favorable. Patients with lower incomes had greater comorbidity burden. That income was not associated with measures of morbidity and mortality from COVID-19 is a remarkable and encouraging finding. Academic medical centers may mitigate detrimental effects of socioeconomic disparities on COVID-19 seen at the community level.

Therapeutic Approaches to the Neurologic Manifestations of COVID-19.

As of May 2022, there have been more than 527 million infections with severe acute respiratory disease coronavirus type 2 (SARS-CoV-2) and over 6.2 million deaths from Coronavirus Disease 2019 (COVID-19) worldwide. COVID-19 is a multisystem illness with important neurologic consequences that impact long-term morbidity and mortality. In the acutely ill, the neurologic manifestations of COVID-19 can include distressing but relatively benign symptoms such as headache, myalgias, and anosmia; however, entities such as encephalopathy, stroke, seizures, encephalitis, and Guillain-Barre Syndrome can cause neurologic injury and resulting disability that persists long after the acute pulmonary illness. Furthermore, as many as one-third of patients may experience persistent neurologic symptoms as part of a Post-Acute Sequelae of SARS-CoV-2 infection (Neuro-PASC) syndrome. This Neuro-PASC syndrome can affect patients who required hospitalization for COVID-19 or patients who did not require hospitalization and who may have had minor or no pulmonary symptoms. Given the large number of individuals affected and the ability of neurologic complications to impair quality of life and productivity, the neurologic manifestations of COVID-19 are likely to have major and long-lasting personal, public health, and economic consequences. While knowledge of disease mechanisms and therapies acquired prior to the pandemic can inform us on how to manage patients with the neurologic manifestations of COVID-19, there is a critical need for improved understanding of specific COVID-19 disease mechanisms and development of therapies that target the neurologic morbidities of COVID-19. This current perspective reviews evidence for proposed disease mechanisms as they inform the neurologic management of COVID-19 in adult patients while also identifying areas in need of further research.

Evolution of neurologic symptoms in non-hospitalized COVID-19 "long haulers".

OBJECTIVE: We characterized the evolution of neurologic symptoms and self-perceived recovery of non-hospitalized COVID-19 "long haulers" 6-9 months after their initial Neuro-COVID-19 clinic evaluation. METHODS: In this follow-up study on the first 100 patients, 50 SARS-CoV-2 laboratory-positive (SARS-CoV-2+ ), and 50 laboratory-negative (SARS-CoV-2- ), evaluated at our Neuro-COVID-19 clinic between May and November 2020, patients completed phone questionnaires on their neurologic symptoms, subjective impression of recovery and quality of life. RESULTS: Of 52 patients who completed the study (27 SARS-CoV-2+ , 25 SARS-CoV-2- ) a median 14.8 (range 11-18) months after symptom onset, mean age was 42.8 years, 73% were female, and 77% were vaccinated for SARS-CoV-2. Overall, there was no significant change in the frequency of most neurologic symptoms between first and follow-up evaluations, including "brain fog" (81 vs. 71%), numbness/tingling (69 vs. 65%), headache (67 vs. 54%), dizziness (50 vs. 54%), blurred vision (34 vs. 44%), tinnitus (33 vs. 42%), and fatigue (87 vs. 81%). However, dysgeusia and anosmia decreased overall (63 vs. 27%, 58 vs. 21%, both p < 0.001). Conversely, heart rate and blood pressure variation (35 vs. 56%, p = 0.01) and gastrointestinal symptoms (27 vs. 48%, p = 0.04) increased at follow-up. Patients reported improvements in their recovery, cognitive function, and fatigue, but quality of life measures remained lower than the US normative population (p < 0.001). SARS-CoV-2 vaccination did not have a positive or detrimental impact on cognitive function or fatigue. INTERPRETATION: Non-hospitalized COVID-19 "long haulers" continue to experience neurologic symptoms, fatigue, and compromised quality of life 14.8 months after initial infection.

Persistent viral RNA shedding of SARS-CoV-2 is associated with delirium incidence and six-month mortality in hospitalized COVID-19 patients.

BACKGROUND: Persistent viral RNA shedding of SARS-CoV-2 following COVID-19 has increasingly been recognized, with limited understanding of its implications on outcomes in hospitalized COVID-19 patients. METHODS: We retrospectively assessed for persistent viral shedding across Northwestern Medicine Healthcare (NMHC) patients between March and August 2020. We assessed for predictors of persistent viral shedding, in-hospital delirium, and six-month mortality using binary logistic regression. RESULTS: Of the 2,518 hospitalized patients with an RT-PCR-confirmed diagnosis of COVID-19, 959 underwent repeat SARS-CoV-2 RT-PCR at least fourteen days from initial positive testing. Of those, 405 (42.2%) patients were found to have persistent viral shedding. Persistent viral shedding was associated with male sex, increased BMI, diabetes mellitus, chronic kidney disease, and exposure to corticosteroids during initial COVID-19 hospitalization. Persistent viral shedding was independently associated with incidence of in-hospital delirium after adjusting for factors including severity of respiratory dysfunction (OR 2.45; 95% CI 1.75, 3.45). Even after adjusting for age, severity of respiratory dysfunction, and occurrence of in-hospital delirium, persistent viral shedding remained significantly associated with increased six-month mortality (OR 2.43; 95% CI 1.42, 4.29). CONCLUSIONS: Persistent viral shedding occurs frequently in hospitalized COVID-19 patients and is associated with in-hospital delirium and increased six-month mortality.

Stringent public health measures during COVID-19 across ischemic stroke care systems: the potential impact of patient perceptions on health care-seeking behaviors.

Decreases in acute stroke presentations have been reported during the coronavirus disease 2019 (COVID-19) pandemic surges. A recent study by Bojti et al. (GeroScience. 2021;43:2231-2248) sought to understand the relationship of public health mandates in Hungary as they were implemented with acute ischemic stroke admissions and interventions during two separate COVID-19 waves. We sought to perform a similar analysis of changes in ischemic stroke care at two distinct medical institutions in the USA. Two separate institutions and systems of ischemic stroke care were evaluated through a regional comprehensive stroke center telestroke service and a Veterans Affairs (VA) inpatient stroke and neurorehabilitation service. Telestroke consultations in a single system in Chicago, IL, were significantly decreased during the first COVID-19 wave during severely restricted public health mandates (z-score < - 2), and were less depressed during a subsequent wave with less severe restrictions (z-score approaching - 1), which resembles findings in Hungary as reported by Bojti et al. In contrast, inpatient admissions during the first and second COVID-19 waves to a VA stroke and neurorehabilitation service in Oklahoma City remained unchanged. The Chicago and Hungary patterns of stroke presentations suggest that public perceptions, as informed by regional health mandates, might influence healthcare-seeking behavior. However, the VA experience suggests that specific patient populations may react differently to given public health mandates. These observations highlight that changes in stroke presentation during the COVID-19 pandemic may vary regionally and by patient population as well as by the severity of public health mandates implemented. Further study of COVID-19-related public health policies on acute stroke populations is needed to capture the long-term impact of such policies. Learning from the real-time impact of pandemic surges and public health policy on presentation of acute medical conditions, such as ischemic stroke, may prove valuable for designing effective policies in the future.

Plasma Biomarkers of Neuropathogenesis in Hospitalized Patients With COVID-19 and Those With Postacute Sequelae of SARS-CoV-2 Infection.

BACKGROUND AND OBJECTIVES: Although patients hospitalized with COVID-19 frequently present with encephalopathy, those with mild initial COVID-19 disease who never required hospitalization also often develop neurologic symptoms as part of postacute sequelae of severe acute respiratory coronavirus type 2 (SARS-CoV-2) infection (neuro-PASC). The pathogenic mechanisms of COVID-19 encephalopathy and neuro-PASC are unknown. We sought to establish biochemical evidence of CNS injury in those patients and their association with neuropsychiatric manifestations and SARS-CoV-2 antigenemia. METHODS: We recruited hospitalized, posthospitalized, and nonhospitalized patients with confirmed diagnosis of COVID-19 with neurologic symptoms in addition to healthy control (HC) subjects. Plasma neurofilament light chain (pNfL), plasma glial fibrillary acidic protein (pGFAP), and plasma SARS-CoV-2 Nucleocapsid antigen (pN Ag) were measured by HD-X Simoa analyzer (Quanterix) and compared with neuropsychiatric symptoms, patient-reported quality-of-life measures, and standardized cognitive assessments. Neuroglial scores (pGFAP/pNfL) were calculated to estimate the relative contribution of astroglial and neuronal involvement. RESULTS: We enrolled a total of 64 study participants, including 9 hospitalized patients with COVID-19 encephalopathy (CE), 9 posthospitalization neuro-PASC (PNP) patients, 38 nonhospitalized neuro-PASC (NNP) patients, and 8 HC subjects. Patients with CE were older, had higher pNfL and pGFAP concentrations, and more frequent pN Ag detection than all neuro-PASC groups. PNP and NNP patients exhibited similar PASC symptoms, decreased quality-of-life measures, and cognitive dysfunction, and 1 of the 38 (2.6%) NNP patients had pN Ag detectable 3 weeks postsymptoms onset. Patients with neuro-PASC presenting with anxiety/depression had higher neuroglial scores, which were correlated with increased anxiety on quality-of-life measures. DISCUSSION: pNfL, pGFAP, and pN Ag measurements indicate neuronal dysfunction and systemic involvement in hospitalized COVID-19 patients with encephalopathy. Detection of SARS-CoV-2 N Ag in blood 3 weeks after symptoms onset in a nonhospitalized patient suggests that prolonged antigenic stimulation, or possibly latent infection, may occur. Anxiety was associated with evidence of astroglial activation in patients with neuro-PASC. These data shed new light on SARS-Cov-2 neuropathogenesis and demonstrate the value of plasma biomarkers across the COVID-19 disease spectrum.

The Relationship Between Limited English Proficiency and Outcomes in Stroke Prevention, Management, and Rehabilitation: A Systematic Review.

INTRODUCTION: Individuals with limited English proficiency (LEP) face structural challenges to communication in English-speaking healthcare environments. We performed a systematic review to characterize the relationship between LEP and outcomes in stroke prevention, management, and recovery. METHODS: A systematic review was conducted using the PubMed, Embase, Scopus, and Web of Science databases. Titles and abstracts from articles identified were read and selected for full text review. Studies meeting inclusion criteria were reviewed in full for study design, aim, and outcomes. RESULTS: Of 891 unique articles, 20 were included. Eleven articles did not provide information about interpreter availability or usage, limiting the ability to draw conclusions about the effect of LEP on measured outcomes in these studies. Overall, studies demonstrated that English proficiency is associated with better outcomes in preventive aspects of stroke care such as stroke symptom awareness, anticoagulation maintenance, and knowledge of warfarin indication. Some acute stroke care metrics were independent of English proficiency in seven studies while other evidence showed associations between interpreter requirement and quality of inpatient care received. LEP and English-proficient groups show similar mortality despite greater lengths of stay and greater proportions of care in dedicated stroke units for LEP patients. Post-stroke quality of life can be worse for those with LEP, and language barriers can negatively impact patient and provider experiences of rehabilitation. CONCLUSIONS: Stroke patients with LEP face barriers to equitable care at multiple stages. While some studies demonstrate worse outcomes for LEP patients, equitable care was shown in multiple studies frequently in the setting of a high degree of interpreter availability. Patients with LEP will benefit from tailored education regarding stroke symptom recognition and medication regimens, and from provision of translated written educational material. Inequities in inpatient care and rehabilitation exist despite similar mortality rates in four studies. Future studies should report interpreter availability and usage within LEP groups and whether patient interactions were language-concordant or discordant in order to allow for more generalizable and reliable conclusions.

T cell responses to SARS-CoV-2 in people with and without neurologic symptoms of long COVID.

Many people experiencing long COVID syndrome, or post-acute sequelae of SARS-CoV-2 infection (PASC), suffer from debilitating neurologic symptoms (Neuro-PASC). However, whether virus-specific adaptive immunity is affected in Neuro-PASC patients remains poorly understood. We report that Neuro-PASC patients exhibit distinct immunological signatures composed of elevated humoral and cellular responses toward SARS-CoV-2 Nucleocapsid protein at an average of 6 months post-infection compared to healthy COVID convalescents. Neuro-PASC patients also had enhanced virus-specific production of IL-6 from and diminished activation of CD8+ T cells. Furthermore, the severity of cognitive deficits or quality of life disturbances in Neuro-PASC patients were associated with a reduced diversity of effector molecule expression in T cells but elevated IFN-γ production to the C-terminal domain of Nucleocapsid protein. Proteomics analysis showed enhanced plasma immunoregulatory proteins and reduced pro-inflammatory and antiviral response proteins in Neuro-PASC patients compared with healthy COVID convalescents, which were also correlated with worse neurocognitive dysfunction. These data provide new insight into the pathogenesis of long COVID syndrome and a framework for the rational design of predictive biomarkers and therapeutic interventions.

Management of Cerebral Edema, Brain Compression, and Intracranial Pressure.

PURPOSE OF REVIEW: This article reviews the pathophysiology and management of cerebral edema, brain compression, and elevated intracranial pressure (ICP). It also provides a brief introduction to the concept of the glymphatic system and select cellular contributors to cerebral edema. RECENT FINDINGS: Cerebral edema and brain compression should be treated in a tiered approach after the patient demonstrates a symptomatic indication to start treatment. All patients with acute brain injury should be treated with standard measures to optimize intracranial compliance and minimize risk of ICP elevation. When ICP monitors are used, therapies should target maintaining ICP at 22 mm Hg or less. Evidence exists that serial clinical examination and neuroimaging may be a reasonable alternative to ICP monitoring; however, clinical trials in progress may demonstrate advantages to advanced monitoring techniques. Early decompressive craniectomy and hypothermia are not neuroprotective in traumatic brain injury and should be reserved for situations refractory to initial medical interventions. Medical therapies that acutely lower plasma osmolality may lead to neurologic deterioration from osmotic cerebral edema, and patients with acute brain injury and renal or liver failure are at elevated risk. SUMMARY: A tiered approach to the management of cerebral edema and brain compression can reduce secondary brain injury when implemented according to core physiologic principles. However, our knowledge of the pathophysiology of acute brain injury is incomplete, and the conceptual framework underlying decades of clinical management may need to be revised in response to currently evolving discoveries regarding the pathophysiology of acute brain injury.

Acute-care hospital reencounters in COVID-19 patients.

Acute-care hospital reencounters (ACHEs)-encompassing emergency department visits, observation stays, and hospital readmissions-following COVID-19 hospitalization may exacerbate health care system strain and impair recovery from illness. We sought to characterize these reencounters and factors associated with reencounters. We identified the first consecutive 509 patients hospitalized for COVID-19 within an IL hospital network, and examined ACHEs, experienced within 30 days and 4 months of index hospitalization. We identified independent predictors of reencounter using binary logistic regression. Of 509 patients, 466 (91.6%) were discharged alive from index COVID-19 hospitalization. Within 30 days and 4 months, 12.4% and 21.5% of patients, respectively, experienced ACHEs. The median time to first ACHE was 24.2 (IQR 6.5, 55) days. COVID-19 symptom exacerbation was the leading reason for early ACHE (44.8%). Reencounters, both within 30 days and 4 months, were associated with a history of a neurological disorder before COVID-19 (OR 2.78 [95% CI 1.53, 5.03] and OR 2.75 [95% CI 1.67, 4.53], respectively). Older patients and those with diabetes mellitus, chronic obstructive pulmonary disease, or organ transplantation tended towards more frequent ACHEs. Steroid treatment during COVID-19 hospitalization demonstrated reduced odds of 30-day reencounter (OR 0.31 [95% CI 0.091, 0.79]). Forty-nine patients had repeat SARS-CoV-2 nasopharyngeal testing during a reencounter; twelve (24.5%) patients had positive reencounter tests and experienced more frequent reencounters than those testing negative. COVID-19 symptom exacerbation is a leading cause of early ACHE after COVID-19 hospitalization, and steroid use during index hospitalization may reduce early reencounters. Neurologic illness before COVID-19 predicts ACHEs.

Prothrombin Complex Concentrate for Emergent Reversal of Intracranial Hemorrhage in Patients with Ventricular Assist Devices.

BACKGROUND: Intracranial hemorrhage (ICH) is a devastating complication for patients with ventricular assist devices (VADs). The safety of emergent anticoagulation reversal with four-factor prothrombin complex concentrate (PCC) and optimal timing of anticoagulation resumption are not clear. In addition, lactate dehydrogenase (LDH) is used as a biomarker for thromboembolic risk, but its utility in guiding anticoagulation management after reversal with PCC has not be described. METHODS: We retrospectively reviewed a consecutive series of patients with VADs presenting with ICH between 2014 and 2020 who received four-factor PCC for rapid anticoagulation reversal. We collected the timing of PCC administration, timing of resumption of anticoagulation, survival, occurrence of thromboembolic events, and LDH levels throughout hospitalization. RESULTS: We identified 16 ICH events in 14 patients with VADs treated with rapid anticoagulation reversal using four-factor PCC (11 intraparenchymal, 4 subdural, 1 subarachnoid hemorrhage). PCC was administered at a mean of 3.3 ± 0.3 h after imaging diagnosis of ICH. Overall mortality was 63%. Survivors had higher presenting Glasgow Coma Scale (median 15, interquartile range [IQR] 15-15 versus 14, IQR 8-14.7, P = 0.041). In all six instances where the patient survived, anticoagulation was resumed on average 9.16 ± 1.62 days after reversal. There were no thromboembolic events prior to resumption of anticoagulation. Three events occurred after anticoagulation resumption and within 3 months of reversal: VAD thrombosis in a patient with thrombosis at the time of reversal, ischemic stroke, and readmission for elevated LDH in the setting of subtherapeutic international normalized ratio. CONCLUSIONS: Our limited series found no thromboembolic complications immediately following anticoagulation reversal with PCC prior to resumption of anticoagulation. LDH trends may be useful to monitor thromboembolic risk after reversal.