Purpose of Review:There is no consensus or standardized framework to characterize disease activity in CNS neurosarcoidosis, and the existing literature is highly heterogeneous. Here, we aimed to aggregate all longitudinal monitoring metrics in neurosarcoidosis through a systematic review. The review protocol is registered in PROSPERO (ID:533857). Articles were included if they incorporated at least 1 longitudinal monitoring or outcome metric relevant to neurosarcoidosis disease activity. In addition, we aimed to establish an evidence-based clinical framework for characterizing, monitoring, and communicating neurosarcoidosis disease activity, applicable to both clinical care and research. Recent Findings:Of 387 articles initially identified, 67 met the inclusion criteria. Most studies focused on metrics within a single domain (clinical, imaging, or laboratory) or analyzed multiple domains independently. Often, the definitions were not formally outlined. Only 11 studies included a multidomain monitoring metric. Our proposed framework integrates 3 critical domains for assessing the neurosarcoidosis disease activity: (1) clinical, (2) imaging, and (3) laboratory and supports a standardized characterization of the disease, especially when domain results are discordant. The overarching goal in defining the elements of each domain was to prioritize specificity in attributing activity to neurosarcoidosis while minimizing the risk of misattribution. Each domain includes criteria for 4 categories of disease status: "improved," "stable," "worsened," or "resolved." The overall disease status of activity or inactivity is then determined by reconciling the independent domains into a summary disease activity assessment, communicated with additional clinical context, including immune treatment status and neuroanatomic localization. Sustained clinical stability of persistent neurologic symptoms or signs in the absence of MRI or CSF activity is considered in the summary assessment to reflect inactive disease with sustained neurologic deficits. Summary:A systematic review highlighted substantial heterogeneity in how CNS neurosarcoidosis disease activity is measured, with many studies lacking formal definitions and often reporting activity only within isolated domains. This proposed framework integrates multiple domains to comprehensively characterize CNS neurosarcoidosis disease activity. With further validation, this approach has the potential to standardize research practices and improve clinical reasoning and communication.

Background and Objectives Multiple sclerosis (MS) is a chronic progressive, demyelinating autoimmune CNS disease. Autoantibodies to the motif P-(SA)-x-(SGA)-R-(SN)-(LRKH) are a class of predictive markers specific to MS that could add to emerging diagnostic criteria for MS. In this study, we describe the discovery of an MS patient-derived monoclonal antibody (mAb) specific to this motif from memory B cells, and we develop a proof-of-principle autoantibody test to report the prevalence of seropositivity, predict MS early in disease, and identify underlying tolerance-breaking antigens in Epstein-Barr virus (EBV) and the CNS. Methods Peptide tetramers containing the motif were used to screen activated memory B cells, collected from a patient with MS, on the Beacon Optofluidic system. A mAb to the motif and serum samples from clinically diagnosed patients with MS and healthy controls were used to qualify a Luminex xMAP autoantibody serologic test. Antigen discovery methods included phage-immunoprecipitation sequencing (PhIP-Seq), biolayer interferometry, human protein microarrays, isoelectric focusing gels and blots, and immunofluorescence staining of mouse brain cell cultures. Results A mAb cloned from an MS patient's memory B cells binds diverse peptides containing the MS signature motif with affinities ranging from 2 to 25 nM. Consensus peptides defined by alanine scanning PhIP-Seq were used to develop an autoimmune IgG test with a sensitivity equivalent to 0.5 ng/mL mAb, a precision of <11%, and a positivity rate of 11% among a cohort of 179 patients with MS (n = 91 healthy and n = 49 unrelated neurologic disease serum samples were negative). Utility of the assay for prodromal MS was demonstrated using retrospective, longitudinal samples from cases in the Department of Defense Serum Repository. The mAb identified EBV tegument protein BRRF2 as a tolerance-breaking antigen with nanomolar affinity, containing the motif with reactivity to oligoclonal bands in CSF from MS signature-positive patients. Immunocytochemical staining of mixed mouse neuronal cells showed the dominant cross-reactive human antigen to be vimentin. Discussion We describe a test for MS signature autoantibodies that could be used to support MS diagnosis, prodromal research, and early interventions. The integration of this assay with other emerging biomarkers will advance progress toward a combined predictive risk score for MS.

BACKGROUND:TB meningitis (TBM) has up to 50% mortality in people living with HIV. We investigated differences in cerebrospinal fluid (CSF) host immune responses associated with short-term mortality. METHODS:We enrolled a prospective cohort of adults with definite, probable and possible HIV-related TBM in Kampala, Uganda. Metagenomic next-generation sequencing (mNGS) of bulk CSF RNA was used to detect co-infecting or alternate CNS pathogens and refine cohort diagnosis. Host transcriptomic profiles from the refined cohort were then compared between 14-day survivors and non-survivors. RESULTS:CSF mNGS reclassified or excluded 14% of participants based on pathogen detection, yielding 110 participants for transcriptomic analysis, of whom 23% (n=25) died within 14 days. More than 2000 genes were differentially expressed in the CSF based on 14-day mortality (adjusted p-value <0.05). Survivors upregulated T-cell receptor signaling (LCK, FYN, LAT), T-cell survival and differentiation (IL7, CD27, IL12RB1), B-cell receptor signaling (CD81, PLCG2, TNFRSF13C), cytotoxic lymphocyte and NK cell genes (KLRD1, ULBP1), TNF signaling, and class I MHC antigen processing pathways, while downregulating neutrophil chemoattractant CXCL1 and classical complement genes C4A and C4B. Unsupervised clustering identified a hypoinflammatory subgroup with significantly elevated mortality. CONCLUSIONS:Short-term TBM survival was associated with upregulation of adaptive immunity - including T-cell, B-cell, NK cell, and cytotoxic lymphocyte signaling - alongside TNF signaling and IFN-γ-driven class I MHC antigen processing pathways, with concurrent restraint of complement and neutrophil pathways. This supports investigation of targeted immunomodulatory agents that preserve protective responses while selectively dampening injurious innate pathways, rather than broad immunosuppression with corticosteroids.

Abstract Objective To characterize the clinical, radiological, and pathological features of Neuro-Ocular Vasculopathy Associated with Fanconi Anemia (NOVA-FA). Methods Six patients with FA and neurological symptoms were phenotyped using retrospective chart review of clinical notes, neuroimaging, fluorescein angiogram, CSF analysis, and advanced research techniques including extensive infectious testing. Biopsies were reviewed in two patients. Results NOVA-FA is defined by neurological symptoms, retinal vasculopathy, accumulation of punctate cerebellar lesions and/or large mass-like lesions with surrounding vasogenic edema. Histopathology showed vasculopathy without inflammation. Treatments with immunosuppressants appeared largely ineffective. Imaging and pathology suggest a non-inflammatory small vessel vasculopathy as the primary pathology. Interpretation NOVA-FA is a recently identified condition that affects a subset of patients with FA and results in significant disability, including death. The etiology remains unknown, although the condition mimics features of the syndrome “retinal vasculopathy and cerebral leukodystrophy” which is due to dysfunction in DNA repair mechanisms. There is currently no known effective treatment. Key messages What is already known on this topic Fanconi anemia is an inherited DNA-repair disorder, and only scattered case reports and small series have described an acquired neurological and ocular condition in a subset of these patients, and often presumed to be inflammatory. A consistent clinical-radiological definition, an understanding of the underlying mechanism, and evidence to guide treatment have been lacking. What this study adds This series of six patients provides the most detailed clinical, radiological and pathological characterization of the syndrome to date, proposes the name Neuro-Ocular Vasculopathy Associated with Fanconi Anemia (NOVA-FA) with provisional diagnostic criteria, and shows that histopathology, CSF and serum biomarkers, infectious testing and treatment response together point to a non-inflammatory small vessel vasculopathy rather than a primary immune-mediated or infectious process, closely mirroring the DNA-repair disorder RVCL. How this study might affect research, practice or policy The findings argue against reflexive immunosuppression, support earlier recognition of NOVA-FA through defined criteria, and reframe it as a DNA-repair-driven vasculopathy, motivating natural-history and mechanistic studies and the evaluation of vascular-targeted therapies as FA life expectancy rises and this phenotype becomes more common. Social Media Summary If Published None of the co-authors have a X handle that we would like to be tagged. There are scant case reports about this emerging neurologic syndrome in patients with Fanconi Anemia. This study contains the most robust neurological phenotyping of these patients and explores in-depth evaluations for molecular presence of inflammation. Draft: A novel progressive neuro-ocular vasculopathy in Fanconi Anemia (NOVA-FA) presents with enhancing brain lesions and retinal changes. Likely due to microvascular DNA repair failure, not inflammation. #FanconiAnemia #Neurovascular #RareDisease

Background Central nervous system (CNS) infections are diagnostically challenging due to their nonspecific clinical presentations and wide array of potential pathogens. The rising population of immunocompromised patients further complicates this landscape, increasing the prevalence of atypical and opportunistic infections that are often missed by conventional testing.Objective This article provides guidance on the use and clinical interpretation of cerebrospinal fluid (CSF) metagenomic next-generation sequencing (mNGS) in suspected CNS infections.Discussion We highlight the paradigm shift from targeted molecular testing to agnostic mNGS, emphasizing key factors that impact diagnostic utility, including specimen handling, neuroanatomical factors, host inflammatory response, and pathogen kinetics. Using illustrative cases, we demonstrate how these biological and technical variables influence test sensitivity and result adjudication. We further discuss the impact of mNGS on clinical decision-making and current limitations regarding cost and turnaround time.Conclusions Cerebrospinal fluid mNGS is a transformative diagnostic tool, particularly for unusual presentations and in immunocompromised hosts. However, it does not replace clinical judgment and requires careful multidisciplinary interpretation. When integrated thoughtfully with clinical and laboratory data, mNGS can meaningfully reduce the diagnostic gap in CNS infections.

OBJECTIVES:Prolonged disorders of consciousness are common in critically ill patients receiving mechanical ventilation and are often attributed to prolonged sedative exposure in the setting of decreased drug clearance and/or reduced metabolism. Here, in a large sample of critically ill COVID patients obtained over a short period, we tested the assumption that prolonged unconsciousness following benzodiazepine and/or propofol sedation can be attributed to residual exposure. Further, we examine associations between clinical variables on time to recovery of consciousness (RoC) as a framework for the broader critically ill population. DESIGN:Retrospective cohort study. SETTING:Massachusetts General Hospital, Weill Cornell Medicine, Columbia University Irving Medical Center. PATIENTS:Seven hundred eighty-four patients with COVID-19 critical illness in Spring-Summer 2020. INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:We estimated the latest expected RoC (LERoC) using models of sedation exposure that account for sedative-specific pharmacokinetics and critical illness. Our primary exposure variable was a time-weighted dose of analgosedative agents at benzodiazepine and/or propofol cessation; our primary outcome was time to RoC. We estimated relative risks for late RoC (i.e., after LERoC) via multinomial logistic regression. Among individuals with late RoC, we fit a multivariate subdistribution hazard model for time to RoC. Seventy-three percent of patients had RoC before hospital discharge, yet 34% of patients achieving RoC did not do so within pharmacologically plausible sedative elimination times. Patients with late RoC were older and exhibited hypoxemia and acute kidney injury. Patients with dexmedetomidine as an adjunct sedative had a disproportionately larger incidence of early recovery. Patients with early vs. late RoC did not have significantly different discharge dispositions. CONCLUSIONS:In our cohort, the time to RoC was commonly prolonged beyond that expected from sedation exposures alone. These data may aid clinicians and families with expectations of RoC and warrant investigation of alternative determinants of delayed RoC in this population.

To establish a comprehensive research protocol for clinical assessment of patients with neurosarcoidosis (NS) to precisely characterize clinical phenotypes, pathogenic mechanisms, and biomarkers in a longitudinal observational cohort study.

Congenital heart disease is associated with an increased risk of cerebrovascular events. The authors investigated the incidence of stroke and transient ischemic attack (TIA) in adults with congenital heart disease (ACHD). A systematic review was performed per Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to identify all studies reporting the incidence of stroke and TIA in ACHD. Two independent reviewers screened studies, which were included if patients were of age 16 years or older with congenital heart disease and if the outcome was stroke or TIA. Random-effects meta-analysis was conducted to estimate the pooled incidence rate of stroke and TIA with 95% CIs. The Newcastle-Ottawa Scale for Risk of Bias was applied. This systematic review is registered (CRD42022322144). Of 11,028 identified abstracts, 27 studies met inclusion criteria. Twenty-one studies reported mean or median age, which was <60 years in 19 studies. Thirty-nine estimates of incidence rates from 24 studies were entered in the meta-analysis. The pooled incidence rate estimate of stroke and TIA was 0.58 per 100 person-years, with significant heterogeneity between studies (95% CI: 0.39-0.86; I2: 97.8%; P < 0.001). Secondary analyses were performed stratified by outcome subtype. The pooled incidence rate of ischemic stroke was estimated at 0.59 per 100 person-years (95% CI: 0.36-0.95; I2: 98%; P = 0.01). This meta-analysis describes the incidence rate of stroke and TIA in the ACHD population. High-quality studies are needed to identify which ACHD patients are at the highest risk and to develop effective strategies for primary stroke prevention in this population.

BACKGROUND AND OBJECTIVES:Neutropenia is described as a rare adverse event associated with B cell-depleting therapy (BCDT) use in patients with multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). However, little is known about longitudinal clinical outcomes. We estimated the real-world incidence of neutropenia among patients with neuroinflammatory disease treated with BCDT and characterized the clinical course. METHODS:We conducted a retrospective cohort study using electronic medical records to estimate the incidence rate of neutropenia in adults with MS/NMOSD from a neuroimmunology clinic in California between January 6, 2006, and November 2, 2015, treated with ocrelizumab, rituximab, ofatumumab, ublituximab, or inebilizumab. Each clinical course (recurrence, time to recovery of absolute neutrophil count [ANC], postneutropenia treatment) of neutropenia was then presented in a case series. RESULTS:In this cohort of 1,825 patients (6,009 person-years on BCDT), the largest cohort addressing this question to date, 37 developed neutropenia. The estimated incidence rate of neutropenia was 0.62 (95% CI 0.45-0.85) per 100 person-years. The median time from last infusion of current BCDT was 4 months (interquartile range [IQR] 1-6). The median nadir ANC was 390 (IQR 40-960); the nadir ANC was 0 for 6 patients (16%). All patients ultimately recovered to normal counts, except 2 patients developing fluctuating ANCs for months. Among the 32 patients not receiving filgrastim, the median time to ANC recovery was 11 days (95% CI 7-26). Course severity was asymptomatic/mild in 32% (n = 12) while 54% (n = 20) required hospitalization. A confirmed simultaneous infection or infectious prodrome occurred in 23 (62%). After recovery, 30 patients (81%) continued BCDT and 2 (7%) changed within BCDT class. Neutropenia recurred in 13 patients (35%), including 3 who discontinued BCDT after initial neutropenia. The estimated incidence rate of recurrent neutropenia was 0.22 (95% CI 0.13-0.39) per 100 person-years. The mean (SD) time to recurrence from initial neutropenia was 251 (SD: 355) days. DISCUSSION:This study is comprehensive and reflects a large cohort, examining incidence rates of neutropenia with BCDT in MS and NMOSD. Overall, neutropenia was still rare, occurring at a rate of 0.66 per 100 person-years, and infections were associated triggers in some patients. Yet, of relevance to clinicians, neutropenia was not benign: half required hospitalization and 35% experienced recurrence, which is higher than what was reported in clinical trials.

Background Congenital heart disease is associated with an increased risk of cerebrovascular events. Objectives The authors investigated the incidence of stroke and transient ischemic attack (TIA) in adults with congenital heart disease (ACHD). Methods A systematic review was performed per Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to identify all studies reporting the incidence of stroke and TIA in ACHD. Two independent reviewers screened studies, which were included if patients were of age 16 years or older with congenital heart disease and if the outcome was stroke or TIA. Random-effects meta-analysis was conducted to estimate the pooled incidence rate of stroke and TIA with 95% CIs. The Newcastle-Ottawa Scale for Risk of Bias was applied. This systematic review is registered (CRD42022322144). Results Of 11,028 identified abstracts, 27 studies met inclusion criteria. Twenty-one studies reported mean or median age, which was <60 years in 19 studies. Thirty-nine estimates of incidence rates from 24 studies were entered in the meta-analysis. The pooled incidence rate estimate of stroke and TIA was 0.58 per 100 person-years, with significant heterogeneity between studies (95% CI: 0.39-0.86; I2: 97.8%; P < 0.001). Secondary analyses were performed stratified by outcome subtype. The pooled incidence rate of ischemic stroke was estimated at 0.59 per 100 person-years (95% CI: 0.36-0.95; I2: 98%; P = 0.01). Conclusions This meta-analysis describes the incidence rate of stroke and TIA in the ACHD population. High-quality studies are needed to identify which ACHD patients are at the highest risk and to develop effective strategies for primary stroke prevention in this population.

To present a detailed overview of the clinical presentation, radiological findings, and underlying pathology of Fanconi Anemia Associated Neurological Syndrome (FANS).

Introduction: Congenital cardiac lesions result in abnormal flow patterns that increase risk of cerebrovascular events. We investigated the incidence of stroke and transient ischemic attack (TIA) in adults with congenital heart disease (ACHD). Methods: A systematic review was performed per PRISMA guidelines to identify all studies reporting the incidence of stroke and TIA in ACHD. Two independent reviewers screened studies, which were included if patients were age 16 and older with congenital heart disease, and if the outcome was stroke or TIA. Random-effects meta-analysis was conducted to estimate the pooled incidence rate of stroke and TIA with 95% confidence intervals. The Newcastle-Ottawa Scale for risk of bias was applied. This systematic review is registered (CRD42022322144). Results: Of 11,028 identified abstracts, 27 studies met inclusion criteria. 22 studies reported mean or median age, which was less than 60 years in 18 studies. 39 estimates of incidence rates from 24 studies were entered in the meta-analysis. The pooled incidence rate estimate of stroke and TIA was 0.58 per 100 person years, with significant heterogeneity between studies (95% CI 0.39-0.86, I2 97.8%, p<0.001). Secondary analyses were performed stratified by CHD and outcome subtype. The pooled incidence rate of ischemic stroke was estimated at 0.59 per 100 person years (95% CI 0.36-0.95, I2 98%, p=0.01). Conclusions: This meta-analysis found that the incidence rate of stroke and TIA is higher in ACHD than age-adjusted global estimates, and similar to the American Heart Association reported global ischemic stroke incidence rate for individuals >60 years (0.52 per 100 person years).

This systematic review evaluates the evidence for accuracy of automated analyzers that estimate cerebrospinal fluid (CSF) white blood cell counts (WBC) compared to manual microscopy. Inclusion criteria of original research articles included human subjects, English language, and manual microscopy comparator. PUBMED, EMBASE and Cochrane Review databases were searched through 2019 and QUADAS-2 Tool was used for assessment of bias. Data were pooled and analyzed by comparison method, using random effects estimation. Among 652 titles, 554 abstracts screened, 104 full-text review, 111 comparisons from 41 studies were included. Pooled estimates of sensitivity and specificity (n = 7) were 95% (95%-CI 93%-97%) and 84% (95%-CI: 64%-96%), respectively. Pooled R2 estimates (n = 29) were 0.95 (95%-CI: 0.95-0.96); Pooled spearman rho correlation (n = 27) estimates were 0.95 (95% CI 0.95-0.96). Among those comparisons using Bland-Altman analysis (n = 11) pooled mean difference was estimated at 0.98 (95% CI-0.54-2.5). Among comparisons using Passing-Bablok regressions (n = 14) the pooled slope was estimated to be 1.05 (95% CI 1.03-1.07). Q tests of homogeneity were all significant with the exception of the Bland-Altman comparisons (I2 10%, p value 0.35). There is good overall accuracy for CSF WBC by automated hematologic analyzers. These findings are limited by the small sample sizes and inconsistent validation methodology in the reviewed studies.