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Although B cells are implicated in multiple sclerosis (MS) pathophysiology, a predictive or diagnostic autoantibody remains elusive. Here, the Department of Defense Serum Repository (DoDSR), a cohort of over 10 million individuals, was used to generate whole-proteome autoantibody profiles of hundreds of patients with MS (PwMS) years before and subsequently after MS onset. This analysis defines a unique cluster of PwMS that share an autoantibody signature against a common motif that has similarity with many human pathogens. These patients exhibit antibody reactivity years before developing MS symptoms and have higher levels of serum neurofilament light (sNfL) compared to other PwMS. Furthermore, this profile is preserved over time, providing molecular evidence for an immunologically active prodromal period years before clinical onset. This autoantibody reactivity was validated in samples from a separate incident MS cohort in both cerebrospinal fluid (CSF) and serum, where it is highly specific for patients eventually diagnosed with MS. This signature is a starting point for further immunological characterization of this MS patient subset and may be clinically useful as an antigen-specific biomarker for high-risk patients with clinically- or radiologically-isolated neuroinflammatory syndromes.

The benefits of coronavirus disease 2019 (COVID-19) vaccination significantly outweigh its risks on a public health scale, and vaccination has been crucial in controlling the spread of SARS-CoV-2. Nonetheless, several reports of adverse events following vaccination have been published.To summarize reports to date and assess the extent and quality of evidence regarding possible serious adverse neurological events following COVID-19 vaccination, focusing on Food and Drug Administration (FDA)-approved vaccines in the United States (BNT162b2, mRNA-1273, and Ad26.COV2.S).A review of literature from five major electronic databases (PubMed, Medline, Embase, Cochrane Library, and Google Scholar) was conducted between December 1, 2020 and June 5, 2022. Articles included in the review were systematic reviews and meta-analysis, cohort studies, retrospective studies, case–control studies, case series, and reports. Editorials, letters, and animal studies were excluded, since these studies did not include quantitative data regarding adverse side effects of vaccination in human subjects.Of 149 total articles and 97 (65%) were case reports or case series. Three phase 3 trials initially conducted for BNT162b2, MRNA-1273, and Ad26.COV2.S were included in the analysis.The amount and quality of evidence for possible neurological adverse events in the context of FDA-approved COVID-19 vaccinations is overall low tier. The current body of evidence continues to suggest that COVID-19 vaccinations have a high neurological safety profile; however, the risks and benefits of vaccination must continue to be closely monitored.

BackgroundAntiretroviral therapy (ART) suppresses plasma and cerebrospinal fluid (CSF) HIV replication with occasional asymptomatic episodes of detectable HIV RNA known as asymptomatic (AS) escape. Neurosymptomatic (NS) CSF escape is a rare exception in which CNS HIV replication occurs in the setting of neurologic impairment. The origins of NS escape are not fully understood.MethodsUsing a large cohort of PLWH (n=111), including elite controllers (n=4), viral controllers (n=4), ART untreated subjects (n=18), HIV-associated dementia (n=4), ART suppressed (n=16), AS escape (n=19), NS escape (n=35), secondary escape (n=5) subjects, and HIV-negative controls (n=6), we investigated immunoreactivity to self-antigens in the CSF of NS escape by employing neuroanatomic CSF immunostaining and massively multiplexed self-antigen serology (PhIP-Seq). Additionally, we utilized pan-viral serology (VirScan) to deeply profile the CSF anti-viral antibody response and metagenomic next-generation sequencing (mNGS) for pathogen detection.ResultsWe detected Epstein-Barr virus (EBV) DNA more frequently in the CSF of NS escape subjects than in AS escape controls. Based on immunostaining and PhIP-Seq, there was evidence for increased immunoreactivity against self-antigens in NS escape CSF. Finally, VirScan revealed several immunodominant epitopes that map to the HIV env and gag proteins in the CSF of PLWH.DiscussionWe deployed agnostic tools to study whether there was evidence for a neuroinvasive co-infection and/or autoimmunity in HIV escape syndromes. We more frequently detected EBV DNA and immunoreactivity to self-antigens in NS escape. Whether these additional inflammatory markers are byproducts of an HIV-driven inflammatory process or whether they independently contribute to the neuropathogenesis of NS escape will require further study.

Prospective studies of encephalitis are rare in regions where encephalitis is prevalent, such as low middle-income Southeast Asian countries. We compared the diagnostic yield of local and advanced tests in cases of pediatric encephalitis in Myanmar.Children with suspected subacute or acute encephalitis at Yangon Children's Hospital, Yangon, Myanmar, were prospectively recruited from 2016-2018. Cohort 1 (n = 65) had locally available diagnostic testing, whereas cohort 2 (n = 38) had advanced tests for autoantibodies (ie, cell-based assays, tissue immunostaining, studies with cultured neurons) and infections (ie, BioFire FilmArray multiplex Meningitis/Encephalitis multiplex PCR panel, metagenomic sequencing, and pan-viral serologic testing [VirScan] of cerebrospinal fluid).A total of 20 cases (13 in cohort 1 and 7 in cohort 2) were found to have illnesses other than encephalitis. Of the 52 remaining cases in cohort 1, 43 (83%) had presumed infectious encephalitis, of which 2 cases (4%) had a confirmed infectious etiology. Nine cases (17%) had presumed autoimmune encephalitis. Of the 31 cases in cohort 2, 23 (74%) had presumed infectious encephalitis, of which one (3%) had confirmed infectious etiology using local tests only, whereas 8 (26%) had presumed autoimmune encephalitis. Advanced tests confirmed an additional 10 (32%) infections, 4 (13%) possible infections, and 5 (16%) cases of N-methyl-D-aspartate receptor antibody encephalitis.Pediatric encephalitis is prevalent in Myanmar, and advanced technologies increase identification of treatable infectious and autoimmune causes. Developing affordable advanced tests to use globally represents a high clinical and research priority to improve the diagnosis and prognosis of encephalitis. ANN NEUROL 2022.

International audience; Varicella vaccine meningitis is an uncommon delayed adverse event of vaccination. Varicella vaccine meningitis has been diagnosed in 12 children, of whom 3 were immunocompromised. We now report two additional cases of vaccine meningitis in twice-immunized immunocompetent children and we perform further testing on a prior third case. We used three methods to diagnose or investigate cases of varicella vaccine meningitis, none of which have been used previously on this disease. These include metagenomic next-generation sequencing and cytokine multiplex profiling of cerebrospinal fluid and immunology exome analysis of white blood cells. In one new case, the diagnosis was confirmed by metagenomic next-generation sequencing of cerebrospinal fluid. Both varicella vaccine virus and human herpesvirus 7 DNA were detected. We performed cytokine multiplex profiling on the cerebrospinal fluid of two cases and found ten elevated biomarkers: interferon gamma, interleukins IL-1RA, IL-6, IL-8, IL-10, IL-17F, chemokines CXCL-9, CXCL-10, CCL-2, and G-CSF. In a second new case, we performed immunology exome sequencing on a panel of 356 genes, but no errors were found. After a review of all 14 cases, we concluded that (i) there is no common explanation for this adverse event, but (ii) ingestion of an oral corticosteroid burst 3–4 weeks before onset of vaccine meningitis may be a risk factor in some cases.

Objectives Tuberculous meningitis(TBM) is a common cause of meningitis in sub-Saharan Africa. CSF PCR with GeneXpert RIF/MTB Ultra is only 70% sensitive for detection of definite/probable TBM. Many infections can mimic TBM. Metagenomic next generation sequencing(mNGS) can detect the whole diversity of infectious microbes, but can be insensitive to TB in CSF. We assessed whether leveraging CSF mNGS to identify infections combined with a machine learning classifier(MLC), based on host transcriptomic data generated by mNGS, could enhance diagnostic accuracy for TBM. Methods Prospectively enrolled 347 HIV-infected Ugandan adults with subacute meningitis: RNA/DNA libraries were made from CSF and deep sequenced. Non-human sequences were interrogated to identify pathogens. A host transcriptomic MLC was developed from human RNA transcripts using 70 cases. The MLC and mNGS reporting thresholds were then tested on 108 blinded cases within the cohort. Results mNGS was 75% concordant(27/36) for detecting TB in definite TBM cases and 59% concordant(30/51) in definite/probable TBM combined. 3 TB and 3 non-TB pathogens were detected in the probable TBM group. In the possible TBM/indeterminant groups, mNGS identified 3 cases of TBM and 17 other pathogens. The combined mNGS and host-MLC displayed 83.3%(5/6) sensitivity, 86.8%(59/68) specificity, with an area under the ROC curve of 0.83(p=0.009). Conclusion mNGS identified an array of infectious TBM mimics, including many treatable and vaccine preventable pathogens. mNGS was 75% concordant with definite TBM. We further enhanced the sensitivity of the CSF mNGS assay by developing the first CSF-based host MLC to discriminate between TBM and its mimics

Author(s): Crawford, Emily D; Acosta, Irene; Ahyong, Vida; Anderson, Erika C; Arevalo, Shaun; Asarnow, Daniel; Axelrod, Shannon; Ayscue, Patrick; Azimi, Camillia S; Azumaya, Caleigh M; Bachl, Stefanie; Bachmutsky, Iris; Bhaduri, Aparna; Brown, Jeremy Bancroft; Batson, Joshua; Behnert, Astrid; Boileau, Ryan M; Bollam, Saumya R; Bonny, Alain R; Booth, David; Borja, Michael Jerico B; Brown, David; Buie, Bryan; Burnett, Cassandra E; Byrnes, Lauren E; Cabral, Katelyn A; Cabrera, Joana P; Caldera, Saharai; Canales, Gabriela; Castaneda, Gloria R; Chan, Agnes Protacio; Chang, Christopher R; Charles-Orszag, Arthur; Cheung, Carly; Chio, Unseng; Chow, Eric D; Citron, Y Rose; Cohen, Allison; Cohn, Lillian B; Chiu, Charles; Cole, Mitchel A; Conrad, Daniel N; Constantino, Angela; Cote, Andrew; Crayton-Hall, Tre'Jon; Darmanis, Spyros; Detweiler, Angela M; Dial, Rebekah L; Dong, Shen; Duarte, Elias M; Dynerman, David; Egger, Rebecca; Fanton, Alison; Frumm, Stacey M; Fu, Becky Xu Hua; Garcia, Valentina E; Garcia, Julie; Gladkova, Christina; Goldman, Miriam; Gomez-Sjoberg, Rafael; Gordon, M Grace; Grove, James CR; Gupta, Shweta; Haddjeri-Hopkins, Alexis; Hadley, Pierce; Haliburton, John; Hao, Samantha L; Hartoularos, George; Herrera, Nadia; Hilberg, Melissa; Ho, Kit Ying E; Hoppe, Nicholas; Hosseinzadeh, Shayan; Howard, Conor J; Hussmann, Jeffrey A; Hwang, Elizabeth; Ingebrigtsen, Danielle; Jackson, Julia R; Jowhar, Ziad M; Kain, Danielle; Kim, James YS; Kistler, Amy; Kreutzfeld, Oriana; Kulsuptrakul, Jessie; Kung, Andrew F

Key Points Question Are anti–SARS-CoV-2 or antineural antibodies present in the cerebrospinal fluid of pediatric patients with COVID-19 and neuropsychiatric symptoms? Findings In this case series of 3 pediatric patients with subacute neuropsychiatric impairment, 2 had intrathecal anti–SARS-CoV-2 antibodies as well as intrathecal antineural antibodies. Anti–transcription factor 4 (TCF4) autoantibodies in one patient who responded to immunotherapy were validated. Meaning A subset of pediatric patients with COVID-19 and subacute neuropsychiatric symptoms have intrathecal antineural autoantibodies, suggesting central nervous system autoimmunity in pediatric patients with COVID-19 and recent neuropsychiatric symptoms., This case series examines whether anti–SARS-CoV-2 and autoreactive antibodies are present in the cerebrospinal fluid (CSF) of pediatric patients with COVID-19 and subacute neuropsychiatric dysfunction., Importance Neuropsychiatric manifestations of COVID-19 have been reported in the pediatric population. Objective To determine whether anti–SARS-CoV-2 and autoreactive antibodies are present in the cerebrospinal fluid (CSF) of pediatric patients with COVID-19 and subacute neuropsychiatric dysfunction. Design, Setting, and Participants This case series includes 3 patients with recent SARS-CoV-2 infection as confirmed by reverse transcriptase–polymerase chain reaction or IgG serology with recent exposure history who were hospitalized at the University of California, San Francisco Benioff Children’s Hospital and for whom a neurology consultation was requested over a 5-month period in 2020. During this period, 18 total children were hospitalized and tested positive for acute SARS-CoV-2 infection by reverse transcriptase–polymerase chain reaction or rapid antigen test. Main Outcomes and Measures Detection and characterization of CSF anti–SARS-CoV-2 IgG and antineural antibodies. Results Of 3 included teenaged patients, 2 patients had intrathecal anti–SARS-CoV-2 antibodies. CSF IgG from these 2 patients also indicated antineural autoantibodies on anatomic immunostaining. Autoantibodies targeting transcription factor 4 (TCF4) in 1 patient who appeared to have a robust response to immunotherapy were also validated. Conclusions and Relevance Pediatric patients with COVID-19 and prominent subacute neuropsychiatric symptoms, ranging from severe anxiety to delusional psychosis, may have anti–SARS-CoV-2 and antineural antibodies in their CSF and may respond to immunotherapy.

Individuals with coronavirus disease 2019 (COVID-19) frequently develop neurological symptoms, but the biological underpinnings of these phenomena are unknown. Through single-cell RNA sequencing (scRNA-seq) and cytokine analyses of cerebrospinal fluid (CSF) and blood from individuals with COVID-19 with neurological symptoms, we find compartmentalized, CNS-specific T cell activation and B cell responses. All affected individuals had CSF anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies whose target epitopes diverged from serum antibodies. In an animal model, we find that intrathecal SARS-CoV-2 antibodies are present only during brain infection and not elicited by pulmonary infection. We produced CSF-derived monoclonal antibodies from an individual with COVID-19 and found that these monoclonal antibodies (mAbs) target antiviral and antineural antigens, including one mAb that reacted to spike protein and neural tissue. CSF immunoglobulin G (IgG) from 5 of 7 patients showed antineural reactivity. This immune survey reveals evidence of a compartmentalized immune response in the CNS of individuals with COVID-19 and suggests a role of autoimmunity in neurologic sequelae of COVID-19., Graphical abstract, Neurological symptoms are frequent in hospitalized individuals with acute COVID-19. Song et al. find that, compared with control individuals, those with COVID-19 with neurologic symptoms have divergent immune responses between the CNS and periphery, including high rates of antineural autoantibodies in their CSF.

On the assumption that a hologram is a superposition of zone plates, one from each point in the object, the authors have produced, by sequential printing of zone plates, holograms which reconstruct a pattern of several bright points on a dark field. The pattern may be prescribed in advance and may be three dimensional. The validity of the method is examined mathematically.