Neurology® Neuroimmunology & Neuroinflammation最新文献

{"title":"The Inner Nuclear Layer in Pediatric Multiple Sclerosis.","authors":"Hannah Hummel-Abmeier, Sabine Naxer, Ella Maria Kadas, Hanna Zimmermann, Bianca Knaack, Peter Huppke, Antonia Kowallick, Kolja Meier, Alexander Ulrich Brandt, Friedemann Paul, Michael Schittkowski, Frederike Cosima Oertel, Jutta Gärtner","doi":"10.1212/NXI.0000000000200387","DOIUrl":"10.1212/NXI.0000000000200387","url":null,"abstract":"<p><strong>Background and objectives: </strong>Pediatric onset multiple sclerosis (POMS) leads to optic nerve and retinal damage from optic neuritis (ON) and potential subclinical disease activity. Neuroaxonal retinal damage manifests in peripapillary retinal nerve fiber layer (pRNFL) and macular ganglion cell and inner plexiform layer (GCIP) thinning. Inner nuclear layer (INL) thickness has been suggested to increase with inflammatory activity or after acute ON, and decrease from chronic neurodegeneration. Macular microcysts in the INL have been described in patients with adult MS. The objective of this study was to investigate the INL in a large cohort of POMS as a potential biomarker for evaluation of disease course and therapeutic success.</p><p><strong>Methods: </strong>For this cross-sectional case-control study, we prospectively recruited 153 patients with POMS and 92 controls, including asymptomatic healthy volunteers and children admitted to the hospital with nonretinal disorders. Optical coherence tomography was performed including intraretinal segmentation. Visual function was determined as best corrected visual acuity (BCVA).</p><p><strong>Results: </strong>Eyes of children with POMS with prior ON had increased INL thickness (44.31 µm) compared with control eyes (42.96 µm, <i>p</i> = 0.014), whereas pRNFL (83 µm, <i>p</i> < 0.001) and GCIP thickness (68.42 µm, <i>p</i> < 0.001) were reduced compared with control eyes (pRNFL 97 µm, GCIP 78.53 µm). In eyes without history of ON, INL and other layer thicknesses were not different from controls. pRNFL (B = -2, <i>p</i> < 0.001) and GCIP loss (B = -1.6, <i>p</i> < 0.001), but not INL, were associated with worse BCVA. We found macular microcysts in 1 eye of 1 patient with a history of severe ON (0.3%). INL thickness was not associated with age, sex, disease duration, immunotherapy, disability or the MRI parameters T2 lesion count, T2 lesion volume, contrast-enhancing lesions, or contrast-enhancing lesion volume.</p><p><strong>Discussion: </strong>The INL in POMS shows changes similar to what has been reported in adults, with macular microcysts being much rarer. A lack of cross-sectional association between INL thickness and disease severity may represent the early disease stage with neuroinflammation instead of neurodegeneration being in focus.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 3","pages":"e200387"},"PeriodicalIF":7.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11949277/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-Cell RNA Sequencing in Incontinentia Pigmenti With Neonatal Encephalopathy Reveals Broad Immune Activation Moderated by Steroids.","authors":"Shekeeb S Mohammad, Velda Han, Brian Gloss, Brooke Keating, Hiroya Nishida, Xianzhong Lau, Ruwani Dissanayake, Shrujna Patel, Russell C Dale","doi":"10.1212/NXI.0000000000200358","DOIUrl":"10.1212/NXI.0000000000200358","url":null,"abstract":"<p><strong>Background and objectives: </strong>DNA variations in the NF-kappa-B essential modulator (<i>NEMO</i>) gene are linked to incontinentia pigmenti (IP) and also immunodeficiency and autoinflammatory conditions. Some patients with IP present with neonatal vasculitis-like brain changes, although pathogenesis is unclear. We investigated cell-specific gene expression in a neonate with IP, who had encephalopathy, seizures, and vasculitis-like brain changes, and responded to steroid treatment.</p><p><strong>Methods: </strong>Single-cell RNA (ribonucleic acid) sequencing (scRNAseq), using the HIVE single-cell system, was performed on a neonate with IP, before and after steroid treatment, compared with a sex-matched healthy control toddler.</p><p><strong>Results: </strong>A total of 20,411 cells were sequenced and clustered into 10 cell types. In IP compared with control, upregulated significant gene set enrichment analysis gene ontology pathways (FDR <0.05) included defense response, complement activation, humoral immune response, and phagocytosis across all cell types. After steroid treatment, these pathways were predominantly downregulated in monocytes and neutrophils. The upregulated genes in IP that became downregulated after steroid treatment were interferon-related genes, oligoadenylate synthases, and immunoglobulin genes.</p><p><strong>Discussion: </strong>IP-associated loss of <i>NEMO</i> function is associated with a proinflammatory phenotype, that is moderated by steroids. scRNAseq provides a rationale for immune modulation in an n = 1 setting and valuable insights into the pathogenesis and therapeutics of this rare disease.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 3","pages":"e200358"},"PeriodicalIF":7.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11876987/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143527898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-Cell Transcriptomics Identifies a Prominent Role for the MIF-CD74 Axis in Myasthenia Gravis Thymus.","authors":"Paula Terroba-Navajas, I-Na Lu, Isaak Quast, Michael Heming, Christian W Keller, Lennard Ostendorf, Anja Erika Hauser, Ronja Mothes, Helena Radbruch, Frauke Stascheit, Andreas Georg Otto Meisel, Heinz Wiendl, Gerd Meyer Zu Hörste, Nick Willcox, Jan D Lünemann","doi":"10.1212/NXI.0000000000200384","DOIUrl":"10.1212/NXI.0000000000200384","url":null,"abstract":"<p><strong>Background and objectives: </strong>Myasthenia gravis (MG) is an autoimmune disease most frequently caused by autoantibodies (auto-Abs) against the acetylcholine receptor (AChR) located at the neuromuscular junction. Thymic follicular hyperplasia is present in most of the patients with early-onset AChR-Ab⁺ MG (EOMG), but its cellular and molecular drivers and development remain poorly understood.</p><p><strong>Methods: </strong>We constructed a single cell-based transcriptional profile of lymphoid cell types in thymi from 11 immunotherapy-naïve patients with EOMG. Multiplex histology and ELISA were used to determine migration inhibitory factor (MIF) levels.</p><p><strong>Results: </strong>Within EOMG thymi, we consistently observed 6 distinct clusters of B-cell populations maturing toward germinal center (GC)-associated and Ab-secreting cells, featuring prominent GC activity, as indicated by substantial clonal expansions and cycling B-cell subsets. Cell-cell interactome predictions identified strong interactions between T cells and GC-associated and memory B cells, dominated by B-cell prosurvival signaling through the MIF-CD74 axis. Multiplex histology confirmed abundant expression of CD74 in MG thymic B cells. Circulating MIF levels in EOMG correlated with higher disease severity as assessed by Myasthenia Gravis Foundation of America status.</p><p><strong>Discussion: </strong>Our data not only illustrate and define hyperplastic thymic niches in MG as favorable environments for pathogenic B-cell proliferation, maturation, and persistence but also suggest that the MIF-CD74 axis should be investigated for potential novel therapeutic targeting in EOMG.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 3","pages":"e200384"},"PeriodicalIF":7.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11978437/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SARS-CoV-2 Vaccines and Multiple Sclerosis: An Update.","authors":"Tobias Monschein, Tobias Zrzavy, Paulus S Rommer, Sven G Meuth, Andrew Chan, Thomas Berger, Hans-Peter Hartung","doi":"10.1212/NXI.0000000000200393","DOIUrl":"https://doi.org/10.1212/NXI.0000000000200393","url":null,"abstract":"<p><p>The highly contagious zoonosis coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was declared a pandemic by the World Health Organization on March 11, 2020, and has led to a global health crisis with nearly 777 million confirmed infections and over 7 million deaths worldwide by November 10, 2024.^1-3 Over time, various variants emerged, with Omicron and its sublines dominating the world over the past 3 years.⁴ In addition, there is increasing evidence regarding the immune response of SARS-CoV-2 vaccines, especially for people with multiple sclerosis (MS) receiving disease-modifying therapies. Hence, with this review, we aim to provide an updated overview and recommendations for clinical practice regarding MS and SARS-CoV-2 vaccines, including efficacy and safety, SARS-CoV-2 variants, vaccine hesitancy, and the immune response under treatment with respective disease-modifying therapies.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 3","pages":"e200393"},"PeriodicalIF":7.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12051395/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144032912","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abnormal Brain MRI in Anti-NMDA Receptor Encephalitis: Clinical and Prognostic Implications.","authors":"Laura Khatib, Julie Pique, Nicolas Lundahl Ciano-Petersen, Guillaume Criton, Cristina Birzu, Mélodie Aubart, Marie Benaiteau, Geraldine Picard, Romain Marignier, Clarisse Carra-Dalliere, Xavier Ayrignac, Dimitri Psimaras, Pierre M Labauge, Jerome Honnorat, Francois Cotton, Bastien Joubert","doi":"10.1212/NXI.0000000000200378","DOIUrl":"10.1212/NXI.0000000000200378","url":null,"abstract":"<p><strong>Background and objectives: </strong>Abnormal brain MRI is associated with poor outcomes in anti-N-methyl-d-aspartate receptor encephalitis (NMDARE). We aimed to characterize the lesions on brain MRI in NMDARE and to assess the clinical and prognostic associations.</p><p><strong>Methods: </strong>This retrospective cohort study included patients with NMDARE identified at the French Reference Center for Autoimmune Encephalitis, with at least a one-year follow-up, and with available brain MRI results. In case of brain extralimbic lesion, the image files were reviewed when available. Clinical data were collected from medical records. Multivariable logistic regression analysis was used to study the outcomes at 2-year follow-up; recovery was defined as modified Rankin Scale score ≤1.</p><p><strong>Results: </strong>Among the 255 patients included, 37 (14.5%) had limbic hyperintensities and 41 (16.1%) had extralimbic lesions that included multiple sclerosis (MS)-like lesions (14/41, 34.1%); extensive lesions (5/41, 12.2%); and poorly demarcated fluffy lesions, either multifocal (10/41, 24.4%) or involving the cerebral cortex or cerebellum (6/41 each, 14.6%). Extralimbic lesions coexisting with limbic lesions (19/41 patients, 46.3%) were mostly fluffy lesions (11/19, 57.9%). Ten patients had overlapping demyelinating syndromes: 4 with MS, 4 with myelin oligodendrocyte glycoprotein-associated disorder, and 2 with neuromyelitis optica spectrum disorder; all had MS-like (7/10 patients) or extensive (3/10 patients) lesions, and none had fluffy lesions. Extralimbic lesions were associated with symptoms nontypical for NMDARE (23/41, 56.1%, <i>p</i> < 0.001), especially cerebellar ataxia (17/41, 41.5%) and motor impairment (12/41, 29.3%). At 2 years, patients with MS-like or extensive lesions had a lower recovery rate (5/12, 41.7%, and 1/4, 25%, respectively) compared with the patients without extralimbic lesions (124/162, 76.5%; <i>p</i> = 0.014 and <i>p</i> = 0.047, respectively). In multivariable analysis, MS-like lesions, but not hippocampal nor fluffy lesions, were associated with absence of recovery at 2 years (adjusted OR 0.1, 95% CI 0.03-0.42, <i>p</i> = 0.002; extensive lesions [n = 4] not included in the analysis).</p><p><strong>Discussion: </strong>Brain MRI lesions in NMDARE include limbic hyperintensities and 3 patterns of extralimbic lesions, which are associated with nontypical NMDARE symptoms. Moreover, MS-like and extensive lesions, but not fluffy nor hippocampal lesions, are associated with overlapping demyelinating syndromes and poor clinical outcomes at 2 years. These findings can have practical implications on the monitoring of patients with NMDARE.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 3","pages":"e200378"},"PeriodicalIF":7.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11867192/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143502423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abatacept Induces Long-Term Reconstitution of the B-Cell Niche in a Patient With CTLA-4 Haploinsufficiency: A Case Report.","authors":"Steffen Pfeuffer, Christopher Nelke, Marc Pawlitzki, Tobias Ruck, Christina B Schroeter, Christian Thomas, Guido Kobbe, Sascha Dietrich, Alexander A Zimprich, Heinz Wiendl, Sven G Meuth","doi":"10.1212/NXI.0000000000200351","DOIUrl":"10.1212/NXI.0000000000200351","url":null,"abstract":"<p><strong>Objectives: </strong>Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) haploinsufficiency is a rare genetic condition characterized by development of immune cytopenia, hypogammaglobulinemia, and/or lymphoproliferative disorder, as well as multiple autoimmunity. Treatment with abatacept was shown to alleviate autoimmune conditions, yet its long-lasting impact on bone marrow function remains undetermined.</p><p><strong>Methods: </strong>We here present the case of a now 39-year-old woman with CTLA-4 haploinsufficiency with predominant CNS affection, yet multiorgan autoimmunity and lymphopenia. We conducted single-cell RNA sequencing (scRNA-seq) of peripheral mononuclear blood cells before and after abatacept induction.</p><p><strong>Results: </strong>After several high-efficacy immunosuppressive treatments with little-to-no response, she started abatacept in 2017 and experienced ongoing remission including resolution of pre-existing immune cytopenia and hypogammaglobulinemia. Using scRNA-seq, we were able to demonstrate reconstitution of peripheral B cells accompanied by reduction of CD8⁺ T cells. CD4⁺ and CD8⁺ T cells were characterized by downregulation of pathways involved in activation of innate immune cells.</p><p><strong>Discussion: </strong>Our findings demonstrate long-lasting resolution of lymphopenia after abatacept treatment in CTLA-4 haploinsufficiency despite severity and duration of symptoms. Thus, abatacept should be considered throughout before stem cell transplantation also in CTLA-4 haploinsufficiency with severe symptoms.</p><p><strong>Classification of evidence: </strong>As a single report without controls, this report provides class IV evidence that abatacept might revert lymphopenia in patients with CTLA-4 haploinsufficiency.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 2","pages":"e200351"},"PeriodicalIF":7.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11655169/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142847393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Contribution of Blood Biomarkers to Multiple Sclerosis Diagnosis.","authors":"Manuel Comabella, Agustín Pappolla, Enric Monreal, Nicolás Fissolo, Augusto Cesaar Sao-Avilés, Georgina Arrambide, Pere Carbonell-Mirabent, Lucía Gutierrez, Álvaro Cobo-Calvo, Carmen Tur, Javier Villacieros-Álvarez, Ángela Vidal-Jordana, Joaquín Castilló, Ingrid Galán, Mercedes Espiño, Helena Ariño, Luca Bollo, Marta Rodríguez Barranco, Luciana Soledad Midaglia, René Carvajal, Noelia Villarrubia, José Ignacio Fernández Velasco, Breogán Rodríguez Acevedo, Lucienne F Costa Frossard, Andreu Vilaseca, Cristina Auger, Ana Zabalza, Susana Sainz De La Maza, Neus Mongay-Ochoa, Jordi Río, Jaume Sastre-Garriga, Àlex Rovira, Mar Tintoré, Luisa M Villar, Xavier Montalban","doi":"10.1212/NXI.0000000000200370","DOIUrl":"10.1212/NXI.0000000000200370","url":null,"abstract":"<p><strong>Background and objectives: </strong>Invasive procedures may delay the diagnostic process in multiple sclerosis (MS). We investigated the added value of serum neurofilament light chain (sNfL), glial fibrillary acidic protein (sGFAP), chitinase-3-like 1 (sCHI3L1), and the immune responses to the Epstein-Barr virus-encoded nuclear antigen 1 to current MS diagnostic criteria.</p><p><strong>Methods: </strong>In this multicentric study, we selected patients from 2 prospective cohorts presenting a clinically isolated syndrome (CIS). Patients were classified as (1) not presenting dissemination in space (DIS) nor dissemination in time (DIT) (noDIS and noDIT); (2) presenting DIS without DIT (DIS and noDIT); and (3) presenting both (DIS and DIT), which were used as a reference. sNfL, sGFAP, and sCHI3L1 levels were measured with single-molecule array immunoassays and EBNA1-specific IgG levels with ELISA. Biomarker levels were compared between groups using linear regression models. Receiver operating characteristic curve analyses and Youden Index were used to determine cutoff values associated with MS diagnosis during follow-up.</p><p><strong>Results: </strong>We included 181 patients (66.3% females, mean [SD] age of 35.0 [9.7] years). At baseline, 25 (13.8%) were classified as noDIS and noDIT, 62 (34.3%) as DIS and noDIT, and 94 (51.9%) as DIS and DIT. Only sNfL Z-scores discriminated between groups (DIS and DIT vs DIS and noDIT [<i>p</i> = 0.002], DIS and DIT vs noDIS and noDIT [<i>p</i> < 0.001], and DIS and noDIT vs noDIS and noDIT [<i>p</i> = 0.026]). In noDIS and noDIT patients (median interquartile range [IQR] follow-up of 8.1 [5.0-11.7] years), high sNfL Z-scores best predicted MS diagnosis (specificity [SP] and 95% CI of 93.3% [68.1-99.8] and positive predictive value [PPV] of 87.5% [47.3-99.7]). Among DIS and noDIT patients (median [IQR] follow-up of 6.8 [4.0-9.1] years), high sNfL Z-scores best predicted MS diagnosis (SP of 80% [28.4-99.5] and PPV of 97.3% [85.8-99.9]) without considering oligoclonal band (OB) status. In the subset of patients of this group with negative OBs, a combination of high sNfL Z-scores and sGFAP levels predicted MS diagnosis (SP of 100% [39.8-100] and PPV of 100% [54.1-100]).</p><p><strong>Discussion: </strong>These results suggest that sNfL and sGFAP may be incorporated in particular scenarios to diagnose MS in patients with CIS not fulfilling current diagnostic criteria.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 2","pages":"e200370"},"PeriodicalIF":7.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11781269/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143067123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aberrant Complement Activation Is Associated With Structural Brain Damage in Multiple Sclerosis.","authors":"Johanna Oechtering, Sabine Anna Schaedelin, Kerstin Stein, Aleksandra Maleska Maceski, Lester Melie-Garcia, Pascal Benkert, Alessandro Cagol, Selina Leber, Riccardo Galbusera, Esther Ruberte, Wayne Hu, Ferhan Qureshi, Annette Orleth, Lilian Demuth, Eline Willemse, Ingmar Heijnen, Axel Regeniter, Tobias J Derfuss, Bettina Fischer-Barnicol, Lutz Achtnichts, Stefanie Mueller, Robert Hoepner, Patrice H Lalive, Claire Bridel, Marcus D'Souza, Caroline Pot, Renaud A Du Pasquier, Claudio Gobbi, Chiara Zecca, Heinz Wiendl, Johanna Maria Lieb, Christina Lamers, Ludwig Kappos, Marten Trendelenburg, David Leppert, Cristina Granziera, Jens Kuhle, Jan D Lünemann","doi":"10.1212/NXI.0000000000200361","DOIUrl":"https://doi.org/10.1212/NXI.0000000000200361","url":null,"abstract":"<p><strong>Background and objectives: </strong>Levels of activated complement proteins in the CSF are increased in people with multiple sclerosis (MS) and are associated with clinical disease severity. In this study, we determined whether complement activation profiles track with quantitative MRI metrics and liquid biomarkers indicative of disease activity and progression.</p><p><strong>Methods: </strong>Complement components and activation products (Factor H and I, C1q, C3, C4, C5, Ba, Bb, C3a, C4a, C5a, and sC5b-9) and liquid biomarkers (neurofilament light chain, glial fibrillary acidic protein [GFAP], CXCL-13, CXCL-9, and IL-12b) were quantified in the CSF of 112 patients with clinically isolated syndromes and 127 patients with MS; longitudinal MRIs according to a standardized protocol of the Swiss MS cohort were assessed. We used multivariable models to analyze associations of the 12 complement parameters as individual independent variables and longitudinal brain volumes, T2-weighted (T2w) lesion volumes, contrast-enhancing (CELs) and paramagnetic rim lesions (PRLs), and molecular biomarkers as dependent variables, respectively.</p><p><strong>Results: </strong>Strongest associations with accelerated brain atrophy were found for C4a: doubling of C4a CSF levels was associated with an additional brain volume loss of -0.24% (95% CI -0.31% to -0.16%; <i>p</i> < 0.0001) per year, followed by Ba and C3a (-0.22% [-0.29% to -0.15%]) and -0.13% ([-0.21 to -0.06]; both <i>p</i> < 0.001). Doubling of C3a, Ba, and C4a levels correlated with 2.2- (1.6-3.0; <i>p</i> < 0.0001), 2.0- (1.3-3.1; <i>p</i> = 0.0038), and 1.8-fold (1.2-2.6; <i>p</i> = 0.0029) increased longitudinal T2w lesion volumes; C3a and Ba were associated with 2.5- (1.4-4.6; <i>p</i> = 0.0022) and 3.3-fold (1.5-7.2; <i>p</i> = 0.0024) higher odds for CELs and 2.6- (1.7-4.0; <i>p</i> < 0.0001) and 2.3-fold (1.3-4.3; <i>p</i> = 0.006) increased PRL incidence rates. C1q, C3a, and C4a were associated with higher GFAP levels, and CXCL-13, CXCL-9, and IL-12b analyses showed consistent patterns with strongest associations for C1q, followed by Ba, C3a, and C4a.</p><p><strong>Discussion: </strong>Intrathecal complement activation is consistently associated with MRI metrics and liquid biomarkers indicative for MS disease activity and progression. Our results demonstrate that aberrant complement activation is strongly associated with structural brain damage in MS. Therapeutic targeting of the complement system might limit disability accumulation due to MS.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 2","pages":"e200361"},"PeriodicalIF":7.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142927652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mood Disorder and Multimorbidity Complicating a Multiple Sclerosis Diagnosis: From the National Multiple Sclerosis Society Case Conference Proceedings.","authors":"Jonathan D Krett, Claire Riley, Scott S Zamvil, Myla D Goldman, Scott D Newsome, Shiv Saidha","doi":"10.1212/NXI.0000000000200376","DOIUrl":"10.1212/NXI.0000000000200376","url":null,"abstract":"<p><p>A 28-year-old Black woman presented with both typical and atypical features of multiple sclerosis in the setting of multimorbidity including psychiatric history, complicating diagnosis and treatment. This case illustrates the importance of differential diagnosis and longitudinal follow-up before committing to disease-modifying therapy. Individualized treatment decision-making is highlighted.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 2","pages":"e200376"},"PeriodicalIF":7.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11820807/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel Approaches to Treatment of Immune-Mediated Chronic Intestinal Pseudo-Obstruction.","authors":"Andreu Vilaseca, Paula Arranz, Arnau Llaurado, Ana Zabalza, Elianet Gisell Fonseca, Inmaculada Medina, Maria Amelia Gómez Lorente, Luis Alcalá-González, Natalia Borruel, José Luis Fernández-Forcelledo, Helena Ariño, Thais Armangue, Xavier Montalban, Francesc Graus, Carolina Malagelada","doi":"10.1212/NXI.0000000000200369","DOIUrl":"10.1212/NXI.0000000000200369","url":null,"abstract":"<p><strong>Background and objectives: </strong>The optimal immunosuppressive treatment for autoimmune chronic intestinal pseudo-obstruction (CIPO) is unknown due to lack of clinical trials. Even less data exist on treatment recommendations for patients who do not respond to first-line immunotherapy.</p><p><strong>Methods: </strong>We describe 4 patients with autoimmune CIPO treated with vedolizumab (3/4), a monoclonal antibody that interferes the lymphocyte trafficking to the gastrointestinal tract, or rituximab (1/4) who did not respond to steroids or IV immunoglobulins. We made a systematic review of previously published cases of CIPO treated with these biological agents.</p><p><strong>Results: </strong>Vedolizumab was effective in 2 of 3 patients but failed in a child with nonparaneoplastic anti-Hu-associated CIPO, who had generalized dysautonomia. The 2 patients who responded to vedolizumab had an isolated CIPO, and they did not present neuronal antibodies. Rituximab was prescribed in a case of anti-Hu-associated, nonparaneoplastic CIPO, who showed a complete clinical response after this treatment. Our review of the literature retrieved 4 previous cases of autoimmune CIPO treated with rituximab but none treated with vedolizumab. All patients treated with rituximab had Hu antibodies. Two patients showed a clinical response to the treatment with rituximab.</p><p><strong>Discussion: </strong>Our findings underscore the potential efficacy of rituximab and vedolizumab in the management of autoimmune CIPO refractory to first-line treatments.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 2","pages":"e200369"},"PeriodicalIF":7.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11805607/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}