Neurology® Neuroimmunology & Neuroinflammation最新文献

{"title":"Functional Profiling of Acetylcholine Receptor Antibodies Informs Therapeutic Outcome of FcRn Inhibitor Therapy in Myasthenia Gravis.","authors":"Veronica Morcone, Jacopo Morroni, Giuseppe Valenzano, Sofia Marini, Silvia Falso, Martina Marini, Federico Habetswallner, Giorgia Farì, Cinzia Carrozza, Raffaele Iorio","doi":"10.1212/NXI.0000000000200616","DOIUrl":"10.1212/NXI.0000000000200616","url":null,"abstract":"<p><strong>Background and objectives: </strong>Myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junction most commonly associated with acetylcholine receptor (AChR) antibodies (AChR-Abs), detected in up to 80% of patients. The emergence of targeted therapies, such as neonatal Fc receptor (FcRn) inhibitors, highlights the need for standardized functional assays capable of dissecting AChR-Ab pathogenic mechanisms. By selectively reducing circulating IgG through FcRn blockade, these agents differ fundamentally from conventional immunosuppressants, emphasizing the need to characterize antibody-mediated AChR dysfunction and complement activation as potential markers of therapeutic response. However, current functional assays often rely on transiently transfected or heterogeneous cell systems, limiting reproducibility and scalability. A stably transfected human cell line expressing physiologically clustered adult AChRs could fill this methodological gap and enable standardized, quantitative evaluation of antibody effector functions.</p><p><strong>Methods: </strong>We generated a stable rhabdomyosarcoma (RD) cell line expressing clustered human adult AChRs (hAChR-RDcl) using the <i>P</i><i>iggyBac</i> transposon system for genomic integration of AChR subunit genes. The hAChR-RDcl line was applied to functional cell-based assays using serum samples from 30 patients with AChR-MG before and after one treatment cycle with efgartigimod. Clinical efficacy was assessed by Quantitative Myasthenia Gravis (QMG) and MG Activities of Daily Living (MG-ADL) scores.</p><p><strong>Results: </strong>The hAChR-RDcl cell line showed stable transcription and surface expression of adult AChR subunits, confirmed by RT-qPCR, α-bungarotoxin binding, and antibody-specific reactivity (mAb637 and patient serum samples). Baseline functional assays identified blocking antibodies in 15 of 30 (50%), internalizing antibodies in 20 of 30 (66.7%), and complement-activating antibodies in 14 of 30 (46.6%) samples. After efgartigimod treatment, all 3 antibody-mediated mechanisms were significantly reduced. Patients with persistent complement activity after treatment experienced more severe symptoms (higher QMG scores) compared with those showing other antibody-mediated pathogenetic mechanisms or complete suppression of antibody effector functions.</p><p><strong>Discussion: </strong>The hAChR-RDcl cell line represents a reliable and scalable platform for standardized functional profiling of AChR-Abs. Functional characterization of AChR-Abs provides a translational approach to monitor therapeutic responses and elucidate the mechanisms underlying FcRn inhibitor efficacy in MG.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"13 4","pages":"e200616"},"PeriodicalIF":8.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13276697/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148272455","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":"Clinical Spectrum of Anti-SEZ6L2 Syndrome: A Case Report With Brain Volumetry and Systematic Literature Review.","authors":"Juri Luis Habicht, Guido Cammá, Katharina Wurdack, Bianca Teegen, Harald Prüss, Carsten Finke","doi":"10.1212/NXI.0000000000200614","DOIUrl":"10.1212/NXI.0000000000200614","url":null,"abstract":"<p><strong>Background and objectives: </strong>Anti-seizure-related 6 homolog like 2 (SEZ6L2) antibodies are a rare cause of immune-mediated cerebellar syndromes. The clinical phenotype, diagnostic features, and outcomes have not been systematically synthesized, and the evidence is limited to case reports and case series. We, therefore, aimed to (1) characterize the clinical course and longitudinal brain volumetric changes in a patient with anti-SEZ6L2 syndrome and (2) systematically review the published evidence regarding clinical features, diagnostics, treatment, and outcomes.</p><p><strong>Methods: </strong>We performed a single-patient observational study with serial clinical assessments and cross-sectional and longitudinal MRI volumetry and compared the findings with those from age-matched and sex-matched healthy controls. In addition, we conducted a PRISMA-compliant systematic review of MEDLINE and EMBASE from 1964 to December 1, 2025, including published reports of patients with anti-SEZ6L2 antibodies. Data were synthesized descriptively, and because of disease rarity, this case was included in aggregated analyses.</p><p><strong>Results: </strong>A 45-year-old man developed a severe subacute cerebellar syndrome with cognitive, psychiatric, pyramidal, and parkinsonian features. The peak SARA score was 30, and the peak modified Rankin Scale (mRS) score was 5. Despite sequential immunotherapy, only mild improvement occurred and substantial disability persisted. Longitudinal MRI volumetry demonstrated progressive cerebellar atrophy relative to healthy controls, while whole-brain and subcortical volumes remained within normal range. The systematic review identified 21 previously reported patients, yielding 22 including the current case. Cerebellar syndrome was present in all patients; cognitive symptoms were reported in 14 of 22 (64%), parkinsonism in 8 of 22 (36%), and psychiatric symptoms in 6 of 22 (27%). Cerebellar atrophy was reported in 19 of 22 (86%). Two patients had temporally associated tumors. CSF pleocytosis was present in 7 of 21 (33%). The median peak SARA score was 27 (interquartile range [IQR] 23-30; n = 7) and improved to 20 (IQR 18-22), whereas the median mRS score remained 4 at both peak disease and follow-up (n = 11). Among 21 patients with outcome data, 2 (9.5%) died of tumor-related complications, 2 (9.5%) deteriorated neurologically, 8 (38.1%) stabilized, and 9 (42.9%) improved.</p><p><strong>Discussion: </strong>Anti-SEZ6L2 syndrome is characterized by severe cerebellar dysfunction frequently accompanied by parkinsonism, cognitive, and psychiatric features. This case demonstrated progressive cerebellar atrophy on longitudinal volumetry despite immunotherapy. Our systematic synthesis highlights that noncerebellar manifestations are common, and that substantial long-term disability often persists despite partial improvement in ataxia severity.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"13 4","pages":"e200614"},"PeriodicalIF":8.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13262669/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148227195","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":"Functional Connectivity Alterations of the Central Autonomic Network in Multiple Sclerosis: Links to Fatigue and Aerobic Training Effects.","authors":"Giorgio Guido, Paola Valsasina, Tetsu Morozumi, Paolo Preziosa, Francesco Romanò, Maria A Rocca, Massimo Filippi","doi":"10.1212/NXI.0000000000200585","DOIUrl":"10.1212/NXI.0000000000200585","url":null,"abstract":"<p><strong>Background and objectives: </strong>Autonomic dysfunction is common in multiple sclerosis (MS), and autonomic symptoms are independent contributors to MS fatigue. Aerobic training (AT) has been shown to reduce fatigue severity and to promote functional network reorganization in MS. We explored resting-state (RS) functional connectivity (FC) of the central autonomic network (CAN) in MS, its relationship with fatigue severity, and its modifications after AT vs non-AT.</p><p><strong>Methods: </strong>Seventy-five patients with MS (38 with relapsing-remitting [RR] and 37 with progressive [P]) underwent 3T RS functional MRI at baseline and at the end of AT (24 training sessions, 2-3 times per week for 2-3 months) or non-AT of equivalent duration. Sixty-seven matched healthy controls (HCs) served as a reference for baseline RS FC. At both visits, all patients were assessed using the Modified Fatigue Impact Scale (MFIS). Seed-based RS FC used core CAN modulatory regions: left/right ventromedial prefrontal cortex (vmPFC), mid-cingulate cortex (MCC), amygdala, hypothalamus, and anterior and posterior insula.</p><p><strong>Results: </strong>Compared with HCs, patients with MS showed increased baseline RS FC of the right amygdala, anterior insula, and vmPFC with superior frontal gyri, precentral gyri and right precuneus. Considering disease phenotype, we found a divergent behavior of baseline RS FC in the interaction analysis (<i>p</i> < 0.05, corrected), with patients with RRMS showing predominantly increased RS FC of the amygdala, anterior insula, and MCC with supplementary motor areas (SMAs) and deep gray matter, whereas patients with PMS showed widespread baseline RS FC decrease, particularly involving posterior insula connections with the cerebellum and parietal regions, and MCC connections with frontotemporal areas. In patients with RRMS, increased baseline CAN RS FC inversely correlated with fatigue severity (r = range -0.33/-0.54, <i>p</i> range = 0.046/0.001), while no significant correlations were found in patients with PMS. In patients who underwent AT, decreased hypothalamic network RS FC at follow-up vs baseline was observed (<i>p</i> < 0.001, significant time-by-treatment interaction vs non-AT), with more prominent changes in patients with RRMS compared with patients with PMS. No correlations were found between longitudinal RS FC modifications and concomitant fatigue changes.</p><p><strong>Discussion: </strong>CAN dysregulation is present in MS, with distinct RS FC abnormalities characterizing patients with RRMS and PMS and correlating with fatigue severity. AT modulates CAN RS FC, particularly in patients with RRMS.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"13 4","pages":"e200585"},"PeriodicalIF":8.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13174567/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147874765","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":"Lifespan Modeling of Choroid Plexus Volume in Multiple Sclerosis and Its Dynamic Associations With Clinical, MRI, and HLA Susceptibility.","authors":"Paolo Preziosa, Gianluca Corazzolla, Alessandro Meani, Monica Margoni, Loredana Storelli, Elisabetta Pagani, Martina Rubin, Ferdinando Clarelli, Elisabetta Mascia, Melissa Sorosina, Federica Esposito, Massimo Filippi, Maria A Rocca","doi":"10.1212/NXI.0000000000200593","DOIUrl":"10.1212/NXI.0000000000200593","url":null,"abstract":"<p><strong>Background and objectives: </strong>The choroid plexus (ChP) regulates CSF production and CNS homeostasis. In multiple sclerosis (MS), ChP enlargement occurs early in the disease course, yet its normative lifespan trajectory and relationship with MS-specific features remain poorly defined. We aimed to define the normative ChP volume model, to characterize its trajectory across the healthy lifespan, and to assess ChP enlargement in MS using z-scores, evaluating associations with demographic, clinical, MRI, and genetic variables, including human leukocyte antigen (HLA) and non-HLA polygenic risk scores (PRSs).</p><p><strong>Methods: </strong>This monocentric retrospective cross-sectional study included 461 healthy controls (HCs) and 727 patients with MS (age 18-70 years) who underwent 3T brain MRI and neurologic assessment. ChP volumes were quantified using ASCHOPLEX, normalized for head size, and modeled in HCs. We derived age-related normalized ChP volume (NChPV) trajectory across adulthood. Z-scores for patients with MS were computed. PRSs were calculated from established MS susceptibility loci, encompassing both HLA and non-HLA regions.</p><p><strong>Results: </strong>In HCs, normalized brain volume, lateral ventricle volume, and its squared term were independently associated with NChPV (R² = 0.54). Model-derived NChPV trajectory remained stable until age 35 and then increased nonlinearly (p-FDR<0.002), with annualized growth rates rising from 0.24% at age 35 to over 0.7% in later decades. Patients with MS had significantly higher NChPV z-scores than controls (estimated mean [EM] z-score = 0.452, p-FDR<0.001), consistently across phenotypes (<i>p</i> = 0.744) and ages, with no evidence of age-dependent variation (β = 0.02 × 10^-2, <i>p</i> = 0.957). In cross-sectional analyses, NChPV z-scores, already elevated 1 year after disease onset (EM z-scores = 0.252, p-FDR<0.001), increased further up to 5 years after disease onset (EM z-scores = 0.463, p-FDR<0.001), before plateauing. Higher z-scores were associated with greater T2-hyperintense white matter lesion volume (β = 0.012 × 10^-2, <i>p</i> < 0.001) and HLA genetic burden (standardized β = 0.097, <i>p</i> = 0.038), but not non-HLA PRSs (<i>p</i> ≥ 0.177).</p><p><strong>Discussion: </strong>We provided a normative ChP volume model, characterized its trajectory across the healthy lifespan, and showed early, consistently higher ChP volume in patients with MS across ages and disease durations in cross-sectional analyses, linked to inflammatory lesion burden and HLA-mediated genetic risk. The ChP may represent a noninvasive biomarker of neuroinflammation and HLA-related immunogenetic background in MS.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"13 4","pages":"e200593"},"PeriodicalIF":8.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13235301/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148150730","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":"Focal Motor Seizures as a Manifestation of Rheumatoid Meningitis: From the National Multiple Sclerosis Society Case Conference Proceedings.","authors":"Iwalewa G Moninuola, Mohammad T Shujaat, Saman Ahmadian, Scott S Zamvil, Claire Riley, Myla D Goldman, Tirisham Victoria Gyang","doi":"10.1212/NXI.0000000000200604","DOIUrl":"10.1212/NXI.0000000000200604","url":null,"abstract":"<p><p>We describe a 65-year-old man with rheumatoid arthritis presenting with focal motor seizures and progressive right frontoparietal leptomeningeal enhancement. Biopsy was consistent with an inflammatory process. He improved with corticosteroids and rituximab. Our case highlights consideration of CNS involvement of rheumatoid arthritis in patients presenting with new neurologic symptoms.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"13 4","pages":"e200604"},"PeriodicalIF":8.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13240708/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148163923","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":"HTLV-1-Infected CD4⁺ T Cells Drive Spontaneous Lymphoproliferation and Virus-Specific CD8⁺ Cytotoxic T Lymphocyte Expansion in HAM/TSP.","authors":"Mika Dozono, Satoshi Nozuma, Takashi Yoshida, Daisuke Kodama, Toshio Matsuzaki, Eiji Matsuura, Masakazu Tanaka, Hiroshi Takashima, Ryuji Kubota","doi":"10.1212/NXI.0000000000200581","DOIUrl":"10.1212/NXI.0000000000200581","url":null,"abstract":"<p><strong>Background and objectives: </strong>Spontaneous lymphoproliferation (SP) is an ex vivo phenomenon where lymphocytes proliferate without exogenous stimulation in peripheral blood mononuclear cells (PBMCs) from patients with human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP). SP is thought to reflect spinal cord pathology in HAM/TSP, but its cellular mechanisms remain unclear.</p><p><strong>Methods: </strong>PBMCs from 30 patients with HAM/TSP, 12 asymptomatic HTLV-1 carriers, and 8 healthy controls (HCs) were labeled with a proliferation tracer and cultured for 6 days without exogenous stimulation. Flow cytometry was used to identify T-cell subsets, HTLV-1-infected cells, and HTLV-1-specific cytotoxic T lymphocytes (CTLs). Additional analyses included CTL antigen specificity, proviral load (PVL), phenotypic profiling (differentiation, activation, exhaustion markers), and cytokine/chemokine quantification in culture supernatants.</p><p><strong>Results: </strong>CD8⁺ T cells exhibited greater proliferation than CD4⁺ T cells during SP. Among proliferating CD4⁺ T cells, 38.15% were CADM1+, 61.84% were Tax+, and PVL analysis indicated that nearly all proliferating CD4⁺ T cells were HTLV-1 infected. The frequency of HTLV-1 Tax 301-309-specific CTLs among CD8⁺ T cells increased from 3.81% to 17.67% during SP. After a subsequent resting phase, IFN-γ responses were detected in 37.38% of CD8⁺ T cells to a Tax peptide mixture and in 33.42% to an HTLV-1 bZIP factor peptide mixture, together accounting for over 70% of proliferating CD8⁺ T cells. Sorted CD4⁺ T cells proliferated independently, whereas sorted CD8⁺ T cells did not; however, coculture with CD4⁺ T cells restored CD8⁺ T-cell proliferation. Proliferating infected cells exhibited a Th1 phenotype, and most proliferating T cells coexpressed activation and exhaustion markers with memory phenotypes. IL-6 and IFN-γ levels were significantly elevated in culture supernatants from patients with HAM/TSP compared with HCs. IFN-γ levels in SP supernatants correlated with CSF PVL. SP responses in HTLV-1 carriers were attenuated, with reduced proliferation compared with patients with HAM/TSP.</p><p><strong>Discussion: </strong>SP is driven by HTLV-1-infected CD4⁺ T cells, which are essential for sustaining HTLV-1-specific CD8⁺ CTL expansion. This phenomenon appears to recapitulate certain immunologic features of neuroinflammation in HAM/TSP. This ex vivo model may help evaluate therapies targeting HTLV-1-infected cells and immune-mediated pathology.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"13 4","pages":"e200581"},"PeriodicalIF":8.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13138836/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147818393","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":"Clinical Manifestations, Tumor Associations, and Long-Term Outcomes of Anti-KLHL11 Encephalitis.","authors":"Mengzhi Jin, Tessa Brand, Ece Erdag Turgeon, Alexander C Havelaar, Robin W Van Steenhoven, Mariska M P Nagtzaam, Suzanne C Franken, Sarah H B Abu Hassan, Anna E M Bastiaansen, Juliette Brenner, Peter A E Sillevis Smitt, Esther de Graaff, Sharon Veenbergen, Juna M de Vries, Jeroen Kerstens, Maarten J Titulaer","doi":"10.1212/NXI.0000000000200597","DOIUrl":"10.1212/NXI.0000000000200597","url":null,"abstract":"<p><strong>Background and objectives: </strong>Anti-Kelch-like protein 11 (KLHL11) encephalitis was discovered in middle-aged men with testicular seminoma and rhombencephalitis, defining a new type of paraneoplastic neurologic syndrome (PNS), but diagnostic criteria and treatment outcomes remain largely unclear. This study aimed to comprehensively describe the initial presentations and subsequent clinical courses, ancillary findings, treatments, and outcomes of patients with anti-KLHL11 encephalitis.</p><p><strong>Methods: </strong>We tested 1,361 patients with clinical features or tumors that could be associated with anti-KLHL11 encephalitis (1,164 CSF and 680 serum). The retrospective analysis included 458 serum and 288 CSF samples from 473 patients between January 2010 and July 2020, while prospective screening for anti-KLHL11 antibodies was regularly performed since July 2020. Anti-KLHL11-abs was screened using KLHL11 overexpression cell-based assay. Detailed clinical and paraclinical information was collected.</p><p><strong>Results: </strong>Seventeen anti-KLHL11 encephalitis patients were identified. The median age of patients was 59 (IQR 48-72; range 28-76) years, and 12 individuals (n = 12, 71%) were male. Common phenotypes were cerebellar ataxia (n = 12, 71%), brainstem encephalitis (n = 12, 71%), opsoclonus-myoclonus syndrome (n = 8, 47%), and limbic encephalitis (n = 3, 18%). Meningitis was observed in one patient. Concurrent antibodies included those against N-methyl-D-aspartate receptor (n = 2), glial fibrillary acidic protein (n = 1), and contactin-associated protein-like 2 (n = 1). MRI was abnormal in 8 cases (47%), showing T2/FLAIR hyperintensity in the rhombencephalon (n = 3, 18%), limbic system (n = 4, 24%), or cerebellar atrophy (n = 2, 12%). Tumors were identified in 10 cases (59%), including seminoma (n = 5, 29%), ovarian teratoma (n = 1, 6%), urological (renal cell carcinoma and urothelial cell carcinoma, both n = 1, 12%), small-cell lung cancer, and carcinoma of unknown primary (all n = 1). Fifteen patients received first-line immunotherapies (88%), and 6 patients also received second-line immunotherapy (35%). Improvement or stabilization was achieved in 10 (7 and 3, respectively, 67%) patients. The median follow-up duration was 20 months (range 1.5-180). Six patients died within the first 12 months, related to encephalitis (n = 3, 18%) or cancer (n = 3, 18%).</p><p><strong>Discussion: </strong>Anti-KLHL11 encephalitis mainly related to infratentorial encephalitis but can also present as limbic encephalitis and rarely as meningitis. Early diagnosis enables early oncological and immunologic treatment, hopefully improving outcomes.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"13 4","pages":"e200597"},"PeriodicalIF":8.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13224743/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148056052","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":"Serum Glial Fibrillary Acidic Protein and Retinal Neuronal Loss as Additive Prognostic Markers of Disability in Multiple Sclerosis.","authors":"Shaumiya Sellathurai, Kean Schoenholzer, Federico Burguet Villena, Nuria Cerdá-Fuertes, Lisa Hofer, Sabine Anna Schaedelin, Veronika Kana, Pradesta Mahenthiran, Marcus D'Souza, Aleksandra Maleska Maceski, Tobias J Derfuss, Johanna Oechtering, Konstantin Gugleta, Ludwig Kappos, Axel Petzold, Cristina Granziera, Pascal Benkert, Jens Kuhle, Athina Papadopoulou","doi":"10.1212/NXI.0000000000200571","DOIUrl":"10.1212/NXI.0000000000200571","url":null,"abstract":"<p><strong>Background and objectives: </strong>In people with multiple sclerosis (pwMS), optical coherence tomography (OCT) quantifies loss of neurons (macular ganglion cell-inner plexiform layer [mGCIPL]) and axons (peripapillary retinal nerve fiber layer [pRNFL]) in the retina. Serum glial fibrillary acidic protein (sGFAP) is a promising astrocytic biomarker to capture disease progression in pwMS. We aimed to investigate the relationship between OCT markers and sGFAP in pwMS and explore their additive value in predicting disability progression.</p><p><strong>Methods: </strong>PwMS and healthy controls underwent OCT at baseline (BL), excluding eyes with inter-eye asymmetry. Age, sex, and body mass index-adjusted Z scores of sGFAP were calculated. Cross-sectional and longitudinal associations between sGFAP and retinal layers were estimated using linear regression- and mixed-effects models (LMM). The additive effect of BL-OCT and BL-sGFAP on the trajectory of the Expanded Disability Status Scale (EDSS) was estimated using LMM, whereby pwMS were stratified into: group (1): low sGFAP Z score (<3rd quartile, <Q3) and thick mGCIPL (>Q1); group (2): high sGFAP Z score (≥Q3) and thick mGCIPL or low sGFAP Z Score and thin mGCIPL (≤Q1); and group (3): high sGFAP and thin mGCIPL.</p><p><strong>Results: </strong>Two hundred and sixty-one pwMS (mean age: 48 years (y), female: 63%, on disease-modifying treatment: 80%, mean thickness of pRNFL: 94 μm and mGCIPL: 66 μm) and 52 controls (age: 52 years, female: 65%, pRNFL: 101 μm, mGCIPL: 72 μm) were included. At BL, pRNFL (β = -0.01, <i>p</i> = 0.042) and mGCIPL (β = -0.02, <i>p</i> = 0.013) were negatively associated with sGFAP Z scores in pwMS, but not in controls (<i>p</i> = 0.950, <i>p</i> = 0.386). BL-mGCIPL was also associated with sGFAP trajectories (β = -0.003, <i>p</i> = 0.044), over a median follow-up of 2.9 years. Compared with pwMS with good results in both markers (group 1), those with either high sGFAP or thin mGCIPL had a steeper EDSS increase (β = 0.030, <i>p</i> = 0.048), while pwMS with both high sGFAP and thin mGCIPL (group 3) showed the steepest trajectory of the EDSS (β = 0.101, <i>p</i> < 0.001).</p><p><strong>Discussion: </strong>Our findings show a close relationship between astrocytic activation/injury and neurodegeneration in the CNS, measured at the retinal level. Moreover, they highlight an additive role of mGCIPL and sGFAP for identification of pwMS at higher risk of disability worsening.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"13 4","pages":"e200571"},"PeriodicalIF":8.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13182739/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147932226","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":"Real-World Multicenter Cohort Study of Inebilizumab vs Low-Dose Rituximab in Neuromyelitis Optica Spectrum Disorders.","authors":"Qiao Xu, Linming Zhang, Xinyi Duan, Kai Zhou, Zhizhong Li, Xiaolin Yang, Jing Wang, Jinyu Jiang, Ke Xu, Gang Yu, Peng Zheng, Yongmei Li, Xinyue Qin, Jingyuan Li, Wen Ya Wang, He Zhao, Dehui Huang, Hao Qu, Haibing Xiao, Bin Li, Lei Wu, Jinzhou Feng","doi":"10.1212/NXI.0000000000200586","DOIUrl":"10.1212/NXI.0000000000200586","url":null,"abstract":"<p><strong>Background and objectives: </strong>Inebilizumab and rituximab (RTX) are anti-CD19 and anti-CD20 B cell-depleting antibodies, respectively. They are both used in the treatment of neuromyelitis optica spectrum disorders (NMOSD). However, limited data on both drugs exist regarding real-world clinical applications. This study aimed to assess the efficacy and safety of inebilizumab vs low-dose RTX in NMOSD patients through a retrospective-prospective multicenter analysis.</p><p><strong>Methods: </strong>This study collected data on aquaporin-4 immunoglobulin G seropositive NMOSD patients from 6 cities in China among those receiving either inebilizumab or low-dose RTX (500 mg), with a 1-year follow-up. Analyses assessed outcomes using inverse probability of treatment weighting and doubly robust models.</p><p><strong>Results: </strong>We included a total of 229 patients, comprising 119 treated with inebilizumab and 110 with low-dose RTX. The cohort was predominantly female (217/229, 94.76%). The median follow-up duration was 12.0 months (range: 4.0-12.0) in the inebilizumab group and 12.0 months (range: 7.0-12.0) in the low-dose RTX group. Relapses occurred in 8/119 (6.72%) inebilizumab recipients vs 24/110 (21.82%) low-dose RTX recipients (hazard ratio [HR] 3.77, 95% confidence interval [CI] 1.56-9.14; <i>p</i> = 0.003). Adjusted annualized relapse rates were significantly lower in the inebilizumab group (0.06) than in the low-dose RTX group (0.24), corresponding to an incidence rate ratio (IRR) of 3.65 (95% CI 1.59-8.39; <i>p</i> = 0.003). Adverse events (AEs) occurred in 35 patients (29.42%) with inebilizumab, including 2 serious adverse events (SAEs; 1.68%), vs 44 patients (40.00%) with low-dose RTX (4 SAEs [3.64%]). Both AE and SAE rates showed no statistical difference between groups. The rate of patients with at least 1 infection in inebilizumab group was lower than that in the low-dose RTX group (<i>p</i> = 0.003).</p><p><strong>Discussion: </strong>In this short-term study, inebilizumab demonstrated greater efficacy in reducing relapse risk, along with significantly lower rates of key adverse events, compared with low-dose RTX in patients with NMOSD. These findings support the use of inebilizumab as an effective and well-tolerated therapeutic option in a broader NMOSD population.</p><p><strong>Classification of evidence: </strong>This short-term study with a 12-month observation period provides Class III evidence that in patients with NMOSD, inebilizumab is more effective than low-dose RTX in reducing relapses.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"13 4","pages":"e200586"},"PeriodicalIF":8.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13127679/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147777167","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":"High-Affinity Human Germline and Mutated Autoantibodies Commonly Cross-React to Self-Antigens in 5 Subgroups of Autoimmune Encephalitis.","authors":"Laura Stöffler, Jakob Kreye, Friederike A Arlt, Elisa Sanchez-Sendin, Julius Hoffmann, Hans-Christian Kornau, Marieluise Kirchner, Philipp Mertins, Scott van Hoof, Stephanie Wernick, Marie Homeyer, Sebastian Momsen Reincke, Harald Prüss","doi":"10.1212/NXI.0000000000200608","DOIUrl":"10.1212/NXI.0000000000200608","url":null,"abstract":"<p><strong>Background and objectives: </strong>Antineuronal autoantibodies targeting surface membrane proteins are the hallmark of an increasing number of autoimmune encephalitides. The autoantibodies can be directly pathogenic and cause various symptoms ranging from epilepsy and psychosis to amnesia and autonomic dysfunction. It is largely unclear how the humoral autoimmune response is triggered and propagated.</p><p><strong>Methods: </strong>We analyzed whether affinity maturation leads to increasing affinity of encephalitis-related autoantibodies to their receptors by determining the binding strength of patient-derived monoclonal autoantibodies and their germline ancestors from 11 patients with NMDAR, LGI1, mGluR5, CASPR2, and GABA_AR encephalitis. In addition, binding to foreign and self-antigens was assessed.</p><p><strong>Results: </strong>For most autoantibodies, affinity maturation generated or increased binding to neuronal surface antigens. However, high numbers of somatic hypermutations were not necessarily needed, as half of germline-encoded variants already recognized the respective antigen with strong binders in all groups. 10%-15% of reverted and mutated monoclonal autoantibodies recognized nuclear antigens, and one-third were reactive to mammalian tissues other than brain. Immunoprecipitation combined with mass spectrometry identified the nuclear antigen proteins major vault protein and translocated promotor region as targets of selected germline ancestors.</p><p><strong>Discussion: </strong>The findings suggest analogous immunologic mechanisms across 5 different encephalitides, with high-affinity autoantibodies already in the germline pool and frequent reactivity to nuclear antigens. Future studies should determine the contribution of immunologic checkpoint deficiencies, as seen in one patient with a pathogenic immune checkpoint mutation.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"13 4","pages":"e200608"},"PeriodicalIF":8.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13276698/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148272435","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}