Neurology® Neuroimmunology & Neuroinflammation最新文献

Background and objectives: Neuromyelitis optica spectrum disorder (NMOSD) is a severe autoimmune disease mainly driven by aquaporin-4 antibodies (AQP4-IgG). During an attack, AQP4-IgG activates the complement system, leading to astrocyte destruction, inflammation, neuronal damage, and thus devastating and often irreversible neurologic deficits. Terminal complement inhibitors such as eculizumab and ravulizumab effectively prevent relapses, yet their therapeutic potential in stopping ongoing complement-mediated injury during acute attacks remains insufficiently explored.

Methods: We conducted a multinational retrospective case series across NMOSD-specialized centers in 6 countries, analyzing 33 AQP4-IgG-positive patients (mean age: 48.1 years; 28 women) treated with component 5 (C5) inhibition during or shortly after acute relapse (mean 20.1 days from symptom onset; range 2-62). Eculizumab was used in 25 patients and ravulizumab in 8. Two additional patients were excluded because of delayed treatment initiation beyond 62 days.

Results: Lesion locations included myelitis (57.6%) and optic neuritis (30.3%). Expanded Disability Status Scale scores worsened from a pre-relapse median of 0 (interquartile range [IQR] 0-2) to a nadir of 6.5 (IQR 3.5-8), improving to 3.5 (IQR 3-6.5) at 1-3 months and 2.5 (IQR 2-6) at 6 months. All patients stabilized clinically; 20 continued C5 inhibition as attack-preventing therapy. Good, moderate, and poor/absent recovery were observed in 15, 11, and 7 patients, respectively. Earlier treatment was associated with better outcomes: treatment within 21 days yielded an odds ratio of 1.58 (95% CI 0.32-8.52) for good response. Plasma exchange was administered in 57.6% and was associated with higher overall response rates, but not with good response alone.

Discussion: These findings highlight the potential of complement inhibition as a treatment option for acute NMOSD attacks, particularly in patients with insufficient response to standard therapies. Given the absence of clinical worsening and the encouraging course observed in most of the patients, further investigation into the role of C5 inhibition in acute attack management is warranted.

Classification of evidence: This retrospective case series provides Class IV evidence that the C5 complement inhibitors eculizumab or ravulizumab may improve disability in patients with NMOSD when given during or shortly after acute relapse.

Background and objectives: Complement-targeting therapies are pivotal in managing neuromyelitis optica spectrum disorder (NMOSD), calling for a deeper understanding of complement activation across idiopathic inflammatory demyelinating diseases (IIDDs) of the CNS. C4d, a covalently bound complement split product, offers prolonged detectability at activation sites. This study explores whether C4d immunohistochemistry (IHC) extends the detection window for complement activation in CNS biopsies of IIDDs and evaluates its usefulness as a fluid biomarker.

Methods: Forty-four IIDD biopsies with active demyelination were analyzed for complement deposition using IHC for C9neo and C4d. C4d levels were also quantified in blood and CSF of patients with IIDDs. The persistence of C4d in CNS tissue was further evaluated in an in vivo NMOSD model.

Results: C4d IHC enhanced the sensitivity to detect complement activation, surpassing C9neo by twofold in NMOSD and by sixfold in ADEM, while remaining undetectable in MS biopsies. Exclusive C4d immunopositivity at the glia limitans distinguished NMOSD from ADEM. Furthermore, CSF C4d levels were significantly elevated in both seronegative and seropositive NMOSD compared with MS.

Discussion: C4d detection extends the window for identifying complement activation in CNS biopsies of IIDDs and emerges as a valuable CSF biomarker, enhancing diagnostic precision, autoantibody target identification, and patient stratification for complement-targeting therapies.

Background and objectives: Seronegative autoimmune encephalitis (AE), defined by an appropriate clinical phenotype in the absence of known neuronal autoantibodies, poses diagnostic and therapeutic challenges due to clinical heterogeneity and lack of definitive biomarkers. We conducted a systematic review and meta-analysis of individual patient data to characterize the phenotypes, treatment responses, and prognostic factors in seronegative AE.

Methods: We included 213 cases from 30 studies published between 2014 and 2024 and 11 from a local cohort meeting Graus criteria for seronegative AE. We extracted details on clinical and paraclinical features, immunotherapy, and outcomes measured via the modified Rankin Scale (mRS) and Clinical Assessment Scale for Autoimmune Encephalitis (CASE). Multivariate regression and dimensionality reduction analyses identified prognostic markers.

Results: Of 224 patients (median age 49 years, 50.9% male), 72 (32.1%) had limbic encephalitis (LE) and 152 (67.9%) had antibody-negative probable AE (ANPRA). Good outcome (mRS score ≤2) was more common in LE (49/72, 68.1%) than in ANPRA (76/154, 50.0%) (p < 0.05). Delayed immunotherapy was associated with an increased risk of poor outcome. Additional predictors of poor prognosis included age older than 60 years, the ANPRA subtype, an underlying tumor, striatocapsular or thalamic involvement on MRI, and presentation with refractory status epilepticus. Dimensionality and clustering analysis identified heterogeneity among seronegative AE, with 3 distinct subtypes.

Discussion: Seronegative AE comprises clinically and prognostically distinct subtypes. Early immunotherapy is the key modifiable factor influencing outcome. We advocate for biomarker discovery and prospective, systematically reported cohort studies to improve stratification and treatment strategies in this diagnostically challenging population.

Background and objectives: Spinal cord injury (SCI) is associated with severe immunologic changes, such as SCI-induced immune deficiency syndrome, which heightens susceptibility to infections. However, the immune components underlying this immune reorganization remain poorly defined. This study aimed to characterize immune remodeling in patients with SCI across different time points postinjury.

Methods: High-dimensional flow cytometric profiling was performed on peripheral blood samples from patients with SCI in a cross-sectional observational study to assess immune changes at different postinjury time points. Patients in the subacute phase (22-67 days of postinjury [dpi]) and chronic phase (≥365 dpi) were compared with healthy, sex-matched, and age-matched controls.

Results: Alterations in the T-cell and natural killer (NK) cell compartments were observed, particularly in the subacute phase postinjury. Memory T cells and NK cells showed elevated expression of the NAD⁺ metabolizing enzyme CD38 and immune checkpoint molecules, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1), indicating immune activation and possible exhaustion. Coexpression of CD38 and CTLA-4 on T cells was rare, suggesting distinct activation and inhibitory states. In chronic patients, we observed decreased frequencies of NK cells with no substantial changes in T cells and B cells. Notably, changes in CD38, CTLA-4, and PD-1 were no longer found in patients in the chronic phase.

Discussion: These findings reveal noteworthy changes in immune cell activation and exhaustion markers that may contribute to immune vulnerability after SCI, offering novel insights into potential therapeutic targets, such as NAD⁺ metabolism and immune checkpoint modulation.

Background and objectives: Multiple sclerosis (MS) is more prevalent in women, with a female-to-male ratio of 3:1. The molecular mechanisms driving this sex difference are still mostly unknown. MS results from immune dysfunction, with an imbalance in effector and regulatory T cells. Among the latter, Type I regulatory T cells (Tr1) are dysfunctional in people with MS (pwMS), secreting less IL-10, a potent anti-inflammatory cytokine, than in healthy donors. Our objectives were to explore the effect of biological sex on Tr1 cell differentiation in healthy donors and pwMS.

Methods: CD4⁺ T cells were isolated from peripheral blood mononuclear cells, and Tr1 differentiation was induced by costimulation with the complement regulator CD46 or IL-27. The frequency of Tr1 cells and their production of IL-10 and IFN-γ were examined. The impact of the PI3K/mTOR pathway on male and female Tr1 cells was also studied.

Results: We found that healthy female Tr1 cells produce less IL-10 than male cells (16 women and 16 men, 18-45 years old, p = 0.0053). This sex difference was only observed when Tr1 cells were differentiated by CD46 costimulation. Mechanistically, this sex difference in IL-10 expression by Tr1 cells was due to the differential activity of a negative feedback loop targeting PI3K signaling in male vs female Tr1 cells. In contrast to findings in healthy donors, no sex difference in IL-10 production was observed when CD4⁺ T cells from pwMS (12 women and 12 men, 18-48 years old) were differentiated to Tr1 cells via the CD46 pathway, further emphasizing the dysregulation of Tr1 generation in MS. However, PI3Kδ inhibition in MS cells also revealed a sex bias, as it reduced IL-10 production by IL-27-induced Tr1 cells only in men (7 men and 5 women, p = 0.0043), while increasing IL-10 levels in the CD46 pathway in both sexes (8 men and 11 women).

Discussion: We demonstrate that sex influences IL-10 production by Tr1 cells via the PI3K pathway, potentially contributing to the greater susceptibility of women to MS. Furthermore, our data suggest that targeting PI3Kδ may represent a novel therapeutic strategy to boost IL-10 production in female pwMS.

Background and objectives: Double seronegative NMOSD (DS-NMOSD) lacks approved disease-modifying treatments, and limited data exist on optimal relapse-prevention strategies. In this multicenter, international, retrospective cohort study, we sought to compare the real-world effectiveness of anti-CD20 agents vs nonspecific immunosuppressants as disease-modifying strategies for relapse prevention in DS-NMOSD.

Methods: A retrospective cohort database was constructed using standardized data collection from medical records across collaborating centers in the United States, Brazil, the United Kingdom, Thailand, Turkiye, and China. Patients meeting IPND-2015 NMOSD criteria with negative serum aquaporin-4 and myelin oligodendrocyte glycoprotein antibody testing via cell-based assays and at least 12 months of follow-up were reviewed. The primary outcome was the incidence rate ratio (IRR) of relapses; secondary outcomes included the annualized relapse rate (ARR) and time to relapse.

Results: A total of 103 patients with DS-NMOSD met study criteria, with a median follow-up of 6 years. Anti-CD20 therapy was associated with a significantly lower IRR (0.02, 95% CI 0.01-0.04) and ARR (0.17, 95% CI 0.07-0.40) compared with nonspecific immunosuppressants (0.76, 95% CI 0.40-1.43) after adjusting for covariates. Survival analysis demonstrated a prolonged relapse-free interval with anti-CD20 agents.

Discussion: Our findings support the use of B-cell depletion as a potentially superior relapse-prevention strategy in DS-NMOSD, highlighting its potential as a first-line therapy.

Classification of evidence: This study provides Class IV evidence that, in patients with DS-NMOSD, treatment with a DMT reduces relapse incidence rate ratio compared with no treatment and anti-CD20 DMTs are associated with a lower relapse incidence rate ratio compared with nonspecific immunosuppressants.

Background and objectives: Severe optic neuritis (ON) is a common clinical manifestation in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and neuromyelitis optica spectrum disorder (NMOSD). Given distinct prognoses and often the necessity of early plasma exchange in NMOSD, prompt differentiation is crucial. In this study, we investigated the utility of optical coherence tomography (OCT) in differentiating between first acute NMOSD-ON and MOGAD-associated optic neuritis (MOGAD-ON), as well as specific factors associated with disc edema.

Methods: In this retrospective multicenter study, 111 adult patients with MOGAD or aquaporin-4 antibody-positive NMOSD who experienced a first ON and underwent OCT within 2 weeks of symptom onset were included from 14 centers across 8 countries. Peripapillary retinal nerve fiber layer (pRNFL) thickness in µm was analyzed, including the average of both eyes in cases of bilateral manifestation.

Results: Eighty-three patients with MOGAD (51 women; 124 ON eyes; bilateral ON 48.2%) and 28 with NMOSD (24 women; 36 ON eyes; bilateral ON 21.4%) were enrolled. A significant increase in pRNFL thickness (>2SD), suggestive of disc edema, was observed in 73.4% of MOGAD-ON eyes and 11.1% of NMOSD-ON eyes (p < 0.001). The pRNFL thickness cutoff of 117.5 µm provided 92.9% specificity and 71.1% sensitivity in distinguishing between MOGAD-ON and NMOSD-ON (area under the curve = 0.838). There was no association between pRNFL thickening and MOG-IgG titer (high vs low), body mass index, or the delay between ON onset and OCT. Simultaneous bilateral MOGAD-ON was associated with significantly more pronounced pRNFL thickening.

Discussion: Acute-stage OCT contributes to the rapid and accurate differentiation between MOGAD-ON and NMOSD-ON prior to antibody confirmation, which can be critical for timely therapeutic decisions.

Background and objectives: Opsoclonus-myoclonus-ataxia syndrome (OMAS) is a rare pediatric autoimmune neurologic disorder, with 40%-50% of cases occurring as a paraneoplastic syndrome in the setting of neuroblastoma or other neuroblastic tumors. The strong clinical similarities between idiopathic and paraneoplastic OMAS have led to the hypothesis that neuroblastoma may initially be present in idiopathic cases but spontaneously regress before OMAS onset. Both B- and T-cell mechanisms appear to contribute to OMAS autoimmunity, although their precise roles remain unknown. The aim of this study was to investigate similarities and differences between idiopathic and paraneoplastic OMAS by analyzing HLA profiles and T-cell receptor (TCR) repertoires in a Spanish pediatric cohort.

Methods: Children with OMAS were enrolled in a nationwide prospective study (2013-2024). Neural autoantibody testing was performed in all patients. HLA genotyping was performed using next-generation sequencing (GenDx/Illumina) and compared with a reference Spanish population (n = 4,335). The Benjamini-Hochberg false discovery rate method was used to control for multiple comparisons across HLA antigens. TCR repertoires were analyzed in peripheral blood samples of 12 patients using the Adaptive Biotechnologies immunoSEQ assay. The bioinformatics tool Grouping of Lymphocyte Interactions by Paratope Hotspots (GLIPH2) was used to identify shared motifs within CDR3β-TCR sequences.

Results: Among 25 children with OMAS (median age 22 months [interquartile range (IQR): 15-38]), 12 (48%) had neuroblastoma and 3 (12%) had neuronal antibodies (one with anti-Hu, one with anti-myelin oligodendrocyte glycoprotein, one against unknown neuronal surface antigens). Some HLA class II antigens (DRB1*08, DRB1*10, and DQB1*04) were consistently overrepresented in patients with OMAS compared with Spanish controls (all p-adjusted <0.05). Distinct HLA antigens were associated with idiopathic OMAS (HLA-DRB1*08, HLA-DQB1*04), while paraneoplastic OMAS was linked to HLA-DRB1*10 (all p-adjusted <0.05), suggesting subgroup-specific genetic risks. TCR analysis revealed that patients with paraneoplastic OMAS showed greater TCR repertoire similarity, whereas shared sequences were rare in idiopathic OMAS.

Discussion: Despite similar clinical presentations, idiopathic and paraneoplastic OMASs appear to have distinct immunopathogenic mechanisms. In paraneoplastic OMAS, enrichment of specific HLA antigens and convergent TCR profiles supports antigen-driven T cell-mediated autoimmunity.

Background and objectives: Although anti-Ma2 antibodies (Ma2-Abs) typically associate with paraneoplastic encephalitis, a subset of patients with Ma2-Abs does not have any detectable tumor. The clinical specificities of these idiopathic cases are unknown. The aim of this study was to describe clinical phenotypes and outcomes of patients with idiopathic Ma2-Abs (I-Ma2) compared with patients with paraneoplastic Ma2-Abs (PNS-Ma2).

Methods: A retrospective review of the French Reference Center of Paraneoplastic Neurologic Syndromes and Autoimmune Encephalitis database was conducted to identify cases of Ma2-Abs-mediated syndromes diagnosed between January 2002 and December 2022. A systematic review of the existing literature was also performed to assess for reported I-Ma2 cases.

Results: Seventy patients with neurologic syndromes harboring Ma2-Abs were identified (50/70 men, 71.4%; median age 60 years, interquartile range (IQR) 47-67.5). Malignancies were detected in 46 of 70 (65.7%). When compared with the PNS-Ma2 cohort, the I-Ma2 cohort less frequently had an acute/subacute disease progression (5/20, 25%, vs 26/46, 56.5%; p = 0.037) and the time to diagnosis was longer (10 months, IQR 4-20, vs 3.5 months, IQR 1-6; p = 7.94 x 10^-10). No differences were found in the subtype of clinical symptoms between patients with and without cancer. However, monofocal involvement, predominantly isolated limbic encephalitis, was more frequent in patients with I-Ma2 vs the PNS-Ma2 cohort (13/20, 65%, vs 18/46, 39.1%; p = 0.05). The other discriminative paraclinical finding was EEG alteration, which was more frequently abnormal in patients with I-Ma2 (I-Ma2 11/20, 55%, vs PNS-Ma2 12/46, 26%; p = 0.047). There were no differences in brain MRI and CSF inflammation. Systematic review of the literature revealed a longer follow-up, a greater use of second-line immunotherapies, and a higher proportion of patients with I-Ma2 in the French cohort (proportion of French I-Ma2 20/66 (30.3%) vs 10/109 (10.9%) in the literature, p = 0.00325, respectively).

Discussion: Patients with I-Ma2 are more common than anticipated and have insidious disease onset and a tendency for monofocal nervous system involvement. Recognition of patients with I-Ma2 is delayed and must be improved.