Neurology® Neuroimmunology & Neuroinflammation最新文献

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: 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.

Objectives: Anti-CD20 therapies for multiple sclerosis (MS) are highly effective at preventing disease activity. Recognizing infectious complications of these therapies is essential.

Methods: Three MS centers shared deidentified clinical data on persons with MS (pwMS) receiving ocrelizumab who developed enterovirus encephalitis.

Results: Five pwMS (4 with relapsing-remitting MS, 1 with secondary progressive MS) on ocrelizumab were identified. At diagnosis, the median age was 34 years (range, 30-57), the median MS duration was 5 years (range, 2-13), and the median ocrelizumab exposure was 3 years (range, 2-7). Four had young children who were recently ill, including 2 with hand, foot, and mouth disease. MRI brain revealed new nonenhancing T2 hyperintensities in the thalamus (2), substantia nigra (2), cerebellum (2), and pons (1). All had CSF pleocytosis (median, 57/mcL; range, 33-175). Enterovirus was detected by reverse-transcription PCR in CSF (4) and blood (2). Hypogammaglobulinemia was present in 4 patients tested; 1 also had neutropenia. Three received IV immunoglobulin. At follow-up (median, 7 months; range, 3-15), 1 patient had fully recovered and 4 had residual symptoms (cognitive, 1; gait impairment, 3).

Discussion: Enterovirus encephalitis is a rare but serious complication in pwMS receiving ocrelizumab; hypogammaglobulinemia may increase risk. Clinician awareness and prompt testing may improve outcomes.

Objectives: Disability in neuromyelitis optica spectrum disorder (NMOSD) is traditionally considered relapse-driven, but recent studies have suggested possible subclinical progression. Whether this translates into clinically meaningful disability worsening remains unclear, and quantitative data on progression independent of relapse activity (PIRA) in NMOSD are limited. We investigated the frequency and clinical relevance of PIRA in a large cohort with long-term follow-up.

Methods: We retrospectively analyzed 281 patients with AQP4-IgG-positive NMOSD with ≥2 years of follow-up. Significant Expanded Disability Status Scale (EDSS) worsening occurred following conventional thresholds, using a roving baseline. PIRA was defined as EDSS worsening without relapse between assessments, confirmed ≥6 months later, sustained, and not attributable to confounders. Relapse-associated worsening (RAW) was defined when the best EDSS score assessed ≥6 months after relapse still met the threshold.

Results: The mean follow-up duration was 11.3 ± 5.1 years, and the mean relapse-free duration was 8.3 ± 5.2 years. A total of 1,662 EDSS assessments were performed, with a median of 5 per patient (interquartile range, 4-7). Seven patients (2.5%) met PIRA criteria. Despite no treatment escalation, none worsened further. Among 194 patients with relapses, 70 (36.1%) experienced RAW.

Discussion: PIRA was rare, even with extended observation using a formal framework, reaffirming relapse as the principal driver of disability and supporting continued focus on relapse prevention.

Background and objectives: Paramagnetic rim lesions (PRLs), visible on susceptibility-based imaging (SbI), reflect chronic active inflammation in multiple sclerosis (MS). In adult-onset MS, PRLs are associated with a more aggressive disease course.The objectives of this study were to assess the prevalence of PRLs in children with MS and to examine how baseline PRL count relates to clinical disability and brain tissue volume loss, both cross-sectionally and over short-term follow-up.

Methods: We retrospectively analyzed pediatric patients from 4 UK tertiary neuroimmunology centers who met the 2017 McDonald diagnostic criteria and had 3D T1-weighted, T2-weighted, fluid-attenuated inversion recovery, and SbI MRI available. PRLs were identified per North American Imaging in MS criteria and anatomically classified. Brain volumes were segmented using Mindglide, with z-scores derived from NIH normative data. Associations between baseline PRL burden, clinical variables, and brain volumes were assessed using univariable and multivariable stepwise regression. Linear mixed-effects models evaluated the predictive value of baseline PRL burden on longitudinal brain volume changes.

Results: Fifty-four patients (mean age 14.0 ± 2.2 years; 75.9% female) were included. At least 1 PRL was seen in 74.1% of patients, with a median number of 2 PRLs (interquartile range [IQR] = 0-6), predominantly in periventricular regions, and accounting for 25% of total T2-weighted hyperintense lesions. In multivariable Poisson regression, at baseline, shorter disease duration (incidence rate ratio [IRR] = 0.987, 95% CI 0.975-0.999, p = 0.035), and greater number (IRR 1.045, 95% CI 1.035-1.054, p < 0.001) and volume (IRR 1.018, 95% CI 1.004-1.032, p = 0.012) of T2-hyperintense lesions were associated with higher PRL count. Cross-sectionally, a higher PRL count was associated with lower cortical (β = -0.139, 95% CI -0.231 to -0.047, p = 0.016) and deep (β = -0.096, 95% CI -0.166 to -0.026, p = 0.032) gray matter volume z-scores. No significant association was observed between clinical disability and PRL count. In 45 patients followed up for a median 17 months (IQR 12-24), a higher baseline PRL count predicted greater deep gray matter volume loss over time (β = -0.020, 95% CI -0.034 to -0.006, p = 0.036).

Discussion: PRLs are common in pediatric MS and are linked to greater lesion burden and gray matter atrophy. These findings suggest that PRLs are promising imaging biomarkers of more severe brain tissue damage although their ability to predict future disability requires confirmation in longer term studies.

Background and objectives: Immune reconstitution therapies for multiple sclerosis (MS) are based on selective lymphocyte reduction, followed by repopulation and rescue of immune tolerance. Among these therapies, cladribine is an adenosine analog that interferes with cell division and depletes several lymphocyte subtypes. Regulatory T cells (Tregs), physiologically devoted to immune suppression, are dysfunctional in the context of MS. In this study, we explored the effects of cladribine on Treg dynamics and phenotype.

Methods: In vivo, deep immunophenotyping was conducted on peripheral blood of patients with MS (n = 11), longitudinally collected before and after 6 and 12 months of cladribine therapy. In vitro, expanded Tregs were treated with cladribine and analyzed for their phenotypic, molecular, and metabolic profiles.

Results: In vivo, Tregs were overall less sensitive than conventional T cells (Tconvs) to the depleting effects of cladribine. This phenomenon was particularly evident in the subset of the resting (rest) Tregs. At baseline, while activated (act) Tregs presented markers of proliferation, senescence, and survival, restTregs highly expressed the antiapoptotic protein Bcl2 and the quiescence marker Bach2. In vitro, cladribine strongly reduced Treg viability while inducing a program of senescence and dysfunction and compromising their metabolic fitness. When Treg dynamics were analyzed ex vivo in relation to neuroinflammation and response to therapy, restTregs exhibited resistance to depletion in nonresponders, in association with increasing expression of Bcl2.

Discussion: These results indicate that the efficacy of cladribine therapy may require reduction and repopulation of the Treg compartment, an event that may be hindered by restTreg resistance, which is supported by antiapoptotic signals.

Background and objectives: In multiple sclerosis (MS), a variety of immunosuppressive treatments are available. While effective, these approaches often lead to sustained impairment of essential components of the immune system, posing long-term safety concerns. Consequently, there is a growing interest in alternative therapeutic approaches that selectively limit pathogenic B-cell functions while preserving their physiologic roles. In this study, we investigated the therapeutic potential of inhibiting the enzyme Bruton tyrosine kinase (BTK), a key signaling molecule in both B-cell and myeloid cell activation.

Methods: The effects of the BTK inhibitor evobrutinib were evaluated in various experimental in vivo models of CNS demyelination, each representing different aspects of disease pathology as well as a naïve healthy condition. The impact on disease onset and severity was determined, and phenotypical alterations in different cell populations were assessed via flow cytometry. Furthermore, functional changes in both murine and human myeloid cells induced by BTK inhibition under specific Fc receptor-dependent stimulation were analyzed in in vitro settings using flow cytometry.

Results: In a naïve, healthy environment, evobrutinib promoted the development of regulatory B-cell properties. In various experimental models of CNS demyelination, BTK inhibition limited the differentiation of proinflammatory B cells while supporting their regulatory properties. Beyond modulating B-cell responses, BTK inhibition also attenuated the activation of myeloid cells after Fc receptor-mediated antigen uptake, a process assumed to be of importance in conditions, such as neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein-antibody associated disease. In addition, BTK inhibition was shown to suppress the secretion of proinflammatory cytokines and reduce antigen presentation, further dampening pathogenic immune responses.

Discussion: These findings highlight the potential of BTK inhibition as a selective and sustainable immunomodulatory strategy for both B cells and myeloid cells in the context of chronic CNS inflammation. Despite their efficacy, broad-spectrum immunosuppressive therapies often fail to provide targeted immune modulation. By contrast, BTK inhibition promotes regulatory B-cell properties while leaving other B-cell functions intact, providing the basis for its broad use-potentially in combination with established anti-inflammatory agents.

Background and objectives: Spinal cord leptomeningeal enhancement (LME) can be observed in children with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and with seronegative myelitis. We investigated whether the presence of spinal cord LME in MOGAD and seronegative myelitis is associated with distinct clinical, CSF, and MRI findings.

Methods: Study participants were identified among the 490 children and adolescents recruited to the Canadian Pediatric Demyelinating Disease study following an incident attack of CNS demyelination. Inclusion criteria for this study were: (1) evidence of spinal cord lesions on MRI, (2) available postgadolinium MRI sequences, and (3) available MOG and aquaporin-4 (AQP4) antibody results. None of the AQP4 antibody-positive participants met our inclusion criteria and only 1 participant with multiple sclerosis exhibited LME. We therefore focused the study on children with MOGAD and seronegative myelitis and compared the clinical, CSF, and MRI features between participants with and without LME.

Results: Our cohort included 33 participants with MOGAD (median age 5.9 years, 55% women) and 45 with seronegative myelitis (median age 11.9 years, 33% women). Spinal cord LME was detected in 20/33 (61%) participants with MOGAD and 14/45 (31%) with seronegative myelitis. Among children with MOGAD, those with LME were more likely than those without LME to have longitudinally extensive myelitis ([LETM], 19/20 vs 8/13, p = 0.024); H-sign (15/20 vs 5/13, p = 0.036), tumefactive cord lesions (10/20 vs 1/13, p = 0.021); complete cross-sectional involvement (16/20 vs 5/13, p = 0.026); nodular lesional enhancement (7/20 vs 0/13, p = 0.026); and more spinal cord lesions (p = 0.036). LME in MOGAD was not associated with greater CSF protein content or cell count nor predicted relapse rate or clinical recovery. Children with seronegative myelitis and LME were more likely than those without LME to have tumefactive lesions (6/14 vs 4/31, p = 0.048) and complete cross-section involvement (11/14 vs 13/31, p = 0.028) but did not differ in terms of H-sign, LETM, lesional enhancement, or number of lesions.

Discussion: The presence of spinal cord LME is associated with more extensive spinal cord abnormalities on MRI in children with MOGAD and to a lesser extent in those with seronegative myelitis. The biological underpinnings of this finding and its clinical implications should be assessed in further studies.