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The aim of this study is to highlight findings of retrograde maculopathy (RM) on optical coherence tomography (OCT) as a sequela of neuromyelitis optica associated optic neuropathy. We report two patients with demyelinating lesions involving the visual pathways due to neuromyelitis optica in whom RM was seen, and in whom the location of the RM corresponded to their visual deficits. In one case, we describe a patient who had a demyelinating chiasmal lesion with bitemporal hemianopia and who had corresponding binasal RM. In another case, we describe a patient who had generalized vision loss in the right eye and who had corresponding diffuse RM in the right macula. RM is a potential sequela of severe optic neuropathy in neuromyelitis optica and topographically corresponds to severe visual field defects, as well as severe ganglion cell complex loss. Providers should recognize this finding and be aware that they do not need to pursue diagnostic evaluation due to concern for primary macular disease.
Ravulizumab, a complement component 5 inhibitor, was approved for the treatment of adults with anti-aquaporin-4 antibody-positive (AQP4-Ab+) neuromyelitis optica spectrum disorder (NMOSD) based on results of the primary treatment period (PTP) of CHAMPION-NMOSD, a phase 3, open-label, external placebo-controlled trial. Here, we report the final efficacy and safety results of CHAMPION-NMOSD (PTP and the long-term extension [LTE]). Adult patients with AQP4-Ab+ NMOSD received an IV, weight-based loading dose of ravulizumab on day 1 and a maintenance dose on day 15 and every 8 weeks thereafter. After completion of the PTP (up to 2.5 years), patients could enter the LTE. The primary endpoint was time to first adjudicated on-trial relapse. The placebo group of the eculizumab phase 3 trial PREVENT was used as an external comparator because eculizumab availability at CHAMPION-NMOSD initiation precluded the use of concurrent placebo control. Of 58 patients enrolled in the trial, 56 entered and 55 completed the LTE. The overall median (range) follow-up was 170.3 (11.0-243.0) weeks, with 100.8 (53-137) weeks during the LTE. No patient receiving ravulizumab had an adjudicated on-trial relapse throughout the PTP (84.0 patient-years) and LTE (105.7 patient-years); relative reduction in risk of relapse vs placebo (n = 47) was 98.9% (95% CI 91.8-100; p < 0.0001). Treatment-emergent adverse events (TEAEs) and serious TEAEs were reported in 94.8% and 27.6% of patients, respectively, during the PTP and LTE. Most TEAEs were grade 1 and unrelated to ravulizumab. One patient discontinued ravulizumab because of TEAEs. Two cases of meningococcal infection occurred during the PTP; none occurred in the LTE. One death due to hypertensive heart disease (unrelated to ravulizumab) occurred during the LTE. Long-term ravulizumab treatment (median follow-up, >3 years) continued to show significant relapse risk reduction in patients with AQP4-Ab+ NMOSD, and the safety profile was consistent with the known safety profile for ravulizumab. ClinicalTrials.gov, NCT04201262; EudraCT: 2019-003352-37. Submitted December 11, 2019. First patient enrolled: December 13, 2019. clinicaltrials.gov/study/NCT04201262. This study provides Class III evidence that long-term ravulizumab treatment, as compared with placebo, decreases the probability of clinical relapse in patients with AQP4-Ab+ NMOSD.
Neuromyelitis optica spectrum disorder (NMOSD) is a severe condition usually associated with aquaporin-4 (AQP4) antibodies. A clinical presentation suggestive of NMOSD can also be associated with myelin oligodendrocyte glycoprotein (MOG) antibodies (MOGAD). NMOSD can be diagnosed in the absence of autoantibodies (double-negative NMOSD [DN-NMOSD]), but this subgroup has been poorly investigated. We conducted a systematic review and meta-analysis to define the clinical spectrum, prognosis, and treatment response in DN-NMOSD vs AQP4-NMOSD/MOGAD. We searched on PubMed, Scopus, Embase, Google Scholar, Cochrane Library, and ClinicalTrials.gov databases of studies on patients fulfilling inclusion criteria. Patient characteristics, outcome measures, and treatment regimens were extracted. We included 41 of 1,027 articles screened and analyzed 671 patients with DN-NMOSD (median age 38.6 years [range IQR: 32.5-42.85]; female-to-male ratio 1.5:1; median follow-up 44.4 months [range 1-600]), 73.6% of which relapsed. In the meta-analysis, mean annualized relapse rate (ARR) was higher, albeit not significantly, in DN-NMOSD (1.08; 95% CI 0.73-1.43) vs AQP4-NMOSD (0.84; 95% CI 0.45-1.23) and MOGAD (0.61; 95% CI 0.39-0.83, p = 0.08). Administration of maintenance immunosuppression in DN-NMOSD led to a significant ARR reduction (pooled rate ratio 0.19, 95% CI 0.07-0.49; p = 0.001), with high heterogeneity (I2 = 90%, p < 0.0001). In meta-regression, no covariates were associated with ARR reduction, including the administration of specific drugs (rituximab, p = 0.288; azathioprine, p = 0.291; mycophenolate, p = 0.918). The pooled mean difference in pre‑ and post‑maintenance treatment Expanded Disability Status Scale values indicated a significant change in disability in MOGAD (-0.93, 95% CI -1.67 to -0.19, p = 0.02) but not in AQP4-NMOSD (-0.62, 95% CI -1.85 to 0.61, p = 0.27) or DN-NMOSD (-0.52 (95% CI -1.30 to 0.25, p = 0.16). DN-NMOSD is a heterogenous, severe and highly relapsing disease, where attacks lead to irreversible dysfunction. The administration of maintenance immunotherapy reduces the relapse risk and should be considered early to prevent further disability.
Neuromyelitis optica spectrum disorder (NMOSD) is a rare antibody-mediated neuro-autoimmune disease. Monoclonal antibodies targeting B cell antigens CD19 and CD20, the interleukin-6 receptor, or the complement cascade are used as preventive therapies to reduce relapse rates. We conducted a network meta-analysis (NMA) to compare the effect of rituximab on time to first relapse with ravulizumab, eculizumab, inebilizumab, and satralizumab in patients with NMOSD who are aquaporin-4 (AQP4)-IgG-positive. A systematic search was conducted in PubMed, Scopus, CINAHL, EMBASE, Web of Science, the Cochrane Library, and gray literature sources up to October 31, 2024, and updated on November 1, 2025, following PRISMA guidelines. A network meta-analysis of randomized and open-label trials was conducted to compare time to first relapse between rituximab and other monoclonal antibody therapies. From 6337 records, 3825 duplicates were removed; 2512 were screened, 2327 excluded, leaving eight trials. The prior treatment, relapse history, and definitions and adjudication of relapse varied across studies. Rituximab showed higher hazard ratio (HR) point estimates for time to first relapse compared with ravulizumab with or without immunosuppressive therapies (IST) (HR 5.00, 95% CI 0.25, 101.01) and eculizumab ± IST (HR 1.17, 95% CI 0.12, 10.89), but were lower compared with satralizumab ± IST (HR 0.29, 95% CI 0.04, 2.23). In patients not receiving IST, rituximab showed numerically higher HR compared with ravulizumab (HR 3.33, 95% CI 0.13, 83.16) and eculizumab (HR 1.59, 95% CI 0.05, 50.17), but lower point estimates compared with inebilizumab (HR 0.31, 95% CI 0.04, 2.31) and satralizumab (HR 0.27, 95% CI 0.03, 2.21). This NMA showed hazard ratio point estimates favoring eculizumab and ravulizumab over rituximab. However, wide, overlapping confidence intervals and between-study heterogeneity indicate substantial uncertainty. Head-to-head trials or registry-based studies are needed to determine the most effective treatment for AQP4-IgG-positive NMOSD.
Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune condition driven by aquaporin-4 immunoglobulin G (AQP4-IgG). The current treatment paradigm focuses on mitigating clinical relapses and disability accumulation, leaving the underlying serological activity unaddressed. This study evaluated the capacity of satralizumab to achieve a comprehensive remission, as defined by the Serological, Relapse, and Accumulated-disability Remission (SERA-3) target. In this multicenter, real-world cohort study, patients with NMOSD from three tertiary centers in China initiating satralizumab were enrolled. AQP4-IgG levels were measured at baseline, 6, and 12 months. Clinical efficacy [annualized relapse rate (ARR), Expanded Disability Status Scale (EDSS)] and safety were evaluated. Heterogeneity in antibody response was analyzed, and baseline characteristics potentially associated with titer reduction were explored. Of the 19 patients who were AQP4-IgG seropositive at baseline, 7 (36.84%) met the strict definition of SERA-3 Complete. Of these, 4 patients achieved seroconversion at month 6 and remained seronegative through month 12, whereas 3 first achieved seroconversion at month 12. An additional 5 (26.32%) showed a reduction in AQP4-IgG titers. Satralizumab treatment was associated with marked clinical benefit. Among 33 patients included in the clinical efficacy analysis, 27 (81.82%) remained relapse-free during follow-up, median ARR decreased from 0.92 (IQR 0.56-1.59) to 0 (IQR 0-0), and EDSS scores remained stable in most patients. Exploratory analyses suggested that patients achieving serological response were older at disease onset (57.42 ± 17.82 versus 42 ± 14.24 years, p = 0.039) and had experienced fewer pre-treatment relapses (median 2 versus 5, p = 0.049). Satralizumab was generally well tolerated, including in older patients. Our findings support SERA-3 as a potential treatment framework for NMOSD. Satralizumab was associated with attainment of serological, relapse, and disability remission in a substantial proportion of patients, supporting further prospective evaluation of SERA-3 as a hypothesis-generating outcome framework.
Neuromyelitis Optica Spectrum Disease (NMOSD) is a highly disabling autoimmune disease. Many patients engage in social withdrawal due to disease-related concerns and physical limitations, leading to widespread social avoidance behaviors that further exacerbate psychological distress. Psychological resilience, as a critical individual capacity for coping with adversity, may play a significant role in regulating this process. This study aims to identify the coexistence patterns of psychological resilience and social avoidance in NMOSD patients and explore the specific predictors of these subgroups. A cross-sectional study was conducted to recruit 216 NMOSD patients via WeChat groups from October 10 to 30, 2023. Data were collected using questionnaires, including sociodemographic characteristics, disease-related variables, and scales for psychological resilience, social support, social avoidance, anxiety, and depression. Latent profile analysis (LPA) was employed to explore potential profile patterns of psychological resilience and social avoidance in NMOSD patients, followed by multivariate logistic regression analysis to identify factors influencing these profiles. The results of LPA indicate that the three types are the most suitable, and their characteristics were HR-LSA Group (High Resilience, Low Social Avoidance) (25.9%), MR-MSA Group (Moderate Resilience, Moderate Social Avoidance) (47.7%) and LR-HSA Group (Low Resilience, High Social Avoidance) (26.4%). Different patterns were related to depression score, social support and relapse frequency. These findings enhance clinicians' understanding of the coexistence of psychological resilience and social avoidance, and provide valuable references for implementing appropriate management and support interventions for different patterns.
Despite the estimated 776 million coronavirus disease 2019 (COVID-19) cases globally, little is known about its impact on immune-mediated neurological disorders such as neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody disorder (MOGAD). Scattered case reports, and reviews address this association, but none have collectively examined the impact of COVID-19 infection or vaccination on established and new-onset NMOSD and MOGAD. Reviewing all published reports of COVID-19 infection and vaccination in NMOSD and MOGAD from December 2019 to October 2024, this report examined the effects of infection and vaccination on patients with established disease and the occurrence of new-onset NMOSD and MOGAD. Outcomes associated with COVID-19 infection in NMOSD and MOGAD patients revealed similar hospitalization rates but a notable difference in deaths in NMOSD patients treated with rituximab. Following COVID-19 infection, twice as many patients developed new-onset MOGAD compared to NMOSD, with a similar larger number of patients who developed MOGAD than NMOSD post-COVID-19 vaccination. While the heavy female predominance in NMOSD is well-established, a greater ratio of male to female patients developed MOGAD post-infection and post-vaccination. Clinicians should closely monitor NMOSD patients with COVID-19 infection, particularly those receiving B-cell depleting therapies, among whom mortality was more frequently reported. The rise in NMOSD and MOGAD following COVID-19 infection and vaccination cases warrants further investigation of the underlying immunological mechanisms. Molecular mimicry and a bystander immune-mediated injury likely play a greater role in central nervous system damage than does direct viral injury.
Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory disease of the central nervous system (CNS) characterized by recurrent optic neuritis and myelitis. Blood-brain barrier (BBB) disruption is a key pathological feature of NMOSD, but the role of neutrophil extracellular traps (NETs) in this process remains poorly defined. Serum proteomic profiling in patients with acute NMOSD revealed enrichment of the NET formation pathway. Neutrophils from these patients showed an increased propensity for NETosis, accompanied by elevated myeloperoxidase-DNA complexes, neutrophil elastase-DNA complexes, and cell-free DNA in serum, as well as increased neutrophil elastase-DNA complex levels in cerebrospinal fluid. In a murine NMOSD model, neutrophil depletion, peptidylarginine deiminase 4 inhibition (Cl-amidine), and NET degradation (DNase I) each attenuated astrocyte loss, demyelination, neuroinflammation, and BBB disruption. In vitro, patient-derived NETs downregulated tight junction proteins in bEnd.3 endothelial cells through mechanisms associated with myeloperoxidase and neutrophil elastase, while c-Jun N-terminal kinase inhibition mitigated NET-induced endothelial barrier disruption. Together, these findings suggest that aberrant NETosis may contribute to BBB disruption in acute NMOSD and support further investigation of NET-associated pathways as potential therapeutic targets.
Neuromyelitis optica spectrum disorder (NMOSD) is a rare central nervous system autoimmune disease characterized by aquaporin-4 antibody-mediated astrocyte injury. Although genetic risk variants in the major histocompatibility complex (MHC) region have been consistently implicated in NMOSD susceptibility, the cellular context in which these genetic risk factors operate in the brain remains uncharacterized. We aimed to identify cell-type-specific genetic associations between brain gene expression and NMOSD risk through a systematic Mendelian randomization screen. Cis-eQTL summary statistics from control-only single-nucleus RNA sequencing data of 183 individuals across eight major brain cell types were used as exposures, and the largest European-ancestry NMOSD GWAS (215 cases, 1244 controls) as the outcome. Two-sample Mendelian randomization was performed using the Wald ratio method with Bonferroni correction (P < 2.87 × 10⁻⁵). Steiger directionality testing was performed. Colocalization analysis (coloc.abf) was performed for the Bonferroni-significant loci. Exploratory subtype-stratified analyses were conducted for Bonferroni-significant exposures using NMOSD-IgG+ (132 cases) and NMOSD-IgG- (83 cases) GWAS data. Of 1465 cell-type-gene exposures screened, three reached Bonferroni significance, all in the MHC region: HLA-DRB1 in excitatory neurons (OR = 2.50, 95% CI 1.84-3.41), HLA-B in oligodendrocytes (OR = 0.23, 95% CI 0.12-0.44), and HLA-B in inhibitory neurons (OR = 0.32, 95% CI 0.20-0.51). Steiger testing supported the assumed direction of effect for all three. All three associations were substantially stronger in NMOSD -IgG+ and attenuated or absent in NMOSD -IgG-. Colocalization supported a shared causal signal for HLA-DRB1 in excitatory neurons (PP.H4 = 0.90) but not for either HLA-B association (PP.H4 <0.5), consistent with the latter tagging the shared risk haplotype. Cell-type-specific Mendelian randomization identified three MHC-region genetic associations with NMOSD that exhibited clear AQP4-IgG+ subtype specificity, providing a cell-type-resolved perspective on the genetic architecture of seropositive NMOSD. Because of the extensive linkage disequilibrium across the MHC, these signals most plausibly tag the shared HLA-DRB1×03:01/HLA-B*08:01 risk haplotype rather than reflecting independent cell-type-specific causal effects, and should be regarded as hypothesis-generating.
Neuromyelitis optica spectrum disorder (NMOSD) is a rare, severe autoimmune disease of the central nervous system more prevalent in African and Asian ancestries. The data within the Vietnamese community remain limited. To evaluate the clinical, laboratory, and radiological profiles of a Vietnamese NMOSD cohort, identifying patterns of diagnostic delays, misdiagnosis, and immunotherapy adherence. This retrospective study re-evaluated patients admitted to a tertiary hospital from January 2019 to August 2024 meeting the 2015 diagnostic criteria. Data were collected from records, phone interviews, or follow-ups. We identified 40 patients with 106 disease attacks (73 documented). The female-to-male ratio was 39:1; mean onset age was 44.83 ± 14.07 years. Transverse myelitis was most common initially (57.5%) and overall (63.6%). Aquaporin-4 antibody was positive in 91.9%. Longitudinally extensive transverse myelitis appeared in 83.7% of abnormal spinal MRIs; brain MRI abnormalities in 74%. Only 20% of patients received an accurate etiological diagnosis at onset, with a mean diagnostic delay 24.15 ± 41.1 months. Relapses occurred within the first year in 60% of patients, and within five years in 83.3%. Preventive treatment was prescribed to 85%; long-term adherence was 60% with rituximab showing the highest adherence (15 patients). NMOSD in Vietnamese patients features a marked female predominance, prominent spinal cord involvement, high relapse rates, and low accurate etiological diagnosis rates at onset. Long-term treatment non-compliance, limited antibody test availability, and low physician awareness likely remain major clinical challenges.
Background/Objectives: Our prior epigenome-wide association study (EWAS) on multiple sclerosis (MS) identified myeloid-associated methylation signatures and an association with enhancer regions. Here we compared differential DNA methylation across three central nervous system inflammatory disorders: MS, neuromyelitis optica (NMO), and neurologic post-acute sequelae of COVID-19 (neuro-PASC). Methods: Whole-blood DNA was profiled on Infinium MethylationEPIC arrays. Analyses included EWAS at the CpG level, differentially methylation region (DMR) analysis, and gene regulatory-element enrichment using Locus Overlap Analysis (LOLA). Limma linear models were adjusted for race, EPIC array version, age, sex, disease-modifying treatment class, and blood cell composition. Results: All three diseases were associated with broad CpG-level differential methylation. The most robust findings were disease-specific DMR signatures in gene regulatory regions. All three diseases shared Lamin B1-anchored chromatin states as an architectural genomic feature but differed in immune regulatory transcription factor binding sites (TFBS), RNA polymerase (Pol II) occupancy, and DNase accessibility. MS was enriched for TFBS in myeloid CEBPB and SPI1/PU.1 and lymphocyte-associated RUNX3, EBF1, and BATF. MS hypomethylated DMRs were concentrated at active enhancers and myeloid TFBS, suggestive of chronic myeloid activation. NMO showed the clearest promoter and B lymphocyte associated profile. Neuro-PASC was associated with hematopoietic DNase accessibility and TFBS for BATF and EBF1. Conclusions: These results suggest that DNA methylation in MS, NMO, and neuro-PASC differ meaningfully in regulatory architecture rather than conforming to a single shared disease-associated methylation model. A long-term goal is to develop immune therapies for newly recognized diseases such as neuro-PASC.
To investigate the mediating effects of symptom clusters on the relationship between anxiety/depression and quality of life (QOL) among Chinese patients with neuromyelitis optica spectrum disorder (NMOSD). NMOSD is a rare and severe inflammatory demyelinating disease of the central nervous system, predominantly affecting the optic nerves and spinal cord. Patients with NMOSD often experience significant neurological disability and a high burden of psychiatric comorbidities, including anxiety and depression, which are associated with lower QOL. Although anxiety and depression are established correlates of QOL in NMOSD, the pathways linking them through symptom clusters remain unexplored. A cross-sectional design. A total of 140 participants diagnosed with NMOSD were recruited through online convenience sampling. Data were collected using standardized tools, including the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7) for assessing anxiety and depression, the 36-item Short-Form Health Survey (SF-36) for evaluating QOL, and a self-administered NMOSD symptom scale for identifying symptom clusters. Mediation analyses were performed using the SPSS PROCESS macro with bias-corrected bootstrap methods. Patients with NMOSD had a QOL score of 97.76 ± 8.24. Educational level and primary caregivers were identified as factors associated with QOL. This study revealed significant negative correlations between anxiety/ depression and QOL, with mediation observed through distinct symptom clusters. Anxiety exhibited complete mediation via somatosensory and motor symptom clusters, with partial mediation through bladder-rectal symptoms. Depression demonstrated complete mediation through somatosensory, motor, visual-memory, and bladder-rectal symptom clusters. Notably, sleep-related symptom clusters did not show significant mediating effects. Symptom clusters may mediate the associations between anxiety/depression and QOL. The study underscores the importance of considering both psychological distress and physical symptoms in relation to QOL in NMOSD patients. Future research is needed to validate these findings in larger, diverse cohorts and to explore targeted interventions aimed at optimizing functional outcomes in this population.
Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing autoimmune disease in which disability is largely relapse-driven. The effect of relapse burden on post-relapse recovery remains unclear. This retrospective cohort study included adult patients with NMOSD who experienced clinical relapse at a tertiary care center in Northern Thailand between 2015 and 2024. Relapse episodes were stratified by prior relapse burden into no prior relapse, low relapse burden (1-2 prior relapses), and high relapse burden (>2 prior relapses). Outcomes included Expanded Disability Status Scale (EDSS) at relapse nadir and at 90 and 180 days. Unfavorable outcome was defined as EDSS ≥6. Recovery was assessed using the Recovery Index (RI). A total of 148 patients contributed 493 relapse episodes. Higher relapse burden was associated with progressively greater proportions of unfavorable outcomes at 90 and 180 days (P<0.001). At 90 days, unfavorable outcomes occurred in 4.7%, 12.0%, and 34.9% of no-prior-relapse, low-relapse-burden, and high-relapse-burden episodes, respectively. At 180 days, corresponding proportions were 2.0%, 8.3%, and 27.8%. EDSS at nadir and follow-up increased stepwise with higher relapse burden, whereas RI was progressively lower at both time points (all P<0.001). Each additional prior relapse and delayed intravenous methylprednisolone initiation >14 days after relapse onset were independently associated with unfavorable outcomes at both 90 and 180 days. Higher prior relapse burden was associated with more severe attacks, greater post-relapse disability, and less complete recovery. Relapse prevention, early attack recognition, and timely acute treatment may reduce disability accumulation in NMOSD.
Neuromyelitis optica spectrum disorder (NMOSD) imposes a significant burden on health-related quality of life (HRQoL). However, comprehensive studies examining HRQoL and its biopsychosocial determinants in Chinese NMOSD patients remain scarce. In this cross-sectional study, 216 Chinese patients with NMOSD underwent clinical evaluation for neurological disability (EDSS) and completed a battery of standardized self-report measures. These scales assessed HRQoL (SF-36), basic activities of daily living (BADL), depressive symptoms (PHQ-9), anxiety (GAD-7), sleep quality (PSQI), psychological resilience (CD-RISC), perceived social support (PSSS), general alienation (GAS), and social avoidance and distress (SAD). Multiple stepwise linear regression analyses were employed to identify independent associated factors of the Physical (PCS) and Mental (MCS) Component Summaries of the SF-36. The cohort (median age 37, 85.2% female) showed significantly reduced median PCS (55.5) and MCS (51.0), with role-physical (25.0) and role-emotional (33.3) most impaired. In multivariate analysis, older age (β = -0.194), depressive symptoms (PHQ-9; β = -0.290), social avoidance (SAD; β = -0.128), and poor sleep (PSQI; β = -0.282) independently associated worse PCS (adjusted R 2 = 0.402). For MCS (adjusted R 2 = 0.576), depressive symptoms (β = -0.439), social avoidance (β = -0.135), poor sleep quality (β = -0.267), and lower resilience (CD-RISC; β = 0.127) were significant associated factors. (all p < 0.05). Psychosocial factors critically influence HRQoL in Chinese NMOSD patients. Multidimensional, culturally sensitive interventions targeting mental health, sleep, and social functioning may provide insights for improving patient outcomes.
Neuromyelitis optica spectrum disorder is an astrocytopathy associated with aquaporin-4 immunoglobulin G (AQP4-IgG). Although live cell-based serum assays have improved antibody detection, the diagnostic value of cerebrospinal fluid (CSF) AQP4-IgG testing remains uncertain. To assess its incremental utility, we retrospectively identified patients who underwent paired serum and CSF AQP4-IgG testing using live cell-based assays. Among 606 paired serum-CSF samples, 7 were serum-positive. Of these, 5 of 7 were also CSF-positive. The two remaining serum-positive patients were CSF-negative. No CSF-restricted cases were identified. Despite a low number of serum-positive cases, our findings add to an existing body of evidence supporting limiting routine CSF AQP4-IgG testing.
Aquaporin-4-immunoglobulin G-seropositive neuromyelitis optica spectrum disorder (AQP4-IgG+ NMOSD) is a relapse-associated inflammatory disease in which attacks drive irreversible disability. Treatment discontinuation occurs in practice, and data on outcomes after withdrawal are limited. We retrospectively reviewed adults with AQP4-IgG+ NMOSD who had discontinued maintenance immunotherapy and had at least 6 months of follow-up. Clinical characteristics, treatment exposure, relapses, and disability outcomes were collected. Relapse-free survival was analysed using the Kaplan-Meier method. Among 292 patients with AQP4-IgG+ NMOSD, 22 met the inclusion criteria. Median age at discontinuation was 48.8 years (interquartile range [IQR] 28.9-65.5) and 19 patients (86.4%) were female. Twelve of 22 patients (54.5%) relapsed after discontinuation, whereas 10 (45.5%) remained relapse-free. The relapse-free probability was 81.0% at 1 year (95% CI, 56.9-92.4), 56.3% at 5 years (95% CI, 32.6-74.5), and 48.2% at 10 years (95% CI, 24.0-68.9). In subgroup analysis, patients who remained relapse-free had lower Expanded Disability Status Scale (EDSS) scores at nadir (4.0 [3.5-4.0] vs 5.0 [4.0-6.0], p = 0.032). EDSS scores worsened in 5 of 12 relapsing patients (41.7%) but in none of the 10 non-relapsing patients; within-group change was significant in the relapse group (p = 0.027). Maintenance immunotherapy discontinuation in AQP4-IgG+ NMOSD was associated with a high risk of relapse, frequently resulting in disability worsening. These findings emphasize the need for careful consideration before treatment withdrawal, even among patients with prolonged clinical remission.
Neuromyelitis optica spectrum disorder (NMOSD) is a chronic inflammatory autoimmune disease affecting the central nervous system (CNS), characterized by anti-aquaporin 4 (AQP4) antibody-mediated damage to astrocytes, resulting in subsequent demyelination. Our prior work identified the protective effects of the apolipoprotein E130-149 (ApoE130-149) peptide in NMOSD mice by promoting astrocyte-microglia intercellular communication. However, its therapeutic potential is restricted due to the limited penetration of the blood-brain barrier (BBB) with systemic administration. Here, we designed a heavy-chain ferritin (HFn)-based nanocarrier containing the ApoE130-149 peptide (HFn-ApoE130-149), specifically engineered for CNS delivery. HFn-ApoE130-149 was constructed through genetic engineering by fusing the coding sequence of HFn with that of the ApoE130-149 peptide in a recombinant plasmid. An acute NMOSD mouse model was induced by transcranial co-injection of AQP4-IgG and human complement (hC) into the brain. The distribution of Cy5.5-labeled HFn-ApoE130-149 post intravenous injection was tracked using in vivo fluorescence imaging to confirm its presence in the brain and peripheral organs. Lesions in the brain were quantified using T2-weighted 7 Tesla magnetic resonance imaging (7T-MRI). Neuropathological features of NMOSD were evaluated by immunostaining of brain sections. Neuroinflammation and immune cell infiltration were analyzed via flow cytometry. The key signaling pathways regulated by HFn-ApoE130-149 were investigated through Western blot (WB) analysis. The interaction between HFn-ApoE130-149 and its receptors was validated through co-immunoprecipitation and visualized on microglia using proximity ligation assay (PLA). Finally, the therapeutic effect on spatial learning and memory was evaluated using the Morris water maze (MWM) test. The HFn-ApoE130-149 effectively crossed the BBB, attenuated lesion progression and demyelination, as well as preserved AQP4 expression and astrocytic integrity in NMOSD mice. The treatment induced a spatial and phenotypic restructuring of the astrocytic response, notably reducing excessive astrocyte accumulation around lesions while encouraging a proliferative and reparative phenotype. Furthermore, HFn-ApoE130-149 influenced microglial polarization towards an anti-inflammatory state, reducing infiltration of peripheral immune cells. Mechanistically, HFn-ApoE130-149 exerted its anti-inflammatory effects through the low-density lipoprotein receptor-related protein 1 (LRP1) -nuclear factor kappa B (NF-κB) signaling axis in microglia. Functional binding of HFn-ApoE130-149 to LRP1 suppressed inhibitor of NF-κB (IκBα) phosphorylation, thereby inhibiting NF-κB nuclear translocation and the subsequent release of pro-inflammatory cytokines, including interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). Knocking down LRP1 reversed these effects, highlighting the importance of the LRP1-NF-κB signaling axis in the nanotherapeutic's efficacy. Treatment with HFn-ApoE130-149 improved spatial learning and rescued memory deficits in NMOSD mice. This study demonstrates that the engineered nanodrug HFn-ApoE130-149 is a promising targeted therapy for alleviating NMOSD pathology by enhancing BBB penetration and suppressing neuroinflammation through the LRP1-NF-κB signaling axis.
We report an optimized implementation of spectral-domain quantum optical coherence tomography (SD-QOCT) capable of acquiring axial scans (A-scans) of multilayer samples in the absence of mechanical scanning, at an unprecedented speed. Implementing a novel strategy, we demonstrate a proof-of-concept system that integrates a diffraction grating, a high-resolution intensified CCD camera and a high-flux photon-pair source operating in the VIS-NIR region (≈800 nm). This configuration enables the acquisition of an entire marginal SD-QOCT interferogram in a single camera exposure, yielding a transverse A-scan with a record acquisition time of 100 ms for a mirror sample, which extends to 10 s for a glass coverslip, and a penetration depth of ≈4 mm. The measured interferometric response shows excellent agreement with the theoretical model. These results represent a decisive step toward the practical deployment of SD-QOCT as a competitive imaging modality for biomedical applications.
This study aimed to explore the significance of anti-connective tissue antibodies in the clinical diagnosis and evaluation of neuromyelitis optica spectrum disorder (NMOSD). Demographic and clinical data from 205 patients with aquaporin-4 immunoglobulin G (AQP4-IgG)-positive NMOSD were collected. Variables included sex, age, clinical symptoms/signs, connective tissue antibody status, inflammatory markers, cerebrospinal fluid (CSF) cell counts/oligoclonal band status, spinal cord lesion location/length, Expanded Disability Status Scale scores at onset and first relapse (18-month follow-up), and time to first relapse. Among the 205 patients, 108 (52.7%) were positive for anti-connective tissue antibodies (CTD abs+). Compared with anti-connective tissue antibodies (CTD abs-) patients, the CTD abs+ group had higher lymphocyte counts (1.82 ± 0.14 vs. 1.73 ± 0.07, p < 0.01), higher monocyte-to-lymphocyte ratios [0.27 (0.2) vs. 0.24 (0.16), p = 0.037], and higher CSF white blood cell counts [10 (22) vs. 6 (18)/106/L, p = 0.035]. They also showed a higher rate of oligoclonal band positivity (27.78% vs. 10.31%, p = 0.002), a higher proportion of patients with an increased 24-hour intrathecal synthesis rate (54.6% vs. 40.2%, p = 0.039), and higher CSF immunoglobulin levels [5.755 (6.37) vs. 4.15 (3.53) mg/dL, p < 0.001] at initial onset. No significant differences were observed between the CTD abs+ and CTD abs- groups in the distribution of lesions or the length of affected spinal cord vertebral segments at initial onset. However, patients in the CTD abs+ group had higher Expanded Disability Status Scale scores at first relapse and a higher annualized relapse rate over the 18-month follow-up period(p < 0.05for both). In summary, among AQP4-IgG-positive patients with NMOSD, CTD abs+ was associated with higher lymphocyte counts, a higher MLR, higher CSF white blood cell counts, higher CSF immunoglobulin levels, a higher 24-hour intrathecal IgG synthesis rate, and higher OCB positivity. CTD abs positivity may therefore indicate a more severe inflammatory profile; however, it does not appear to predict earlier relapse, but does appear to predict a higher annualized relapse rate.
Neuromyelitis Optica spectrum disorder (NMOSD) is primarily afflicted on women during their reproductive ages and complicates multiple aspects of their pregnancies. To provide an updated assessment of conception attempts and pregnancy outcomes in a Middle Eastern group of women with NMOSD. Retrospective observational study including all female NMOSD referrals of the Isfahan MS clinic from 1998 to 2024. Those with definitive diagnosis and attempting conception from one year before their NMOSD onset onwards were deemed eligible. Methodical history taking and medical records at the clinic were used to gather information on clinical characteristics, pregnancy history, and demographics. Fecundity, pregnancy complication(s) and outcome, neonatal health status, and clinical markers of disease status (relapse rate and disability worsening) were among the outcomes. 31 pregnancies were reported in 18 participants from a year before NMOSD onset onwards, 15 (48.4%) of which led to live childbirth. All pregnancies were conceived under 12 months, except for one (3.2%). Eight of these 18 participants also reported 12 pregnancies more than a year before their NMOSD onset, with eight (66.7%) leading to live childbirth. In this subgroup (n = 8), regression analysis revealed a significant negative effect of NMOSD onset on live childbirth (miscarriage OR = 4.41; 95% CI: 1.11, 17.54; p = 0.035). Gestational hypertension and/or preeclampsia (26.7%), late preterm labor (6.7%), and intrauterine growth restriction (13.3%) complicated post-NMOSD pregnancies, yet, no stillbirths and/or neonatal complications were reported. Although not achieving statistical significance (p values > 0.05), a trend towards higher relapse rate was observed both during and after pregnancy. Four participants further experienced EDSS worsening one year postpartum. Unintentional rituximab exposure during the first trimester of one pregnancy was associated with no maternal, fetal or neonatal complications. In line with prior evidence from other regions, the present study revealed high occurrence rate of certain adverse pregnancy outcomes in Iranian women with NMOSD. Findings emphasize the necessity of close monitoring of pregnancies in women with NMOSD, and could pave the way for better management of NMOSD during pregnancy.