Peripheral GFAP and NfL as early biomarkers for dementia: longitudinal insights from the UK Biobank.

BACKGROUND: Peripheral glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) are sensitive markers of neuroinflammation and neuronal damage. Previous studies with highly selected participants have shown that peripheral GFAP and NfL levels are elevated in the pre-clinical phase of Alzheimer's disease (AD) and dementia. However, the predictive value of GFAP and NfL for dementia requires more evidence from population-based cohorts. METHODS: This was a prospective cohort study to evaluate UK Biobank participants enrolled from 2006 to 2010 using plasma GFAP and NfL measurements measured by Olink Target Platform and prospectively followed up for dementia diagnosis. Primary outcome was the risk of clinical diagnosed dementia. Secondary outcomes were cognition. Linear regression was used to assess the associations between peripheral GFAP and NfL with cognition. Cox proportional hazard models with cross-validations were used to estimate associations between elevated GFAP and NfL with risk of dementia. All models were adjusted for covariates. RESULTS: A subsample of 48,542 participants in the UK Biobank with peripheral GFAP and NfL measurements were evaluated. With an average follow-up of 13.18 ± 2.42 years, 1312 new all-cause dementia cases were identified. Peripheral GFAP and NfL increased up to 15 years before dementia diagnosis was made. After strictly adjusting for confounders, increment in NfL was found to be associated with decreased numeric memory and prolonged reaction time. A greater annualized rate of change in GFAP was significantly associated with faster global cognitive decline. Elevation of GFAP (hazard ratio (HR) ranges from 2.25 to 3.15) and NfL (HR ranges from 1.98 to 4.23) increased the risk for several types of dementia. GFAP and NfL significantly improved the predictive values for dementia using previous models (area under the curve (AUC) ranges from 0.80 to 0.89, C-index ranges from 0.86 to 0.91). The AD genetic risk score and number of APOE*E4 alleles strongly correlated with GFAP and NfL levels. CONCLUSIONS: These results suggest that peripheral GFAP and NfL are potential biomarkers for the early diagnosis of dementia. In addition, anti-inflammatory therapies in the initial stages of dementia may have potential benefits.

Correlation between severe attacks and serum aquaporin-4 antibody titer in neuromyelitis optica spectrum disorder.

Aquaporin 4-immunoglobulin G (AQP4-IgG) specifically targets aquaporin 4 in approximately 80% of Neuromyelitis Optica Spectrum Disorder (NMOSD) cases. NMOSD is presently categorized as anti-AQP4-antibody (Ab) positive or negative based on AQP4-Ab presence. The association between antibody titers and patient prognosis remains unclear. Therefore, the present study explores the correlation between severe attacks and serum AQP4 Ab titers in patients with neuromyelitis optica spectrum disorder. Data were gathered retrospectively from 546 patients with NMOSD between September 1, 2009, and December 1, 2021. Patients were categorized based on their AQP4-Ab titers: AQP4 titer ≥ 1:320 were classified as the high-titer group, AQP4 (+ +), and AQP4 titer of ≤ 1:100 were classified as the low-titer group, AQP4 ( +). Clinical characteristics and prognoses between the two groups were compared. Patients with AQP4 ( +) exhibited few severe optic neuritis (SON) attacks (false discovery rate [FDR] corrected p < 0.001), a reduced percentage experiencing SON attacks, and a lower incidence of visual disability than patients with AQP4 (+ +). Patients with AQP4 (+ +) and AQP4 ( +) NMOSD exhibited significant difference in annual recurrence rate (ARR) (FDR-corrected p < 0.001). The lower AQP4 Ab titer group demonstrated reduced susceptibility to severe relapse with conventional immunosuppressive agents and rituximab (RTX) than the higher titer group. No significant differences in sex, age at onset, coexisting connective tissue diseases, motor disability, or mortality rates were observed between the two groups. Higher AQP4 Ab titers correlated with increased disease severity and visual disability in patients with NMOSD.

MicroRNAs in spermatogenesis dysfunction and male infertility: clinical phenotypes, mechanisms and potential diagnostic biomarkers.

Infertility affects approximately 10-15% of couples worldwide who are attempting to conceive, with male infertility accounting for 50% of infertility cases. Male infertility is related to various factors such as hormone imbalance, urogenital diseases, environmental factors, and genetic factors. Owing to its relationship with genetic factors, male infertility cannot be diagnosed through routine examination in most cases, and is clinically called 'idiopathic male infertility.' Recent studies have provided evidence that microRNAs (miRNAs) are expressed in a cell-or stage-specific manner during spermatogenesis. This review focuses on the role of miRNAs in male infertility and spermatogenesis. Data were collected from published studies that investigated the effects of miRNAs on spermatogenesis, sperm quality and quantity, fertilization, embryo development, and assisted reproductive technology (ART) outcomes. Based on the findings of these studies, we summarize the targets of miRNAs and the resulting functional effects that occur due to changes in miRNA expression at various stages of spermatogenesis, including undifferentiated and differentiating spermatogonia, spermatocytes, spermatids, and Sertoli cells (SCs). In addition, we discuss potential markers for diagnosing male infertility and predicting the varicocele grade, surgical outcomes, ART outcomes, and sperm retrieval rates in patients with non-obstructive azoospermia (NOA).

Clinical features and prognosis of Tibetan patients with neuromyelitis optica spectrum disorder are different from those of Han Chinese patients.

We compared the prognosis of Tibetan and Han Chinese patients with neuromyelitis optica spectrum disorder (NMOSD). The Expanded Disability Status Scale (EDSS) score at each attack, response to immunosuppressive therapy, risk of first relapse, severe attack, visual disability, motor disability, and total risk of disability were compared between Tibetan and Han Chinese patients. Tibetan patients showed higher EDSS during acute attacks. Annualized relapse rate did not differ between groups. Risk of severe attack, visual disability, and total risk of disability were higher in Tibetan patients. Tibetan patients with NMOSD have a higher risk of poor prognosis than Han Chinese patients.

Causal relationship between multiple sclerosis and cortical structure: a Mendelian randomization study.

BACKGROUND: Observational studies have suggested an association between multiple sclerosis (MS) and cortical structure, but the results have been inconsistent. OBJECTIVE: We used two-sample Mendelian randomization (MR) to assess the causal relationship between MS and cortical structure. METHODS: MS data as the exposure trait, including 14,498 cases and 24,091 controls, were obtained from the International Multiple Sclerosis Genetics Consortium. Genome-wide association study (GWAS) data for cortical surface area (SAw/nw) and thickness (THw/nw) in 51,665 individuals of European ancestry were obtained from the ENIGMA Consortium. The inverse-variance weighted (IVW) method was used as the primary analysis for MR. Sensitivity analyses were conducted to evaluate heterogeneity and pleiotropy. Enrichment analysis was performed on MR analyses filtered by sensitivity analysis. RESULTS: After IVW and sensitivity analysis filtering, only six surviving MR results provided suggestive evidence supporting a causal relationship between MS and cortical structure, including lingual SAw (p = .0342, beta (se) = 5.7127 (2.6969)), parahippocampal SAw (p = .0224, beta (se) = 1.5577 (0.6822)), rostral middle frontal SAw (p = .0154, beta (se) = - 9.0301 (3.7281)), cuneus THw (p = .0418, beta (se) = - 0.0020 (0.0010)), lateral orbitofrontal THw (p = .0281, beta (se) = 0.0025 (0.0010)), and lateral orbitofrontal THnw (p = .0417, beta (se) = 0.0029 (0.0014)). Enrichment analysis suggested that leukocyte cell-related pathways, JAK-STAT signaling pathway, NF-kappa B signaling pathway, cytokine-cytokine receptor interaction, and prolactin signaling pathway may be involved in the effect of MS on cortical morphology. CONCLUSION: Our results provide evidence supporting a causal relationship between MS and cortical structure. Enrichment analysis suggests that the pathways mediating brain morphology abnormalities in MS patients are mainly related to immune and inflammation-driven pathways.

COVID-19 susceptibility, hospitalization, and severity and the risk of brain cortical structure: a mendelian randomization study.

BACKGROUND: Observational studies have reported structural changes in the brains of patients with COVID-19; it remains unclear whether these associations are causal. AIM: We evaluated the causal effects of COVID-19 susceptibility, hospitalization, and severity on cortical structures. DESIGN: Mendelian randomization (MR) study. METHODS: Data on the different COVID-19 phenotypes were obtained from the latest large-scale genome-wide association study (GWAS) (R7) of the COVID-19 Host Genetics Initiative. Brain structure data, including cortical thickness (TH) and surface area (SA), were obtained from the ENIGMA Consortium. Additionally, we employed the round 5 dataset released in January 2021 as the validation cohort. The inverse-variance weighted (IVW) method was used as the primary analysis in MR. Sensitivity analyses were conducted to evaluate heterogeneity and pleiotropy. We performed enrichment analysis on the MR analyses that passed the sensitivity analysis filtering. RESULTS: After IVW and sensitivity analyses, we observed causal associations between COVID-19 susceptibility and rostral middle frontal SAw (P = 0.0308, ß=-39.1236), cuneus THw (P = 0.0170, ß=-0.0121), medial orbitofrontal THw (P = 0.0002, ß = 0.0225), postcentral THw (P = 0.0217, ß= -0.0106), temporal pole THw (P = 0.0077, ß = 0.0359), medial orbitofrontal SAnw (P = 0.0106, ß= -24.0397), medial orbitofrontal THnw (P = 0.0007, ß = 0.0232), paracentral SAnw (P = 0.0483, ß= -20.1442), rostral middle frontal SAnw (P = 0.0368, ß= -81.9719), and temporal pole THnw (P = 0.0429, ß = 0.0353). COVID-19 hospitalization had causal effects on medial orbitofrontal THw (P = 0.0053, ß = 0.0063), postcentral THw (P = 0.0143, ß= -0.0042), entorhinal THnw (P = 0.0142, ß = 0.0142), medial orbitofrontal THnw (P = 0.0147, ß = 0.0065), and paracentral SAnw (P = 0.0119, ß= -7.9970). COVID-19 severity had causal effects on rostral middle frontal SAw (P = 0.0122, ß=-11.8296), medial orbitofrontal THw (P = 0.0155, ß = 0.0038), superior parietal THw (P = 0.0291, ß= -0.0021), lingual SAnw (P = 0.0202, ß=-11.5270), medial orbitofrontal THnw (P = 0.0290, ß = 0.0039), paracentral SAnw (P = 0.0180, ß= -5.7744), and pars triangularis SAnw (P = 0.0151, ß=-5.4520). CONCLUSION: Our MR results demonstrate a causal relationship between different COVID-19 phenotypes and cortical structures.

Patterns of neuromyelitis optica spectrum disorder attacks in different age groups and sexes depending on the status of immunosuppressive therapy: A retrospective cohort study.

BACKGROUND AND PURPOSE: The association between onset age and sex with relapse risk in neuromyelitis optica spectrum disorder (NMOSD) remains inconclusive. We aimed to describe the clinical features of patients with NMOSD in different age groups and sexes and to analyse relapse characteristics pre- and post-immunosuppressive therapy (IST). METHODS: Patients with NMOSD were retrospectively reviewed from our clinical centre's database. Demographic and clinical data, attack presentation, and disease course pre- and post-IST were investigated. We also analysed the effect of onset age on the annualized relapse rate and relapse risk according to sex and IST status. Interactions on the additive scale between onset age and sex were analysed. A restricted cubic spline was used to analyse potential nonlinear correlations. Longitudinal changes in the Expanded Disability Status Scale score across NMOSD attacks were analysed using linear mixed-effect models. RESULTS: In total, 533 patients experienced 1394 attacks pre-IST and 753 relapses post-IST. Older age at onset was correlated with more myelitis attacks but fewer optic neuritis attacks, with no sex-related differences in attack presentation. Pre-IST, relapse risk increased with age at onset in women, while a U-shaped correlation between onset age and relapse risk was found in men. Post-IST, an inverted U-shaped association between the predicted relapse risk and onset age was observed in women. Conversely, a negative correlation between the predicted relapse risk and onset age was found in men. Overall, a higher ratio of myelitis attacks was found post-IST. CONCLUSIONS: Patients of different onset ages and sexes had different relapse patterns before and after IST.

Cerebrospinal fluid oligoclonal bands in Chinese patients with multiple sclerosis: the prevalence and its association with clinical features.

Background: Cerebrospinal fluid oligoclonal band (CSF-OCB) is an established biomarker in diagnosing multiple sclerosis (MS), however, there are no nationwide data on CSF-OCB prevalence and its diagnostic performance in Chinese MS patients, especially in the virtue of common standard operation procedure (SOP). Methods: With a consensus SOP and the same isoelectric focusing system, we conducted a nationwide multi-center study on OCB status in consecutively, and recruited 483 MS patients and 880 non-MS patients, including neuro-inflammatory diseases (NID, n = 595) and non-inflammatory neurological diseases (NIND, n=285). Using a standardized case report form (CRF) to collect the clinical, radiological, immunological, and CSF data, we explored the association of CSF-OCB positivity with patient characters and the diagnostic performance of CSF-OCB in Chinese MS patients. Prospective source data collection, and retrospective data acquisition and statistical data analysis were used. Findings: 369 (76.4%) MS patients were OCB-positive, while 109 NID patients (18.3%) and 6 NIND patients (2.1%) were OCB-positive, respectively. Time from symptom onset to diagnosis was significantly shorter in OCB-positive than that in OCB-negative MS patients (13.2 vs 23.7 months, P=0.020). The prevalence of CSF-OCB in Chinese MS patients was significantly higher in high-latitude regions (41°-50°N)(P=0.016), and at high altitudes (>1000m)(P=0.025). The diagnostic performance of CSF-OCB differentiating MS from non-MS patients yielded a sensitivity of 76%, a specificity of 87%. Interpretation: The nationwide prevalence of CSF-OCB was 76.4% in Chinese MS patients, and demonstrated a good diagnostic performance in differentiating MS from other CNS diseases. The CSF-OCB prevalence showed a correlation with high latitude and altitude in Chinese MS patients.

The effectiveness of teriflunomide in patients with multiple sclerosis in China: a real-world comparison to no DMT treatment in the first year after diagnosis.

Background: Teriflunomide is a first-line oral immunomodulatory agent approved in China for the treatment of relapsing multiple sclerosis. Objective: To compare the treatment outcomes of teriflunomide and no disease-modifying therapy (DMT) treatment (in first year) in multi-center real-world Chinese multiple sclerosis patients. Design: Retrospective study. Methods: This study was conducted in five tertiary hospitals in different geographical regions of China. We collected clinical data of patients treated with teriflunomide and no DMT treatment (in first year) between 1 January 2017 and 31 August 2021. The effectiveness of teriflunomide was described. Potential factors influencing the effectiveness of teriflunomide were investigated. Results: A total of 372 patients treated with teriflunomide and 148 no DMT treatment patients were included. A total of 292 patients were treated with teriflunomide for at least 6 months, described as a stable teriflunomide cohort. The annualized relapse rate was significantly lower in the stable teriflunomide cohort than in the no DMT treatment cohort (0.23 ± 0.47 versus 0.87 ± 0.67, p < 0.001). The mean Expanded Disability Status Scale (EDSS) score of the stable teriflunomide cohort (1.77 ± 1.62) was slightly different from that of the no DMT treatment cohort (2.09 ± 2.00). A previous annualized relapse rate of ⩾1, a previous EDSS score of ⩾2, and a long disease duration of ⩾5 years were associated with better clinical effectiveness. Conclusion: Teriflunomide is associated with a lower relapse rate and less disability accumulation in Chinese patients with multiple sclerosis.

COVID-19 and the risk of neuromyelitis optica spectrum disorder: a Mendelian randomization study.

Background: An increasing number of studies have elucidated a close nexus between COVID-19 phenotypes and neuromyelitis optica spectrum disorder (NMOSD), yet the causality between them remains enigmatic. Methods: In this study, we conducted a Mendelian randomization (MR) analysis employing summary data sourced from genome-wide association studies (GWAS) pertaining to COVID-19 susceptibility, hospitalization, severity, and NMOSD. The primary MR analysis employed the Inverse variance weighted (IVW) approach, which was supplemented by MR-Egger, weighted median, simple mode, and weighted mode methods. We implemented various sensitivity analyses including Cochran's Q test, MR-PRESSO method, MR-Egger intercept, leave-one-out analysis, and funnel plot. Results: The MR results demonstrated a nominal association between COVID-19 susceptibility and the risk of AQP4+ NMOSD, as evidenced by the IVW method (OR = 4.958; 95% CI: 1.322-18.585; P = 0.018). Conversely, no causal association was observed between COVID-19 susceptibility, hospitalization, or severity and the increased risk of NMOSD, AQP4-NMOSD, or AQP4+ NMOSD. The comprehensive sensitivity analyses further bolstered the robustness and consistency of the MR estimates. Conclusion: Our findings provide compelling evidence for a causal effect of COVID-19 phenotype on AQP4+ NMOSD, shedding new light on the understanding of the comorbidity between COVID-19 and NMOSD.

Association between COVID-19 and myasthenia gravis (MG): A genetic correlation and Mendelian randomization study.

BACKGROUND: Observational studies have suggested an association between coronavirus disease 2019 (COVID-19) and myasthenia gravis (MG). Here, we aimed to estimate the genetic correlation and causal relationship between COVID-19 susceptibility, hospitalization, severity, and MG phenotypes using linkage disequilibrium score regression (LDSC) and Mendelian randomization (MR) approach. METHODS: Summary statistics of COVID-19 susceptibility, hospitalization, and severity were used as instrumental variables for exposure traits. Large-scale genome-wide association study (GWAS) data for MG were used as outcome traits. The inverse variance weighted approach was used for the main MR analysis, complemented by MR-Egger, weighted median, simple mode, and weighted mode methods. Sensitivity analysis was implemented using Cochran's Q test, MR-PRESSO method, and MR-Egger intercept test. RESULTS: LDSC analysis did not reveal any genetic correlation among COVID-19 susceptibility, hospitalization, severity, and MG phenotypes, including MG, early-onset MG, and late-onset MG (p > .05). Our MR analysis did not provide evidence supporting a causal effect of COVID-19 susceptibility, hospitalization, or severity on MG phenotypes (p > .05). Extensive sensitivity analysis strengthened the robustness and consistency of the MR estimates. CONCLUSION: Our study did not find evidence of a genetic correlation or causal relationship among COVID-19 susceptibility, hospitalization, severity, and MG. Future studies with more GWAS data are needed to evaluate the association between COVID-19 phenotypes and MG and its subgroups.

Case Report: Long segmental lesions of the spinal cord caused by exposure to xylene.

Xylene has the potential to cause nervous system disturbances since it is a lipophilic substance with high affinity for lipid-rich tissue, such as the brain. Involvement in the spinal cord, especially long segmental spinal cord lesions that permeate almost the entire cervical and thoracic spinal cord, is extremely rare. We report two cases of occupational exposure to excessive xylene, both of which presented with severe and rapidly progressive numbness and weakness in the limbs that, more importantly, led to poor outcomes: one died and the other was left severely disabled. In both, spinal magnetic resonance imaging showed long segmental lesions in the cervicothoracic spinal cord. These findings may provide some insights into the effects of xylene as an isolated agent on the spinal cord injury.

Immune Repertoire Profiling Reveals Its Clinical Application Potential and Triggers for Neuromyelitis Optica Spectrum Disorders.

BACKGROUND AND OBJECTIVES: Neuromyelitis optica spectrum disorders (NMOSD) is widely recognized as a CNS demyelinating disease associated with AQP4-IgG (T cell-dependent antibody), and its trigger is still unclear. In addition, although the treatment of NMOSD currently can rely on traditional immunosuppressive and modulating agents, effective methods to predict the efficacy of these therapeutics are lacking. METHODS: In this study, high-throughput T-cell receptor (TCR) sequencing was performed on peripheral blood from 151 pretreatment patients with AQP4-IgG+ NMOSD and 151 healthy individuals. We compared the TCR repertoire of those with NMOSD with that of healthy individuals and identified TCR clones that were significantly enriched in NMOSD. In addition, we treated 28 patients with AQP4-IgG+ NMOSD with immunosuppressants and followed up for 6 months to compare changes in NMOSD-specific TCRs (NMOSD-TCRs) before and after treatment. Moreover, we analyzed transcriptome and single-cell B-cell receptor (BCR) data from public databases and performed T-cell activation experiments using antigenic epitopes of cytomegalovirus (CMV) to further explore the triggers of AQP4-IgG+ NMOSD. RESULTS: Compared with healthy controls, patients with AQP4-IgG+ NMOSD had significantly reduced diversity and shorter CDR3 length of TCRß repertoire. Furthermore, we identified 597 NMOSD-TCRs with a high sequence similarity that have the potential to be used in the diagnosis and prognosis of NMOSD. The characterization of NMOSD-TCRs and pathology-associated clonotype annotation indicated that the occurrence of AQP4-IgG+ NMOSD may be associated with CMV infection, which was further corroborated by transcriptome and single-cell BCR analysis results from public databases and T-cell activation experiments. DISCUSSION: Our findings suggest that the occurrence of AQP4-IgG+ NMOSD may be associated with CMV infection. In conclusion, our study provides new clues to uncover the causative factors of AQP4-IgG+ NMOSD and provides a theoretical foundation for treating and monitoring the disease.

Initial BMI effects on clinical presentation and prognosis in neuromyelitis optica spectrum disorder.

OBJECTIVE: To investigate the correlation among body mass index at onset, clinical features, and prognosis in patients with neuromyelitis optica spectrum disorder. METHOD: This retrospective cohort studied patients with neuromyelitis optica spectrum disorder from January 2015 to January 2022, grouping them by body mass index at onset. Demographics and clinical records were reviewed. Anderson-Gill, Kaplan-Meier, and Cox models evaluated the body mass index's effect on relapse risk and long-term outcomes. RESULTS: Of 246 patients with 799 neuromyelitis optica spectrum disorder attacks study, 36 patients had low, 133 had normal, 77 had high body mass index, with a mean onset age of 40 ± 13 years, and the population was 88% female. The medium follow-up time was 49 months; AQP4-IgG was found in 193 (78%) patients. Onset and relapse of area postrema syndrome were less frequent in patients with a normal body mass index. The annual relapse rate after immunosuppressive therapy was significantly lower in patients with a low body mass index. In the multivariable analysis, statistical correlation still existed between body mass index at onset and risk of relapse (HR = 1.03, 95% CI: 1.03-1.03, P < 0.001), risk of severe attack (HR = 0.92, 95% CI: 0.86-0.98, P = 0.013), risk of visual disability (HR = 0.9, 95% CI: 0.81-1, P = 0.047), and overall risk of disability (HR = 0.89, 95% CI: 0.82-0.98, P = 0.015) after adjusting various variables. INTERPRETATION: Lower body mass index at onset was associated with less frequent relapse but poor prognosis.

Granzyme B + CD8 + T cells with terminal differentiated effector signature determine multiple sclerosis progression.

BACKGROUND: Multiple sclerosis (MS) leads to demyelination and neurodegeneration with autoimmune responses in central nervous system. Patients begin with a relapsing-remitting (RR) course, and more than 80% of them may advance to secondary progressive MS (SPMS), which is characteristic for the gradual decline of neurological functions without demonstrated treating method to prevent. This study aims to investigate the contribution of peripheral CD8 + T cells during the conversion from RRMS to SPMS, as well as reveal potential diagnostic signature in distinguishing SPMS. METHODS: Single-cell RNA sequencing was employed to reveal the heterogeneity of CD8 + T cells between SPMS and RRMS. In addition, flow cytometry was used to further characterized CD8 + T cell dynamic changes in patients. T cell receptor sequencing was performed to detect the clonal expansion of MS. Using Tbx21 siRNA, T-bet was confirmed to manipulate GzmB expression. The correlation between GzmB + CD8 + T cell subsets and clinical characteristics of MS and their potential diagnostic value for SPMS were evaluated by generalized linear regression models and receiver operating characteristic (ROC) curve respectively. RESULTS: Other than diminished naïve CD8 + T cell, elevating of activated CD8 + T cell subsets were observed in SPMS patients. Meanwhile, this aberrant amplified peripheral CD8 + T cells not only exhibited terminal differentiated effector (EMRA) phenotype with GzmB expression, but also possessed distinct trajectory from clonal expansion. In addition, T-bet acted as a key transcriptional factor that elicited GzmB expression in CD8 + TEMRA cells of patients with SPMS. Finally, the expression of GzmB in CD8 + T cells was positively correlated with disability and progression of MS, and could effectively distinguish SPMS from RRMS with a high accuracy. CONCLUSIONS: Our study mapped peripheral immune cells of RRMS and SPMS patients and provided an evidence for the involvement of GzmB + CD8 + TEMRA cells in the progression of MS, which could be used as a diagnostic biomarker for distinguishing SPMS from RRMS.

Visual disability in neuromyelitis optica spectrum disorders: prognostic prediction models.

Background and objectives: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory disease of the central nervous system characterized by simultaneous or consecutive episodes of acute optic neuritis and transverse myelitis. Attacks of NMOSD can result in the accrual of severe visual disability over time. This study aimed to develop and validate prognostic models for visual disability risk within 1, 3, and 5 years. Methods: Medical records of NMOSD patients were retrospectively analyzed. The least absolute shrinkage and selection operator (LASSO) regression algorithm and univariate and multivariate Cox regression analyses were performed to select predictors of visual disability. Two models predicting the probability of visual disability in 1, 3, and 5 years were developed based on different selections and displayed as nomograms. Risk scores were calculated for every patient, and a cut-off point was obtained to recognize patients at high risk. Results: In total, 161 (25.2%) patients developed visual disabilities during the follow-up period. Four visual disability-related factors were selected using LASSO regression: optic neuritis (ON) onset, higher annual relapse rate (ARR) before maintenance therapy, no maintenance immune suppression therapy (IST), and initial severe attack. Three additional predictors were determined using multivariate Cox regression: male sex, age at first onset, and positive AQP4-IgG serology. Discrimination and calibration were satisfied, with concordance indexes (C-index) close to 0.9 in both models. Decision curve analysis showed good clinical usefulness in both models, and Kaplan-Meier curves showed satisfactory discrimination between patients with high risk and low risk by the cut-off points. Conclusion: This study reported predictors of visual disability and generated nomograms. High-risk patients need more active treatment and management to avoid unfavorable outcomes.