Acute Neuromyelitis Optica Spectrum Disorders Research Articles

4-Octyl itaconate inhibits inflammation via the NLRP3 pathway in neuromyelitis optica spectrum disorders.

Neuromyelitis optica spectrum disorders (NMOSD) are rare inflammatory astrocytic diseases of the central nervous system (CNS). The roles of immune response gene-1 (IRG1) and the IRG1-itaconic acid-NLRP3 inflammatory pathway in the pathogenesis of NMOSD and the effects of 4-octyl itaconate (4-OI) on the NLRP3 inflammatory pathway in NMOSD are unclear. This study aimed to determine the role of IRG1 and the activation status of the NLRP3 inflammatory pathway in acute-onset NMOSD and to investigate the inhibitory effects of 4-OI on NLRP3 inflammasome activation via the IRG1-itaconic acid-NLRP3 pathway in monocytes and macrophages by using in vitro models. Peripheral blood mononuclear cells (PBMCs) and serum were collected from patients with acute NMOSDs and healthy controls (HC), followed by monocyte typing and detection of the expression of NLRP3-related inflammatory factors. Subsequently, the effects of 4-OI on the IRG1-itaconic acid-NLRP3 pathway were investigated in peripheral monocytes from patients with NMOSD and in macrophages induced by human myeloid leukemia mononuclear cells (THP-1 cells) via in vitro experiments. Patients with acute NMOSD exhibited upregulated IRG1 expression. In particular, the upregulation of the expression of the NLRP3 inflammasome and proinflammatory factors was notable in monocytes in acute NMOSD patients. 4-OI inhibited the activation of the IRG1-itaconic acid-NLRP3 inflammatory pathway in the PBMCs of patients with NMOSD. 4-OI could effectively inhibit NLRP3 signaling, leading to the inhibition of proinflammatory cytokine production in patients with NMOSD-derived PBMCs and in a human macrophage model. Thus, 4-OI and itaconate could have important therapeutic value for the treatment of NMOSD in the future.

Serum Albumin Level Can Predict Immunotherapy Response of Neuromyelitis Optica Spectrum Disorders in the Acute Phase.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune demyelinating disease of the central nervous system. However, few biomarkers have been found to predict the outcome of immunotherapy. We investigated the relationship between the serum albumin (S-Alb) and response to immunotherapy in acute NMOSD patients. A total of 107 consecutive Chinese patients with acute NMOSD diagnosed between January 2013 and January 2022 were included in our prospective observational study. S-Alb was measured by the use of bromocresol green and immunoturbidimetric methods on admission. The immunotherapy response was assessed by the percentage change in the expanded disability status scale (EDSS) score from admission to discharge after treatment. We evaluated the association between S-Alb and immunotherapy response through multivariate logistic regression analysis. S-Alb levels were significantly lower in patients who were resistant to immunotherapy than in those who were responsive to treatment (p<0.001). S-Alb levels were positively related to a favorable response to immunotherapy (r=0.386, p<0.001). The odds ratio (95% CI) for the association between S-Alb level and response to immunotherapy was 1.27 (95% CI=1.08, 1.50; p=0.004) after adjusting for potential factors. ROC analysis showed that patients with S-Alb levels lower than 40.85 g/L were likely to be resistant to immunotherapy. Our study indicated that a higher S-Alb was an independent indicator of response to immunotherapy in acute NMOSD patients.

Association Between Serum Interleukin-32 Level and Disease Status in Cases with Neuromyelitis Optica Spectrum Disorders.

Various cytokines are involved in the pathogenesis of neuromyelitis optica spectrum disorders (NMOSD), but whether serum interleukin-32 (IL-32) level is related to disease activity in cases with NMOSD remains poorly understood. Thus, we investigated the underlying role of IL-32 in NMOSD cases. Our observation recruited 32 cases with acute NMOSD, 36 NMOSD cases in remission, and 60 healthy individuals in this study. Serum concentrations of IL-32 were detected using ELISA. The associations among IL-32 levels and clinical characteristics were assessed by Spearman correlation coefficient and logistic regression analysis. IL-32 concentrations were strongly increased in cases with acute NMOSD [(52.06 ± 16.56) pg/mL] and NMOSD in remission [(25.78 ± 8.31) pg/mL] compared with healthy controls [(10.83 ± 6.94) pg/mL] (all p <0.001). ROC analysis suggested that the AUC for IL-32 and the combined diagnosis of acute NMOSD was 0.811 (P = 0.026, 95% CI 0.673-0.949), with a sensitivity of 0.800 and a specificity of 0.806. The level of IL-32 was positively correlated with EDSS scores in patients with acute NMOSD (r = 0.620, p < 0.001). EDSS score was independently associated with increased serum levels of LI-32 (B = 1.529, p < 0.001). Higher level of IL-32 is related to disease severity in NMOSD. Therefore, serum IL-32 may be a novel biomarker for acute NMOSD.

Combined platelet-to-lymphocyte ratio and blood-brain barrier biomarkers as indicators of disability in acute neuromyelitis optica spectrum disorder.

Neuromyelitis optica spectrum disorder (NMOSD) is a complex neuroinflammatory disease characterized by severe disability. In this study, we investigated the relationship between cerebrospinal fluid (CSF)/serum albumin quotient (Qalb) and platelet to lymphocyte ratio (PLR) in assessing disease severity. A retrospective analysis of 72 NMOSD patients and 72 healthy controls was conducted, and patients were divided into two groups based on their Expanded Disability Status Scale (EDSS) scores. NMOSD patients had significantly higher levels of serum PLR, neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and C-reactive protein (CRP) compared to healthy controls (all P<0.01). Patients in the EDSS≥4 group exhibited significantly elevated levels of Qalb, QIgG, QIgA, QIgM, and PLR (P=0.000, P<0.0001, P=0.0019, P=0.0001, respectively). Spearman's correlation test revealed significant positive associations between Qalb, QIgG, QIgA, QIgM, PLR, and EDSS score. Specifically, Qalb (r=0.571; P<0.001), QIgG (r=0.551; P<0.001), QIgA (r=0.519; P<0.001), and QIgM (r=0.541; P<0.001) demonstrated significant positive correlations with EDSS score, while PLR exhibited a moderate positive correlation (r=0.545; P<0.001) with EDSS score and a mild positive association (r=0.387; P<0.001) with Qalb. The increase of Qalb was positively correlated with the increased EDSS score (r=0.528, P=0.001), as well as the increase of QIgG (r=0.509, P=0.001), and the increase of QIgA (r=0.4989, P=0.03). ROC analysis indicated that Qalb, QIgG, QIgA, QIgM, and PLR levels could effectively serve as indicators of NMOSD severity (all P<0.0001). Multivariate analysis confirmed the independent significance of Qalb and PLR in assessing disease severity (P=0.000). These findings provide valuable insights into the risk and pathogenesis of NMOSD and highlight the potential of Qalb and PLR as independent markers for disease severity assessment in NMOSD patients.

Safety and Efficacy of Inebilizumab in AQP4+ NMOSD Participants with History of Immunosuppression Treatment Prior to N-MOmentum Study (P13-5.003)

Safety and Efficacy of Inebilizumab in AQP4+ NMOSD Participants with History of Immunosuppression Treatment Prior to N-MOmentum Study (P13-5.003)

Granulocyte activation markers in cerebrospinal fluid differentiate acute neuromyelitis spectrum disorder from multiple sclerosis

BackgroundGranulocyte invasion into the brain is a pathoanatomical feature differentiating neuromyelitis optica spectrum disorder (NMOSD) from multiple sclerosis (MS). We aimed to determine whether granulocyte activation markers (GAM) in cerebrospinal...

The Characteristics of Cognitive Proficiency in Patients with Acute Neuromyelitis Optica Spectrum Disease and its Correlation with Serum Aquaporin-4 Antibody Titer.

To explore the characteristics and dynamic evolution of cognitive impairment in patients with neuromyelitis optica spectrum disorder (NMOSD). Twenty-five patients with acute NMOSD and 30 age-matched healthy individuals were consecutively recruited in this study. The Montreal Cognitive Assessment (MoCA), Chinese Version of Rey Auditory Vocabulary Learning Test (CRAVLT), Verbal Fluency Test (VFT), Digital Span Test (DST), Paced Auditory Serial Addition Task 3/2s version (PASAT-3/2), Rey-Osterrieth Complex Figure Test (ROCF) and Stroop Color and Word Test (CWT) were used to evaluate cognitive function. The correlations between cognitive function and serum aquaporin-4 (AQP-4) antibody titer were analyzed. Sixty-four percent of patients with acute NMOSD had cognitive dysfunction. MoCA (p &lt; 0.001), CRAVLT-N7 (p = 0.004), CRAVLT-N8 (p = 0.011), ROCF-C (p = 0.005), ROCF-R (p &lt; 0.001), PASAT-3 (p = 0.013), PASAT-2 (p = 0.001) and CWT-A (p = 0.017) were significantly worse in patients with acute NMOSD than those in control group. During follow-up visits, significant differences of serum AQP-4 antibody titers were still noted in NMOSD patients (p &lt; 0.001), while no significant differences were found by MoCA. A high number of patients with acute NMOSD suffer from cognitive dysfunction. Serum AQP-4 antibody titers can decrease during disease remission, while obvious cognitive decline in these patients still exists.

Identification of double-stranded DNA in the cerebrospinal fluid of patients with acute neuromyelitis optica spectrum disorder

Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory disease of the central nervous system (CNS) characterized by severe myelitis and optic neuritis. Double-stranded DNA (dsDNA) is involved in the pathogenesis of various autoimmune diseases, such as systemic lupus erythematosus. However, its role in NMOSD remains unclear. In this study, the concentration of dsDNA in the cerebrospinal fluid (CSF) was quantified in 23 patients with NMOSD and 16 patients with other neurological diseases (ONDs). CSF dsDNA levels in patients with NMOSD (median: 0.03 ng/µL) were significantly higher than those in patients with ONDs (median: 0.01 ng/μl). CSF dsDNA levels showed no significant difference before and after treatment. Elevation of CSF dsDNA levels may suggest its essential role in the augmentation of CNS inflammation in patients with NMOSD.

The utility of diffusion-weighted imaging in patients with spinal cord infarction: difference from the findings of neuromyelitis optica spectrum disorder

BackgroundMagnetic resonance imaging (MRI) plays a crucial role in diagnosing spinal cord infarction (SCI). However, the findings are often indistinguishable from those of other intramedullary diseases, such as neuromyelitis optica spectrum disorder (NMOSD). Although diffusion-weighted imaging (DWI) is a promising technique, the utility for discriminating SCI from NMOSD remains unclear because the DWI findings of acute NMOSD lesions have not been investigated in detail.MethodsClinical and MRI findings were retrospectively evaluated in 15 and 12 patients with acute SCI and NMOSD, respectively. First, clinical characteristics were compared between the SCI and NMOSD groups. Second, MRI abnormalities were examined to find differences between these groups. Third, in the SCI group, factors influencing T2 and DWI abnormalities were analyzed using the mixed-effects logistic regression analysis.ResultsThe proportion of female patients was higher in the NMOSD group (92%) than in the SCI (40%). The time from symptom onset to nadir was smaller in the SCI group (median [interquartile range]; 4 [0.1–8.3] hours) than in the NMOSD (252 [162–576]). On T2-weighted images, SCI lesions had smaller length than NMOSD (2 [1–2] and 5 [2–7] vertebral segments, respectively). Focal lesions within the T9–L2 level were found only in patients with SCI. DWI hyperintensity was observed both in the SCI (frequency, 100%) and NMOSD (60%) groups. On apparent diffusion coefficient (ADC) maps, the hyperintensities of SCI had corresponding hypointensities, whereas those of NMOSD were isointense and a large portion of NMOSD lesions had hyperintense signals. Owl’s eyes sign and pencil-like hyperintensity, typically reported as T2 findings suggestive of SCI, were also found on DWI. Posterior linear hyperintensity was frequently detected on DWI in patients with posterior spinal artery infarction. The presence of MRI abnormality revealing SCI was modeled with the time from symptom onset, imaging sequence and plane, and affected vascular territory.ConclusionsDWI and ADC maps help distinguish SCI from NMOSD. The time from symptom onset, imaging sequence, and imaging plane should be considered when MRI findings are interpreted in patients with suspected SCI.

Lymphocyte Subsets Are Associated with Disease Status in Neuromyelitis Optica Spectrum Disorders

Objective: At present, studies on lymphocytes are mostly conducted on CD19⁺ B cells and CD27⁺ B cells in neuromyelitis optica spectrum disorders (NMOSDs), but the exact changes in lymphocyte subsets (CD19⁺ B cells, CD3⁺ T cells, CD4⁺ Th cells, CD8⁺ Ts cells, the CD4⁺/CD8⁺ ratio, and NK [CD56+ CD16] cells) have rarely been studied. This study aimed to assess lymphocyte subset changes in patients with NMOSD. Methods: We performed a cross-sectional study of consecutive patients with acute NMOSD (n = 41), chronic NMOSD (n = 21), and healthy individuals (n = 44). Peripheral blood samples were obtained upon admission, and lymphocyte subsets were analyzed by flow cytometry. Levels of lymphocyte subsets among 3 groups were compared and its correlation with the length of spinal cord lesions was analyzed. Results: The levels of peripheral blood CD19⁺ B cells were significantly higher in patients with acute and chronic NMOSD than in healthy controls (HCs) (17.91 ± 8.7%, 13.08 ± 7.562%, and 12.48 ± 3.575%, respectively; p < 0.001) and were positively correlated with the length of spinal cord lesions in acute NMOSD (r = 0.433, p < 0.05). The peripheral blood CD4⁺/CD8⁺ ratio was significantly lower in patients with acute NMOSD and chronic NMOSD than in HCs (1.497 ± 0.6387, 1.33 ± 0.5574, and 1.753 ± 0.659, respectively; p < 0.05), and the levels of peripheral blood NK (CD56+ CD16) cells were significantly lower in patients with acute and chronic NMOSD than in HCs (13.6 ± 10.13, 11.11 ± 7.057, and 14.7 [interquartile range = 9.28], respectively; p < 0.01). Conclusions: The levels of certain subsets of peripheral blood lymphocytes are associated with disease status in NMOSD.

Intravenous immunoglobulin for acute attacks in neuromyelitis optica spectrum disorders (NMOSD)

BackgroundDuring acute attacks of neuromyelitis optica spectrum disorder (NMOSD), intravenous immunoglobulin (IVIG) maybe useful building on experience treating autoimmune disorders. MethodsWe conducted a retrospective study of several treatment modes for NMOSD attacks at Beijing Tiantan Hospital and Tianjin Medical University General Hospital. Clinical outcomes were defined as the short-term remission status. The good (GR), moderate (MR) or poor remission (PR) was respectively defined to triple-grade based on percentage change of initial and follow-up Expanded Disability Status Scale (EDSS) scores. ResultsA total of 243 attacks was analyzed in 198 patients from 2014 to 2019. Treatment groups included 153 attacks given high-dose intravenous steroids (HD-S), 14 given IVIG, 69 episodes of IVIG plus HD-S and 7 treated with plasma exchange. The proportion of patients with better outcomes were significantly lower in IVIG alone group than HD-S alone group (p = 0.004). However, sequential treatments for IVIG and HD-S yielded a higher likelihood of clinical improvement in severe attacks with EDSS ≥ 6.5 (OR = 5.85, p = 0.007). ConclusionThese results did not support IVIG-alone therapy as a first-line option for acute NMOSD. However, adding HD-S to IVIG therapy was superior to HD-S alone for patients with high-onset EDSS.

Lower serum interleukin-22 and interleukin-35 levels are associated with disease status in neuromyelitis optica spectrum disorders.

AimsThe exact pathogenesis of neuromyelitis optica spectrum disorder (NMOSD) remains unclear. A variety of cytokines are involved, but few studies have been performed to explore the novel roles of interleukin‐22 (IL‐22) and interleukin‐35 (IL‐35) in NMOSD. Therefore, this study was designed to investigate serum levels of IL‐22 and IL‐35, and their correlations with clinical and laboratory characteristics in NMOSD.MethodsWe performed a cross‐section study, 18 patients with acute NMOSD, 23 patients with remission NMOSD, and 36 healthy controls were consecutively enrolled. Serum levels of IL‐22 and IL‐35 were measured by enzyme‐linked immunosorbent assay (ELISA). The correlations between serum IL‐22 and IL‐35 levels and clinical and laboratory characteristics were evaluated by Spearman's rank or Pearson's correlation coefficient.ResultsThe serum levels of IL‐22 and IL‐35 were significantly lower in patients with acute NMOSD and remission NMOSD than in healthy controls (IL‐22: 76.96 ± 13.62 pg/mL, 87.30 ± 12.79 pg/mL, and 94.02 ± 8.52 pg/mL, respectively, P < .0001; IL‐35: 45.52 ± 7.04 pg/mL, 57.07 ± 7.68 pg/mL, and 60.05 ± 20.181 pg/mL, respectively, P < .0001). Serum levels of IL‐35 were negatively correlated with EDSS scores and cerebrospinal fluid protein levels (r = −.5438, P = .0002 and r = −.3523, P = .0258, respectively) in all patients.ConclusionsLower serum levels of IL‐22 and IL‐35 are associated with disease status in NMOSD. Additionally, lower serum levels of IL‐35 are associated with disease severity in NMOSD.

Outcomes from acute attacks of neuromyelitis optica spectrum disorder correlate with severity of attack, age and delay to treatment

Neuromyelitis optica spectrum disorder (NMOSD) attacks lead to incremental loss of function of the optic nerves and spinal cord. The standard of care for treatment of acute attacks to mitigate damage is high dose corticosteroids and, if needed, plasma exchange. Although the inclination among clinicians is to treat relapses as soon as they start, there is no previously published evidence to conclude that earlier treatment with corticosteroids is more effective in the long term. In this study, we correlated neurological outcomes from acute NMOSD relapses with delay to treatment, as well as demographic and clinical characteristics that influence prognosis.

Markedly increased IP-10 production by blood-brain barrier in neuromyelitis optica.

ObjectiveSevere damage to the blood-brain barrier (BBB) allows anti-aquaporin 4 (AQP4) antibodies to access the astrocytic endfeet in neuromyelitis optica (NMO). In the current study, we identified the pathogenic cytokines/chemokines that are responsible for the BBB malfunction induced by NMO sera.MethodsWe measured the levels of 27 cytokines/chemokines in human brain microvascular endothelial cells (BMECs) after exposure to sera obtained from patients with the acute and stable phases of anti-AQP4 antibody-positive NMO spectrum disorder (NMOSD), multiple sclerosis (MS) patients and healthy controls (HC) using a multiplexed fluorescent bead-based immunoassay system.ResultsThe induced protein (IP)-10 level in the cells was markedly increased following exposure to acute phase NMOSD sera. Other cytokines/chemokines including interleukin (IL)-6 and monocyte chemotactic protein (MCP)-1 were also significantly increased in the acute NMOSD group compared to both the MS and HC groups. The up-regulation of the IP-10 levels in the cells after exposure to the acute-phase NMOSD sera was also observed using another specified ELISA, and this effect was significantly decreased during the remission phase in the individual NMOSD patients. Furthermore, the increase in the level of IP-10 after exposure to the sera was significantly correlated with the cerebrospinal fluid/serum albumin ratio.ConclusionsSera from the acute phase of NMO markedly increased the autocrine secretion of IP-10 by BMECs. The over-production of IP-10 in BMECs may play an important role in the pathogenesis of NMO and may therefore help to mediate the trafficking of T cells expressing its receptor across the BBB.

Aquaporin-4 antibody-positive myelitis initially biopsied for suspected spinal cord tumors: Diagnostic considerations

Two patients with longitudinally extensive myelopathy were initially biopsied for suspected spinal cord tumors. Both patients were later diagnosed with neuromyelitis optica spectrum disorders (NMOSD) supported by their AQP4-seropositivity. Pathological review of both biopsies revealed demyelinated lesions with thickened vessel walls and tissue rarefaction. Immunohistochemical staining demonstrated findings compatible with acute NMOSD lesions in one case while the other case exhibited findings consistent with chronic NMOSD lesions. A pre-biopsy differential diagnosis of longitudinally extensive spinal cord tumors should include NMOSD. Specific biopsy features, such as cystic changes with vascular wall thickening and astrocyte injury, should raise suspicion for NMOSD.