Relapse-Independent disease activity in neuromyelitis optica spectrum disorder: A systematic review.

INTRODUCTION: Neuromyelitis Optica Spectrum Disorders (NMOSD) is a neuroinflammatory condition characterized by optic neuritis and transverse myelitis. While the current approach to NMOSD focuses on relapse-associated worsening (RAW), recent evidence indicates Relapse-Independent Disease Activity (RIDA) in patients. METHOD: Databases including Embase, PubMed, Scopus, and Web of Sciences were systematically searched up to December 2023. No restrictions were applied. Inclusion criteria focused on studies reporting evidence of RIDA in NMOSD patients. Data extraction involved details such as study title, author, participant characteristics, treatment, evaluation methods, positive findings according to RIDA, and prevalence of findings in NMOSD patients. This study is conducted following the PRISMA guidelines with a registered protocol on PROSPERO (ID = CRD42023492352). RESULT: Of 802 studies, 38 were included in the systematic review, covering 1881 NMOSD patients. AQP4-IGg status was positive in 90.6 % of the patients. Ocular findings indicative of RIDA were reported in 23 studies, including thinning of GCIPL, RNFL, GCC, and GCL layers, foveal and macular shape and volume abnormalities, vessel loss, and visual evoked potentials (VEPs) abnormalities. MRI findings supporting the RIDA were reported in 13 studies, including new lesion incidence and brain and spinal cord atrophy. Serum and CSF RIDA-supporting findings were reported in five studies, including elevation in sGFAP and sNFL. Biopsies and autopsies suggested inflammatory processes in relapse-free patients in 2 studies. The predominant manifestation of RIDA in NMOSD was identified in the visual system, suggesting the impaired retinal glial cells like Müller cells during the relapse-free period in NMOSD. INTERPRETATION: Our systematic review provides valuable insights into RIDA in NMOSD. Establishing guidelines for the diagnosis and treatment of RIDA is crucial. Further studies are needed to provide robust evidence on RIDA in NMOSD patients.

Polyautoimmunity and multiple autoimmune syndrome in patients with neuromyelitis optica spectrum disorder.

BACKGROUND: The coexistence of neuromyelitis optica spectrum disorders (NMOSD) with other autoimmune diseases (AID) has been increasingly reported. The prevalence and significance of this association are not fully understood. OBJECTIVES: This study aimed to compare the clinical and laboratory characteristics in NMOSD patients with and without AID. METHODS: Retrospective cross-sectional observational study was conducted involving adults meeting NMOSD criteria followed in a neuroimmunology clinic at a tertiary center. Descriptive analysis of clinical/paraclinical/treatment/outcome data collected from the medical records was compared between NMOSD patients with AID (polyautoimmunity) and those without AID. RESULTS: From a cohort of 46 NMOSD patients, 16 (34.8 %) patients, mostly women around 40 years of age, presented with polyautoimmunity: 10 anti-AQP4 positive, 4 anti-MOG positive, and 2 seronegative. Five different organ -specific AID, and six systemic AID were identified in the polyautoimmunity patients group, in addition to 6 cases of multiple autoimmune syndrome. The AID manifestation preceded NMOSD in 10 (62.5 %) patients, with a median interval of 7 years. The NMOSD with polyautoimmunity and NMOSD without AID groups had similar initial clinical manifestations with optic neuritis and/or myelitis being most frequent. Inflammatory CSF, namely elevated proteins, was more common in the polyautoimmunity group (13.0 % in NMOSD vs. 31.3 % in NMOSD+AID, p = 0.003). After a 10±6 years follow-up period, more patients with polyautoimmunity had a relapsing disease (75.0 % in NMOSD vs. 46.7 % in NMOSD+AID, p = 0.012) but no difference in the functional outcome evaluated by the EDSS score was identified. CONCLUSIONS: Polyautoimmunity was common in AQP4 positive NMOSD patients leading to a significantly higher risk of disease recorrence. The presence of polyautoimmunity and multiple autoimmune syndrome in NMOSD patients suggests the existence of common susceptibility factors or pathophysiological mechanisms, emphasizing the importance of a multidisciplinary approach to those patients.

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

Background: 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. Methods: 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. Results: 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). Conclusion: Higher level of IL-32 is related to disease severity in NMOSD. Therefore, serum IL-32 may be a novel biomarker for acute NMOSD.

[Modern pathogenetic treatment of rare demyelinating diseases]. / Sovremennoe patogeneticheskoe lechenie redkikh demieliniziruyushchikh zabolevanii.

Rare demyelinating diseases are a group of diseases whose pathogenesis is based on the process of demyelination. This group of diseases includes acute multiple encephalomyelitis (ADEM), opticoneuromyelitis spectrum diseases (NMOSD) and anti-myelin-oligodendrocyte glycoprotein-associated diseases (MOG-antibodies-associated diseases - MOGAD). Recently, new biological drugs for pathogenetic therapy have been developed, which have shown their effectiveness and good tolerability in comparison with therapy with first- and second-line drugs. Aim of the study - analysis of modern possibilities of pathogenetic treatment of patients with ADEM, seronegative and seropositive patients with NMOSD. The analysis was carried out on the basis of English-language publications in PubMed published over the past five years. This review summarizes current ideas about the possibilities of pathogenetic treatment of rare diseases. The advantages of using ravulizumab over other representatives of a new biological therapy associated with the use of monoclonal antibodies are shown. The analyzed data allow us to conclude that there is a significant development of pathogenetic treatment options for ZSONM. However, the effectiveness of new therapeutic biological drugs is still limited due to the lack of a large amount of clinical data to confirm, which creates the need to continue analyzing the experience of their use.

[The diagnostic effectiveness of criteria for neuromyelitis optica spectrum disorders in the Russian clinical practice]. / Diagnosticheskaya effektivnost' kriteriev zabolevanii spektra optikoneiromielita v rossiiskoi klinicheskoi praktike.

OBJECTIVE: To compare the diagnostic criteria of 2006 (DC 2006) and 2015 (DC 2015) in the Russian population of patients with suspected neuromyelitis optica spectrum disorders (NMOSD), with the calculation of their sensitivity, specificity, accuracy and predictive value. MATERIAL AND METHODS: We reviewed medical records of suspected NMOSD patients who were therefore examined for the presence of serum autoantibodies targeting the aquaporin-4 water channel protein (AQP4-IgG) in 6 specialized Russian (Nizhny Novgorod and Moscow) medical centers. One hundred patients (78 female), aged 17 to 74 years (mean 38.1±13.3 years), were included. The follow-up period ranged from 4 to 108 months (mean 59.7±31.6 months). RESULTS: During the follow-up the diagnosis of NMOSD was confirmed in 32 people, and 68 patients had diagnoses different from NMOSD. At the disease onset, 68.8% of patients were seropositive for AQP4-IgG. The mean time for confirming NMOSD diagnosis was 15.2±14.2 months. At the disease onset, 36% of patients fulfilled the DC 2015, the diagnosis was subsequently confirmed in 77.8% out of them. 26% of the patients fulfilled the DC 2006, the diagnosis was subsequently confirmed in 84.6% out of them. The sensitivity of DC 2006/DC 2015 was 69%/88%, specificity 94%/88%, accuracy 86%/88%, negative predictive value 85%/94%, positive predictive value 86%/78%. CONCLUSION: The specificity, sensitivity and accuracy of modern diagnostic criteria for NMOSD In Russian patients is comparable to those obtained in foreign studies. DC 2015 helps to diagnose NMOSD earlier than DC 2006, but they have a lower specificity.

Prognostic factors associated with disability in a cohort of neuromyelitis optica spectrum disorder and MOG-associated disease from a nationwide Portuguese registry.

INTRODUCTION: Neuromyelitis optica spectrum disorders (NMOSD) and MOG-associated disease (MOGAD) are an increasingly recognized group of demyelinating disorders of the central nervous system. Previous studies suggest that prognosis is predicted by older age at onset, number of relapses, the severity of the first attack and autoantibody status. OBJECTIVE: To study prognostic factors associated with disability progression and additional relapses in the 3-year follow-up of a national NMOSD/MOGAD cohort. RESULTS: Out of 180 of the initial Portuguese cohort, data on 82 patients was available at the end of the follow-up period (2019-2022). Two patients died. Twenty (24.4%) patients had one or more attack in this period (25 attacks in total), mostly transverse myelitis (TM) (56.0%) or optic neuritis (32.0%). MOGAD was significantly associated with a monophasic disease course (p = 0.03), with milder attacks (p = 0.01), while AQP4 + NMOSD was associated with relapses (p = 0.03). The most common treatment modalities were azathioprine (38.8%) and rituximab (18.8%). AQP4 + NMOSD more frequently required chronic immunosuppressive treatment, particularly rituximab (p = 0.01). Eighteen (22.5%) had an EDSS ≥6 at the end of the follow-up. AQP4 + NMOSD (p < 0.01) and the occurrence of transverse myelitis (TM) during disease (p = 0.04) correlated with an EDSS≥6 at the end of the follow-up period. MOGAD was significantly associated with an EDSS<6 (p < 0.01), and MOG+ cases that reached an EDSS>6 were significantly older (64.0 ± 2.8 versus 31.0 ± 17.1, p = 0.017). A bivariate logistic regression model including the serostatus and TM attacks during disease history successfully predicted 72.2% of patients that progressed to an EDSS≥6. CONCLUSION: This study highlights that myelitis predict increased disability (EDSS≥6) in NMOSD/MOGAG and AQP4 positivity is associated with increased disability.

Interleukin-6 Immunology in Macrophage Activation Syndrome Related to Neuroimmunological Diseases.

Macrophage activation syndrome (MAS) involves an excessive amount of acute inflammatory responses to inflammatory cytokines, particularly interleukin-6 (IL-6). IL-6 is also strongly associated with the pathophysiology of certain neuroimmunological diseases. However, there have so far been few reports of MAS being accompanied by neuroimmunological diseases. We herein report two cases of MAS comorbid with myasthenia gravis or neuromyelitis optica spectrum disorders, IL-6 related neuroimmunological diseases. Standard immunosuppressive therapies could not stabilize the symptoms in our cases until antibodies against the IL-6 receptor were administered. This finding suggests that it is important to consider the underlying pathophysiology of MAS in relation to these neuroimmunological diseases when treating affected patients.

Neuromyelitis optica spectrum disorder: Exploring the diverse clinical manifestations and the need for further exploration.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disorder characterized by inflammatory assaults on the central nervous system (CNS), particularly on the optic nerves and spinal cord. In recent years, a wider range of clinical manifestations of this complex disease have been observed, emphasizing the importance of gaining a more profound understanding beyond optic neuritis (ON) and transverse myelitis (TM). CURRENT KNOWLEDGE: This study explores the many clinical symptoms of NMOSD, including common and uncommon presentations. Distinctive aspects of ON, TM, and diencephalic/brainstem syndromes are examined, highlighting their unique characteristics in contrast to conditions such as multiple sclerosis. We also discuss extra-CNS involvement, such as unusual signs, including muscle involvement, retinal injury, auditory impairment, and rhinological symptoms. AIMS AND OBJECTIVES: Our study intends to highlight the wide range and complexity of NMOSD presentations, emphasizing the significance of identifying unusual symptoms for precise diagnosis and prompt management. The specific processes that contribute to the varied clinical presentation of NMOSD are not well understood despite existing information. This emphasizes the necessity for more study to clarify the mechanisms that cause different symptoms and discover new treatment targets for this complex autoimmune disorder. CONCLUSION: It is essential to acknowledge the complex and varied clinical manifestations of NMOSD to enhance diagnosis, treatment, and patient results. By enhancing our comprehension of the fundamental processes and investigating innovative therapeutic approaches, we may aim to enhance the quality of life for persons impacted by this illness.

Pregnancy characteristics in Egyptian female patients with NMOSD.

Background: Neuromyelitis optica spectrum disorder (NMOSD) primarily affects women of childbearing age. Objectives: Studying the potential relationship between NMOSD and pregnancy characteristics and outcomes. Subjects and methods: This is a retrospective cohort study that was conducted on 66 married female patients diagnosed with NMOSD. All patients underwent a thorough review of their demographic and clinical history through their medical records and personal interviews. Additionally, a complete neurological examination was performed, along with the expanded disability status scale (EDSS) and a pregnancy registry questionnaire. Results: After comparing married patients before and after disease onset, there was a significant increase in the number of abortions and the percentage of cesarean sections, as well as a decrease in the percentage of breastfeeding after disease onset. The p values were .02, <.001, and <.001, respectively, with odds ratios of 2.03, 5.13, and 6.17. Additionally, there was a rise in the occurrence of postpartum relapses, which accounted for 66% of all relapses after the disease onset. Most of these relapses (88.7%) occurred within the first 3 months postpartum. Conclusion: Presence of NMOSD increased the percentage of miscarriage, delivery by cesarean section, and decreased the chance of breastfeeding. In addition, pregnancy increases NMOSD relapse and subsequent disability.

The burden of psychiatric morbidity in Multiple Sclerosis, AQP4-antibody NMOSD and MOGAD before and after neurological diagnosis.

BACKGROUND: Psychiatric comorbidities are common in Multiple Sclerosis (MS) and are increasingly recognised in Aquaporin-4-Antibody Neuromyelitis Optica Spectrum Disorders (AQP4-Ab NMOSD) and Myelin Oligodendrocyte Glycoprotein-Antibody Associated Disease (MOGAD). However, it is unclear if these psychiatric comorbidities predate neurological diagnosis or classical neurological symptoms that are conventionally used to establish the onset of these central nervous system inflammatory demyelinating diseases. We sought to: (1) assess the frequency and incidence of psychiatrist-diagnosed psychiatric disorders before and after formal MS, AQP4-Ab NMOSD, and MOGAD diagnosis, and (2) identify potential factors associated with the presence of pre-existing psychiatric morbidity and depression severity at the first clinical visit for MS patients. METHODS: A retrospective observational study was performed on MS, AQP4-Ab NMOSD, and MOGAD patients seen at the National Neuroscience Institute (NNI) Singapore. Individuals with psychiatrist-diagnosed psychiatric disorders before and after neurological diagnosis were identified. Demographic, clinical data, and Patient Health Questionnaire (PHQ)-9 score at first clinic visit were collected and analysed. RESULTS: Three hundred and ninety-nine patients (249 MS, 102 AQP4-Ab NMOSD, 48 MOGAD) were included. A higher proportion of MS patients (13/249, 5.2%) had psychiatric disorders before neurological diagnosis, compared to AQP4-Ab NMOSD (1/102, 1.0%) and MOGAD (0/48, 0.0%) (p = 0.054). Within MS patients, univariate logistic regression revealed that age, sex, race, MS subtype, initial MRI lesion load, and interval between classical MS symptom onset to MS diagnosis were not associated with pre-existing psychiatric disorders. Mean PHQ-9 score for MS patients at their first MS consult was 4.4 (cut-off for no/minimal depression is ≤4); no clinical factors were predictive of higher PHQ-9 scores on univariate linear regression. The proportion of MS patients (29/236, 12.2%) who developed psychiatric illness after neurological diagnosis was not different from AQP4-Ab NMOSD (9/101, 8.9%) (p > 0.999), while this was significantly higher compared to MOGAD (0/48, 0.0%) (p = 0.021). The incidence rate of psychiatric diseases after neurological diagnosis, accounting for follow up time, was also similar between MS and AQP4-Ab NMOSD (incidence rate ratio 1.2; 95% confidence interval 0.54 - 2.8; p = 0.689). CONCLUSION: There is a significant psychiatric burden prior to MS diagnosis compared to AQP4-Ab NMOSD and MOGAD. The increased frequency of psychiatric comorbidity after NMOSD diagnosis merits further study to investigate the determinants of this phenomenon.

Diagnostic criteria for optic neuritis in the acute and subacute phase: clinical uses and limitations.

BACKGROUND: A recent international consensus panel proposed diagnostic criteria for optic neuritis and a new classification. We aimed to investigate the clinical relevance of these diagnostic criteria and classification, in a cohort of patients hospitalized for a suspected diagnosis of optic neuritis. METHODS: We included all patients hospitalized between 2017 and 2022 in our tertiary center for (sub)acute loss of visual acuity suggestive of optic neuritis. Clinical and paraclinical criteria obtained within the first 3 months of symptoms were collected, as well as the final diagnosis which could be optic neuritis or non-optic neuritis. We constructed a contingency table comparing diagnoses based on physician experience to those based on the recently proposed criteria. The subtypes of optic neuritis based on the new classification were compared to subtypes based on the clinician experience. RESULTS: Two hundred fifty-seven patients were included in this study. Prevalence of optic neuritis in our cohort was 88.3%. Sensitivity and specificity of a correct diagnosis using the new criteria were, respectively, 99.5% and 86.7%. The proposed diagnostic criteria overdiagnosed four patients with optic neuritis and missed the diagnosis in one patient. According to the recent classification, idiopathic optic neuritis and clinical isolated syndrome were reclassified mainly as single isolated optic neuritis. CONCLUSION: In our specific cohort of patients hospitalized for acute and subacute optic neuropathy highly suspect of optic neuritis, we found that recently proposed diagnostic criteria and classification of optic neuritis are relevant for our clinical practice. Our interpretation of clinical requirement for definite and possible optic neuritis diagnosis might explain our excellent sensitivity and our high percentage of definite optic neuritis, relative to previous publications. The moderate specificity (86.7%) underlines the importance to include all contextual data in consideration for the diagnosis. The simplification of subgroups is useful, but our study highlights the complexity to find the adequate subgroup for seronegative NMOSD.

GV-971 attenuates the progression of neuromyelitis optica in murine models and reverses alterations in gut microbiota and associated peripheral abnormalities.

AIMS: Growing evidence suggests that an imbalanced gut microbiota composition plays a crucial role in the development of neuromyelitis optica spectrum disorders (NMOSD), an inflammatory demyelinating disease primarily affecting the optic nerves and central nervous system (CNS). In light of this, we explored the potential therapeutic benefits of GV-971 in NMOSD. GV-971 is a drug used for treating mild-to-moderate Alzheimer's disease, which targets the gut-brain axis and reduces neuroinflammation. METHODS: To evaluate GV-971's effects, we employed the experimental autoimmune encephalomyelitis (EAE) mouse model to establish NMOSD animal models. This was achieved by injecting NMO-IgG into aged mice (11 months old) or using NMO-IgG along with complement injection and microbubble-enhanced low-frequency ultrasound (MELFUS) techniques in young mice (7 weeks old). We assessed the impact of GV-971 on incidence rate, clinical scores, body weight, and survival, with methylprednisolone serving as a positive control. In NMOSD models of young mice, we analyzed spinal cord samples through H&E staining, immunohistochemistry, and Luxol Fast Blue staining. Fecal samples collected at different time points underwent 16S rRNA gene sequencing, while plasma samples were analyzed using cytokine array and untargeted metabolomics analysis. RESULTS: Our findings indicated that GV-971 significantly reduced the incidence of NMOSD, alleviated symptoms, and prolonged survival in NMOSD mouse models. The NMOSD model exhibited substantial neuroinflammation and injury, accompanied by imbalances in gut microbiota, peripheral inflammation, and metabolic disorders, suggesting a potentially vicious cycle that accelerates disease pathogenesis. Notably, GV-971 effectively reduces neuroinflammation and injury, and restores gut microbiota composition, as well as ameliorates peripheral inflammation and metabolic disorders. CONCLUSIONS: GV-971 attenuates the progression of NMOSD in murine models and reduces neuroinflammation and injury, likely through its effects on remodeling gut microbiota and peripheral inflammation and metabolic disorders.

Neuromyelitis Optica spectrum disorder complicated with pure red cell aplasia: a case report.

BACKGROUND: Pure red cell aplasia (PRCA) in neuromyelitis optica spectrum disorder (NMOSD) has not been reported before. This study presents a patient with NMOSD who developed PRCA. CASE PRESENTATION: A 54-year-old female was admitted in January 2023 for dysuria and progressive numbness and weakness of lower limbs. She had difficulty standing and walking in a straight line. Both lower limbs were positive for the Babinski and Chaddock signs. MRI showed abnormal signals in the spinal cord. Aquaporin-4-IgG (AQP-4-IgG) was positive (1:320), and NMOSD was confirmed. Intravenous immunoglobulin and methylprednisolone were given, and the symptoms improved. She received maintenance treatment with methylprednisolone tablets, and the dosage was gradually reduced. She was readmitted for fatigue, palpitations, and shortness of breath in May 2023. Bone marrow aspiration and biopsy showed elevated erythroid precursors and erythroid hypoplasia, with normal megakaryocytes and myeloid precursors. Chest CT showed no mediastinal lymph node enlargement or thymoma. PRCA secondary to NMOSD was diagnosed. Recombinant human erythropoietin was given. Her condition improved after 1.5 months, as indicated by blood cell count and imaging. CONCLUSIONS: This case suggests that PRCA can be secondary to NMOSD. A comprehensive immune function and bone marrow evaluation might be necessary if abnormal blood cells are found while managing NMOSD.

Blood-based inflammatory protein biomarker panel for the prediction of relapse and severity in patients with neuromyelitis optica spectrum disorder: A prospective cohort study.

BACKGROUND: To date, most existing models for predicting neuromyelitis optica spectrum disorder (NMOSD) are based primarily on clinical characteristics. Blood-based NMOSD severity and prognostic predictive immune- and inflammation-related biomarkers are needed. We aimed to investigate the associations between plasma inflammatory biomarkers and relapse and attack severity in NMOSD. METHODS: This two-step, single-center prospective cohort study included discovery and validation cohorts. We quantified 92 plasma inflammatory proteins by using Olink's proximity extension assay and identified differentially expressed proteins in the relapse group (relapse within 1 year of follow-up) and severe attack group. To define a new molecular prognostic model, we calculated the risk score of each patient based on the key protein signatures and validated the results in the validation cohort. RESULTS: The relapse prediction model, including FGF-23, DNER, GDNF, and SLAMF1, predicted the 1-year relapse risk. The severe attack prediction model, including PD-L1 and MCP-2, predicted the severe clinical attack risk. Both the relapse and severe attack prediction models demonstrated good discriminative ability and high accuracy in the validation cohort. CONCLUSIONS: Our discovered biomarker signature and prediction models may complement current clinical risk stratification approaches. These inflammatory biomarkers could contribute to the discovery of therapeutic interventions and prevent NMOSD progression.

Human NMO-IgG Induced Different Pathological and Immunological Changes in the CNS and Peripheral Tissues of Mice.

OBJECTIVES: The majority of neuromyelitis optica spectrum disorders (NMOSD) patients are seropositive for aquaporin-4 (AQP4)-specific antibodies [also named neuromyelitis optica immunoglobulin G antibodies (NMO-IgG)]. Although NMO-IgG can induce pathological changes in the central nervous system (CNS), the immunological changes in the CNS and peripheral tissue remain largely unknown. We investigated whether NMO-IgG binds to tissue expressing AQP4 and induces immunological changes in the peripheral tissue and CNS. METHODS: C57BL/6 female mice were assigned into an NMOSD or control group. Pathological and immunological changes in peripheral tissue and CNS were measured by immunostaining and flow cytometry, respectively. Motor impairment was measured by open-field test. RESULTS: We found that NMO-IgG did bind to astrocyte- and AQP4-expressing peripheral tissue, but induced glial fibrillary acidic protein and AQP4 loss only in the CNS. NMO-IgG induced the activation of microglia and modulated microglia polarization toward the classical (M1) phenotype, but did not affect innate or adaptive immune cells in the peripheral immune system, such as macrophages, neutrophils, Th17/Th1, or IL-10-producing B cells. In addition, NMOSD mice showed significantly less total distance traveled and higher immobility time in the open field. CONCLUSIONS: We found that injection of human NMO-IgG led to astrocytopathic lesions with microglial activation in the CNS. However, there were no significant pathological or immunological changes in the peripheral tissues.

Comparison of inebilizumab or rituximab in addition to glucocorticoid therapy for neuromyelitis optica spectrum disorders.

AIM: To investigate the short-term efficacy and safety of inebilizumab for neuromyelitis optica spectrum disorders (NMOSD). METHODS: A total of 33 patients with NMOSD treated with inebilizumab (Group INB, n=15) or rituximab (Group RTX, n=18) in addition to high-dose glucocorticoids were included. Both groups underwent hormone shock therapy during the acute phase. Subsequently, Group INB received inebilizumab injections during the remission phase, while Group RTX received rituximab injections. A comparison of aquaporins 4 (AQP4) titer values, peripheral blood B lymphocyte counts, and visual function recovery was conducted before and 8wk after treatment. Additionally, adverse reactions and patient tolerability were analyzed after using inebilizumab treatment regimes. RESULTS: Following inebilizumab treatment, there was a significantly improvement in the visual acuity of NMOSD patients (P<0.05), accompanied by a notable decrease in AQP4 titer values and B lymphocyte ratio (P<0.05). Moreover, inebilizumab treatment showed a partial effect in preventing optic nerve atrophy (P<0.05). However, there were no significant differences in other therapeutic effects compared to rituximab, which has previously demonstrated substantial therapeutic efficacy (P>0.05). Furthermore, inebilizumab exhibited higher safety levels than that of rituximab injections. CONCLUSION: The combination of inebilizumab and high-dose glucocorticoids proves to be effective. In comparison to rituximab injections, inebilizumab displays better tolerance and safety. Moreover, it demonstrates a partial effect in preventing optic nerve atrophy. Thus, it stands as an effective method to reduce the disability rates and improve the daily living ability of patients with NMOSD.

Longitudinal change of serum NfL as disease activity biomarker candidate in MOGAD: A descriptive cohort study.

BACKGROUND: Myelin oligodendrocyte glycoprotein antibody (MOG-IgG)-associated disease (MOGAD) is an autoinflammatory disease of the central nervous system. MOGAD often follows a relapsing course that can lead to severe disability, but monophasic disease is possible as well. Currently, there is an unmet clinical need for disease activity biomarkers in MOGAD. Serum neurofilament light chain (sNfL) is a sensitive biomarker for neuroaxonal damage. However, data on longitudinal change of sNfL as disease activity biomarker for MOGAD are scarce. OBJECTIVE: To describe the longitudinal course of sNfL in adult patients with MOGAD in an active as well as a stable disease state in relation to clinical parameters and serum MOG-IgG titers. METHODS: We conducted a retrospective, exploratory, monocentric cohort study of adult patients with MOGAD. Cohort 1 consisted of five patients in whom NfL was tested as part of their routine clinical workup, all of which had active disease (maximum 6 months since last attack, median 3 months). Cohort 2 comprised 13 patients, which were tested for NfL in the context of a longitudinal study at predefined time intervals, mostly during remission (median 10 months since last attack). sNfL was measured using single molecule array (Simoa) technology at least at two time points (median 3) within a median observation time of 5 months in cohort 1, and at baseline and after a median duration of 12 months in cohort 2. MOG-IgG titers were measured by a fixed cell-based assay. RESULTS: Change in sNfL correlated positively with change in MOG-IgG titers (rho=0.59, p = 0.027). The variability of sNfL (difference between highest and lowest level) during the observation period was higher in patients who had an attack within six months before baseline (median 37 [interquartile range [IQR] 10-64] pg/ml vs. 2.3 [IQR 1-5] pg/ml, p = 0.006). sNfL increased in patients with an attack during the observation period. Patients with baseline sNfL measurement within two weeks after attack symptom onset displayed relatively low initial sNfL with an increase afterwards. CONCLUSIONS: Longitudinal sNfL change correlates with MOG-IgG titer change and may be a promising biomarker candidate for disease activity in MOGAD. Increasing sNfL levels might be utilized to adjudicate suspected attacks. In acute attacks, sNfL increase may occur with a delay after symptom onset.

Retinal structural thicknesses reflect clinically relevant microstructural white matter abnormalities in neuromyelitis optica spectrum disorders.

BACKGROUND: Thinning of retinal thickness seen on optical coherence tomography (OCT) is frequent in patients with neuromyelitis optica spectrum disorder (NMOSD). We explored the association between OCT metrics, MRI measurements and clinical outcomes in NMOSD. METHODS: 44 NMOSD and 60 controls underwent OCT and MR imaging. Mean peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell complex (GCC) thicknesses were measured. Diffusion tensor imaging (DTI) and diffusion kurtosis imaging (DKI) was used to measure the white matter microstructural integrity. In NMOSD patients, Expanded Disability Status Scale (EDSS) was used to quantify disability. Visual acuity (VA) was also performed for all participants. RESULTS: pRNFL thickness was positively associated with mean diffusivity in left posterior thalamic radiation (pp = 0.010) and axial kurtosis in inferior cerebellar peduncle (p = 0.023). Similarly, GCC thickness in NMOSD patients was positively associated with fractional anisotropy in right superior longitudinal fascicules (p = 0. 041) and axial kurtosis of left cerebellar peduncle (p = 0.011). CONCLUSIONS: In NMOSD, pRNFL and GCC reflect integrity of clinically relevant white matter structures underlying the value of OCT metrics as markers of neuronaxonal loss and disability.

Mechanisms of gastrointestinal toxicity in neuromyelitis optica spectrum disorder patients treated with mycophenolate mofetil: insights from a mouse model and human study.

Mycophenolate mofetil (MMF) is commonly utilized for the treatment of neuromyelitis optica spectrum disorders (NMOSD). However, a subset of patients experience significant gastrointestinal (GI) adverse effects following MMF administration. The present study aims to elucidate the underlying mechanisms of MMF-induced GI toxicity in NMOSD. Utilizing a vancomycin-treated mouse model, we compiled a comprehensive data set to investigate the microbiome and metabolome in the GI tract to elucidate the mechanisms of MMF GI toxicity. Furthermore, we enrolled 17 female NMOSD patients receiving MMF, who were stratified into non-diarrhea NMOSD and diarrhea NMOSD (DNM) groups, in addition to 12 healthy controls. The gut microbiota of stool samples was analyzed using 16S rRNA gene sequencing. Vancomycin administration prevented weight loss and tissue injury caused by MMF, affecting colon metabolomes and microbiomes. Bacterial ß-glucuronidase from Bacteroidetes and Firmicutes was linked to intestinal tissue damage. The DNM group showed higher alpha diversity and increased levels of Firmicutes and Proteobacteria. The ß-glucuronidase produced by Firmicutes may be important in causing gastrointestinal side effects from MMF in NMOSD treatment, providing useful information for future research on MMF. IMPORTANCE: Neuromyelitis optica spectrum disorder (NMOSD) patients frequently endure severe consequences like paralysis and blindness. Mycophenolate mofetil (MMF) effectively addresses these issues, but its usage is hindered by gastrointestinal (GI) complications. Through uncovering the intricate interplay among MMF, gut microbiota, and metabolic pathways, this study identifies specific gut bacteria responsible for metabolizing MMF into a potentially harmful form, thus contributing to GI side effects. These findings not only deepen our comprehension of MMF toxicity but also propose potential strategies, such as inhibiting these bacteria, to mitigate these adverse effects. This insight holds broader implications for minimizing complications in NMOSD patients undergoing MMF therapy.

Possible Roles of Extracellular Vesicles in the Pathogenesis and Interventions of Immune-Mediated Central Demyelinating Diseases.

Multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) are two of the most devastating immune-mediated central demyelinating disorders. NMOSD was once considered as a variant of MS until the discovery of an antibody specific to the condition. Despite both MS and NMOSD being considered central demyelinating disorders, their pathogenesis and clinical manifestations are distinct, however the exact mechanisms associated with each disease remain unclear. Extracellular vesicles (EVs) are nano-sized vesicles originating in various cells which serve as intercellular communicators. There is a large body of evidence to show the possible roles of EVs in the pathogenesis of several diseases, including the immune-mediated central demyelinating disorders. Various types of EVs are found across disease stages and could potentially be used as a surrogate marker, as well as acting by carrying a cargo of biochemical molecules. The possibility for EVs to be used as a next-generation targeted treatment for the immune-mediated central demyelinating disorders has been investigated. The aim of this review was to comprehensively identify, compile and discuss key findings from in vitro, in vivo and clinical studies. A summary of all findings shows that: 1) the EV profiles of MS and NMOSD differ from those of healthy individuals, 2) the use of EV markers as liquid biopsy diagnostic tools appears to be promising biomarkers for both MS and NMOSD, and 3) EVs are being studied as a potential targeted therapy for MS and NMOSD. Any controversial findings are also discussed in this review.