A review of current evidence on established and emerging fluid biomarkers in NMOSD and MOGAD, with emphasis on analytical performance, biological relevance, and clinical utility, and outlines priorities for future research.
Abstract
Neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD) are inflammatory disorders of the CNS with distinct immunopathologic mechanisms and treatment responses and partially overlapping clinical phenotypes. The identification of aquaporin-4 (AQP4)-IgG and MOG-IgG has transformed disease classification and diagnosis, enabled a classification of antibody-defined subgroups, and facilitated the development of targeted therapies. However, optimal use of these biomarkers in clinical practice requires careful interpretation within the appropriate clinical and radiologic context. This review synthesizes current evidence on established and emerging fluid biomarkers in NMOSD and MOGAD, with emphasis on analytical performance, biological relevance, and clinical utility. We review antibody detection using cell-based assays, highlighting differences between live and fixed platforms and the impact of antigen conformation on sensitivity and specificity, particularly for MOG-IgG. Common causes of false-positive and false-negative results are discussed, including low-titer reactivity, testing in low pretest probability populations, treatment-related antibody titer reduction, and assay-specific limitations. The diagnostic challenges posed by indiscriminate testing in adult cohorts with multiple sclerosis, in whom disease prevalence markedly exceeds that of MOGAD, are emphasized. We also discuss the role of repeat testing during acute attacks and paired serum-CSF analysis in improving diagnostic confidence when results are equivocal or discordant. Beyond disease-defining antibodies, we examine biomarkers of tissue injury and immune activation. Serum and CSF neurofilament light chain and glial fibrillary acidic protein provide complementary measures of neuroaxonal and astrocytic damage and show associations with attack severity, disease activity, relapse risk, and long-term disability. Cytokines, chemokines, and complement components reflect inflammatory pathways, including IL-6–driven immune activation in NMOSD and MOGAD and complement-mediated astrocytopathy in NMOSD, and may support mechanistic stratification and treatment monitoring in both conditions. We further review the contribution of CSF analysis, neuropathology, genetics, and antigen discovery platforms to refine disease classification, particularly in seronegative or atypical presentations. Finally, we outline priorities for future research, including assay harmonization, standardized sampling protocols, longitudinal biomarker profiling, and integrative multiomic approaches. Collectively, advances in biomarker science have the potential to improve diagnostic precision, guide individualized therapeutic strategies, and support de-escalation decisions in NMOSD and MOGAD.
Antibody-mediated inflammatory diseases of the CNS, including aquaporin-4 antibody neuromyelitis optica spectrum disorder (AQP4-Ab NMOSD) and myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD), have undergone major therapeutic transformation with the advent of sensitive antibody assays and targeted immunotherapies. These advances have markedly reduced relapse rates and improved long-term outcomes. With improved disease control, questions regarding optimal treatment duration and the possibility of de-escalation or discontinuation are increasingly relevant. In AQP4-Ab NMOSD, relapses are typically severe and disabling, and most observational studies show a high risk of reactivation after tapering or withdrawal. Thus, discontinuation is never recommended. Successful de-escalation has been reported in selected patients with prolonged remission, although relapse risk persists, underscoring the need for individualized decisions and close monitoring. In contrast, MOGAD is clinically heterogeneous. Many patients, particularly children, experience a monophasic illness with good recovery, whereas relapse risk in adults appears to decline after several years. De-escalation strategies can thus be applied for anti-CD20 and IVIG. Recent cohort studies suggest that even discontinuation may be feasible after 2 to 5 years of remission in children and adults, especially in those who become seronegative for myelin oligodendrocyte glycoprotein immunoglobulin G. In seronegative NMOSD, the evidence base is limited and prognosis uncertain; attacks can be severe, no therapies are specifically approved, and although some experts suggest that discontinuation may be considered after 5 years of stability, this remains guided by expert opinion alone. Treatment de-escalation is sometimes necessary because of adverse effects, comorbidities, infections, treatment fatigue, or life circumstances such as pregnancy. In pregnancy, management requires balancing maternal disease control with fetal safety, with strategies ranging from continuation of selected therapies to temporary tapering or deferral. Monitoring with MRI, OCT, and emerging fluid biomarkers offers potential to detect early recurrence of disease activity, although none are validated for routine use. Prospective studies, real-world registry data, and dedicated trials are urgently needed to inform safe and patient-centered de-escalation/discontinuation strategies.
Y. Hacohen, G. Androdias, G. Arrambide et al.· Neurology· 0 citations
DN-NMOSD is a heterogenous, severe and highly relapsing disease, where attacks lead to irreversible dysfunction, and the administration of maintenance immunotherapy reduces the relapse risk and should be considered early to prevent further disability.
A. Malvaso, F. Bovis, Giacomo Greco et al.· Neurology(R) neuroimmunology...· 0 citations
MOGAD is a rare autoimmune encephalomyelitis that shares similar clinical manifestations with other central nervous system demyelinating diseases. However, they must be distinguished due to their distinct pathogenesis and treatment methods. Currently, the clinical diagnosis of MOGAD primarily relies on patients’ clinical manifestations and imaging features, with biomarker application being relatively limited. Meanwhile, research on MOGAD biomarkers has advanced rapidly, with findings mainly focusing on imaging features, antibody titers, nerve cell markers, cytokines, and inflammatory cell ratios. These biomarkers can distinguish among various autoimmune with similar clinical manifestations and exhibit certain specificity. If these biomarker findings are applied to the clinical diagnosis of MOGAD, they could enhance diagnostic accuracy and support earlier and more accurate diagnosis, while providing a scientific basis for evaluating disease progression and prognosis. We discuss the biomarkers and emerging biomarkers of MOGAD, emphasizing the specific changes and aspects that may be applicable to clinical diagnosis and treatment.
Qingying Zheng, Muzi Wen, Xinyi Zheng et al.· Frontiers in Immunology· 0 citations
BACKGROUND
Neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are rare autoimmune disorders of the central nervous system whose diagnosis increasingly relies on highly sensitive antibody assays and timely access to targeted therapies. Despite major advances in the diagnosis and management of these disorders worldwide, substantial challenges continue to compromise patient care across Latin America (LATAM).
METHODS
This consensus-informed regional perspective was developed as an initiative of the European Charcot Foundation (ECF) Young Investigators/Fellows, following discussions held during the "2025 Update on NMOSD & MOGAD" ECF Meeting in São Paulo/Brazil, and in collaboration with international and Latin American experts. This manuscript synthesizes current evidence on the epidemiology, clinical characteristics, diagnosis, treatment, and healthcare challenges of NMOSD and MOGAD in LATAM, together with a consensus-informed assessment of regional priorities and unmet needs.
KEY FINDINGS
Recent epidemiological studies have improved understanding of the burden of NMOSD and MOGAD across LATAM. Nevertheless, delayed diagnosis, disease misclassification, unequal access to specialized neuroimmunology services, and considerable variability in antibody testing methodologies remain major barriers to optimal patient management. Although commercial fixed cell-based assays (fixed-CBAs) have become increasingly available throughout the region, access to gold-standard live cell-based assays (live-CBAs) remains restricted to a limited number of specialized centers, potentially compromising diagnostic accuracy in some settings. Likewise, despite growing evidence supporting early initiation of highly effective therapies, particularly for AQP4-IgG-positive NMOSD, access to these treatments is limited in many locations, resulting in continued reliance on conventional immunosuppressive agents.
CONCLUSIONS
Based on the available evidence and expert consensus, this regional perspective identifies two strategic priorities for advancing the diagnosis and management of NMOSD and MOGAD in LATAM: (I) expanding access to locally performed live-CBA and (II) ensuring equitable access to highly effective emerging therapies. Together, these priorities have the potential to harmonize clinical practice and reduce healthcare disparities across countries. They may also foster regional neuroimmunology collaborations, facilitating the generation of reliable region-specific real-world evidence, ultimately benefiting patients with NMOSD and MOGAD throughout LATAM.
Vinícius Boldrini, S. Samadzadeh, Edgar Carnero Contentti et al.· Multiple Sclerosis and Relat...· 0 citations
The identification of autoantibodies against aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) has been essential in distinguishing neuromyelitis optica spectrum disorder (NMOSD) and MOG antibody-associated disease (MOGAD) from classical multiple sclerosis (MS), with important implications for treatment. However, for several patients within this disease spectrum, the target of the autoimmune response remains unknown. Here, we describe the modulator of VRAC current 1 (MLC1), a membrane protein with extracellular epitopes enriched at astrocytic end feet, as an autoantigen. Serum MLC1 antibodies were verified with a cell-based assay, identifying four MLC1 immunoglobulin G (IgG)-positive patients among 297 patients with inflammatory autoimmune diseases of the central nervous system who were screened. All four MLC1 IgG-positive patients exhibited overlapping yet atypical clinical features of MS and NMOSD and tested negative for AQP4 and MOG antibodies. Moreover, treatment with a monoclonal MLC1 antibody induced astrocytopathy in mouse cerebellar slice cultures and in a rat encephalitis model. Thus, MLC1 antibodies identify a subset of patients with an NMOSD-like phenotype, underscoring their potential as a disease marker with pathogenic relevance.
H. Wong, Samantha Ho, Qian Yu et al.· Science Translational Medici...· 0 citations
Background Anti-GD1a antibodies are associated with a range of immune-mediated neuropathies, particularly acute motor axonal neuropathy (AMAN) and other Guillain-Barré syndrome (GBS) variants. However, their full clinical spectrum and prognostic significance remain unclear due to limited systematic studies. Here, we investigated the clinical phenotypes, serological profiles, cerebrospinal fluid (CSF) characteristic, and therapeutic outcomes associated with anti-GD1a antibodies. Methods The clinical, paraclinical and therapeutic data were retrospectively collected and analyzed from 19 Chinese patients who tested positive for anti-GD1a antibodies. Results The mean age at onset in this cohort was 50.6 years. Among the 19 patients, 14 (74%) presented with acute syndromes. The remaining five patients (26%) exhibited features consistent with chronic neuropathies. Common manifestations included absent tendon reflexes (84%), limb weakness (84%), sensory impairment (58%), and cranial nerve involvement (53%). Isolated anti-GD1a antibody positivity was observed in only 5 patients, while others had co-existing antiganglioside antibodies, most commonly anti-GQ1b, and anti-GM1. Electrophysiological studies revealed axonal and demyelinating neuropathic patterns. Patients with cranial nerve involvement and albuminocytologic dissociation were associated with higher modified Erasmus GBS Outcome Score (mEGOS). Immunotherapy was effective in acute cases, with 57% achieving complete recovery at 6-month follow-up. Conclusions Patients seropositive for anti-GD1a antibody exhibits significant clinical and electrophysiological heterogeneity and frequently coexists with other antiganglioside antibodies. Acute presentations generally respond well to immunotherapy, while chronic cases require individualized management.
Xujun Chu, Xinyu Liu, Z. Zeng et al.· Frontiers in Immunology· 0 citations