Myelin oligodendrocyte glycoprotein antibody-associated disorder (MOGAD) was a newly identified disorder of neuroimmunology condition with evolving diagnostic and management guidelines. Initially, classified under seronegative neuromyelitis optica spectrum disorders (NMOSD) (1), MOG antibodies were later recognized as distinct markers in cases negative for AQP4-IgG. MOGAD has a global prevalence of 1.3–2.5 per 100,000 and an annual incidence of 1.6–3.4 per million (2). According to recent diagnostic criteria of 2023 internaltional consensus (3), MOGAD clinically presents with diverse manifestations including, optic neuritis (ON), transverse myelitis, acute disseminated encephalomyelitis (ADEM), and cortical encephalitis along with positive MOG-IgG seropositivity via cell-based assay (CBA). ON is a common initial symptom in MOGAD especially in adults, while children often present with ADEM. Symptoms include vision loss, retro-orbital pain, and color vision loss. Bilateral ON is more frequent in MOGAD patients, and relapses are typically unilateral (3). Currently, there are limited clinical, and radiological biomarkers exist to predict disease course, severity, or relapses. Identifying accessible and reproducible biomarkers is essential for guiding diagnosis and treatment. Our study compiles existing research on biomarkers relevant to MOGAD to improve clinical diagnosis, management strategies, and relapse prevention while highlighting future research challenges ( Table 1 ).

Experts recommend high-dose corticosteroids as first-line treatment for acute MOGAD attacks. A study found that intravenous methylprednisolone (IVMP) expedited visual recovery in patients with acute ON, but did not improve long-term visual outcome (42) or reduce thinning of the peri-papillary retinal nerve fiber layer (43–45). Patients with recent MOGAD attacks are at risk for relapse after discontinuing or reducing corticosteroid therapy. Relapsing optic neuritis occurs in 30-50% of patients with MOG-IgG (7, 44, 46). To reduce relapse risk, corticosteroids should be gradually tapered over 2–3 months. The recent study revealed that a daily dose of 12.5 mg of prednisone for adults (or 0.16 mg/kg/day for children) taken for at least 3 months at the initial attack of MOGAD helps delay the first relapse (47). Plasmapheresis (PLEX) and immuno-adsorption (IA) are proposed as therapeutic options for those failing IVMP treatment (48, 49). These methods have been successful in treating immune-mediated neurological diseases, including acute NMOSD attacks. However, it’s difficult to predict if a newly diagnosed patient will develop a relapsing course, as approximately 25% of MOGAD patients become seronegative and are more likely to have monophasic disease (2, 17, 50).

Cobo-Calvo et al. found that adults are at a higher risk of relapse and may experience worse clinical outcomes than children (2). Long-term immunotherapy is typically initiated after a second MOGAD attack (51). Common therapies include oral steroids, azathioprine, mycophenolate mofetil, and B cell-targeting biologics like rituximab (RTX) and IL-6 receptor antagonist like tocilizumab (51, 52). Maintenance therapy with oral corticosteroids has been associated with a reduction in relapse rate. RTX reduces relapses and EDSS scores in MOGAD (53, 54), though to a lesser extent than in NMOSD. Maintenance IVIG therapy was associated with a reduced relapse rate in adult MOGAD patients (55), and IL-6 inhibitors like tocilizumab and satralizumab (56) may be effective in MOGAD maintenance therapy. Recent studies have introduced tocilizumab as a new drug that has been used in many cases with multiple relapse cases of MOGAD in both adults and pediatrics (56–60) including life-threatening conditions. In this situation, it’s worth noting that managing MOGAD with steroids or IVIG during the initial attack may lower the risk of relapse. However, a relapse could occur as the dosage is gradually reduced. Therefore, the approach to dose adjustment could also be viewed as a potential biomarker for MOGAD.

Relapse refers to a new clinical attack occurring over 30 days after a previous attack, more common in the first 6 months. They can occur within 2 months of oral corticosteroid therapy tapering or cessation (7, 13), with some patients experiencing early relapses and others experiencing ongoing relapses beyond 12 months (61). The age of the initial attack and the characteristics of the attack may influence the relapse risk but no single factor reliably predicts the progression of the disease (51). Patients with optic neuritis seem to be more likely to experience early relapses compared to those with transverse myelitis or ADEM (13, 62). A study using brain MRI scans found that clinically silent brain lesions were present in a minority of children with MOG-IgG (14% of patients, 4% of all scans). 44% of silent lesions were detected within 3 months of the first attack, and 66% within the first year (63). The study recommends not diagnosing relapsing MOGAD solely on MRI and restricting it to patients with clinically relapsing disease (3). Longitudinal MOG-IgG seropositivity is associated with relapsing MOG, but many remain seropositive and do not relapse (61, 64). Thus, the clinical features including ON, TM, and ADEM while paraclinical features with neuroimaging features, including MRI and OCT findings, may serve as biomarkers for relapse in MOGAD, distinguishing it from other neuroinflammatory disorders (65, 66). Notably, relapses in MOGAD are not reliably predicted by factors such as age, gender, race, the intensity of the initial episode, antibody titer, or treatment modalities (67).

More research is required to fully understand the pathophysiology and severity of MOGAD. Identifying novel biomarkers in MOGAD is crucial for accurate diagnosis, prognosis, and treatment monitoring. Recently some of the new biomarkers have been implemented for the diagnosis of MOGAD. Lin et.al (68) found that the higher platelet-lymphocyte ratio(PLR) was linked to MOGAD relapse, and neutrophil-lymphocyte ratio(NLR) assists in distinguishing between MOGAD and MS at the onset of the disease. The temporal correlation of NLR with MOGAD activity could be used as a supportive biomarker for acute relapse (69). In addition, acute-phase MOGAD may be distinguished by the mRNA levels of higher neurofilament light chain (NFLs) in serum and CSF, decreased endothelial growth factor receptor (EGFR), and a lower EGFR/NFLs ratio in serum. The MOGAD patients’ serum and CSF have higher mRNA levels of NFLs, which aid in differentiating the ADEM-like phenotype. Furthermore, Wang et al. (70) mentioned that in pediatrics MOGAD, the serum EGFR/NFLs mRNA ratio is a good indicator of the severity of the condition. Further investigations are warranted to elucidate the pathological mechanisms underlying these associations. Moreover, Chang et al. (71) showed that sNfL and sGFAP levels are linked to disease severity in AQP4-ab-positive NMOSD and MOGAD patients, with the sGFAP/sNfL ratio indicating distinct disease pathogenesis. Ziaei et al. (72) also found high sNfL levels close to clinical or MRI events in pediatrics onset multiple sclerosis and MOGAD, supporting sNfL as a biomarker of disease activity. Concerning more, Wang et al. stated that the blood-brain barrier may become dysfunctional as a result of serum and CSF levels of IL-33, which can then cause intrathecal production of immunoglobulin in AQP4+NMOSD and MOGAD, particularly in MOGAD. It may have served as a biomarker for demyelinating disorders of the central nervous system, at least in a part (73). On the other hand, another study reveals that Th2, Th17, and CD4+ cells contribute to the pathogenesis of MOGAD in children. The recombinant human (rh)-MOG protein elicits a different response from regulatory T-cells in MOG non-relapsing (MOGNR) and MOG relapsing (MOGR), suggesting that MOGR may have lost its tolerance to the MOG autoantigen, potentially causing relapses (74). Neuroinflammatory conditions require activated microglia for demyelination, and the secreted ectodomain of soluble triggering receptor expressed on myeloid cells 2 (sTREM2) is associated with abnormal biological pathways. Cerebrospinal fluid (CSF) sTREM2 concentration is higher in neuroinflammatory and neurodegeneration diseases. Increased CSF and serum sTREM2 concentration in pediatric patients suggests microglia activation in MOGAD. CSF sTREM2 levels significantly correlated with clinical inflammatory indexes and adapted modified Rankin Scale score, indicating the potential value of sTREM2 as a severity biomarker (75).

Advances in high-throughput technologies, including genomics, proteomics, and metabolomics, hold promise for identifying novel biomarkers in MOGAD. Collaborative efforts are needed to establish large-scale longitudinal cohorts to validate candidate biomarkers and elucidate their clinical utility. Integration of multi-modal biomarker panels may enhance diagnostic accuracy and facilitate personalized therapeutic approaches in MOGAD. We can hereby find some future challenges regarding the MOGAD biomarkers in the recent published articles. Wang et al. (76) in 2024 studies using Gene Ontology, InterPro, and Kyoto Encyclopaedia Genes and Genomes identified 429 differentially expressed proteins (DEPs) in the MOG group among them 149 upregulated and 280 downregulated proteins. Functional analysis showed that the dysregulated proteins were mostly involved in cell adhesion, axon guidance, complement and coagulation cascades, and glycosphingolipid production in MOG patients. Hence, the proteomic changes seen in CSF samples from children with MOGAD that were discovered in the current study may present chances to create new biomarker candidates in the future. Additionally, Yandamuri et al. (77), in 2023 studied high-throughput assays that measured complement activity, complement-dependent cytotoxicity (CDC), antibody-dependent cellular phagocytosis (ADCP), and antibody-dependent cellular cytotoxicity (ADCC) of MOG-expressing cells. The study showed cytotoxicity is not solely dependent on MOG autoantibody quantity, engagement of effector functions is bimodal, and CDC and ADCP magnitudes increase closer to relapse. Future relapse risks can be predicted by assays that quantify CDC and ADCP. Furthermore, Liyanage et al. (78), in 2024 resulted in non-P42 MOG-IgG epitope status remained unchanged from onset throughout the disease course and was a strong predictor of a relapsing course in patients with unilateral optic neuritis and can predict a relapsing course. Patients with unilateral optic neuritis, the most frequent MOGAD phenotype, can reliably be tested for non-P42 MOG-IgG epitope at onset, regardless of age and sex. Hence, early detection and specialized management in these patients could minimize disability and improve long-term outcomes. Moreover, Ding et al. (79), in 2024 used Automated fibre quantification (AFQ) to investigate white matter damage in pediatrics MOGAD using Diffusion tensor imaging (DTI) metrics. It identified demyelination-dominated microscopic integrity damage. The study also analyzed potential neurological function alterations and their relationship with clinical disability in vulnerable fiber tracts. The microstructural injury of these fiber tracts might be the underlying cause for abnormal neurological function in MOGAD. Certain fiber tracts showed specific DTI metrics patterns, promising potential biomarkers for future research.

Biomarkers are promising for diagnosing and managing MOGAD patients, aiding disease progression prediction and relapse outcomes. However, more novel biomarkers are needed for future evaluation. Our study has critically summarized the possible new biomarkers for MOGAD which will help in current neuroscience.