MOG antibody-associated disease (MOGAD) is a central nervous system (CNS) demyelinating disease characterized by the presence of IgG autoantibodies against myelin oligodendrocyte glycoprotein (MOG). It is a distinct disease entity from multiple sclerosis (MS) and aquaporin-4 (AQP4) antibody-positive NMOSD (neuromyelitis optica spectrum disorder), with different pathophysiology, clinical course, and prognosis. International diagnostic criteria were established in 2023 4). “Anti-MOG antibody-positive optic neuritis” is known as a differential diagnosis for atypical optic neuritis.
The global annual incidence of MOGAD is estimated at approximately 1.6–4.8 per million people, and the prevalence at 1.3–2.5 per 100,000 people 1). Age of onset shows a bimodal distribution, with peaks in children aged 5–10 years and adults aged 20–45 years. The median age of onset overall is 20–30 years.
In children under 11 years, MOGAD accounts for about 50% of acute demyelinating syndromes 1). The most common initial symptom in adults is optic neuritis (30–60%), followed by transverse myelitis (10–25%). In children under 11 years, acute disseminated encephalomyelitis (ADEM) accounts for about 45% of initial presentations. A Dutch study reported that the incidence of MOG-positive acute demyelinating syndrome was 0.31 per 100,000 children versus 0.13 per 100,000 adults, indicating higher incidence in children.
Regarding sex distribution, the male-to-female ratio is approximately 1:1, in contrast to the strong female predominance (F:M 7–9:1) seen in AQP4 antibody-positive NMOSD.
Early MOG-IgG research was challenging due to technical limitations of Western blotting and ELISA. The advent of live cell-based assays (live CBA) enabled the detection of clinically meaningful MOG-IgG, establishing it as a disease entity independent of MS and AQP4-positive NMOSD.
It is an independent disease with differences in target antigen, pathology, sex ratio, steroid responsiveness, and prognosis. MOGAD is an oligodendrocyte disease targeting MOG, AQP4-positive NMOSD is an astrocyte disease targeting AQP4, and MS is a demyelinating disease dominated by CD8-positive T cells. MOGAD has nearly equal sex distribution (1:1), high steroid responsiveness, and better visual prognosis than AQP4-positive NMOSD.
The clinical presentation of MOGAD varies significantly with age of onset.
ADEM-like phenotype (common in children under 11)
Typical age: Mainly under 11 years. Accounts for 40–50% of all pediatric MOGAD.
Main symptoms: Altered consciousness or behavioral changes not explained by fever alone. Signs of encephalopathy may be subtle and manifest as behavioral changes.
MRI findings: Bilateral, poorly demarcated T2 hyperintense lesions (>2 cm). Confluent lesions involving deep white matter and gray matter (thalamus, basal ganglia).
Optic neuritis phenotype (age 11 and older, adults)
Typical age: Age 11 and older, and adults. Accounts for 30–60% of adult MOGAD.
Main symptoms: Acute vision loss, eye movement pain (73–92%), headache, bilateral involvement (31–84%).
Fundoscopic findings: Optic disc edema in 45–92% (75–86% in children). Moderate to severe disc edema may be accompanied by peripapillary hemorrhages.
Myelitis type (all ages)
Frequency: 20–40% in adults, 15–20% in children.
Characteristic findings: LETM (T2 hyperintensity spanning ≥3 vertebral segments) in approximately 70%. H sign (gray matter–restricted T2 hyperintensity forming an H shape on axial sections) shows a marked age difference: 100% in children vs. 12.5% in adults2).
Conus involvement: Highly specific for MOGAD. Contrast enhancement is seen in about 50%.
Subjective symptoms:
Clinical findings:
A clinical comparison with major diseases is shown below.
| Item | MOG-ON | AQP4-ON | MS-ON |
|---|---|---|---|
| Bilateral involvement | 31–84% | 13–82% | Extremely rare |
| Optic disc edema | 45–92% | 7–52% | 11–14% |
| Eye pain | 73–92% | 28–50% | 10–46% |
| Sex ratio (F:M) | 1:1 | 7-9:1 | 3:1 |
| Lesion location | Anterior (intraorbital) | Posterior (canalicular/intracranial) | Anterior to middle |
| Perioptic neuritis | Frequent | Rare | Not reported |
| Visual prognosis | Good (20/30 to 20/25) | Poor (counting fingers) | Good |
Both diseases can present with optic disc edema, leading to overlapping clinical features. NAION is characterized by painless onset, age >50 years, and vascular risk factors such as sleep apnea, while MOG-ON frequently involves eye movement pain and occurs in younger individuals. Anti-MOG antibody testing is useful for differentiation.
MOG is a minor transmembrane protein expressed on the outermost layer of CNS myelin and on the surface of oligodendrocytes. Due to its exposed position to the immune system, it is a frequent target of autoantibodies. MOG-IgG antibodies target this protein, causing demyelination through complement activation and cell-mediated cytotoxicity 1).
Breakdown of immune tolerance in the peripheral circulation activates self-reactive lymphocytes, leading to migration of immune cells into the CNS. Infections and vaccinations may trigger the autoimmune cascade through bystander activation or molecular mimicry.
The risk of onset and relapse of MOGAD may increase during the postpartum period. In a literature review of 47 cases, 21 were diagnosed postpartum, and rebound from immunosuppression during pregnancy is considered a possible mechanism 9).
Through bystander activation and molecular mimicry, infections and vaccinations may trigger an autoimmune cascade. Cases have been reported after COVID-19 infection and SARS-CoV-2 mRNA vaccination, both showing good response to steroid therapy8, 10).
A definitive diagnosis requires the presence of MOG-IgG in serum, detected by cell-based assay (CBA), in patients with appropriate clinical presentation.
The following five items serve as differential indicators for atypical optic neuritis. If applicable, further evaluation including anti-AQP4 and anti-MOG antibody testing is recommended.
Performing anti-MOG antibody testing in all cases with bilateral ON, recurrent ON, or optic disc edema can detect all MOG-ON and requires testing only 50% of ON cases.
The international diagnostic criteria by Banwell et al. 2023 (Lancet Neurology)4) consist of the following two steps.
Definite diagnosis: Typical clinical presentation (optic neuritis, myelitis, ADEM, brainstem/cerebellar symptoms, cortical encephalitis, or unifocal/multifocal brain lesions) + CBA titer ≥1:100 or live CBA positive
Supportive diagnosis (if titer unknown, low-positive, or CSF-only positive): requires one or more supportive clinical/MRI findings
| Phenotype | Supportive clinical/MRI findings |
|---|---|
| Optic neuritis | Bilateral simultaneous, longitudinal optic nerve involvement (>50%), perioptic sheath enhancement, optic disc edema |
| Myelitis | LETM, central spinal cord lesion/H sign, conus medullaris lesion |
| Brain/brainstem/cerebral symptoms | Ill-defined T2 hyperintensity, deep gray matter lesion, pontine/cerebellar peduncle/medullary T2 hyperintensity, cortical lesion ± leptomeningeal enhancement |
Validation data for diagnostic criteria (Varley et al. 2024, 539 cases) 2)
| Measure | Children (135 cases) | Adults (404 cases) | Overall |
|---|---|---|---|
| Sensitivity | 100% | 91.9% | 96.5% |
| Specificity | 98.8% | 98.9% | 98.9% |
| PPV | 98% | 89.4% | 94.3% |
| NPV | 100% | 99.2% | 99.3% |
| Accuracy | 99.2% | 98.3% | 98.5% |
Compared with MOG-Ab testing alone, the 2023 diagnostic criteria significantly improved specificity in adults (98.9% vs 95.6%, p=0.0005). Children have more supportive findings than adults (p=0.0011) 2).
False positivity occurs in 1–2% of disease control groups. The concordance rate for borderline positivity between different assays is only 33%. It is important to limit testing to cases with high pretest probability and confirm consistency with clinical findings. If there is reason to suspect MOGAD, retest using a CBA method that can provide quantitative data.
First-line: Intravenous Methylprednisolone (IVMP)
MOGAD is highly steroid-sensitive. IVMP is used in almost all acute cases.
Second-line: If IVMP-resistant
Timing of Treatment Initiation
Approximately 50% of cases follow a monophasic course, so maintenance therapy is usually started after the second clinical event. If the first attack is severe with residual disability, it may be considered exceptionally from the first episode 3).
Oral Corticosteroids
While steroid sensitivity is high, steroid dependence is also high, complicating management.
Immunosuppressants (Steroid-Sparing Agents)
Maintenance IVIG
A large international retrospective study showed a significant reduction in annual relapse rate 1). A dose-response relationship was observed, with significantly fewer relapses at doses of 1 g/kg or more every 4 weeks.
It reduces the relapse rate, but some patients relapse despite B-cell depletion. In a meta-analysis (19 studies), the annual relapse rate reduction was significantly smaller in MOGAD compared to AQP4-positive NMOSD, and the biological efficacy is considered limited in MOGAD1).
Tocilizumab (IL-6 receptor antibody)
Relapse prevention effects for up to 29 months have been reported (off-label use). IL-6 receptor inhibitors tend to be clinically preferred as maintenance therapy in MOGAD3).
About MS treatments
Disease-modifying drugs for MS are ineffective in MOGAD and may exacerbate the disease, similar to AQP4-positive NMOSD.
Management by a multidisciplinary team including pediatric neurology, ophthalmology, rehabilitation medicine, and psychology is recommended. Attention to growth and development, school support, psychological health, vision training, and family burden is important.
After acute IVMP, transition to oral prednisolone and gradual tapering is performed. The European Pediatric MOG Consortium recommends a total tapering period of at least 3 months; shorter periods increase the risk of relapse. With adequate maintenance for 6 months, 95% remain relapse-free for over 1 year. In children, the decision should be made in consultation with the attending physician, considering long-term side effects.
MOG is a minor transmembrane protein expressed on the outermost layer of CNS myelin sheaths and on the surface of oligodendrocytes. MOGAD is an oligodendrogliopathy, fundamentally different in pathogenesis from AQP4 antibody-positive NMOSD (an astrocytopathy) and MS (a CD8-positive T cell-dominant demyelinating disease)3).
MOG is not expressed in the retina. Other mechanisms, such as glutamate excitotoxicity, are presumed for retinal ganglion cell degeneration.
Variable granulocyte infiltration, MOG-containing macrophages, complement and Ig deposition, variable oligodendrocyte and axonal destruction, and astrogliosis are observed1). Precursor oligodendrocytes may be present without active remyelination.
Below is a pathophysiological comparison between MOGAD and AQP4-positive NMOSD.
| Item | MOGAD | AQP4-positive NMOSD |
|---|---|---|
| Target antigen | MOG | AQP4 |
| Target cell | Oligodendrocyte | Astrocyte |
| Complement activation | Present (weak) | Present (strong) |
| Main infiltrating cells | CD4+ T cells, macrophages | Granulocytes |
| Intrathecal antibody production | Present | Absent |
| GFAP biomarker | Normal | Elevated |
| Severity of nerve damage | Relatively mild | Severe |
The H sign (T2 hyperintensity localized to gray matter forming an H shape on axial spinal cord sections) is observed in 30–50% of MOGAD patients. It is less frequent in AQP4-positive NMOSD and absent in MS, making it a highly specific imaging finding for MOGAD 11). The marked age difference of 100% in children versus 12.5% in adults with myelitis is thought to be related to age-dependent differences in MOG expression distribution.
Varley et al. (2024) retrospectively evaluated 539 cases (135 children, 404 adults) from 1,879 MOG-Ab tested patients 2). In children, supportive findings were more frequent than in adults (p=0.0011), and in the myelitis type, the H sign showed a marked difference: 100% in children vs. 12.5% in adults. In relapsing disease, supportive findings increased at follow-up (median 2 to 3.5, p=0.03). All 5 false-positive cases were ultimately diagnosed with MS (OCB positive, MS-typical brain MRI).
Heroor et al. (2024) reported a case of PAMM (paracentral acute middle maculopathy) complicating MOG-ON in a 25-year-old woman 7). Complete recovery was achieved one month after IVMP 1 g × 5 days. It was suggested that inflammatory edema due to perioptic neuritis may cause decreased blood flow in the superficial capillary plexus.
In MOGAD after COVID-19, a pattern of transient MOG-IgG positivity has been suggested 10). In vaccine-associated MOGAD, the possibility of blood-brain barrier disruption and autoantibody production due to mRNA vaccines is being considered 8). In a literature review of 47 cases, 21 were diagnosed postpartum, suggesting an increased risk of onset and relapse in the postpartum period 9).
In children, 75–96% achieve complete recovery, with a better prognosis than in adults. However, in cases with a relapsing or multiphasic course, the complete recovery rate decreases to 31–50%. Reports indicate that the relapse rate can reach up to 70% over long-term follow-up exceeding 5 years, highlighting the importance of long-term monitoring and continuation of maintenance therapy.
