What is Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease (MOGAD)?

What is MOGAD (Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease)?

MOGAD is a distinct autoimmune inflammatory demyelinating disease of the central nervous system caused by antibodies against myelin oligodendrocyte glycoprotein (MOG), presenting most commonly with optic neuritis, myelitis, brainstem encephalitis, or acute disseminated encephalomyelitis (ADEM), and is fundamentally different from both multiple sclerosis and aquaporin-4-positive neuromyelitis optica spectrum disorders in its immunopathogenesis, treatment response, and prognosis. 1, 2

Disease Pathophysiology

MOGAD is caused by pathogenic antibodies targeting full-length MOG protein, a molecule located on the outer membrane of myelin sheaths in the brain, spinal cord, and optic nerves. 1, 2 The disease demonstrates:

• Direct pathogenic impact of MOG-IgG antibodies through immunological mechanisms 2
• Discrete histopathological features with primary demyelination showing intralesional complement and IgG deposits, distinct from MS pathology 1, 2
• Near-complete absence of aquaporin-4 (AQP4) antibodies, distinguishing it from neuromyelitis optica spectrum disorders 1, 2

Clinical Presentations

Optic Neuritis (Most Common in Adults)

• Severe visual deficit or blindness during or after acute episodes 3
• Bilateral involvement is characteristic 1
• Prominent papilledema, papillitis, or optic disc swelling on fundoscopy 1
• Longitudinally extensive optic nerve lesions with perioptic gadolinium enhancement on MRI 3
• May present as chronic relapsing inflammatory optic neuropathy (CRION) 3

Transverse Myelitis

• Longitudinally extensive transverse myelitis (LETM) affecting ≥3 vertebral segments 1, 3
• Conus medullaris lesions are particularly characteristic 3
• Permanent sphincter and/or erectile disorders can occur 1, 3

Acute Disseminated Encephalomyelitis (ADEM) - Most Common in Children

• Large, confluent T2 brain lesions 1, 3
• Disturbance of consciousness, behavioral changes, or epileptic seizures 1, 3
• Can manifest as "recurrent ADEM," "multiphasic ADEM," or "ADEM-ON" (ADEM with recurrent optic neuritis) 1, 3

Brainstem Encephalitis

• Area postrema syndrome with intractable nausea, vomiting, or hiccups 1, 3
• Acute respiratory insufficiency in severe cases 1, 3

Cortical Encephalitis

• Cortical/subcortical white matter lesions with seizures 3

Disease Course Patterns

Adults typically experience a relapsing course in at least 80% of cases, while children more commonly have monophasic disease, particularly with ADEM presentations. 2 Key course characteristics include:

• 33% of adult patients meet McDonald's criteria for MS at some point during disease course 2
• 15% meet Barkhof's criteria for MS, leading to frequent historical misdiagnosis 2
• High risk of flare-ups after steroid cessation, requiring careful monitoring and slow tapering 1, 4
• Steroid-dependent symptoms with frequent relapses after intravenous methylprednisolone withdrawal 1, 3

Age-Related Epidemiology

MOGAD is significantly more frequent in young children (up to 70% of acquired demyelinating disease) compared to adults (≤1% in Western countries, ≤5% in Asian countries), with frequency declining with age. 1, 3

Distinguishing Laboratory Features

Cerebrospinal Fluid

• Neutrophilic CSF pleocytosis or white cell count >50/μl (median 33 cells/μl, range 6-306) 3, 2
• Absence of CSF-restricted oligoclonal bands, particularly in continental European patients 1, 3
• Neutrophil granulocytes present in 64.3% of patients with pleocytosis 2

Antibody Testing

• Cell-based assays (CBA) using full-length human MOG are mandatory for diagnosis—peptide-based or denatured protein assays are unreliable 2
• Serum is the specimen of choice, not CSF, as MOG-IgG is produced mostly extrathecally with higher serum titers 2
• MOG-IgG titers are disease-activity dependent and should be retested during acute attacks, treatment-free intervals, or 1-3 months after plasma exchange/IVIG if initially negative but clinical suspicion remains high 4

Critical Diagnostic Pitfalls

Progressive disease course is very atypical for MOGAD and should prompt consideration of alternative diagnoses. 3 Common misdiagnosis scenarios include:

• Phenotypic overlap with MS occurs in 33% of cases meeting McDonald's criteria 2
• Post-vaccination onset can occur 4 days to 4 weeks after vaccination 1, 3
• Co-existence with teratoma or NMDAR encephalitis is possible but rare 1, 3

Treatment Implications

Acute Management

• High-dose intravenous methylprednisolone is first-line for acute attacks 4
• Plasma exchange or immunoadsorption should be initiated early if steroids fail, as MOG-IgG positive patients show particular responsiveness to antibody-depleting treatments 4
• Slow steroid taper is mandatory due to high risk of flare-ups after rapid cessation 4

Long-Term Prevention

• Preventive therapy is reserved for relapsing disease only in MOGAD 4
• Rituximab, IVIG, and oral immunosuppressants show observational benefit 4

Critical Therapeutic Contraindications

Beta-interferons, natalizumab, and fingolimod (MS-approved drugs) can exacerbate MOGAD due to differences in immunopathogenesis and should be avoided. 1, 4, 2 This represents a critical distinction from MS management.

Prognosis

MOGAD has a more favorable prognosis than neuromyelitis optica spectrum disorder, with lower disability scores at follow-up even with brainstem involvement. 4 Unlike MS, brainstem involvement in first event does not indicate worse prognosis in MOGAD. 4