What is Myelin Oligodendrocyte Glycoprotein (MOG)-associated Encephalomyelitis (MOG-EM)?

MOG-EM: A Distinct Autoimmune CNS Demyelinating Disease

MOG-EM (Myelin Oligodendrocyte Glycoprotein-associated Encephalomyelitis) is a distinct autoimmune inflammatory demyelinating disease of the central nervous system, characterized by antibodies against full-length MOG protein, presenting most commonly with optic neuritis, myelitis, brainstem encephalitis, or ADEM-like presentations—and critically, it is immunopathogenetically distinct from both multiple sclerosis and aquaporin-4-positive neuromyelitis optica spectrum disorders. 1

Disease Definition and Pathophysiology

MOG-EM is now recognized as a disease entity in its own right based on converging evidence from multiple domains 1:

• Immunological studies demonstrate direct pathogenic impact of MOG-IgG antibodies 1
• Neuropathological studies reveal discrete histopathological features distinct from MS 1
• Serological studies show lack of aquaporin-4 (AQP4)-IgG in almost all MOG-IgG-positive patients 1
• Cohort studies demonstrate differences in clinical presentation, treatment response, and prognosis compared to MS and NMOSD 1

MOG is a glycoprotein expressed exclusively on the outer membrane of myelin sheaths in the brain, spinal cord, and optic nerves, making it a vulnerable target for autoimmune attack 2.

Clinical Phenotypes

Most Common Presentations

Optic neuritis is the most frequent presenting phenotype in adults 3, 2:

• Often presents with severe visual deficit or blindness during acute episodes 3
• Frequently shows perioptic gadolinium enhancement and longitudinally extensive optic nerve lesions on MRI 3
• May present as chronic relapsing inflammatory optic neuropathy (CRION) 3

Transverse myelitis can manifest as 3:

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

Acute disseminated encephalomyelitis (ADEM) is the most common presentation in children 3, 2:

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

Brainstem encephalitis may involve 3:

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

Cortical encephalitis is a rare but recognized phenotype 3, 4:

• Cortical/subcortical white matter lesions 3
• Seizures, headache, and fever as presenting symptoms 4
• May be misdiagnosed as viral encephalitis initially 4

Disease Course Patterns

Adults typically experience a relapsing course in at least 80% of cases 5:

• 33% of adult patients meet McDonald's criteria for MS at some point 1
• 15% meet Barkhof's criteria for MS 1
• This phenotypic overlap historically led to frequent misdiagnosis as MS 1

Children more commonly have monophasic disease, particularly with ADEM presentations 1, 2.

Steroid-dependent course is characterized by frequent flare-ups after intravenous methylprednisolone withdrawal 3.

Distinguishing Features from MS and NMOSD

CSF Characteristics

• Neutrophilic pleocytosis or white cell count >50/μl is common 3
• Usually lacks CSF-restricted oligoclonal bands, particularly in continental European patients 3
• White cell counts can range from 6-306 cells/μl (median 33) 1
• Neutrophil granulocytes present in 64.3% of patients with pleocytosis 1

Epidemiology

• Significantly more frequent among young children with acquired demyelinating disease (up to 70%) than adults 3
• In adults: ≤1% prevalence in Western countries, ≤5% in Asian countries 3

Critical Red Flags

Progressive disease course is very atypical for MOGAD and should prompt consideration of alternative diagnoses 3, 6.

Diagnostic Testing

Gold Standard Assay

Cell-based assays (CBA) using full-length human MOG are the only recommended approach 6:

• Must employ full-length human MOG as target antigen, not peptides or denatured protein 6
• Fc-specific or IgG1-specific secondary antibodies are highly recommended to avoid cross-reactivity with IgM and IgA 6

Specimen Selection

Serum is the specimen of choice, not CSF 6:

• MOG-IgG is produced mostly extrathecally, resulting in higher serum titers than CSF 6
• Shipment at 4°C or on dry ice is advisable if samples don't arrive within 1-2 days 6

Test Only for MOG-IgG

• MOG-IgM and MOG-IgA testing is currently NOT recommended 6
• Clinical relevance of isolated MOG-IgM or -IgA results is unknown 6

Timing Considerations

MOG-IgG concentrations are disease-activity dependent 6:

• Higher concentrations during acute attacks than remission 6
• Lower concentrations while on immunosuppression 6
• May transiently vanish after plasma exchange 6
• If negative but MOGAD suspected: retest during acute attacks, treatment-free intervals, or 1-3 months after plasma exchange/IVIG 6

Interpretation Pitfalls

Low-titer results (1:160-1:320) require careful clinical correlation 6:

• Use a second (or third) methodologically different cell-based assay if results are discrepant 6
• IVIG pretreatment may cause false-negative or false-positive results 6
• Screening large unselected populations significantly reduces positive predictive value 1

Documentation requirements: All results should document immunoglobulin class detected, assay type, antigenic substrate, biomaterial used, titer/concentration, assay-specific cut-offs, and performing laboratory 6.

Therapeutic Implications

Why Accurate Diagnosis Matters

Misclassification as MS has critical therapeutic consequences 1:

• Some MS-approved drugs might be ineffective or even harmful in MOG-EM due to differences in immunopathogenesis 1
• MOG-EM is associated with high risk of flare-ups after cessation of steroid treatment, requiring close monitoring and careful steroid tapering 1
• Patients may be particularly responsive to antibody-depleting treatments (plasma exchange, immunoadsorption) 1
• B cell-targeted therapies like rituximab may be more appropriate 1
• IVIG may be especially effective in children 1

Acute Treatment

High-dose steroids and plasma exchange are effective for acute attacks 2, 5.

Long-term Management

Rituximab and other immunosuppressants are used off-label for attack prevention 5.

Prognosis

MOG-EM is associated with better overall long-term prognosis than AQP4-IgG-positive NMOSD, though both can quickly lead to permanent disability if left untreated 5. Severe ambulatory and visual disability is less frequent than in NMOSD 2. In children, ADEM usually presents as a one-time incident with good recovery 2.