What is Mogad?

What is MOGAD?

MOGAD (Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease) is a distinct autoimmune demyelinating disorder of the central nervous system, separate from both multiple sclerosis and aquaporin-4 positive neuromyelitis optica spectrum disorder, characterized by the presence of MOG-IgG antibodies detected via cell-based assays. 1

Disease Definition and Pathophysiology

MOGAD is now recognized as a disease entity in its own right, distinct from classic MS and AQP4-IgG-positive NMOSD, based on evidence showing discrete histopathological features (primary demyelination with intralesional complement and IgG deposits), different target antigens (MOG vs. AQP4), and distinct clinical spectra 1. The disease is characterized by antibodies against full-length, conformationally intact human MOG protein, rather than the linearized or denatured MOG peptides previously associated with MS 1.

Clinical Presentations

The clinical phenotype of MOGAD is broad and includes several distinct presentations:

• Optic neuritis (ON) is the most common presentation in adults, often characterized by recurrent episodes, prominent papilledema/papillitis/optic disc swelling, and frequently bilateral simultaneous involvement 1, 2
• Acute disseminated encephalomyelitis (ADEM) is the most common presentation in young children, with the disease being significantly more frequent among pediatric populations (up to 70% of acquired demyelinating disease in young children, with frequency declining with age) 1, 3
• Transverse myelitis, particularly longitudinally extensive transverse myelitis (LETM), which is common in both MOG-EM and AQP4-NMOSD but rarely occurs in MS 1
• Brainstem encephalitis and encephalitis with various manifestations 1, 3
• Atypical presentations including focal seizures (rarely as the first manifestation, preceding typical symptoms by 8-48 months), peripheral neuropathy, and cortical encephalitis 4, 3

Disease Course

The disease course varies significantly:

• Monophasic course occurs in approximately 40-50% of patients, with some cases showing permanent disappearance of MOG-IgG following clinical recovery, particularly in children and juveniles with ADEM 1, 4
• Relapsing course occurs in 50-60% of patients, especially those with persistently positive MOG-IgG antibodies, with approximately 44-83% of patients experiencing relapsing episodes within 8 months, mostly involving the optic nerve 4, 3
• In adults, MOG-EM follows a relapsing course in most cases, and 33% of adult patients meet McDonald's criteria for MS at least once over the disease course, leading to frequent historical misclassification 1

Diagnostic Criteria

For a diagnosis of MOG-EM, all three of the following criteria must be met: 1

1. Monophasic or relapsing acute ON, myelitis, brainstem encephalitis, or encephalitis, or any combination of these syndromes
2. MRI or electrophysiological findings (visual evoked potentials in patients with isolated ON) compatible with CNS demyelination
3. Seropositivity for MOG-IgG as detected by means of a cell-based assay employing full-length human MOG as target antigen

Antibody Testing Recommendations

Serum is the recommended specimen of choice for MOG-IgG testing, with shipment at 4°C or on dry ice advisable if samples do not arrive within 1-2 days 1. CSF is not usually required since MOG-IgG is produced mostly extrathecally, resulting in lower CSF than serum titers 1.

Testing for MOG-IgG (not IgM or IgA) is recommended, as the clinical relevance of isolated MOG-IgM or -IgA results is unknown 1. MOG-IgG serum concentrations depend on disease activity (higher during acute attacks than remission) and treatment status (lower while on immunosuppression), and may transiently vanish after plasma exchange 1, 5.

Key Diagnostic Red Flags

Several findings should prompt MOG-IgG testing 1:

• Simultaneous bilateral acute ON or unusually high ON frequency
• Particularly severe visual deficit/blindness during or after acute ON
• Longitudinally extensive transverse myelitis (LETM)
• Prominent papilledema/papillitis/optic disc swelling during acute ON
• Neutrophilic CSF pleocytosis or CSF white cell count >50/μl (which can mimic CNS infection) 1, 5
• Lack of CSF-restricted oligoclonal bands (applies to continental European patients only) 1
• Frequent flare-ups after intravenous methylprednisolone or steroid-dependent symptoms 1
• Clear increase in relapse rate following treatment with interferon-beta or natalizumab in patients diagnosed with MS 1

Important Diagnostic Pitfalls

AQP4-IgG/MOG-IgG "double-positive" test results are extremely rare and should prompt retesting for both antibodies, as this is considered a red flag 1. Before making a diagnosis of MOG-EM, all available clinical, radiological, electrophysiological, and laboratory data must be considered, and differential diagnoses (including neurosarcoidosis, Behçet syndrome, vasculitis, CNS lymphoma, and CNS infections) must be excluded 1.

If MOG-IgG is negative but MOG-EM is still suspected, re-testing during acute attacks, during treatment-free intervals, or 1-3 months after plasma exchange or IVIG is recommended 1, 5. Positive test results should always be interpreted in the context of the patient's overall presentation, and if red flags are present, re-testing using a second methodologically different cell-based assay is advisable 1.

Treatment Implications

Recognition of MOGAD is critical because misclassification as MS has therapeutic implications 1:

• Some drugs approved for MS (particularly interferon-beta and natalizumab) might be ineffective or even harmful in MOGAD 1
• MOGAD is associated with a high risk of flare-ups after cessation of steroid treatment and requires close monitoring and careful steroid tapering 1, 5
• Patients may be particularly responsive to antibody-depleting treatments (plasma exchange or immunoadsorption), B cell-targeted therapies (rituximab), IVIG, and immunosuppressive treatments 1, 2

Prognosis

Although the nadir of vision loss is severe with MOG-IgG optic neuritis, recovery is typically better than AQP4-IgG optic neuritis, resulting in a favorable overall prognosis 2. MOGAD generally responds well to immunotherapy and has a good functional prognosis compared to NMOSD 3. However, patients with relapsing disease often need chronic immunotherapy, with rituximab, azathioprine, mycophenolate mofetil, and monthly IVIG being the most commonly utilized treatments 2.