Neuromyelitis Optica Spectrum Disorder and Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease

Medical Experts

Author

Moscon

Justin D. Moscon, MD

Anatomic and Clinical Pathology Resident, University of Utah and ARUP Laboratories

Contributor

Peterson

Lisa K. Peterson, PhD, D(ABMLI)

Associate Professor (Clinical), University of Utah

Head of Clinical Operations, Immunology Division, ARUP Laboratories

Contributor

SmithT

Tammy Smith, MD, PhD

Assistant Professor of Neurology, Division of Neuroimmunology, University of Utah

GRECC Investigator, George E. Wahlen Department of Veterans Affairs Medical Center

Clinical Consultant, Autoimmune Neurology, ARUP Laboratories

Neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are immune-mediated inflammatory diseases that primarily target the optic nerve and spinal cord. NMOSD and MOGAD are often mistaken for multiple sclerosis (MS) because of overlapping symptoms (e.g., optic neuritis and transverse myelitis), but they can be differentiated by clinical course, imaging characteristics, and the presence of aquaporin-4 receptor (AQP4) or myelin oligodendrocyte glycoprotein (MOG) immunoglobulin G (IgG) autoantibodies. An accurate diagnosis is important as the treatment strategies for NMOSD, MOGAD, and MS differ.

Quick Answers for Clinicians

How are neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein antibody-associated disease diagnosed?

Diagnosis of both neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is based on core clinical characteristics, antibody status, and features detected by magnetic resonance imaging (MRI). All of these components are included in the international diagnostic criteria for these two conditions.^, Laboratory testing involves determining aquaporin-4 receptor (AQP4) and myelin oligodendrocyte glycoprotein (MOG) immunoglobulin G (IgG) serum antibody status; the presence of AQP4 or MOG IgG is confirmatory for NMOSD or MOGAD, respectively, in the appropriate clinical setting.^,

Which specimen type is preferred for aquaporin-4 receptor and myelin oligodendrocyte glycoprotein antibody testing?

Serum is the optimal and most cost-effective specimen for both aquaporin-4 receptor (AQP4) and myelin oligodendrocyte glycoprotein (MOG) immunoglobulin G (IgG) testing. Cerebrospinal fluid (CSF) IgG testing adds little if any sensitivity. In rare cases, CSF MOG IgG can support a diagnosis of MOG antibody-associated disease (MOGAD) in seronegative patients with supporting clinical and radiologic features.^,

Which differential diagnoses should be considered when investigating neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein antibody-associated disease?

Early in the course of the disease, it may be difficult to distinguish neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) from multiple sclerosis (MS) because all of these disorders may cause optic neuritis and myelitis. Clinical characteristics, laboratory testing, and magnetic resonance imaging (MRI) findings can assist in differentiating these diseases. Other disorders that may present similarly to these demyelinating diseases of the central nervous system (CNS) include non-MOGAD acute disseminated encephalomyelitis, systemic lupus erythematosus, sarcoidosis, and paraneoplastic disorders.

Indications for Testing

NMOSD

NMOSD can affect individuals in any demographic but is most common among women who are middle aged and older; the average age of onset is approximately 40 years. Testing for NMOSD should be considered in patients presenting with optic neuritis, transverse myelitis, area postrema syndrome, and/or other acute brain stem syndromes. Symptomatic narcolepsy or acute cerebral syndrome should also prompt testing if NMOSD-typical brain lesions are present on magnetic resonance imaging (MRI).^,

MOGAD

The clinical features of MOGAD may overlap with those of NMOSD, but MOGAD often has more extensive optic nerve involvement (and optic neuritis is often bilateral) and is thought to have a lower tendency for relapse. In contrast to NMOSD, MOGAD affects men and women at equal rates and occurs at a younger age. All patients who meet criteria for NMOSD without AQP4 IgG should be evaluated for MOGAD; however, testing for MOGAD should not be limited to patients who meet NMOSD criteria. Due to the rarity of other autoimmune demyelinating diseases in children, MOGAD testing is advised in all children younger than 12 years with acute central nervous system (CNS) demyelination. In adults, indications for MOG IgG testing begin with any combination of optic neuritis, myelitis, and encephalitis, with evidence of CNS demyelination on imaging or by visual evoked potential (VEP). If these are present, additional characteristic clinical or MRI findings should prompt MOG IgG testing. MOG IgG testing is not recommended in the routine evaluation of MS when typical features of MS are present.

Criteria for Diagnosis

NMOSD

In 2015, the International Panel for NMO Diagnosis (IPND) released updated NMOSD diagnostic criteria for adult patients. The criteria allow for diagnosis with the detection of at least one of six core clinical characteristics and AQP4 IgG antibodies. Diagnostic requirements are more stringent for patients who are AQP4 IgG seronegative or have an unknown AQP4 IgG status.

Diagnostic Criteria for NMOSD in Adult Patients
NMOSD With AQP4 IgG	NMOSD Without AQP4 IgG^a (Negative or Unknown AQP4 IgG Status)
One or more core clinical characteristics^b AQP4 IgG-positive test result (cell-based assay by IFA or FACS preferred) Alternative diagnoses excluded	At least 1 of the first 3 core clinical characteristics^b (optic neuritis, acute myelitis with LETM, or area postrema syndrome) Dissemination in space (at least 2 different core clinical characteristics^b) MRI findings consistent with respective core clinical characteristics^b Negative test result for AQP4 IgG or testing unavailable Exclusion of alternative diagnoses
^aFor additional MRI requirements for NMOSD without AQP4 IgG and NMOSD with unknown AQP4 IgG status, refer to the IPND’s consensus diagnostic criteria for NMOSD. ^bCore clinical characteristics include optic neuritis, acute myelitis, area postrema syndrome (episodes of otherwise unexplained intractable nausea and vomiting or hiccups), acute brain stem syndrome, symptomatic narcolepsy or acute diencephalic clinical syndrome with NMOSD-typical diencephalic MRI lesions, and symptomatic cerebral syndrome with NMOSD-typical brain lesions. FACS, fluorescence-activated cell sorting; IFA, immunofluorescence assay; LETM, longitudinally extensive transverse myelitis Source: Wingerchuk, 2015

MOGAD

Diagnostic criteria for MOGAD that are designed to apply to both adult and pediatric patients have been proposed by an international panel of experts. A diagnosis of MOGAD should supersede AQP4 IgG-negative NMOSD in patients who meet criteria for both, due to recognition that MOGAD represents a distinct disorder with differing pathogenesis and clinical course.

Diagnostic Criteria for MOGAD
1. Any core demyelinating event^a 2. Clear positive^b MOG IgG serology by cell-based assay OR Low^c positive MOG IgG in serum or Positive MOG IgG in CSF AND At least 1 supportive clinical or MRI finding Negative AQP4 IgG serology 3. Alternative diagnosis excluded	Supportive Imaging and Clinical Findings Optic neuritis Bilateral or longitudinal involvement Perineural optic sheath enhancement Optic disc edema Brain Ill-defined, T2-hyperintense lesions in white matter, pons, middle cerebellar peduncle, or medulla Cortical lesion or involvement of deep gray matter Myelitis Extensive longitudinal involvement H-sign on MRI Central cord or conus lesion
^aCore demyelinating events include optic neuritis, myelitis, ADEM, cerebral, brain stem, or cerebellar deficits associated with T2-hyperintense lesions, and cerebral cortical encephalitis. ^bClear-positive titer ≥1:100 in a fixed cell-based assay, or as defined by individual assay cut-offs. ^cLow-positive titer ≥1:10 but <1:100 in a fixed cell-based assay, or as defined by individual assay cut-offs. A positive serum MOG IgG with unknown/unreported titers should be considered low positive. ADEM, acute disseminated encephalomyelitis; CSF, cerebrospinal fluid Source: Banwell, 2023

Diagnostic Criteria for MOGAD

1. Any core demyelinating event^a

2. Clear positive^b MOG IgG serology by cell-based assay OR

Low^c positive MOG IgG in serum or

Positive MOG IgG in CSF

AND

At least 1 supportive clinical or MRI finding
Negative AQP4 IgG serology

3. Alternative diagnosis excluded

Supportive Imaging and Clinical Findings

Optic neuritis

Bilateral or longitudinal involvement
Perineural optic sheath enhancement
Optic disc edema

Brain

Ill-defined, T2-hyperintense lesions in white matter, pons, middle cerebellar peduncle, or medulla
Cortical lesion or involvement of deep gray matter

Myelitis

Extensive longitudinal involvement
H-sign on MRI
Central cord or conus lesion

^aCore demyelinating events include optic neuritis, myelitis, ADEM, cerebral, brain stem, or cerebellar deficits associated with T2-hyperintense lesions, and cerebral cortical encephalitis.

^bClear-positive titer ≥1:100 in a fixed cell-based assay, or as defined by individual assay cut-offs.

^cLow-positive titer ≥1:10 but <1:100 in a fixed cell-based assay, or as defined by individual assay cut-offs. A positive serum MOG IgG with unknown/unreported titers should be considered low positive.

ADEM, acute disseminated encephalomyelitis; CSF, cerebrospinal fluid

Source: Banwell, 2023

Laboratory Testing

While completing clinically indicated testing to rule out infection, vasculitis, and other diseases that may mimic NMOSD or MOGAD, AQP4 IgG and/or MOG IgG serum antibody status should be determined. Cell-based detection methods are strongly recommended because of their greater sensitivity and specificity when compared with enzyme-linked immunosorbent assays (ELISAs). Both fixed and live cell-based assays can be used to meet diagnostic criteria.^, Fixed cell-based assays are more widely available and offer high sensitivity and specificity. Studies have shown a high degree of agreement between the two methodologies.^,

Diagnosis

Antibody Testing

Aquaporin-4 Receptor IgG Antibody

AQP4 IgG detection is confirmatory for NMOSD in the appropriate clinical setting. Serum testing is generally sufficient; CSF AQP4 IgG testing adds little if any sensitivity. Patients should be tested during attacks and before beginning immunosuppressive therapy to avoid confounding test interpretation. The absence of AQP4 antibodies does not rule out the diagnosis of NMOSD because false-negative results may occur in the setting of immunosuppression. Retesting should be considered before B-cell- or antibody-targeted therapies are instituted and should be considered in patients with seronegative results who relapse.

Myelin Oligodendrocyte Glycoprotein IgG Antibody

MOG IgG detection is required to diagnose MOGAD. As with AQP4 IgG testing, serum testing is generally more sensitive than CSF testing. Because MOG IgG titers vary with disease activity, retesting during an acute attack is recommended if initial testing is negative but clinical suspicion of MOGAD remains high. Serum antibody concentrations may temporarily fall below cutoff following treatment. Alternate diagnoses should be considered if MOG IgG levels are borderline positive, especially if clinical findings are atypical. Other laboratory findings that should prompt retesting include MOG IgG positivity in CSF but not serum and dual AQP4 IgG/MOG IgG positivity. For other clinical and imaging findings that warrant confirmatory testing of MOG IgG positivity, refer to the “red flags” table in the MOG Encephalomyelitis: International Recommendations on Diagnosis and Antibody Testing article.

Cerebrospinal Fluid Analysis

CSF analysis can help to distinguish NMOSD and MOGAD from MS by showing an absence of oligoclonal bands, pleocytosis of ≥50 white blood cells per microliter, and/or the presence of neutrophils. The IPND considers the absence of CSF oligoclonal bands as supportive evidence for NMOSD or MOGAD and the presence of these bands as suggestive of MS.

Typical CSF Parameters for MS, NMOSD, and MOGAD
Parameter	MS	NMOSD	MOGAD
Pleocytosis (≥50 cells/μL)	Rare	Common	Common
Cell type	Lymphocytosis	Neutrophils common	Neutrophils common
Protein level	Normal	May be elevated	May be elevated
Oligoclonal bands	Present in >80% of patients	Typically absent, but may be present in <30% of cases	Typically absent, but may be present in <20% of cases
Oligoclonal bands that disappear with time	No	Yes	Yes
Kappa free light chains	High	Low	Very low
APQ4 IgG	Not present	Typically present	Not present
MOG IgG	Typically absent	Not present	Present
Sources: Wingerchuk, 2015; Jarius, 2023; Tournier, 2026

Monitoring

AQP4 IgG and MOG IgG antibody titers may assist in monitoring disease course and prognosis, but their role is imperfect. Antibody titers may increase but may not be predictive of relapses or attacks. AQP4 and/or MOG IgG antibodies may become undetectable with immunosuppression, but this change does not necessarily indicate clinical remission. Patients with MOGAD who become seronegative have a lower risk of relapse.