Neuromyelitis Optica Spectrum Disorders

Neuromyelitis optica spectrum disorders (NMOSDs) are immune-mediated chronic and often relapsing inflammatory diseases that target the optic nerve and spinal cord. These disorders may affect individuals in any demographic group but are most common among middle-aged and older women; the average age of onset is approximately 40 years.  NMOSDs are often mistaken for multiple sclerosis (MS) because of overlapping symptoms (eg, optic neuritis and transverse myelitis), but can be differentiated by clinical course, the presence and extent of lesions in the brain and/or spinal cord, optic neuritis, and the presence of aquaporin-4 receptor (AQP4) or myelin oligodendrocyte glycoprotein (MOG) IgG autoantibodies. Treatment strategies for NMOSDs and MS differ: NMOSDs require immunosuppressive therapy or plasmapheresis, and MS requires immune-modulation therapy.  Some MS therapies can aggravate NMOSDs, so early diagnosis is essential to ensure proper medical management.

 

Quick Answers for Clinicians

How are neuromyelitis optica spectrum disorders diagnosed?

A neuromyelitis optica spectrum disorder (NMOSD) diagnosis is based on core clinical characteristics, antibody status, and features as detected by magnetic resonance neuroimaging. All of these components are included in the International Panel for NMO Diagnosis (IPND) 2015 revised consensus criteria.  Laboratory testing involves determining aquaporin-4 receptor (AQP4) IgG and myelin oligodendrocyte glycoprotein (MOG) IgG serum antibody status; the presence of AQP4 or MOG IgG is confirmatory for NMOSDs in the appropriate clinical setting. 

Which specimen type is preferred for aquaporin-4 receptor antibody testing?

Serum is the optimal and most cost-effective specimen for aquaporin-4 receptor (AQP4) IgG testing.  Cerebrospinal fluid (CSF) IgG testing adds little if any sensitivity. 

Are genetic factors involved in neuromyelitis optica spectrum disorders?

Neuromyelitis optica spectrum disorders (NMOSDs) are generally sporadic diseases, but familial cases have been reported. There is a negative association with HLA-DRB1*1501, the allele most strongly associated with multiple sclerosis (MS). NMOSDs appear to be associated with HLA-DRB1*03, which has also been linked to other autoimmune conditions. 

Which differential diagnoses should be considered when investigating neuromyelitis optica spectrum disorders?

Early in the course of the disease, it may be difficult to distinguish neuromyelitis optica spectrum disorders (NMOSDs) from multiple sclerosis (MS) because both disorder types may cause optic neuritis and myelitis. Laboratory testing and brain magnetic resonance imaging (MRI) can assist in differentiating the two diseases. Other disorders that may present similarly to NMOSDs include acute disseminated encephalomyelitis, systemic lupus erythematosus, sarcoidosis, and paraneoplastic disorders. 

Indications for Testing

Testing for NMOSDs should be considered in patients presenting with optic neuritis, transverse myelitis, and/or area postrema clinical syndrome, which consists of intractable hiccups or nausea and vomiting. 

Criteria for Diagnosis

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 either AQP4 IgG seronegative or who have an unknown AQP4 IgG status. 

Diagnostic Criteria for NMOSDs in Adult Patients
NMOSD with AQP4 IgG NMOSD Without AQP4 IgGa

(Negative or Unknown AQP4 IgG Status)

One or more core clinical characteristicsb

AQP4 IgG-positive test result (cell-based assay by IFA or FACS preferred)

Alternative diagnoses excluded

2 or more core clinical characteristicsb that occur as a result of 1 or more clinical attacks that meet the following criteria:

  • At least 1 of the first 3 core clinical characteristicsb (optic neuritis, acute myelitis with LETM, or area postrema syndrome)
  • Dissemination in space (at least 2 different core clinical characteristicsb)
  • MRI findings consistent with respective core clinical characteristicsb

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 NMOSDs. 

bCore clinical characteristics include optic neuritis, acute myelitis, area postrema syndrome (episode of otherwise unexplained intractable nausea and vomiting or hiccups), acute brainstem 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; MRI, magnetic resonance imaging

Source: Wingerchuk, 2015 

Laboratory Testing

After pursuing nonspecific testing to rule out infection, vasculitis, and other diseases that may mimic NMOSDs in presentation, AQP4 IgG and MOG IgG serum antibody status should be determined.

Diagnosis

Antibody Testing

Aquaporin-4 Receptor IgG Antibody

AQP4 IgG antibody detection is confirmatory for NMOSDs in the appropriate clinical setting. AQP4 IgG testing is generally negative in patients with MS, whereas approximately 75% of patients with NMOSDs express antibodies to the AQP4 receptor. Cell-based detection methods are strongly recommended because of their greater sensitivity and specificity when compared with enzyme-linked immunosorbent assays (ELISAs). If ELISA testing yields a low-titer positive result, confirmatory testing is recommended, ideally using one or more different AQP4 IgG assay techniques. Serum testing is generally sufficient; cerebrospinal fluid (CSF) AQP4 IgG testing adds little if any sensitivity.  Patients should be tested during attacks and before beginning immunosuppressive therapy to avoid conversion to a seronegative status. The absence of AQP4 antibodies does not rule out the diagnosis of NMOSD because false-negative results may occur in the setting of immunosuppression. Occasionally, patients without detectable serum AQP4 IgG are later found to be seropositive; antibody levels increase with clinical relapse and decrease with immunosuppressive therapy. Retesting should be considered before B-cell- or antibody-targeted therapies are instituted and in patients with seronegative results who relapse. 

Myelin Oligodendrocyte Glycoprotein IgG Antibody

A minority of individuals who present with clinical symptoms suggestive of NMOSDs but are AQP4 IgG seronegative will have detectable serum MOG IgG antibodies. The clinical features of MOG IgG-associated NMOSD overlap with those of AQP4 IgG-associated NMOSD, but differences include greater optic nerve involvement and a reduced tendency for relapse; in addition, MOG IgG-associated NMOSD has a lower incidence in women and occurs at a younger age.   As with AQP4 IgG antibodies, the absence of MOG IgG antibodies does not rule out the diagnosis of NMOSD, and retesting should be considered before beginning antibody-targeted therapies. 

Cerebrospinal Fluid Analysis

CSF analysis can help to distinguish NMOSDs from MS by showing an absence of oligoclonal bands, or, in a small number of patients, a prominent pleocytosis during relapse that may be neutrophil predominant.  The IPND considers the absence of CSF oligoclonal bands as supportive evidence for NMOSD and the presence of these bands a suggestive sign of MS. 

Typical CSF Parameters for MS and NMOSDs
Parameter MS NMOSDs
Pleocytosis (≥50 cells/mm3) Rare Common
Cell type Lymphocytosis Neutrophil-predominant pleocytosis
Protein level Normal Elevated
Oligoclonal bands Present in >80% of patients Typically absent, but may be present in <30% of cases
Oligoclonal bands that disappear with time No Yes
IgG ormal Typically elevated
IgG index Elevated in >90% of cases Elevated in 10-30% of cases
NMOSD autoantibody (AQP4)a Usually not present May be present
NMOSD autoantibody (MOG) Usually not present May be present

aNMOSD autoantibody testing using CSF concurrently with AQP4 serum tests increases sensitivity for NMOSDs.

Sources: Weinshenker ; Wingerchuk ; Trebst ; Sellner 

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 does not necessarily indicate clinical response. 

ARUP Lab Tests

Antibody Tests

Useful for initial evaluation of NMOSDs

Use for evaluation of optic neuritis, acute myelitis, spinal cord lesions, or autoimmune encephalitis

Useful in the interpretation of low-positive ELISA results when suspicion for disease is low or questionable

Aids in the evaluation of NMO and NMOSDs

Use in conjunction with serum autoantibody tests to diagnose NMOSDs

Useful for initial evaluation of central nervous system (CNS) demyelinating disease or autoimmune encephalitis

Use for managing response to treatment in individuals who are antibody positive

Aids in the initial evaluation of autoimmune disorders or inflammatory CNS demyelinating disease, including NMOSDs and NMOSD-like disorders

CSF Analysis

Medical Experts

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References