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.
In 2015, the International Panel for NMO Diagnosis (IPND) released updated NMOSD diagnostic criteria for adult patients. The criteria allow for diagnosis with the occurrence of at least one of six core clinical characteristics and the detection of AQP4 IgG antibodies. Diagnostic requirements are more stringent for patients who are either AQP4 IgG seronegative or who have an unknown AQP4 IgG status.
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.
Aquaporin-4 Receptor IgG Antibody
AQP4 IgG antibody detection is confirmatory for NMOSDs in the appropriate clinical setting. AQP4 IgG is generally negative in patients with MS, while 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 to enzyme-linked immunosorbent assays (ELISAs). If low-titer positive ELISA results are detected, 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, as 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 seronegative patients 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 a lower incidence in women, younger age, greater optic nerve involvement, and a reduced tendency for relapse. 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
|Pleocytosis (≥50 cells/mm3)
||Present in >80% of patients
||Typically absent, but may be present in <30% of cases
|Oligoclonal bands that disappear with time
||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
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.