Test Catalog

Test ID: NMOFC    
Neuromyelitis Optica (NMO)/Aquaporin-4-IgG Fluorescence-Activated Cell Sorting (FACS) Assay, Spinal Fluid

Useful For Suggests clinical disorders or settings where the test may be helpful

Diagnosis of a neuromyelitis optica spectrum disorder (NMOSD)

 

Diagnosis of autoimmune AQP4 channelopathy

 

Distinguishing NMOSD from multiple sclerosis early in the course of disease

Testing Algorithm Delineates situations when tests are added to the initial order. This includes reflex and additional tests.

When the results of this assay require further evaluation, NMOTC / Neuromyelitis Optica (NMO)/Aquaporin-4-IgG Fluorescence-Activated Cell Sorting (FACS) Assay Titer, Spinal Fluid will be performed at an additional charge.

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Neuromyelitis optica (NMO), sometimes called Devic disease or opticospinal multiple sclerosis (MS) is a severe, relapsing, autoimmune, inflammatory and demyelinating central nervous system disease that predominantly affects optic nerves and spinal cord.(1) The disorder is now recognized as a spectrum of autoimmunity (termed NMO spectrum disorders: NMOSD) targeting the astrocytic water channel aquaporin-4 (AQP4).(1,2) Brain lesions are observed in >60% of patients with NMOSD and approximately 10% will be MS-like.(3) Children tend to have greater brain involvement than adults and brain lesions are more symptomatic than is typical for adult patients.(4) Extensive cerebral white matter signal abnormalities are sometimes encountered, most commonly in children, and are sometimes associated with encephalopathy. Circumventricular organs (CVO; eg, area postrema) are preferentially involved.

 

Symptoms and signs attributable to area postrema involvement include intractable hiccups, nausea and vomiting, and these may occur in isolation, herald the onset of NMO, or occur in association with the more classical optic neuritis or Longitudinally Extensive Transverse Myelitis (LETM).(5) Magnetic resonance imaging typically reveals large inflammatory spinal cord lesions involving 3 or more vertebral segments.

 

During acute attacks, the cerebrospinal fluid contains inflammatory cells, but usually lacks evidence of intrathecal IgG synthesis. The clinical course is characterized by relapses of optic neuritis or transverse myelitis, or both. Many patients with NMOSD are misdiagnosed as having MS. Importantly, the prognosis and optimal treatments for the 2 diseases differ. NMOSD typically has a worse natural history than MS, with frequent and early relapses. NMOSD attacks are often severe resulting in a rapid accumulation of disability (blindness and paraplegia). More effective treatments combined with earlier and more accurate diagnosis has led to improved outcomes. Currently, in the AQP4-IgG era, 5 years after onset, approximately 30% of NMO patients will require a cane to walk and 10% will be wheelchair bound.

 

Treatments for NMOSD include corticosteroids and plasmapheresis for acute attacks and mycophenolate mofetil, azathioprine, and rituximab for relapse prevention. Beta-interferon, a treatment promoted for MS, exacerbates NMOSD. Therefore, early diagnosis and initiation of NMO-appropriate immunosuppressant treatment is important to optimize the clinical outcome by preventing further attacks. Skeletal muscle abnormalities with hyerCKemia have been reported in a few NMOSD patients. Recent reports indicate focal retinal vascular attenuation, inner nuclear layer thickening and microcystic edema in some NMO patients.

 

Detection of AQP4-IgG by NMO/AQP4 FACS in cerebrospinal fluid (CSF) allows distinction from MS and is indicative of an NMOSD.

 

Though serum is optimal for AQP4-IgG testing, occasionally physicians submit only CSF for testing. A previous study, based on our first-generation indirect immunofluorescence assay compared the frequencies of AQP4-IgG in serum and CSF. The positivity rate was greater for serum alone than for CSF alone.(6) However, testing of CSF was helpful when the serum was negative. Detection of AQP4-IgG in CSF allowed unambiguous distinction of NMO from MS. CSF testing offered the additional advantage of generally lacking the nonorgan-specific IgG autoantibodies (eg, antinuclear, antimitochondrial, and smooth muscle) that are common in serum of patients with NMO and also with classic paraneoplastic autoimmune disorders. Recent AQP4 FACS analysis of paired CSF and serum samples from 66 patients submitted for AQP4-IgG testing reveals a slightly better detection rate in serum (n=59) compared with CSF (n=55). All 7 patients who tested negative in serum also tested negative in CSF.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

Negative

Interpretation Provides information to assist in interpretation of the test results

A positive value is consistent with a neuromyelitis optica spectrum disorder (NMOSD) and justifies initiation of appropriate immunosuppressive therapy at the earliest possible time. This allows early initiation and maintenance of optimal therapy.

 

This autoantibody is not found in healthy subjects.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

A negative result does not exclude a diagnosis of neuromyelitis optica spectrum disorder (NMOSD). Recommend serum be tested if CSF tests negative and neuromyelitis optica spectrum disorder is suspected. AQP4-IgG antibodies may drop below detectable levels in setting of therapies for acute attack (IV methylprednisolone or plasmapheresis) or attack prevention (immunosuppressants).

Supportive Data

Recent AQP4 FACS analysis of paired cerebrospinal fluid (CSF) and serum samples from 66 patients submitted for AQP4-IgG testing reveals a slightly better detection rate in serum (n=59) compared with CSF (n=55). All 7 patients who tested negative in serum also tested negative in CSF.

 

AQP4 FACS analysis was done for CSF samples from 26 random patients with a diagnosis of NMO. All samples except 1 were tested with our validated AQP4 cell-binding assay (CBA). A total of 18 samples (69.23%) were positive by FACS, while only 14 samples (56%) were positive by CBA. All 8 samples that were negative by FACS also tested negative by CBA.

 

To measure the specificity, AQP4 FACS analysis was done for CSF of 27 patients with the diagnosis of normal pressure hydrocephalus. None of the samples were positive by this assay (specificity=100%).

Clinical Reference Recommendations for in-depth reading of a clinical nature

1. Wingerchuk DM, Lennon VA, Lucchinetti CF, et al: The spectrum of neuromyelitis optica. Lancet Neurol 2007;6:805-815

2. Lennon VA, Wingerchuk DM, Kryzer TJ, et al: A serum autoantibody marker of neuromyelitis optica; distinction from multiple sclerosis. Lancet 2004;364:2106-2112

3. Pittock SJ, Weinshenker BG, Lucchinetti CF, et al: Neuromyelitis optica brain lesions localized at sites of high aquaporin 4 expression. Arch Neurol 2006 Jul; 63(7):964-968

4. McKeon A, Lennon VA, Lotze T, et al: CNS aquaporin-4 autoimmunity in children. Neurology 2008 Jul 8;71(2):93-100

5. Apiwattanakul M, Popescu BF, Matiello M, et al: Intractable vomiting as the initial presentation of NMO. Ann Neurol 2010 Nov;68(5):757-761

6. McKeon A, Pittock SJ, Lennon VA: CSF complements serum for evaluating paraneoplastic antibodies and NMO-IgG. Neurology 2011 Mar 22;76(12):1108-1110