Neuromyelitis optica

Diagnostic workup
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By Tiffani Stroup DO and Adil Javed MD PhD

A serum marker for neuromyelitis optica, the NMO-IgG antibody, is available commercially. The sensitivity and specificity of this antibody have been examined in neuromyelitis optica, multiple sclerosis, transverse myelitis, and other autoimmune systemic diseases. NMO-IgG antibody has a sensitivity of 73% and specificity of 91% for distinguishing neuromyelitis optica from multiple sclerosis (Lennon et al 2004). It has a sensitivity of 46% and specificity of 91% when differentiating neuromyelitis optica from those patients at high-risk for developing neuromyelitis optica, ie, patients with transverse myelitis spanning 3 or more vertebral lengths or recurrent optic neuritis and no brain parenchyma lesion.

Since Lennon and colleagues discovered the aquaporin-4 antibody with a tissue-based assay in 2004, further laboratory tests have been developed with increased sensitivity and specificity (Lennon et al 2004). A review of all available laboratory assays testing for aquaporin-4 antibody includes sensitivities that range from 12.5% to 100% and specificity of greater than 96%. Current available lab tests include cell-based assays, tissue-based assays, and ELISA (a protein-based assay). Cell-based assays using fluoroimmunocytochemistry or flow cytometry have a median sensitivity of 78.1% (range 50-100) and a median specificity of 100% (range 95.4-100). Tissue-based assays using immunohistochemisty have a median sensitivity of 61% (range 37.5-95) and a median specificity of 100% (93.3-100). Lastly, ELISA has a median sensitivity of 51.4% (range 48.3-75.8) and a median specificity of 100% (range 97.7-100). Thus, patients with high clinical suspicion for neuromyelitis optica who have previously tested negative for aquaporin-4 antibody should have retesting with a cell-based assay (Jarius and Wildemann 2013).

Patients with cancer can have the NMO-IgG antibody without having neuromyelitis optica. Similarly, there is an overlap between having neuromyelitis optica and having cancer. This raises the possibility that the NMO-IgG antibody at times represents a paraneoplastic antibody (Pittock and Lennon 2008).

Diagnostic workup for neuromyelitis optica requires a careful history, clinical presentation, characteristic MRI features, spinal fluid analysis, and extensive blood workup.

Table 3. Diagnostic Evaluation for Neuromyelitis Optica

History and physical exam
History including travel and vaccinations
General physical and neurologic exam

Basic studies
Complete blood count
Comprehensive metabolic panel
Urine analysis
Chest x-ray
B12 level
Thyroid studies

Infectious studies
Purified protein derivative (in high risk groups)
Lyme serology
Rapid plasma reagin
CSF: gram stain and culture
Fungal stain and culture
Acid-fast bacilli stain and culture
Polymerase chain reaction for Herpes simplex virus, varicella zoster virus, and Epstein-Barr virus

CSF workup
Cell count and differential
Immunoglobulin G index
Oligoclonal bands

Rheumatologic workup
Erythrocyte sedimentation rate
Antinuclear antibodies
Double-stranded DNA
Extractable nuclear antigens
Sjögren antibodies (SSA/SSB)
Rheumatoid factor
P-antineutrophil cytoplasmic antibodies
Antiphospholipid antibodies
Thyroid peroxidase antibodies
Angiotensin-converting enzyme levels

Special serology
Neuromyelitis optica-IgG
Paraneoplastic antibodies

MRI studies
Contrast enhanced MRI of the brain with fat-sat orbital views of the optic nerves
Cervical and thoracic spine

Evoked potentials
Visual and somatosensory

Special studies
Minor salivary gland biopsy (see text)
Optical coherence tomography

History of illness needs to query the travel history and exposure to infectious agents. Radiographically, there are distinct differences between multiple sclerosis and neuromyelitis optica. In comparison to multiple sclerosis, optic neuritis in neuromyelitis optica more often affects the posterior optic nerves, the optic chiasm, and simultaneously affects both optic nerves. Acute spinal cord lesions are typically longitudinally extensive, centrally located, edematous, involve gray matter, hypointense on T1, and have partial enhancement with gadolinium. Chronic lesions may have cord atrophy and cavitation. Brain lesions can be seen in nearly 50% of neuromyelitis optica patients at disease onset, occur with higher frequency over time, and may appear multiple sclerosis-like in 10% of cases (Tackley et al 2014). In the brain, lesions preferentially affect the medullary periaqueductal gray, area postrema, hypothalamus, and splenium of the corpus callosum. On MRI, these lesions have cloud-like enhancement and display vasogenic edema (Uzawa et al 2014). Pediatric neuromyelitis optica, which is rare, may present with cortical lesions. Magnetic resonance spectroscopy may be helpful to differentiate spinal cord lesions in neuromyelitis optica from multiple sclerosis, which shows a decreased myoinositol peak in neuromyelitis optica lesions versus a decreased NAA peak in multiple sclerosis lesions (Tackley et al 2014).

CSF analysis in neuromyelitis optica shows a unique pattern in comparison to other demyelinating diseases (see Table 1). In neuromyelitis optica, CSF shows pleocytosis of 30 to 50 cells/µL with high percentage of granulocytes and eosinophils (Weinshenker 2003). This is in contrast to multiple sclerosis, where CSF pleocytosis is mild (usually less than 10 cells/µL) and more than 90% of the cells are lymphocytes. In neuromyelitis optica, CSF protein is usually mildly elevated and oligoclonal bands are typically absent. About 30% of patients with neuromyelitis optica may have positive oligoclonal bands during an acute attack. However, if oligoclonal bands are present, they tend to disappear over time, especially during disease stability (Bergamaschi et al 2004). This is in sharp contrast to multiple sclerosis, where oligoclonal bands persist regardless of disease status. CSF immunoglobulin G synthesis rate is not routinely elevated in neuromyelitis optica, and if so, is at a low level. The albumin CSF/serum ratio, which is a marker of blood-brain barrier breakdown, is elevated in more than half of patients studied with neuromyelitis optica. Elevation of certain CSF markers correlates with the length of transverse myelitis during acute relapses, including albumin CSF/serum ratio, total protein, and L-lactate (Jarius et al 2011). Other uniquely elevated measures in acute attacks of neuromyelitis optica compared to multiple sclerosis include IL-6 and glial fibrillary acidic protein (Sato et al 2014; Uzawa et al 2014).

Neuromyelitis optica is associated with several connective tissue diseases, most commonly Sjögren disease and lupus. There is evidence that neuromyelitis optica is a presenting manifestation of an underlying connective tissue disease, even before the diagnosis of connective tissue disease is made. In a large case series of primary Sjögren disease with neurologic involvement, 56 out of 82 patients had CNS disease (Delalande et al 2004). CNS disease preceded the diagnosis of Sjögren disease in 45 of these patients (80%). More importantly, SSA/SSB was positive only in 43% of the cases but a positive salivary gland biopsy was evident in 95%. Hence, a positive salivary gland biopsy is a more reliable indicator of underlying Sjögren disease than serological testing.

Sjögren disease and neuromyelitis optica may be more closely linked than previously described. In 2008, our lab investigated the prevalence of positive lip biopsies in patients with neuromyelitis optica or longitudinally extensive transverse myelitis with clinical suspicion for Sjögren disease. Between 2004 and 2007, we evaluated 25 patients who met diagnostic criteria for neuromyelitis optica (16 patients) or longitudinally extensive transverse myelitis (9 patients) who noted sicca symptoms. None of these patients had clinical or laboratory evidence of other connective tissue disorders, such as systemic lupus erythematosus, rheumatoid arthritis, or scleroderma. All patients had serologic testing for SSA/B antibodies and NMO-IgG antibody. Sixteen patients had biopsies of their minor salivary glands. Biopsy results were considered positive if there was evidence of severe inflammation (a “focus score” of 3 or higher on a scale of 0-4, with higher scores indicating more inflammatory infiltrates). Of the 25 patients with sicca complaints, only 4 patients (16%) fulfilled diagnostic criteria for Sjögren disease, based on the European or International Sjögren’s Disease criteria. Of the 20 patients with sicca complaints who had a salivary gland biopsy, 16 patients (80%) met criteria for severe inflammation of the minor salivary glands. This included 9 out of 12 patients with neuromyelitis optica and 7 out of 8 patients with longitudinally extensive transverse myelitis. Our findings suggest that there may be subclinical evidence of Sjögren disease in patients with neuromyelitis optica who have sicca complaints. This also suggests that there may be additional evidence of a systemic autoimmune disease in neuromyelitis optica patients and overlapping pathogenic mechanisms (Javed et al 2008b).

Optical coherence tomography is a noninvasive method of evaluating the thickness of the retinal nerve fiber layer. In multiple sclerosis, there is atrophy of the retinal nerve fiber layer in eyes affected by optic neuritis as well as eyes unaffected by optic neuritis, reflecting chronic, subclinical axonal loss (Pueyo et al 2008). In comparison of patients with optic neuritis, the retinal nerve fiber layer in neuromyelitis optica patients is thinner than in patients with multiple sclerosis, which is thinner than in normal controls. This is consistent with observations that recovery from optic neuritis is worse in neuromyelitis optica (Jacob et al 2013). After the first attack of optic neuritis, some authors have proposed that a cutoff of 15 µm thinning of the retinal nerve fiber layer compared to normal suggests NMOSD rather than multiple sclerosis (Ratchford et al 2009). In neuromyelitis optica, the retinal nerve fiber layer thickness correlates not only with visual acuity but also with number of attacks and the expanded disability scale score (de Seze et al 2008; Merle et al 2008).

In This Article

Historical note and nomenclature
Clinical manifestations
Clinical vignette
Pathogenesis and pathophysiology
Differential diagnosis
Diagnostic workup
Prognosis and complications
References cited