Neuromyelitis Optica Spectrum Disorder (NMOSD)


Neuromyelitis optica spectrum disorder (NMOSD) is a rare chronic inflammatory central nervous system (CNS) disorder. Autoantibodies (Abs) against the astrocyte aquaporin-4 (AQP4) water channel are seen in most NMOSD cases, and patients often experience repeated episodes of severe optic neuritis and/or myelitis.

A diagnosis of NMOSD requires the presence of 1 of the 6 core clinical symptoms: longitudinally extensive transverse myelitis (LETM), optic neuritis, area postrema syndrome, and symptomatic brainstem, diencephalic, or cerebral syndromes with AQP4-Abs. The criteria are more strict in seronegative individuals, and magnetic resonance imaging (MRI) criteria must also be met.2 

A thorough clinical history and examination, assessment of typical physical characteristics, and a variety of specialized tests are used to make a diagnosis of NMOSD, including antibody tests, cerebrospinal fluid (CSF) examinations, MRI, and optical coherence tomography (OCT).3

Antibody Testing

Blood tests to identify the autoantibody, NMO-immunoglobulin (Ig) G, help to distinguish NMOSD from other neurological disorders including multiple sclerosis (MS). They also aid in the early detection of NMOSD.4 Blood serological testing for AQP4-Ab or NMO-IgG are positive in 60% to 90% of individuals who fulfill the clinical and radiologic criteria for NMOSD. Female patients and relapsing disease cases appear to have higher frequencies of AQP4-Ab. Various approaches for testing serum AQP4-Ab are currently available, and they can be classified as cell-, tissue-, or protein-based.

The methods for NMO-IgG detection include fluorescence-activated cell sorting (FACS),  enzyme-linked immunosorbent assay (ELISA), and immunofluorescence.6

The sensitivity and specificity of the FACS assay are observed to be more than 80% and more than 99%, respectively. Serum shows higher sensitivity than CSF for detecting NMO-IgG levels.7

In the CNS, myelin oligodendrocyte glycoprotein (MOG) is expressed on the surface of oligodendrocytes and myelin. The development of cell-based assays (CBA) has made it easier to identify Abs against human MOG expressed in its conformational state, which is important for diagnostic purposes. MOG-Abs are seen in roughly 40% of NMOSD patients who are AQP4-seronegative.2 To eliminate cross-reactivity with IgM and IgA antibodies, CBAs targeting full-length human MOG and the usage of IgG1-specific secondary antibodies are highly recommended.1

Non-organ-specific antibodies, such as anti-nuclear, anti-double-stranded DNA, anti-Ro, and anti-La, can also be observed in patients with NMOSD.2

Cerebrospinal Fluid Examination

A spinal tap and CSF study can be used to distinguish NMOSD from MS.4 The CSF shows moderate pleocytosis with a predominance of lymphocytes and monocytes that is more pronounced in NMOSD than in MS, but not as much as in infectious myelitis. During acute relapses in AQP4-Ab-positive NMOSD cases, however, cell counts are within the normal range in roughly 40% of samples.5

Interleukin-6 (IL-6) and soluble IL-6 receptor levels in the CSF of NMOSD cases were recently discovered to be greater than those in MS cases, suggesting that they may be helpful in distinguishing NMOSD from other demyelinating disorders.5

Other Biomarkers

Sensitive and specific biomarkers are required for disease diagnosis, relapse prediction, disease course prognosis, and treatment response. Besides NMO-IgG and anti-MOG, other biomarkers include cytokines, chemokines, B-cell markers, and blood-brain barrier breakdown markers such as matrix metalloproteinase-9 (MMP-9), intercellular adhesion molecule-1 (ICAM-1), vascular endothelial growth factor-A (VEGF-A), and vascular cell adhesion molecule-1 (VCAM-1).8

High neurofilament (NF) heavy chain levels in the serum are observed in NMOSD, indicating poor prognosis. Astrocytic markers, such as glial fibrillary acidic protein (GFAP) and S100B, have been identified in the CSF in many inflammatory CNS diseases. Their values are increased in AQP4-IgG–seropositive cases of NMOSD.8

Neuroimaging

MRI scans are performed to assess the optic nerves, spinal cord, and brain for the presence of characteristic or highly suggestive NMOSD patterns in specific CNS regions.4,6

The most distinctive neuroimaging hallmark of NMOSD is the identification of an LETM spinal cord lesion accompanied by acute myelitis, which is exceedingly rare in adult MS. These lesions usually affect the central grey matter and accompany spinal cord swelling, central hypointensity on T1-weighted sequences, and enhancement after intravenous gadolinium injection. A cervical lesion that extends into the brainstem is typical.9

In the brain, NMOSD shows lesions in the third and fourth ventricles’ periependymal surfaces, area postrema, corpus callosum, thalamus, and hypothalamus. Subcortical or deep white matter abnormalities can also be observed.1

Findings on orbital MRI include increased T2 signal and gadolinium enhancement of the optic nerve as indicators of optic neuritis in NMOSD.1

Optical Coherence Tomography

Following episodes of optic neuritis, OCT is helpful in demonstrating substantial damage to the retinal nerve fiber layer and ganglion cell layer in both AQP4 NMOSD and MOG-encephalomyelitis. These findings coincide with the degree of visual function and quality of life.1

Electrophysiology

In NMOSD, visual evoked potentials are often altered. It was concluded in a recent study that 40% of cases had delayed P100 latencies, whereas 25% had lower amplitudes or absent potentials.5

References

  1. Borisow N, Mori M, Kuwabara S, Scheel M, Paul F. Diagnosis and treatment of NMO spectrum disorder and MOG-encephalomyelitis. Front Neurol. 2018;9:888. doi:10.3389/fneur.2018.00888
  2. Huda S, Whittam D, Bhojak M, Chamberlain J, Noonan C, Jacob A. Neuromyelitis optica spectrum disorders. Clin Med (Lond). 2019;19(2):169-176. doi:10.7861/clinmedicine.19-2-169
  3. Neuromyelitis optica spectrum disorder. National Organization for Rare Disorders. Accessed October 14, 2021.
  4. Neuromyelitis optica – diagnosis and treatment. Mayo Clinic. Accessed October 14, 2021.
  5. Trebst C, Jarius S, Berthele A, et al.; Neuromyelitis Optica Study Group (NEMOS). Update on the diagnosis and treatment of neuromyelitis optica: recommendations of the Neuromyelitis Optica Study Group (NEMOS). J Neurol. 2014;261(1):1-16. doi:10.1007/s00415-013-7169-7
  6. Neuromyelitis optica (NMO) spectrum disorders. Mayo Clinic Laboratories. September 2016. Accessed October 14, 2021.
  7. Neuromyelitis optica (NMO)/aquaporin-4-IgG fluorescence-activated cell sorting (FACS) assay, serum. Mayo Clinic Laboratories. Accessed October 14, 2021.
  8. Melamed E, Levy M, Waters PJ, et al. Update on biomarkers in neuromyelitis optica. Neurol Neuroimmunol Neuroinflamm. 2015;2(4):e134. doi:10.1212/NXI.0000000000000134
  9. Wingerchuk DM, Banwell B, Bennett JL, et al.; International Panel for NMO Diagnosis. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology. 2015;85(2):177-189. doi:10.1212/WNL.0000000000001729

Reviewed by Kyle Habet, MD, on 10/14/2021.