Sign Up for a Free Account
  • Updated 04.05.2023
  • Released 06.16.1997
  • Expires For CME 04.05.2026

Neuromyelitis optica spectrum disorders



Neuromyelitis optica, historically known as Devic disease, is an inflammatory disease of the central nervous system. The terminology neuromyelitis optica has been replaced by neuromyelitis optica spectrum disorder (NMOSD) to account for disease states associated with the presence of aquaporin-4 (AQP4) autoantibody with a single bout of optic neuritis, longitudinal transverse myelitis, brainstem inflammation, diencephalon involvement, or diffuse brain inflammation. In the past 5 years, there have been significant advances in the understanding of the pathophysiology of neuromyelitis optica spectrum disorder, which have led to the approval of three disease-modifying treatments for this condition by the U.S. Food and Drug Administration (FDA).

Neuromyelitis optica spectrum disorder is a devastating neurologic disease that leaves many patients with permanent vision loss and paralysis. The pathologic hallmark of neuromyelitis optica spectrum disorder is damage to astrocytes by the anti-aquaporin-4 (AQP4) antibody. The antibody causes tissue injury in the CNS by one of several distinct mechanisms. The most destructive mechanism of injury is through binding of this IgG type 1 antibody to the components of the complement pathway, with C5b involved in the formation of the membrane attack complex and causing lysis of the astrocyte (lytic pathway), and C5a serving as a chemoattractant for other inflammatory immune cells (neutrophils, eosinophils, T cells, monocytes) (29). Noncomplement-mediated mechanisms of injury include internalization of the antibody-AQP4 complexes along with the excitatory amino acid transporter 2 (EAAT2) coupled to the AQP4 water channel, which leads to dysregulation of glutamate buffering and cytotoxicity (33); antibody-mediated reactive astrocytosis; microglial activation; local IL-6 production (09); and epitope spreading (101) secondary to the release of self-antigens during an inflammatory response and further injury to other cell types, such as oligodendrocytes. These noncomplement-mediated mechanisms of injury constitute the sublytic astrocytopathy in neuromyelitis optica spectrum disorder.

Given the pathogenic role of the AQP4 antibody in neuromyelitis optica spectrum disorder, it is generally thought that the disease is caused by abnormal autoreactivity of B cells, which are either generated through aberrant central tolerance (ie, poor clonal deletion) or breakthrough of peripheral tolerance later in life. There is an important role of T cells as well. T cells can drive antibody responses (74). AQP4-specific antibodies are IgG1, a T-cell dependent Ig subclass (71). Patients with neuromyelitis optica spectrum disorder have AQP4-reactive T cells. The T-cell responses in neuromyelitis optica spectrum disorder are polarized towards highly inflammatory Th17 cells, which probably play an important role in the blood-brain barrier breakdown (69; 102). The TCR repertoire in neuromyelitis optica spectrum disorder shows an increased clonality in the CD4 and CD8 compartments, not only in the periphery but also in the CNS, suggesting an antigen-driven expansion of these clones (55). Other cells of innate immunity are recruited to the CNS by chemokines, including neutrophils, eosinophils, and mast cells, which cause further destruction through degranulation.

During the period June 2019 to August 2020, three drugs were approved by the FDA for treatment of AQP4-positive neuromyelitis optica spectrum disorder, which is a rather historic event considering that the disease was first comprehensively described in 1894, and it was treated with off-label agents for decades. Several of these off-label treatments are effective in curtailing neuromyelitis optica spectrum disorder relapses and are largely based on small open-label trials and anecdotal experience. Randomized, placebo-controlled, phase 3 trials of the current FDA-approved disease-modifying treatments for neuromyelitis optica spectrum disorder clearly demonstrate the magnitude of effectiveness of these agents. The side effect profile is also carefully studied in these prospectively planned studies. Long-term safety and efficacy data are now available for the three FDA-approved agents for AQP4-positive neuromyelitis optica spectrum disorder. Safety profiles and efficacy were maintained in the open-label extension periods for eculizumab, inebilizumab, and satralizumab (111; 50; 85; 117).

In this article, the pathophysiology and diagnostic criteria of neuromyelitis optica spectrum disorder are reviewed. New updates include discussion of the sublytic astrocytopathy component of the pathophysiology of this disease and long-term safety and efficacy data for the three FDA-approved agents for AQP4-positive neuromyelitis optica spectrum disorder.

Key points

• There is some overlap in the clinical phenotype of patients who have auto-antibodies against myelin oligodendrocyte glycoprotein (anti-MOG) and those with AQP4 antibodies, but these are distinct pathophysiological and clinical entities.

• Aggressive treatment at the onset of a relapse, including steroids, plasma exchange, and early initiation of prophylactic therapy leads to better recovery and lower long-term disability for patients with neuromyelitis optica spectrum disorder.

• Pregnancy is an important consideration when treating women with neuromyelitis optica spectrum disorder. Unlike multiple sclerosis, disease activity does not decrease during pregnancy and can leave women with severe disability. Treatment approach should be individualized.

Historical note and terminology

Thomas Albutt is given credit for initially describing the syndrome now called neuromyelitis optica (03). Albutt observed that some patients with myelitis had coexistent funduscopic abnormalities, and these patients had a more severe disease course. Eugene Devic, a French physician, was initially interested in studying typhoid fever. Devic’s eponymic distinction later emerged after he summarized the known cases of neuromyelitis optica along with his own observations in 1894 and presented them at the French Congress of Medicine in Lyon, coining the terms “neuro-myélite” and “neuroptico-myélite” (18). In 1907, the term Devic disease was first used, and since then, Devic’s name has been associated with this disease.

This is an article preview.
Start a Free Account
to access the full version.

  • Nearly 3,000 illustrations, including video clips of neurologic disorders.

  • Every article is reviewed by our esteemed Editorial Board for accuracy and currency.

  • Full spectrum of neurology in 1,200 comprehensive articles.

  • Listen to MedLink on the go with Audio versions of each article.

Questions or Comment?

MedLink®, LLC

3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122

Toll Free (U.S. + Canada): 800-452-2400

US Number: +1-619-640-4660



ISSN: 2831-9125