Neuromyelitis optica (NMO), 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 The terminology neuromyelitis optica has been replaced by neuromyelitis optica spectrum disorder (NMOSD) to account for disease states associated with the presence of aquaporin-4 (AQP4) autoantibody but having a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 dramatic advances in the understanding of the pathophysiology of this disease, related diseases that share similar phenotype (ie, anti-MOG syndromes), and FDA-approved treatments that demonstrate high efficacy.
Neuromyelitis optica spectrum disorder is a devastating disease and leaves many patients with permanent vision loss and paralysis. Neuromyelitis optica spectrum disorder is conceptualized as an astrocytopathy, by virtue of the auto-antibody AQP4 against the AQP4 membrane protein expressed at high concentrations on the foot processes of astrocytes along the endothelial lining of the blood-brain barrier. The pathophysiology of neuromyelitis optica spectrum disorder initially involves breakdown of the blood-brain barrier by some trigger, probably infection or some inflammatory event, followed by influx of AQP4 antibody in to the CNS. During a relapse, there is increased production of the AQP4 antibody. The AQP4 antibody is pathogenic. Once bound to the AQP4 on astrocytes, it triggers complement-dependent destruction of the astrocytes (06). There is spillover of inflammation to the oligodendrocytes causing secondary damage or demyelination. Hence, the primary pathologic process involved in neuromyelitis optica spectrum disorder is astrocytic destruction by complement; demyelination is secondary (63; 68; 80).
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, 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 (70). AQP4-specific antibodies are IgG1, a T-cell dependent Ig subclass (66). 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 (64; 95). 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 (49). Other cells of innate immunity are recruited to the CNS by chemokines including neutrophils, eosinophils, and mast cells, which cause further destruction through degranulation.
From June 2019 to August 2020, 3 drugs were approved by the FDA for treatment of AQP4 positive neuromyelitis optica spectrum disorder, which is a rather historic event considering that neuromyelitis optica was first described comprehensively in 1894 and for decades it was treated with off-label agents. Several of these off-label treatments are effective in curtailing neuromyelitis optica relapses, largely based on small open-label trials and anecdotal experience. Randomized, placebo-controlled, phase 3 trials of the approved agents for neuromyelitis optica spectrum disorder clearly demonstrate the magnitude of drug effectiveness and also demonstrate the consequences of relapses on disability. The side effect profile is also carefully studied in these prospectively planned studies.
Herein, the pathophysiology and diagnostic criteria of neuromyelitis optica spectrum disorder are reviewed. New updates include 3 FDA-approved treatments for neuromyelitis optica spectrum disorder in patients who are positive for AQP4 antibody.
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• 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.
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• 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.
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• 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 co-existent funduscopic abnormalities, and these patients tended to have a more severe disease course. Eugene Devic, a French physician, was initially interested in studying typhoid fever. But 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” (17). In 1907, the term Devic disease was first used, and since then, Devic’s name has been associated with this disease.