ReviewNeuromyelitis optica: Concept, immunology and treatment
Introduction
Neuromyelitis optica (NMO), also known as Devic’s disease, is an idiopathic autoimmune inflammatory disorder of the central nervous system (CNS) that predominantly affects the optic nerves and spinal cord.1 NMO is one of the major neuroimmunological diseases in Asia. The original description of NMO was reported by Devic in 1894,2 and until recently, NMO was considered a rare variant of multiple sclerosis (MS). However, in 2004 the Mayo Clinic group found NMO-immunoglobulin G (IgG) in the sera of NMO patients, which binds at or near the blood–brain barrier in the mouse brain.3 In 2005, the epitope of NMO-IgG was identified as aquaporin-4 (AQP4), a water channel densely expressed in astrocytic foot processes at the blood–brain barrier.4 This identification of the disease-specific autoantibody was a breakthrough in NMO research and prompted a revision of the diagnostic criteria for NMO in 2006.1 The number of publications on NMO is increasing dramatically. NMO is now considered as an anti-AQP4 antibody-mediated astrocytopathy, and different from a demyelinating disorder such as MS.5
In recent years, the clinical,1, 6, 7, 8, 9, 10 immunological,11, 12, 13, 14 and pathological profiles of NMO,15, 16 and its response to treatment17, 18, 19, 20, 21, 22 have been analysed; NMO is now generally distinguished from MS (Table 1). This review focuses on the current advances in NMO research and its clinical characteristics, immunology, neuroimaging and pathophysiology.
Section snippets
History
Eugène Devic, a French physician, reported a patient with NMO in 1894,2 a 45-year-old woman who developed acute transverse myelitis and a day later, bilateral optic neuritis. Unfortunately this patient died. Pathological examination showed extensive demyelination and necrosis in the spinal cord and optic nerves. Some similar patients had been described before Devic’s report.23, 24 Gault analysed the clinical data of 17 patients with similar clinical features, including Devic’s patient and
Epidemiology
Fig. 1 shows MS (angle brackets) and NMO (grey rectangles) prevalence in the world. The global MS prevalence data were provided by MS International Federation and the World Health Organization (WHO) in 2012.77 High-latitude regions, such as North America, Europe and Australia have high MS prevalence, whereas low-latitude regions such as Asia show a low prevalence. MS prevalence is 1.5 per 100,000 in China, 3.0 in India, 5.0 in Korea and 8.0 in Japan, whereas the prevalence in Western countries
Neuromyelitis optica diagnostic criteria
The 2006 revised NMO diagnostic criteria1 (Table 2) are now commonly used to diagnose NMO. NMO is characterized by the co-occurrence of severe optic neuritis and myelitis, mostly observed as longitudinally extensive transverse myelitis (LETM).1 Most NMO patients have autoantibodies against AQP4 in their serum.4 Therefore, the NMO diagnostic criteria requires the presence of both optic neuritis and myelitis and fulfilment of at least two of the three supportive criteria: MRI evidence of a
Clinical course and prognosis
NMO has a generally poor prognosis and poor response to therapy compared with MS. Approximately 50% of patients have severe visual defects or motor impairment within 5 years of onset.9, 41 Median intervals between NMO onset and reaching Expanded Disability Status Scale scores of 3, 6, and 8 are 1, 8, and 22 years, respectively.9 Mortality rate is 16% within 5 years.9 Recently, a large clinical cohort study of 106 AQP4 antibody-seropositive patients from the United Kingdom and Japan has been
Brain lesions
In the past, it has been believed that the brain is not involved in NMO. However, recent studies have shown that more than 60% of NMO patients have brain lesions60, 61 and some characteristic NMO features have been found on MRI (Fig. 5). Brain lesions in NMO are preferentially localized in periventricular regions with high AQP4 expression62 and are often extensive.60 Medullary periaqueductal lesions associated with intractable hiccups and nausea63 and bilateral hypothalamic lesions associated
Pathology
It is now widely accepted that NMO is an inflammatory CNS disease characterized by severe optic neuritis and myelitis and the presence of anti-AQP4 antibody.1 Although NMO has been regarded as a variant of MS for a long time, recent evidence from pathological analyses indicate that NMO is a disease completely different from MS. The target epitope of NMO is AQP4 which is expressed on astrocytes but not myelin.5 Immunopathological studies of NMO lesions have shown an extensive loss of
Treatment
The rarity of NMO has precluded large-scale randomized trials to rationalize the treatment strategy. In general, intravenous high-dose methylprednisolone is used for treatment of acute NMO, but in patients resistant to treatment, plasma exchange should be performed immediately to achieve clinical improvement.70 Maintenance treatments for preventing NMO relapses include low-dose oral corticosteroids, azathioprine, mitoxantrone, cyclophosphamide, mycophenolate mofetil18, 19, 20, 21 and rituximab
Conclusions
Anti-AQP4 antibody measurement is important for the diagnosis of NMO and for deciding on effective therapy. Development of the AQP4 antibody assay has led to the recognition of atypical presentations of NMO that are beyond the traditional view. NMO is a relatively rare disease but better understanding of its pathogenesis will continue to improve treatment choices. From a diagnostic standpoint, diagnostic markers other than anti-AQP4 antibody and new diagnostic methods for diagnosis of
Conflicts of interest/disclosures
The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication.
Acknowledgement
This work was partly supported by the Ministry of Education, Science and Technology (Akiyuki Uzawa) [Grant Number 24790873].
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2023, International ImmunopharmacologySparser macula microvasculature in neuromyelitis optica spectrum disorder occurs independently of optic neuritis
2022, Multiple Sclerosis and Related DisordersCitation Excerpt :We speculate that these microvascular changes in the macula may signify initial sites of damage in NMOSD. The pathology of NMOSD is characterized by a multifocal process with immune activation and vascular injury, leading to vascular obstruction, mainly targeting microvessels (Jasiak-Zatonska et al., 2016; Uzawa et al., 2014). Microvascular injury and endothelial activation, leading to vascular damage cause rarefication in capillaries, vessel wall thickening due to smooth muscle, and intimal proliferation with luminal narrowing, which lead to tissue ischemia (Hillebrand et al., 2019).
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2022, Multiple Sclerosis and Related DisordersCitation Excerpt :NMOSD is distinguished from demyelinating CNS diseases by the existence of aquaporin 4-immunoglobulin G (AQP4-IgG), a serologic antibody against AQP4 (Patterson and Goglin, 2017). According to previous statistics, approximately 20% of NMOSD patients are serologically negative for AQP4-IgG and have antibodies against myelin oligodendrocyte glycoprotein (MOG) or no recognizable antibodies (Jiao et al., 2013) (Uzawa et al., 2014). A cohort study demonstrates a slightly elevated proportion of patients with AQP4-IgG among Asians with idiopathic demyelinating CNS disorders than whites (Uzawa et al., 2014).
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2020, Multiple Sclerosis and Related DisordersCitation Excerpt :The typical manifestations of NMOSD include optic nerve attacks with blindness or vision loss, attacks of spinal cord resulting in motor impairment, sensory disorder, urination/defecation function disturbance, and vomiting, and intractable nausea resulted from brain stem attacks. ( Jarius et al. 2012), (Uzawa, Mori, and Kuwabara 2014), (Kremer et al. 2014), (Schmidt et al. 2017) In addition, there are some other disturbing symptoms, for example, fatigue, pain, itch, depression, yawning and sleep disorders. ( Akaishi et al. 2015), (Elsone et al. 2013), (Lana-Peixoto et al. 2014), (Song et al. 2015) AQP4-Ab (aquaporin-4 antibody) in serum as a key marker, is found in around 80% of NMOSD cases (Tan et al. 2016).
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2020, Multiple Sclerosis and Related DisordersCitation Excerpt :The proper differentiation between MS and NMOSD is crucial for therapy planning. Several maintenance therapies approved for MS have been found ineffective or even aggravating the severity of clinical symptoms in NMOSD (Uzawa et al., 2014). Furthermore, recently published results of clinical trials have proved effectiveness of therapeutic approaches based on the pathomechanism of NMOSD such as intervention in the cascade of complement (Pittock et al., 2019)