Review
Neuromyelitis optica: Concept, immunology and treatment

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Abstract

Neuromyelitis optica (NMO) is an inflammatory disorder of the central nervous system (CNS) that predominantly affects the optic nerves and spinal cord. Previously, it has been considered to be a severe variant of multiple sclerosis (MS), especially common in Asia. However, the finding that most NMO patients have autoantibodies against aquaporin-4 (AQP4) has improved our knowledge of its pathogenesis and led to the concept that NMO is a disease distinct from MS. Although the 2006 NMO revised criteria are useful for diagnosing NMO, their usefulness in the diagnosis of early-stage NMO is limited. Hence, there is an urgent need for new and more precise diagnostic methods. Interleukin-6 may play important roles in NMO pathogenesis, as it is involved in the survival of plasmablasts that produce anti-AQP4 antibody in the peripheral circulation and in the enhancement of inflammation in the CNS. Severe blood–brain barrier disruption in NMO allows the anti-AQP4 antibody to access the astrocytic endfeet. The anti-AQP4 antibody causes astrocytic damage through complement activation. Thus, NMO is an astrocytopathic, rather than a demyelinating, disease. Some brain lesions specific to NMO have recently been reported. Significant advances in the understanding of NMO pathogenesis are beginning to improve existing treatment strategies and will help develop new treatments. This review focuses on the current advances in NMO research and its clinical characteristics, immunological findings, neuroimaging and pathophysiology.

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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