Neuromyelitis optica: Concept, immunology and treatment

Journal of Clinical Neuroscience xxx (2013) xxx–xxx

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Review

Neuromyelitis optica: Concept, immunology and treatment Akiyuki Uzawa ⇑, Masahiro Mori, Satoshi Kuwabara Department of Neurology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8670, Japan

a r t i c l e

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Article history: Received 21 August 2012 Accepted 1 December 2012 Available online xxxx Keywords: Aquaporin-4 antibody Astrocyte Blood–brain barrier Glial fibrillary acidic protein Interleukin-6 Neuromyelitis optica

a b s t r a c t 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. Ó 2013 Elsevier Ltd. All rights reserved.

1. 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,1,6–10 immunological,11–14 and pathological profiles of NMO,15,16 and its response to treatment17–22 ⇑ Corresponding author. Tel.: +81 43 226 2129; fax: +81 43 226 2160. E-mail address: [email protected] (A. Uzawa).

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. 2. 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 coined the term ‘‘NMO’’ for this disease.25 Since then, the terms ‘‘NMO’’ and ‘‘Devic’s disease’’ have been used worldwide. Devic’s disease was initially treated as a monophasic disease and a rare variant of MS. However, later studies revealed that most patients have a relapsing–remitting course26 mimicking MS. There has been a long-standing controversy as to whether NMO is a variant of MS or not. 3. Epidemiology Fig. 1 shows MS (angle brackets) and NMO (grey rectangles) prevalence in the world. The global MS prevalence data were

0967-5868/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jocn.2012.12.022

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Table 1 Differences between neuromyelitis optica/neuromyelitis optica spectrum disorder and multiple sclerosis

Disease onset Female ratio Severity (visual and motor disability) Prognosis Anti-AQP4 antibody positivity Epidemiology CSF findings

Blood–brain barrier disruption Coexisting systemic autoimmune disease Brain MRI findings

Spinal MRI findings Treatment for preventing relapses

NMO/NMOSD

MS

Adults Very high (> 90%) Severe

Young adults High (75%) Mild-moderate

Relatively poor 70–90% Frequent in Asian OCB negative (<15%) IL-6 high GFAP high Severe Relatively frequent (SS, SLE, MG, etc.) Symmetric lesions Extensive lesions Cloud like enhancement Medullary periaqueductal lesion Bilateral hypothalamic lesion Callosal splenial lesion LETM (>3 vertebral segments) Prednisolone, rituximab, immunosuppressive drugs

Relatively good Negative Frequent in Caucasian OCB positive (>80%) IL-6 low GFAP low Moderate Relatively rare Periventricular lesions Ovoid lesions

Small lesions Interferon beta, fingolimod, rituximab, natalizumab

NMO = neuromyelitis optica, NMOSD = NMO spectrum disorder, MS = multiple sclerosis, AQP4 = aquaporin 4, CSF = cerebrospinal fluid, OCB = oligoclonal bands, IL6 = interleukin-6, GFAP = glial fibrillary acidic protein, SS = Sjögren syndrome, SLE = systemic lupus erythematosus, MG = myasthenia gravis, LETM = longitudinally extensive transverse myelitis.

Fig. 1. Map showing multiple sclerosis (angle brackets) and neuromyeltis optica (grey rectangles) prevalence (per 100,000) in the world.

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 is over 10 times higher than that in Asia. However, NMO frequency is more or less the same worldwide. Some population-based studies have reported an NMO prevalence of 0.5 per 100,000 in Cuba,27 1.0 in Mexico,28 2.0 in the UK,29 1.4–2.8 in the USA26 and 4.4 in Denmark.7 Although the detailed epidemiology of NMO in Japan has not been published, the ratio of (NMO and NMO spectrum disorders)/MS is 66/189 at our hospital. The estimated NMO prevalence in Japan

from our hospital data is 2.8 per 100,000. NMO frequency does not vary much worldwide but the NMO/MS ratio is markedly higher in Japan than that in Western countries. In other Asian cohorts, there was a high proportion of AQP4-antibody-positive patients among the local cohort of idiopathic demyelinating CNS diseases (40.3% in Chinese,30 39.3% in Thailand31 and 33.1% in Korean32) when compared with Caucasian cohorts. NMO is one of the major neuroimmunological diseases in Asia. Seasonal variation in relapse frequency is seen for MS with an apparent increase in summer and few presentations in winter, but is not observed for patients with NMO. Meteorological factors and viral infections may contribute to the seasonality of MS exacerbation, but do not affect NMO relapse frequency.33

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4. Neuromyelitis optica diagnosies 4.1. 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 contiguous spinal cord lesion extending over three or more vertebral segments; negative results for the diagnostic criteria for MS on brain MRI34 conducted at onset; and NMO-IgG (or anti-AQP4 antibody) seropositivity.1 We examined the clinical progression of a cohort of 43 Japanese patients with NMO who fulfilled the 2006 NMO diagnostic criteria (Table 3).6 At follow-up, 85.7% of NMO patients had LETM on spinal MRI, 58.1% were negative for Paty’s criteria on brain MRI,34 and 93.0% were positive for anti-AQP4 antibody. Most data agreed with the results of similar studies of Caucasian patients,8 except for antiAQP4 positivity data, which was higher in the Japanese cohort. The median intervals from disease onset until development of both optic neuritis and myelitis, presentation of LETM, and fulfilment of the 2006 NMO criteria were 17, 35, and 28 months, respectively. Brain MRI at onset that was negative for Paty’s criteria seemed to be very specific for the diagnosis of NMO.6 However, such brain MRI data were sometimes unavailable because MRI had not been conducted at disease onset or was not obtainable. For these patients, fulfilling the 2006 NMO criteria was somewhat difficult because they must have both LETM and positive anti-AQP4 antibody titres. Although early diagnosis and intensive immunosupressive treatments are considered to be necessary for NMO patients, the current 2006 NMO criteria1 may be insufficient for diagnosis of early-stage NMO.6 Considering the disease severity, this drawback highlights the importance of identifying new biomarkers for diagnosis of early-stage NMO. Cerebrospinal fluid (CSF) interleukin (IL)-611,12 and glial fibrillary acidic protein (GFAP)12,35 appear to be potential candidates of such markers. The development of new diagnostic methods for diagnosis of early-stage NMO is important, particularly for anti-AQP4 antibody-negative patients. 4.2. Detection methods for anti-aquaporin-4 antibody Measurement of anti-AQP4 antibody titres is crucial for differentiating NMO, MS, and other inflammatory diseases. Highly sensitive and specific AQP4 antibody assays are indispensable for early and accurate diagnosis of NMO and NMO spectrum disorders, and they clearly affect treatment strategies. Anti-AQP4 antibody titres have been examined using different techniques, including mouse-brain tissue-based indirect immunofluorescence,3 AQP4transfected cell-based,36 radioimmunoprecipitation,37 enzymelinked immunosorbent,38 and fluoroimmunoprecipitation assays.39 Specificities of all these assays are excellent; however, cell-based assays are more sensitive (73–77%) than the others (50–68%).40 We must be aware that 20–30% of NMO patients are anti-AQP4 antibody negative and alternative early diagnostic markers are required for such patients. 5. Clinical features 5.1. Clinical course and prognosis NMO has a generally poor prognosis and poor response to therapy compared with MS. Approximately 50% of patients have severe

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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 reported. After a median disease duration of 75 months, 18% had developed permanent bilateral visual disability (visual acuity in best eye worse than 6/36), 34% had permanent motor disability (unable to walk further than 100 m unaided), 23% had become wheelchair dependent and 9% had died. Age at disease onset and genetic factors are important in determining clinical outcomes in AQP4 disease.42 Other negative prognostic factors are a high relapse rate in the first year of the disease, severity of the first attack, poor recovery after the first attack, high CSF IL-6 levels (Fig. 2) and a high number of brain lesions.8,9,41,43 Myelitis is more frequently the initial inflammatory event of NMO in older patients, whereas optic neuritis is more frequent in younger patients.6,10 Although the reasons for these differences are not clear, it is important to consider NMO as a possible diagnosis for older patients with myelitis or young patients with optic neuritis. A significantly increased annual relapse rate and numerous patients with NMO spectrum disorder onset within 1 year after pregnancy have been reported. Thus, delivery adversely affects the course of NMO spectrum disorder. Therefore, maintaining or starting immunotherapy immediately after delivery is recommended.44 5.2. Immunological findings T cells may be implicated in NMO pathogenesis and the peripheral immune response, including breaking tolerance and anti-AQP4 antibody production. Cytokines play a fundamental role in the differentiation of naive T cells, while chemokines are involved in the regulation of immune responses by recruitment and activation of different cell types. B cells may be involved in NMO pathogenesis; B cell depletion caused by rituximab has been reported to prevent NMO relapse.22 It is necessary to establish whether the immunological changes occur inside or outside the CNS. 5.2.1. Serology Serum IL-6 levels are elevated in the relapse phase of NMO12 (Fig. 3a) and IL-6 enhances the survival of plasmablasts and their production of anti-AQP4 antibody.45 T helper cell (Th) 1 dominance of chemokine receptors on blood T cells and the correlation between CXCR3+ T cells (Th1 and cytotoxic T cell [Tc] 1) and disease activity have been confirmed by analysing chemokine receptors on peripheral blood lymphocytes during the relapse phase in MS patients. However, such deviations in the Th1/Th2 balance have not been observed in NMO patients.13 Although Th17 bias in peripheral blood in NMO has been reported, this bias is also observed in MS.46–48 Serum B cell-activating factor (BAFF) levels, a key molecule involved in the differentiation and survival of B cells, are significantly elevated in NMO.14 5.2.2. Cerebrospinal fluid A significant difference exists between some CSF cytokine/chemokine levels in NMO and MS patients,11,12 supporting the view that these two diseases have different background immunology and pathophysiology. In NMO, Th2-related cytokines/chemokines and Th17-related cytokines/chemokines such as IL-6 (Fig. 3b), IL8 and granulocyte colony-stimulating factor, are significantly upregulated, but elevation in IL-17 levels has not been confirmed.12 Among the significantly elevated CSF cytokines/chemokines, IL-6 has been shown to have a strong correlation with some NMO variables, such as CSF GFAP and CSF cell counts

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Table 2 Revised diagnostic criteria for neuromyelitis optica1 Optic neuritis Acute myelitis At least two of the following three supportive criteria: 1. Contiguous spinal cord MRI lesion extending over three vertebral segments 2. Onset brain MRI not meeting the diagnostic criteria for MS* 3. NMO-IgG/AQP4 antibody seropositive status MS = multiple sclerosis, NMO = neuromyelitis optica, IgG = immunoglobulin G, AQP4 = aquaporin 4. Brain MRI studies are evaluated using Paty’s criteria,34 which require presence of four or more white matter lesions or three lesions when one is periventricular.

*

gressive weakness with CNS inflammation, axonal degeneration and loss of myelin.49 Ex vivo experiments on the spinal cords of mice, with slices exposed to NMO-IgG and complement, have shown NMO-like lesions and severity of NMO lesions increased after IL-6 addition.50 These findings raise the idea that an IL-6 pathway blocker such as tocilizumab (an anti-IL-6 receptor monoclonal antibody) could be a promising new pharmacological treatment for NMO. CSF BAFF levels are enhanced in both NMO and MS patients but are higher in patients with NMO than in patients with MS,14 which may indicate that BAFF is produced in CNS lesions in both NMO and MS. 5.3. Blood–brain barrier disruption

(Fig. 3c).12 It is noteworthy that elevated CSF IL-6 levels have been found in 82.3% of NMO patients, but no such increase has been observed in MS patients (with the cut-off level defined as mean + 3 standard deviations of the IL-6 level for control patients).12 CSF IL-6 levels can also predict recovery from NMO relapses and the relapse-free proportion (Fig. 2).43 The CSF/serum ratio of IL-6 is remarkably elevated in NMO patients, suggesting that IL-6 is mainly produced in the CNS in NMO.12 However, it has not been established which cells produce IL-6 in the peripheral circulation and the CNS. These findings indicate that CSF IL-6 is involved in NMO pathogenesis and could be used as a biomarker to differentiate NMO from MS. Interestingly, another study revealed that IL-6 infusion into the spinal subarachnoid space of rats induced pro-

Anti-AQP4 antibody is over 500 times more concentrated in plasma than in CSF, which suggests that it is mainly produced peripherally and enters the CNS secondarily.51 This indicates that blood–brain barrier disruption is necessary for the anti-AQP4 antibody to enter the CNS; this process might be a part of NMO pathogenesis. We have reported severe blood–brain barrier disruption in NMO patients and shown that CSF levels of soluble intercellular adhesion molecule-1 and soluble vascular cell adhesion molecule1 are significantly increased in NMO. This increase is correlated with blood–brain barrier disruption markers such as CSF cell counts, albumin quotient and gadolinium-enhanced lesions on MRI (Fig. 4).52 Hence, monitoring adhesion molecule levels could

Table 3 The clinical course in Japanese neuromyelitis optica patients based on the 2006 neuromyelitis optica diagnostic criteria

NMO diagnosis Major criteria Supportive criteria

ON + myelitis LETM MRI negative for Paty’s criteria Anti-AQP4 Ab

Onset (%)

Onset–1 year (%)

Onset–2 years (%)

Onset–3 years (%)

Onset 5 years (%)

Onset 10 years (%)

Onset endpoint (%)

0.0 9.3 17.1

28.6 44.2 22.9

50.0 60.5 34.3

57.1 67.4 42.9

85.7 79.1 54.3

92.9 93.0 65.7

100.0 100.0 85.7

100.0

96.8

93.5

83.9

83.9

74.2

58.1

NA

NA

NA

NA

NA

NA

93.0

NMO = neuromyelitis optica, LETM = longitudinally extensive transverse myelitis, ON = optic neuritis, anti-AQP4 Ab = anti-aquaporin-4 antibody, NA = not available.

Fig. 2. Graphs showing cerebrospinal fluid (CSF) interleukin (IL)-6 levels associated with improvement in the Expanded Disability Status Scale scores (DEDSS) and relapsefree proportion in patients with neuromyelitis optica (NMO). (Left) NMO patients with low CSF IL-6 levels [NMO(IL-6)low] showed significantly larger DEDSS than those with high CSF IL-6 levels [NMO(IL-6)high]. (Right) Kaplan–Meier survival curve for relapse-free proportion after relapse in the NMO(IL-6)low and NMO(IL-6)high groups. The NMO(IL-6)low group showed higher relapse-free proportions than the NMO(IL-6)high group. (Reproduced with permission; Uzawa et al. CSF interleukin-6 level predicts recovery from neuromyelitis optica relapse. J Neurol Neurosurg Psychiatry 2012;83:339–40).

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Fig. 3. (a, b) Serum and cerebrospinal fluid (CSF) interleukin (IL)-6 levels in patients with neuromyelitis optica (NMO), multiple sclerosis (MS) and other neurological disorders (ONDs). Patients with NMO had higher serum and CSF IL-6 levels than those with MS or ONDs. (c) There was a significant correlation between the log CSF IL-6 levels and CSF glial fibrillary acidic protein (GFAP) levels and CSF cell counts in NMO. (Reproduced with permission; Uzawa et al. Cytokine and chemokine profiles in neuromyelitis optica: significance of interleukin-6. Mult Scler 2010;16:1443–52).

be useful for the evaluation of blood–brain barrier disruption and prediction of CNS inflammation severity in NMO. The factors involved in the blood–brain barrier pathway could be promising targets for new pharmacological treatments for NMO. However, the primary disruption of the blood–brain barrier in NMO may not be caused by the anti-AQP4 antibody itself for the following reasons: (1) astrocytes are the outer components of the blood–brain barrier and are difficult to access from the peripheral blood; (2) animal models of NMO have not been established by the administration of anti-AQP4 antibody into the peripheral circulation;53 and (3) there are reports of patients with anti-AQP4 antibody detected years before NMO onset.54,55 Interestingly, the sera from NMO patients are known to reduce the expression of tight junction proteins and disrupt the blood–brain barrier through upregulation of autocrine vascular endothelial growth factor in human brain microvascular endothelial cells.56 However, anti-AQP4 antibody itself cannot bind to brain microvascular endothelial cells, suggesting that autoantibodies other than AQP4 antibody may contribute to blood–brain barrier disruption in NMO. 5.4. Coexisting systemic autoimmune diseases NMO patients often have autoantibodies which are also detected in systemic lupus erythematosus (SLE), Sjögren syndrome (SS) and myasthenia gravis (MG). Pittock et al. reported that in 153 US patients with NMO spectrum disorders (78 patients had NMO and 75 had LETM), NMO-IgG was detected in 66.7%, antinuclear antibodies in 43.8%, and SSA antibodies in 15.7%.57 Antinu-

clear and SSA antibodies are more frequent in NMO-IgG seropositive patients than in NMO-IgG seronegative patients. NMO-IgG has not been detected in controls with SS or SLE but without optic neuritis or myelitis. These findings indicate that NMO patients are at risk of developing these autoimmune diseases. The evidence for the coexistence of NMO and MG has been accumulating and it may be more frequent than hitherto believed. In most reported patients, MG had preceded NMO onset by several years and had been in remission, and the patients with MG had undergone thymectomy before NMO onset.55,58,59 Therefore, NMO should be considered when myelitis is encountered in patients with MG. 6. Neuroimaging 6.1. 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 with narcolepsy-like hypersomnia64 are relatively specific to NMO. The most prominent and specific feature of NMO brain abnormalities shown on MRI is a ‘‘cloud-like enhancement’’ – multiple patchy enhancing lesions

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Fig. 4. Soluble intercellular adhesion molecule 1 (sICAM-1) and soluble vascular cell adhesion molecule 1 (sVCAM-1) levels in cerebrospinal fluid (CSF). (a, b) Patients with neuromyelitis optica (NMO) had significantly higher CSF sICAM-1 and sVCAM-1 levels than those with multiple sclerosis (MS) or other non-inflammatory neurological disorders (ONDs). (c, d) NMO patients with enhancing lesions on MRI had higher CSF sICAM-1 and sVCAM-1 levels than those without enhancing lesions. (Reproduced with permission; Uzawa et al. Markedly elevated soluble intercellular adhesion molecule 1, soluble vascular cell adhesion molecule 1 levels, and blood-brain barrier breakdown in neuromyelitis optica. Arch Neurol 2011;68:913–7).

with blurred margin – found in 90% of the patients with positive contrast enhancement, and possibly caused by blood–brain barrier disruption.60 Although callosal lesions are common in NMO and MS patients, typical callosal abnormalities found in NMO are splenial lesions, diffusely spreading corpus callosum lesions, edematous lesions, and heterogeneous lesions.65,66 These features are useful for distinguishing NMO from MS.

6.2. Spinal lesion Myelitis in NMO is often transverse and extends over three or more vertebral segments, as shown on MRI (Fig. 5).1,36 Such longitudinally extensive spinal cord lesions are extremely rare in MS.1

The spinal lesions in NMO show swelling and are partly gadolinium-enhanced in the acute phase. Central grey matter involvement, cord atrophy, and cavity formation, which are not typical for MS, are commonly seen in chronic-stage NMO.67

6.3. Optic nerve(s) lesion Optic neuritis in NMO is often severe and causes permanent blindness.1,10,36 MRI has revealed a higher likelihood of NMO-related optic neuritis affecting posterior parts of the optic nerve, including the chiasm, and a higher frequency of simultaneous bilateral disease than MS-related optic neuritis.68 Recent reports have proven that retinal nerve fibre layer thickness measured by

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Fig. 5. Characteristic features of neuromyelitis optica (NMO) demonstrated by MRI. (a) Axial gadolinium-enhanced T1-weighted brain MRI showing cloud-like enhancement, (b) axial fluid-attenuated inversion recovery (FLAIR) brain MRI showing extensive periventricular brain lesions, (c) sagittal FLAIR brain MRI showing diffuse and heterogeneous hyperintense lesions with cystic lesions in the genu and splenium of the corpus callosum, (d) sagittal T2-weighted spinal MRI showing spinal lesion with swelling and extending over three vertebral segments, and (e) axial T2-weighted spinal MRI showing centrally located, central grey matter spinal lesion, (f) which is partly gadolinium-enhanced on axial T1-weighted images with contrast.

Fig. 6. Kaplan–Meier survival curve for relapse-free proportion in patients with neuromyelitis optica (NMO) and multiple sclerosis (MS) during pre- and post-interferon beta (IFNB)-1b treatment. There was no increase in relapse-free proportion following IFNB-1b treatment in NMO patients, whereas MS patients showed significantly increased relapse-free proportion after treatment. (Reproduced with permission; Uzawa et al. Different responses to interferon beta-1b treatment in patients with neuromyelitis optica and multiple sclerosis. Eur J Neurol 2010;17:672–6). N.S. = not significant.

optical coherence tomography is a good surrogate marker of neural damage caused by NMO.69 7. 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 immunoreactivity to AQP415,16 and GFAP,15 especially in the perivascular regions with the deposition of immunoglobulins and activated complements, and a relative preservation of the staining of myelin

basic protein in acute NMO lesions. Compared with the losses of GFAP, the areas with the loss of myelin basic protein are much smaller.15 These characteristic pathological features have not been seen in MS and suggest that massive astrocytic damage associated with humoral immunity may be of primary importance in the development of NMO lesions and that the myelin damage may be a secondary phenomenon. 8. 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

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Fig. 7. Proposed diagnostic scheme for neuromyelitis optica (NMO) and related disorders. Patients with central nervous system inflammation who fulfill NMO diagnostic criteria are classified as NMO, those with anti-aquaporin 4 (AQP4) antibody positivity but lacking other criteria as NMO spectrum disorders (NMOSD) and those presenting some of the characteristic features of NMO as ‘‘high-risk NMO’’. SLE = systemic lupus erythematosus, SS = Sjögren syndrome, MG = myasthenia gravis, CSF = cerebrospinal fluid.

include low-dose oral corticosteroids, azathioprine, mitoxantrone, cyclophosphamide, mycophenolate mofetil18–21 and rituximab (a CD20-monoclonal antibody to deplete B cells).22 Interferon beta, the most commonly used therapy for MS, appears to be ineffective in preventing relapses in NMO patients (Fig. 6)17 and is generally harmful in NMO. Moreover, natalizumab and fingolimod, which are effective in preventing MS relapses, can exacerbate NMO.71,72 Novel treatments with eculizumab (anti-complement-monoclonal antibody),73 tocilizumab (anti-IL-6 receptor monoclonal antibody),74 aquaporumab (high-affinity monoclonal antibody against anti-AQP4 antibody)75 and sivelestat (neutrophil elastase inhibitor)76 might be useful to suppress relapses in NMO patients who cannot tolerate standard immunosuppression therapy. We propose a diagnostic scheme for NMO, NMO spectrum disorders and high-risk NMO patients, as shown in Fig. 7. If some of the criteria for ‘‘high-risk NMO’’ are fulfilled, we should monitor the patients carefully because they are likely to develop NMO. Importantly, we should not hesitate to use imuunosuppressive treatment for patients with NMO and NMO spectrum disorders

because early intensive treatment is important to prevent severe relapses of the disease.

9. 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 early-stage NMO are necessary, especially for anti-AQP4 antibody-negative NMO patients. Recently, some unique features of NMO have been reported; immunological research has revealed the importance of IL-6 in NMO pathogenesis, neuroimaging studies have delivered some specific features of NMO, and pathological and experimental

Please cite this article in press as: Uzawa A et al. Neuromyelitis optica: Concept, immunology and treatment. J Clin Neurosci (2013), http://dx.doi.org/ 10.1016/j.jocn.2012.12.022

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Please cite this article in press as: Uzawa A et al. Neuromyelitis optica: Concept, immunology and treatment. J Clin Neurosci (2013), http://dx.doi.org/ 10.1016/j.jocn.2012.12.022