Why is this important to me?
Demyelinating diseases, which include MS and neuromyelitis optica spectrum disorder (NMOSD), involve inflammation of parts of the central nervous system (brain and spinal cord) and destruction of myelin, the fat-like substance that wraps around and protects nerve fibers. Nerve fibers that have lost their myelin do not function properly, leading to symptoms in patients. Distinguishing MS from NMOSD is important because treatments are not the same. Ethnic differences are seen in the prevalence (the proportion of a population with a disease), genetics, and clinical features of demyelinating diseases.
What is the objective of this study?
Distinguishing MS from NMOSD
Although MS and NMOSD can be difficult to distinguish, they are different and have different responses to treatment. For example, NMOSD primarily affects the optic nerves and spinal cord, whereas MS can affect these as well as other parts of the central nervous system. Regarding treatments, interferon-β, natalizumab, and fingolimod are effective if you have MS but are ineffective or harmful if you have NMOSD. Thus, distinguishing one from the other is important. One way to distinguish MS from NMOSD is by testing for a marker called AQP-4. AQP-4 is detected if you have NMOSD but not MS. The test is not perfect, as up to 40% of people with NMOSD test negative for AQP-4. Similar numbers of Japanese patients and North American patients with NMOSD test positive for AQP-4.
MS is the most common chronic central nervous system disease that causes disability in young people in Western countries. The prevalence of MS varies widely across the globe and is less common in Asian countries than in Western countries. Primary progressive MS is also less common in Asian populations. However, the prevalence of MS in Asian countries is increasing, especially in Japan, which has the highest prevalence among East Asian countries. NMOSD is similarly common among different ethnic groups.
No single gene causes MS, but some genetic variants are associated with an increased risk for MS. The contributions of genetic variants that increase the risk of MS in European populations are largely unexplored in Asian populations. Genetic factors likely influence the risk and course of NMOSD as well. One study showed that compared to Japanese patients, patients with NMOSD from the United Kingdom had worse disease, worse attacks, and more relapses. The genetics of NMOSD are poorly understood, and studies with large groups of people from various ethnic populations will be needed.
After excluding NMOSD, the features of MS including age of onset, female:male ratio, response to interferon-β, clinical outcome, and imaging results were shown to be similar in Caucasian and Korean populations. However, severe disability and progressive MS are less common in Asian populations than in Western populations, hinting at important genetic and/or environmental factors that influence clinical outcomes.
How did the authors study this issue?
In this review, the authors discussed differences in NMOSD and MS between Asian and Western populations in terms of epidemiology, genetics, and clinical features.
Demyelinating Diseases in Asia
Current Opinion in Neurology
Hirofumi Ochi and Kazuo Fuijhara
Inflammatory demyelinating diseases (IDDs) of the central nervous system (CNS) comprise a heterogeneous group of disorders. Multiple sclerosis (MS) is a major inflammatory disease of the CNS in which immune reaction toward myelin or oligodendrocyte plays a crucial pathogenetic role . Although MS is the most common chronic disabling disease of the CNS in young adults in Western countries, it has been rare in Asia . Additionally, severe and selective involvement of optic nerve and spinal cord has long been recognized as a major clinical phonotype in Asian population, and this type of ‘MS’ has been referred to as opticospinal MS (OSMS) . OSMS accounted for 15–56% of ‘MS’ cases in Asian countries [3,4]. Neuromyelitis optica (NMO) is a disease characterized by severe optic neuritis and transverse myelitis in Western countries and often follows a relapsing course. In addition to the predilection for optic nerve and spinal cord, OSMS and NMO have similar features such as female preponderance, higher age at onset than Caucasian MS, severe functional disability, polymorphonuclear pleocytosis and absence of oligoclonal immunoglobulin G (IgG) bands (OCB) in the cerebrospinal fluid (CSF) . Thus, there has been a controversy as to whether OSMS is the same entity as NMO described in Western countries, and whether OSMS/NMO is an MS variant or a distinct disease.
However, the discovery of highly NMO-specific autoantibody against aquaporin-4 (AQP4), the most abundant water channel in the CNS, especially in endfeet of astrocytes, revolutionized our understanding of NMO [5,6]. This autoantibody is the first disease-specific diagnostic biomarker in IDD of the CNS and is detected in NMO but not in prototypic MS . Moreover, the pathogenic role of this antibody in NMO has been elucidated [7,8], and NMO is currently recognized as an autoimmune astrocytopathic disease. After the discovery of AQP4-antibody, clinical, pathological, MRI, immunological, and other laboratory features of NMO distinct from MS have been identified [9**]. AQP4-antibody also broadened the spectrum of NMO to include limited forms of the disease termed ‘NMO spectrum disorder (NMOSD)’ . Moreover, AQP4-antibody has a significant therapeutic implication because such disease-modifying drugs (DMDs) for MS as interferon (IFN)-b, natalizumab, and fingolimod are ineffective or harmful in NMO/NMOSD . Thus, the detection of AQP4- antibody is crucial in differentiating NMO/NMOSD from MS and promptly initiating immunosuppressive therapy for NMO/NMOSD. As for whether OSMS is the same entity as NMO, AQP4-antibody seropositivity in Japanese OSMS (58%) did not differ significantly from that of North American patients with NMO (73%) . Given the clinical similarities between the two conditions, OSMS is basically the same disease entity as NMO. However, whether all OSMS cases are identical to NMO is still debatable. Because both optic neuritis and myelitis are common manifestations of MS as well , OSMS is actually an admixture of MS and NMO, and some OSMS patients without AQP4-antibody should be classified into MS. In addition, NMOSD with brain lesions may be misdiagnosed with MS.
Although the detection of AQP4-antibody has facilitated the early distinction between NMO/NMOSD and MS, a major concern is that up to 40% of patients with NMO/NMOSD remain seronegative for AQP4-antibody despite repeated tests with highly sensitive cell-based assays [13,14**,15,16]. Approximately 90% of NMO patients and over 50% of NMOSD patients are seropositive for AQP4-antibody [17,18]. The definition of seronegative NMO depends largely on assay sensitivity and patient selection; seronegative NMO is closer to seropositive NMO than to MS and is incorporated into the new diagnostic criteria for NMOSD proposed by the International Panel on NMO Diagnosis [19**]. However, recent studies have revealed the clinical differences between seronegative and seropositive NMO [13,20,21]. In those studies, seronegative NMO was characterized by no female preponderance, frequent monophasic course, frequent simultaneous occurrence of optic neuritis and myelitis at onset, and less frequent severe visual impairment as compared with seropositive cases. As seronegative NMO may be heterogeneous, sorting out its heterogeneity is likely to have clinical implications. More recently, autoantibody against myelin oligodendrocyte glycoprotein (MOG) was reported in the sera of adult patients with NMO/NMOSD phenotype [22,23]. Compared with NMO/NMOSD with AQP4-antibody, MOG-antibody-seropositive NMO/NMOSD have such clinical features as lack of female preponderance, fewer relapses, and better outcome [24*,25*]. Since the ratios of NMO/NMOSD to MS are much higher in Asia than in Western countries, NMO/NMOSD is a major diagnostic challenge in IDD of the CNS in this region. The discovery of these two autoantibodies has surely opened a new avenue of research for the pathogeneses of IDD of the CNS and has essential clinical implications.
This article will review the evolving epidemiological, genetic, and clinical research on IDD of the CNS in Asia.
The prevalence of MS varies considerably around the world. Although Asia has been a low-risk area of MS, MS prevalence in this region appears to be highly variable. According to the Atlas of MS 2013  launched by the Multiple Sclerosis International Federation, MS prevalence is the highest in Middle East and the lowest in East Asia. Middle Eastern countries are categorized as a low to moderate risk area; however, recent epidemiological surveys indicate a moderate to high prevalence in these countries [26* ]. In addition, MS prevalence has increased significantly in recent years in East Asian countries as well, in particular in Japan. Previous studies from Hong Kong showed that MS prevalence was less than 1/100,000 before 2000; however, a more recent survey revealed a slightly higher prevalence of 1.38/100 000 in Shanghai in 2004–2005 . Similarly, MS prevalence in Taiwan increased from 1.9/100,000 in 1995–2002 to 2.96/100,000 in 2005 . In Korea, studies conducted before 1990 showed MS prevalence of less than 2.5/100,000, while the nation-wide survey in 2005 demonstrated an increase in the prevalence (3.6/100 000) . Japan has the highest MS prevalence among East Asian countries, wherein MS patients have dramatically increased in the last decades. Early epidemiological surveys in Japan done before the early 1980s showed MS prevalence of 0.7–4.0/ 100,000 with a North-South gradient . According to the nation-wide survey in 2004, the estimated crude prevalence was 7.7/100,000; however, this survey was conducted without regard for NMO. Thus, given the NMO prevalence in Japan, it was probably less than 5/100 000 at that time. The number of patients with MS and NMO listed in the Japanese national registry has increased year by year and surpassed 19,000 in 2014 (Fig. 1). The first-ever nation-wide survey of NMO/NMOSD was conducted in Japan in 2012–2013, and the estimated number of NMO/NMOSD patients was 4370 . Taken together, MS prevalence in Japan has dramatically increased in the past decades, and it would be estimated at approximately 10/100,000 at present. Although both genetic and environmental factors contribute to the pathogenesis of MS, further studies are needed to clarify the cause for the remarkable increase in Japanese MS prevalence.
Epidemiological data on NMO remains limited. Although NMO occurs worldwide, it has been suggested that NMO has a predilection for nonwhite. In Asian countries, NMO prevalence was 2.6/100,000 in South India, and 3.65/100,000 in Japan [30,31]. Population-based studies of NMO showed the prevalence rates ranging from 0.52/ 100,000 in Cuba to 4.4/100,000 in Southern Denmark [32**]. Interestingly, the Cuban study showed lack of significant difference in NMO prevalence between white and non-white. Collectively, there seems to be no major difference in NMO prevalence in various ethnic groups. However, larger population-based studies are needed to clarify the role of ethnicity in NMO. On the other hand, the proportion of NMO among IDDs of the CNS varies largely in different geographic regions: 1.2% in Italy, 1–2% in the USA, 13.7% in India, and 39.3% in Thailand [32**]. In a reflection of the lower MS prevalence in Asia, the ratios of NMO/NMOSD to MS in Asia are much higher than those in Western countries. In Malaysia, the ratios were 41% in Malays, 63% in Chinese, and 20% in Indians, indicating the influence of ethnic backgrounds on the ratio of NMO/NMOSD to MS .
The fact that familial occurrence of MS is highly variable in different geographic locations and ethnicities indicates that both genetic and environmental factors play a significant role in the cause of MS . Familial MS is estimated at 15–20% in Caucasian MS, but is much lower in Asia (1.1% in Japan, 5% in Malaysia) [33,34]. Extensive evidence confirms the genetic contribution to the susceptibility to MS, and a remarkable progress has been made by the large-scale genome-wide association studies (GWAS) of MS in European descent. GWAS demonstrated that the main susceptibility signal maps to the human leukocyte antigen (HLA)- DRB1 gene in the class II region of the major histocompatibility complex (MHC) and identified more than 100 additional common genetic variations outside the MHC region . However, these European non-MHC MS susceptibility variants are largely unexplored in Asian populations. As for the MHC, HLA-DRB1 1501 has the strongest association with MS in northern Han Chinese population as well as in Caucasian populations [36,37]. On the other hand, DRB1 0405 is the top MS risk allele in Japanese, whereas DRB1 1501 is also found to be associated with MS susceptibility in Japanese patients without DRB1 0405 [38,39]. HLA allele is also associated with a distinct clinical phenotype in Japanese population [38,40* ]. DRB1 0405-positive patients showed a younger onset age, fewer brain lesions, less frequent CSF abnormalities (OCB positivity and/ or increased IgG index), and a milder clinical course than patients without this allele. On the contrary, DRB1 1501-positive patients often had brain lesions fulfilling the Barkhof criteria and the CSF abnormalities, which are similar to DRB1 1501-positive Caucasian MS.
Epidemiological studies have suggested different proportions of NMO in IDD of the CNS in various ethnic groups. However, the genetic basis for this difference is largely unknown. The early Japanese study found the association between HLA-DPB1 0501 and OSMS . Even after the discovery of AQP4-antibody, this allele was associated with Japanese NMO . This result was replicated in southern Han Chinese . In contrast to Asian population, HLA-DRB1 03 allele was shown to be associated with NMO in French Caucasian , French Afro-Caribbean , and Brazilian Mulatto . Non-HLA single nucleotide polymorphisms (SNPs) in NMO have been studied less, but GWAS of Korean NMO showed that a common promoter SNP in CYP7A1 has a protective effect against NMO , which was replicated in Han Chinese patients . Collectively, the genetics of NMO is not well understood, and studies in large cohorts in various ethnic groups are required to clarify how the genetic factors influence NMO.
CLINICAL AND LABORATORY FEATURES
Before the discovery of AQP4-antibody and wide recognition of NMO/NMOSD, clinical features of ‘MS’ in Asia had been considered to be different from those in Western MS. However, those studies on ‘MS’ were conducted without regard to NMO/ NMOSD. Considering the high ratios of NMO/ NMOSD to MS in Asia, it is critical to exclude NMO/NMOSD to clarify the clinical features of MS in this region. Recently, the clinical profile of Korean MS patients was reported to be essentially similar to that in Caucasian population after the careful exclusion of NMO/NMOSD, including the age of onset, the female-to-male ratio, MRI features, therapeutic response to IFN-b, and the clinical outcome . The MRI features are comparable to reports from Taiwan and Malaysia that showed that the type and distribution of brain lesions are very much similar to those in Western MS [33,50]. In a subsequent retrospective study, the investigators demonstrated that both the 2005 and 2010 McDonald criteria are useful to predict conversion to clinically definite MS in Korean patients with clinically isolated syndrome (CIS) with sensitivity (71.4 and 75.5%, respectively) and specificity (57.8 and 60%, respectively) which are similar to those in Caucasian patients [51*]. In contrast, another study from Taiwan showed the 53% sensitivity of 2005 McDonald criteria, which was slightly less sensitive as compared with Caucasian population (64–75%) because of relatively few brain plaques . In addition, a comparative study on disease severity in the United Kingdom and Japan suggested that Japanese MS patients might have a milder disease as compared with those in the United Kingdom even if taking the use of DMDs into consideration [52*]. As for the clinical course, primary progressive MS is more common in Western countries (5.5–20%)  as compared with Asian countries (3% in Japan, 3% in Korea, 2.9% in Malaysia, and 5.3% in India) [33,49,52*,54].
A comparative study between the United Kingdom and Japan showed that genetic factors are likely to influence the course and prognosis of AQP4-antibody-seropositive patients with NMO/ NMOSD . Patients from the United Kingdom cohort had a more severe disease, more severe onset attacks, and a higher mean annualized relapse rate despite earlier immunosuppressive therapy, as compared with those from the Japanese cohort. Among the United Kingdom cohort, AfroCaribbean patients had a significantly younger onset age and a greater likelihood of developing visual disability than Caucasian or Japanese patients. Prospective studies are needed to elucidate how genetic and environmental factors contribute to the clinical features and outcome in MS and NMO/NMOSD.
Antibody against conformationally intact MOG detected in human MOG-transfected cell-based assays was positive in about one-third of pediatric patients with IDD of the CNS such as CIS, MS, and acute disseminated encephalomyelitis, but rarely detectable in adult patients . Two studies from Austria and United Kingdom showed that such a MOG-antibody was detected in some patients without AQP4-antibody manifesting clinical and neuroimaging features of NMO/ NMOSD [22,23]. Shortly thereafter, several large-scale studies demonstrated the presence of the conformation-sensitive MOG-antibody in a reaction of patients with NMO/NMOSD phenotype [24*,25* ,57–61]. Despite different ethnic groups studied in these reports, MOG-antibody-seropositive patients had similar clinical features, including no female preponderance, fewer relapses, and better outcome as compared with those with AQP4- antibody [23,24*,25*]. Additionally, other features, such as frequent monophasic course, bilateral simultaneous optic neuritis, concurrent development of optic neuritis and transverse myelitis, and spinal cord lesions localized in the lower thoracic cord or conus medullaris, were also illustrated in MOG-antibody-seropositive NMO/ NMOSD patients as compared with AQP4-antibody-seropositive ones [57–61]. Interestingly, some NMO cases originally described by Gault also exhibited these features . Optic neuritis is a common manifestation in both AQP4-antibody-seropositive and MOG-antibody-seropositive patients with NMO/NMOSD. MRI and optical coherence tomographic differences in the two conditions have been recently reported. MOGantibody-seropositive optic neuritis, as compared with AQP4-antibody-seropositive optic neuritis, more frequently exhibited severe optic nerve swelling with perineural enhancement [63* ,64*] but less severe retinal neuronal loss evaluated by optical coherence tomography [63*]. MOG-antibody-seropositive optic neuritis affected multiple segments of the optic nerve but spared the optic chiasm, whereas chiasmal involvement was frequent in AQP4-antibody-positive optic neuritis [59,63*]. Collectively, MOG-antibody may define a new nosological entity in IDD of the CNS.
Prevalence of MS has been low but is increasing in Asia. The proportions of NMO/NMOSD in IDD of the CNS in Asia are much higher than those in Western countries, and it is critically important to distinguish NMO/NMOSD from MS by testing AQP4-antibody. A fraction of AQP4 antibody seronegative NMO/NMOSD patients are positive for MOG-antibody and they have some unique features. The clinical features of Asian MS seem to be essentially similar to Western MS after careful exclusion of NMO/NMOSD, although severe disability and progressive MS may be less common in Asia than in the West, suggesting genetic and/or environmental differences.
Financial support and sponsorship
This work was supported in part by the Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Technology of Japan and the Grants-in-Aid for Scientific Research from the Ministry of Health, Welfare and Labor of Japan.
Conflicts of interest
H.O. has no conflicts of interest. K.F. serves on scientific advisory boards for Bayer Schering Pharma, Biogen Idec, Mitsubishi Tanabe Pharma Corporation, Novartis Pharma, Chugai Pharmaceutical, Ono Pharmaceutical, Nihon Pharmaceutical, Merck Serono, Alexion Pharmaceuticals, Medimmune, and Medical Review; has received funding for travel and speaker honoraria from Bayer Schering Pharma, Biogen Idec, Eisai Inc., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma, Astellas Pharma Inc., Takeda Pharmaceutical Company Limited, Asahi Kasei Medical Co., Daiichi Sankyo, and Nihon Pharmaceutical; serves as an editorial board member of Clinical and Experimental Neuroimmunology (2009–present) and an advisory board member of Sri Lanka Journal of Neurology; has received research support from Bayer Schering Pharma, Biogen Idec Japan, Asahi Kasei Medical, The Chemo-Sero-Therapeutic Research Institute, Teva Pharmaceutical, Mitsubishi Tanabe Pharma, Teijin Pharma, Chugai Pharmaceutical, Ono Pharmaceutical, Nihon Pharmaceutical, and Genzyme Japan; is funded by the Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Technology of Japan and by the Grants-in-Aid for Scientific Research from the Ministry of Health, Welfare and Labor of Japan.
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64. * Kim SM, Woodhall MR, Kim JS, et al. Antibodies to MOG in adults with inflammatory demyelinating disease of the CNS. Neurol Neuroimmunol Neuroinflamm 2015; 2:e163. This study shows myelin oligodendrocyte glycoprotein antibody-seropositive patients have a disease distinct from multiple sclerosis and aquaporin-4 antibody-seropositive patients. Isolated optic neuritis is the most common symptomatic clinical manifestation in myelin oligodendrocyte glycoprotein antibodyseropositive patients and one-third of this group shows perineural enhancement that extends around the soft tissue of the optic nerve.