Heterogeneity and continuum of multiple sclerosis phenotypes in Japanese according to the results of the fourth nationwide survey

doi:10.1016/j.jns.2009.01.008

Journal of the Neurological Sciences

Volume 280, Issues 1–2, 15 May 2009, Pages 22-28

https://doi.org/10.1016/j.jns.2009.01.008 Get rights and content

Abstract

There are two distinct phenotypes of multiple sclerosis (MS) in Asians, optic-spinal MS (OSMS) and conventional MS (CMS). In 2004, we performed the fourth nationwide epidemiological survey of MS. The epidemiological features were reported elsewhere; here we report the characteristic features of patients with each MS phenotype, classified according to the clinically estimated sites of involvement and MRI findings. Among 1493 MS patients collated, 57.7% were classified as having CMS and 16.5% were classified as having OSMS. Based on MRI findings, MS patients were further subdivided into those with OSMS with or without longitudinally extensive spinal cord lesions (LESCLs) and those with CMS with or without LESCLs. Although disease duration did not differ significantly among the four groups, EDSS scores were significantly higher in patients with LESCLs than in those without LESCLs, irrespective of OSMS or CMS phenotype. Similar trends were found for the frequencies of bilateral visual loss, transverse myelitis, and marked CSF pleocytosis and neutrophilia. Increased IgG index, brain lesions fulfilling the Barkhof criteria and secondary progression were more commonly found in CMS patients than in OSMS patients, while negative brain MRIs were more commonly encountered in OSMS patients than CMS patients, irrespective of the presence of LESCLs. These findings suggest that demographic features not only vary based on CMS or OSMS phenotype, but also with the presence or absence of LESCLs, and that nonetheless, these four phenotypes constitute a continuum.

Introduction

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). MS is rare in Asians, but when it appears, involvement of the optic nerve and spinal cord is destructive [1]. There are two distinct subtypes of MS in Asians: the optic-spinal form (OSMS), which shows selective involvement of the optic nerve and spinal cord, and the conventional form (CMS), which affects multiple sites of the central nervous system (CNS), including the cerebrum and cerebellum [2]. The two subtypes have distinct clinical and neuroimaging features. OSMS is characterized by a higher age at onset, greater female preponderance and higher Kurtzke's Expanded Disability Status Scale (EDSS) score [3] compared with CMS [1], [2]. Longitudinally extensive spinal cord lesions (LESCLs) extending over three or more vertebral segments are more commonly found in patients with OSMS than CMS patients [1]. However, reflecting the pronounced spinal cord damage seen in Asians, one-fourth of CMS patients also have such LESCLs [4], [5].

In Japan, nationwide surveys of MS were conducted in 1972, 1982, 1989 and 2004 using essentially identical criteria [6], [7], [8]. In the fourth survey, we disclosed a four-fold increase in the estimated number of clinically definite MS patients (9900; crude MS prevalence, 7.7/100,000) in 2003 compared with 1972, and a shift in the peak age at onset from early 30 s in 1989 to early 20 s in 2003 [8], suggesting an increase in susceptibility to this disease among the younger generation. In this study, a successive decrease in optic-spinal involvement in clinically definite MS patients was also revealed, while the absolute numbers of CMS patients and those with MS-like brain lesions fulfilling the Barkhof criteria were found to increase rapidly with advancing year of birth. Also, the frequency of LESCLs was found to be significantly higher in OSMS patients than in CMS patients in this nationwide survey.

We recently reported that there are distinct subtypes of MS according to clinical and MRI findings using our institutional series of MS patients [9], [10]. Therefore, in the present study, we aimed to clarify the characteristic features of each MS phenotype classified according to the clinically estimated sites of involvement and MRI findings unique to Asian MS patients, such as the presence or absence of LESCLs, using collated MS cases from the fourth nationwide survey of MS in Japan.

Section snippets

Survey procedures

The fourth nationwide survey of MS was conducted by the Research Committees of Neuroimmunological Diseases and of Epidemiology of Intractable Diseases, sponsored by the Ministry of Health, Labor and Welfare, Japan. The study was approved by the Kyushu University Ethics Committee. The survey was undertaken in two steps: first, a preliminary survey was undertaken to ascertain the approximate number of MS patients in Japan, and second, a survey was conducted using a questionnaire sheet for each

Demographic features of each MS subtype

Based on the MRI findings, MS patients were subdivided into those with OSMS with or without LESCLs and those with CMS with or without LESCLs (Table 1). The proportion of females was significantly greater among OSMS or CMS patients with LESCLs than among CMS patients without LESCLs (P^corr < 0.05 in OSMS with LESCLs and P^corr < 0.05 in CMS with LESCLs). Age at onset was significantly higher in OSMS patients with LESCLs than in other patient groups (P^corr < 0.05). The peak age at onset was early 20 s

Discussion

In the present study, using MS cases collated in the fourth nationwide survey in Japan, we disclose that distinct demographic features vary not only with clinical phenotype, such as OSMS and CMS, but also with the characteristic MRI findings, such as LESCLs and Barkhof brain lesions.

The present study had some limitations, primarily because the response rate in the second survey was not high. Concerning the relatively low response rate to this type of nationwide epidemiological survey in Japan,

Acknowledgments

This work was supported in part by grants from the Research Committees of Neuroimmunological Diseases and of Epidemiology of Intractable Diseases, the Ministry of Health, Labour and Welfare, Japan.

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We retrospectively enrolled RRMS patients who initiated oral DMDs (fingolimod or dimethyl fumarate) at our hospital between January 2012 and December 2019. Clinical data and smoking status at oral DMD initiation were collected up to December 2020. We conducted survival analyses for relapse and any disease activity, defined as relapse or MRI disease activity, among patients with distinct smoking statuses.
We enrolled 103 RRMS patients under oral DMDs including 19 (18.4%) current smokers at baseline. Proportions of relapses and any disease activity during follow-up were higher in current smokers (relapse: p = 0.040, any disease activity: p = 0.004) and time from initiating oral DMDs to relapse was shorter in current smokers (log-rank test: p = 0.011; Cox proportional hazard analysis: hazard ratio (HR) 2.72 [95% confidence interval (CI) 1.22–6.09], p = 0.015) than in non-smokers. Time from initiating oral DMDs to any disease activity was also shorter in current smokers (log-rank test: p = 0.016; Cox proportional hazard analysis: HR 2.18 [95% CI 1.14–4.19], p = 0.019) than in non-smokers. The survival curves for relapse and any disease activity were not different between the former smoker and never-smoker groups. Multivariate survival analysis showed current smoking was an independent risk factor for relapse or any disease activity after adjusting for covariates (relapse: HR 2.54 [95% CI 1.06–6.10], p = 0.037; any disease activity: HR 3.47 [95% CI 1.27–9.50], p = 0.015).
Smoking was a risk factor for disease activity in RRMS patients under oral DMD treatment. RRMS patients should be advised to stop smoking even after the initiation of DMDs.
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NMOSD was clearly delineated from MS on the bases of clinico-radiological criteria in 1999, and the availability of antibodies against AQP4 and MOG strengthened this distinction. Although transitional patients sharing a continuum of NMOSD and MS features have been described (Ishizu et al., 2009), MS-like NMOSD remains highly uncommon in patients with non-Asian ancestry. In contrast, 26.1% of Chinese NMOSD displayed short segment myelitis at onset, which often delayed AQP4-Ab ordering and final NMOSD diagnosis (Fang, W. et al., 2020), as in our patient 1.
Initial clinical manifestations of NMOSD may rarely overlap with MS. Fingolimod may trigger severe attacks in patients with NMOSD previously misdiagnosed as MS. These cases are rare and their pathophysiology remains elusive.
We recruited all NMOSD patients treated by fingolimod in a single-center cohort of Afro-Caribbean neuro-inflammatory patients in Fort-de-France (French West Indies). Six patients were collected from the literature.
Among 622 patients followed locally for MS, 101 received fingolimod and two suffered severe attacks revealing a typical NMOSD presentation. These two patients were found to have AQP4-IgG. The risk of misdiagnosed NMOSD in MS in our high-risk Afro-Caribbean patients was estimated to be 1.9% (0 to 4.7%). Among the whole cohort, relapses occurred within a month after fingolimod initiation in five patients. All attacks were severe and contrasted with previously benign attacks, suggesting a shift to a more severe disorder. An unusual finding in these patients was large brain lesions.
AQP4-IgG should be obtained before initiation of fingolimod in high-risk patients, especially in those from areas of high NMOSD prevalence.
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When cases are identified, Matsuoka and colleagues (2008) showed that PP patients had higher EDSS scores compared to both CMS and OSMS groups. In the fourth Japanese nationwide survey, CMS represented 57.7% of the patients, whereas 16.5% were classified as having OSMS (Ishizu et al., 2009). Interestingly, several CMS patients presented longitudinally extensive spinal cord lesions (LESCLs), which is a frequent finding in OSMS, and EDSS scores were correlated with the presence of LESCLs regardless of subtype.
There is evidence of an increased prevalence and disease burden of Multiple Sclerosis (MS) in parts of the world where the risk was once considered low, such as Latin America (LA), Sub-Saharan Africa, Asia and the Middle East-North Africa (MENA). Despite the growing number of clinical reports, the phenotype and course of MS in these regions remains understudied compared with Europe and North America. We aimed to investigate MS phenotypes and long-term clinical outcomes across these regions.
A Boolean search of the medical literature was conducted between January 1980 and April 30, 2020. PubMed, SCOPUS, Global Health, and the Cochrane databases, were used to identify all relevant citations. Articles were collated and managed on Covidence® software. We independently appraised the articles for meeting study criteria and for quality using the Critical Appraisal Skills Program (CASP) and the Specialist Unit for Review Evidence (SURE) system.
A total of 1,639 studies were imported for screening. After removing 545 duplicates, two authors assessed 1,094 abstracts and selected 515 for full-text screening. 72 articles met study criteria, including 19 studies from LA, 4 from sub-Saharan Africa, 24 from Asia and 25 from MENA. The overall sex ratio was 2.5:1 (female: male). Disability was assessed using the Expanded Disability Status Scale (EDSS). Longitudinal disability progression and time to standard endpoints was compared by region and with relevant Western reports. Patients with MS living in the MENA region appear to reach disability milestones faster than those in the Western world, although this finding is not uniform. South Asia shows distinct disability features compared with East Asia, more closely resembling those of the West. Disease morbidity in East Asia appears more benign than in the West after careful exclusion of neuromyelitis optica spectrum disorder cases. Populations in LA tend to have similar MS features to the Western world, but some exceptions exist, including African descendants that reach disability milestones earlier. Using all studies with appropriate survival analysis, the mean time to EDSS 6.0 was 16.97 years with a heterogeneity index of 24.59.
The clinical phenotypes and disability progression of MS in LA, Africa, Asia and the MENA region have similarities to Western MS. In some regions and subpopulations there is evidence of a more aggressive course, possibly due to a combination of genetic and environmental factors. More population-based longitudinal data are needed, particularly in Sub-Saharan Africa.
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Month of birth in multiple sclerosis with and without longitudinally extensive spinal cord lesions: A study of a Japanese national survey
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The total number of births and their annual monthly distribution corresponding to the median year of birth in each group served as the control data. The diagnostic criteria for MS in the present survey were as follows: [1] symptoms and signs owing to multifocal inflammatory lesions in the CNS (dissemination in space); [2] remissions and exacerbations (dissemination in time); and [3] other diseases such as acute disseminated encephalomyelitis were excluded [26]. Although the diagnostic criteria were originally adopted for clinically definite MS, they were also applicable in patients with NMO.
Month of birth has been associated with the environmental factors for multiple sclerosis (MS). This study aimed to investigate whether individuals with MS had significantly different frequencies of birth in a particular month of the year, and whether month-of-birth patterns were influenced by the longitudinally extensive spinal cord lesions (LESCL) status relative to the general population in the same Japanese birth cohort.
In this study, performed as a part of the fourth Japanese nationwide survey of MS, patients were divided into two groups according to the presence (n = 307) or absence (n = 906) of LESCLs that were diagnosed on the basis of magnetic resonance imaging findings. The number of births in every month was counted for both groups. Control data were obtained from birth records of the Japanese general population of the median years of birth of each group. Differences in the month-of-birth distributions between the patients and the general population were assessed using the chi-square test.
In MS patients without LESCLs, significantly more patients were born in January and June, whereas significantly fewer patients were born in May, compared to the general population. The seasonal patterns of birth were not in association with those of ambient ultraviolet (UV) radiation. No significant differences were found for the month-of-birth distributions between MS patients with LESCLs and the general population.
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The prevalence of NMO in 2001 and 2006 was the same at 0.6/100,000 persons (95% CI, 0.1 to 2.0). It had been considered that there were two distinct subtypes of MS in Asians: OSMS, which shows selective involvement of the optic nerve and spinal cord, and the conventional form (CMS), which affects multiple sites of the central nervous system, including the cerebrum and cerebellum [19,20]. Longitudinally extensive spinal cord lesions (LESCLs) extending over three or more vertebral segments are more commonly found in patients with OSMS than in those with CMS [21].
To carry out the third epidemiologic surveillance of multiple sclerosis (MS) in Tokachi province, on the northernmost island of Japan, and to compare the results of the present survey on the prevalence, incidence, and characteristics of MS and neuromyelitis optica (NMO) with those of previous surveys performed in 2001 and 2006.
A data processing sheet was sent to all MS-related institutions in Tokachi province, and all sheets were collected in March 2011. The criteria of Poser were used for diagnosing MS and the criteria proposed by Wingerchuk for diagnosing NMO. We then compared the results of the present survey with those of previous surveys performed in 2001 and 2006 in the same community.
Fifty-seven patients diagnosed with MS according to the criteria of Poser were identified. The prevalence was 16.2/100,000 in 2011, which was higher than in the previous studies. The female/male ratio of MS was 2.63, 2.75, and 3.38 in 2001, 2006, and 2011, respectively. Three patients fulfilled the criteria for diagnosis of NMO in 2011; the prevalence of NMO was 0.9/100,000.
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¹: These authors contributed equally to this work.

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Heterogeneity and continuum of multiple sclerosis phenotypes in Japanese according to the results of the fourth nationwide survey

Abstract

Introduction

Section snippets

Survey procedures

Demographic features of each MS subtype

Discussion

Acknowledgments

Lancet Neurol

J Neurol Sci

J Neuroimmunol

J Neurol Sci

Lancet

Lancet Neurol

Western versus Asian types of multiple sclerosis: immunogenetically and clinically distinct disorders

Ann Neurol

Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS)

Neurology

Nationwide survey of multiple sclerosis in Japan. Clinical analysis of 1,084 cases

Neurology

Nationwide survey of multiple sclerosis in Japan: reappraisal of clinical features

J Trop Geogr Neurol

Association of the HLA-DRB1 alleles with characteristic MRI features of Asian multiple sclerosis

Mult Scler