Epidemiology and genetic aspects of multiple sclerosis in India.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system with a complex pathophysiology. Considered a rare disease in India in the past, studies over time suggest an increase in subjects with MS in India, although the observations are limited by the lack of formally conducted epidemiological studies and the absence of a nationwide registry. The current World Health Organization (WHO) Multiple Sclerosis International Federation (MSIF) "Atlas of MS" 2013 estimates a prevalence rate of 5-20 per 100,000, which also seems an underestimate. Although there have been reports of phenotypic differences between MS in Indians and the Western counterparts, recent studies report a reasonable similarity in disease types and characteristics. A few studies on the genetics of MS have been reported, including human leukocyte antigen (HLA) associations and non-major histopathology complex (MHC) disease loci. The current review discusses the pivotal studies of the past, newer observations on MS from India, and the need for a national registry.

Introduction

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system with a complex pathophysiology and interplay of environmental and genetic factors in disease etiopathogenesis.[12] The disease adds to the disability and productive burden of any country by afflicting the young and dynamic population. Epidemiological studies provide an almost global map of the distribution of a disease. The incidence and prevalence of MS is variable across the globe and include low-, middle-, and high-prevalence zones.[2] MS was thought to be rare in India in the past, until the pivotal initial studies by Singh et al.[3] and Bharucha et al.[4] were published. The last decade has seen an increase in the number of MS cases being reported in both adult and pediatric populations, and this is likely related to the following: Emergence and easy availability of magnetic resonance imaging (MRI); increase in the number of neurologists; and improved diagnostic criteria, techniques, and awareness about the illness. This has, ultimately, led to more cases being reported from across the whole country.[5] This article aims to provide an overview of studies on MS in the country [Table 1]; how this disease has evolved over time; the prevalence, genetic aspects, phenotypic presentation, and other factors related to MS.

Table 1

Important studies on MS conducted from India

Incidence and Prevalence

In the 1980s, the prevalence of MS in India was estimated to be nearly 1/100,000. Evidence collected from hospitals throughout India suggests that the number of MS patients diagnosed annually has nearly doubled. There are no large-scale studies from India on the incidence and prevalence of MS. In an earlier study by Singhal et al. the prevalence of MS was estimated to be approximately 1.33/100,000.[6] Another hospital-based study from northwestern India observed that MS constituted 1.58% of the total neurology admissions from 1968 to 1977.[7] These data were compared with more recent data collected from the same institute in the period 1993-1997,[8] and an increase was found, to 2.54% of neurology admissions. The current World Health Organization (WHO) Multiple Sclerosis International Federation (MSIF) “Atlas of MS” 2013 quotes prevalence rates of 5-20 per 100,000, which is much higher than the studies reported previously.[9] This also seems an underestimate due to the lack of well-conducted epidemiological studies. Previously conducted studies had estimated that MS may be more common in northern as compared to southern India, where 3.2 cases were seen yearly, compared to 4.15 cases in the north.[10] Two community-based prevalence studies by Barucha et al.[11] and Wadia et al.[12] used Schumacher's criteria among the Parsi population in the late 80s and revealed a prevalence of 21-58/100,000. Using Poser's criteria, Gangopadhya et al.[1314] reported an incidence of 0.32% of all hospital admissions and 0.62/100,000 of neurology clinic patients with the mean age at onset of 31.83 years in males and 29.11 years in females. Initial studies from Vellore and northern India reported a higher male-to-female ratio as against studies from the western part of India.[15] The mean age of onset in all the studies was 27-29 years.[6815] The mean age in the recent study from the All India Institute of Medical Science (AIIMS) registry by Singhal and Bhatia et al. quoted a slightly higher age range of 33 ± 9 years.[16] There was also a female preponderance, with a male-to-female ratio of 0.65. Syal et al.[8] reported the age of onset to be 28.49 ± 9.54 years and the female-to-male ratio of 1.32:1.

Phenotypic Variability

Initial reports about MS in India from all the studies in the 70s mainly emphasized the opticospinal variant in the country. Singhal et al. reported that 71% of the patients seen in western India had this phenotype.[6] The Vellore group also reported a higher visual involvement of 42% as compared to the then available European and American data.[15] However, a study analyzing the symptoms at onset in patients admitted to a national hospital in southern India showed a dramatic reduction in spinal cord dysfunction by almost 50%.[17] A multicentric study by Jain and Maheshwari reported that among nine centers and 354 cases, optic neuritis was seen as the initial presentation in about 22.2-58% of the cases in five centers.[10] Singhal and Wadia also found that a relatively high proportion of patients had bilateral optic nerve involvement in the west/western.[18] Studies done in the MRI era from New Delhi, India, reported that the involvement of the brainstem and other systems was as frequent in our MS population and that it was not only the opticospinal disease that was common in this part of the continent.[81719] Various studies reporting visual impairment have been published from India, with Syal's study showing a frequency of 23.6% from the northwestern region and another study showing 44% from the south.[820] Bhatia et al. found optic neuritis in 26% of the patients, making it the second most common initial neurological symptom in MS patients.[19] From the eastern region, Gangopadhya et al. reported a frequency of 33.3%.[13] The recent literature from the AIIMS registry showed that brainstem involvement was as frequent as visual impairment and that relapsing/remitting multiple sclerosis (RRMS) was the most frequent disease type.[16] The improved diagnostic aid with enhanced MRI techniques and the application of the sensitive revised McDonald's criteria[21] in these studies is the likely explanation for the observed phenotypic change.

Environmental Factors

It is believed that exposure to some environmental factors in genetically susceptible individuals may lead to the development of MS. Therefore, studying the predisposing factors in a population may provide important insights into the causation of the disease.[2223] In India, no specific studies on the environmental factors have been reported so far. Khadilkar et al.[24] reported that there was a significant history of mumps among patients with MS compared with controls. Although history of measles and chicken pox was higher in patients with MS than controls, it was statistically not significant. From their data set of 63 MS patients they reported that there were 10 smokers in the MS group, compared to 4 among the controls. They also reported that there was a significant higher family history of MS and other autoimmune disease among the patients as compared to controls.

Higher prevalence of MS is seen in patients with higher socioeconomic status and better sanitary conditions. In a study, 30 patients with probable MS from Mumbai, India were followed up for a period of 15 years. MS was more frequent in patients with better socioeconomic status in the Parsi community.[18] Epidemiological and experimental data support the role of vitamin D as a potentially important environmental risk factor for MS. A study by Pandit et al. measured serum 25-hydroxyvitamin D, i.e., 25(OH)D levels and reported that patients with MS had significantly lower 25(OH)D levels than matched controls, and patients in relapse had a significantly lower vitamin D level compared to those in remission. Vitamin D deficiency was seen in a higher proportion of cases than among controls. Higher quartiles of vitamin D showed an inverse relationship with MS.[25] Previous studies have shown that United Kingdom (UK)- and North America-born children of Asians have higher prevalence of MS, indicating that MS is more common as distance from the equator increases, and that a certain ethnicity may confer some degree of protection against the increased risk of MS.[2728]

Genetic Susceptibility

The likelihood of an individual developing MS is strongly influenced by her or his ethnic background and family history of disease, suggesting that genetic susceptibility is a key determinant of risk. Various human leukocyte antigens (HLAs) that have been noted to be more common in MS are being studied worldwide, but the role of HLA genes in the Indian population has not been adequately reported. Only a few studies from India have identified an immunological and genetic basis for MS.

Wadia et al. observed that there is a significant relative risk of MS among Indians with the HLA-B12 haplotype. This antigen was detected in 80% of cases, compared with 15% of controls.[14] These preliminary findings seem to point to a different immunogenetic profile of Indian MS patients in comparison with Western and Japanese series.[28] Another study by the same group showed that the lower incidence of MS in India may have genetic implications. HLA-A3 and HLA-B7 haplotypes were found to be lower among Indians than among Caucasians. It was also observed that the Parsi community had a higher incidence of MS, and the high association of HLA-B12 was reported among these patients.[29]

Kankonkar et al.[30] analyzed the HLA-DRB1 allele associations among non-Parsi MS patients and compared them with controls. HLA serologic as well as DRB1 typing was followed. The study revealed a significant increase of HLA-A11, and further molecular subtyping of HLA-DRB1*15 among the patients revealed two novel alleles, DRB1*1506 and DRB1*1508, along with the commonly reported DRB1*1501 for the first time in MS patients, which had been hitherto unidentified from other parts of India and the world. The association of MS with the HLA class II loci DR and DQ were studied in the Asian Indian population in the UK. The putative haplotype, DRB1*1501.DQA1*0102.DQB 1*0602, was found to be nominally associated with MS. The data suggested that other genetic and/or environmental factors may be more important in predisposing to MS in Asian Indians living in the UK.

Pandit et al.[31] found the role of non-major histopathology complex (MHC) disease susceptibility loci in the Asian population and that the disease-identifying genes in the Indian population were similar to those in the West. They tested for 15 loci outside the MHC in 197 Indian patients and 197 controls. It was found that the single nucleotide polymorphism (SNP) in IL7R (interleukin-7 receptor) showed a strong protective effect and was similar to the one reported from the West.[31]

Conclusion

MS exists in India, although its prevalence is lower than among European and American populations. The phenotypic presentation of MS in India seems quite similar to the West, and it has also been observed that some of the genes in Indian patients are similar to those seen in the Western patient population. Large epidemiological studies are needed to study MS incidence and prevalence in India. Collaborations among the neurologists and MS registries across the country are not only critical for knowing the epidemiological status of the disease in the country but would also pave the way for research in genetics, drug development, and in exploring the pathogenesis of this complex disease. New methods such as a genome-wide association study (GWAS), a tool for investigating the genetic architecture of polygenic disease in humans,[32] is being used for the identification of genetic factors of disease susceptibility, clinical phenotypes, and treatment response in MS. The ability of a GWAS to explore the variation between patients and controls has presented a common path for the identification of genetic susceptibility for complex diseases such as MS. The results may open new avenues for the clinical implications of MS-associated genetic variants reported from a large GWAS.

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Conflicts of interest

There are no conflicts of interest.