Multiple Sclerosis Podcast: Epidemiology Kevin Yen Neurology R1 University of Alberta

Introduction Multiple Sclerosis (MS) is the most common immune-mediated inflammatory demyelinating disease affecting the central nervous system (CNS) The exact cause and pathophysiology of MS is currently under research The working theory is that a combination of genetic and environmental factors activate immune cells to attack the CNS causing neuro-degeneration

Goals for this Lecture To go over the basic pattern and statistics of MS population Identify a few potential risk factors for developing MS And clarify common misconceptions about MS risk factors and statistics.

Prevalence and Incidence Prevalence and incidence of MS varies geographically In North America, it is estimated 400,000 people are affected with MS Worldwide, estimated to be 2.5 million people The rate of MS in US is approximated 100/100,000 The rates of MS are higher in the northern states compared to the southern states, 120 vs. 60 In Canada, the rate of MS is estimated to be greater than 200/100,000 www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/neurology/multiple_sclerosis/

Age of Onset MS can present 10-80 years of age Majority of the patient usually present 15-45 years of age Mean age of onset: 28- 31 years in various studies Rare to have cases present at age <10 and >70 Overall, female present few years earlier than male Different types of MS have different age of onset Relapsing-remitting MS 25 – 29 Primary progressive MS 39 - 41 Ramagopalan SV, Sadovnick AD. Epidemiology of multiple sclerosis. Neurol Clin 2011; 29:207.

Gender Mean age of onset is earlier in females MS affects female more often than male Estimated 2:1 In fact, studies have shown increasing incidence in female It is unknown why females are affected more frequently Alonso A, Hernán MA. Temporal trends in the incidence of multiple sclerosis: a systematic review. Neurology 2008; 71:129.

Genetics- Part 1 MS is not consider a hereditary condition However, a number of genes have been shown to increase risk of MS Genetic variation in Major Histocompatibility complex (MHC) are suspected to be related to MS presentation In particular, the HLA-DRB1 locus Some alleles are shown to be protective of MS while others are shown to increase the risk of MS Other genes in other loci are currently under research International Multiple Sclerosis Genetics Consortium, Hafler DA, Compston A, et al. Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med 2007; 357:851. International Multiple Sclerosis Genetics Consortium, Wellcome Trust Case Control Consortium 2, Sawcer S, et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 2011; 476:214.

Genetics- Part 2 Overall, chance of developing MS is higher in relatives of MS patients Data for familial MS differ between studies Estimated to be at least 2% absolute risk increase from sporadic Up to 4% of asymptomatic relatives will have MS-like lesions on MRI Up to 10% of asymptomatic relatives with multiple family members with MS Dizygotic twins and sibling both show 5% risk of developing MS However, monozygotic twins show 20-30% risk of developing MS Sadovnick AD, Armstrong H, Rice GP, et al. A population-based study of multiple sclerosis in twins: update. Ann Neurol 1993; 33:281. Nielsen NM, Westergaard T, Rostgaard K, et al. Familial risk of multiple sclerosis: a nationwide cohort study. Am J Epidemiol 2005; 162:774.

Autoimmune Disorder Currently there is conflicting evidence regarding the link between MS and other autoimmune disorder Some studies have shown that MS patients are more likely to develop autoimmune disorders Common disorder are psoriasis, thyroid disease, inflammatory bowel disease, and uveitis Other studies have also shown that patient with autoimmune disorders are more likely to develop MS Some of these disorders are type 1 diabetes mellitus and inflammatory bowel disease Heinzlef O, Alamowitch S, Sazdovitch V, et al. Autoimmune diseases in families of French patients with multiple sclerosis. Acta Neurol Scand 2000; 101:36. Ramagopalan SV, Dyment DA, Valdar W, et al. Autoimmune disease in families with multiple sclerosis: a population-based study. Lancet Neurol 2007; 6:604.

Geographic Many study show that MS prevalence and incidence vary geographically There is an observation showing increase prevalence and incidence of MS with increasing latitude from south to north Following areas with prevalence >60/100,000 Northern US Southern Canada Europe Russia New Zealand Southeast Australia Currently unknown as to why there is a geographic variability genetic difference/ethnicity vs. variable surveillance? Ebers GC. Environmental factors and multiple sclerosis. Lancet Neurol 2008; 7:268. Simpson S Jr, Blizzard L, Otahal P, et al. Latitude is significantly associated with the prevalence of multiple sclerosis: a meta-analysis. J Neurol Neurosurg Psychiatry 2011; 82:1132.

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Sunlight Exposure Many studies have found an inverse relationship between sun exposure (ultraviolet radiation) or serum vitamin D level and the prevalence of MS Many studies have also found an inverse relationship between sun exposure (ultraviolet radiation) or serum vitamin D level and MS disease activity/progression Overall the hypothesis is that sun exposure (ultraviolet radiation) or serum vitamin D level may be protective of MS These finding support the observation that MS prevalence varies with latitude Currently still under research Ascherio A, Munger KL. Environmental risk factors for multiple sclerosis. Part II: Noninfectious factors. Ann Neurol 2007; 61:504.

Viral Infection Some studies hypothesize that viral infections could be the stimulus leading to activation of MS Some of virus in question include Epstein-Barr virus and varicella zoster virus No specific study has been able to prove direct causation of these virus to MS activation Hernán MA, Zhang SM, Lipworth L, et al. Multiple sclerosis and age at infection with common viruses. Epidemiology 2001; 12:301.

Vaccinations The idea that vaccines cause MS came from the hypothesis that vaccines might stimulate the immune system which leads to the activation of MS Overall there has been no substantial evidence supporting the association between vaccines and MS No associations with HBV, HPV, Tetanus, and several other vaccines with MS Also, no association between several different vaccines and MS relapse in patients with MS Also, there is no association between hepatitis B infection and MS Confavreux C, Suissa S, Saddier P, et al. Vaccinations and the risk of relapse in multiple sclerosis. Vaccines in Multiple Sclerosis Study Group. N Engl J Med 2001; 344:319.

Other Associations with MS Some research have looked at the association between smoking and MS Overall no formal conclusion has been reached Difference in microbiome have been proposed to be linked with MS Some studies hypothesize that certain birth months maybe associated with risk of developing MS April and May Overall, more research needed to conclude the association between these factors and MS

Summary MS affects females more than males, 2:1 Mean age of onset is between 20-30 There are both genetic and environmental factors that contribute to the development of MS Incidence and prevalence vary geographically likely due to an inverse relationship between UV radiation exposure and vitamin D level The relationship between viral infections and MS are still under research No proven risk of MS with vaccinations

Thank you for your time Kevin Yen R1