Epidemiology of Multiple Sclerosis

Susana Otero Romero

Catalonia MS Center (CEM-Cat)

Epidemiology Department

Vall d’Hebron University Hospital

MS Preceptorship 2011

Serono Symposia International Foundation

Barcelona 7-9 June

Basic concepts in epidemiology

Epidemiology studies the occurrence of disease in a

given population/ different populations

Basic concepts in epidemiology

Prevalence:

- Proportion of individuals that have the disease at a given moment in a certain

population.

- Burden of disease (cases per 100.000 inhabitants)

Incidence:

- New diagnosis in a susceptible population during a period of time.

- Risk (cases per 100.000 and year).

Basic concepts on epidemiology

“How” (DESCRIPTIVE EPIDEMIOLOGY)

“Why” (ANALITIC EPIDEMIOLOGY)

Risk factors: environmental and genetic factors linked to the disease.

Deaths

Duration

Incidence

Prevalence

Increase in prevalence:

- more incident cases

- longer patients survival.

Basic concepts: descriptive epidemiology

Prospective registries

Population based and continuously updated

Well defined inclusion and exclusion criteria

Long time follow-up

Prevalence and incidence data

Survival analysis

Cohort studies

Population based patient samples for specific studies

Completeness

Limited amount of clinical data

Small stable populations

High commitment

Flacheneker P JNeurol 2008

Hurwitz B Neurology 2011

Prospective registries: Danish MS Register (1956)

Inclusion: All Danish citizens who have received a diagnosis of MS or

suspected MS by a neurologist or a department of neurology

Sources of notification:

All Danish Departments of neurology (N=15)

Danish MS rehabilitation hospitals (N=2)

Practising neurologists

Linkage to:

MS treatment Registry

National patients Registry

Population registries (civil registration, causes of death..)

Koch-Henriksen, Dan Med Bull 2001

Prospective registries: Danish MS Register (1956)

Prevalence in 2005: 155/100,000

0

2

4

6

8

10

12

1950 1960 1970 1980 1990 2000

Koch-Henriksen, 2010

Prevalence Incidence

Completeness of registration: 90-95%

Women

Men

Prospective registries: Catalonia MS Register (2009)

Inclusion: CIS after January 2009. Patients are followed until possible

conversion to MS, based on McDonald diagnostic criteria (2005)

Sources of notification:

Specialized MS units and neurology departments in Catalonia (N=30)

Cases are declared on-line using proprietary software www.epidemcat.cat

Otero S. Rev Neurol 2010

New cases according to month at onset

MS

DIS or DIT

CIS

2009 2010 2011

0

5

10

15

20

25 4

2

Incidence (per 100,000 inhab and year)

N

Repeated transversal studies

Methodological approach to characterize the change epidemiology of the disease

Bufill et al. Prevalence of multiple sclerosis in the region of

Osona, Catalonia, northern Spain. JNNP, 1995

Otero et al. Increase in prevalence of multiple sclerosis over

a 17 year period in Osona shire, Catalonia (Spain). Submitted

Prevalence day 31st December 1991

Prevalence MS cases Prevalence MS cases Prevalence

Total 42 58 120 91.2

Women 28 75.5 71 107.4

Men 14 40 49 74.6

Sex ratio

Age at onset (mean, years)

Disease duration (mean, years)

EDSS 3.4

Prevalence day 31st December 2008

2

31

12

4

1.4

32

15

* *

* Cases per 100.000 inhabitants

Basic concepts: analytic epidemiology

CIS EM

Pre-clinic Clinic Pre-pathologic

Onset

Induction period Latency period Evolution period

“MS TRAIT”

Pre and

perinatal Childhood Adolescence Adulthood

Predisposing “risk”

factors

Trigger factors Evolution factors

Analytic epidemiology

Ecological studies

Patterns of disease occurrence in relation to population level variables

(sun, diet, infection..)

Hypothesis formulation, NOT individual risk for disease

Case-control and cohort studies

Exposure data collected for disease and disease-free groups at

individual-level

Indentifies the excess of risk between groups.

Classic epidemiological data

Classic data

Different methodology (study period, case ascertainment methods, diagnostic

and classification criteria, not standardized rates..)

Genetic factors (ethnic distribution)

Environmental factors

Worldwide distribution of MS prevalence from Kurtzke and Wallin.

Kurtzke J. Journal of virology, 2000

1. Concordance 25-30% in monozygotic twins and 2-5% in dizygotic twins

(Sadovnick et al; 1993: 281-5)

2. Migration studies

3. Clusters and epidemics

But, genetics can’t explain it all...

Classical data: Genetics versus environment

MS affects persons of Scandinavian and Finnish origin (Davenport,

1922) and prevalence is higher in areas with Scandinavian descent

population (Bulman, 1992)

MS is rare in black population (Poser, 1993) and never reported in

certain ethnic groups (Inuits, New Zealand Maoris..)

Strong association with HLA class II DRB1*1501

Familiar clustering

1. Concordance 25-30% in monozygotic twins and 2-5% in dizygotic twins

(Sadovnick et al; 1993: 281-5)

2. Migration studies

3. Clusters and epidemics

Classic data: Migration studies

European migrants to South Africa (1940)

Change in MS risk upon migration from high to low risk area, or vice versa

The change in risk is “age at migration-dependent”

< 15 years Prev = 13/100.000 inhabitants (same as native-born white South Africans)

> 15 years Prev = 30-80 /100.000 inhabitants (as expected in their home lands)

Age at

migration

Returned migration to French West Indies (Guadalupe and Martinique) after

years in mainland France (1999)

Age of migration before 15 years (P= 140/100.000 hab)

Migrants (P = 40 / 100.000 hab)

Age of migration after 15 years

Non- Migrants (P = 20 / 100.000 hab)

Cabre P. Brain, 2005

Dean G. BMJ, 1971

Classic data: Clusters and epidemics

Faroes Islands (1943) Shetland and Orkneys (1911-1985)

Cook SD . Acta Neurol Scand, 1988 Kurtzke JF, J Clin Epidemiol, 2001

Specific concerns:

Access to neurologist? (increase due to a under-diagnosis in the previous years)

Cases confirmed? (other neurological disease mimicking MS)

Did MS occur before moving to the epidemic area?

Classic data: first etiologic hypothesis

Non-infectious factors

Sun Vitamin D

Diet

Smoking

Toxic (occupational exposure)

Hormones

Stress

Infections

- Polio hypothesis: MS caused by pathogen that increases risk if acquired

in late childhood or adult life

- Prevalence hypothesis: MS cause by a pathogen that is more common

in areas of high risk for MS.

Recent epidemiological data

Recent epidemiology

Global increase in MS incidence and prevalence

Increase in sex ratio

Latitudinal gradient attenuation

New insights on risk factors

Increasing trends, latitudinal gradient and sex-ratio

MS incidence studies published between 1966 and 2007

Alonso A. Neurology, 2008

Sex ratio 1.7 1.9

Increasing trends, latitudinal gradient and sex-ratio

Koch-Henriksen Lancet Neurol, 2010

Incidence in western Europe and

North America by year

Incidence in western Europe by

latitude

1

2

4

6

8

10

12

14

Sex-ratio (female:male) by year

Diagnostic techniques (MRI)

Higher accessibility to healthcare

Increase in number and quality of epidemiological studies

Common diagnostic criteria

Population-based

Prospective MS registries

Improved case ascertainment

Improved case ascertainment or real increase in MS risk?

Global changes in risk factors

Specific changes in women? ( lifestyle, reproductive factors, smoking

habits..)

Specific changes in tropical and sub-tropical areas? (improved hygiene,

indoor occupations..)

Increased MS risk

Recent approaches on risk factors

Non-infectious factors:

- Vitamin D (“we keep blaming it on the sunshine”)

- Smoking

Infections:

Polio Hypothesis Hygiene Hypothesis

- Epstein Barr Virus

- The role of parasite infections

Latitude, sun and Vitamin D (25OHD)

Kimlin M. Molecular Aspects of Medicine, 2008

Sun exposure provides 80-90% of the vitamin D

Areas > 40º shortage of Vit D effective radiation and suboptimal population

Vit D serum levels during winter months

Cannell JJ. Epidemiol Infect. 2006

Latitud: 45º

Sun, vitamin D and MS: ecological studies

Pierrot-Deseilligni. Brain, 2010

Vitamin D and MS: cohort studies

25(OH)D serum levels and Vitamin D supplementation in MS risk

Munget K..JAMA, 2006

Department of defense USA (N=257)

Munger et al. Neurology, 2004

Nurses Health Study (N=187.563)

Vitamin D and MS: cohort studies

Handel, A. Nat. Rev. Neurol, 2010

Canadian (N= 17 874) and British (N=11 502) retrospective cohort

Hygiene hypothesis : The lack of infectious exposures in early life may be a critical

factor for the development of MS in a genetically predisposed individual

Infections: Epstein Barr Virus

Thacker E Ann Neurol 2006;59:499 Lynn et al. JAMA 2005;293:2496-2500

Infections: parasites

Protective role of parasites

- down-modulation of the hosts immune system

- modification of clinical course of established MS

- therapeutic approach (experience in other autoimmune disease)

Correale J. Ann Neurol, 2007

Conclusions

- First MS epidemiological studies show a irregular disease distribution, that should be

interpreted with caution due to methodological limitations.

- Observed epidemiological patterns strongly suggest a role of the environment acting

on genetically predisposed individuals.

- Recent epidemiological data show a global increase in MS incidence, sex-ratio and

attenuation in the latitudinal gradient.

- The increase in MS incidence could be due in part to a better case ascertainment but

also a global change in risk factors.

- Further descriptive and analytic studies on populations with homogeneous ethnic

composition and comparable methodology are needed in order to give new insights on

risk factors and their interaction with genetics.

Thank you for your attention