Advertisement

Multiple sclerosis incidence: A systematic review of change over time by geographical region

Open AccessPublished:May 28, 2022DOI:https://doi.org/10.1016/j.msard.2022.103932

      Highlights

      • Trends in MS incidence rates over time have not been examined on a global basis.
      • Our systematic review included 65 regional estimates across 24 countries.
      • By absolute number of studies, the predominant pattern was increasing MS incidence.
      • No pattern was seen with consistent case definitions/high population coverage.
      • There were few eligible studies to assess change in incidence in many regions.

      Abstract

      Background

      The incidence of multiple sclerosis (MS) has reportedly increased over time; however, change in MS incidence has not been rigorously assessed globally.

      Methods

      We followed the guidelines for the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. Two independent reviewers systematically searched Scopus, PubMed and Web of Science for peer-reviewed publications in English from 1 January 1985 to 24 September 2020 reporting MS incidence for at least two contiguous five-year periods with clearly-defined case ascertainment. The outcome was change in MS incidence rate according to geographical region.

      Results

      We identified 64 papers providing 65 regional estimates (including three paediatric-onset MS) across 24 countries covering ∼3% of the world's population (in 2000/1 or closest available total population for the entire country), with quality (adapted Newcastle-Ottawa Scale) ranging from sufficient to good. Studies were mainly from Italy (n=14 including San Marino), Norway (n=10) or Canada (n=9), with no studies in the Africa or South-East Asia regions. Of the 62 whole-of-population estimates, MS incidence rates: significantly increased in 38 (61%), significantly decreased in 13 (21%) and remained stable in 11 (18%). In the paediatric-onset studies, MS incidence was stable in two (67%) and increased in one (33%). Many estimates derived from only selected (often small) regions of a country. For 42 (68%) of the whole-of-population estimates (and two of the paediatric-onset estimates) a consistent case definition or diagnostic criteria over the entire study period was explicitly reported. Across the n=9 whole-of-population estimates based on a consistent case definition for the duration of the study period, and including a substantial proportion of the population of a country (≥one-third), incidence rates were stable in n=3, increased in n=3 and decreased in n=3. Studies using a consistent case definition covered ∼2.7% of the global population; incidence rates were stable in 0.9% of the global population, decreased in studies covering 1%, and increased in those covering 0.8% of the global population.

      Conclusion

      The studies reporting change in MS incidence rate over time were limited by world region and the proportion of the global population covered. Although by number of studies, the predominant pattern was increasing MS incidence, in studies where a consistent case definition was used across the duration of the study and with high population coverage, no predominant pattern of MS incidence was evident.

      Keywords

      Abbreviations:

      MS (Multiple sclerosis)

      1. Introduction

      Multiple sclerosis (MS) is an inflammatory and neurodegenerative disorder of the central nervous system, affecting around 2.8 million people worldwide (

      The Multiple Sclerosis International Federation (MSIF). Atlas of MS, 3rd Edition: Mapping multiple sclerosis around the world key epidemiology findings, 2020, https://www.msif.org/wp-content/uploads/2020/10/Atlas-3rd-Edition-Epidemiology-report-EN-updated-30-9-20.pdf.

      ). Over the past four decades, technological advances (
      • Cortese R.
      • Collorone S.
      • Ciccarelli O.
      • Toosy AT.
      Advances in brain imaging in multiple sclerosis.
      ), revised diagnostic criteria (
      • Brownlee W.J.
      • Hardy T.A.
      • Fazekas F.
      • Miller DH.
      Diagnosis of multiple sclerosis: progress and challenges.
      ), better access to specialist health care (
      • Marrie R.A.
      • Cutter G.
      • Tyry T.
      • Hadjimichael O.
      • Campagnolo D.
      • Vollmer T.
      Changes in the ascertainment of multiple sclerosis.
      ), and availability of disease modifying drugs to treat MS (
      • Wallin M.T.
      • Culpepper W.J.
      • Nichols E.
      • Bhutta Z.A.
      • Gebrehiwot T.T.
      • Hay S.I.
      • et al.
      Global, regional, and national burden of multiple sclerosis 1990–2016: a systematic analysis for the global burden of disease study 2016.
      ), have increased the recognition and diagnosis of MS (
      • Giovannoni G.
      • Butzkueven H.
      • Dhib-Jalbut S.
      • Hobart J.
      • Kobelt G.
      • Pepper G.
      • et al.
      Brain health: time matters in multiple sclerosis.
      ;
      • Elian M.
      • Dean G.
      To tell or not to tell the diagnosis of multiple sclerosis.
      ;
      • Sencer W.
      Suspicion of multiple sclerosis. To tell or not to tell?.
      ).
      The prevalence of MS appears to have increased over time, likely a combined result of earlier detection and diagnosis, improved disease management and life expectancy, and improvements in data quality and accuracy (

      The Multiple Sclerosis International Federation (MSIF). Atlas of MS, 3rd Edition: Mapping multiple sclerosis around the world key epidemiology findings, 2020, https://www.msif.org/wp-content/uploads/2020/10/Atlas-3rd-Edition-Epidemiology-report-EN-updated-30-9-20.pdf.

      ). Trends in MS incidence rate over time are less clear.
      Variation in MS incidence rate according to geographic region is well-described, typically being higher with greater distance from the Equator (
      • Simpson S.
      • Wang W.
      • Otahal P.
      • Blizzard L.
      • van der Mei I.A.F.
      • Taylor B.V.
      Latitude continues to be significantly associated with the prevalence of multiple sclerosis: an updated meta-analysis.
      ). However, although systematic reviews have quantified MS incidence rates in different geographical regions (
      • Evans C.
      • Beland S.G.
      • Kulaga S.
      • Wolfson C.
      • Kingwell E.
      • Marriott J.
      • et al.
      Incidence and prevalence of multiple sclerosis in the Americas: a systematic review.
      ;
      • Kingwell E.
      • Marriott J.J.
      • Jette N.
      • Pringsheim T.
      • Makhani N.
      • Morrow S.A.
      • et al.
      Incidence and prevalence of multiple sclerosis in Europe: a systematic review.
      ;
      • Makhani N.
      • Morrow S.A.
      • Fisk J.
      • Evans C.
      • Beland S.G.
      • Kulaga S.
      • et al.
      MS incidence and prevalence in Africa, Asia, Australia and New Zealand: a systematic review.
      ), and compared incidence across countries and regions (
      • Alonso A.
      • Hernán MA.
      Temporal trends in the incidence of multiple sclerosis: a systematic review.
      ;
      • Koch-Henriksen N.
      • Sorensen PS.
      The changing demographic pattern of multiple sclerosis epidemiology.
      ), changes in incidence rates over time, globally, have not been examined. We performed a systematic review of the peer-reviewed literature from 1985 to 2020 to examine trends over time in MS incidence rates, globally and within geographic regions.

      2. Methods

      2.1 Search strategy and selection criteria

      The review protocol was prospectively registered on PROSPERO (CRD42020152035) and we followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      • Group P.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      ). We searched three databases (Scopus, PubMed and Web of Science) using the terms ‘multiple sclerosis, MS, and incidence’ and the reference lists of recent meta-analyses of MS incidence. Full text articles published in English from 1 January, 1985 to 24 September, 2020 were potentially eligible. The study start (1985) broadly corresponded with the use of MRI in clinical practice to aid MS diagnosis (in high-income countries) (
      • Kingwell E.
      • Marriott J.J.
      • Jette N.
      • Pringsheim T.
      • Makhani N.
      • Morrow S.A.
      • et al.
      Incidence and prevalence of multiple sclerosis in Europe: a systematic review.
      ).

      2.2 Study inclusion criteria

      Study inclusion criteria were: MS incidence reported for at least ten years of observation (including at least two contiguous five-year periods); a defined geographical region covered, with a well-defined underlying study population (by geography and time period); clearly stated data source(s) and case ascertainment method(s), with cases identified using internationally recognised MS diagnostic criteria (e.g., Schumacher, Poser, or McDonald) or a validated algorithm applied to hospital or physician-based medical records or health administrative data. Studies were excluded if: case ascertainment was clearly limited in scope (e.g., from only one of several possible clinics or hospitals in a region and/or the geographic region a clinic/hospital served was poorly defined); incidence estimates were likely to be unstable due to the underlying population being small and/or with limited follow-up (defined as <100,000 person-years); the source population was not representative of the geographic region for the time period (e.g., military cohorts); or, case identification was by self-report.

      2.3 Identification of studies

      Two researchers (JL and HSN) independently screened titles, followed by abstracts and full texts. Duplicates were removed and disagreements were resolved by consensus. Articles reporting unique results were included.

      2.4. Data extraction and quality assessment

      For each included study, two authors (JL and HSN) extracted the following data: the primary author; year of publication; study location; the case definition or diagnostic criteria and data source(s); MS case characteristics (number, sex, race, age at symptom onset, or if unavailable, MS diagnosis), total population number; measurement period; crude MS incidence rates; and sex and/or age standardised MS incidence rates (noting the standard population used, where available). Where incidence rates were reported graphically only, GetData Graph Digitizer version 2.26.0.20 was used to extract the relevant data. Where study authors reported more than five-year blocks of incidence, data for all of the most recent five-year blocks were extracted (e.g., if eighteen years, the last fifteen were extracted). Each study's findings were reported by country or region (using the six World Health Organization regions, as used in the Atlas of MS 3rd Edition) (

      The Multiple Sclerosis International Federation (MSIF). Atlas of MS, 3rd Edition: Mapping multiple sclerosis around the world key epidemiology findings, 2020, https://www.msif.org/wp-content/uploads/2020/10/Atlas-3rd-Edition-Epidemiology-report-EN-updated-30-9-20.pdf.

      ), and countries with eight or more studies (Italy, Canada and Norway) were mapped.
      The adapted Newcastle-Ottawa Scale (
      • Xiang F.
      • Lucas R.
      • Hales S.
      • Neale R.
      Incidence of nonmelanoma skin cancer in relation to ambient UV radiation in white populations, 1978-2012: empirical relationships.
      ;

      Wells G., Shea B., O'Connell D., Peterson J., Welch V., Losos M., et al. (2020) The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analysis [10 October 2020]. Available from: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp.

      ) was used to assess study quality and risk of bias, based on five categories: diagnostic criteria or case ascertainment; representativeness of the study sample; definition of the study location; adequacy of data reporting across the study years; and incidence data report method (unadjusted/crude and adjusted/age and/or sex-specific). Each category was graded from good to insufficient quality (A to C; in the Supplement). Any study scoring grade C (‘insufficient’) in any single category was excluded.

      2.5. Analysis

      We used simple linear regression (
      • Marrie R.A.
      • O'Mahony J.
      • Maxwell C.
      • Ling V.
      • Yeh E.A.
      • Arnold D.L.
      • et al.
      Incidence and prevalence of MS in children: a population-based study in Ontario, Canada.
      ) to estimate the average annual change in incidence within each study, with 95% confidence intervals and p-values, and graphed the available data points (and trend line) to allow the reader to visualise the trends (provided in the Supplementary data). A p-value of <0.05 was considered to denote a statistically significant change in incidence over time. Where data were provided only as the mean for a period, we assigned that value to each year in the period, and used those data in the regression analysis. We used these results to provide a qualitative summary for each study of the incidence trend over time.

      3. Results

      We identified 65 regional estimates (including three for paediatric-onset MS (
      • Marrie R.A.
      • O'Mahony J.
      • Maxwell C.
      • Ling V.
      • Yeh E.A.
      • Arnold D.L.
      • et al.
      Incidence and prevalence of MS in children: a population-based study in Ontario, Canada.
      ;
      • Boesen M.S.
      • Magyari M.
      • Koch-Henriksen N.
      • Thygesen L.C.
      • Born A.P.
      • Uldall P.V.
      • et al.
      Pediatric-onset multiple sclerosis and other acquired demyelinating syndromes of the central nervous system in Denmark during 1977-2015: a nationwide population-based incidence study.
      ;
      • Alroughani R.
      • Akhtar S.
      • Ahmed S.F.
      • Behbehani R.
      • Al-Abkal J.
      • Al-Hashel J.
      Incidence and prevalence of pediatric onset multiple sclerosis in Kuwait: 1994-2013.
      )) from 24 countries spanning four continents (Table 1 and PRISMA study flow chart provided in the Supplement). The combined total underlying population was ∼180 million people, representing ∼3% of the world's population in 2000 (

      United Nations (2017). Department of Economic and Social Affairs, Population Division. World Population Prospects: The 2017 Revision, Volume I: Comprehensive Tables (ST/ESA/SER.A/399).

      ) (or closest available year). Using the six World Health Organization regions (also adopted by the Atlas of MS 3rd Edition) (

      The Multiple Sclerosis International Federation (MSIF). Atlas of MS, 3rd Edition: Mapping multiple sclerosis around the world key epidemiology findings, 2020, https://www.msif.org/wp-content/uploads/2020/10/Atlas-3rd-Edition-Epidemiology-report-EN-updated-30-9-20.pdf.

      ) to summarise findings, the eligible studies in this systematic review covered (by population, in the year 2000): 3% of the Americas Region, ∼15% of the Europe Region, ∼4% of the Eastern Mediterranean Region and ∼1% of the Western Pacific Region. No eligible studies in the Africa and South-East Asia Regions were identified. Over half the MS incidence estimates (n=33) came from three countries: Italy (n=15, including two regional estimates in Mount Etna and San Marino) (
      • Cocco E.
      • Sardu C.
      • Massa R.
      • Mamusa E.
      • Musu L.
      • Ferrigno P.
      • et al.
      Epidemiology of multiple sclerosis in south-western Sardinia.
      ;
      • Granieri E.
      • Casetta I.
      • Govoni V.
      • Tola M.R.
      • Marchi D.
      • Murgia S.B.
      • et al.
      The increasing incidence and prevalence of MS in a Sardinian province.
      ;
      • Granieri E.
      • Economou N.T.
      • De Gennaro R.
      • Tola M.R.
      • Caniatti L.
      • Govoni V.
      • et al.
      Multiple sclerosis in the province of Ferrara: evidence for an increasing trend.
      ;
      • Grassivaro F.
      • Puthenparampil M.
      • Pengo M.
      • Saiani M.
      • Venturini M.
      • Stropparo E.
      • et al.
      Multiple sclerosis incidence and prevalence trends in the province of Padua, Northeast Italy, 1965-2018.
      ;
      • Nicoletti A.
      • Patti F.
      • Lo Fermo S.
      • Messina S.
      • Bruno E.
      • Quattrocchi G.
      • et al.
      Increasing frequency of multiple sclerosis in Catania, Sicily: a 30-year survey.
      ;
      • Nicoletti A.
      • Bruno E.
      • Nania M.
      • Cicero E.
      • Messina S.
      • Chisari C.
      • et al.
      Multiple sclerosis in the Mount Etna region: possible role of volcanogenic trace elements.
      ;
      • Nicoletti A.
      • Rascuna C.
      • Boumediene F.
      • Vasta R.
      • Cicero C.E.
      • Lo Fermo S.
      • et al.
      Incidence of multiple sclerosis in the province of Catania. A geo-epidemiological study.
      ;
      • Patti F.
      • Caserta C.
      • Colandonio S.
      • Iudica M.L.
      • Maimone D.
      • Lo Fermo S.
      • et al.
      Prevalence and incidence of multiple sclerosis in the city of Biancavilla.
      ;
      • Pugliatti M.
      • Sotgiu S.
      • Solinas G.
      • Castiglia P.
      • Pirastru M.I.
      • Murgia B.
      • et al.
      Multiple sclerosis epidemiology in Sardinia: evidence for a true increasing risk.
      ;
      • Pugliatti M.
      • Riise T.
      • Sotgiu M.A.
      • Sotgiu S.
      • Satta W.M.
      • Mannu L.
      • et al.
      Increasing incidence of multiple sclerosis in the province of Sassari, Northern Sardinia.
      ;
      • Ranzato F.
      • Perini P.
      • Tzintzeva E.
      • Tiberio M.
      • Calabrese M.
      • Ermani M.
      • et al.
      Increasing frequency of multiple sclerosis in Padova, Italy: a 30 year epidemiological survey.
      ;
      • Salemi G.
      • Ragonese P.
      • Aridon P.
      • Scola G.
      • Saporito V.
      • Conte S.
      • et al.
      Incidence of multiple sclerosis in Bagheria City, Sicily, Italy.
      ;
      • Solaro C.
      • Ponzio M.
      • Moran E.
      • Tanganelli P.
      • Pizio R.
      • Ribizzi G.
      • et al.
      The changing face of multiple sclerosis: prevalence and incidence in an aging population.
      ;
      • Granieri E.
      • Monaldini C.
      • De Gennaro R.
      • Guttmann S.
      • Volpini M.
      • Stumpo M.
      • et al.
      Multiple sclerosis in the Republic of San Marino: a prevalence and incidence study.
      ), Norway (n=10) (
      • Benjaminsen E.
      • Olavsen J.
      • Karlberg M.
      • Alstadhuag KB.
      Multiple sclerosis in the far north - incidence and prevalence in Nordland Country, Norway, 1970-2010.
      ;
      • Celius E.G.
      • Vandvik B.
      Multiple sclerosis in Oslo, Norway: prevalence on 1 January 1995 and incidence over a 25-year period.
      ;
      • Dahl O.P.
      • Aarseth J.H.
      • Myhr K.M.
      • Nyland H.
      • Midgard R.
      Multiple sclerosis in Nord-Trondelag County, Norway: a prevalence and incidence study.
      ;
      • Flemmen H.O.
      • Simonsen C.S.
      • Berg-Hansen P.
      • Moen S.M.
      • Kersten H.
      • Heldal K.
      • et al.
      Prevalence of multiple sclerosis in rural and urban districts in Telemark county, Norway.
      ;
      • Grytten N.
      • Aarseth J.H.
      • Lunde H.M.
      • Myhr KM.
      A 60-year follow-up of the incidence and prevalence of multiple sclerosis in Hordaland County, Western Norway.
      ;
      • Lund C.
      • Nakken K.O.
      • Edland A.
      • Celius EG.
      Multiple sclerosis and seizures: incidence and prevalence over 40 years.
      ;
      • Risberg G.
      • Aarseth J.H.
      • Nyland H.
      • Lauer K.
      • Myhr K.M.
      • Midgard R.
      Prevalence and incidence of multiple sclerosis in Oppland County: a cross-sectional population-based study in a landlocked county of Eastern Norway.
      ;
      • Simonsen C.S.
      • Edland A.
      • Berg-Hansen P.
      • Celius EG.
      High prevalence and increasing incidence of multiple sclerosis in the Norwegian county of Buskerud.
      ;
      • Vatne A.
      • Mygland A.
      • Ljostad U.
      Multiple sclerosis in Vest-Agder County, Norway.
      ;
      • Willumsen J.S.
      • Aarseth J.H.
      • Myhr K.M.
      • Midgard R.
      High incidence and prevalence of MS in More and Romsdal County, Norway.
      ) and Canada (n=9) (
      • Marrie R.A.
      • O'Mahony J.
      • Maxwell C.
      • Ling V.
      • Yeh E.A.
      • Arnold D.L.
      • et al.
      Incidence and prevalence of MS in children: a population-based study in Ontario, Canada.
      ;
      • Al-Sakran L.H.
      • Marrie R.A.
      • Blackburn D.F.
      • Knox K.B.
      • Evans C.D.
      Establishing the incidence and prevalence of multiple sclerosis in Saskatchewan.
      ;
      • Hader W.J.
      • Yee I.M.L.
      Incidence and prevalence of multiple sclerosis in Saskatoon, Saskatchewan.
      ;
      • Kingwell E.
      • Zhu F.
      • Marrie R.A.
      • Fisk J.D.
      • Wolfson C.
      • Warren S.
      • et al.
      High incidence and increasing prevalence of multiple sclerosis in British Columbia, Canada: findings from over two decades (1991-2010).
      ;
      • Marrie R.A.
      • Fisk J.D.
      • Stadnyk K.J.
      • Yu B.N.
      • Tremlett H.
      • Wolfson C.
      • et al.
      The Incidence and Prevalence of Multiple Sclerosis in Nova Scotia, Canada.
      ;
      • Rotstein D.L.
      • Chen H.
      • Wilton A.S.
      • Kwong J.C.
      • Marrie R.A.
      • Gozdyra P.
      • et al.
      Temporal trends in multiple sclerosis prevalence and incidence in a large population.
      ;
      • Widdifield J.
      • Ivers N.M.
      • Young J.
      • Green D.
      • Jaakkimainen L.
      • Butt D.A.
      • et al.
      Development and validation of an administrative data algorithm to estimate the disease burden and epidemiology of multiple sclerosis in Ontario, Canada.
      ;
      • Sloka J.S.
      • Pryse-Phillips W.E.
      • Stefanelli M.
      Incidence and prevalence of multiple sclerosis in Newfoundland and Labrador.
      ;
      • Warren S.
      • Svenson L.W.
      • Warren K.
      Contribution of incidence to increasing prevalence of multiple sclerosis in Alberta, Canada.
      ).
      Table 1Characteristics of longitudinal studies of multiple sclerosis incidence over time (1985–2020) by global regions.
      Primary author, year of publication; locationCase definition or diagnostic criteriaCase ascertainment data sourceTime period; calendar yearsMean annual incidence per 100,000 population during period (95% CI provided where available)
      Absolute annual change is the coefficient of the linear trend line across the data points provided for each year or 5-year period; standardised incidence rates used where provided, otherwise, crude incidence rates.
      Absolute annual change estimate (95% CI) p valueIncidence trend
      Qualitative summary based on the regression coefficient, 95% confidence interval for the absolute annual change, and p-value. IPMSSG = International pediatric MS Study Group.
      CrudeStandardised
      Americas Region
      Al-Sakran 201819

      Saskatchewan, Canada
      ‘Marrie algorithm’: ≥3 hospital, physician, or MS DMD claims (prescriptions filled) (
      • Marrie R.A.
      • Yu N.
      • Blanchard J.
      • Leung S.
      • Elliott L.
      The rising prevalence and changing age distribution of multiple sclerosis in Manitoba.
      )

      ‘CCDSS algorithm’: ≥1 hospital or ≥5 physician claims within 2 years

      ICD-9/10 codes 340/G35
      Province-wide health administrative data, including hospital, physician and prescription claims2004–2008NR18.84
      Age- and sex-standardised to the Canadian population, Census 2001.


      (Marrie algorithm)
      Age- and sex-standardised to the Canadian population, Census 2001.


      16.23
      Age- and sex-standardised to the Canadian population, Census 2001.
      (CCDSS)
      –0.76 (-1.21, -0.30) p=0.005

      (Marrie algorithm)

      -0.89 (-1.21, -0.56) p<0.001

      (CCDSS)
      Incidence decreased

      Marrie algorithm

      (2004–2013)

      2009–2013NR14.43
      Age- and sex-standardised to the Canadian population, Census 2001.


      (Marrie algorithm)

      11.78
      Age- and sex-standardised to the Canadian population, Census 2001.
      (CCDSS)
      Incidence decreased

      CCDSS

      (2004–2013)
      Hader 200721

      Saskatoon, Saskatchewan, Canada
      Allison and Millar, 1954;

      Schumacher;

      Poser
      Regional hospital records, family physicians, neurologists, nursing homes, Home Care Program, MS Society and a provincial MS Treatment Database (est. 1997)1990–19999.20

      (7.90–10.70)
      NR-0.12 (-0.16, -0.07) p<0.001

      Incidence decreased

      (1990–2004)
      2000–20047.90

      (6.20–9.90)
      NR
      Kingwell 201522

      British Columbia, Canada
      ≥ 7 MS claims (ICD-9/10 codes 340/G35) for people who were resident in British Columbia for >3 years following the first MS or demyelinating disease claim; ≥ 3 MS claims for those with ≤ 3 years of residency (akin to the Marrie algorithm)Health administrative data, including hospital, physician and prescriptions filled1999–20038.288.18
      Age- and sex-standardised to the Canadian population, Census 2001.
      -0.12 (-0.36, 0.12) p=0.29

      Incidence stable

      (1999–2008)
      2004–20087.527.36
      Age- and sex-standardised to the Canadian population, Census 2001.


      Marrie 201323

      Nova Scotia, Canada
      ≥ 7 MS claims (ICD-9/10 codes 340/G35) for people with >3 years of administrative data; ≥ 3 MS claims for those with ≤ 3 years of data (akin to the Marrie algorithm)Health administrative data including hospital, physician claims and MS clinic data1996–2000NR11.44
      Age- and sex-standardised to the Canadian population, Census 2001.
      -0.34 (-0.56, -0.12) p=0.005Incidence decreased

      (1995–2010)
      2001–2005NR10.13
      Age- and sex-standardised to the Canadian population, Census 2001.
      2006–2010NR8.30
      Age- and sex-standardised to the Canadian population, Census 2001.


      Rotstein 201824

      Ontario, Canada
      ≥1 hospital or ≥5 physician claims for MS (ICD-9/10 codes 340/G35) within 2 years; (restricted to: ≥20 years); akin to the CCDSS algorithmProvince-wide health administrative data including hospital and physician claims1999–2003NR16.20
      Age- and sex-standardised to the Ontario population, Canadian Census 2001.
      -0.24 (-0.51, 0.03) p=0.08

      Incidence stable
      2004–2008NR14.37
      Age- and sex-standardised to the Ontario population, Canadian Census 2001.
      (1999–2013)
      2009–2013NR14.47
      Age- and sex-standardised to the Ontario population, Canadian Census 2001.
      Widdifield 201525

      Ontario, Canada
      ≥1 hospital or ≥5 physician claims for MS (ICD-9/10 codes 340/G35) within 2 years; (restricted to: ≥20 years); akin to the CCDSS algorithmProvince-wide health administrative data including hospital and physician claims2001–200515.3015.00
      Age- and sex-standardised to the Ontario population, Census 1991.
      0.15 (-0.40, 0.71) p=0.55Incidence stable
      2006–201015.1415.62
      Age- and sex-standardised to the Ontario population, Census 1991.


      (2001–2010)
      Sloka 200526

      Newfoundland and Labrador, Canada
      PoserHospital records; 8 of the 9 practicing neurologists; regional MS clinic/MS registry1987–199118.47NR1.00 (0.29, 1.71) p=0.009Incidence increased
      1992–199626.76NR(1987–2001)
      1997–200128.33NR
      Warren 200827

      Alberta, Canada
      ≥1 hospital or ≥2 physician claims for MS (ICD-9 code 340)Province-wide health administrative data including hospital and physician claims1990–1994NR20.80
      Age- and sex-standardised to the Canadian population, Census 1996.
      0.25 (0.09, 0.41) p=0.005Incidence increased
      1995–1999NR22.66
      Age- and sex-standardised to the Canadian population, Census 1996.
      (1990–2004)
      2000–2004NR23.30
      Age- and sex-standardised to the Canadian population, Census 1996.
      Cabre 200928

      French West Indies (Martinique and Guadeloupe)
      McDonald 2005Inflammatory CNS diseases registry (1992–2007) based on: hospital records, open-care neurologists, health records, health insurance organisations, MS patient associationsJuly1992-June19970.93

      (0.76–1.20)
      NR0.07 (0.05, 0.08) p<0.001Incidence increased (1992–2006)
      July1997-June20021.20

      (1.01–1.39)
      NR
      July2002-June20071.67

      (1.46–1.88)
      NR
      Gracia 200929

      Republic of Panama
      Poser;

      McDonald 2001 (used from 2003)
      Clinical files from the National Public Health System and private practice1991–19950.20NR0.02 (0.01, 0.35) p=0.006Incidence increased
      1996–20000.34NR(1991–2005)
      2001–20050.42NR
      Europe Region
      Joensen 201130

      Faroe Islands
      Poser (applied from 1943–1986);

      Poser, McDonald and Thompson (used 1986–2007)
      Hospital records, government disability registry, private neurologist1993–20024.90

      (2.90–7.00)
      NR-0.22 (-0.32, -0.13) p<0.001Incidence decreased

      (1993–2007)
      2003–20072.40

      (2.10–3.30)
      NR
      Koch-Henriksen 201831

      Denmark
      Allison and Millar, 1954 (for MS onset before 1994);

      Poser (for MS onset 1994–2004); McDonald (for MS onset 2005-end); (initially all ages, then restricted to: 10–64 years)
      Danish MS Registry1990–1999Female 11.33

      (10.93–11.75)

      Male 5.65

      (5.37–5.95)

      8.29
      Age-standardised to the European Standard Population (2013).
      (8.05–8.54)
      0.09 (0.06, 0.11) p<0.001Incidence increased

      (1990–2009)
      2000–2009Female 12.33

      (11.91–12.75)

      Male 6.08

      (5.79–6.38)
      9.43
      Age-standardised to the European Standard Population (2013).
      (9.17–9.69)

      Krökki 201132

      Northern Ostrobothnia, Northern Finland
      Poser;

      McDonald 2001
      Hospital records1993–19974.55NR0.26 (0.07, 0.46) p=0.01Incidence increased
      1998–20027.15NR(1993–2007)
      2003–20077.46NR
      Sarasoja 200433

      Central Finland

      (4 districts)
      PoserHospital records1989–19933.68

      (2.30–5.10)
      NR0.84 (0.45, 1.22) p=0.001Incidence increased (1989–1998)
      1994–19989.20

      (7.40–10.90)
      NR


      Benedikz 200234

      Iceland
      PoserNationwide survey of MS (hospital records)1986–19905.28NR-0.36 (-0.44, -0.28) p<0.001Incidence decreased

      (1986–2000)
      1991–19953.71NR
      1996–20001.28NR
      Benjaminsen 201435

      Nordland County, Norway
      Poser;

      McDonald (used from 2001)
      Hospitals records1985–19895.00

      (3.80–6.40)
      5.40
      Age-standardised to the European Standard Population (1976).
      0.25 (0.20, 0.29) p<0.001Incidence increased

      (1985–2009)
      1990–19945.30

      (4.04–6.72)
      5.40
      Age-standardised to the European Standard Population (1976).
      1995–19997.20

      (5.73–8.85)
      7.30
      Age-standardised to the European Standard Population (1976).
      2000–20047.40

      (5.94–9.12)
      7.60
      Age-standardised to the European Standard Population (1976).
      2005–200910.10

      (8.36–12.98)
      10.70
      Age-standardised to the European Standard Population (1976).
      Celius 200136

      Oslo, Norway
      PoserOslo MS-Registry including hospital records, patient registries, private neurologists, MS rehabilitation and nursing homes, patient societies, disability pension records from the National Health Insurance Administration1987–19917.20

      (5.00–10.20)
      NR0.23 (0.12, 0.33) p=0.001Incidence increased

      (1987–1996)
      1992–19968.70

      (6.30–11.90)
      NR
      Dahl 200437

      Nord-Trøndelag County, Norway
      PoserHospitals, outpatient clinic and the sole private neurologist records1989–19934.70

      (3.20–6.70)
      5.10
      Age-standardised to the European Standard Population (1976).
      0.08 (0.04, 0.11) p=0.001Incidence increased

      (1989–1998)
      1994–19985.30

      (3.70–7.50)
      5.60
      Age-standardised to the European Standard Population (1976).
      Flemmen 202038

      Telemark County, Norway
      ICD-10 code G35 (1999–2019) and fulfilled McDonald criteria 2010, 2017

      Or

      ICD-9 code 340 (1993–1998) with a ‘verified MS diagnosis’ (criteria NR)
      BOT-MS project database (records from 2 regional hospitals and majority of MS patients at Oslo University Hospital)1999–20038.20

      (3.90–12.60)
      8.40
      Age-standardised to the European Standard Population (2013).
      (4.00–12.80)
      0.33 (0.25, 0.41) p<0.001Incidence increased

      (1999–2018)
      2004–200811.80

      (6.60–17.00)
      11.80
      Age-standardised to the European Standard Population (2013).
      (6.60–17.10)
      2009–201311.10

      (6.10–16.10)
      11.30
      Age-standardised to the European Standard Population (2013).
      (6.20–16.30)
      2014–201813.90

      (8.30–19.50)
      14.40
      Age-standardised to the European Standard Population (2013).
      (8.70–20.00)

      Grytten 201639

      Hordaland County, Western Norway
      Poser (used through to 2002);

      McDonald 2010 (used from 2003 onwards)
      Hospital records; All patients referred from GPs and private neurologists1988–19927.52NR-0.09 (-0.15, -0.04) p=0.002Incidence decreased
      1993–19978.39NR(1988–2012)
      1998–20026.82NR
      2003–20078.19NR
      2008–20125.24NR
      Lund 201440

      Vestfold County, Norway
      Poser (used from 1983–2002);

      also classified by McAlpine for comparison with other studies (used from 1953–1982)
      Hospital records, private neurologists, nursing homes, a rehabilitation institute, National MS Registry1988–19926.05NR-0.16 (-0.22, -0.10) p<0.001Incidence decreased
      1993–19974.34NR(1988–2002)
      1998–20024.24NR
      Risberg 201141

      Oppland County, Norway
      PoserHospitals and GP records1989–19936.50

      (4.90–8.30)
      6.60
      Age-standardised to the European Standard Population (1976).
      0.15 (0.08, 0.22) p=0.001Incidence increased

      (1989–1998)
      1994–19987.40

      (5.80–9.40)
      7.60
      Age-standardised to the European Standard Population (1976).
      Simonsen 201742

      Buskerud County, Norway
      Poser (before 2001);

      McDonald 2001, 2005, 2010 (after 2001)
      Hospital and private neurology records2003–200710.20NR0.44 (0.24, 0.64) p=0.001Incidence increased
      2008–201213.10NR(2003–2012)
      Vatne 201143

      Vest-Agder County, Norway
      PoserHospital and neurological specialist records1996–2000 (5 years)7.207.50
      Age-standardised to the European Standard Population (1976).
      (4.20–13.50)
      0.07 (0.04, 0.10) p=0.001Incidence increased
      2001–2006 (6 years)7.508.00
      Age-standardised to the European Standard Population (1976).
      (4.60–14.20)
      (1996–2006)
      Willumsen 202044

      Møre and Romsdal County, Norway
      Allison and Millar, 1954;

      McAlpine; Schumacher;

      Poser;

      McDonald 2001, 2005, 2010, 2017
      Data from previously published studies (1950–1991),

      2 unpublished master's theses (presented in 2009 and 2011),

      subsequent years: hospital records and outpatient clinics
      1985–19897.00

      (5.60–8.60)
      7.60
      Age-standardised to the European Standard Population (2013).
      0.29 (0.23, 0.35) p<0.001Incidence increased

      (1985–2014)
      1990–19949.40

      (7.80–11.40)
      9.70
      Age-standardised to the European Standard Population (2013).
      1995–19997.50

      (6.10–9.20)
      7.80
      Age-standardised to the European Standard Population (2013).
      2000–200412.50

      (10.60–14.70)
      12.90
      Age-standardised to the European Standard Population (2013).
      2005–200913.70

      (11.70–15.90)
      14.30
      Age-standardised to the European Standard Population (2013).
      2010–201413.60

      (11.70–15.80)
      14.20
      Age-standardised to the European Standard Population (2013).




      Boström 200945

      Värmland County, Western Sweden
      PoserHospital records, the sole private neurologist, larger health care centers1991–19956.46

      (5.14–7.78)
      NR-0.01 (-0.02, -0.01) p=0.001Incidence decreased

      (1991–2000)
      1996–20006.39

      (5.06–7.72)
      NR
      Svenningsson 201546

      Västerbotten County, North Sweden
      Poser (used before 2002);

      McDonald 2005, 2010 (used from 2002 onwards);

      Used ICD-8/9/10 code for MS
      Swedish MS registry and national health administrative data, including hospital and outpatients1991–19955.66NR0.09 (-0.02, 0.21) p=0.11

      Incidence stable
      1996–20004.56NR(1991–2010)
      2001–20055.77NR
      2006–20106.96NR
      Vrabec-Matković 200647

      Bjelovar-Bilogora County, Croatia
      PoserHospital records, MS Society registry1987–19911.94NR0.04 (0.03, 0.06) p<0.001Incidence increased
      1992–19962.36NR(1987–2001)
      1997–20012.40NR
      Klupka-Sarić 200748

      Western Herzegovina,

      Bosnia-Herzegovina
      McDonald 2001Hospital records, regional medical centre, outpatient services1994–19981.6

      (0.00–3.30)
      NR0.05 (-0.15, 0.24) p=0.61Incidence stable

      (1994–2003)
      1999–20031.7

      (0.00–3.40)
      NR
      Debouverie 200749

      Lorraine, France
      PoserLorraine MS Regional Network of neurologists (hospital records, MS centres, neurologists records, other healthcare professionals and MS Association)1993–19975.33NR0.19 (0.04, 0.35) p=0.02Incidence increased
      1998–20026.45NR(1993–2002)

      Daltrozzo 201850

      Bavaria, Germany
      ICD-10 code G35: in at least two separate quarterly periods, not necessarily the same yearAmbulatory claims data2006–201017.1816.70
      Age-standardised to the European Standard Population (2013).
      0.01 (-0.18, 0.20) p=0.91Incidence stable
      2011–201517.4017.01
      Age-standardised to the European Standard Population (2013).
      (2006–2015)
      Kotzamani 201251

      Crete, Greece
      McDonald 2001, 2005MS Epidemiology Program Project of Crete (including major medical centres of Crete)1985–1989

      Female 3.50

      Male 1.70
      NR0.18 (0.15, 0.22) p<0.001

      (Male)

      0.23 (0.20, 0.27) p<0.001

      (Female)
      Incidence increased

      Male and Female
      1990–1994

      Female 4.10

      Male 2.40
      NR(1985–2004)
      1995–1999

      Female 5.70

      Male 4.10
      NR
      2000–2004

      Female 7.10

      Male 4.30
      NR
      Papathanasopoulos 200852

      Western Greece, Prefectures of Aitolokarnania, Achaia and Ilia, Greece
      Poser;

      McDonald 2001, 2005
      Hospital clinic records1987–19912.993.24
      Age-standardised to 2006–7 European population (EUROSTAT; December 3, 2007).
      0.47 (0.27, 0.66) p<0.001Incidence increased
      1992–19967.017.53
      Age-standardised to 2006–7 European population (EUROSTAT; December 3, 2007).
      (1987–2006)
      1997–20016.917.54
      Age-standardised to 2006–7 European population (EUROSTAT; December 3, 2007).
      2002–200610.0810.74
      Age-standardised to 2006–7 European population (EUROSTAT; December 3, 2007).
      Piperidou 200353

      Province of Evros, North-Eastern Greece
      PoserHospital records, outpatient clinic, private neurologists, Greek MS Association1989–19932.09

      (1.17–3.44)
      NR-0.01 (-0.15, 0.13) p=0.87Incidence stable

      (1989–1999)
      1994–19992.36

      (1.44–3.65)
      NR
      Cocco 201154

      South-Western part of Sardinia, Italy
      McDonald 2001, 2005Two MS referral centres, rehabilitation centres1988–1997NR5.94
      Total population of the South-Western Sardinia Population Cocco et al., 2011.
      0.16 (0.11, 0.21) p<0.001Incidence increased
      1998–2007NR8.07
      Total population of the South-Western Sardinia Population Cocco et al., 2011.
      (1988–2007)
      Granieri 200055

      Province of Nuoro, Sardinia, Italy
      Allison and Millar, 1954;

      Schumacher;

      Poser

      Hospital records, neurologists records, health records, National Pension Institute and National Health Insurance Scheme, MS Association1985–19896.60

      (5.30–8.10)
      NR-0.03 (-0.04, -0.02) p<0.001Incidence decreased

      (1985–1995)
      1990–19956.40

      (5.25–7.80)
      NR
      Granieri 200756

      Province of Ferrara, Emilia-Romagna Region, North-eastern Italy
      PoserHospitals, MS Centers, healthcare records, National Health Insurance Scheme, Italian MS Association, Telephone Surveys with health professionals1990–19943.443.40
      Age-standardised to the European Standard Population (1976).
      0.14 (0.07, 0.20) p=0.001Incidence increased
      1995–19994.154.30
      Age-standardised to the European Standard Population (1976).


      (1990–1999)


      Grassivaro 201957

      Province of Padua (Padova), Northeast Italy
      McDonald 2001, 2005Neurological centres, drug-dispensing records, outpatient records of neurorehabilitation services, chronic care services, local branch of the Italian Society for MS, archives of the National Pension Institute and National Health Insurance1990–1999

      4.10

      NR0.12 (0.10, 0.13) p<0.001

      Incidence increased

      (1990–2015)
      2000–20095.50

      NR
      2011–20156.50NR
      Nicoletti 201158

      City of Catania, Sicily, Italy
      PoserNeurological departments, Italian MS Association and clinical records1985–19892.30

      (1.60–3.10)
      2.20
      Age-standardised to the Italian population, Census 2001.
      0.29 (0.25, 0.33) p<0.001Incidence increased (1985–2004)
      1990–19943.90

      (3.00–5.00)
      3.90
      Age-standardised to the Italian population, Census 2001.
      1995–19995.50

      (4.40–6.70)
      5.70
      Age-standardised to the Italian population, Census 2001.
      2000–20047.00

      (4.30–10.20)
      6.80
      Age-standardised to the Italian population, Census 2001.
      Nicoletti 201359

      Mount Etna Regions, Catania, Sicily, Italy
      PoserHospitals, MS Centers and Italian MS Association1990–1999 Western Flank4.203.70
      Age- and sex-standardised to the Italian population, National Census 2011.
      0.02 (0.01, 0.02) p<0.001

      (Western Flank)

      0.04 (0.03, 0.05) p<0.001

      (Eastern Flank)
      Incidence increased

      Western and Eastern Flank
      2000–2009 Western Flank4.403.90
      Age- and sex-standardised to the Italian population, National Census 2011.
      (1990–2009)
      1990–1999 Eastern Flank5.505.10
      Age- and sex-standardised to the Italian population, National Census 2011.
      2000–2009 Eastern Flank6.405.60
      Age- and sex-standardised to the Italian population, National Census 2011.
      Nicoletti 202060

      Province of Catania, Sicily, Italy
      McDonald 2001Neurological

      divisions and MS Centers of Catania
      2005–20108.70

      (7.97–9.42)
      NR-0.15 (-0.22, -0.08) p=0.001Incidence decreased (2005–2015)
      2011–20157.60

      (6.86–8.32)
      NR
      Patti 201961

      City of Biancavilla, Catania, Sicily, Italy
      Assessed separately using McDonald criteria 2001 and 2017Standardised database management system used by the main MS Centers in Italy1992–19966.30 (2001 criteria)

      4.50 (2017 criteria)
      NR0.55 (0.48, 0.63) p<0.001

      (2001 criteria)

      0.51 (0.43, 0.59) <0.001

      (2017 criteria)

      Incidence increased

      2001 and 2017 criteria

      (1992–2018)

      1997–2001

      7.10 (2001 criteria)

      10.70 (2017 criteria)
      NR
      2002–2006

      8.80 (2001 criteria)

      9.60 (2017 criteria)
      NR
      2007–2011

      14.50 (2001 criteria)

      13.60 (2017 criteria)
      NR
      2012–201817.40 (2001 criteria)

      16.80 (2017 criteria)
      NR
      Pugliatti 200162

      Province of Sassari, Northern Sardinia, Italy
      PoserHospital records, neurological clinic, private neurologists, GPs National MS Society1988–19926.20

      (5.30–7.30)
      NR0.09 (0.05, 0.13) p=0.001Incidence increased

      (1988–1997)
      1993–19976.80

      (5.80–7.90)
      NR
      Pugliatti 200563

      Province of Sassari, Northern Sardinia, Italy
      PoserMS registry1985–19896.50

      (5.40–7.60)
      6.00
      Age-standardised to the Italian population, Census 2001.
      -0.02 (-0.3, -0.00) p=0.01Incidence decreased

      (1985–1999)
      1990–19946.50

      (5.40–7.60)
      6.10
      Age-standardised to the Italian population, Census 2001.
      1995–19996.10

      (5.10–7.20)
      5.80
      Age-standardised to the Italian population, Census 2001.
      Ranzato 200364

      Province of Padova (Padua), Northeast Italy
      PoserHospital records, health records, Association if Invaliding Disease of Padova, National Pension Institute and National Health Insurance Scheme, Italian MS Society1985–19892.60

      (2.08–3.12)
      NR0.14 (0.01, 0.19) p<0.001Incidence increased

      (1985–1999)
      1990–19943.90

      (3.19–4.61)
      NR
      1995–19994.20

      (3.74–4.66)
      NR
      Salemi 200065

      Bagheria City, Palermo, Sicily, Italy
      PoserHospital records, out-patient neurology clinic, GPs & neurologists were ‘informed’, rehabilitation archives,

      public & private MRI centres, Office for Handicapped People, social workers, television channel
      1985–19893.50

      (1.50–6.90)
      NR0.27 (0.15, 0.40) p=0.001Incidence increased

      (1985–1994)
      1990–19945.30

      (2.70–9.20)
      NR
      Solaro 201566

      Province of Genoa, Italy
      PoserHospital records, regionally serving neurologists, health records, disability pension records, Italian MS Society1998–20026.82NR-0.05 (-0.34, 0.25) p=0.72Incidence stable
      2003–20076.26NR(1998–2007)
      Granieri 200867

      Republic of San Marino
      PoserHospital records (private & public), telephone surveys of neurologists, ophthalmologists, GPs, pharmacists, social workers1990–199410.80

      (6.00–19.00)
      NR-0.32 (-0.49, -0.15) p=0.001Incidence decreased

      (1990–2005)
      1995–19996.20

      (2.80–12.60)
      NR
      2000–20056.80

      (3.20–11.40)
      NR
      1999–20031.7

      (0.00–3.40)
      NR
      Valadkeviciene 201868

      Lithuania
      ICD-10 code G35: newly diagnosed MS in ambulatory serviceCompulsory Health Insurance System including ambulatory and stationary visits2001–20055.485.36
      Age-standardised to the European Standard Population (2013).
      0.47 (0.32, 0.63) p<0.001Incidence increased
      2006–20106.626.42
      Age-standardised to the European Standard Population (2013).
      (2001–2015)
      2011–20159.859.69
      Age-standardised to the European Standard Population (2013).
      Kramer 201269

      Netherlands
      International Classification for Primary Care (records for more than 400 GPs in the Netherlands)Integrated Primary Care Information database (a GP research database)1999–20033.97NR0.61 (0.15, 1.06) p=0.02Incidence increased
      2004–20086.67NR(1999–2008)
      Izquierdo 201570

      Northern Seville District of Andalucia, Southern Spain
      PoserHospital records, public and private neurologists1991–2000Female 4.30

      (3.60–4.90)

      Male 2.50

      (2.00–2.90)
      NR0.36 (0.17, 0.54) p=0.001

      (Female)

      -0.00 (-0.12, 0.11) p=0.96

      (Male)
      Incidence increased

      Female

      (1991–2010)
      2001–2010Female 8.80

      (7.84–9.69)

      Male 2.80

      (2.30–3.40)
      NRIncidence increased

      Male

      (1991–2010)

      Modrego 200371

      Bajo Aragon, Teruel, Central-Eastern Spain
      Poser (used from 1994–2002);

      criteria not specified (1984–1993)
      Hospital (inpatient and outpatient) records1988–19923.20NR0.05 (-0.40, 0.51) p=0.81Incidence stable

      (1988–2002)
      1993–19975.01NR
      1998–20024.37NR
      Hirst 200972

      Cardiff, South East Wales, United Kingdom
      Poser;

      McDonald 2001
      Hospital records, GP notifications, consultant neurologists1988–19924.90NR0.28 (0.22, 0.34) p<0.001Incidence increased
      1993–19975.70NR(1988–2007)
      1998–20027.15NR
      2003–20078.75NR
      Mackenzie 201473

      United Kingdom
      General Practice Research Database Read codes for confirmed diagnosis of MS beginning with F20General Practice Research Database, hospital records1991–1995Female 13.95

      Male 6.69
      NR-0.11 (-0.21, -0.00) p=0.05

      (Female)

      -0.12 (-0.20, -0.05) p=0.004

      (Male)
      Incidence decreased

      (1991–2010)
      1996–2000Female 13.23

      Male 6.07
      NRFemale

      Incidence decreased

      (1991–2010)
      2001–2005Female 13.26

      Male 5.26
      NRMale
      2006–2010Female 12.14

      Male 4.99
      NR
      Eastern Mediterranean Region
      Cheraghmakani 202074

      Mazandaran Province, Northern Iran
      McDonald 2001Provincial MS Society (‘collaborates with Mazandaran University of Medical Sciences, Neurology Association and other healthcare organisations’)2009–20135.484.64
      Age-standardised to the WHO World Standard Population 2000–2025.
      0.08 (-0.09, 0.24) p=0.31Incidence stable
      2014–20185.804.98
      Age-standardised to the WHO World Standard Population 2000–2025.
      (2009–2018)




      Elhami 201175

      Tehran, Northern Iran
      Poser (used up to 2001);

      McDonald 2001, 2005
      National MS Society (‘works in close cooperation with government; Iranian Neurological Association encourages neurologists to refer to the society’)1989–19931.011.00
      Age-standardised to the WHO World Standard Population 2000–2025.
      0.20 (0.16, 0.25) p<0.001Incidence increased
      1994–19982.352.21
      Age-standardised to the WHO World Standard Population 2000–2025.
      (1989–2008)
      1999–20034.023.49
      Age-standardised to the WHO World Standard Population 2000–2025.
      2004–20085.084.09
      Age-standardised to the WHO World Standard Population 2000–2025.


      Izadi 201576

      Fars Province, Southern Iran
      McDonald 2010MS centre referred by neurologists, Fars MS Society2003–20073.42NR0.87 (0.64, 1.09) p<0.001Incidence increased
      2008–20127.73NR(2003–2012)
      Mohebi 201977

      Tehran, Iran
      McDonald 2001MS Society1992–19962.480.18 (0.08, 0.28) p=0.001Incidence increased
      1997–20014.20(1992–2016)
      2002–20066.45
      2007–20117.49
      2012–20165.52
      Western Pacific Region
      Ribbons 201778

      Newcastle, Australia
      Poser;

      McDonald 2010
      Public & private neurologists, private GPs, hospital discharge records and MS outpatient clinic database1986–19962.442.44 (1.68–3.47)0.24 (0.19, 0.29) p<0.001Incidence increased
      2001–20116.706.70
      Age-standardised to the Australian population, Census 2011.
      (5.39–8.01)

      (1986–2011)
      Houzen 201879

      Tokachi Province, Hokkaido, Northern Japan
      PoserMS-related institutions (inpatient and outpatient clinical records)1985–19890.22

      (0.06–0.56)
      NR0.02 (0.01, 0.02) p<0.001

      Incidence increased (1985–2014)
      1990–19940.45

      (0.19–0.89)
      NR
      1995–19990.61

      (0.30–1.29)
      NR
      2000–20040.72

      (0.38–1.23)
      NR
      2005–20090.79

      (0.43–1.33)
      NR
      2010–20140.68

      (0.35–1.19)
      NR
      Fang 202080

      Taiwan
      ≥1 hospital or ≥3 outpatient claims (ICD-9 codes 340) within 2 yearsNational Health Insurance Research Database2006–20101.631.47
      Age-standardised to the WHO World Standard Population 2000–2025.
      0.01 (-0.02, 0.04) p=0.38Incidence stable
      2011–20151.691.52
      Age-standardised to the WHO World Standard Population 2000–2025.
      (2006–2015)
      Paediatric-only studies
      Marrie 201818

      Ontario, Canada
      Marrie algorithm ≥3 hospital or physician claims for MS (ICD-9/10 codes 340/G35)

      CCDSS algorithm ≥1 hospital or ≥5 physician claims (ICD-9/10 codes 340/G35) within 2 years; (restricted to: 0–18 years)
      Province-wide health administrative including hospital and physician claims2005–2009NR1.68
      Age- and sex standardised to the Canadian population, Census 2006.


      (Marrie algorithm)

      1.17
      Age- and sex standardised to the Canadian population, Census 2006.
      (CCDSS)
      -0.012 (-0.13, 0.10) p=0.81

      (Marrie algorithm)

      -0.002 (-0.10, 0.10) p=0.97

      (CCDSS)

      Incidence stable

      Marrie algorithm

      (2005–2013)
      2010–2014NR1.57
      Age- and sex standardised to the Canadian population, Census 2006.


      (Marrie algorithm)

      1.01
      Age- and sex standardised to the Canadian population, Census 2006.
      (CCDSS)
      Incidence stable

      CCDSS

      (2005–2013)
      Boesen 201881

      Denmark
      Allison and Millar, 1954 (used until 1994);

      Poser (used 1994–2004);

      McDonald (used from 2005); (restricted to: <18 years)
      Danish MS Registry (all Danish departments of neurology contribute)1986–1990Female 0.94

      Male 0.46
      NR0.009 (-0.02,0.35) p=0.47

      (Female)

      -0.002 (-0.02, 0.01) p=0.79

      (Male)
      Incidence stable

      (1986–2015)
      1991–1995Female 1.36

      Male 0.59
      NR
      1996–2000Female 1.65

      Male 0.63
      NR
      2001–2005Female 1.28

      Male 0.57
      NR
      2006–2010Female 1.58

      Male 0.43
      NR
      2011–2015Female 1.14

      Male 0.44
      NR
      Alroughani 201582

      Kuwait
      IPMSSG consensus definition 2007 (
      • Krupp L.B.
      • Banwell B.
      • Tenembaum S.
      • et al.
      Consensus definitions proposed for pediatric multiple sclerosis and related disorders.
      ) (restricted to: <18 years at MS onset)
      Kuwait National MS Registry (hospital and MS clinic databases)1994–19980.66NR0.07 (0.03, 0.10) p=0.001Incidence increased
      1999–20031.29NR(1994–2013)
      2004–20081.45NR
      2009–20131.77NR
      CCDSS=Canadian Chronic Disease Surveillance System. NR=not reported. CNS=central nervous system. DMD=disease modifying drug (used in the treatment of MS). ICD=International Classification of Diseases. BOT-MS = Buskerud (Vestre Viken Hospital Trust in Drammen), Telemark (Telemark Hospital Trust in Skien), Oslo University Hospital. ESP=European Standard Population. WHO=World Health Organization. GP=general practitioner.
      # Absolute annual change is the coefficient of the linear trend line across the data points provided for each year or 5-year period; standardised incidence rates used where provided, otherwise, crude incidence rates.
      low asterisk Qualitative summary based on the regression coefficient, 95% confidence interval for the absolute annual change, and p-value. IPMSSG = International pediatric MS Study Group.
      a Age- and sex-standardised to the Canadian population, Census 2001.
      b Age- and sex-standardised to the Ontario population, Canadian Census 2001.
      c Age- and sex-standardised to the Ontario population, Census 1991.
      d Age- and sex-standardised to the Canadian population, Census 1996.
      e Age-standardised to the European Standard Population (2013).
      f Age-standardised to the European Standard Population (1976).
      g Age-standardised to 2006–7 European population (EUROSTAT; December 3, 2007).
      h Total population of the South-Western Sardinia Population Cocco et al., 2011.
      i Age-standardised to the Italian population, Census 2001.
      j Age- and sex-standardised to the Italian population, National Census 2011.
      k Age-standardised to the WHO World Standard Population 2000–2025.
      l Age-standardised to the Australian population, Census 2011.
      m Age- and sex standardised to the Canadian population, Census 2006.

      3.1 Whole-of-population studies

      Estimates of the number of reported incident MS cases (and the periods of study) varied greatly, from a low of 20 (1985–1994) in Bagheria City, Italy (
      • Salemi G.
      • Ragonese P.
      • Aridon P.
      • Scola G.
      • Saporito V.
      • Conte S.
      • et al.
      Incidence of multiple sclerosis in Bagheria City, Sicily, Italy.
      ), to a high of 18,105 (2006–2015) in Bavaria, Germany (
      • Daltrozzo T.
      • Hapfelmeier A.
      • Donnachie E.
      • Schneider A.
      • Hemmer B.
      A Systematic Assessment of Prevalence, Incidence and Regional Distribution of Multiple Sclerosis in Bavaria from 2006 to 2015.
      ) (Table 2). Nine studies reported incidence rates only, and not the absolute number of incident MS cases (
      • Rotstein D.L.
      • Chen H.
      • Wilton A.S.
      • Kwong J.C.
      • Marrie R.A.
      • Gozdyra P.
      • et al.
      Temporal trends in multiple sclerosis prevalence and incidence in a large population.
      ;
      • Simonsen C.S.
      • Edland A.
      • Berg-Hansen P.
      • Celius EG.
      High prevalence and increasing incidence of multiple sclerosis in the Norwegian county of Buskerud.
      ;
      • Vatne A.
      • Mygland A.
      • Ljostad U.
      Multiple sclerosis in Vest-Agder County, Norway.
      ;
      • Klupka-Sarić I.
      • Ristić S.
      • Sepcić J.
      • Kapović M.
      • Peterlin B.
      • Materljan E.
      • et al.
      Epidemiology of multiple sclerosis in western Herzegovina.
      ;
      • Kotzamani D.
      • Panou T.
      • Mastorodemos V.
      • Tzagournissakis M.
      • Nikolakaki H.
      • Spanaki C.
      • et al.
      Rising incidence of multiple sclerosis in females associated with urbanization.
      ;
      • Cocco E.
      • Sardu C.
      • Massa R.
      • Mamusa E.
      • Musu L.
      • Ferrigno P.
      • et al.
      Epidemiology of multiple sclerosis in south-western Sardinia.
      ;
      • Grassivaro F.
      • Puthenparampil M.
      • Pengo M.
      • Saiani M.
      • Venturini M.
      • Stropparo E.
      • et al.
      Multiple sclerosis incidence and prevalence trends in the province of Padua, Northeast Italy, 1965-2018.
      ;
      • Izadi S.
      • Nikseresht A.R.
      • Poursadeghfard M.
      • Borhanihaghighi A.
      • Heydari ST.
      Prevalence and incidence of multiple sclerosis in Fars Province, Southern Iran.
      ;
      • Mohebi F.
      • Eskandarieh S.
      • Mansournia M.A.
      • Mohajer B.
      • Sahraian MA.
      Multiple sclerosis in Tehran: rising prevalence alongside stabilizing incidence - true increase or enhanced diagnosis?.
      ). Less than half of the estimates were in the form of age and sex-standardised incidence rates (n=26, 42%), using a variety of standard populations (Table 1).
      Table 2Incident multiple sclerosis over time: average annual number of incident cases over total time period and approximate proportion of total country population covered by the regional study (year 2000/1 or closest available total population for the entire country).
      Broad study location (number of studies); total general underlying population, plus calendar year; percentage of country's population covered by the studyRegional study location

      [population]
      Total number incident MS cases/ total time period in years (study calendar years and other relevant detail)Average annual number of casesApproximate proportion of total country population covered by regional study
      (denominator=year 2000/1, or closet available total population for the entire country)
      Americas Region
      Canada (8)

      Total Canada population

      2000=30,736,000
      Total population at mid-year by region in United Nations (United Nations, 2017)


      2001=31,081,887
      Statistics Canada - https://www150.statcan.gc.ca/n1/daily-quotidien/010925/dq010925a-eng.htm


      Approximate proportion of total (unique) country population covered by regional studies in Canada=69%
      Saskatchewan (
      • Al-Sakran L.H.
      • Marrie R.A.
      • Blackburn D.F.
      • Knox K.B.
      • Evans C.D.
      Establishing the incidence and prevalence of multiple sclerosis in Saskatchewan.
      )

      [1021,992
      Statistics Canada - https://www150.statcan.gc.ca/n1/daily-quotidien/010925/dq010925a-eng.htm
      ]
      2226/13

      (2001–2013; Marrie case definition)

      1903/13

      (2001–2013; CCDSS case definition)
      171.2



      146.4
      3.3%

      Saskatoon (
      • Hader W.J.
      • Yee I.M.L.
      Incidence and prevalence of multiple sclerosis in Saskatoon, Saskatchewan.
      )

      [196,81018]
      254/15

      (1990–2004)
      16.90.6%
      British Columbia (
      • Kingwell E.
      • Zhu F.
      • Marrie R.A.
      • Fisk J.D.
      • Wolfson C.
      • Warren S.
      • et al.
      High incidence and increasing prevalence of multiple sclerosis in British Columbia, Canada: findings from over two decades (1991-2010).
      )

      [4058,833
      Statistics Canada - https://www150.statcan.gc.ca/n1/daily-quotidien/010925/dq010925a-eng.htm
      ]
      3284/10

      (1999–2008)
      328.413.2%

      Nova Scotia (
      • Marrie R.A.
      • Fisk J.D.
      • Stadnyk K.J.
      • Yu B.N.
      • Tremlett H.
      • Wolfson C.
      • et al.
      The Incidence and Prevalence of Multiple Sclerosis in Nova Scotia, Canada.
      )

      [941,199
      Statistics Canada - https://www150.statcan.gc.ca/n1/daily-quotidien/010925/dq010925a-eng.htm
      ]
      1441/16

      (1995–2010)
      90.13.1%

      Ontario (
      • Rotstein D.L.
      • Chen H.
      • Wilton A.S.
      • Kwong J.C.
      • Marrie R.A.
      • Gozdyra P.
      • et al.
      Temporal trends in multiple sclerosis prevalence and incidence in a large population.
      )

      [11,685,304
      Statistics Canada - https://www150.statcan.gc.ca/n1/daily-quotidien/010925/dq010925a-eng.htm
      ]
      Standardised incidence only reported

      (1999–2013)
      Ontario (
      • Widdifield J.
      • Ivers N.M.
      • Young J.
      • Green D.
      • Jaakkimainen L.
      • Butt D.A.
      • et al.
      Development and validation of an administrative data algorithm to estimate the disease burden and epidemiology of multiple sclerosis in Ontario, Canada.
      )

      [11,685,304
      Statistics Canada - https://www150.statcan.gc.ca/n1/daily-quotidien/010925/dq010925a-eng.htm
      ]
      15,677/10

      (2001–2010)
      1567.738.0%

      Newfoundland and Labrador (
      • Sloka J.S.
      • Pryse-Phillips W.E.
      • Stefanelli M.
      Incidence and prevalence of multiple sclerosis in Newfoundland and Labrador.
      )

      [537,221
      Statistics Canada - https://www150.statcan.gc.ca/n1/daily-quotidien/010925/dq010925a-eng.htm
      ]
      571/44

      (1958–2001)
      13.01.7%

      Alberta (
      • Warren S.
      • Svenson L.W.
      • Warren K.
      Contribution of incidence to increasing prevalence of multiple sclerosis in Alberta, Canada.
      )

      [3009,249
      Statistics Canada - https://www150.statcan.gc.ca/n1/daily-quotidien/010925/dq010925a-eng.htm
      ]
      9307/15

      (1990–2004)
      620.59.8%

      French West Indies (1)

      Total Caribbean population 2000=38,404,000
      Total population at mid-year by region in United Nations (United Nations, 2017)


      Martinique and Guadeloupe population 2000=812,000

      Approximate proportion of total (unique) country population covered by regional studies in the Caribbean=2%
      Martinique and Guadeloupe (
      • Cabre P.
      Environmental changes and epidemiology of multiple sclerosis in the French West Indies.
      )

      Martinique [387,000
      Total population at mid-year by region in United Nations (United Nations, 2017)
      ]

      Guadeloupe [425,000
      Total population at mid-year by region in United Nations (United Nations, 2017)
      ]
      92/15 (Martinique)

      38/15 (Guadeloupe)

      (July 1992-June 2007)
      6.1

      2.5
      2.1%

      (Martinique & Guadeloupe)

      Republic of Panama (1)

      Total population 2000=3030,000
      Total population at mid-year by region in United Nations (United Nations, 2017)


      Republic of Panama=100% covered
      Republic of Panama (
      • Gracia F.
      • Castillo L.C.
      • Benzadon A.
      • Larreategui M.
      • Villareal F.
      • Triana E.
      • et al.
      Prevalence and incidence of multiple sclerosis in Panama (2000-2005.
      )

      144/16

      (1990–2005)
      9.0100%
      Europe Region
      Denmark (2)

      Total Denmark population 2000=5341,000
      Total population at mid-year by region in United Nations (United Nations, 2017)


      Total Denmark population 2010=5547,68329

      Faroe Islands Population 2000=47,000
      Total population at mid-year by region in United Nations (United Nations, 2017)


      Denmark=100% covered
      Faroe Islands, Denmark (
      • Joensen P.
      Multiple sclerosis: variation of incidence of onset over time in the Faroe Islands.
      )
      28/15

      (1993–2007)
      1.90.9%

      Denmark (
      • Koch-Henriksen N.
      • Thygesen L.C.
      • Stenager E.
      • Laursen B.
      • Magyari M.
      Incidence of MS has increased markedly over six decades in Denmark particularly with late onset and in women.
      )
      9434/20

      (1990–2009)
      471.7100%

      Finland (2)

      Total Finland population 2000=5188,000
      Total population at mid-year by region in United Nations (United Nations, 2017)


      Central Finland population 2000=1981,855
      http://pxnet2.stat.fi/PXWeb/pxweb/en/StatFin/StatFin__vrm__vaerak/statfin_vaerak_pxt_11ra.px


      Vaasa=154,373
      http://pxnet2.stat.fi/PXWeb/pxweb/en/StatFin/StatFin__vrm__vaerak/statfin_vaerak_pxt_11ra.px


      Seinäjoki=170,600
      http://pxnet2.stat.fi/PXWeb/pxweb/en/StatFin/StatFin__vrm__vaerak/statfin_vaerak_pxt_11ra.px


      Uusimaa=1391,199
      http://pxnet2.stat.fi/PXWeb/pxweb/en/StatFin/StatFin__vrm__vaerak/statfin_vaerak_pxt_11ra.px


      Approximate proportion of total (unique) country population covered by regional studies in Finland=45%
      Northern Ostrobothnia, Northern Finland (
      • Krokki O.
      • Bloigu R.
      • Reunanen M.
      • Remes A.M.
      Increasing incidence of multiple sclerosis in women in Northern Finland.
      )

      [372,639
      http://www.stat.fi/index_en.html
      ]
      374/16

      (1992–2007)
      23.47.2%
      Central Finland (
      • Sarasoja T.
      • Wikstrom J.
      • Paltamaa J.
      • Hakama M.
      • Sumelahti M.L.
      Occurrence of multiple sclerosis in central Finland: a regional and temporal comparison during 30 years.
      ) (also included Vaasa, Seinäjoki, and Uusimaa)

      [1981,855
      http://pxnet2.stat.fi/PXWeb/pxweb/en/StatFin/StatFin__vrm__vaerak/statfin_vaerak_pxt_11ra.px
      ]
      146/10

      (1989–1998)
      14.638.2%

      Iceland (1)

      Total Iceland population 2000=280,000
      Total population at mid-year by region in United Nations (United Nations, 2017)


      Iceland=100% covered
      Iceland (
      • Benedikz J.
      • Stefansson M.
      • Guomundsson J.
      • Jonasdot tir A.
      • Fossdal R.
      • Gulcher J.
      • et al.
      The natural history of untreated multiple sclerosis in Iceland. A total population-based 50 year prospective study.
      )
      372/50

      (1950–1999)
      7.4100%
      Norway (10)

      Total Norway population 1 Jan 2001=4503,436
      https://www.ssb.no/en/befolkning/artikler-og-publikasjoner/_attachment/146,776?_ts=143c3b051c8


      Approximate proportion of total (unique) country population covered by regional studies in Norway=56%
      Nordland County (
      • Benjaminsen E.
      • Olavsen J.
      • Karlberg M.
      • Alstadhuag KB.
      Multiple sclerosis in the far north - incidence and prevalence in Nordland Country, Norway, 1970-2010.
      )

      [238,295
      https://www.ssb.no/en/befolkning/artikler-og-publikasjoner/_attachment/146,776?_ts=143c3b051c8
      ]
      416/25

      (1985–2009)
      16.65.3%

      Oslo (
      • Celius E.G.
      • Vandvik B.
      Multiple sclerosis in Oslo, Norway: prevalence on 1 January 1995 and incidence over a 25-year period.
      )

      [508,726
      https://www.ssb.no/en/befolkning/artikler-og-publikasjoner/_attachment/146,776?_ts=143c3b051c8
      ]
      374/10

      (1987–1996)
      37.411.3%

      Nord-Trøndelag County (
      • Dahl O.P.
      • Aarseth J.H.
      • Myhr K.M.
      • Nyland H.
      • Midgard R.
      Multiple sclerosis in Nord-Trondelag County, Norway: a prevalence and incidence study.
      )

      [127,261
      https://www.ssb.no/en/befolkning/artikler-og-publikasjoner/_attachment/146,776?_ts=143c3b051c8
      ]
      64/10

      (1989–1998)
      6.42.8%
      Telemark County (
      • Flemmen H.O.
      • Simonsen C.S.
      • Berg-Hansen P.
      • Moen S.M.
      • Kersten H.
      • Heldal K.
      • et al.
      Prevalence of multiple sclerosis in rural and urban districts in Telemark county, Norway.
      )

      [165,595
      https://www.ssb.no/en/befolkning/artikler-og-publikasjoner/_attachment/146,776?_ts=143c3b051c8
      ]
      380/20

      (1999–2018)
      19.03.7%

      Hordaland County (
      • Grytten N.
      • Aarseth J.H.
      • Lunde H.M.
      • Myhr KM.
      A 60-year follow-up of the incidence and prevalence of multiple sclerosis in Hordaland County, Western Norway.
      )

      [438,312
      https://www.ssb.no/en/befolkning/artikler-og-publikasjoner/_attachment/146,776?_ts=143c3b051c8
      ]
      1558/61

      (1953–2013)
      25.59.7%

      Vestfold County (
      • Lund C.
      • Nakken K.O.
      • Edland A.
      • Celius EG.
      Multiple sclerosis and seizures: incidence and prevalence over 40 years.
      )

      [215,030
      https://www.ssb.no/en/befolkning/artikler-og-publikasjoner/_attachment/146,776?_ts=143c3b051c8
      ]
      504/21

      (1983–2003)
      24.04.8%

      Oppland County (
      • Risberg G.
      • Aarseth J.H.
      • Nyland H.
      • Lauer K.
      • Myhr K.M.
      • Midgard R.
      Prevalence and incidence of multiple sclerosis in Oppland County: a cross-sectional population-based study in a landlocked county of Eastern Norway.
      )

      [183,419
      https://www.ssb.no/en/befolkning/artikler-og-publikasjoner/_attachment/146,776?_ts=143c3b051c8
      ]
      127/10

      (1989–1998)
      12.74.1%

      Buskerud County (
      • Simonsen C.S.
      • Edland A.
      • Berg-Hansen P.
      • Celius EG.
      High prevalence and increasing incidence of multiple sclerosis in the Norwegian county of Buskerud.
      )

      [238,833
      https://www.ssb.no/en/befolkning/artikler-og-publikasjoner/_attachment/146,776?_ts=143c3b051c8
      ]
      Average annual crude incidence 11.8 per 100,000

      (2003–2012)
      29.6
      estimated from the average incidence for the period from the relevant paper and the average population for the period from the relevant national statistics organization.
      5.3%

      Vest-Agder County (
      • Vatne A.
      • Mygland A.
      • Ljostad U.
      Multiple sclerosis in Vest-Agder County, Norway.
      )

      [156,878
      https://www.ssb.no/en/befolkning/artikler-og-publikasjoner/_attachment/146,776?_ts=143c3b051c8
      ]
      Estimated

      (1996–2006)
      11.5
      estimated from the average incidence for the period from the relevant paper and the average population for the period from the relevant national statistics organization.
      3.5%

      Møre and Romsdal County (
      • Willumsen J.S.
      • Aarseth J.H.
      • Myhr K.M.
      • Midgard R.
      High incidence and prevalence of MS in More and Romsdal County, Norway.
      )

      [243,810
      https://www.ssb.no/en/befolkning/artikler-og-publikasjoner/_attachment/146,776?_ts=143c3b051c8
      ]
      785/30

      (1985–2014)
      26.25.4%

      Sweden (2)

      Total Sweden population 2000=8882,000
      Total population at mid-year by region in United Nations (United Nations, 2017)


      Approximate proportion of total (unique) country population covered by regional studies in Sweden=6%
      Värmland County (
      • Bostrom I.
      • Callander M.
      • Kurtzke J.F.
      • Landtblom A.M.
      High prevalence of multiple sclerosis in the Swedish county of Varmland.
      )

      [275,003
      https://www.citypopulation.de/en/sweden/
      ]
      181/10

      (1991–2000)
      18.13.1%

      Västerbotten County (
      • Svenningsson A.
      • Salzer J.
      • Vagberg M.
      • Sundstrom P.
      • Svenningsson A.
      Increasing prevalence of multiple sclerosis in Vasterbotten County of Sweden.
      )

      [255,640
      https://www.citypopulation.de/en/sweden/
      ]
      201/13

      (1998–2010)
      15.52.9%

      Croatia (1)

      Total Croatia population 2000=4428,000
      Total population at mid-year by region in United Nations (United Nations, 2017)


      Approximate proportion of total (unique) country population covered by regional studies in Croatia=3%
      Bjelovar-Bilogora County, Croatia (
      • Vrabec-Matkovic D.
      • Ivanusa Z.
      • Sarko B.
      • Golubic J.
      • Sklebar D.
      Epidemiology of multiple sclerosis in the Bjelovar-Bilogora County.
      )

      [133,084 in 2001
      https://www.dzs.hr/eng/censuses/Census2001/Popis/E01_01_01/E01_01_01.html
      ]
      47/15

      (1987–2001)
      3.13.0%

      Bosnia-Herzegovina (1)

      Total Bosnia-Herzegovina population 2000=3767,000
      Total population at mid-year by region in United Nations (United Nations, 2017)
      Western Herzegovina (
      • Klupka-Sarić I.
      • Ristić S.
      • Sepcić J.
      • Kapović M.
      • Peterlin B.
      • Materljan E.
      • et al.
      Epidemiology of multiple sclerosis in western Herzegovina.
      )

      [300,746 in 200348]
      Average annual crude incidence 1.6 per 100,000

      (1994–2003)
      4.7
      estimated from the average incidence for the period from the relevant paper and the average population for the period from the relevant national statistics organization.
      8.0%
      France (1)

      Total France population 2000=59,608,000
      Total population at mid-year by region in United Nations (United Nations, 2017)


      Approximate proportion of total (unique) country population covered by regional studies in France=4%
      Lorraine, France (
      • Debouverie M.
      • Pittion-Vouyovitch S.
      • Louis S.
      • Roederer T.
      • Guillemin F.
      Increasing incidence of multiple sclerosis among women in Lorraine, Eastern France.
      )

      [2310,376 in 199949]
      1375/10

      (1993–2002)
      137.53.9%
      Germany (1)

      Total Germany population 2000=

      81,488,000
      Total population at mid-year by region in United Nations (United Nations, 2017)


      Approximate proportion of total (unique) country population covered by regional studies in Germany=15%
      Bavaria, Germany (
      • Daltrozzo T.
      • Hapfelmeier A.
      • Donnachie E.
      • Schneider A.
      • Hemmer B.
      A Systematic Assessment of Prevalence, Incidence and Regional Distribution of Multiple Sclerosis in Bavaria from 2006 to 2015.
      )

      [12,329,714 in 2001
      https://www.citypopulation.de/en/germany/admin/09__bayern/
      ]
      18,105/10

      (2006–2015)
      1810.515.1%
      Greece (3)

      Total Greece population

      2000=11,142,000
      Total population at mid-year by region in United Nations (United Nations, 2017)


      Approximate proportion of total country population covered by regional studies in Greece=13%
      Crete, Greece (
      • Kotzamani D.
      • Panou T.
      • Mastorodemos V.
      • Tzagournissakis M.
      • Nikolakaki H.
      • Spanaki C.
      • et al.
      Rising incidence of multiple sclerosis in females associated with urbanization.
      )

      [579,672 in 2001
      https://www.statistics.gr/en/statistics/-/publication/SPO18/2001
      ]
      Incidence as reported in Table 1

      (1985–2008)
      23.1
      estimated from the average incidence for the period from the relevant paper and the average population for the period from the relevant national statistics organization.
      5.2%
      Western Greece, Greece, Prefectures of Aitolokarnania, Achaia and Ilia (
      • Papathanasopoulos P.
      • Gourzoulidou E.
      • Messinis L.
      • Georgiou V.
      • Leotsinidis M.
      Prevalence and incidence of multiple sclerosis in western Greece: a 23-year survey.
      )

      [740,506 in 200152]
      800/20

      (1987–2006)
      40.06.6%

      Province of Evros, North-Eastern Greece (
      • Piperidou H.N.
      • Heliopoulos I.N.
      • Maltezos E.S.
      • Milonas IA.
      Epidemiological data of multiple sclerosis in the province of Evros, Greece.
      )

      [144,402 in 2001
      https://www.statistics.gr/en/statistics/-/publication/SPO18/2001
      ]
      35/11

      (1989–1999)
      3.21.3%
      Italy (13)

      Total Italy population 21/10/2001 census=56,995,744
      https://www.citypopulation.de/en/italy/admin/


      Total Italy population in 2007=58,438,310
      https://data.worldbank.org/indicator/SP.POP.TOTL?locations=IT


      Total Italy population in 2011=59,433,744
      https://www.citypopulation.de/en/italy/admin/


      Approximate proportion of total country population covered by regional studies in Italy=7%
      South-Western part of Sardinia (
      • Cocco E.
      • Sardu C.
      • Massa R.
      • Mamusa E.
      • Musu L.
      • Ferrigno P.
      • et al.
      Epidemiology of multiple sclerosis in south-western Sardinia.
      )

      [138,765 in 200754]
      Crude mean annual incidence 9.7 per 100,000

      (1988–2007)
      13.5
      estimated from the average incidence for the period from the relevant paper and the average population for the period from the relevant national statistics organization.
      0.2%
      Province of Nuoro (
      • Granieri E.
      • Casetta I.
      • Govoni V.
      • Tola M.R.
      • Marchi D.
      • Murgia S.B.
      • et al.
      The increasing incidence and prevalence of MS in a Sardinian province.
      )

      [221,062
      https://www.citypopulation.de/en/italy/admin/
      ]
      195/11

      (1985–1995)
      17.70.4%
      Province of Ferrara (
      • Granieri E.
      • Economou N.T.
      • De Gennaro R.
      • Tola M.R.
      • Caniatti L.
      • Govoni V.
      • et al.
      Multiple sclerosis in the province of Ferrara: evidence for an increasing trend.
      )

      [344,323
      https://www.citypopulation.de/en/italy/admin/
      ]
      135/10

      (1990–1999)
      13.50.6%
      Province of Padua (Padova) (
      • Grassivaro F.
      • Puthenparampil M.
      • Pengo M.
      • Saiani M.
      • Venturini M.
      • Stropparo E.
      • et al.
      Multiple sclerosis incidence and prevalence trends in the province of Padua, Northeast Italy, 1965-2018.
      )

      [849,857
      https://www.citypopulation.de/en/italy/admin/
      ]
      Crude incidence as reported in Table 1

      (1990–2015)
      28.1
      estimated from the average incidence for the period from the relevant paper and the average population for the period from the relevant national statistics organization.
      1.5%
      City of Catania (
      • Nicoletti A.
      • Patti F.
      • Lo Fermo S.
      • Messina S.
      • Bruno E.
      • Quattrocchi G.
      • et al.
      Increasing frequency of multiple sclerosis in Catania, Sicily: a 30-year survey.
      )

      [313,11057]
      306/20

      (1985–2004)
      15.30.5%
      Mount Etna Regions, Catania (
      • Nicoletti A.
      • Bruno E.
      • Nania M.
      • Cicero E.
      • Messina S.
      • Chisari C.
      • et al.
      Multiple sclerosis in the Mount Etna region: possible role of volcanogenic trace elements.
      )

      [52,561 Western flank average population 1980–200959]

      [43,797 Eastern flank average population 1980–200959]
      46/20

      (1990–2009; Western Flank)

      53/20 (Eastern Flank)

      (1990–2009)
      2.3

      2.7
      0.09%

      Western flank

      0.07%

      Eastern flank
      Province of Catania (
      • Nicoletti A.
      • Rascuna C.
      • Boumediene F.
      • Vasta R.
      • Cicero C.E.
      • Lo Fermo S.
      • et al.
      Incidence of multiple sclerosis in the province of Catania. A geo-epidemiological study.
      )

      [1054,778
      https://www.citypopulation.de/en/italy/admin/
      ]
      973/11

      (2005–2015)
      88.51.9%
      City of Biancavilla (
      • Patti F.
      • Caserta C.
      • Colandonio S.
      • Iudica M.L.
      • Maimone D.
      • Lo Fermo S.
      • et al.
      Prevalence and incidence of multiple sclerosis in the city of Biancavilla.
      )

      [22,480
      http://population.city/italy/biancavilla/
      ]
      71/27

      (1992–2018)
      2.60.04%
      Province of Sassari (
      • Pugliatti M.
      • Sotgiu S.
      • Solinas G.
      • Castiglia P.
      • Pirastru M.I.
      • Murgia B.
      • et al.
      Multiple sclerosis epidemiology in Sardinia: evidence for a true increasing risk.
      )

      [460,660
      https://www.citypopulation.de/en/italy/admin/
      ]
      298/10

      (1988–1997)
      29.80.8%
      Province of Sassari (
      • Pugliatti M.
      • Riise T.
      • Sotgiu M.A.
      • Sotgiu S.
      • Satta W.M.
      • Mannu L.
      • et al.
      Increasing incidence of multiple sclerosis in the province of Sassari, Northern Sardinia.
      )

      [460,660
      https://www.citypopulation.de/en/italy/admin/
      ]
      430/15

      (1985–1999)
      28.70.8%
      Province of Padova (Padua) (
      • Ranzato F.
      • Perini P.
      • Tzintzeva E.
      • Tiberio M.
      • Calabrese M.
      • Ermani M.
      • et al.
      Increasing frequency of multiple sclerosis in Padova, Italy: a 30 year epidemiological survey.
      )

      [849,857
      https://www.citypopulation.de/en/italy/admin/
      ]
      580/20

      (1980–1999)
      29.01.5%
      Bagheria City (
      • Salemi G.
      • Ragonese P.
      • Aridon P.
      • Scola G.
      • Saporito V.
      • Conte S.
      • et al.
      Incidence of multiple sclerosis in Bagheria City, Sicily, Italy.
      )

      [50,850
      http://population.city/italy/bagheria/
      ]
      20/10

      (1985–1994)
      2.00.09%
      Province of Genoa (
      • Solaro C.
      • Ponzio M.
      • Moran E.
      • Tanganelli P.
      • Pizio R.
      • Ribizzi G.
      • et al.
      The changing face of multiple sclerosis: prevalence and incidence in an aging population.
      )

      [878,082
      https://www.citypopulation.de/en/italy/admin/
      ]
      575/10

      (1998–2007)
      57.51.5%
      Republic of San Marino (1)

      Total Republic of San Marino population 2000=27,000
      Total population at mid-year by region in United Nations (United Nations, 2017)


      Republic of San Marino=100% covered
      Republic of San Marino (
      • Granieri E.
      • Monaldini C.
      • De Gennaro R.
      • Guttmann S.
      • Volpini M.
      • Stumpo M.
      • et al.
      Multiple sclerosis in the Republic of San Marino: a prevalence and incidence study.
      )
      33/16

      (1990–2005)
      2.1100%
      Lithuania (1)

      Total Lithuania population

      2000=3502,000
      Total population at mid-year by region in United Nations (United Nations, 2017)


      Lithuania=100% covered
      Lithuania (
      • Valadkeviciene D.
      • Kavaliunas A.
      • Kizlaitiene R.
      • Jocys M.
      • Jatuzis D.
      Incidence rate and sex ratio in multiple sclerosis in Lithuania.
      )
      162+343/2

      (2001 and 2015)
      252.5100%
      Netherlands (1)

      Total Netherlands population

      2000=15,926,000
      Total population at mid-year by region in United Nations (United Nations, 2017)


      Netherlands=100% covered
      Netherlands (
      • Kramer M.A.
      • van der Maas N.A.
      • van Soest E.M.
      • Kemmeren J.M.
      • de Melker H.E.
      • Sturkenboom M.C.
      Incidence of multiple sclerosis in the general population in the Netherlands, 1996-2008.
      )
      84/13

      (1996–2008)
      6.5100%
      Spain (2)

      Total Spain population 2000=40,904,000
      Total population at mid-year by region in United Nations (United Nations, 2017)


      Approximate proportion of total country population covered by regional studies in Spain=<1%
      Northern Seville District of Andalucia, Southern Spain (
      • Izquierdo G.
      • Venegas A.
      • Sanabria C.
      • Navarro G.
      Long-term epidemiology of multiple sclerosis in the Northern Seville District.
      )

      [163,324 in 2001 (
      • Izquierdo G.
      • Venegas A.
      • Sanabria C.
      • Navarro G.
      Long-term epidemiology of multiple sclerosis in the Northern Seville District.
      )]
      156/20

      (1991–2010)
      7.80.4%
      Bajo Aragon, Teruel, Central-Eastern Spain (
      • Modrego P.J.
      • Pina M.A.
      Trends in prevalence and incidence of multiple sclerosis in Bajo Aragon, Spain.
      )

      [58,666 in 2001 (
      • Modrego P.J.
      • Pina M.A.
      Trends in prevalence and incidence of multiple sclerosis in Bajo Aragon, Spain.
      )]
      42/19

      (1984–2002)
      2.20.1%
      United Kingdom (2)

      Total United Kingdom population

      2000=58,951,000
      Total population at mid-year by region in United Nations (United Nations, 2017)
      Cardiff, South East Wales, United Kingdom (
      • Modrego P.J.
      • Pina M.A.
      Trends in prevalence and incidence of multiple sclerosis in Bajo Aragon, Spain.
      )

      [424,633 in 2001 (
      • Hirst C.
      • Ingram G.
      • Pickersgill T.
      • Swingler R.
      • Compston D.A.
      • Robertson NP.
      Increasing prevalence and incidence of multiple sclerosis in South East Wales.
      )]
      582/23

      (1985–2007)
      25.30.7%
      United Kingdom=100% coveredUnited Kingdom (
      • Mackenzie I.S.
      • Morant S.V.
      • Bloomfield G.A.
      • MacDonald T.M.
      • O'Riordan J.
      Incidence and prevalence of multiple sclerosis in the UK 1990-2010: a descriptive study in the general practice research database.
      )
      1538/14

      (1997–2010)
      109.9100%
      Eastern Mediterranean Region
      Iran (4)

      Total Iran population 2011=75,149,669
      https://www.amar.org.ir/Portals/1/census/2016/Census_2016_Selected_Findings.pdf


      Approximate proportion of total country population covered by regional studies in Iran=26%
      Mazandaran Province, Northern Iran (
      • Cheraghmakani H.
      • Baghbanian S.M.
      • HabibiSaravi R.
      • Azar A.
      • Ghasemihamedani F.
      Age and sex-adjusted incidence and yearly prevalence of multiple sclerosis (MS) in Mazandaran province, Iran: an 11-years study.
      )

      [3073,943
      https://www.amar.org.ir/Portals/1/census/2016/Census_2016_Selected_Findings.pdf
      ]
      1791/10

      (2009–2018)
      179.14.1%
      Tehran, Northern Iran (
      • Elhami S.R.
      • Mohammad K.
      • Sahraian M.A.
      • Eftekhar H.
      A 20-year incidence trend (1989-2008) and point prevalence (March 20, 2009) of multiple sclerosis in Tehran, Iran: a population-based study.
      )

      [12,183,391
      https://www.amar.org.ir/Portals/1/census/2016/Census_2016_Selected_Findings.pdf
      ]
      7501/20

      (1989–2008)
      375.116.2%
      Fars Province, Southern Iran (
      • Izadi S.
      • Nikseresht A.R.
      • Poursadeghfard M.
      • Borhanihaghighi A.
      • Heydari ST.
      Prevalence and incidence of multiple sclerosis in Fars Province, Southern Iran.
      )

      [4596,658
      https://www.amar.org.ir/Portals/1/census/2016/Census_2016_Selected_Findings.pdf
      ]
      Crude incidence as in Table 1

      (2003–2012)
      251.8
      estimated from the average incidence for the period from the relevant paper and the average population for the period from the relevant national statistics organization.
      6.1%
      Tehran, Iran (
      • Mohebi F.
      • Eskandarieh S.
      • Mansournia M.A.
      • Mohajer B.
      • Sahraian MA.
      Multiple sclerosis in Tehran: rising prevalence alongside stabilizing incidence - true increase or enhanced diagnosis?.
      )

      [12,183,391
      https://www.amar.org.ir/Portals/1/census/2016/Census_2016_Selected_Findings.pdf
      ]
      Crude incidence as in Table 1

      (1996–2013)
      621.2
      estimated from the average incidence for the period from the relevant paper and the average population for the period from the relevant national statistics organization.
      16.2%
      Western Pacific Region
      Australia (1)

      Total Australia population

      2000=19,066,000
      Total population at mid-year by region in United Nations (United Nations, 2017)


      Approximate proportion of total country population covered by regional studies in Australia=<1%
      Newcastle, Australia (
      • Ribbons K.
      • Lea R.
      • Tiedeman C.
      • Mackenzie L.
      • Lechner-Scott J.
      Ongoing increase in incidence and prevalence of multiple sclerosis in Newcastle, Australia: a 50-year study.
      )

      [136,413 in 2001
      https://profile.id.com.au/newcastle/population?EndYear=2001&DataType=UR
      ]

      132/22

      (1986–2011)
      6.00.7%
      Japan (1)

      Total Japan population

      2000=127,534,000
      Total population at mid-year by region in United Nations (United Nations, 2017)


      Approximate proportion of total country population covered by regional studies in Japan=<1%
      Tokachi Province, Hokkaido, Northern Japan (
      • Houzen H.
      • Kondo K.
      • Horiuchi K.
      • Niino M.
      Consistent increase in the prevalence and female ratio of multiple sclerosis over 15 years in northern Japan.
      )

      [360,992 average population 2000–2004 (
      • Boesen M.S.
      • Magyari M.
      • Koch-Henriksen N.
      • Thygesen L.C.
      • Born A.P.
      • Uldall P.V.
      • et al.
      Pediatric-onset multiple sclerosis and other acquired demyelinating syndromes of the central nervous system in Denmark during 1977-2015: a nationwide population-based incidence study.
      )]
      62/30

      (1985–2014)
      2.10.3%
      Taiwan (1)

      Total Taiwan population

      2000=21,840,000
      Total population at mid-year by region in United Nations (United Nations, 2017)


      Taiwan=100% covered
      Taiwan (
      • Fang C.W.
      • Wang H.P.
      • Chen H.M.
      • Lin J.W.
      • Lin WS.
      Epidemiology and comorbidities of adult multiple sclerosis and neuromyelitis optica in Taiwan, 2001-2015.
      )
      3844/10

      (2006–2015)
      384.4100%
      Paediatric-only studies
      Canada (1)

      Total Canada population

      2001=31,081,887
      Statistics Canada - https://www150.statcan.gc.ca/n1/daily-quotidien/010925/dq010925a-eng.htm
      Ontario (
      • Marrie R.A.
      • O'Mahony J.
      • Maxwell C.
      • Ling V.
      • Yeh E.A.
      • Arnold D.L.
      • et al.
      Incidence and prevalence of MS in children: a population-based study in Ontario, Canada.
      )

      [2900,00018]
      554/12

      (2003–2014; Marrie case definition)

      360/12

      (2003–2014; CCDSS case definition)
      46.2

      30.0
      9.4%

      (population aged ≤18 years)
      Denmark (1)

      Total Denmark population 2010=5547,683 (
      • Boesen M.S.
      • Magyari M.
      • Koch-Henriksen N.
      • Thygesen L.C.
      • Born A.P.
      • Uldall P.V.
      • et al.
      Pediatric-onset multiple sclerosis and other acquired demyelinating syndromes of the central nervous system in Denmark during 1977-2015: a nationwide population-based incidence study.
      )
      Denmark (
      • Boesen M.S.
      • Magyari M.
      • Koch-Henriksen N.
      • Thygesen L.C.
      • Born A.P.
      • Uldall P.V.
      • et al.
      Pediatric-onset multiple sclerosis and other acquired demyelinating syndromes of the central nervous system in Denmark during 1977-2015: a nationwide population-based incidence study.
      )

      (paediatric-only population)

      [1818,787 (
      • Sencer W.
      Suspicion of multiple sclerosis. To tell or not to tell?.
      )]
      364/39

      (1977–2015)

      84/8

      (2008–2015)
      9.3

      10.5
      32.8%

      (population aged <18 years)
      Kuwait (1)

      Total Kuwait population 2000=2051,000
      Total population at mid-year by region in United Nations (United Nations, 2017)


      Kuwait=19.9% covered
      Kuwait (
      • Alroughani R.
      • Akhtar S.
      • Ahmed S.F.
      • Behbehani R.
      • Al-Abkal J.
      • Al-Hashel J.
      Incidence and prevalence of pediatric onset multiple sclerosis in Kuwait: 1994-2013.
      )

      (paediatric-only population)

      (407,380 (
      • Alroughani R.
      • Akhtar S.
      • Ahmed S.F.
      • Behbehani R.
      • Al-Abkal J.
      • Al-Hashel J.
      Incidence and prevalence of pediatric onset multiple sclerosis in Kuwait: 1994-2013.
      )) /2051,000
      Total population at mid-year by region in United Nations (United Nations, 2017)
      )
      119/20

      (1994–2013)
      6.019.9%

      (population aged <18 years)
      CCDSS=Canadian Chronic Disease Surveillance System.
      low asterisk (denominator=year 2000/1, or closet available total population for the entire country)
      ^ estimated from the average incidence for the period from the relevant paper and the average population for the period from the relevant national statistics organization.
      a Total population at mid-year by region in United Nations (

      United Nations (2017). Department of Economic and Social Affairs, Population Division. World Population Prospects: The 2017 Revision, Volume I: Comprehensive Tables (ST/ESA/SER.A/399).

      )
      b Statistics Canada - https://www150.statcan.gc.ca/n1/daily-quotidien/010925/dq010925a-eng.htm
      c http://www.stat.fi/index_en.html
      d http://pxnet2.stat.fi/PXWeb/pxweb/en/StatFin/StatFin__vrm__vaerak/statfin_vaerak_pxt_11ra.px
      e https://www.ssb.no/en/befolkning/artikler-og-publikasjoner/_attachment/146,776?_ts=143c3b051c8
      f https://www.citypopulation.de/en/sweden/
      g https://www.dzs.hr/eng/censuses/Census2001/Popis/E01_01_01/E01_01_01.html
      h https://www.citypopulation.de/en/germany/admin/09__bayern/
      i https://www.statistics.gr/en/statistics/-/publication/SPO18/2001
      j https://www.citypopulation.de/en/italy/admin/
      k https://data.worldbank.org/indicator/SP.POP.TOTL?locations=IT
      l http://population.city/italy/biancavilla/
      m http://population.city/italy/bagheria/
      n https://www.amar.org.ir/Portals/1/census/2016/Census_2016_Selected_Findings.pdf
      o https://profile.id.com.au/newcastle/population?EndYear=2001&DataType=UR
      Eight studies reported country-wide case ascertainment; (
      • Cabre P.
      Environmental changes and epidemiology of multiple sclerosis in the French West Indies.
      ;
      • Koch-Henriksen N.
      • Thygesen L.C.
      • Stenager E.
      • Laursen B.
      • Magyari M.
      Incidence of MS has increased markedly over six decades in Denmark particularly with late onset and in women.
      ;
      • Benedikz J.
      • Stefansson M.
      • Guomundsson J.
      • Jonasdot tir A.
      • Fossdal R.
      • Gulcher J.
      • et al.
      The natural history of untreated multiple sclerosis in Iceland. A total population-based 50 year prospective study.
      ;
      • Granieri E.
      • Monaldini C.
      • De Gennaro R.
      • Guttmann S.
      • Volpini M.
      • Stumpo M.
      • et al.
      Multiple sclerosis in the Republic of San Marino: a prevalence and incidence study.
      ;
      • Valadkeviciene D.
      • Kavaliunas A.
      • Kizlaitiene R.
      • Jocys M.
      • Jatuzis D.
      Incidence rate and sex ratio in multiple sclerosis in Lithuania.
      ;
      • Kramer M.A.
      • van der Maas N.A.
      • van Soest E.M.
      • Kemmeren J.M.
      • de Melker H.E.
      • Sturkenboom M.C.
      Incidence of multiple sclerosis in the general population in the Netherlands, 1996-2008.
      ;
      • Mackenzie I.S.
      • Morant S.V.
      • Bloomfield G.A.
      • MacDonald T.M.
      • O'Riordan J.
      Incidence and prevalence of multiple sclerosis in the UK 1990-2010: a descriptive study in the general practice research database.
      ;
      • Fang C.W.
      • Wang H.P.
      • Chen H.M.
      • Lin J.W.
      • Lin WS.
      Epidemiology and comorbidities of adult multiple sclerosis and neuromyelitis optica in Taiwan, 2001-2015.
      ) the remainder had an approximate coverage of 0.04% to 38% of the total country population (Table 2). Case ascertainment source(s) varied from single (e.g., regional MS Society records (
      • Mohebi F.
      • Eskandarieh S.
      • Mansournia M.A.
      • Mohajer B.
      • Sahraian MA.
      Multiple sclerosis in Tehran: rising prevalence alongside stabilizing incidence - true increase or enhanced diagnosis?.
      )) to multiple sources (e.g., hospital, physician and prescription databases (
      • Al-Sakran L.H.
      • Marrie R.A.
      • Blackburn D.F.
      • Knox K.B.
      • Evans C.D.
      Establishing the incidence and prevalence of multiple sclerosis in Saskatchewan.
      )). When clinical diagnostic criteria were used, these were largely reflective of the era; Poser (1983) criteria were most common, followed by McDonald (2001–2017), Allison and Millar (1954) and Schumacher (1965). Other approaches included validated algorithms, typically based on administrative data from hospital and/or physician claims, using International Classification of Diseases (ICD) diagnostic codes to identify MS cases (
      • Al-Sakran L.H.
      • Marrie R.A.
      • Blackburn D.F.
      • Knox K.B.
      • Evans C.D.
      Establishing the incidence and prevalence of multiple sclerosis in Saskatchewan.
      ;
      • Kingwell E.
      • Zhu F.
      • Marrie R.A.
      • Fisk J.D.
      • Wolfson C.
      • Warren S.
      • et al.
      High incidence and increasing prevalence of multiple sclerosis in British Columbia, Canada: findings from over two decades (1991-2010).
      ;
      • Marrie R.A.
      • Fisk J.D.
      • Stadnyk K.J.
      • Yu B.N.
      • Tremlett H.
      • Wolfson C.
      • et al.
      The Incidence and Prevalence of Multiple Sclerosis in Nova Scotia, Canada.
      ;
      • Rotstein D.L.
      • Chen H.
      • Wilton A.S.
      • Kwong J.C.
      • Marrie R.A.
      • Gozdyra P.
      • et al.
      Temporal trends in multiple sclerosis prevalence and incidence in a large population.
      ;
      • Widdifield J.
      • Ivers N.M.
      • Young J.
      • Green D.
      • Jaakkimainen L.
      • Butt D.A.
      • et al.
      Development and validation of an administrative data algorithm to estimate the disease burden and epidemiology of multiple sclerosis in Ontario, Canada.
      ;
      • Warren S.
      • Svenson L.W.
      • Warren K.
      Contribution of incidence to increasing prevalence of multiple sclerosis in Alberta, Canada.
      ).
      According to the results from the linear regression analysis, over time and across all whole-of-population estimates (n=62), MS incidence rates: significantly increased (n=38), significantly decreased (n=13), or remained stable (n=11).
      Of the 62 regional estimates, 42 were explicitly reported to be based on a consistent case definition or diagnostic criteria to identify MS cases over the entire study period covered. These estimates covering ∼2.7% of the global population.; 57% (n=24/42) showed increasing incidence rates (covering 0.8% of the global population), 21% (n=9/42) stable incidence rates (0.9% of the global population), and 21% (n=9/42) decreasing incidence rates (1.0% of the global population). Nine of these studies each covered a substantial proportion (≥one-third) of the country's population (and in total, 1.9% of the global population). Three studies showed stable incidence rates (
      • Rotstein D.L.
      • Chen H.
      • Wilton A.S.
      • Kwong J.C.
      • Marrie R.A.
      • Gozdyra P.
      • et al.
      Temporal trends in multiple sclerosis prevalence and incidence in a large population.
      ;
      • Widdifield J.
      • Ivers N.M.
      • Young J.
      • Green D.
      • Jaakkimainen L.
      • Butt D.A.
      • et al.
      Development and validation of an administrative data algorithm to estimate the disease burden and epidemiology of multiple sclerosis in Ontario, Canada.
      ;
      • Fang C.W.
      • Wang H.P.
      • Chen H.M.
      • Lin J.W.
      • Lin WS.
      Epidemiology and comorbidities of adult multiple sclerosis and neuromyelitis optica in Taiwan, 2001-2015.
      ), three increasing incidence rates (
      • Sarasoja T.
      • Wikstrom J.
      • Paltamaa J.
      • Hakama M.
      • Sumelahti M.L.
      Occurrence of multiple sclerosis in central Finland: a regional and temporal comparison during 30 years.
      ;
      • Valadkeviciene D.
      • Kavaliunas A.
      • Kizlaitiene R.
      • Jocys M.
      • Jatuzis D.
      Incidence rate and sex ratio in multiple sclerosis in Lithuania.
      ;
      • Kramer M.A.
      • van der Maas N.A.
      • van Soest E.M.
      • Kemmeren J.M.
      • de Melker H.E.
      • Sturkenboom M.C.
      Incidence of multiple sclerosis in the general population in the Netherlands, 1996-2008.
      ) and three decreasing incidence rates (
      • Benedikz J.
      • Stefansson M.
      • Guomundsson J.
      • Jonasdot tir A.
      • Fossdal R.
      • Gulcher J.
      • et al.
      The natural history of untreated multiple sclerosis in Iceland. A total population-based 50 year prospective study.
      ;
      • Granieri E.
      • Monaldini C.
      • De Gennaro R.
      • Guttmann S.
      • Volpini M.
      • Stumpo M.
      • et al.
      Multiple sclerosis in the Republic of San Marino: a prevalence and incidence study.
      ;
      • Mackenzie I.S.
      • Morant S.V.
      • Bloomfield G.A.
      • MacDonald T.M.
      • O'Riordan J.
      Incidence and prevalence of multiple sclerosis in the UK 1990-2010: a descriptive study in the general practice research database.
      ).
      Thus, for the whole-of-population estimates, from studies using a consistent case definition over time, and covering a substantial proportion of the country's population, there was no predominant pattern of trend in MS incidence over time. In studies covering a smaller proportion of the country's population or not using a consistent case definition across the whole study period, the predominant trend was increasing incidence over time.
      A greater proportion of studies undertaken wholly prior to the mid-point of our period of interest (2003), and using a consistent case definition across the study periods, showed increasing incidence (23 estimates; 69% increasing, 9% stable, 22% decreasing) compared to those with contiguous study periods wholly after 2003 (7 estimates; 29% increasing, 42% stable, 29% decreasing). Furthermore, when grouping these studies by latitude band (<30, 30–50, >50 degrees), stable or decreasing incidence was more common in the highest latitude band (n=19 estimates; 53% increasing, 16% stable, 32% decreasing) compared to the middle latitude band (n=22 estimates; 64% increasing, 23% stable, 14% decreasing), with too few studies in the lowest latitude band (n=2; 1 increasing, 1 stable) to allow assessment.

      3.1.1 Italy

      Twelve of the regional estimates in this region derived from studies explicitly reporting consistent methods to identify cases over time (ten Poser criteria and two McDonald criteria). Of these, incidence rates significantly increased in eight (1985–2018) (
      • Granieri E.
      • Economou N.T.
      • De Gennaro R.
      • Tola M.R.
      • Caniatti L.
      • Govoni V.
      • et al.
      Multiple sclerosis in the province of Ferrara: evidence for an increasing trend.
      ;
      • Nicoletti A.
      • Patti F.
      • Lo Fermo S.
      • Messina S.
      • Bruno E.
      • Quattrocchi G.
      • et al.
      Increasing frequency of multiple sclerosis in Catania, Sicily: a 30-year survey.
      ;
      • Nicoletti A.
      • Bruno E.
      • Nania M.
      • Cicero E.
      • Messina S.
      • Chisari C.
      • et al.
      Multiple sclerosis in the Mount Etna region: possible role of volcanogenic trace elements.
      ;
      • Patti F.
      • Caserta C.
      • Colandonio S.
      • Iudica M.L.
      • Maimone D.
      • Lo Fermo S.
      • et al.
      Prevalence and incidence of multiple sclerosis in the city of Biancavilla.
      ;
      • Pugliatti M.
      • Sotgiu S.
      • Solinas G.
      • Castiglia P.
      • Pirastru M.I.
      • Murgia B.
      • et al.
      Multiple sclerosis epidemiology in Sardinia: evidence for a true increasing risk.
      ;
      • Ranzato F.
      • Perini P.
      • Tzintzeva E.
      • Tiberio M.
      • Calabrese M.
      • Ermani M.
      • et al.
      Increasing frequency of multiple sclerosis in Padova, Italy: a 30 year epidemiological survey.
      ;
      • Salemi G.
      • Ragonese P.
      • Aridon P.
      • Scola G.
      • Saporito V.
      • Conte S.
      • et al.
      Incidence of multiple sclerosis in Bagheria City, Sicily, Italy.
      ), significantly decreased in three (1985–2015) (
      • Nicoletti A.
      • Rascuna C.
      • Boumediene F.
      • Vasta R.
      • Cicero C.E.
      • Lo Fermo S.
      • et al.
      Incidence of multiple sclerosis in the province of Catania. A geo-epidemiological study.
      ;
      • Pugliatti M.
      • Riise T.
      • Sotgiu M.A.
      • Sotgiu S.
      • Satta W.M.
      • Mannu L.
      • et al.
      Increasing incidence of multiple sclerosis in the province of Sassari, Northern Sardinia.
      ;
      • Granieri E.
      • Monaldini C.
      • De Gennaro R.
      • Guttmann S.
      • Volpini M.
      • Stumpo M.
      • et al.
      Multiple sclerosis in the Republic of San Marino: a prevalence and incidence study.
      ), and remained stable in one (1998–2007) (
      • Solaro C.
      • Ponzio M.
      • Moran E.
      • Tanganelli P.
      • Pizio R.
      • Ribizzi G.
      • et al.
      The changing face of multiple sclerosis: prevalence and incidence in an aging population.
      ).
      Studies covered approximately 7% of Italy's population, ranging from 0.04% to 1.9% for individual regional estimates (Fig. 1; Table 2). Of the 15 regional estimates in Italy and San Marino, MS incidence significantly increased in ten (including both geographical locations in Mount Etna) (
      • Cocco E.
      • Sardu C.
      • Massa R.
      • Mamusa E.
      • Musu L.
      • Ferrigno P.
      • et al.
      Epidemiology of multiple sclerosis in south-western Sardinia.
      ;
      • Granieri E.
      • Economou N.T.
      • De Gennaro R.
      • Tola M.R.
      • Caniatti L.
      • Govoni V.
      • et al.
      Multiple sclerosis in the province of Ferrara: evidence for an increasing trend.
      ;
      • Grassivaro F.
      • Puthenparampil M.
      • Pengo M.
      • Saiani M.
      • Venturini M.
      • Stropparo E.
      • et al.
      Multiple sclerosis incidence and prevalence trends in the province of Padua, Northeast Italy, 1965-2018.
      ;
      • Nicoletti A.
      • Patti F.
      • Lo Fermo S.
      • Messina S.
      • Bruno E.
      • Quattrocchi G.
      • et al.
      Increasing frequency of multiple sclerosis in Catania, Sicily: a 30-year survey.
      ;
      • Nicoletti A.
      • Bruno E.
      • Nania M.
      • Cicero E.
      • Messina S.
      • Chisari C.
      • et al.
      Multiple sclerosis in the Mount Etna region: possible role of volcanogenic trace elements.
      ;
      • Patti F.
      • Caserta C.
      • Colandonio S.
      • Iudica M.L.
      • Maimone D.
      • Lo Fermo S.
      • et al.
      Prevalence and incidence of multiple sclerosis in the city of Biancavilla.
      ;
      • Pugliatti M.
      • Sotgiu S.
      • Solinas G.
      • Castiglia P.
      • Pirastru M.I.
      • Murgia B.
      • et al.
      Multiple sclerosis epidemiology in Sardinia: evidence for a true increasing risk.
      ;
      • Ranzato F.
      • Perini P.
      • Tzintzeva E.
      • Tiberio M.
      • Calabrese M.
      • Ermani M.
      • et al.
      Increasing frequency of multiple sclerosis in Padova, Italy: a 30 year epidemiological survey.
      ;
      • Salemi G.
      • Ragonese P.
      • Aridon P.
      • Scola G.
      • Saporito V.
      • Conte S.
      • et al.
      Incidence of multiple sclerosis in Bagheria City, Sicily, Italy.
      ), significantly decreased in four (
      • Granieri E.
      • Casetta I.
      • Govoni V.
      • Tola M.R.
      • Marchi D.
      • Murgia S.B.
      • et al.
      The increasing incidence and prevalence of MS in a Sardinian province.
      ;
      • Nicoletti A.
      • Rascuna C.
      • Boumediene F.
      • Vasta R.
      • Cicero C.E.
      • Lo Fermo S.
      • et al.
      Incidence of multiple sclerosis in the province of Catania. A geo-epidemiological study.
      ;
      • Pugliatti M.
      • Riise T.
      • Sotgiu M.A.
      • Sotgiu S.
      • Satta W.M.
      • Mannu L.
      • et al.
      Increasing incidence of multiple sclerosis in the province of Sassari, Northern Sardinia.
      ;
      • Granieri E.
      • Monaldini C.
      • De Gennaro R.
      • Guttmann S.
      • Volpini M.
      • Stumpo M.
      • et al.
      Multiple sclerosis in the Republic of San Marino: a prevalence and incidence study.
      ) and remained stable in one (
      • Solaro C.
      • Ponzio M.
      • Moran E.
      • Tanganelli P.
      • Pizio R.
      • Ribizzi G.
      • et al.
      The changing face of multiple sclerosis: prevalence and incidence in an aging population.
      ). Within Sicily, the MS incidence rate increased over time in five small regional studies (from 1985–2018) (
      • Nicoletti A.
      • Patti F.
      • Lo Fermo S.
      • Messina S.
      • Bruno E.
      • Quattrocchi G.
      • et al.
      Increasing frequency of multiple sclerosis in Catania, Sicily: a 30-year survey.
      ;
      • Nicoletti A.
      • Bruno E.
      • Nania M.
      • Cicero E.
      • Messina S.
      • Chisari C.
      • et al.
      Multiple sclerosis in the Mount Etna region: possible role of volcanogenic trace elements.
      ;
      • Patti F.
      • Caserta C.
      • Colandonio S.
      • Iudica M.L.
      • Maimone D.
      • Lo Fermo S.
      • et al.
      Prevalence and incidence of multiple sclerosis in the city of Biancavilla.
      ;
      • Salemi G.
      • Ragonese P.
      • Aridon P.
      • Scola G.
      • Saporito V.
      • Conte S.
      • et al.
      Incidence of multiple sclerosis in Bagheria City, Sicily, Italy.
      ). However, in the province-wide study in Catania, Sicily with 973 incident cases (2005–2015) (
      • Nicoletti A.
      • Rascuna C.
      • Boumediene F.
      • Vasta R.
      • Cicero C.E.
      • Lo Fermo S.
      • et al.
      Incidence of multiple sclerosis in the province of Catania. A geo-epidemiological study.
      ), the MS incidence rate significantly decreased (Fig. 1).
      Fig 1
      Fig. 1Map of Italy summarising studies of multiple sclerosis incidence over time and the main findings.

      3.1.2 Canada

      Of the eight studies in Canada, seven explicitly used consistent methods to identify cases across the course of the study (six used algorithms and one Poser criteria); the MS incidence rates were stable in three studies (1999–2013) (
      • Kingwell E.
      • Zhu F.
      • Marrie R.A.
      • Fisk J.D.
      • Wolfson C.
      • Warren S.
      • et al.
      High incidence and increasing prevalence of multiple sclerosis in British Columbia, Canada: findings from over two decades (1991-2010).
      ;
      • Rotstein D.L.
      • Chen H.
      • Wilton A.S.
      • Kwong J.C.
      • Marrie R.A.
      • Gozdyra P.
      • et al.
      Temporal trends in multiple sclerosis prevalence and incidence in a large population.
      ;
      • Widdifield J.
      • Ivers N.M.
      • Young J.
      • Green D.
      • Jaakkimainen L.
      • Butt D.A.
      • et al.
      Development and validation of an administrative data algorithm to estimate the disease burden and epidemiology of multiple sclerosis in Ontario, Canada.
      ), significantly increased in two (1987–2004) (
      • Sloka J.S.
      • Pryse-Phillips W.E.
      • Stefanelli M.
      Incidence and prevalence of multiple sclerosis in Newfoundland and Labrador.
      ;
      • Warren S.
      • Svenson L.W.
      • Warren K.
      Contribution of incidence to increasing prevalence of multiple sclerosis in Alberta, Canada.
      ), and significantly decreased in two (1996–2013) (
      • Al-Sakran L.H.
      • Marrie R.A.
      • Blackburn D.F.
      • Knox K.B.
      • Evans C.D.
      Establishing the incidence and prevalence of multiple sclerosis in Saskatchewan.
      ;
      • Marrie R.A.
      • Fisk J.D.
      • Stadnyk K.J.
      • Yu B.N.
      • Tremlett H.
      • Wolfson C.
      • et al.
      The Incidence and Prevalence of Multiple Sclerosis in Nova Scotia, Canada.
      ).
      Studies covered approximately 69% of Canada's population (Fig. 2; Table 2), with individual estimates for 0.6% to 38% of the population. Three estimates showed stable incidence (1999–2013), (
      • Kingwell E.
      • Zhu F.
      • Marrie R.A.
      • Fisk J.D.
      • Wolfson C.
      • Warren S.
      • et al.
      High incidence and increasing prevalence of multiple sclerosis in British Columbia, Canada: findings from over two decades (1991-2010).
      ;
      • Rotstein D.L.
      • Chen H.
      • Wilton A.S.
      • Kwong J.C.
      • Marrie R.A.
      • Gozdyra P.
      • et al.
      Temporal trends in multiple sclerosis prevalence and incidence in a large population.
      ;
      • Widdifield J.
      • Ivers N.M.
      • Young J.
      • Green D.
      • Jaakkimainen L.
      • Butt D.A.
      • et al.
      Development and validation of an administrative data algorithm to estimate the disease burden and epidemiology of multiple sclerosis in Ontario, Canada.
      ), three significantly decreased (1990–2013) (
      • Al-Sakran L.H.
      • Marrie R.A.
      • Blackburn D.F.
      • Knox K.B.
      • Evans C.D.
      Establishing the incidence and prevalence of multiple sclerosis in Saskatchewan.
      ;
      • Hader W.J.
      • Yee I.M.L.
      Incidence and prevalence of multiple sclerosis in Saskatoon, Saskatchewan.
      ;
      • Marrie R.A.
      • Fisk J.D.
      • Stadnyk K.J.
      • Yu B.N.
      • Tremlett H.
      • Wolfson C.
      • et al.
      The Incidence and Prevalence of Multiple Sclerosis in Nova Scotia, Canada.
      ), and two significantly increased (1987–2004) (
      • Sloka J.S.
      • Pryse-Phillips W.E.
      • Stefanelli M.
      Incidence and prevalence of multiple sclerosis in Newfoundland and Labrador.
      ;
      • Warren S.
      • Svenson L.W.
      • Warren K.
      Contribution of incidence to increasing prevalence of multiple sclerosis in Alberta, Canada.
      ).
      Fig 2
      Fig. 2Map of Canada summarising studies of multiple sclerosis incidence over time and the main findings.

      3.1.3 Norway

      Five studies in Norway explicitly used consistent methods (Poser criteria) to identify cases over time. Of these studies, MS incidence significantly increased in four studies (1987–2006) (
      • Celius E.G.
      • Vandvik B.
      Multiple sclerosis in Oslo, Norway: prevalence on 1 January 1995 and incidence over a 25-year period.
      ;
      • Dahl O.P.
      • Aarseth J.H.
      • Myhr K.M.
      • Nyland H.
      • Midgard R.
      Multiple sclerosis in Nord-Trondelag County, Norway: a prevalence and incidence study.
      ;
      • Risberg G.
      • Aarseth J.H.
      • Nyland H.
      • Lauer K.
      • Myhr K.M.
      • Midgard R.
      Prevalence and incidence of multiple sclerosis in Oppland County: a cross-sectional population-based study in a landlocked county of Eastern Norway.
      ;
      • Vatne A.
      • Mygland A.
      • Ljostad U.
      Multiple sclerosis in Vest-Agder County, Norway.
      ), and significantly decreased in one (1988–2002) (
      • Lund C.
      • Nakken K.O.
      • Edland A.
      • Celius EG.
      Multiple sclerosis and seizures: incidence and prevalence over 40 years.
      ). Studies covered ∼56% of Norway's population (Fig. 3; Table 2), with individual estimates covering 2.8% to 11%. In Norway, MS incidence rates increased over time in eight counties (from 1985–2018) (
      • Benjaminsen E.
      • Olavsen J.
      • Karlberg M.
      • Alstadhuag KB.
      Multiple sclerosis in the far north - incidence and prevalence in Nordland Country, Norway, 1970-2010.
      ;
      • Celius E.G.
      • Vandvik B.
      Multiple sclerosis in Oslo, Norway: prevalence on 1 January 1995 and incidence over a 25-year period.
      ;
      • Dahl O.P.
      • Aarseth J.H.
      • Myhr K.M.
      • Nyland H.
      • Midgard R.
      Multiple sclerosis in Nord-Trondelag County, Norway: a prevalence and incidence study.
      ;
      • Flemmen H.O.
      • Simonsen C.S.
      • Berg-Hansen P.
      • Moen S.M.
      • Kersten H.
      • Heldal K.
      • et al.
      Prevalence of multiple sclerosis in rural and urban districts in Telemark county, Norway.
      ;
      • Risberg G.
      • Aarseth J.H.
      • Nyland H.
      • Lauer K.
      • Myhr K.M.
      • Midgard R.
      Prevalence and incidence of multiple sclerosis in Oppland County: a cross-sectional population-based study in a landlocked county of Eastern Norway.
      ;
      • Simonsen C.S.
      • Edland A.
      • Berg-Hansen P.
      • Celius EG.
      High prevalence and increasing incidence of multiple sclerosis in the Norwegian county of Buskerud.
      ;
      • Vatne A.
      • Mygland A.
      • Ljostad U.
      Multiple sclerosis in Vest-Agder County, Norway.
      ;
      • Willumsen J.S.
      • Aarseth J.H.
      • Myhr K.M.
      • Midgard R.
      High incidence and prevalence of MS in More and Romsdal County, Norway.
      ) covering ∼41% of the population, but significantly decreased in two southern counties (from 1988–2012), covering ∼15% of the total Norwegian population (
      • Grytten N.
      • Aarseth J.H.
      • Lunde H.M.
      • Myhr KM.
      A 60-year follow-up of the incidence and prevalence of multiple sclerosis in Hordaland County, Western Norway.
      ;
      • Lund C.
      • Nakken K.O.
      • Edland A.
      • Celius EG.
      Multiple sclerosis and seizures: incidence and prevalence over 40 years.
      ).
      Fig 3
      Fig. 3Map of Norway summarising studies of multiple sclerosis incidence over time and the main findings.

      3.1.4 Denmark, Iceland, Finland and Sweden

      Of the seven studies in this region, three explicitly used a consistent case definition throughout the study; the incidence rate significantly decreased (1986–2000) in two studies (
      • Benedikz J.
      • Stefansson M.
      • Guomundsson J.
      • Jonasdot tir A.
      • Fossdal R.
      • Gulcher J.
      • et al.
      The natural history of untreated multiple sclerosis in Iceland. A total population-based 50 year prospective study.
      ;
      • Bostrom I.
      • Callander M.
      • Kurtzke J.F.
      • Landtblom A.M.
      High prevalence of multiple sclerosis in the Swedish county of Varmland.
      ), and significantly increased in one study (1989–1998) (
      • Sarasoja T.
      • Wikstrom J.
      • Paltamaa J.
      • Hakama M.
      • Sumelahti M.L.
      Occurrence of multiple sclerosis in central Finland: a regional and temporal comparison during 30 years.
      ). Across all included studies in Denmark, the MS incidence rates significantly increased in a large study within the general population (1990–2009) (
      • Koch-Henriksen N.
      • Thygesen L.C.
      • Stenager E.
      • Laursen B.
      • Magyari M.
      Incidence of MS has increased markedly over six decades in Denmark particularly with late onset and in women.
      ), and significantly decreased in the Faroe Islands, although the latter was based on 28 incident cases identified over a 15-year period (1993–2007) (
      • Joensen P.
      Multiple sclerosis: variation of incidence of onset over time in the Faroe Islands.
      ). A significant decrease in the MS incidence rate was reported in a population-wide study in Iceland (1986–2000) (
      • Benedikz J.
      • Stefansson M.
      • Guomundsson J.
      • Jonasdot tir A.
      • Fossdal R.
      • Gulcher J.
      • et al.
      The natural history of untreated multiple sclerosis in Iceland. A total population-based 50 year prospective study.
      ), while significant increases were found in Northern (1993–2007) (
      • Krokki O.
      • Bloigu R.
      • Reunanen M.
      • Remes A.M.
      Increasing incidence of multiple sclerosis in women in Northern Finland.
      ) and Central Finland (1989–1998) (
      • Sarasoja T.
      • Wikstrom J.
      • Paltamaa J.
      • Hakama M.
      • Sumelahti M.L.
      Occurrence of multiple sclerosis in central Finland: a regional and temporal comparison during 30 years.
      ), covering 45% of Finland's population. The two Swedish studies each covered ∼3% of Sweden's population and reported similar numbers of incident cases (from 15 to 18 cases per year; totalling 181 (Bostrom et al., 2009) and 201 (Svenningsson et al., 2015) cases). However, the MS incidence rate significantly decreased in Western Sweden (Värmland County; 1991–2000) (
      • Bostrom I.
      • Callander M.
      • Kurtzke J.F.
      • Landtblom A.M.
      High prevalence of multiple sclerosis in the Swedish county of Varmland.
      ), but remained stable in Northern Sweden (Västerbotten County; 1991–2010) (
      • Svenningsson A.
      • Salzer J.
      • Vagberg M.
      • Sundstrom P.
      • Svenningsson A.
      Increasing prevalence of multiple sclerosis in Vasterbotten County of Sweden.
      ).

      3.1.5 Latin America and the Caribbean

      In both of the identified studies from this region, the MS incidence rate significantly increased over three consecutive 5-year periods. However, the study in Martinique and Guadeloupe covered only ∼2% of the total Caribbean population (
      • Cabre P.
      Environmental changes and epidemiology of multiple sclerosis in the French West Indies.
      ), whereas the study in the Republic of Panama was country-wide (
      • Gracia F.
      • Castillo L.C.
      • Benzadon A.
      • Larreategui M.
      • Villareal F.
      • Triana E.
      • et al.
      Prevalence and incidence of multiple sclerosis in Panama (2000-2005.
      ). Only the Caribbean study used a consistent case definition (2005 McDonald criteria) over time (1992–2007) (
      • Cabre P.
      Environmental changes and epidemiology of multiple sclerosis in the French West Indies.
      ). There were no eligible studies from South America.

      3.1.6 Germany, Croatia, Bosnia-Herzegovina, France, Greece, Lithuania, the Netherlands, Spain and the United Kingdom

      Of the thirteen studies in this region, nine explicitly used a consistent definition to identify cases over time, including Poser criteria (
      • Vrabec-Matkovic D.
      • Ivanusa Z.
      • Sarko B.
      • Golubic J.
      • Sklebar D.
      Epidemiology of multiple sclerosis in the Bjelovar-Bilogora County.
      ;
      • Debouverie M.
      • Pittion-Vouyovitch S.
      • Louis S.
      • Roederer T.
      • Guillemin F.
      Increasing incidence of multiple sclerosis among women in Lorraine, Eastern France.
      ;
      • Piperidou H.N.
      • Heliopoulos I.N.
      • Maltezos E.S.
      • Milonas IA.
      Epidemiological data of multiple sclerosis in the province of Evros, Greece.
      ;
      • Izquierdo G.
      • Venegas A.
      • Sanabria C.
      • Navarro G.
      Long-term epidemiology of multiple sclerosis in the Northern Seville District.
      ), McDonald Criteria (2001) (
      • Klupka-Sarić I.
      • Ristić S.
      • Sepcić J.
      • Kapović M.
      • Peterlin B.
      • Materljan E.
      • et al.
      Epidemiology of multiple sclerosis in western Herzegovina.
      ), or diagnostic codes e.g., ICD (
      • Daltrozzo T.
      • Hapfelmeier A.
      • Donnachie E.
      • Schneider A.
      • Hemmer B.
      A Systematic Assessment of Prevalence, Incidence and Regional Distribution of Multiple Sclerosis in Bavaria from 2006 to 2015.
      ;
      • Valadkeviciene D.
      • Kavaliunas A.
      • Kizlaitiene R.
      • Jocys M.
      • Jatuzis D.
      Incidence rate and sex ratio in multiple sclerosis in Lithuania.
      ), Read, (
      • Mackenzie I.S.
      • Morant S.V.
      • Bloomfield G.A.
      • MacDonald T.M.
      • O'Riordan J.
      Incidence and prevalence of multiple sclerosis in the UK 1990-2010: a descriptive study in the general practice research database.
      ) or International Classification for Primary Care codes (
      • Kramer M.A.
      • van der Maas N.A.
      • van Soest E.M.
      • Kemmeren J.M.
      • de Melker H.E.
      • Sturkenboom M.C.
      Incidence of multiple sclerosis in the general population in the Netherlands, 1996-2008.
      ). Of these studies, the incidence rate significantly increased in five (1987–2015) (
      • Vrabec-Matkovic D.
      • Ivanusa Z.
      • Sarko B.
      • Golubic J.
      • Sklebar D.
      Epidemiology of multiple sclerosis in the Bjelovar-Bilogora County.
      ;
      • Debouverie M.
      • Pittion-Vouyovitch S.
      • Louis S.
      • Roederer T.
      • Guillemin F.
      Increasing incidence of multiple sclerosis among women in Lorraine, Eastern France.
      ;
      • Valadkeviciene D.
      • Kavaliunas A.
      • Kizlaitiene R.
      • Jocys M.
      • Jatuzis D.
      Incidence rate and sex ratio in multiple sclerosis in Lithuania.
      ;
      • Kramer M.A.
      • van der Maas N.A.
      • van Soest E.M.
      • Kemmeren J.M.
      • de Melker H.E.
      • Sturkenboom M.C.
      Incidence of multiple sclerosis in the general population in the Netherlands, 1996-2008.
      ;
      • Izquierdo G.
      • Venegas A.
      • Sanabria C.
      • Navarro G.
      Long-term epidemiology of multiple sclerosis in the Northern Seville District.
      ), was stable in three (1989–2015) (
      • Klupka-Sarić I.
      • Ristić S.
      • Sepcić J.
      • Kapović M.
      • Peterlin B.
      • Materljan E.
      • et al.
      Epidemiology of multiple sclerosis in western Herzegovina.
      ;
      • Daltrozzo T.
      • Hapfelmeier A.
      • Donnachie E.
      • Schneider A.
      • Hemmer B.
      A Systematic Assessment of Prevalence, Incidence and Regional Distribution of Multiple Sclerosis in Bavaria from 2006 to 2015.
      ;
      • Piperidou H.N.
      • Heliopoulos I.N.
      • Maltezos E.S.
      • Milonas IA.
      Epidemiological data of multiple sclerosis in the province of Evros, Greece.
      ) and significantly decreased in one (1991–2010) (
      • Mackenzie I.S.
      • Morant S.V.
      • Bloomfield G.A.
      • MacDonald T.M.
      • O'Riordan J.
      Incidence and prevalence of multiple sclerosis in the UK 1990-2010: a descriptive study in the general practice research database.
      ).
      There were six single studies for (or within) a specific country for this region, covering from 3% to 100% of that country's population (table 2). In these studies the MS incidence rate was: stable in Bavaria, Germany (2006–2015) (
      • Daltrozzo T.
      • Hapfelmeier A.
      • Donnachie E.
      • Schneider A.
      • Hemmer B.
      A Systematic Assessment of Prevalence, Incidence and Regional Distribution of Multiple Sclerosis in Bavaria from 2006 to 2015.
      ) and Western Herzegovina, Bosnia-Herzegovina (1994–2003), (
      • Klupka-Sarić I.
      • Ristić S.
      • Sepcić J.
      • Kapović M.
      • Peterlin B.
      • Materljan E.
      • et al.
      Epidemiology of multiple sclerosis in western Herzegovina.
      ) and significantly increased over time in Bjelovar-Bilogora County, Croatia (1987–2001) (
      • Vrabec-Matkovic D.
      • Ivanusa Z.
      • Sarko B.
      • Golubic J.
      • Sklebar D.
      Epidemiology of multiple sclerosis in the Bjelovar-Bilogora County.
      ), Lorraine, France (1993–2002), (
      • Debouverie M.
      • Pittion-Vouyovitch S.
      • Louis S.
      • Roederer T.
      • Guillemin F.
      Increasing incidence of multiple sclerosis among women in Lorraine, Eastern France.
      ) Lithuania (2001–2015) (
      • Valadkeviciene D.
      • Kavaliunas A.
      • Kizlaitiene R.
      • Jocys M.
      • Jatuzis D.
      Incidence rate and sex ratio in multiple sclerosis in Lithuania.
      ) and the Netherlands (1999–2008) (
      • Kramer M.A.
      • van der Maas N.A.
      • van Soest E.M.
      • Kemmeren J.M.
      • de Melker H.E.
      • Sturkenboom M.C.
      Incidence of multiple sclerosis in the general population in the Netherlands, 1996-2008.
      ). For Greece, three studies covered ∼13% of the population (
      • Kotzamani D.
      • Panou T.
      • Mastorodemos V.
      • Tzagournissakis M.
      • Nikolakaki H.
      • Spanaki C.
      • et al.
      Rising incidence of multiple sclerosis in females associated with urbanization.
      ;
      • Papathanasopoulos P.
      • Gourzoulidou E.
      • Messinis L.
      • Georgiou V.
      • Leotsinidis M.
      Prevalence and incidence of multiple sclerosis in western Greece: a 23-year survey.
      ;
      • Piperidou H.N.
      • Heliopoulos I.N.
      • Maltezos E.S.
      • Milonas IA.
      Epidemiological data of multiple sclerosis in the province of Evros, Greece.
      ). The MS incidence rate was stable in the Province of Evros, North-Eastern Greece (1989–1999), a region that covered ∼1.3% of Greece's population (
      • Piperidou H.N.
      • Heliopoulos I.N.
      • Maltezos E.S.
      • Milonas IA.
      Epidemiological data of multiple sclerosis in the province of Evros, Greece.
      ). For the two other studies covering a larger population size, the MS incidence rates significantly increased in Crete (1985–2004; 5.2% of Greece's population) (
      • Kotzamani D.
      • Panou T.
      • Mastorodemos V.
      • Tzagournissakis M.
      • Nikolakaki H.
      • Spanaki C.
      • et al.
      Rising incidence of multiple sclerosis in females associated with urbanization.
      ) and Western Greece (1987–2006; 6.6%) (
      • Papathanasopoulos P.
      • Gourzoulidou E.
      • Messinis L.
      • Georgiou V.
      • Leotsinidis M.
      Prevalence and incidence of multiple sclerosis in western Greece: a 23-year survey.
      ). Two studies in Spain covered ∼0.5% of the total population; the MS incidence rates were stable in Central-Eastern Spain (Bajo Aragon, Teruel, 1988–2002; 42 incident cases), (
      • Modrego P.J.
      • Pina M.A.
      Trends in prevalence and incidence of multiple sclerosis in Bajo Aragon, Spain.
      ) but showed a significant increase in a larger study in Southern Spain (Northern Seville District of Andalucia, 1991–2010; 156 incident cases) (
      • Izquierdo G.
      • Venegas A.
      • Sanabria C.
      • Navarro G.
      Long-term epidemiology of multiple sclerosis in the Northern Seville District.
      ). In a UK-wide study, there was a significant decrease in the MS incidence rate (1991–2010), (
      • Mackenzie I.S.
      • Morant S.V.
      • Bloomfield G.A.
      • MacDonald T.M.
      • O'Riordan J.
      Incidence and prevalence of multiple sclerosis in the UK 1990-2010: a descriptive study in the general practice research database.
      ) while a smaller study in South East Wales (Cardiff unitary authority, covering <1% of the UK's population) showed a significant increase in the MS incidence rate (1988–2007) (
      • Hirst C.
      • Ingram G.
      • Pickersgill T.
      • Swingler R.
      • Compston D.A.
      • Robertson NP.
      Increasing prevalence and incidence of multiple sclerosis in South East Wales.
      ).

      3.1.7 Eastern Mediterranean region

      Of the four studies in Iran, three explicitly used a consistent case definition throughout, i.e., McDonald criteria (
      • Cheraghmakani H.
      • Baghbanian S.M.
      • HabibiSaravi R.
      • Azar A.
      • Ghasemihamedani F.
      Age and sex-adjusted incidence and yearly prevalence of multiple sclerosis (MS) in Mazandaran province, Iran: an 11-years study.
      ;
      • Izadi S.
      • Nikseresht A.R.
      • Poursadeghfard M.
      • Borhanihaghighi A.
      • Heydari ST.
      Prevalence and incidence of multiple sclerosis in Fars Province, Southern Iran.
      ;
      • Mohebi F.
      • Eskandarieh S.
      • Mansournia M.A.
      • Mohajer B.
      • Sahraian MA.
      Multiple sclerosis in Tehran: rising prevalence alongside stabilizing incidence - true increase or enhanced diagnosis?.
      ). Of these studies where change over time could be reliably determined, the incidence rate increased in two (1992–2016), (
      • Izadi S.
      • Nikseresht A.R.
      • Poursadeghfard M.
      • Borhanihaghighi A.
      • Heydari ST.
      Prevalence and incidence of multiple sclerosis in Fars Province, Southern Iran.
      ;
      • Mohebi F.
      • Eskandarieh S.
      • Mansournia M.A.
      • Mohajer B.
      • Sahraian MA.
      Multiple sclerosis in Tehran: rising prevalence alongside stabilizing incidence - true increase or enhanced diagnosis?.
      ) and remained stable in one (2009–2018) (
      • Cheraghmakani H.
      • Baghbanian S.M.
      • HabibiSaravi R.
      • Azar A.
      • Ghasemihamedani F.
      Age and sex-adjusted incidence and yearly prevalence of multiple sclerosis (MS) in Mazandaran province, Iran: an 11-years study.
      ). Across all studies in Iran, the MS incidence rate remained stable over time in Mazandaran Province, Northern Iran (2009–2018), (
      • Cheraghmakani H.
      • Baghbanian S.M.
      • HabibiSaravi R.
      • Azar A.
      • Ghasemihamedani F.
      Age and sex-adjusted incidence and yearly prevalence of multiple sclerosis (MS) in Mazandaran province, Iran: an 11-years study.
      ) and significantly increased in a study covering 22.3% of Iran's population in the Fars Province, Southern Iran (2003–2012), (
      • Izadi S.
      • Nikseresht A.R.
      • Poursadeghfard M.
      • Borhanihaghighi A.
      • Heydari ST.
      Prevalence and incidence of multiple sclerosis in Fars Province, Southern Iran.
      ) and in the two studies in Tehran from 1989–200875 and 1992–2016 (
      • Mohebi F.
      • Eskandarieh S.
      • Mansournia M.A.
      • Mohajer B.
      • Sahraian MA.
      Multiple sclerosis in Tehran: rising prevalence alongside stabilizing incidence - true increase or enhanced diagnosis?.
      )

      3.1.8 Western Pacific region

      Eligible studies were from Australia, Japan and Taiwan. Only two of the three studies in this region explicitly used a consistent method to identify cases across the study (Poser criteria or ICD codes); incidence rate increased (1985–2014) in one, (
      • Houzen H.
      • Kondo K.
      • Horiuchi K.
      • Niino M.
      Consistent increase in the prevalence and female ratio of multiple sclerosis over 15 years in northern Japan.
      ) and remained stable (2006–2015) in the other (
      • Fang C.W.
      • Wang H.P.
      • Chen H.M.
      • Lin J.W.
      • Lin WS.
      Epidemiology and comorbidities of adult multiple sclerosis and neuromyelitis optica in Taiwan, 2001-2015.
      ). The Taiwan-wide study showed stable incidence rate (2006–2015) (
      • Fang C.W.
      • Wang H.P.
      • Chen H.M.
      • Lin J.W.
      • Lin WS.
      Epidemiology and comorbidities of adult multiple sclerosis and neuromyelitis optica in Taiwan, 2001-2015.
      ). In the Tokachi province of Hokkaido, covering 0.3% of Japan's population the MS incidence rate significantly increased (1985–2014) (
      • Houzen H.
      • Kondo K.
      • Horiuchi K.
      • Niino M.
      Consistent increase in the prevalence and female ratio of multiple sclerosis over 15 years in northern Japan.
      ). A study in Newcastle, Australia, covering 0.7% of the country's population, showed a significant increase in MS incidence rate (1986 to 2011) (
      • Ribbons K.
      • Lea R.
      • Tiedeman C.
      • Mackenzie L.
      • Lechner-Scott J.
      Ongoing increase in incidence and prevalence of multiple sclerosis in Newcastle, Australia: a 50-year study.
      ).

      3.2 Paediatric-only studies

      Three studies explicitly studied paediatric-onset MS (most commonly defined as symptom onset <18 years of age) from Canada (2005–2013), (
      • Marrie R.A.
      • O'Mahony J.
      • Maxwell C.
      • Ling V.
      • Yeh E.A.
      • Arnold D.L.
      • et al.
      Incidence and prevalence of MS in children: a population-based study in Ontario, Canada.
      ) Denmark (1986–2015), (