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 (
MSIF, 2020
). Over the past four decades, technological advances (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.
Cortese et al., 2019
), revised diagnostic criteria (- Cortese R.
- Collorone S.
- Ciccarelli O.
- Toosy AT.
Advances in brain imaging in multiple sclerosis.
Ther. Adv. Neurol. Disord. 2019; 12 (1756286419859722)https://doi.org/10.1177/1756286419859722
Brownlee et al., 2017
), better access to specialist health care (Marrie et al., 2005
), and availability of disease modifying drugs to treat MS (Wallin et al., 2019
), have increased the recognition and diagnosis of MS (Giovannoni et al., 2016
; Elian and Dean, 1985
; Sencer, 1988
).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 (
MSIF, 2020
). Trends in MS incidence rate over time are less clear.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.
Variation in MS incidence rate according to geographic region is well-described, typically being higher with greater distance from the Equator (
Simpson et al., 2019
). However, although systematic reviews have quantified MS incidence rates in different geographical regions (Evans et al., 2013
; Kingwell et al., 2013
; Makhani et al., 2014
), and compared incidence across countries and regions (Alonso and Hernán, 2008
; Koch-Henriksen and Sorensen, 2010
), 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 et al., 2009
). 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) (- Moher D.
- Liberati A.
- Tetzlaff J.
- Altman D.G.
- Group P.
Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
PLoS Med. 2009; 6e1000097https://doi.org/10.1371/journal.pmed.1000097
Kingwell et al., 2013
).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) (
MSIF, 2020
), and countries with eight or more studies (Italy, Canada and Norway) were mapped.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.
The adapted Newcastle-Ottawa Scale (
Xiang et al., 2014
; Wells et al., 2020
) 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.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.
2.5. Analysis
We used simple linear regression (
Marrie et al., 2018
) 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 et al., 2018
; Boesen et al., 2018
; Alroughani et al., 2015
)) 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
) (or closest available year). Using the six World Health Organization regions (also adopted by the Atlas of MS 3rd Edition) (MSIF, 2020
) 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) (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.
Cocco et al., 2011
; Granieri et al., 2000
; Granieri et al., 2007
; Grassivaro et al., 2019
; Nicoletti et al., 2011
; Nicoletti et al., 2013
; Nicoletti et al., 2020
; - 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.
Environ. Res. 2020; 182109022https://doi.org/10.1016/j.envres.2019.109022
Patti et al., 2019
; Pugliatti et al., 2001
; Pugliatti et al., 2005
; Ranzato et al., 2003
; Salemi et al., 2000
; Solaro et al., 2015
; Granieri et al., 2008
), Norway (n=10) (Benjaminsen et al., 2014
; Celius and Vandvik, 2001
; Dahl et al., 2004
; Flemmen et al., 2020
; - 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.
Mult. Scler. Relat. Disord. 2020; 45102352https://doi.org/10.1016/j.msard.2020.102352
Grytten et al., 2016
; Lund et al., 2014
; Risberg et al., 2011
; Simonsen et al., 2017
; Vatne et al., 2011
; Willumsen et al., 2020
) and Canada (n=9) (Marrie et al., 2018
; Al-Sakran et al., 2018
; Hader and Yee, 2007
; Kingwell et al., 2015
; Marrie et al., 2013
; Rotstein et al., 2018
; Widdifield et al., 2015
; Sloka et al., 2005
; Warren et al., 2008
).Table 1Characteristics of longitudinal studies of multiple sclerosis incidence over time (1985–2020) by global regions.
| Primary author, year of publication; location | Case definition or diagnostic criteria | Case ascertainment data source | Time period; calendar years | Mean annual incidence per 100,000 population during period (95% CI provided where available) | Absolute annual change estimate (95% CI) p value | Incidence trend | |
| Crude | Standardised | ||||||
| Americas Region | |||||||
| Al-Sakran 201819 Saskatchewan, Canada | ‘Marrie algorithm’: ≥3 hospital, physician, or MS DMD claims (prescriptions filled) ( Marrie et al., 2010 )‘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 claims | 2004–2008 | NR | 18.84 (Marrie algorithm) 16.23 (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) |
| 2009–2013 | NR | 14.43 (Marrie algorithm) 11.78 (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) | 1990–1999 | 9.20 (7.90–10.70) | NR | -0.12 (-0.16, -0.07) p<0.001 | Incidence decreased (1990–2004) |
| 2000–2004 | 7.90 (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 filled | 1999–2003 | 8.28 | 8.18 | -0.12 (-0.36, 0.12) p=0.29 | Incidence stable (1999–2008) |
| 2004–2008 | 7.52 | 7.36 | |||||
| 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 data | 1996–2000 | NR | 11.44 | -0.34 (-0.56, -0.12) p=0.005 | Incidence decreased (1995–2010) |
| 2001–2005 | NR | 10.13 | |||||
| 2006–2010 | NR | 8.30 | |||||
| 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 algorithm | Province-wide health administrative data including hospital and physician claims | 1999–2003 | NR | 16.20 | -0.24 (-0.51, 0.03) p=0.08 | Incidence stable |
| 2004–2008 | NR | 14.37 | (1999–2013) | ||||
| 2009–2013 | NR | 14.47 | |||||
| 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 algorithm | Province-wide health administrative data including hospital and physician claims | 2001–2005 | 15.30 | 15.00 | 0.15 (-0.40, 0.71) p=0.55 | Incidence stable |
| 2006–2010 | 15.14 | 15.62 | (2001–2010) | ||||
| Sloka 200526 Newfoundland and Labrador, Canada | Poser | Hospital records; 8 of the 9 practicing neurologists; regional MS clinic/MS registry | 1987–1991 | 18.47 | NR | 1.00 (0.29, 1.71) p=0.009 | Incidence increased |
| 1992–1996 | 26.76 | NR | (1987–2001) | ||||
| 1997–2001 | 28.33 | NR | |||||
| 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 claims | 1990–1994 | NR | 20.80 | 0.25 (0.09, 0.41) p=0.005 | Incidence increased |
| 1995–1999 | NR | 22.66 | (1990–2004) | ||||
| 2000–2004 | NR | 23.30 | |||||
| Cabre 200928 French West Indies (Martinique and Guadeloupe) | McDonald 2005 | Inflammatory CNS diseases registry (1992–2007) based on: hospital records, open-care neurologists, health records, health insurance organisations, MS patient associations | July1992-June1997 | 0.93 (0.76–1.20) | NR | 0.07 (0.05, 0.08) p<0.001 | Incidence increased (1992–2006) |
| July1997-June2002 | 1.20 (1.01–1.39) | NR | |||||
| July2002-June2007 | 1.67 (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 practice | 1991–1995 | 0.20 | NR | 0.02 (0.01, 0.35) p=0.006 | Incidence increased |
| 1996–2000 | 0.34 | NR | (1991–2005) | ||||
| 2001–2005 | 0.42 | NR | |||||
| Europe Region | |||||||
| Joensen 201130 Faroe Islands | Poser (applied from 1943–1986); Poser, McDonald and Thompson (used 1986–2007) | Hospital records, government disability registry, private neurologist | 1993–2002 | 4.90 (2.90–7.00) | NR | -0.22 (-0.32, -0.13) p<0.001 | Incidence decreased (1993–2007) |
| 2003–2007 | 2.40 (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 Registry | 1990–1999 | Female 11.33 (10.93–11.75) Male 5.65 (5.37–5.95) | 8.29 (8.05–8.54) | 0.09 (0.06, 0.11) p<0.001 | Incidence increased (1990–2009) |
| 2000–2009 | Female 12.33 (11.91–12.75) Male 6.08 (5.79–6.38) | 9.43 (9.17–9.69) | |||||
| Krökki 201132 Northern Ostrobothnia, Northern Finland | Poser; McDonald 2001 | Hospital records | 1993–1997 | 4.55 | NR | 0.26 (0.07, 0.46) p=0.01 | Incidence increased |
| 1998–2002 | 7.15 | NR | (1993–2007) | ||||
| 2003–2007 | 7.46 | NR | |||||
| Sarasoja 200433 Central Finland (4 districts) | Poser | Hospital records | 1989–1993 | 3.68 (2.30–5.10) | NR | 0.84 (0.45, 1.22) p=0.001 | Incidence increased (1989–1998) |
| 1994–1998 | 9.20 (7.40–10.90) | NR | |||||
Benedikz 200234 Iceland | Poser | Nationwide survey of MS (hospital records) | 1986–1990 | 5.28 | NR | -0.36 (-0.44, -0.28) p<0.001 | Incidence decreased (1986–2000) |
| 1991–1995 | 3.71 | NR | |||||
| 1996–2000 | 1.28 | NR | |||||
| Benjaminsen 201435 Nordland County, Norway | Poser; McDonald (used from 2001) | Hospitals records | 1985–1989 | 5.00 (3.80–6.40) | 5.40 | 0.25 (0.20, 0.29) p<0.001 | Incidence increased (1985–2009) |
| 1990–1994 | 5.30 (4.04–6.72) | 5.40 | |||||
| 1995–1999 | 7.20 (5.73–8.85) | 7.30 | |||||
| 2000–2004 | 7.40 (5.94–9.12) | 7.60 | |||||
| 2005–2009 | 10.10 (8.36–12.98) | 10.70 | |||||
| Celius 200136 Oslo, Norway | Poser | Oslo MS-Registry including hospital records, patient registries, private neurologists, MS rehabilitation and nursing homes, patient societies, disability pension records from the National Health Insurance Administration | 1987–1991 | 7.20 (5.00–10.20) | NR | 0.23 (0.12, 0.33) p=0.001 | Incidence increased (1987–1996) |
| 1992–1996 | 8.70 (6.30–11.90) | NR | |||||
| Dahl 200437 Nord-Trøndelag County, Norway | Poser | Hospitals, outpatient clinic and the sole private neurologist records | 1989–1993 | 4.70 (3.20–6.70) | 5.10 | 0.08 (0.04, 0.11) p=0.001 | Incidence increased (1989–1998) |
| 1994–1998 | 5.30 (3.70–7.50) | 5.60 | |||||
| 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) | 1999–2003 | 8.20 (3.90–12.60) | 8.40 (4.00–12.80) | 0.33 (0.25, 0.41) p<0.001 | Incidence increased (1999–2018) |
| 2004–2008 | 11.80 (6.60–17.00) | 11.80 (6.60–17.10) | |||||
| 2009–2013 | 11.10 (6.10–16.10) | 11.30 (6.20–16.30) | |||||
| 2014–2018 | 13.90 (8.30–19.50) | 14.40 (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 neurologists | 1988–1992 | 7.52 | NR | -0.09 (-0.15, -0.04) p=0.002 | Incidence decreased |
| 1993–1997 | 8.39 | NR | (1988–2012) | ||||
| 1998–2002 | 6.82 | NR | |||||
| 2003–2007 | 8.19 | NR | |||||
| 2008–2012 | 5.24 | NR | |||||
| 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 Registry | 1988–1992 | 6.05 | NR | -0.16 (-0.22, -0.10) p<0.001 | Incidence decreased |
| 1993–1997 | 4.34 | NR | (1988–2002) | ||||
| 1998–2002 | 4.24 | NR | |||||
| Risberg 201141 Oppland County, Norway | Poser | Hospitals and GP records | 1989–1993 | 6.50 (4.90–8.30) | 6.60 | 0.15 (0.08, 0.22) p=0.001 | Incidence increased (1989–1998) |
| 1994–1998 | 7.40 (5.80–9.40) | 7.60 | |||||
| Simonsen 201742 Buskerud County, Norway | Poser (before 2001); McDonald 2001, 2005, 2010 (after 2001) | Hospital and private neurology records | 2003–2007 | 10.20 | NR | 0.44 (0.24, 0.64) p=0.001 | Incidence increased |
| 2008–2012 | 13.10 | NR | (2003–2012) | ||||
| Vatne 201143 Vest-Agder County, Norway | Poser | Hospital and neurological specialist records | 1996–2000 (5 years) | 7.20 | 7.50 (4.20–13.50) | 0.07 (0.04, 0.10) p=0.001 | Incidence increased |
| 2001–2006 (6 years) | 7.50 | 8.00 (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 | 1985–1989 | 7.00 (5.60–8.60) | 7.60 | 0.29 (0.23, 0.35) p<0.001 | Incidence increased (1985–2014) |
| 1990–1994 | 9.40 (7.80–11.40) | 9.70 | |||||
| 1995–1999 | 7.50 (6.10–9.20) | 7.80 | |||||
| 2000–2004 | 12.50 (10.60–14.70) | 12.90 | |||||
| 2005–2009 | 13.70 (11.70–15.90) | 14.30 | |||||
| 2010–2014 | 13.60 (11.70–15.80) | 14.20 | |||||
Boström 200945 Värmland County, Western Sweden | Poser | Hospital records, the sole private neurologist, larger health care centers | 1991–1995 | 6.46 (5.14–7.78) | NR | -0.01 (-0.02, -0.01) p=0.001 | Incidence decreased (1991–2000) |
| 1996–2000 | 6.39 (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 outpatients | 1991–1995 | 5.66 | NR | 0.09 (-0.02, 0.21) p=0.11 | Incidence stable |
| 1996–2000 | 4.56 | NR | (1991–2010) | ||||
| 2001–2005 | 5.77 | NR | |||||
| 2006–2010 | 6.96 | NR | |||||
| Vrabec-Matković 200647 Bjelovar-Bilogora County, Croatia | Poser | Hospital records, MS Society registry | 1987–1991 | 1.94 | NR | 0.04 (0.03, 0.06) p<0.001 | Incidence increased |
| 1992–1996 | 2.36 | NR | (1987–2001) | ||||
| 1997–2001 | 2.40 | NR | |||||
| Klupka-Sarić 200748 Western Herzegovina, Bosnia-Herzegovina | McDonald 2001 | Hospital records, regional medical centre, outpatient services | 1994–1998 | 1.6 (0.00–3.30) | NR | 0.05 (-0.15, 0.24) p=0.61 | Incidence stable (1994–2003) |
| 1999–2003 | 1.7 (0.00–3.40) | NR | |||||
| Debouverie 200749 Lorraine, France | Poser | Lorraine MS Regional Network of neurologists (hospital records, MS centres, neurologists records, other healthcare professionals and MS Association) | 1993–1997 | 5.33 | NR | 0.19 (0.04, 0.35) p=0.02 | Incidence increased |
| 1998–2002 | 6.45 | NR | (1993–2002) | ||||
| Daltrozzo 201850 Bavaria, Germany | ICD-10 code G35: in at least two separate quarterly periods, not necessarily the same year | Ambulatory claims data | 2006–2010 | 17.18 | 16.70 | 0.01 (-0.18, 0.20) p=0.91 | Incidence stable |
| 2011–2015 | 17.40 | 17.01 | (2006–2015) | ||||
| Kotzamani 201251 Crete, Greece | McDonald 2001, 2005 | MS Epidemiology Program Project of Crete (including major medical centres of Crete) | 1985–1989 | Female 3.50 Male 1.70 | NR | 0.18 (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 records | 1987–1991 | 2.99 | 3.24 | 0.47 (0.27, 0.66) p<0.001 | Incidence increased |
| 1992–1996 | 7.01 | 7.53 | (1987–2006) | ||||
| 1997–2001 | 6.91 | 7.54 | |||||
| 2002–2006 | 10.08 | 10.74 | |||||
| Piperidou 200353 Province of Evros, North-Eastern Greece | Poser | Hospital records, outpatient clinic, private neurologists, Greek MS Association | 1989–1993 | 2.09 (1.17–3.44) | NR | -0.01 (-0.15, 0.13) p=0.87 | Incidence stable (1989–1999) |
| 1994–1999 | 2.36 (1.44–3.65) | NR | |||||
| Cocco 201154 South-Western part of Sardinia, Italy | McDonald 2001, 2005 | Two MS referral centres, rehabilitation centres | 1988–1997 | NR | 5.94 | 0.16 (0.11, 0.21) p<0.001 | Incidence increased |
| 1998–2007 | NR | 8.07 | (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 Association | 1985–1989 | 6.60 (5.30–8.10) | NR | -0.03 (-0.04, -0.02) p<0.001 | Incidence decreased (1985–1995) |
| 1990–1995 | 6.40 (5.25–7.80) | NR | |||||
| Granieri 200756 Province of Ferrara, Emilia-Romagna Region, North-eastern Italy | Poser | Hospitals, MS Centers, healthcare records, National Health Insurance Scheme, Italian MS Association, Telephone Surveys with health professionals | 1990–1994 | 3.44 | 3.40 | 0.14 (0.07, 0.20) p=0.001 | Incidence increased |
| 1995–1999 | 4.15 | 4.30 | (1990–1999) | ||||
Grassivaro 201957 Province of Padua (Padova), Northeast Italy | McDonald 2001, 2005 | Neurological 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 Insurance | 1990–1999 | 4.10 | NR | 0.12 (0.10, 0.13) p<0.001 | Incidence increased (1990–2015) |
| 2000–2009 | 5.50 | NR | |||||
| 2011–2015 | 6.50 | NR | |||||
| Nicoletti 201158 City of Catania, Sicily, Italy | Poser | Neurological departments, Italian MS Association and clinical records | 1985–1989 | 2.30 (1.60–3.10) | 2.20 | 0.29 (0.25, 0.33) p<0.001 | Incidence increased (1985–2004) |
| 1990–1994 | 3.90 (3.00–5.00) | 3.90 | |||||
| 1995–1999 | 5.50 (4.40–6.70) | 5.70 | |||||
| 2000–2004 | 7.00 (4.30–10.20) | 6.80 | |||||
| Nicoletti 201359 Mount Etna Regions, Catania, Sicily, Italy | Poser | Hospitals, MS Centers and Italian MS Association | 1990–1999 Western Flank | 4.20 | 3.70 | 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 Flank | 4.40 | 3.90 | (1990–2009) | ||||
| 1990–1999 Eastern Flank | 5.50 | 5.10 | |||||
| 2000–2009 Eastern Flank | 6.40 | 5.60 | |||||
| Nicoletti 202060 Province of Catania, Sicily, Italy | McDonald 2001 | Neurological divisions and MS Centers of Catania | 2005–2010 | 8.70 (7.97–9.42) | NR | -0.15 (-0.22, -0.08) p=0.001 | Incidence decreased (2005–2015) |
| 2011–2015 | 7.60 (6.86–8.32) | NR | |||||
| Patti 201961 City of Biancavilla, Catania, Sicily, Italy | Assessed separately using McDonald criteria 2001 and 2017 | Standardised database management system used by the main MS Centers in Italy | 1992–1996 | 6.30 (2001 criteria) 4.50 (2017 criteria) | NR | 0.55 (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 | |||||
| 2012–2018 | 17.40 (2001 criteria) 16.80 (2017 criteria) | NR | |||||
| Pugliatti 200162 Province of Sassari, Northern Sardinia, Italy | Poser | Hospital records, neurological clinic, private neurologists, GPs National MS Society | 1988–1992 | 6.20 (5.30–7.30) | NR | 0.09 (0.05, 0.13) p=0.001 | Incidence increased (1988–1997) |
| 1993–1997 | 6.80 (5.80–7.90) | NR | |||||
| Pugliatti 200563 Province of Sassari, Northern Sardinia, Italy | Poser | MS registry | 1985–1989 | 6.50 (5.40–7.60) | 6.00 | -0.02 (-0.3, -0.00) p=0.01 | Incidence decreased (1985–1999) |
| 1990–1994 | 6.50 (5.40–7.60) | 6.10 | |||||
| 1995–1999 | 6.10 (5.10–7.20) | 5.80 | |||||
| Ranzato 200364 Province of Padova (Padua), Northeast Italy | Poser | Hospital records, health records, Association if Invaliding Disease of Padova, National Pension Institute and National Health Insurance Scheme, Italian MS Society | 1985–1989 | 2.60 (2.08–3.12) | NR | 0.14 (0.01, 0.19) p<0.001 | Incidence increased (1985–1999) |
| 1990–1994 | 3.90 (3.19–4.61) | NR | |||||
| 1995–1999 | 4.20 (3.74–4.66) | NR | |||||
| Salemi 200065 Bagheria City, Palermo, Sicily, Italy | Poser | Hospital records, out-patient neurology clinic, GPs & neurologists were ‘informed’, rehabilitation archives, public & private MRI centres, Office for Handicapped People, social workers, television channel | 1985–1989 | 3.50 (1.50–6.90) | NR | 0.27 (0.15, 0.40) p=0.001 | Incidence increased (1985–1994) |
| 1990–1994 | 5.30 (2.70–9.20) | NR | |||||
| Solaro 201566 Province of Genoa, Italy | Poser | Hospital records, regionally serving neurologists, health records, disability pension records, Italian MS Society | 1998–2002 | 6.82 | NR | -0.05 (-0.34, 0.25) p=0.72 | Incidence stable |
| 2003–2007 | 6.26 | NR | (1998–2007) | ||||
| Granieri 200867 Republic of San Marino | Poser | Hospital records (private & public), telephone surveys of neurologists, ophthalmologists, GPs, pharmacists, social workers | 1990–1994 | 10.80 (6.00–19.00) | NR | -0.32 (-0.49, -0.15) p=0.001 | Incidence decreased (1990–2005) |
| 1995–1999 | 6.20 (2.80–12.60) | NR | |||||
| 2000–2005 | 6.80 (3.20–11.40) | NR | |||||
| 1999–2003 | 1.7 (0.00–3.40) | NR | |||||
| Valadkeviciene 201868 Lithuania | ICD-10 code G35: newly diagnosed MS in ambulatory service | Compulsory Health Insurance System including ambulatory and stationary visits | 2001–2005 | 5.48 | 5.36 | 0.47 (0.32, 0.63) p<0.001 | Incidence increased |
| 2006–2010 | 6.62 | 6.42 | (2001–2015) | ||||
| 2011–2015 | 9.85 | 9.69 | |||||
| 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) | 1999–2003 | 3.97 | NR | 0.61 (0.15, 1.06) p=0.02 | Incidence increased |
| 2004–2008 | 6.67 | NR | (1999–2008) | ||||
| Izquierdo 201570 Northern Seville District of Andalucia, Southern Spain | Poser | Hospital records, public and private neurologists | 1991–2000 | Female 4.30 (3.60–4.90) Male 2.50 (2.00–2.90) | NR | 0.36 (0.17, 0.54) p=0.001 (Female) -0.00 (-0.12, 0.11) p=0.96 (Male) | Incidence increased Female (1991–2010) |
| 2001–2010 | Female 8.80 (7.84–9.69) Male 2.80 (2.30–3.40) | NR | Incidence 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) records | 1988–1992 | 3.20 | NR | 0.05 (-0.40, 0.51) p=0.81 | Incidence stable (1988–2002) |
| 1993–1997 | 5.01 | NR | |||||
| 1998–2002 | 4.37 | NR | |||||
| Hirst 200972 Cardiff, South East Wales, United Kingdom | Poser; McDonald 2001 | Hospital records, GP notifications, consultant neurologists | 1988–1992 | 4.90 | NR | 0.28 (0.22, 0.34) p<0.001 | Incidence increased |
| 1993–1997 | 5.70 | NR | (1988–2007) | ||||
| 1998–2002 | 7.15 | NR | |||||
| 2003–2007 | 8.75 | NR | |||||
| Mackenzie 201473 United Kingdom | General Practice Research Database Read codes for confirmed diagnosis of MS beginning with F20 | General Practice Research Database, hospital records | 1991–1995 | Female 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) |
| 1996–2000 | Female 13.23 Male 6.07 | NR | Female Incidence decreased (1991–2010) | ||||
| 2001–2005 | Female 13.26 Male 5.26 | NR | Male | ||||
| 2006–2010 | Female 12.14 Male 4.99 | NR | |||||
| Eastern Mediterranean Region | |||||||
| Cheraghmakani 202074 Mazandaran Province, Northern Iran | McDonald 2001 | Provincial MS Society (‘collaborates with Mazandaran University of Medical Sciences, Neurology Association and other healthcare organisations’) | 2009–2013 | 5.48 | 4.64 | 0.08 (-0.09, 0.24) p=0.31 | Incidence stable |
| 2014–2018 | 5.80 | 4.98 | (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’) | 1989–1993 | 1.01 | 1.00 | 0.20 (0.16, 0.25) p<0.001 | Incidence increased |
| 1994–1998 | 2.35 | 2.21 | (1989–2008) | ||||
| 1999–2003 | 4.02 | 3.49 | |||||
| 2004–2008 | 5.08 | 4.09 | |||||
| Izadi 201576 Fars Province, Southern Iran | McDonald 2010 | MS centre referred by neurologists, Fars MS Society | 2003–2007 | 3.42 | NR | 0.87 (0.64, 1.09) p<0.001 | Incidence increased |
| 2008–2012 | 7.73 | NR | (2003–2012) | ||||
| Mohebi 201977 Tehran, Iran | McDonald 2001 | MS Society | 1992–1996 | 2.48 | 0.18 (0.08, 0.28) p=0.001 | Incidence increased | |
| 1997–2001 | 4.20 | (1992–2016) | |||||
| 2002–2006 | 6.45 | ||||||
| 2007–2011 | 7.49 | ||||||
| 2012–2016 | 5.52 | ||||||
| Western Pacific Region | |||||||
| Ribbons 201778 Newcastle, Australia | Poser; McDonald 2010 | Public & private neurologists, private GPs, hospital discharge records and MS outpatient clinic database | 1986–1996 | 2.44 | 2.44 (1.68–3.47) | 0.24 (0.19, 0.29) p<0.001 | Incidence increased |
| 2001–2011 | 6.70 | 6.70 (5.39–8.01) | (1986–2011) | ||||
| Houzen 201879 Tokachi Province, Hokkaido, Northern Japan | Poser | MS-related institutions (inpatient and outpatient clinical records) | 1985–1989 | 0.22 (0.06–0.56) | NR | 0.02 (0.01, 0.02) p<0.001 | Incidence increased (1985–2014) |
| 1990–1994 | 0.45 (0.19–0.89) | NR | |||||
| 1995–1999 | 0.61 (0.30–1.29) | NR | |||||
| 2000–2004 | 0.72 (0.38–1.23) | NR | |||||
| 2005–2009 | 0.79 (0.43–1.33) | NR | |||||
| 2010–2014 | 0.68 (0.35–1.19) | NR | |||||
| Fang 202080 Taiwan | ≥1 hospital or ≥3 outpatient claims (ICD-9 codes 340) within 2 years | National Health Insurance Research Database | 2006–2010 | 1.63 | 1.47 | 0.01 (-0.02, 0.04) p=0.38 | Incidence stable |
| 2011–2015 | 1.69 | 1.52 | (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 claims | 2005–2009 | NR | 1.68 (Marrie algorithm) 1.17 (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) |
| 2010–2014 | NR | 1.57 (Marrie algorithm) 1.01 (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) | 1986–1990 | Female 0.94 Male 0.46 | NR | 0.009 (-0.02,0.35) p=0.47 (Female) -0.002 (-0.02, 0.01) p=0.79 (Male) | Incidence stable (1986–2015) |
| 1991–1995 | Female 1.36 Male 0.59 | NR | |||||
| 1996–2000 | Female 1.65 Male 0.63 | NR | |||||
| 2001–2005 | Female 1.28 Male 0.57 | NR | |||||
| 2006–2010 | Female 1.58 Male 0.43 | NR | |||||
| 2011–2015 | Female 1.14 Male 0.44 | NR | |||||
| Alroughani 201582 Kuwait | IPMSSG consensus definition 2007 ( Krupp et al., 2007 ) (restricted to: <18 years at MS onset) | Kuwait National MS Registry (hospital and MS clinic databases) | 1994–1998 | 0.66 | NR | 0.07 (0.03, 0.10) p=0.001 | Incidence increased |
| 1999–2003 | 1.29 | NR | (1994–2013) | ||||
| 2004–2008 | 1.45 | NR | |||||
| 2009–2013 | 1.77 | NR | |||||
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.
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 et al., 2000
), to a high of 18,105 (2006–2015) in Bavaria, Germany (Daltrozzo et al., 2018
) (Table 2). Nine studies reported incidence rates only, and not the absolute number of incident MS cases (Rotstein et al., 2018
; Simonsen et al., 2017
; Vatne et al., 2011
; Klupka-Sarić et al., 2007
; Kotzamani et al., 2012
; Cocco et al., 2011
; Grassivaro et al., 2019
; Izadi et al., 2015
; Mohebi et al., 2019
). 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 study | Regional study location [population] | Total number incident MS cases/ total time period in years (study calendar years and other relevant detail) | Average annual number of cases | Approximate proportion of total country population covered by regional study |
| Americas Region | ||||
| Canada (8) Total Canada population 2000=30,736,000 2001=31,081,887 Approximate proportion of total (unique) country population covered by regional studies in Canada=69% | Saskatchewan ( Al-Sakran et al., 2018 )[1021,992] | 2226/13 (2001–2013; Marrie case definition) 1903/13 (2001–2013; CCDSS case definition) | 171.2 146.4 | 3.3% |
| Saskatoon ( Hader and Yee, 2007 )[196,81018] | 254/15 (1990–2004) | 16.9 | 0.6% | |
| British Columbia ( Kingwell et al., 2015 )[4058,833] | 3284/10 (1999–2008) | 328.4 | 13.2% | |
| Nova Scotia ( Marrie et al., 2013 )[941,199] | 1441/16 (1995–2010) | 90.1 | 3.1% | |
| Ontario ( Rotstein et al., 2018 )[11,685,304] | Standardised incidence only reported (1999–2013) | |||
| Ontario ( Widdifield et al., 2015 )[11,685,304] | 15,677/10 (2001–2010) | 1567.7 | 38.0% | |
| Newfoundland and Labrador ( Sloka et al., 2005 )[537,221] | 571/44 (1958–2001) | 13.0 | 1.7% | |
| Alberta ( Warren et al., 2008 )[3009,249] | 9307/15 (1990–2004) | 620.5 | 9.8% | |
| French West Indies (1) Total Caribbean population 2000=38,404,000 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, 2009 )Martinique [387,000] Guadeloupe [425,000] | 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 Republic of Panama=100% covered | Republic of Panama ( Gracia et al., 2009 ) | 144/16 (1990–2005) | 9.0 | 100% |
| Europe Region | ||||
| Denmark (2) Total Denmark population 2000=5341,000 Total Denmark population 2010=5547,68329 Faroe Islands Population 2000=47,000 Denmark=100% covered | Faroe Islands, Denmark ( Joensen, 2011 ) | 28/15 (1993–2007) | 1.9 | 0.9% |
| Denmark ( Koch-Henriksen et al., 2018 ) | 9434/20 (1990–2009) | 471.7 | 100% | |
| Finland (2) Total Finland population 2000=5188,000 Central Finland population 2000=1981,855 Vaasa=154,373 Seinäjoki=170,600 Uusimaa=1391,199 Approximate proportion of total (unique) country population covered by regional studies in Finland=45% | Northern Ostrobothnia, Northern Finland ( Krokki et al., 2011 )[372,639] | 374/16 (1992–2007) | 23.4 | 7.2% |
| Central Finland ( Sarasoja et al., 2004 ) (also included Vaasa, Seinäjoki, and Uusimaa)[1981,855] | 146/10 (1989–1998) | 14.6 | 38.2% | |
| Iceland (1) Total Iceland population 2000=280,000 Iceland=100% covered | Iceland ( Benedikz et al., 2002 ) | 372/50 (1950–1999) | 7.4 | 100% |
| Norway (10) Total Norway population 1 Jan 2001=4503,436 Approximate proportion of total (unique) country population covered by regional studies in Norway=56% | Nordland County ( Benjaminsen et al., 2014 )[238,295] | 416/25 (1985–2009) | 16.6 | 5.3% |
| Oslo ( Celius and Vandvik, 2001 )[508,726] | 374/10 (1987–1996) | 37.4 | 11.3% | |
| Nord-Trøndelag County ( Dahl et al., 2004 )[127,261] | 64/10 (1989–1998) | 6.4 | 2.8% | |
| Telemark County ( Flemmen et al., 2020 )
Prevalence of multiple sclerosis in rural and urban districts in Telemark county, Norway. Mult. Scler. Relat. Disord. 2020; 45102352https://doi.org/10.1016/j.msard.2020.102352 [165,595] | 380/20 (1999–2018) | 19.0 | 3.7% | |
| Hordaland County ( Grytten et al., 2016 )[438,312] | 1558/61 (1953–2013) | 25.5 | 9.7% | |
| Vestfold County ( Lund et al., 2014 )[215,030] | 504/21 (1983–2003) | 24.0 | 4.8% | |
| Oppland County ( Risberg et al., 2011 )[183,419] | 127/10 (1989–1998) | 12.7 | 4.1% | |
| Buskerud County ( Simonsen et al., 2017 )[238,833] | Average annual crude incidence 11.8 per 100,000 (2003–2012) | 29.6 | 5.3% | |
| Vest-Agder County ( Vatne et al., 2011 )[156,878] | Estimated (1996–2006) | 11.5 | 3.5% | |
| Møre and Romsdal County ( Willumsen et al., 2020 )[243,810] | 785/30 (1985–2014) | 26.2 | 5.4% | |
| Sweden (2) Total Sweden population 2000=8882,000 Approximate proportion of total (unique) country population covered by regional studies in Sweden=6% | Värmland County ( Bostrom et al., 2009 )[275,003] | 181/10 (1991–2000) | 18.1 | 3.1% |
| Västerbotten County ( Svenningsson et al., 2015 )[255,640] | 201/13 (1998–2010) | 15.5 | 2.9% | |
| Croatia (1) Total Croatia population 2000=4428,000 Approximate proportion of total (unique) country population covered by regional studies in Croatia=3% | Bjelovar-Bilogora County, Croatia ( Vrabec-Matkovic et al., 2006 )[133,084 in 2001] | 47/15 (1987–2001) | 3.1 | 3.0% |
| Bosnia-Herzegovina (1) Total Bosnia-Herzegovina population 2000=3767,000 | Western Herzegovina ( Klupka-Sarić et al., 2007 )[300,746 in 200348] | Average annual crude incidence 1.6 per 100,000 (1994–2003) | 4.7 | 8.0% |
| France (1) Total France population 2000=59,608,000 Approximate proportion of total (unique) country population covered by regional studies in France=4% | Lorraine, France ( Debouverie et al., 2007 )[2310,376 in 199949] | 1375/10 (1993–2002) | 137.5 | 3.9% |
| Germany (1) Total Germany population 2000= 81,488,000 Approximate proportion of total (unique) country population covered by regional studies in Germany=15% | Bavaria, Germany ( Daltrozzo et al., 2018 )[12,329,714 in 2001] | 18,105/10 (2006–2015) | 1810.5 | 15.1% |
| Greece (3) Total Greece population 2000=11,142,000 Approximate proportion of total country population covered by regional studies in Greece=13% | Crete, Greece ( Kotzamani et al., 2012 )[579,672 in 2001] | Incidence as reported in Table 1 (1985–2008) | 23.1 | 5.2% |
| Western Greece, Greece, Prefectures of Aitolokarnania, Achaia and Ilia ( Papathanasopoulos et al., 2008 )[740,506 in 200152] | 800/20 (1987–2006) | 40.0 | 6.6% | |
| Province of Evros, North-Eastern Greece ( Piperidou et al., 2003 )[144,402 in 2001] | 35/11 (1989–1999) | 3.2 | 1.3% | |
| Italy (13) Total Italy population 21/10/2001 census=56,995,744 Total Italy population in 2007=58,438,310 Total Italy population in 2011=59,433,744 Approximate proportion of total country population covered by regional studies in Italy=7% | South-Western part of Sardinia ( Cocco et al., 2011 )[138,765 in 200754] | Crude mean annual incidence 9.7 per 100,000 (1988–2007) | 13.5 | 0.2% |
| Province of Nuoro ( Granieri et al., 2000 )[221,062] | 195/11 (1985–1995) | 17.7 | 0.4% | |
| Province of Ferrara ( Granieri et al., 2007 )[344,323] | 135/10 (1990–1999) | 13.5 | 0.6% | |
| Province of Padua (Padova) ( Grassivaro et al., 2019 )[849,857] | Crude incidence as reported in Table 1 (1990–2015) | 28.1 | 1.5% | |
| City of Catania ( Nicoletti et al., 2011 )[313,11057] | 306/20 (1985–2004) | 15.3 | 0.5% | |
| Mount Etna Regions, Catania ( Nicoletti et al., 2013 )[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 et al., 2020 )
Incidence of multiple sclerosis in the province of Catania. A geo-epidemiological study. Environ. Res. 2020; 182109022https://doi.org/10.1016/j.envres.2019.109022 [1054,778] | 973/11 (2005–2015) | 88.5 | 1.9% | |
| City of Biancavilla ( Patti et al., 2019 )[22,480] | 71/27 (1992–2018) | 2.6 | 0.04% | |
| Province of Sassari ( Pugliatti et al., 2001 )[460,660] | 298/10 (1988–1997) | 29.8 | 0.8% | |
| Province of Sassari ( Pugliatti et al., 2005 )[460,660] | 430/15 (1985–1999) | 28.7 | 0.8% | |
| Province of Padova (Padua) ( Ranzato et al., 2003 )[849,857] | 580/20 (1980–1999) | 29.0 | 1.5% | |
| Bagheria City ( Salemi et al., 2000 )[50,850] | 20/10 (1985–1994) | 2.0 | 0.09% | |
| Province of Genoa ( Solaro et al., 2015 )[878,082] | 575/10 (1998–2007) | 57.5 | 1.5% | |
| Republic of San Marino (1) Total Republic of San Marino population 2000=27,000 Republic of San Marino=100% covered | Republic of San Marino ( Granieri et al., 2008 ) | 33/16 (1990–2005) | 2.1 | 100% |
| Lithuania (1) Total Lithuania population 2000=3502,000 Lithuania=100% covered | Lithuania ( Valadkeviciene et al., 2019 ) | 162+343/2 (2001 and 2015) | 252.5 | 100% |
| Netherlands (1) Total Netherlands population 2000=15,926,000 Netherlands=100% covered | Netherlands ( Kramer et al., 2012 ) | 84/13 (1996–2008) | 6.5 | 100% |
| Spain (2) Total Spain population 2000=40,904,000 Approximate proportion of total country population covered by regional studies in Spain=<1% | Northern Seville District of Andalucia, Southern Spain ( Izquierdo et al., 2015 )[163,324 in 2001 ( Izquierdo et al., 2015 )] | 156/20 (1991–2010) | 7.8 | 0.4% |
| Bajo Aragon, Teruel, Central-Eastern Spain ( Modrego and Pina, 2003 )[58,666 in 2001 ( Modrego and Pina, 2003 )] | 42/19 (1984–2002) | 2.2 | 0.1% | |
| United Kingdom (2) Total United Kingdom population 2000=58,951,000 | Cardiff, South East Wales, United Kingdom ( Modrego and Pina, 2003 )[424,633 in 2001 ( Hirst et al., 2009 )] | 582/23 (1985–2007) | 25.3 | 0.7% |
| United Kingdom=100% covered | United Kingdom ( Mackenzie et al., 2014 ) | 1538/14 (1997–2010) | 109.9 | 100% |
| Eastern Mediterranean Region | ||||
| Iran (4) Total Iran population 2011=75,149,669 Approximate proportion of total country population covered by regional studies in Iran=26% | Mazandaran Province, Northern Iran ( Cheraghmakani et al., 2020 )
Age and sex-adjusted incidence and yearly prevalence of multiple sclerosis (MS) in Mazandaran province, Iran: an 11-years study. PLoS One. 2020; 15e0235562https://doi.org/10.1371/journal.pone.0235562 [3073,943] | 1791/10 (2009–2018) | 179.1 | 4.1% |
| Tehran, Northern Iran ( Elhami et al., 2011 )[12,183,391] | 7501/20 (1989–2008) | 375.1 | 16.2% | |
| Fars Province, Southern Iran ( Izadi et al., 2015 )[4596,658] | Crude incidence as in Table 1 (2003–2012) | 251.8 | 6.1% | |
| Tehran, Iran ( Mohebi et al., 2019 )[12,183,391] | Crude incidence as in Table 1 (1996–2013) | 621.2 | 16.2% | |
| Western Pacific Region | ||||
| Australia (1) Total Australia population 2000=19,066,000 Approximate proportion of total country population covered by regional studies in Australia=<1% | Newcastle, Australia ( Ribbons et al., 2017 )[136,413 in 2001] | 132/22 (1986–2011) | 6.0 | 0.7% |
| Japan (1) Total Japan population 2000=127,534,000 Approximate proportion of total country population covered by regional studies in Japan=<1% | Tokachi Province, Hokkaido, Northern Japan ( Houzen et al., 2018 )[360,992 average population 2000–2004 ( Boesen et al., 2018 )] | 62/30 (1985–2014) | 2.1 | 0.3% |
| Taiwan (1) Total Taiwan population 2000=21,840,000 Taiwan=100% covered | Taiwan ( Fang et al., 2020 )
Epidemiology and comorbidities of adult multiple sclerosis and neuromyelitis optica in Taiwan, 2001-2015. Mult. Scler. Relat. Disord. 2020; 45102425https://doi.org/10.1016/j.msard.2020.102425 | 3844/10 (2006–2015) | 384.4 | 100% |
| Paediatric-only studies | ||||
| Canada (1) Total Canada population 2001=31,081,887 | Ontario ( Marrie et al., 2018 )[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 et al., 2018 ) | Denmark ( Boesen et al., 2018 )(paediatric-only population) [1818,787 ( Sencer, 1988 )] | 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 Kuwait=19.9% covered | Kuwait ( Alroughani et al., 2015 )(paediatric-only population) (407,380 ( Alroughani et al., 2015 )) /2051,000) | 119/20 (1994–2013) | 6.0 | 19.9% (population aged <18 years) |
CCDSS=Canadian Chronic Disease Surveillance System.
^ 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
)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, 2009
; Koch-Henriksen et al., 2018
; Benedikz et al., 2002
; Granieri et al., 2008
; Valadkeviciene et al., 2019
; Kramer et al., 2012
; Mackenzie et al., 2014
; Fang et al., 2020
) 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 (- 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.
Mult. Scler. Relat. Disord. 2020; 45102425https://doi.org/10.1016/j.msard.2020.102425
Mohebi et al., 2019
)) to multiple sources (e.g., hospital, physician and prescription databases (Al-Sakran et al., 2018
)). 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 et al., 2018
; Kingwell et al., 2015
; Marrie et al., 2013
; Rotstein et al., 2018
; Widdifield et al., 2015
; Warren et al., 2008
).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 et al., 2018
; Widdifield et al., 2015
; Fang et al., 2020
), three increasing incidence rates (- 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.
Mult. Scler. Relat. Disord. 2020; 45102425https://doi.org/10.1016/j.msard.2020.102425
Sarasoja et al., 2004
; Valadkeviciene et al., 2019
; Kramer et al., 2012
) and three decreasing incidence rates (Benedikz et al., 2002
; Granieri et al., 2008
; Mackenzie et al., 2014
).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 et al., 2007
; Nicoletti et al., 2011
; Nicoletti et al., 2013
; Patti et al., 2019
; Pugliatti et al., 2001
; Ranzato et al., 2003
; Salemi et al., 2000
), significantly decreased in three (1985–2015) (Nicoletti et al., 2020
; - 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.
Environ. Res. 2020; 182109022https://doi.org/10.1016/j.envres.2019.109022
Pugliatti et al., 2005
; Granieri et al., 2008
), and remained stable in one (1998–2007) (Solaro et al., 2015
).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 et al., 2011
; Granieri et al., 2007
; Grassivaro et al., 2019
; Nicoletti et al., 2011
; Nicoletti et al., 2013
; Patti et al., 2019
; Pugliatti et al., 2001
; Ranzato et al., 2003
; Salemi et al., 2000
), significantly decreased in four (Granieri et al., 2000
; Nicoletti et al., 2020
; - 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.
Environ. Res. 2020; 182109022https://doi.org/10.1016/j.envres.2019.109022
Pugliatti et al., 2005
; Granieri et al., 2008
) and remained stable in one (Solaro et al., 2015
). Within Sicily, the MS incidence rate increased over time in five small regional studies (from 1985–2018) (Nicoletti et al., 2011
; Nicoletti et al., 2013
; Patti et al., 2019
; Salemi et al., 2000
). However, in the province-wide study in Catania, Sicily with 973 incident cases (2005–2015) (Nicoletti et al., 2020
), the MS incidence rate significantly decreased (Fig. 1).- 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.
Environ. Res. 2020; 182109022https://doi.org/10.1016/j.envres.2019.109022
Fig. 1Map of Italy summarising studies of multiple sclerosis incidence over time and the main findings.
00443-6&id=gr1.jpg){kind=link}
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 et al., 2015
; Rotstein et al., 2018
; Widdifield et al., 2015
), significantly increased in two (1987–2004) (Sloka et al., 2005
; Warren et al., 2008
), and significantly decreased in two (1996–2013) (Al-Sakran et al., 2018
; Marrie et al., 2013
).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 et al., 2015
; Rotstein et al., 2018
; Widdifield et al., 2015
), three significantly decreased (1990–2013) (Al-Sakran et al., 2018
; Hader and Yee, 2007
; Marrie et al., 2013
), and two significantly increased (1987–2004) (Sloka et al., 2005
; Warren et al., 2008
).
Fig. 2Map of Canada summarising studies of multiple sclerosis incidence over time and the main findings.
00443-6&id=gr2.jpg){kind=link}
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 and Vandvik, 2001
; Dahl et al., 2004
; Risberg et al., 2011
; Vatne et al., 2011
), and significantly decreased in one (1988–2002) (Lund et al., 2014
). 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 et al., 2014
; Celius and Vandvik, 2001
; Dahl et al., 2004
; Flemmen et al., 2020
; - 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.
Mult. Scler. Relat. Disord. 2020; 45102352https://doi.org/10.1016/j.msard.2020.102352
Risberg et al., 2011
; Simonsen et al., 2017
; Vatne et al., 2011
; Willumsen et al., 2020
) covering ∼41% of the population, but significantly decreased in two southern counties (from 1988–2012), covering ∼15% of the total Norwegian population (Grytten et al., 2016
; Lund et al., 2014
).
Fig. 3Map of Norway summarising studies of multiple sclerosis incidence over time and the main findings.
00443-6&id=gr3.jpg){kind=link}
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 et al., 2002
; Bostrom et al., 2009
), and significantly increased in one study (1989–1998) (Sarasoja et al., 2004
). Across all included studies in Denmark, the MS incidence rates significantly increased in a large study within the general population (1990–2009) (Koch-Henriksen et al., 2018
), 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, 2011
). A significant decrease in the MS incidence rate was reported in a population-wide study in Iceland (1986–2000) (Benedikz et al., 2002
), while significant increases were found in Northern (1993–2007) (Krokki et al., 2011
) and Central Finland (1989–1998) (Sarasoja et al., 2004
), 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 et al., 2009
), but remained stable in Northern Sweden (Västerbotten County; 1991–2010) (Svenningsson et al., 2015
).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, 2009
), whereas the study in the Republic of Panama was country-wide (Gracia et al., 2009
). Only the Caribbean study used a consistent case definition (2005 McDonald criteria) over time (1992–2007) (Cabre, 2009
). 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 et al., 2006
; Debouverie et al., 2007
; Piperidou et al., 2003
; Izquierdo et al., 2015
), McDonald Criteria (2001) (Klupka-Sarić et al., 2007
), or diagnostic codes e.g., ICD (Daltrozzo et al., 2018
; Valadkeviciene et al., 2019
), Read, (Mackenzie et al., 2014
) or International Classification for Primary Care codes (Kramer et al., 2012
). Of these studies, the incidence rate significantly increased in five (1987–2015) (Vrabec-Matkovic et al., 2006
; Debouverie et al., 2007
; Valadkeviciene et al., 2019
; Kramer et al., 2012
; Izquierdo et al., 2015
), was stable in three (1989–2015) (Klupka-Sarić et al., 2007
; Daltrozzo et al., 2018
; Piperidou et al., 2003
) and significantly decreased in one (1991–2010) (Mackenzie et al., 2014
).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 et al., 2018
) and Western Herzegovina, Bosnia-Herzegovina (1994–2003), (Klupka-Sarić et al., 2007
) and significantly increased over time in Bjelovar-Bilogora County, Croatia (1987–2001) (Vrabec-Matkovic et al., 2006
), Lorraine, France (1993–2002), (Debouverie et al., 2007
) Lithuania (2001–2015) (Valadkeviciene et al., 2019
) and the Netherlands (1999–2008) (Kramer et al., 2012
). For Greece, three studies covered ∼13% of the population (Kotzamani et al., 2012
; Papathanasopoulos et al., 2008
; Piperidou et al., 2003
). 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 et al., 2003
). 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 et al., 2012
) and Western Greece (1987–2006; 6.6%) (Papathanasopoulos et al., 2008
). 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 and Pina, 2003
) but showed a significant increase in a larger study in Southern Spain (Northern Seville District of Andalucia, 1991–2010; 156 incident cases) (Izquierdo et al., 2015
). In a UK-wide study, there was a significant decrease in the MS incidence rate (1991–2010), (Mackenzie et al., 2014
) 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 et al., 2009
).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 et al., 2020
; - 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.
PLoS One. 2020; 15e0235562https://doi.org/10.1371/journal.pone.0235562
Izadi et al., 2015
; Mohebi et al., 2019
). Of these studies where change over time could be reliably determined, the incidence rate increased in two (1992–2016), (Izadi et al., 2015
; Mohebi et al., 2019
) and remained stable in one (2009–2018) (Cheraghmakani et al., 2020
). 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.
PLoS One. 2020; 15e0235562https://doi.org/10.1371/journal.pone.0235562
Cheraghmakani et al., 2020
) and significantly increased in a study covering 22.3% of Iran's population in the Fars Province, Southern Iran (2003–2012), (- 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.
PLoS One. 2020; 15e0235562https://doi.org/10.1371/journal.pone.0235562
Izadi et al., 2015
) and in the two studies in Tehran from 1989–200875 and 1992–2016 (Mohebi et al., 2019
)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 et al., 2018
) and remained stable (2006–2015) in the other (Fang et al., 2020
). 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.
Mult. Scler. Relat. Disord. 2020; 45102425https://doi.org/10.1016/j.msard.2020.102425
Fang et al., 2020
). In the Tokachi province of Hokkaido, covering 0.3% of Japan's population the MS incidence rate significantly increased (1985–2014) (- 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.
Mult. Scler. Relat. Disord. 2020; 45102425https://doi.org/10.1016/j.msard.2020.102425
Houzen et al., 2018
). 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 et al., 2017
).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 et al., 2018
) Denmark (1986–2015), (