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Incidence and prevalence of multiple sclerosis in Europe: a systematic review Kingwell, Elaine; Marriott, James J; Jetté, Nathalie; Pringsheim, Tamara; Makhani, Naila; Morrow, Sarah A; Fisk, John D; Evans, Charity; Béland, Sarah G; Kulaga, Sophie; Dykeman, Jonathan; Wolfson, Christina; Koch, Marcus W; Marrie, Ruth A Sep 26, 2013

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RESEARCH ARTICLE Open AccessIncidence and prevalence of multiple sclerosis inEurope: a systematic reviewElaine Kingwell1, James J Marriott2*, Nathalie Jetté3,4,5, Tamara Pringsheim4,5,6, Naila Makhani7, Sarah A Morrow8,John D Fisk3,9, Charity Evans10, Sarah Gabrielle Béland11, Sophie Kulaga11, Jonathan Dykeman3, Christina Wolfson12,Marcus W Koch4,5 and Ruth Ann Marrie2AbstractBackground: Multiple sclerosis (MS) is the most common cause of neurological disability in young adultsworldwide and approximately half of those affected are in Europe. The assessment of differential incidence andprevalence across populations can reveal spatial, temporal and demographic patterns which are important foridentifying genetic and environmental factors contributing to MS. However, study methodologies vary and thequality of the methods can influence the estimates. This study aimed to systematically review European studiesof incidence and prevalence of MS and to provide a quantitative assessment of their methodological quality.Methods: A comprehensive literature search was performed to obtain all original population-based studies of MSincidence and prevalence in European populations conducted and published between January 1985 and January2011. Only peer-reviewed full-text articles published in English or French were included. All abstracts werescreened for eligibility and two trained reviewers abstracted the data and graded the quality of each study usinga tool specifically designed for this study.Results: There were 123 studies that met the inclusion criteria. The study estimates were highly heterogeneous,even within regions or countries. Quality was generally higher in the more recent studies, which also tended touse current diagnostic criteria. Prevalence and incidence estimates tended to be higher in the more recentstudies and were higher in the Nordic countries and in northern regions of the British Isles. With rare exceptions,prevalence and incidence estimates were higher in women with ratios as high as 3:1. Few studies examinedethnicity. Epidemiological data at the national level was uncommon and there were marked geographicaldisparities in available data, with large areas of Europe unrepresented and other regions well-represented in theliterature. Only 37% of the studies provided standardized estimates.Conclusions: Despite the breadth of the literature on the epidemiology of MS in Europe, inter-studycomparisons are hampered by the lack of standardization. Further research should focus on regions not yetstudied and the evaluation of ethnic differences in MS prevalence and incidence. National-level studies usingcurrent diagnostic criteria, validated case definitions and similar age- and sex-standardization would allow bettergeographical comparisons.Keywords: Multiple sclerosis, Epidemiology, Europe, Incidence, Prevalence* Correspondence: jmarriott@hsc.mb.ca2Department of Internal Medicine, University of Manitoba, Winnipeg, CanadaFull list of author information is available at the end of the article© 2013 Kingwell et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly cited.Kingwell et al. BMC Neurology 2013, 13:128http://www.biomedcentral.com/1471-2377/13/128BackgroundMultiple sclerosis (MS) is a chronic inflammatory diseaseof the central nervous system that typically presents inthe third or fourth decade of life. It is estimated thatmore than 2 million people have MS worldwide and thedisease is among the most common causes of neurologicaldisability in young adults [1]. The distribution and fre-quency of MS are assessed by estimates of prevalence andincidence. These measures provide essential informationfor health service planning, and can be used to monitor orreveal spatial, temporal and demographic differences inthe distribution of disease. Comparisons of incidence andprevalence in different populations support assessmentsof the relative contribution of genetic and environmentalfactors in MS aetiology [2].MS is recognized worldwide, however reported incidencerates (the proportion of new cases during a defined timeperiod) and prevalence (the proportion of the populationthat has the disease at or during a specified time) varyconsiderably between regions and populations [1]. Theobserved patterns appear consistent with differentialgenetic predispositions and also implicate environmentalrisk factors that modulate the risk of MS at the populationlevel [3]. Results of meta-analyses suggest that the inci-dence of MS has increased over time and provide someevidence that this has primarily resulted from an increasein the incidence of MS among women [4-8]. Europe isconsidered a high prevalence region for MS (defined byKurtzke as a prevalence ≥ 30/100,000 [9]), containingmore than half of the global population of people diag-nosed with MS [1]. Nevertheless, a great deal of uncer-tainty remains about how the risk of MS varies amongEuropean populations. The aim of this study was tosystematically review the prevalence and incidence ofMS across Europe. The quality of the published studiesalong with the temporal and geographical trends wereexamined and priority areas for further epidemiologicalresearch identified.MethodsStudy selectionThis review was part of a larger study on the worldwideincidence and prevalence of MS, which included all ori-ginal population-based studies published in English orFrench between January 1st 1985 and January 31st 2011.The start date of 1985 was chosen in part because theintroduction of magnetic resonance imaging (MRI) atthat time substantially influenced the diagnosis of MSand thus the reliability of case definitions for prevalenceand incidence studies. A comprehensive literature searchwas performed as previously described [10]. The searchterms ‘multiple sclerosis’, ‘incidence’, ‘prevalence’ and‘epidemiology’ were entered in MEDLINE and EMBASEdatabases (see Additional file 1 for detailed search strat-egies), and review articles and bibliographies of originalstudies so identified were hand searched for potentiallyrelevant studies. Studies in which all data collection wascarried out earlier than January 1st 1985 and those thatwere reported solely as conference presentations or ab-stracts were excluded.Two reviewers (RAM, SK or CW) independently screen-ed the abstracts to assess whether each study met alleligibility criteria. If eligibility could not be ascertainedby review of the abstract, the full text of the article wasreviewed. All articles that met eligibility criteria by con-sensus of both reviewers were retained.Data extraction and quality assessmentFor each article, one trained reviewer abstracted data ontoa standardized form, including: study location, prevalenceday or period, sources for case ascertainment, diagnosticcriteria and average age of the study population. Crudeand standardized (when available) prevalence and inci-dence estimates were documented overall and by sex,region, time period and subgroup as applicable. Extracteddata were verified by a second reviewer.Two reviewers independently assessed the qualityof each study using a tool designed for this review(Additional file 2) and based on a scoring system suggestedby Boyle [1]. The questions aimed to evaluate: the validityof the chosen diagnostic criteria, the representativenessof the study population, the inclusion of confidence in-tervals, how well the study population was defined, andthe reliability and completeness of the data. Each studywas scored out of 7 or 8 points based on one potentialaffirmative score per question. One question appliedonly to studies that used health administrative datasources; these studies were scored out of 8 while studiesusing multiple sources of ascertainment were scoredout of 7. Conflicts were resolved by consensus. Data ab-straction and quality reviews were conducted using theweb-based DistillerSR program (Evidence Partners, Ottawa,Canada).All European studies were then selected to facilitatedetailed examination; Russia was included but Turkey,Kazakhstan, Azerbaijan and Georgia were not (theseare included in a separate review of studies from Asia;in preparation). The studies were grouped into eightregions to allow more descriptive analysis: the ItalianPeninsula and Malta; the British Isles; the Nordic region;the Iberian Peninsula; Belgium and France; the CentralEuropean countries; South East Europe; and the Baltic states,including Russia. All data extracted from the Europeanstudies were manually verified by one reviewer (EK).Where possible, female to male prevalence and incidenceratios were calculated from reported data whenever sexratios were not explicitly reported in the manuscripts.Kingwell et al. BMC Neurology 2013, 13:128 Page 2 of 13http://www.biomedcentral.com/1471-2377/13/128Heterogeneity estimates were generated for the preva-lence studies for each European region and for all Europeanstudies combined. Studies that did not report either thecrude estimate with the confidence interval or the numberof cases and the population denominator were excludedfrom these calculations. We examined the resulting I2statistic, which describes the proportion of variation inpoint estimates due to heterogeneity between studiesrather than to sampling error; a χ2 test of homogeneitywas conducted to determine the strength of evidencethat heterogeneity was genuine.ResultsThe initial global literature search yielded 3,256 citationsthrough EMBASE and MEDLINE, and a further 16 refer-ences identified by hand searches (see Figure 1). Thirty-three European studies were excluded because of language(eight from Spain, seven from Russia, five from Poland,three Norwegian, three Ukrainian, two German, oneDanish, one Czech, one Slovakian, one Serbian and onefrom the former Yugoslavia). Of the 183 worldwide studiesthat met the selection criteria, 123 unique studies wereconducted in Europe; all data extracted from the Europeanincidence and prevalence studies, with the assessed qualityscores, are presented in Additional file 3: Table S1and Additional file 4: Table S2 respectively (listedchronologically by year of publication, within country).Even when stratified by region, heterogeneity amongstudies was found to be high (I2 ≥ 84.4%, p<0.0001)(see Figure 2). Given the disparity of the studies (I2 =Records identified through MEDLINE(n=686)Records identified throughEMBASE(n=3239)3925 citations 669 duplicates removed3,256 unique citations evaluated for relevance2781 citations not relevant citations by title or abstract review475 review and original studies deemed potentially relevant368 citations that did not meet eligibility criteria for the review as follows:63 review articles 55 non-English or French (33 from Europe) 53 abstract, letter or editorial 53 not prevalence or incidence study23 not population-based 17 not original data40 data collected prior to 1985 4 papers not available57 from regions other than Europe3 further duplicates removed16 additional potentially relevant studies identified by hand searching references of relevant papers and reviews 491 review and original studies deemed relevant by title & abstract or needed full text to make determination      123 studies included in systematic reviewFigure 1 Flow diagram of selection of MS incidence and prevalence studies January 1 1985 – January 31, 2011.Kingwell et al. BMC Neurology 2013, 13:128 Page 3 of 13http://www.biomedcentral.com/1471-2377/13/12899%, Q =11,633.2, d.f. = 117, p<0.0001), a meta-analysiswas not performed.Prevalence estimates were more frequently reportedthan incidence estimates; 113 of the 123 studies reportedprevalence estimates while 74 reported incidence estimates.Across Europe and over time, point prevalence estimatesvaried considerably. Estimates as low as ≤ 20/100,000 werereported in some studies conducted in the 1980s [11-14],Figure 2 Heterogeneity of prevalence estimates from included studies, stratified by region.Kingwell et al. BMC Neurology 2013, 13:128 Page 4 of 13http://www.biomedcentral.com/1471-2377/13/128and also from more recent studies in Malta [15] and inethnic minority populations of Norway and Bulgaria[16,17]. High estimates of ≥ 200/100,000 were reported inparts of Scotland and Northern Ireland and also withinspecific populations in Scandinavia [18,19] and Sicily [20].Likewise, estimated annual incidence rates ranged widelyfrom < 1/100,000 [11,15] to > 10/100,000 [20-22].In the majority of studies the prevalence of MS washigher in women with sex ratios ranging from 1.1 to 3.The average female to male prevalence ratio overall wasapproximately 2, ranging from 1.6 for South East Europeto 2.7 for studies from Central Europe; average preva-lence ratios across Europe ranged between 1.6 to 2.8 inthe 1980s, 1.8 to 2.5 in the 1990s and 1.8 to 2.4 in the2000s. Exceptions to the excess prevalence of womenwere noted in a small district of Northern Sweden (fe-male to male ratio: 0.76) where several of the identifiedcases were related [18], and among Turkish-speakingcommunities in Cyprus, (female to male ratio: 0.5) [23].Relatively low female to male prevalence ratios (between1 and 1.1) were seen in Greek-speaking communities inCyprus [24], in Catania, Sicily (1989) [13] and in Africanand Asian ethnic populations in Norway [17]. However,when available, sex incidence ratios revealed generallyhigher rates for women that were in keeping with theoverall higher female sex ratio for prevalence. As inci-dence ratios are not subject to survivor bias and are moreetiologically relevant, their discussion is emphasized infavour of prevalence ratios in the description of the re-gional findings below.In most of the reviewed studies cases were ascertainedfrom a variety of sources including hospital and clinicrecords, neurologists and other physicians, patient as-sociations and, in more recent years, from MS registriesor administrative databases. Diagnosis was typically es-tablished through assessment by a health professionalor review of medical records. MS cases were definedmost frequently using the Poser criteria [25] (79% ofstudies), although the inclusion or exclusion of ‘probable’or ‘possible’ MS cases was not consistent across studies.The 2001 McDonald [26], Rose [27] and Schumacher [28]criteria were used in most of the remaining studies whilethe McAlpine [29] or McDonald/Halliday [30] criteriawere used rarely.Study quality scores varied from 1 to the maximum (7 or8), and were somewhat lower for earlier studies comparedto more recent reports. The mean quality score was 4.31(standard deviation [SD]: 0.97) for studies conductedduring or ending in the 1980s in contrast to 4.86 (SD:1.02) for those conducted in the 1990s and 5.35 (SD:1.08) after 2000. Lower quality scores were due to unclearreporting of standardized methods (78% of the studies)or because confidence intervals were not included (25%of the studies). Only 37% of the studies providedstandardized estimates, although the diversity of stand-ard populations chosen by the different studies hindersdirect comparisons’ of estimates. Nevertheless, esti-mates that are standardized to a large standard popula-tion are preferable to crude estimates and these adjustedestimates, when available, are presented in the followingdescriptive summaries.Italian Peninsula and MaltaItaly has been particularly well-studied, although no singlestudy evaluated the complete Italian mainland. Among the28 reviewed studies from this region, nine were conductedin Sicily [13,20,31-37], seven in Northern Italy [38-44],seven in Sardinia [45-51], two in Central Italy [52,53], andone each in the south of Italy [54], San Marino [55] andMalta [15]. The Poser diagnostic criteria were used toidentify cases in 25/28 of the studies. Prevalence estimatesranged from a low of 15.8/100,000 to a high of 197.8/100,000, with the most extreme variation seen betweenthe studies within Sicily [13,20]. Annual incidence esti-mates also varied widely across the region, ranging from0.7 per 100,000 in the Maltese-born population of Malta[15] to 9.2/100,000 in central Sicily [31]. A particularlyhigh incidence estimate of 18.2 per 100,000, for the smalltown of Linguaglossa, Sicily [20], is thought to represent ageographical and temporal cluster of cases.It has been suggested that due to different genetic andenvironmental influences, Sardinia has a higher incidenceand prevalence of MS compared to the rest of Italy [56].Supporting this theory, five of the six studies of theSardinian population have estimated the prevalence ofMS at higher than 100/100,000 [45-47,49,51]. The onlystudy with a lower estimate (69/100,000) was carried outin 1985 [50]. However, when considering the incidence ofMS, the Sardinian estimates (3.4 to 6.8/100,000) were notunlike those seen across the entire Italian peninsula.Female to male ratios for MS incidence tended to belower in Sicily; ranging from 1.19:1 to 1.84:1 [20,31-34,36]but were as high as 3:1 in San Marino [55] and NorthwesternSardinia [51]. The quality scores ranged between 3/7 and6/7 with six of the studies from the Italian peninsula scor-ing 6/7 [33,34,39,51,53]. Ethnicity or race was consideredin only one study from this region in which prevalencewas reported separately for Maltese-born (16.7/100,000)and foreign-born Maltese (166/100,000) residents [15].The British IslesTogether with the Italian peninsula, the British Isles wasthe most studied region with 28 unique prevalence or in-cidence studies. Of these, 13 were from England [57-69],six from Scotland [21,70-74], three from Wales [75-77],three from Northern Ireland [78-80], one from the Repub-lic of Ireland [81], and one from the Channel Islands [82].Kingwell et al. BMC Neurology 2013, 13:128 Page 5 of 13http://www.biomedcentral.com/1471-2377/13/128The remaining study estimated incidence of MS acrossthe UK [83]. Allison and Millar criteria [3] were used,either alone or in combination with Poser criteria, in12/28 studies from this region conducted between 1985and 1996 [61,63-65,67,68,70,72,77,79,80,82].Prevalence estimates in the British Isles ranged from96/100,000 in Guernsey [82] to more than 200/100,000,with the highest estimates originating from Scotland[21] and Northern Ireland [78]. These two countries alsohad the highest annual incidence rates (7.2 to 12.2 per100,000) [21,78].Sequential studies of either the same or overlappingpopulations in the South Glamorgan area of South Wales[75-77], North-Eastern Northern Ireland [78-80], and theLeeds health authority area in England [58,59] all demon-strated increasing prevalence and incidence. For example,in North-Eastern Northern Ireland the prevalence ofMS increased from 138/100,000 in the mid-1980s [79]to 200.5/100,000 in 2004 [78].Annual incidence sex ratios ranged from 1.24:1 inNorth-Eastern Northern Ireland [78] to 2.82:1 in South-EastWales [76]. The quality scores for studies from the BritishIsles ranged from 2/7 to 8/8 with seven (25%) of the 28studies [60,67,71,72,78,81,83] scoring 6 or higher. None ofthe studies from the British Isles reported prevalence or inci-dence by ethnic or racial subgroups.The Nordic regionTwenty-five studies were reviewed from the Nordic region,including nine from Norway [17,84-91], five from Sweden[18,92-95], four from Denmark [96-99], three from Finland[19,22,100], three from Iceland [101-103] and one fromthe Faroe Islands [104]. Most (19/25) of the studies usedthe Poser diagnostic criteria alone or in combinationwith other criteria. Four studies relied solely on McAlpine[90,91,104] or Schumacher [18] criteria. AdministrativeInternational Classification of Diseases (ICD) codes wereused to identify MS cases in two serial studies of theDanish National Hospital Register [97,98].The highest prevalence estimates in the Nordic region(over 200/100,000) were reported in Seinajoki-South,Finland [19] and in a small Northern rural district ofSweden (population denominator 4,744) [18]. Familialfactors were suspected to play a role in the high numberof cases found in both populations according to the studyauthors. The lowest prevalence estimates (20 - 30/100,000) in the Nordic countries were documented inSami, Asian and African ethnic minority groups in Norway,well below the prevalence among ‘Western’ Norwegians(170/100,000) during the same time period [17,89]. Preva-lence estimates were 150/100,000 or greater in the morerecently conducted studies from Norway, Denmark andSweden [17,85,88,95-98].Some of the highest annual incidence estimates in theNordic countries (9.2 and 11.6/100,000) were found inspecific central and Western regions of Finland [22,100].A particularly low incidence was reported for the 1996-2000 time period in Iceland (1.28/100,000) [103]. Thismay be an underestimate however as it was based on theincidence of MS symptom onset rather than year ofdiagnosis; additional cases with onset during this periodmay have been diagnosed after the findings were publishedin 2002. Annual incidence estimates in Iceland fromthe 1980s from the same study [103], as well as from aseparate earlier study [101], both reported rates similar tothat in other Nordic countries (4.1 - 5.3/100,000).For the 11 studies that reported sex specific incidenceor incidence sex ratios, female to male annual incidenceratios ranged between 1.2 and 2.2 with no major regionalor temporal differences. Quality scores ranged from 4/7 to8/8, and seven (28%) of the studies, including all Danishstudies, scored 6/7 or higher [86,88,96-99,104]. MS preva-lence in ethnic minority groups was investigated in thetwo Norwegian studies described above [17,89].Iberian PeninsulaOne study from central Portugal [105] and 15 fromSpain were included in the review. The Spanish studiesincluded 11 conducted on the mainland [14,106-115],three from the Canary Islands [12,116,117] and one fromthe island of Menorca [118]. No studies incorporatedthe entire country of either Spain or Portugal.The lowest prevalence estimates originated from thetwo earliest studies, conducted in the 1980s; from theisland of Lanzarote in the Canary Islands (15/100,000)[12] and from the city of Valencia, Spain (17.7/100,0000)[14]. Prevalence increased over time with the highest es-timates (72 and 77/100,000) observed in the most recentstudies [106,112].Ten studies from Spain studied annual incidence,reporting values ranging from 2.2 to 5.3/100,000[14,106,107,111-113,115-118] with the highest esti-mates from studies concluded after 2000 [106,112,116].Only two studies reported sex-specific incidencefigures. The female to male ratio was 1.73:1 in Menorca[118] and 3.1:1 in Las Palmas City, Gran Canaria [116].Quality scores ranged from 3/7 to 6/7 with three of the15 studies (19%) scoring 6/7 [105,107,112]. One studyfrom this region estimated the prevalence of MS in theminority Roma population in Malaga, Southern Spainin 2002 as 52.9/100,000 [109], which was comparableto estimates in the non-Roma population in the samearea in 1991 (53/100,000) [110].Belgium and FranceOne prevalence study originated from Belgium [119] andfour incidence and/or prevalence studies were from FranceKingwell et al. BMC Neurology 2013, 13:128 Page 6 of 13http://www.biomedcentral.com/1471-2377/13/128[120-123]. One French study utilized an administrativedatabase to report national estimates [123].Prevalence estimates ranged from 80-90/100,000, asobserved in Flanders, Belgium [119] and in mostlySouthern regions of France [123], up to 120-149/100,000(2004) across regions of North-East France [123] andincluding one crude estimate from the Haute-Garonneregion in South West France [122]. The overall prevalenceof MS in France was estimated at 94.7/100,000 [123].The lowest reported annual incidence in this regionwas from the city of Dijon in the mid-1990s (4.3/100,000) [121]. Figures a decade later were higher; 7.5/100,000 for the whole country with regional estimatesranging from 6.1 to 10.8 [123].Annual incidence sex ratios across France in 2004demonstrated considerable variation; ranging from 1.4/100,000 in Corsica to 4.1/100,000 in central France [123].The quality scores for these studies varied between 5/7and 7/8 with two of the studies (40%) scoring 7/8[122,123]. No studies examined ethnic sub-groups ineither Belgium or France.Central European countriesSix studies from Central Europe met selection criteria;one from Switzerland [124], two from Germany [125,126],one from Austria [127] and two from Hungary [128,129].Crude prevalence estimates from this region ranged from62/100,000 to 128/100,000. The lowest estimates origi-nated from Hungary in the 1990s [128,129] and fromGermany in 1986 [125] while the highest estimate, alsofrom Germany, was found in the most recent study (2006)[126]. Annual incidence was estimated in the studies fromHungary and Germany to range between 6/100,000and 7.7/100,000 without any clear temporal differences[125,126,128,129].Two studies provided female to male incidence ratios;a ratio of 3:1 was reported in Germany in 2006 [126]while an earlier study from Hungary completed in 1996reported a ratio of 1.5:1 [129]. Quality scores in the CentralEuropean studies ranged from 1/7 to 6/7 with only onestudy (17%) scoring 6/7 [126]. No studies from thisregion reported prevalence or incidence by ethnic orracial subgroups.South East EuropeFourteen of the studies included in this review werefrom South East Europe, covering the former Yugoslavia[130,131], Croatia [132-134], Slovenia [134], Bosnia andHerzegovina [135,136], Bulgaria [16,137], Romania [11],Greece [138,139], and Greek- and Turkish-speaking com-munities in Cyprus [23,24].Most of the prevalence estimates in South East Europefell between a lower value of approximately 20/100,000,as recorded in Romania [11] and in both rural and urbanRoma populations in Bulgaria [16], and an upper valueof approximately 50/100,000 in other regional studies[23,24,131,133,135-137,139]. However, higher prevalenceestimates (144 and 152/100,000), were documented inthe Gorski Kotar region of North-West Croatia [130,134]and in the neighboring region (the municipalities ofKocevje and Ribnica) in South East Slovenia [134]. Theone-year incidence estimate for 1986 was also moderatelyhigh (3.78/100,000) in these two regions, promptingsuspicion that a strong familial influence is at play inthis isolated population [130]. A study in western Greecealso reported high prevalence (120/100,000) and incidence(9.5/100,000) estimates [138], that were notably higherthan those of a study conducted seven years earlier in thenortheastern region of Evros (prevalence of 38.9/100,000and annual incidence of 2.36/100,000) [139]; possiblyexplained by increased awareness, knowledge and avail-ability of MRI machines [138]. Among the remainingfour studies that measured annual incidence of MS, es-timates ranged from 0.32/100,000 in Romania [11] and0.8/100,000 in Croatia [132] to 1.1 or 1.6/100,000 in re-cent studies from Bosnia and Herzegovina [135,136].One incidence study provided sex-specific data andreported a female to male ratio of 1.69:1 in WesternGreece [138]. Quality scores in South East Europe rangefrom 2/8 to 6/7; only the two studies from Greece[138,139] scoring 6/7. Ethnic differences were highlightedby a 1998 report of MS prevalence among the Roma andnon-Roma population in two regions of Bulgaria. Theprevalence in the Roma (19/100,000) was found to be halfthat of the non-Roma (45/100,000) population in bothregions [16].The Baltic statesOnly one study from the Baltic States, a prevalencestudy in Southern Estonia in 1989, was included [140].Schumacher criteria were used to identify cases, and theestimated prevalence in the entire population was 50/100,000. The quality score for this study was 4/7. Theprevalence of MS in native Estonians was 55/100,000 incontrast to 29/100,000 among those of Russian descent,including those born in Estonia and first-generationRussian immigrants.DiscussionThis systematic review has comprehensively cataloguedthe incidence and prevalence of MS across Europe be-tween January 1985 and January 2011, and unlike priorsystematic reviews [141-143] of this region, has summa-rized methodologies and evaluated study quality usingan objective measure and a predetermined set of criteria.We aimed to describe potential temporal and demogra-phic patterns that could be appreciated at the continentalKingwell et al. BMC Neurology 2013, 13:128 Page 7 of 13http://www.biomedcentral.com/1471-2377/13/128level and to identify gaps in the literature, including re-gions or populations that are under-represented.Some European regions have undergone several MSincidence or prevalence studies over this 27 year period;more than 25 studies originated from each of the BritishIsles, Italy, and the Nordic region. Spain has also been wellrepresented. Variability in representation within individualcountries was marked; of the 28 Italian studies, for ex-ample, 16 were performed in either Sardinia or Sicily,and only 12 on the mainland where most of the Italianpopulation lives. There is a relative paucity of studiesfrom Central and Eastern Europe and the 11 Sicilianstudies equal the total number of studies undertaken inall of France, Belgium, Germany, Switzerland, Austriaand Hungary combined.While much of the literature has focused on specificregions or individual cities within a given country, a fewstudies reported countrywide data [15,55,83,96-99,101,103,123,127]. The extensive population of many Europeancountries limits the capacity to ascertain MS cases at thenational level. Administrative databases offer the means toestimate the burden of MS at this level, but comparabilitybetween studies has been limited due to the various casedefinitions that have been used. These have included thegranting of permanent disability status with MS or theneed for disease modifying therapy [123], the presence ofan incident International Classification of Disease code(ICD) for MS [97,98], and the more typical neurologistconfirmed diagnosis by standard criteria [83,96]. As vali-dated case definitions for MS in administrative data arenow available [144,145], there is the potential forgreater comparability between estimates derived fromthese sources in the future.Ethnic differences were presented in very few reports.Two Norwegian studies assessed MS rates in Asianand African minority groups, or in the indigenousSami, separately from the remainder of the Norwegianpopulation [17,89], and found up to an eight-fold lowerprevalence in those groups. Non-Maltese born resi-dents (mostly originating from Northern Europe) hada 10-times higher prevalence than Maltese-born indi-viduals [15]. Single studies from Spain [109] andBulgaria [16] revealed that prevalence was lower in theRoma compared to non-Roma populations from thesame regions. Lastly, the Estonian report [140] exam-ined Estonian- and Russian-born populations separ-ately and found a lower prevalence in those originatingfrom Russia. Studies such as these provide unique andvaluable information, and can potentially be used todifferentiate the role of genetic and environmental fac-tors in MS.Prevalence and incidence estimates tended to be higherin the Northern regions of the United Kingdom and inthe Nordic Countries, implicating the role of latitude. Thispattern is not uniform however, with higher estimatesoriginating as far south as Sicily and Greece [20,31,138].Although there were some rare reports of lower preva-lence ratios of women to men [18,23], the incidencesex ratios (when available) revealed consistently higherrates of women than men with MS across Europe withno obvious patterns between north and south. Theissues of latitude-dependent gradients in MS incidence,prevalence, and sex ratios, have been addressed in detailby recent reviews [4,146].The assessed quality of these epidemiological studiesvaried both geographically and temporally. The morerecent literature had higher quality scores in general,with the mean scores increasing from 4.31 for studieswith data collection before 1990, to 5.35 in thoseconducted since 2000. The studies from France andBelgium scored high on average; however, these werealso among the most recent. Those originating fromthe British Isles were methodologically weaker overallbut included a greater proportion of earlier studies. Whencomparing estimates between regions it is important torecognize the inter-related issues of the methodologicalquality of the study, the size of the source population, thetime period over which the study was performed and thediagnostic criteria that were used. For example, the Posercriteria were the most widely used (either alone or com-bined with other criteria in 100 of the 123 studies), al-though studies varied regarding inclusion of “probable”and “possible” cases. However, many of the earlier studiesfrom the British Isles relied on the Allison-Millar or Rosecriteria; older criteria that may be more inclusive andthereby might inflate prevalence or incidence estimates[69,72]. However, any such effect depends on whethercases in Allison-Millar’s “possible” or “early” categoriesare included [72,77,80]. The definition of incidence alsovaried, with most studies reporting incidence based onthe date of diagnosis, but others using the date of MSsymptom onset [15,39,40,42,46,55,70,87,101,103,117,118].This latter definition can sometimes result in an apparentdecrease in incidence rates during the most recent timeperiod [103] due to the time-lag between onset and diag-nosis [147-149].The more recent studies reported higher MS preva-lence or incidence estimates. Prevalence estimates wouldbe expected to increase over time if life expectancy ofthose with MS increases; incidence is therefore considereda better indicator of changes in disease rates [4]. However,given the differences in study methodology and quality asdescribed above, it is difficult to determine if the observedchanges in incidence estimates over time are due to realchanges in the risk of MS. Additional factors which canbe related to an earlier diagnosis, including access toneurological care and disease modifying therapies aswell as the availability of MRI, have also changed overKingwell et al. BMC Neurology 2013, 13:128 Page 8 of 13http://www.biomedcentral.com/1471-2377/13/128time. Comparisons are further limited by the lack ofappropriate standardization; only 42% of the prevalencestudies and 22% of the incidence studies included age-and sex-standardized estimates, and among these, a varietyof standard populations were used. The effects of severalof these limitations have previously been highlighted andrecommendations have been made that would allow forreliable comparisons between MS epidemiological studies[142,143,150].This review has some limitations. Once the data abstrac-tion of the 123 unique studies from Europe was complete,considerable inter-study variability was evident, preventinga meaningful quantitative synthesis of the data even withinregions or countries. The included studies are limitedto publications in English or French and, although fewstudies identified in the initial review were excludeddues to language, their exclusion is likely to have biaseddata collection in favour of Western European countries.Of the 33 articles excluded for language, 13 originatedfrom countries not represented in this review; i.e. Russia,the Ukraine, Poland and the Czech Republic or Slovakia.The grouping of countries into eight European regionswas predominantly based on geography for descriptivepurposes, and these groupings may not be appropriatefor all questions related to the distribution of MS withinEurope. Strengths of the study included the comprehen-sive assessment of study quality, and the independent dataabstraction by two reviewers with subsequent verificationby the first author and the comprehensive assessmentof study quality. This quality scoring system not onlyoffers a grading system for existing literature but a guideto improving the design of future MS incidence and preva-lence studies.ConclusionWhile there was marked variability in the methodologicalquality of the studies reviewed, we can report that me-thods seem to have improved over time, as demonstratedby the trend towards higher quality scores in later studies.Most prevalence and incidence estimates are derived fromtowns or regions within a country, but national studieshave become increasingly feasible with the availability oflarge databases and registries. The use of such resourcesmay improve comparability between estimates, althoughattention should be paid to the validity and comparabilityof case definitions. Spatial and temporal comparisonswould be facilitated if studies were to adopt a universalstandard population, and if age- and sex-specific estimateswere uniformly provided. The prevalence and incidence ofMS are not well documented in many regions of Europe.As incidence and prevalence of MS vary considerablybetween different ethnic populations, greater attentionshould also be paid to the ethnic composition of sourcepopulations and cases.Additional filesAdditional file 1: Multiple sclerosis search strategy EMBASE &MEDLINE. Details of search strategy to retrieve abstracts.Additional file 2: Quality assessment form. Questionnaire completedby two independent reviewers for each study.Additional file 3: Table S1. Incidence of multiple sclerosis, Europe,January 1 1985-January 31, 2011.Additional file 4: Table S2. Prevalence of multiple sclerosis, Europe,January 1 1985-January 31, 2011.AbbreviationsICD: International classification of diseases; MS: Multiple sclerosis;SD: Standard deviation.Competing interestsThe authors declare that they have no competing interests.Authors’ contributionsEK and JJM participated in the data abstraction, reviewed and verified allabstracted data, drafted and revised the manuscript. NJ and TP conceived ofthe study and participated in its design and coordination. NM, SM, JF, CEand MWK participated in the data abstraction. SGB and JD participated inthe study design and coordination. SK and CW participated in the studydesign and coordination and reviewed each abstract. RAM conceived of thestudy, participated in its design and coordination and reviewed eachabstract. All authors read and approved the final manuscript.AcknowledgementsThanks to Ms. Diane Lorenzetti, Librarian at University of Calgary whodeveloped the search strategies and to Ms. Ingrid Dixon at the McGill LifeSciences Library who obtained copies of papers that were not availableonline. Thanks to Dr. Parminder Raina and Ms. Mary Gauld, at the EvidenceReview and Synthesis Centre of McMaster University for kindly hosting us onthe DistillerSR system and thanks to Mr. Henry Ebron and Mr. Ian Stefanisonfrom DistillerSR for patiently guiding us through the conduct of a firstproject on the DistillerSR system. This study is part of the NationalPopulation Health Study of Neurological Conditions. We wish toacknowledge the membership of Neurological Health Charities Canada andthe Public Health Agency of Canada for their contribution to the success ofthis initiative.FundingFunding for this study was provided by the Public Health Agency of Canada.Elaine Kingwell was funded by a Michael Smith Foundation for HealthResearch Postdoctoral Fellowship and received funding from the MultipleSclerosis Society of Canada (Postdoctoral Fellowship). Nathalie Jette holds anAlberta Innovates Health Solutions Population Health Investigator Award anda Canada Research Chair Tier 2 in Neurological Health Services Research.Ruth Ann Marrie receives funding from a Don Paty Career DevelopmentAward (Multiple Sclerosis Society of Canada). The opinions expressed in thispublication are those of the authors/researchers, and do not necessarilyreflect the official views of the Public Health Agency of Canada.Author details1Division of Neurology, Faculty of Medicine, University of British Columbia,Vancouver, Canada. 2Department of Internal Medicine, University ofManitoba, Winnipeg, Canada. 3Department of Community Health Sciences,University of Calgary, Calgary, Canada. 4Department of Clinical Neurosciencesand Hotchkiss Brain Institute, University of Calgary, Calgary, Canada. 5Institutefor Public Health, University of Calgary, Calgary, Canada. 6Department ofPediatrics, University of Calgary, Calgary, Canada. 7Division of Neurology andDepartment of Pediatrics, University of Toronto, Toronto, Canada.8Department of Clinical Neurological Sciences, University of Western Ontario,London, Canada. 9Departments of Psychiatry and Medicine, DalhousieUniversity, Halifax, Canada. 10College of Pharmacy and Nutrition, University ofSaskatchewan, Saskatoon, Canada. 11Research Institute of the McGillUniversity Health Centre, McGill University, Montreal, Canada. 12DepartmentKingwell et al. 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BMC Neurology 2013 13:128.Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color figure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionSubmit your manuscript at www.biomedcentral.com/submitKingwell et al. BMC Neurology 2013, 13:128 Page 13 of 13http://www.biomedcentral.com/1471-2377/13/128


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