Accepted Manuscript Title: Multiple sclerosis in Brazil: a systematic review Authors: C.C.F. Vasconcelos MD, MsC, PhD L.C.S. Thuler MD, MSc, PhD B.C. Rodrigues MD A.B. Calmon MD, MSc R.M.P. Alvarenga MD, MSc, PhD PII: DOI: Reference:
S0303-8467(16)30250-5 http://dx.doi.org/doi:10.1016/j.clineuro.2016.07.011 CLINEU 4461
To appear in:
Clinical Neurology and Neurosurgery
Received date: Revised date: Accepted date:
12-12-2014 11-2-2016 3-7-2016
Please cite this article as: Vasconcelos CCF, Thuler LCS, Rodrigues BC, Calmon AB, Alvarenga R.M.P.Multiple sclerosis in Brazil: a systematic review.Clinical Neurology and Neurosurgery http://dx.doi.org/10.1016/j.clineuro.2016.07.011 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1. Multiple sclerosis in Brazil: a systematic review 2. Vasconcelos CCF, Thuler LCS, Rodrigues BC, Calmon AB, Alvarenga RMP 3. Luiz Claudio Santos Thuler (MD, MSc, PhD) - Universidade Federal do Estado do Rio de Janeiro and Instituto Nacional de Câncer - Adress: Rua André Cavalcanti, 37 - Centro - Rio de Janeiro - RJ – Brasil CEP 20231-050, Telefone:+55 (21) 3207-6659 ou +55 (21) 9528-8118. E-mail: [email protected]
4. Bernardo Campos Rodrigues (MD)-Universidade Federal do Estado do Rio de Janeiro - Adress: Rua Mariz e Barros 775- Departamento de Neurologia-Tijuca, Rio de Janeiro, CEP: 20270-901, Telefone and Fax +55 21 2264-2321. E-mail:[email protected]
5. Ana Beatriz Calmon (MD, MSc)-Universidade Federal do Estado do Rio de Janeiro - Adress: Rua Mariz e Barros 775- Departamento de Neurologia-Tijuca, Rio de Janeiro, CEP: 20270-901, Telefone and Fax +55 21 2264-2321. E-mail: [email protected]
6. Regina Maria Papais Alvarenga (MD, MSc, PhD)-Universidade Federal do Estado do Rio de Janeiro and Hospital Federal da Lagoa - Adress: Rua Mariz e Barros 775- Departamento de Neurologia-Tijuca, Rio de Janeiro, CEP: 20270-901, Telefone and Fax +55 21 2264-2321. E-mail: [email protected]
Highlights Profile of MS in Brazil is similar to that observed in high-MS-prevalence areas. Classic predictors of long-term disability were reproduced in Brazil. African ancestry is a risk factor to disability and early progression.
Abstract 7. Background: The natural history of multiple sclerosis (MS) in Brazil have been available in different regions of country. There is no nationwide population-based studies that express general data in Brazil. Objective: To review and synthesize available data about MS in Brazil. Material and Methods: Systematic review was performed through a search of medical literature databases to identify Brazilian studies published during 1990-2012. Data sources: PubMed, SciELO, and Lilacs. Key words: “Brazil” or “Brazilian” combined with the following terms: “multiple sclerosis”, “clinical profile”, “demographic profile”, “natural history”, “clinical course”, “pediatric”, or “familial form”. Results: In total of 45 pediatric and 1,922 adult patients, the median age at onset was 10 years in pediatric patients and 32 years in adult patients. Women were more affected. Motor-control complaints and relapsing-remitting phenotype at onset were the most common. Predictors to disability and progression were number of relapses during the first year of disease, older age, male gender and African ancestry. Conclusions: The profile of the MS in Brazilian seems to correspond to that observed in high-MS-prevalence areas. African ancestry is a risk factor to disability and progression early. In Brazil, factors that limit MS incidence do not interfere with the clinical pattern and outcomes. 8. Key words (6): systematic review, Brazilian profile, multiple sclerosis, clinical course, prognostic factors, natural history 9. 10. CORRESPONDING AUTHOR: Claudia Cristina Ferreira Vasconcelos (MD, MsC, PhD*)- Universidade Federal do Estado do Rio de Janeiro - Adress: Rua Mariz e Barros 775- Departamento de Neurologia-Tijuca, Rio de Janeiro, CEP: 20270-901, Telefone and Fax +55 21 2264-2321. E-mail: [email protected]
Multiple sclerosis (MS) is a disease that affects young adults, causing inflammation of the white and gray matter of the central nervous system (CNS) by means of an autoimmune reaction triggered by the interaction of genetic and environmental factors. Although MS is considered polygenic disease , the human leukocyte antigen class II genes, the DR2 haplotype alleles in particular, are the ones most frequently associated with greater susceptibility to the disease . Among the environmental factors, the most frequent identified as trigger of MS were: the influence of smoking, stress, hygienic conditions, immunizations, and viral infections; additionally poor exposure to the sun in the world’s northernmost and southernmost latitudes and consequent vitamin D deficiency has been investigated. However, to date, the causal relationship between those factors and the disease could not be fully confirmed . The prevalence of MS increases as latitude increases, and it exhibits a particular racial and geographic distribution, occurring more frequently among Caucasians and in the Western countries of the northern hemisphere . MS is not frequent in Brazil, which has a racially mixed population and tropical climate, which are the opposite of the typical conditions of the places with the highest prevalence of MS . The earliest data on MS in Brazil were reported in 1939, when 22 cases were described, two of which were confirmed in anatomical pathological examination  The first Brazilian multicenter study known as the South Atlantic Project (Projeto Atlântico Sul PAS) , whose main aim was to present and describe the clinical and demographic profile of MS in Brazil was conducted from 1995 to 1998. PAS included 22 reference centers across the five Brazilian regions and a total of 602 patients. The results show that 30% of patients 4
had African ancestry, and the clinical, laboratory, and genetic profile of MS in Brazil corresponds to the “Western MS type” . Twenty-one years have passed since PAS and new data on the natural history of MS in Brazil have been available in different regions of country. However, there is no nationwide population-based studies that express general data in Brazil. For this reason, we performed a systematic review of epidemiological studies conducted in different regions of Brazil with in order to observe different aspects of those already obtained by individual studies that analyzed a limited number of patients. 12.
Material and Methods
Study Design: Systemic review of case series. Setting: A comprehensive search using as key words “Brazil” or “Brazilian” combined with the terms “multiple sclerosis”, “clinical profile”, “demographic profile”, “natural history”, “clinical course”, “pediatric”, and “familial form” was performed in the medical literature databases: National Library OF Medicine and The National Institutes Of Health (Medline/PubMed) Literature Latino-Americana e do Caribe em Ciências da Saúde (LILACS) and Scientific Electronic Library Online (SciELO), to identify relevant Brazilian studies published during 1990-2012. Selection strategy: Titles and abstracts in English, Spanish, and Portuguese identified by electronic searches were examined independently by two researchers (CCFV and BCR) to select potentially relevant studies containing demographic (ethnicity and gender), clinical (age and clinical phenotype at onset), and outcome (benign course, time to
disability, and progression phase) information of MS in Brazilian patients. Articles on prevalence that did not contain demographic and clinical data were excluded. From the 81 articles found, 22 studies were selected full reading. To avoid that patients were counted multiple times, three non-longitudinal observational studies were excluded after full reading because of the risk of contain patients and data already presented in a more complete study of the same service or group [7, 8, 9]. Then, 19 studies were included after full reading, being two about case series of pediatric MS . Fourteen non observational studies conducted with adults contained information on demographic (gender and ethnicity) and clinical variables (age at onset, clinical presentation, and clinical phenotypes) [12,8,13.14,15,16,17,18,9,7.19,20,21,22], and three longitudinal observational studies conducted with adults too (analysis of prognosis: time to reach to progression and disability milestones) [23,24,25]. No article mentioned the familial form of MS. Among 14 non-longitudinal observational studies selected, 11 included patients with all three clinical forms of MS (relapsing-remitting, RR; secondary progressive, SP; and primary progressive, PP) [12,8,13,14,15,16,18,9,7,19,20], two only included patients with RRMS [17,21], and one included patients with PPMS . Among the three longitudinal observational studies, two included cases of RRMS only [23,24], and one included cases of PPMS only  (Figure 1). FIGURE-1 Here The data were subjected to three separate analyses: analysis 1, on the pediatric cases described in two non-longitudinal studies (younger than 18 years old); analysis 2, on the adult population in non-longitudinal studies (14 studies); and analysis 3, on the adult population in longitudinal studies (3 studies).
The data from the longitudinal studies included in analysis 3 were not included in analysis 2 because there could be an overlap with the cases of the non-longitudinal studies, in addition to the fact that they examined different clinical forms of MS. The authors adhere to the reporting guidelines by MOOSE (Meta-analysis of Observational Studies in Epidemiology) statement. Statistical analysis: The categorical variables were expressed as percentages, the mean and median values were calculated in the case of continuous variables, and the variables gender and ethnicity were expressed as ratios. All analyses were performed relative to the total population of this study. The data were analyzed using the Statistical Package for the Social Sciences (SPSS), version 14.
Analysis 1: Case series of pediatric MS Data on the gender and mean age at the onset of disease were available for a total of 45 patients [10,11] in whom disease began before 18 years of age. The ratio of females to males was 1.6:1. The median age when the first symptoms manifested was 10 years. These were mainly motor symptoms (47% of the cases), followed by visual or sensory symptoms (22% each), and finally brainstem and cerebellar symptoms (1.8%). Regarding the clinical patterns, 87% corresponded to RRMS, 9% to SPMS, 2% to PPMS, and 2% to the clinically isolated syndrome (data not shown). No article provided information on the children’s ancestry.
Analysis 2: Non-longitudinal MS studies (Data in table 1) Data on the gender and mean age at the onset of disease were available for a total of 1,922 patients, 75% of whom were female, and the female to male ratio was 3:1. The median age of the patients was 32 years old, with mean of 32.8± 3.5 years and a range from 27.9 to 43.9 years. Thirteen studies included data on the ethnicity of the patients [7,8,9,12,13,14,15,16,17,18,19,20,22]. It was equivalent to 1,639 patients, 74.3% of whom were white, and the ratio of whites to non-whites (blacks and mulattos) was 2.9:1. Regarding the clinical phenotype, of the 1,922 patients included in 14 studies, 81% had RRMS, 11% PPMS, and 10% SPMS. Patients with an evolution classified as benign (Expanded Disability Status Scale (EDSS) step 3 or lower and ≥10 years since the onset of disease) were reported in five studies [7,8,12,15,18] with a frequency of 13.6% (104/762 patients). Eleven studies provided data on the initial manifestations of the disease in 1,656 patients [7,8,9,12,13,14,18,19,20,21,22]. Motor disorders were the most frequent symptoms (36%); they were followed by sensory (27%), visual (26%), cerebellar (18%), brainstem (6%), and sphincter disorders (2.5%). No patient exhibited mental disorders. TABLE-1 HERE Analysis 3: Longitudinal MS studies (Data in table 2) The three longitudinal studies assessed prognostic factors. One study  analyzed the time for patients with PPMS to reach EDSS steps 3, 6, and 8 and found that African descent significantly reduced the time to reach EDSS steps 3 and 6. The other two studies [23.24] included patients with RRMS. One assessed the time to reach EDSS steps 6, 7, and 8, 8
and the other study evaluated the time to the onset of the progressive stage of MS. The former included 197 patients and found that male gender and a disease onset that included motor or brainstem symptoms were significantly correlated with greater risk of reaching EDSS steps 6 and 7, while the number of attacks within 5 and 10 years of the onset of disease correlated with increased risk of reaching EDSS step 8. In the second study, which included 150 patients, all of them with more than 10 years since the onset of disease, a multivariate analysis found three factors correlated with increased risk for shorter time to reach to progression: African descent, age 30 years or older, and more than one attack within the first year of disease. TABLE-2 HERE 14.
Until today, in Brazil, information about MS are provided, primarily, from series of case, which are prone to significant bias. Local studies results are not representative of the Brazilian MS profile. Thus, a systematic review has more chances to provide representative and rational data about this disease. Among the 17 studies with adults included in this systematic review [7,9,12,8,13,14,15,16,17,18,19,20,21,22,23,24,25], only two were published before the introduction of disease modifying drugs (DMDs) in Brazil [14,19] . Therefore, the studies on the natural history (progression of disease in the absence of medical intervention) of MS in Brazil are virtually nonexistent. However, the demographic and initial clinical pattern of the disease is not influenced by the use of DMDs. This fact allows us to compare the results of the studies conducted in Brazil with the global data on the natural history of MS. 9
Similar to what has been found in several regions worldwide, in Brazil MS affects females more often , and prevalence studies show that the ratio of females to males is increasing . MS is most frequent among females in all the Brazilian regions, except in the study by Vasconcelos et al (2010), in which the authors found no difference between genders; however, the study included only patients with PPMS, in which the equivalence between genders is well known. The mean ages at the onset of disease reported in the Brazilian studies are in the third and fourth decades of life, in agreement with the global pattern of the disease , which preferentially affects young adults, mostly aged 18 to 55 years. In two studies, one conducted in the northeastern region and another in the southeastern of Brazil [11,20] the mean age of the patients was higher than the median found in the present meta-analysis and in studies on the natural history of the disease . In regard to ethnicity, the predominance of white individuals among MS patients was detected by 11 out of the 13 descriptive studies that reported
white-to-African descent ratio were found as a function of the region where the Brazilian studies were conducted. The white patients frequency was greater in the southern region, where there are fewer African descendants, compared to the northeastern region, where conversely the black and mulattos population predominates, the frequency of African-descendant patients is greater than the frequency of white patients. Those findings show that although MS is more common in Caucasians in Brazil, it might also affect non-Caucasians as a function of local miscegenation. The frequency of the clinical phenotypes agreed with the global pattern [27,28], and the onset of disease was characterized by attacks and relapse in most cases. The frequency of 10
PPMS varied widely (5 to 30%) [7,8,9,12,13,14,15,16,18,19,20,22]. A higher frequency of PPMS was reported in older study , possibly because at that time the difference between the PP and SP forms was not clear, as the consensus that defined the clinical phenotypes of MS was published in 1996 . From that time onward, the phenotypic classification of patients has been increasingly more accurate in international and Brazilian. Among the initial manifestations, as well as observed in international epidemiological studies, the most common were the type motor, sensorial and visual. In any of the 11 studies that have provided this information, there was no reference to mental symptoms [7,8,9,12,13,14,18,19,20,21,22]. Currently greater attention has been given to the early diagnosis of cognitive impairment present at onset; however, this requires application of specific Neuropsychological tests by trained professionals, which on occasion of Brazilian studies was not yet universally and routinely available. In addition, traditionally the EDSS is the most widely used method for quantification of initial symptoms, having limited ability to detect mental changes, since this scale has low sensibility for this type of manifestations. The MS might be clinically silent and only detected by the presence of radiological changes, whereas its clinical expression has mild (causing minimal long-term disability) and benign forms, as well as fulminant and aggressive forms that can manifest at the onset of the disease. The frequency of benign cases in international studies varies widely, from 6% to 64% . Among the 17 Brazilian studies analyzed, five provided information on the frequency of benign cases, which also varied widely (6.8 to 39%) [7,8,12,15,18]. These findings might be due to disagreement and the lack of a specific definition for this form of the disease.
In regard to the predictors of poor clinical progression, the prognostic factors identified by the three longitudinal studies [23,24,25] agree with the factors reported in studies conducted in areas with high prevalence of MS . Greater numbers of attacks in the first year of disease, greater age, and male gender were found to be associated with faster development of disability and progression in the Brazilian population. Similarly, to the situation in North America  and Europe , in Brazil African descent was associated with greater severity of both clinical forms of MS [24,25]. The identification of the pediatric form of MS has increased in the last 15 years, but only two studies [10,11], conducted 12 years apart, investigated pediatric MS in Brazil. The first was published in 1995 and did not report the relative frequency of the pediatric form in relation to the full number of MS cases. In the later study , conducted in 2007, the onset of the disease occurred before 18 years of age in 31 out of the 310 patients included, corresponding to 10% of the sample. The distribution of the patients by age group was as follows: 1% from zero to five years old, 3% from six to 10 years old, and 6% from 11 to 17 years old. The rates of pediatric cases in the international literature are lower, ranging from 0.4 to 5.6% . Nevertheless, they have shown a predominance of cases in children older than 10 years old , similar to what has been found in Brazilian study. As well as results of international studies  the proportion of affected Brazilian girls increased with the age of onset, which is most likely related to hormonal influences. In Brazilian study on the familial form of MS has been published in any journal included in the databases. The only data available in this regard are those supplied by PAS, according to which 5.2% of 303 patients whose family history of MS was investigated had relatives with a formal diagnosis of the disease . 12
The recognition of neuromyelitis optica as distinct disease from MS caused an impact on the epidemiologic profile of idiopathic inflammatory demyelinating diseases of central nervous system. Recent studies have applied new criteria for NMO and demonstrated a greater frequency of NMO cases in non-Caucasian population . For those reasons, the number of cases of MS might have been overestimated, particularly because NMO tends to be more frequent in non-Caucasian populations such as the Brazilian population . Among the limitations in this analysis we can mention little or no information about MS in some Brazilian regions as for example no study in the northern region and only one study in the Midwest region and two studies in the Northeast region. The complex MS diagnosis and the consecutive changes in its criteria in the last two decades can lead to false positive and false negatives. Important information (such as frequency of mono and polysiymptomatic forms, time for diagnostic and values of EDSS) have not been entirely available, while for other available information the collection and classification criteria were not standardized (e.g. ethnicity and clinical forms). Unfortunately, the method used for ethnic classification was not specified in each study analyzed. The ethnic self-declaration method is widely used in different studies on EM. In populations where there is a high degree of miscegenation, as in Brazil, the exclusive use of ethnic self-declaration is not the best one for it, the most accurate method being the genomic ancestry; however, this method is too expensive and applied more frequently in studies of anthropological nature. A Brazilian study about the relationship between self-declared ethnicity, mitochondrial haplogroup and genomic ancestry showed that among the individuals who declared themselves white, a greater contribution of European ancestry was observed, while among those who declared themselves black the African ancestry 13
contribution was predominant . These observations, lead us to consider that although the ethnic self-declaration method is not the most effective, it does not induce major misclassifications. The lack of information about the familial form of MS means that further investigations might improve our knowledge of the genetic component of MS in the Brazilian population. Few studies in Brazil have been devoted to cases of MS starting before 18 years of age. In younger patients, acute disseminated encephalomyelitis occurs more frequently than MS and thus might be considered the first diagnostic choice; resulting in delayed diagnosis of MS. Greater availability of data on pediatric MS in Brazil might contribute to the earlier recognition of this disease. 15.
Based on the present systematic review, the demographic and clinical profile of MS in Brazil seems to correspond to the profile found in the areas with high prevalence of disease. The predictors of long-term disability found in Caucasian populations were also identified in the Brazilian population. African descent was a risk factor for earlier onset of disability and disease progression and should be taken into account in therapeutic decision-making, particularly in the Brazilian areas with greater numbers of Afro-Brazilians. We conclude that in areas with low prevalence of MS, such as Brazil, once the disease manifests, the rarity or absence of factors that contribute to its low occurrence do not interfere with the epidemiological and clinical patterns of the disease. So far and to the best of our knowledge, there has been no analysis specifically investigating of MS in Brazil and we point out that this study with 1,922 adults and 45 pediatric patients is a comprehensive
carried out on the national territory, and it is expected that its results are closer to reality than data provided by individual studies.
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MS-multiple sclerosis; RRMS-relapse remitting multiple sclerosis; PPS-primary progressive multiple sclerosis Figure 1. Flowchart of the selected articles.
Table 1-Demographic and clinical characteristics of pediatric MS published in Brazil Ferreira et al., 2008# (n=31)
Guilhoto et al., 1995* (n=14) Gender Female (n) Male (n) rate Age at onset Mean (years) Median (years) Until 5 years old (%) from 6 to 10 years old (%) from 11 to 17 years (%) Initial symptoms (%) Motor Sensory Visual Cerebellar/Brain stem Clinical patterns at onset (n) CIS RR PP
8 6 1.3:1
20 11 1.8:1
28 17 1.6:1
8.6 NA 4 (28.5) 3 (21.4) 7 (50)
11.7 NA 3 (9.7) 9 (29) 19 (61.3)
10 7 (15.5) 12 (26.6) 26 (57.7)
64.0 21.4 28.5 35.7
38.7 19.4 19.4 22.5
46.6 20.0 22.2 26.6
0 14 0
1 29 1
CIS-clinical isolated syndrome; RR-relapse-remitting; PP-primary progressive; * Poser et al. Criteria (1983) applied; #McDonald Criteria (2001 and /or 2005) applied
Table 2. Demographic and clinical data of Brazilian descriptive studies Author and date
Region of country
Number of cases
Papais-Alvarenga et al.*, 1995 (Hospital da Lagoa)
Oliveira et al.*, 1999 (Universidade Federal de São Paulo) Moreira et al.*, 2000 (Santa Casa de Misericórdia) Arruda et al.*ƨ, 2001 (Hospital de Clínicas)
Age at onset (mean in years)
Ferreira et al.*, 2004 (Hospital da Restauração)
Fragoso et al., 2005 (Centro de Esclerose múltipla de Santos) Grzesiuk et. al *#, 2006 (Centro de Reabilitação Integral Dom Aquino Corrêa) Cardoso et al.#, 2006 (Núcleo de Apoio ao Paciente com Esclerose Múltipla-Bahia) Vasconcelos et al.ƨ, 2006 (Hospital da Lagoa) Santos et al. #, 2007 (Secretaria Estadual de Saúde de Minas Gerais) Alves-Leon et al. #, 2008 (Hospital Universitário Clementino Fraga Filho) Finkelsztejn et al.#, 2009 (Hospital de Clínicas de Porto Alegre) Ribeiro et al.*#, 2011 (Universidade Federal do triangulo Mineiro) Lana-Peixoto et al.*, 2012 (CIEM-universidade Federal de Minas Gerais) Total
Frequency of clinical phenotype at onset
Frequency of benign form
88.6% RRMS 6.8% SPMS 4.5% PPMS 60%RRMS 10% SPMS 30%PPMS 72.8%RRMS 13.6%SPMS 13.6%PPMS 91%RRMS 1% SPMS 8%PPMS 70.3%RRMS 23.7%SPMS 6.8%PPMS 100% RRMS
75% RRMS 20% SPMS 5% PPMS
91.7% RRMS 2.5% SPMS 5.8% PPMS
87% RRMS 17.2% SPMS 13.1% PPMS 82.1%RRMS 10.4%SPMS 7.4% PPMS 88.6% RRMS 5.7% SPMS 5.7% PPMS 63.8% RRMS 19% SPMS 17.1% PPMS 81% RRMS 10% SPMS 11% PPMS
* Poser et al. Criteria (1983) applied; #McDonald Criteria (2001 and /or 2005) applied; Ƨ Thompson et al. Criteria (2000) applied. In relationship to the diagnostic criteria, 5 studies used only Poser criteria (1983), 2 used only McDonald criteria (2001), 3 used Poser criteria (1983) in diagnoses carried out before 2001 e McDonald criteria (2001) or revised McDonald criteria
(2005) in diagnoses carried out after 2001, 3 used only revised McDonald criteria (2005), 1 used Poser criteria (1983) for RR and Thompson criteria (2000) for PP, 1 study used only Thompson criteria because included only PP patients, and 1 study did not reported which criteria were applied.
Table 3. Longitudinal studies and analysis of their data regarding predictors of various MS milestones Study Author, date (region of Brazil)
Number of cases
Outcomes and risk (IC 95%)
Vasconcelos et al.Ƨ, 2010(Southeast)
EDSS 3; OR:1.9 (1.0–3.4); EDSS 6; OR: 2.1 (1.1–4.1); EDSS 8; OR: 4.3 (0.9–18.9)
Damasceno et al #., 2012(Southeast)
EDSS 6; HR:4.39 (2.13–9.03) EDSS 7; HR:4.69 (1.57–14.00) EDSS 8; HR:1.28 (1.022–1.602)
Univariate no of relapses within 5 years of disease onset
EDSS 8; HR:1.19 (1.035–1.373
no of relapses within 10 years of disease onset Vasconcelos et al #., 2012(Southeast)
African ancestry ≥ 2 bouts in the first year Age onset ≥ 30 years
Progression; OR: 2.0 (1.1–3.4) Progression; OR: 2.3 (1.2–4.3) Progression; OR: 2.0 (1.1–3.3)
PPMS: primary progressive multiple sclerosis; RRMS: relapsing-remitting multiple sclerosis; EDSS: Expanded Disability Status Scale; CI: confidence interval; OR: odds ratio; HR: hazard ratio; # Mc Donald et al criteria (2005 and/or 2011) et al criteria applied; Ƨ Thompson et al criteria (2000) applied