Prevalence, Incidence, and Mortality of Multiple Sclerosis in Coimbra, Portugal

Abstract

Multiple sclerosis (MS) is the most common chronic inflammatory, demyelinating, and neurodegenerative disease of the central nervous system in young adults, representing the leading cause of nontraumatic disability in this population. The rising prevalence of MS worldwide makes it critical to recognize the absolute number of patients with MS, demanding the execution of a sustainable healthcare policy. In Portugal, only six studies evaluating MS rates were published, disclosing a prevalence of 64 cases per 100,000 persons and an incidence of 3.1 cases per 100,000 persons/year, but the mortality rates have not been reported. Thus, this observational, cross-sectional study aimed to assess MS prevalence, incidence, and mortality in the city of Coimbra, a region in the center of Portugal. Patients who fulfilled McDonald’s Diagnosis Criteria (2017) for MS were recruited. Inclusion criteria were defined according to prevalence, incidence, and mortality studies. The baseline demographic and clinical characterization of the prevalence study population was performed. The MS prevalence rate in Coimbra was 143.45 cases per 100,000 inhabitants. Between 2018 and 2021, the cumulative incidence was 8.52 new cases per 100,000 persons/year. The mortality rate between 2018 and 2021 was 2.84 deaths per 100,000 inhabitants. MS prevalence and incidence in Coimbra are higher than reported in previous similar studies and comparable to Europe’s mean prevalence and incidence.

Introduction

Multiple sclerosis (MS), the leading cause of nontraumatic disability in young adults, is a chronic inflammatory, demyelinating, and neurodegenerative disease of the central nervous system [1]. The absence of a cure highlights the importance of early recognition, appropriate treatment, and adequate social support. Effective care for patients with MS (pwMS) involves lifelong guidance and treatment, triggering high resource utilization. Therefore, accurately identifying the absolute number of pwMS becomes vital for informed healthcare policy planning.

Epidemiological studies have shed some light on a more comprehensive understanding of the disease risk. According to data from the Atlas of MS (third edition), the global prevalence of MS reached approximately 2.8 million individuals in 2020, reflecting a 30% increase compared to 2013. The estimated prevalence was 35.9 cases per 100,000 persons, with a median incidence of 2.1 per 100,000 persons per year [2]. Factors such as improved screening, earlier diagnosis facilitated by increased sensitivity of diagnostic criteria, and increased survival rates among pwMS contribute to this rise [2]. In Europe, the estimated prevalence of MS is 142.81 per 100,000 persons, with a median incidence of 6.8 per 100,000 persons/year in 2020 [2].

Additionally, geographic variations may play a determining role in the claimed relationship between differential genetic predispositions and the modulation of MS risk at the population level, influenced by environmental risk factors [2, 3]. Historically, Portugal was included in the medium frequency zone for MS by Kurtzke [4]. Currently, the reported prevalence in Portugal is 64 per 100,000 persons [5, 6], which is comparable to the reported prevalence in Eastern European countries [5]. Regarding the incidence of MS, the numbers observed in Portugal (3.1 per 100,000 persons/year) are inferior to those coming from Europe (6.8 per 100,000 persons/year) [2, 5, 7].

The overall survival of pwMS worldwide has been described as reduced, with an all-cause standardized mortality ratio (SMR) of 2.61 [8]. However, studies exploring the overall survival of pwMS in Portugal have not yet been published.

In this study, we hypothesize and intend to confirm that MS prevalence and incidence in Coimbra, in the Center Region of Portugal, are higher than those reported in previous Portuguese studies. Furthermore, we also aimed to assess the mortality rate in pwMS, which remains unknown in Portugal.

Materials and Methods

This observational, cross-sectional, and prevalence study was carried out at Centro Hospitalar Universitário de Coimbra (CHUC), comprising the Neurology Department from the University Hospital of Coimbra and the Child Development Center from the Pediatric Hospital.

Study Area and Population

The city of Coimbra is a Portuguese municipality located in the Coimbra region (Level III region in the European Nomenclature of Territorial Units for Statistics), in the center of Portugal, at 40°12′41″ N latitude, with a population of 140,816 persons (Census 2021), in an area of 319,40 km². Besides the city itself, the Coimbra region comprises another 18 municipalities [9, 10]. In the context of this study, when Coimbra is mentioned, it refers explicitly to the city of Coimbra.

CHUC is the largest Portuguese hospital, receiving patients from the Coimbra region and other districts and reaching over 1.8 million people. It represents the only public hospital in Coimbra (the tertiary referral hospital in the Coimbra region) and the only one with a permanent neurology team in the emergency department.

In Portugal, the expenses of neurological consultations for MS, complementary diagnostic exams, and other consultations related to the disease that are carried out in public hospitals are fully covered by the National Health Service (NHS). Moreover, the disease-modifying therapies (DMT) used in MS are restricted to public hospital use, and the costs are also fully covered through NHS.

Patients Recruitment

The patients’ lists were obtained from Demyelinating Diseases consultations, hospitalizations, and the participants of a disease-modifying drugs survey for MS at the Hospital Pharmacy, between January 1, 2003, and December 31, 2021. Patients that fulfilled the 2017 revised McDonald criteria [11] for MS were selected for inclusion in the studies.

Inclusion criteria were defined according to prevalence, incidence, and mortality studies. The prevalence study included patients diagnosed with MS, residing in Coimbra on December 31, 2021. The incidence study included patients diagnosed with MS between January 1, 2018, and December 31, 2021, who resided in Coimbra at the time of diagnosis. The mortality study included pwMS residing in Coimbra at the time of death between January 1, 2018, and December 31, 2021.

Baseline demographic and clinical characterization was performed for the prevalence study. The MS prevalence rate was calculated using National Institute of Statistics population data, stratified by age group and gender. The MS prevalence, incidence, and mortality rates were calculated considering the population of Coimbra as reported by the National Institute of Statistics (2021 Census), using the formulas:

$$\text{Prevalence}\text{rate}=\frac{\text{Number}\text{of}\text{cases}\text{in}\text{December}31,2021,\text{in}\text{Coimbra}}{\text{Population}\text{who}\text{live}\text{in}\text{Coimbra}\text{in}2021}\times \mathrm{100,000}$$

$$\text{Incidence}\text{rate}=\frac{\text{Number}\text{of}\text{new}\text{cases}}{\text{Number}\text{at}\text{risk}\times \text{Time}\text{at}\text{risk}}\times \mathrm{100,000}$$

$$\text{MS}\text{specific}\text{mortality}\text{rate}=\frac{\text{Total}\text{of}\text{deaths}\text{caused}\text{by}\text{MS}}{\text{Population}\text{who}\text{lived}\text{in}\text{Coimbra}}\times \mathrm{100,000}$$

The standardized MS prevalence was calculated using the direct standardization method and data from the 2013 European population was used to perform these calculations. Considering age prevalences calculated on this study, we calculated expected cases of MS by age groups and calculated a standardized MS prevalence according to the 2013 European population. The mortality rate was stratified by age (<39 years; 39–59 years; ≥60 years).

The years of life lost were calculated using mortality data and considering a life expectancy of 78 years for the male gender and 84 years for the female gender. The difference between life expectancy and age of death for each patient was calculated, and the differences were summed up to indicate the total years of life lost. The SMR was calculated.

Statistical Analysis

A descriptive analysis of all the variables included was performed. For continuous variables, the mean and standard deviation, median and interquartile range, maximum and minimum, according to the normal distribution test (Kolmogorov-Smirnoff test), were used. For categorical variables, absolute and relative frequencies were presented, with a 95% confidence interval. For all analyses performed, a significance level of 0.05 was considered.

Results

Prevalence Study

For the prevalence study, a total of 202 cases of MS were identified. The analysis of the included population revealed that 69.3% were female (n = 140). The mean age of the patients was 48.7 years (±12.8 [46.76; 50.72]), ranging from 24 to 81, with a normal age distribution (p = 0.2), with a mean follow-up time of 12.34 years.

The median age at diagnosis was 37 years (interquartile range 12), ranging from 14 to 61. The most common subtype of MS was relapse-remitting (RRMS 85.15%, n = 172), followed by secondary progressive (SPMS 11.88%, n = 24) and primary progressive (PPMS 2.97%, n = 6). Table 1 presents the MS subtypes and the average follow-up duration stratified by age groups. The proportion of patients with progressive MS rises with age.

Table 1.

MS subtype and average follow-up duration stratified by age group The highest value in each subtype is highlighted

Age group categories	MS subtypes, n (total %, subtype %)			Mean follow-up duration, years [95% CI]
	PPMS	RRMS	SPMS
20–24	0 (0, 0)	3 (1.49, 100)	0 (0, 0)	4.67 [0.0–12.80]
25–29	0 (0, 0)	9 (4.46, 100)	0 (0, 0)	4.33 [0.0–12.46]
30–34	0 (0, 0)	8 (3.96, 100)	0 (0, 0)	7.13 [2.40–11.85]
35–39	0 (0, 0)	20 (9.90, 100)	0 (0, 0)	6.05 [0.69–11.41]
40–44	0 (0, 0)	22 (10.89, 95.65)	1 (0.50, 4.35)	8.52 [4.25–12.79]
45–49	1 (0.50, 3.23)	28 (13.86, 90.32)	2 (0.99, 6.45)	12.35 [9.11–15.60]
50–54	2 (0.99, 5.88)	30 (14.85, 88.24)	2 (0.99, 5.88)	12.94 [9.69–16.19]
55–59	0 (0, 0)	22 (10.89, 91.67)	2 (0.99, 8.33)	15.46 [12.63–18.29]
60–64	0 (0, 0)	20 (9.90, 95.24)	1 (0.50, 4.76)	16.19 [13.47–18.91]
65–69	3 (1.49, 10.34)	10 (4.95, 34.48)	16 (7.92, 55.17)	18.34 [15.80–20.89]
Total	6 (2.97, 2.97)	172 (85.15, 85.14)	24 (11.88, 11.88)	12.34 [11.09–13.59]

The highest value in each subtype is highlighted. CI, confidence interval.

The MS prevalence rate in Coimbra was 143.45 cases per 100,000 persons (Table 2). The prevalence of MS in female and male patients was 185.76 and 92.73 per 100,000 persons, respectively. The female/male ratio was 2.26. The MS prevalence was stratified by age group and gender, and the analysis revealed a significant difference in MS prevalence by age group, with the highest value occurring in the 35–39 age group (p = 0.01). The highest values for MS prevalence by age group in the male gender were in the 35–39 age group (107.09) and, in the female gender, were in the 25–29 age group (242.46). The standardized MS prevalence was 81.54 cases per 100,000 persons.

Table 2.

MS prevalence stratified by age group and gender

Age group categories	Prevalence per 100,000 by age group [95% CI]
	total	male	female
20–24	68.88 [68.09–69.67]	58.08 [56.97–59.19]	80.05 [78.32–81.78]
25–29	140.01 [139.19–140.82]	40.82 [39.68–41.96]	242.46 [240.69–244.24]
30–34	159.36 [158.55–160.17]	81.68 [80.54–82.82]	238.12 [236.36–239.88]
35–39	160.59 [159.85–161.33]	107.09 [106.02–108.15]	211.26 [209.67–212.85]
40–44	103.18 [102.51–103.86]	88.52 [87.55–89.48]	116.85 [115.42–118.29]
45–49	55.37 [54.72–56.01]	47.80 [46.87–48.73]	62.27 [60.90–63.63]
50–54	54.51 [53.85–55.17]	21.38 [20.43–22.33]	84.85 [83.45–86.25]
55–59	39.42 [38.77–40.06]	21.04 [20.10–21.99]	55.60 [54.24–56.96]
60–64	16.54 [15.89–17.19]	14.09 [13.15–15.04]	18.70 [17.33–20.06]
65–69	3.51 [2.84–4.18]	0.00 [0.00–0.00]	6.55 [5.15–7.95]
Total	143.45 [143.21–143.67]	92.73 [92.39–93.07]	185.76 [185.44–186.05]

The highest value in each gender group is highlighted. CI, confidence interval.

Incidence Study

For the incidence study a total of 48 cases of MS were identified. Between 2018 and 2021, the cumulative incidence was 8.52 new cases per 100,000 persons/year (Table 3). The highest incidence was in female patients (5.95), particularly in the age group of 30–34 years (15.53), compared to males (3.19), in which the highest number of new cases was observed in the age group of 45–49 years (6.83).

Table 3.

MS incidence stratified by age group and gender

Age group categories	Incidence per 100,000 by age group [95% CI]
	total	male	female
20–24	2.46 [2.42–2.50]	2.42 [2.37–2.47]	2.50 [2.41–2.59]
25–29	5.19 [5.15–5.23]	2.55 [2.50–2.60]	7.91 [7.82–8.00]
30–34	7.71 [7.67–7.75]	0.00 [0.00–0.00]	15.53 [15.44–15.62]
35–39	8.68 [8.64–8.72]	6.69 [6.64–6.74]	10.56 [10.48–10.64]
40–44	7.12 [7.09–7.15]	5.53 [5.49–5.57]	8.59 [8.52–8.66]
45–49	4.89 [4.86–4.92]	6.83 [6.79–6.87]	3.11 [3.04–3.18]
50–54	7.67 [7.64–7.70]	5.34 [5.30–5.38]	9.79 [9.72–9.84]
55–59	1.64 [1.61–1.67]	0.00 [0.00–0.00]	3.09 [3.02–3.16]
60–64	1.65 [1.62–1.68]	1.76 [1.72–1.80]	1.56 [1.49–1.63]
65–69	0.88 [0.85–0.91]	0.00 [0.00–0.00]	1.64 [1.57–1.71]
Total	8.52 [7.65–9. 40]	3.19 [3.18–3.20]	5.95 [5.93–5.97]

The highest value in each gender group is highlighted. CI, confidence interval.

Mortality Study

For the mortality study, 4 patients were included. The MS-attributable mortality rate between 2018 and 2021 was 2.84 deaths per 100,000 inhabitants (75% female and 25% male). On average, pwMS lived with the disease for 24.75 years and died with 63.25 years. A total of 77 years of life were lost due to premature death. Three female patients have lost 9, 14, and 33 years of life, respectively, and a male patient lost 21 years of life. The proportion of mortality was 13.9 MS-related deaths per 100,000 deaths, and the SMR due to MS was 0.004 (95% confidence interval 0.002–0.006).

Discussion

CHUC is the referral hospital in the central region of Portugal and the only public hospital in Coimbra, where private care does not have a high representation. Therefore, as CHUC receives most pwMS from the center region, either by consultation or at the emergency department, it is expected to comprise all pwMS in the city of Coimbra, allowing the accurate determination of the prevalence and incidence rates. Accordingly, the prevalence rate of MS in Coimbra is 143.45 per 100,000 persons, with an incidence of 8.52 per 100,000 persons/year. Interestingly, the highest prevalence was observed in the age group of 35–39 years within the overall population (160.59 per 100,000 persons), along with the highest incidence (8.68 per 100,000 persons/year). Above these age thresholds the prevalence decreases, which may be explained by the concomitant drop in incidence rates, as well as higher proportion of progressive forms. These findings may reflect the diagnostic challenges in older patients, since cases diagnosed later in life might be more challenging due to overlapping symptoms with other age-related conditions, and there is a higher proportion of progressive subtypes, which often begins with subtle symptoms that may not be immediately recognized as signs of a progressive neurological condition [12].

These prevalence and incidence rates align with the mean estimated prevalence in Europe [2], being significantly higher than those reported in previous Portuguese studies, which confirms our hypothesis. The first Portuguese study published was conducted between 1994 and 1999 in Santarém (Ribatejo, south of Coimbra) and reported an estimated prevalence of 46.3 per 100,000 persons [13]. Later, a study in Lisbon (south of Coimbra) disclosed an estimated prevalence of 41.4 per 100,000 persons [14]. More recently, two studies reported similar prevalence rates, precisely 39.82 per 100,000 persons in Braga (Northwestern Portugal) [15] and 64.4 per 100,000 persons in Entre Douro e Vouga (Northern Portugal) [6].

The standardized MS prevalence (to the European population) in Coimbra was 81.54 cases per 100,000 persons, which was lower than the crude prevalence achieved. This fact is justified by the differences by the calculation methods. For crude prevalence, we used the Coimbra population; for standardized prevalence calculation, we used the European population defined for this method. The standardized prevalence calculation requires the calculation of expected cases to be observed and a recalculation of prevalence according to those cases. This model explains differences in results from crude prevalence rate compared to standardized prevalence rate. When compared to other Portuguese studies, our standardized prevalence in Coimbra is still higher. The reported standardized prevalence of the study in Lisbon using capture-recapture methods was 56.2 per 100,000 persons [14], and of the study in Entre Douro e Vouga was 60.0 per 100,000 per persons [6].

The striking increase in the prevalence and incidence of MS might result from diverse factors. First, Santarém, Lisbon, and Braga studies used previous diagnostic criteria, possibly underestimating the actual MS prevalence and incidence [7, 13–15]. Second, there is a possible underrepresentation of pwMS in the hospitals where these studies were conducted, as several public hospitals are nearby. Accordingly, as the Portuguese NHS, in recent years, has allowed unrestricted access and circulation of patients within public hospitals, pwMS may choose the hospital(s) in which they are followed. Another difference between studies is the inclusion of patients with clinically isolated syndrome (CIS). In this study, patients with CIS were excluded as they did not fulfill the criteria for MS. Similarly, CIS patients were excluded from the study conducted in Lisbon but included in the Braga and Entre o Douro e Vouga studies [6, 7, 14, 15]. Still, the latter’s prevalence rate was also reported upon CIS patients’ removal (58.6 per 100,000 persons) [6].

The circumstance of not having in our country an accurate MS national registry implies that all the Portuguese epidemiological data have to derive from a few, though critical, studies. The analysis of Portuguese epidemiological studies reveals that MS prevalence follows an increasing tendency, which is aligned with the worldwide scenario [6, 13–15]. Accordingly, the prevalence herein reported is similar to the European mean estimative of 142.81 per 100,000 persons and comparable to other Western countries [2], such as Spain, with an estimated MS prevalence of circa 120 (80–180) per 100,000 persons [5, 16], and France (150 per 100,000 persons) [5].

The incidence of MS disclosed in this study is superior to that reported in previous Portuguese studies, which varied from 2.74 to 4.48 per 100,000 persons/year, with a mean estimated incidence rate for Portugal of 3.1 per 100,000 persons/year [5, 7, 15]. It is also slightly higher than the reported incidence rate in Spain (4.20 per 100,000 persons/year) or France (6.2 per 100,000 persons/year), but comparable to the mean estimated incidence in Europe in 2020 of 6.8 per 100,000 persons/year [5]. The female/male ratio was 2.25, similar to the proportion reported in the Atlas of MS site for Europe (2.23) and overall (2.33) [5].

Another interesting finding in this study is the proportion of MS subtypes described. Historically, 5–15% of the cases have been reported to have a primary progressive (PP) onset [17]; however, in our cohort, only 2.97% were classified as PPMS. The same trend was observed in a recent analysis of the Swedish cohort, which reported a decrease in the proportion of PPMS diagnosis from 19.2% to 2.2%, possibly related to a change of the phenotype, or due to a shift in the clinical practice caused by the introduction on DMT, or a combination of the two [18].

This study revealed a mortality rate of 2.84 deaths caused by MS per 100,000 inhabitants and an SMR below one. Still, the small sample used is insufficient to reliably conclude mortality in our population.

It is essential to acknowledge other main limitations of this study. First, as it is hospital based, some pwMS, with or without an established diagnosis, residing in the city of Coimbra, may not have been referred to CHUC. This might apply to older and/or disabled patients with progressive disease subtypes. Even so, it was decided not to include data from primary care databases for methodological reasons as it would not be possible to confirm the diagnosis, which could overestimate the prevalence rate. Second, the lack of cases of people under 18 years of age in our sample prevented the assessment of MS prevalence among the youngest. Still, few studies in pediatric populations reported a very low prevalence ranging from 0.69 to 26.92 per 100,000 persons, with a global prevalence calculated at 8.11 per 100,000 persons [19]. Since there are only 22,913 individuals under 19 years old in Coimbra, it could be speculated that the prevalence would be lower than 4.36 per 100,000 persons [9].

In conclusion, the MS prevalence and incidence in Coimbra, in the Central Region of Portugal, are higher than those reported in previous Portuguese studies and comparable to the mean prevalence and incidence in Europe. With this study, we demonstrated that the epidemiology of MS in Portugal is not homogeneous and static; thus, it is mandatory to implement a national registry of Portuguese pwMS to unravel and anticipate the MS epidemiological trends in Portugal.

Acknowledgments

We would like to thank Evidenze Medical Education and Patient Support team for collaborating with this project, in particular Manuel Bragança Pereira for the statistical analysis of the data.

Statement of Ethics

This research was conducted following the World Medical Association Declaration of Helsinki. This study protocol was reviewed and approved by the Regional Health Administration of Centro Portugal Ethics Committee (94/2018) and by the Ethical Committee of the Faculty of Medicine of the University of Coimbra (CE-010/2018). The study has been granted an exemption from requiring written informed consent, with all the patient data deidentified prior to data collection.

Conflict of Interest Statement

I.C., C.N., C.M., and S.B. have received consulting fees from Biogen, Merck Serono, Novartis, Sanofi Genzyme, Bristol Myers Squibb, Roche, and Janssen. C.C. and C.B. have no conflicts of interest to declare. L.S. has received consulting fees from Biogen, Merck Serono, Novartis, Sanofi Genzyme, Janssen, and Roche.

Funding Sources

Editorial support, in the form of medical writing and editing assistance for manuscript preparation, was funded by Novartis Portugal. Novartis Portugal had no role in any aspect of the design or performance of the study, including data collection, management, analysis, and interpretation or preparation of the manuscript.

Author Contributions

I.C.: study concept and design, study supervision, data acquisition, analysis and interpretation of data, and writing of the original manuscript. C.C. and C.B.: data acquisition. C.N. and C.M.: data acquisition and critical manuscript revision for important intellectual content. L.S.: study concept, design and supervision, and critical manuscript revision for important intellectual content. S.B.: study concept and design, study supervision, data acquisition, analysis and interpretation of data, and critical revision of the manuscript for important intellectual content.

Funding Statement

Editorial support, in the form of medical writing and editing assistance for manuscript preparation, was funded by Novartis Portugal. Novartis Portugal had no role in any aspect of the design or performance of the study, including data collection, management, analysis, and interpretation or preparation of the manuscript.

Data Availability Statement

The research data used in this article are not publicly available on legal and ethical grounds.