The first part of our study describes the epidemiological and demographic data on multiple sclerosis in Latvia. There is an increase in the prevalence of MS in the region of the capital of the republic (about 60%) and large cities, and this trend is explained by factors associated with health services that may affect the diagnosis of MS; readily available compared to rural areas modern diagnostic methods (such as magnetic resonance imaging (MRI) for the public. The high proportion of non-smokers or quitters (about 80%) among patients with multiple sclerosis (MS) may be due to increased awareness of the harmful effects of smoking on health, including its association with multiple sclerosis [16], also because about half of the cohort of patients (47.64%) have higher education. Improved educational campaigns, health promotion efforts, and access to information are also contributing to this trend in Latvia.

In the collection of 288 MS patients, 204 (71%) are women, which corresponds to an average gender ratio of 2.4:1, and this is consistent with most European studies conducted to date [17,18,19]. Among the Baltic countries, our study also confirmed the predominance of women in MS among Latvians; in Lithuania, females were affected from 1.5 to 2 times more often than males [20]. Some possible factors that could contribute to this observed difference include variations in genetic susceptibility among populations, differences in healthcare systems and access to diagnosis, and potential variations in lifestyle or environmental factors.

In our study, no significant differences were found between genders regarding the presence of predominant symptoms at disease onset, however, the number of cases of the disease in the family history of females turned out to be almost 2 times more predominant concerning the male group (13.7% vs. 5.7% of cases). According to a meta-analysis of the worldwide prevalence of familial MS, the ratio of family history in affected females and males was 15.4% /13.7%, respectively [21]. Thus, the number of cases of a family history of MS in Latvian males was about three times lower than that found in other regional studies.

In the first year after disease onset, only one exacerbation was reported in 74.6% of patients from the general group. In the remaining cases, with a prevalence in the group of males almost twice (21.4% vs 11.27%, respectively) no incident was observed. Second exacerbation was registered in half of the cohort (48.7%) within a period of up to one year.

The most common symptom at presentation in our study was found to be optic manifestations (25.18%), followed by sensory disturbances (20.21%) and motor deficit (18%), which prevailed in the male group of patients to the female (23% vs 16%). In this study, we have only focused on the predominant symptom at diagnosis, although multiple symptoms were experienced by the patients. Interestingly, optic symptoms (37.8%) were the most common predominant symptom at diagnosis in Saudi Arabia and were found to be similar to our results [22]. However, according to the data presented in the Atlas of MS [19] the most common initial symptom of MS was sensory loss (40%), as well as motor disorders (39%) as the first clinical manifestation. In some of the available reports evaluating the cohort of Polish MS patients, the first clinical manifestation was usually motor deficit, followed by sensory symptoms and optic neuritis [17]. A study by Brola et al. reports the onset of the disease was also usually monosymptomatic (78.4%) and had the form of motor deficit (34.2%), optic neuritis (25.2%), and sensory disturbances (18.3%) of patients [23]. Therefore, the above distribution of the number and nature of the first symptoms turned out to be slightly different from our results, which may indicate a different initial course of the disease in different populations.

In our study, the nature of the first symptoms of MS reflected the level of EDSS, which characterizes the degree of progression of the disease, already at the first visit; the highest first mean EDSS value was assigned to the motor deficit group (2.91) and the lowest to the sensory impairment group (2.37) of the first symptoms. The first clinical manifestation in the form of a motor deficit was associated with a faster conversion to SPMS (p < 0.001) in Rzepiński et al., [17] study, while the disease onset in the form of optic neuritis was associated with later conversion to SPMS (p = 0.002). In addition, mobility is the most affected function in MS, previously published results have confirmed that mobility is lower in progressive types of MS [23].

In our study cohort, the mean age at the disease onset was 29.40 ± 9.42 years, while the minimum and maximum age of onset of symptoms were seven (7) and 54 years, respectively. These data corresponded with the data presented by Kułakowska et al. (30.4 ± 9.8 years) and Brola et al. (30.8 ± 9.8 years) and were lower than in the group of Termelett et al. (32.4 ± 10.3 years) Debouverie et al. (33 ± 10 years), and Jerković et al. (32.3 ± 10.9 years) [23,24,25,26].

In the case of the Latvian population, no differences were found in the mean age of the disease onset between the genders, however, according to other sources, this parameter was found in such correlation. According to Toncev et al., females in the Serbian district Sumadija were found to be significantly younger than males at disease onset (p = 0.023, [27]).

It is assumed that in the natural course of the disease, the transition from RRMS to SPMS occurs between 5.8 and 19.1 years from the onset of symptoms, with the most likely median for this time being 19 years [28,29,30]. According to our data, the period of the RRMS stage before the transition to the SPMS stage was approximately the same between the genders and was calculated as 13.35 ± 9.05 years with a significant proportion (36.92%) progressing 16 or more years after the onset of the first symptoms. Our data are in good agreement with the results reported by Rzepinski et al., (12.7 ± 7.4 years), obtained in Potemkowski’s group (11.3 ± 4.2 years), for patients in the group of Eriksson et al., (12 ± 1.8 years) [17, 30, 31], and slightly different from the results obtained by Sand et al., (16.7 ± 2.0) years [32].

When considering the dynamics of the main clinical characteristics related to multiple sclerosis in the population of Latvia, their changes in the time from the beginning of the first visit to 20–25 years were studied through visits at five main time points. In the investigated group, the distribution of individual clinical multiple sclerosis variants at the first visit was in the ratio RRMS – 82%, SPMS – 18%, and corresponded to the generally accepted pattern for the MS course [19]. In a period of 20–25 years after the first visit (the start of disease registration), the disease variants were found to be distributed in the ratio: RRMS – 43.4%, SPMS – 56,8%, (Fig. 2). Thus, during the above period, about half of MS patients switched from RRMS to SPMS. There was wide variation in the estimated prevalence of SPMS within and across countries and in the proportion of patients with relapsing SPMS. This may be because of differences in SPMS definition, study design, or study duration, which should be explored in future studies.

In the Latvian disease cohort, the approximate age of transition to the SPMS stage was 42.98 ± 10.55 years and approximately the same between the genders (42.24 ± 10.73 years for females and 44.65 ± 10.07 years for males). Thus, the mean age of onset of SPMS progression in the Latvian MS population was lower compared to the age of patients in the study by Tutunku et.al, who found that 62% of patients with RRMS progressed to SPMS by age 75, with a median age at the onset of progression of 45 years [33]. According to the British Columbia Multiple Sclerosis Database, the median time to SPMS is 21 years and the median age of onset is 54 years [34].

To determine the temporal dynamics of disease progression in the Latvian MS cohort, the collection studied was also divided into three groups according to the level of EDSS; a statistically significant difference (p < 0.00001) was found between all periods (visits) among patients. Thus, it can be concluded that LV diseases cohort cannot maintain a constant EDSS value over time or limit disease in patients with MS. (Fig. 2A); it is also obvious that there are groups of patients with varying degrees of disease progression: over time, at each follow-up visit, the number of patients in the group with low EDSS value (< 3.00), and those with high EDSS value (> 5.00), but there is also a part of patients in the group (with average EDSS 3.00–5.00), which remains at a similar frequency for 20–25 years (Fig. 3B). It can be assumed that these differences may be due to individual features in disease severity at diagnosis, genetic predisposition, environmental influences, access to health care and treatment, adherence to treatment, and lifestyle factors such as diet and exercise [35, 36]. In the Latvian study, gender was not a significant influencing factor on the rate of disease progression over short periods; a slight prevalence of progression rate (p < 0.05) was observed in females compared to males only for a period of 15–20 years from the onset of illness (Table 5, Fig. 4). According to Rzepi´nski et al., faster conversion to SPMS was associated with the male gender in the Polish population [17]; male relapse-onset patients accumulate disability faster than female patients in the Ribbons et al. group [35]. Therefore, the above data turned out to be different from our results, which may indicate a different initial MS course among populations.

In the present study, we also tested for an association between the rate of disease progression and patient age at the time of treatment and/or diagnosis in our cohort of patients (Table 7); according to our data patient age was statistically significantly associated with EDSS value at the first visit, which accordingly affects its size at subsequent visits. Numerous studies support both age-associated cumulative neurodegeneration and unique CNS pathology as the underlying initiators of progression [36]. Older age at onset and longer MS duration are the most significant risk factors associated with progressive disease [34, 37]. Similarly, older age has been negatively associated with lower immune cell activity, along with lower gene expression and recruitment of progenitor oligodendrocytes and differentiation as well as subsequent consequences of reduced repair, remyelination, and other functions necessary to stabilize the relapsing–remitting course of the disease [38]. Thus, the data obtained by us supplement and confirm the significant influence of age-related physiological changes on the course of the disease and the accumulation of disability.

In the past decades, special attention has been paid to the effects of immune-modulating drugs (IMD) in MS patients. In our study, at the first visit, 96% of clinical cases showed clinical disease activity with magnetic resonance activity present in half of the cases (47%). At this time, a line of immunomodulatory and immunosuppressive drug therapy was initiated in almost a third cohort of patients. When considering the progression dynamics of the disease, we did not notice a statistically significant between groups of patients with and without drug therapy in the period from the beginning of therapy to 20–25 years. The obtained results do not give grounds for conclusions about the effectiveness of IMD since the compared groups of treated and untreated patients in our study were not homogeneous in terms of incidence, clinical, and radiological activity.

Several previous studies describing the natural course of multiple sclerosis have found a certain percentage of patients treated with immunosuppressive or immunomodulatory drugs [6, 39]. Both studies excluded a significant effect of the applied treatment on the assessed parameters, since the time of its application was too short, or there was no effect on the increase in disability. In the Polish cohort of RRMS patients, there was no influence of treatment with IMDs on the time to reach 4 and 6 points on the EDSS scale [17]. In this context, our study can also be viewed as an analysis of the natural history of multiple sclerosis in a cohort of Latvian patients.

An interesting fact, however, was the presence of a difference in ∆EDSS at the margin of statistical significance (p = 0.06), between these groups after a period of approximately 5–9 years after the start of therapy. In addition, in the cases of all periods among visits (except V3 > V4), ∆EDSS was on average higher in patients with special drug therapy than in patients without it. This situation in the Latvian population can be explained by a certain difference in the degree of disease progression at the first visit, as well as the presence of resistance to treatment in certain patients: if patients develop resistance to the drug or have persistent disease activity despite treatment, their disease may progress with greater speed.

Our results emphasize the importance of early clinical MS parameters in determining the clinical disease variant and the time to conversion from RRMS to SPMS as well as predicting the rate of disability accrual in patients. In the age of general availability of disease-modifying therapy, their analysis is of particular importance for identifying patients requiring more aggressive treatment, as well as for a selection of proper treatment. In the present study, data on the long-term outcomes of disability in patients with MS in the Latvian population remain overwhelmingly consistent with the results obtained in other regions of the world.

The main limitation of this study was its retrospective nature. Another limitation could be the ratio of patients receiving IMDs, (about 32% in the first visit, as mentioned above), and the choice of therapy by the treating physician (non-randomized study).

Despite the limitations of our sample, this study draws its strength from the fact that it suggests the demographic and medical characteristics of people with MS in Latvia. He offers a unique insight into gender differences in how multiple sclerosis manifests itself. These results may help to assess the prevalence and demographic characteristics of MS in the Baltic region and thus, are expected to stimulate additional research that may help us confirm, understand, and better explain the current findings and their implications for the treatment of multiple sclerosis.