RELAPSES IN MULTIPLE SCLEROSIS

Relapses In multiple sclerosis. Nikolenko O.O., Shulga O.D., Kozliuk V.V., Zheshko O.M., Yurko O.A., Dubinets M.I. Exact causes of contradictions in the understanding of relapsing course as characteristic phenomenon of multiple sclerosis (MS) and primarily relapsing-remitting type are still considered to be “sub rosa”. We tried to determine connection and correlation between seasonal dynamic factors, chronometric parameters of disease progression (age, disease duration) and frequency of relapses and the role of gender differences as well. A four-year prospective study included complete registration of all cases of MS exacerbations in resident patients with a relapsingremmiting course of the disease according to McDonald criteria in Volyn region of Ukraine in 2010. Each patient had neurological score based on EDSS scale to ensure compliance with inclusion criteria. 128 patients (44 males and 84 females) with a remitting-recurring course of the disease were involved in this study. Statistical analysis was performed using SPSS 18, MedCalc and Microsoft Excel software using standard descriptive statistics, correlation and regression analysis. In total, 197 cases of MS relapses were registered. Episodes of relapses prevailed in winter-spring period. Multiple regression model including suggested climate factors showed multiple correlation coefficient – 0.55 (p<0.01). The prevalence of MS was higher in females, while general incidence of recurrences was similar to males. However, relapse rate in different age groups differs: the rate of recurrence increases in women aged after 50 years (mean annualized relapse rate (ARR)=0.66), while it slowly decreases in men with aging. The duration of the disease did not have significant effect on the course of MS in women, whereas weak negative relationship (0.24, p<0.001) between the duration of the disease and the frequency of MS in men was showed. Correspondingly, the average negative correlation (-0.37, p<0.001) was detected between the age of disease onset and the incidence of MS recurrence in males, while this connection was not observed in females. We established that the recurrence of MS is a result of multifactorial influence of external and internal factors. Individual seasonal climate variability did not have sufficient force of influence. Therefore, combined effect of corresponding climate changes played a significant role. Furthermore, it is quite probable that interactions of MS with external factors influencing the human body can be mutually integrated. Реферат. Загострення при розсіяному склерозі. Ніколенко О.О., Шульга О.Д., Козлюк В.В., Жешко О.М., Юрко О.А., Дубінець М.І. Точні причини суперечностей у розумінні загострень як характерного явища розсіяного склерозу (РС) і головним чином рецидивуючого-ремітуючого типу досі вважаються «sub rosa». Ми намагалися визначити зв’язок та кореляцію між сезонними динамічними факторами, хронометричними параметрами прогресування захворювання (віком, тривалістю захворювання) та частотою рецидивів, а також впливом гендерних відмінностей. Чотирирічне проспективне дослідження передбачало повну реєстрацію всіх випадків загострення РС у пацієнтів-резидентів з ремітуючим-рецидивуючим перебігом захворювання за критеріями McDonald 2010 у Волинській області України. Кожен пацієнт був оцінений за шкалою EDSS для забезпечення відповідності критеріям включення. У цьому дослідженні для подальшого аналізу за допомогою статистичних даних було залучено 128 пацієнтів (44 чоловіки та 84 жінки) з ремітуючим-рецидивуючим перебігом захворювання. Статистичний аналіз проводили за допомогою програм SPSS 18, MedCalc та Microsoft Excel, використовуючи стандартну описову статистику, кореляційний та

Multiple sclerosis (MS) is a disease with chronic course and uncertain underlying cause which affects young adults. In the world, there are from 2 to 3 million patients suffering from MS [3,4]. Relapse (exacerbation) is a phenomenon inherent to the clinical course of MS. Relapses of MS result in a number of social and economic consequences. Short-term negative effects of exacerbations include the impossibility of performing routine work and family work due to the hospitalization, often the loss of work through limitation of mobility or ability to drive. Exacerbations in MS also contribute to a number of psychological problems, such as: reduced mood of patients due to uncertainty of disease course and prognosis, anxiety and depression. The longterm effects of exacerbations of MS include shortening of the term to functional dependence and shortening the interval to the progression of MS [3].
Frequency of relapses can be connected with seasonal factors. According to conducted studies [1,6,8,11,12] there are seasonal deviations of relapses.
Chronometric factors associated with increased probability of relapse include early onset and short duration of the disease. There are peculiarities in the dynamics of relapse due to gender: it occurs more frequently in men than in women. There are more significant indicators of early disability, whereas higher frequency of exacerbations in time section is observed in women [7].
The peculiarities of relapses were not studied in population of Ukrainian patients with MS before. The aim of the study was to find out the influence of age, gender, time factors and climate factors on the occurrence of MS relapses in a relapsing-remitting course during 4 years of prospective observation.

MATERIALS AND METHODS OF RESEARCH
Our study included complete and accurate registration of all cases of MS relapses in patients with a relapsing-remitting course of the disease according to McDonald 2010 criteria at Volyn region of Ukraine. Each case of MS relapse was con-firmed by EDSS scale to ensure compliance with inclusive criteria. 128 patients (44 males and 84 females) aged 18-70 years were involved in this study.
Prospective study was conducted from January 2014 to January 2018 in the Multiple Sclerosis Center in Volyn Regional Clinical Hospital (covering the area of 1 million population). Relapses (exacerbations) of MS were regarded as the development of new symptoms or worsening of existing ones, lasted more than 24 hours, without elevation of body temperature or evidence of infection. Relapses, that all patients had undergone were treated as separate cases of exacerbation only if there was about one month interval between them. Pseudoattacks associated with changes in body temperature due to an infectious process and lasting less than 24 hours, were excluded.
We analyzed seasonal dynamics of MS in terms of monthly changes against the climate background, as Volyn region is an endemic zone of multiple sclerosis in Ukraine. Thus, we used aggregated weather data from the manual "Reference data about the climate of Ukraine" [2]. Due to the absence of available similar reports from 2015 to 2017, therefore, data were computed for the period of 2014 to conduct complete assessment of the correlation between individual climate factors and MS relapses.
However, records of the average temperature and precipitation data for 2014-2017, taken from the reports of the Central Geophysical Observatory named after Boris Sreznevsky [5], located in the capital of Ukraine -Kyiv, showed the absence of gross fluctuations in the schedule of climate curves compared to the period of 2014. Therefore, we suggested to cover patterns found in the analysis during the period of 2014 for all time observations (2014-2018). We also offered to consider results of our study of seasonal recurrence of multiple sclerosis as approximate but at the same time as sufficiently indicative due to the afore-mentioned annual climate dynamics during 2014-2018 (Four-Year Plan). 19/ Том XXIV / 3 Patients were divided into two main groups by gender for detailed analysis. Following age categories were introduced: for men -20-39years and ≥40 years; for women -20-39 years and ≥40 years. In addition, there was a group of women aged over 50 years, as menopause period usually begins at this age and significantly affects the level of hormones in the blood. A group of men aged over 50 years were as restriction to the same division. We considered patient's average age at the time of the survey, the average age of the disease onset, as well as the duration of the disease in order to evaluate chronometric rate of the disease. To give an overall assessment of the frequency of exacerbations by sex, we also took into account average annualized relapse rate (ARR), indicator of relapse, regarded as the ratio of total number of patients' exacerbations, males or females, respectively, to number of patients of the same sex in a 4-year period.
Statistical analysis was performed using SPSS 18, Statistica, MedCalc and Microsoft Excel software, standard descriptive statistics, correlation and regression analysis. Potential correlation between the number of monthly relapses and investigated parameters was conducted according to Spearman's correlation coefficient. As already mentioned, climate data were only available for the period of 2014 therefore, methods of logistic regression were not used. But analysis of monthly recurrence using multiple regressions to specifically assess the impact of clinical to changes on the probability of relapse, allowed create climate model of MS relapsing with significant factors -tavg, tmin, wind speed, albedo and partial pressure of water vapor (р<0.01).

RESULTS AND DISCUSSION
In total, 197 exacerbations were registered from January 2014 to January 2018 in patients with remitting-recurring type of MS (N=128). The group aged from 20 to 40 years included 71 patients: 22 men and 49 women respectively; 57 patients aged over 40 years old: 22 men and 35 women; 8 separately categorized women aged over 50 years. The analysis of relapse in males aged over 50 was performed despite small group selection. Thus, 84 women (65,62%) prevailed among examined patients with MS in comparison to 44 men (34,37%), respectively.
Average patient's age in men and women was insignificantly different during the study: males -39 years (95% CI 36.5 to 41.5) and females -38 years (95% CI 36.2 to 39.8). Average age of the onset of the disease was 27 years for men (95% CI 23.2 to 28.8) and 30 years for women (95% CI 27.2 to 30.8). Duration of the disease was 13 years in men (95% CI 9.54 to 14.5) and 8 years in women (95% CI 7.0 to 8.99).
General characteristics data of patients with MS and calculated chronometric parameters of disease are summarized in Table 1. На умовах ліцензії CC BY 4.0

Patients' characteristics
Basic analysis of monthly frequency of MS exacerbations showed prevalence of recurrence in winter (27%) and in spring (32%) during the period from 2014 to 2018. The rarest cases of exacerbations were recorded in summer. Average monthly total exacerbation rate (n=128) was >5 cases per year during February-April and ≤5 cases in other months were noted among all MS patients. Monthly exacerbations in patients varied in women and men (Fig. 1, Fig. 2).

Monthly relapses per patient in women
Monthly meteorological data in Volyn region are shown in Table 2.
Multiple regression model (including climate factors as average and minimal temperature, wind speed, albedo and partial pressure of water vapor) showed multiple correlation coefficient -0.55. Significance level was 0.008.  Results of our study evidently presented statistically significant increase in number of relapses in winter-spring period compared to summer and autumn. These results were similar to previously performed studies and can be partially explained by common triggers of relapses such as lower serum level of vitamin D during winter time and higher prevalence of upper respiratory tract infections in winter and spring [9,13].

Monthly meteorological data in Volyn region of Ukraine (year 2014)
Understanding the role of vitamin D encouraged scientists to divide seasonal models into non-classical climate seasons and seasons with average level of vitamin D [10]. According to our research, there is a slight correlation between frequency of MS recurrences and climate factors having seasonal variabilities.
Statistical analysis of data did not show any differences in frequency of disease relapses due to sexmean annualized relapse rate (ARR) was 0.39 for men and 0.39 for women of all age groups during 4 years.
Relationship between duration of the disease and MS relapses was weak-positive (0.24, p<0.001) in males. Average negative correlation by age (-0.37, p<0.001) was detected between the onset of the disease and the incidence of MS recurrence in males (this may also be associated with the rate of progression in men requiring further investigation). We did not observe this connection in women. Thus, frequency of MS recurrences gradually decreases by 2.5 times in adult males comparing to young ones (however, these data may be related to small number of male patients in this age category); frequency of exacerbations in women is kept at relatively stable level approximately to the age of 50 years. There is increase in frequency of exacerbations by 2 times at the age of menopause. The distribution of ARR is shown in Fig. 5.

Fig. 3. Spearmen's correlation between the proposed climatic factors and the frequency of exacerbations of MS
We assume that occurrence of distinctive pathological mechanisms of relapses in men and women is different, which coincides with results of other studies. Results of other large-scale studies also suggest that hormonal status, having dynamic throughout life, is one of the most important factors influencing duration of the disease and frequency of recurrences [12]. Incidences of relapses increase significantly in women with age. This is probably due to a sharp decrease in the level of sex hormones in the postmenopausal period [6]. Lowered levels of sex hormones quite often is the consequence of MS. MRI revealed presence of pathological basis for the existence of different clinical course of MS: women have more expressed inflammatory processes but less destructive foci than men [15]. Testosterone acts only as a neuroprotector of general action not affecting the focus of MS on MRI; oestriol improves the picture of MRI confirming hypothesis of its effect in demyelination processes. This is associated with higher incidence of exacerbations in men aged up to 40 years compared to men over 40 years of age [14]. It is opposite in women. Features of chronometric indices just follow dynamics of hormonal status throughout life. Testosterone itself is a positive hormone in the aspect of MS [15]. However, it has insignificant effect on demyelinization mechanism. It serves as a suppressing mediator at the onset of the disease, as it causes a cerebrovascular anti-inflammatory effect not affecting destruction site. Estrogen does not have this action. It affects the median stage of pathogenesis -demyelinization as it acts on those cells in pathogenesis chain which start detecting their activity only in the presence of pathological process [14,15]. Both testosterone and estrogen control the level of relapse. And only estrogen does not allow disease; to progress its influence on lesions in MS is confirmed on MRI, explaining lower prevalence of progressive course in women [14]. Our investigation covers significant issues concerming sexual dimorphism of MS, which are not well understood.
In conclusion, the incidence of relapses in MS can be explained by combination of seasonal factors, distinctive hormonal status, determined anatomical and physiological gender peculiarities.

CONCLUSIONS
1. Episodes of MS relapses in both genders prevailed in winter-spring period. The single cases of exacerbations were recorded in summer, especially low rate of relapses was observed during summer in men. Multiple regression model including suggested climate factors showed multiple correlation coefficient -0.55 (p<0.01).
2. The prevalence of MS relapse rate in different age groups differs: the rate of recurrences increases in women aged after 50 years (mean annual relapse rate (ARR) = 0.66), while it slowly decreases in men with aging.
3. The duration of the disease did not have significant effect on the course of MS in women, whereas a weak negative relationship between the duration of the disease and the frequency of MS in men was showed. Correspondingly, the average negative correlation was detected between the age of disease onset and the incidence of MS recurrence in males, while this correlation was not observed in females.
4. We suggested that recurrence of MS is a result of multifactorial influence of combination of external and internal factors.
Funding: This research received no external funding.
Acknowledgments: The authors want to thank patients participated in this study.
Conflicts of interest: The authors declare no conflict of interest.