THE ANALYSIS OF RELATIONSHIP BETWEEN LESION OF FUNCTIONAL SYSTEMS OF NERVOUS SYSTEM AND SEVERITY OF FATIGUE IN PATIENTS WITH MULTIPLE SCLEROSIS

Despite numerous investigations, fatigue remains one of the least studied manifestations of MS. However, significant prevalence of this symptom proves importance of its study. The aim of the study was to define a prognostic assessment of fatigue development accompanying lesions of certain functional systems and degree of disability. Material and methods. 96 patients, aged 15 to 58 years with a diagnosis of MS have been examined. MS patients were examined with the same protocol, using formalized scales. To detect fatigue and determine the degree of its severity was used Fatigue Severity Scale (FSS). The degree of disability in patients was assessed by Kurtzke EDSS (Expanded Disability Status Scale). Statistical methods for the data analysis were also used, including methods of descriptive statistics, probability assessment and prognostic significance of obtained data using odds ratio (OR). Results. Fatigue was detected in 49.1 % of patients with a degree of disability lower than 4 EDSS scores and in 90.4 % of patients with disability higher than 4 EDSS scores (p=0.0027). The assessment of functional systems at the time of observation has statistically significant prognostic values according to the following parameters: pyramidal system lesion (OR=7.43 (2.43–22.76)), coordination disorders (OR=4.60 (1.05–20.25)), cranial nerve lesion (OR=4.33 (1.40–13.39)), (p<0.05). Lesion of the pyramidal and coordination systems at the onset of the disease may increase risk for detection of fatigue higher than 4 scores in the follow-up observation (lesion of pyramidal system – OR=1.62 (0.5–5.25), coordination disorders OR=1.41 (0.58–5.16)). Conclusion. The results of our investigation showed that symptom of fatigue is observed in almost 90 % of MS patients. The study showed that fatigue in MS patients depends on the degree of disability and lesions of certain functional systems.


Introduction
Multiple sclerosis (MS) is a chronic, progressive, inflammatory, autoimmune, neurodegenerative disease of central nervous system, characterized by various levels of physical, emotional, cognitive, and social difficulties.Over the past decades, its incidence and prevalence in the world has increased.Today MS is leading in the structure of neurological pathology and affects about 0.05-0.1 % of adult population [1][2][3].
Today in the world, there are about 3 million people with multiple sclerosis, and in Ukraine the number is approaching 20 thousand people.According to WHO, MS is the major cause of permanent disability of young people among all neurological diseases [4,5].
Fatigue is one of the most complex neurological symptoms and its mechanism of development is one of least studied.Fatigue affects 53-92 % of patients with MS, often limits their social activity, impacts the quality of life, deepens their disability, worsens the course of other symptoms of the disease.Two out of three MS patients consider that fatigue is one of the three major disabling factors; many of them assess fatigue as a leading symptom yet at the onset of the disease [6,7].Fatigue can occur in all MS forms at any stage and is reported to impact employment in 41 % and social functioning in 25 % of MS patients [8].
Fatigue is characterized by a lack of energy, feelings of exhaustion that are unaided by sleep, and the perception that one is unable to perform mental and physical activities [9].Although fatigue has been studied extensively, in part because it affects such a wide range of clinical populations, there has been no unifying framework within which to understand fatigue [10].
Fatigue is a multifactorial phenomenon in MS and is attributed to primary or secondary disease mechanisms [11].Primary factors may include inflammation, demyelination, and destruction of axons in the central nervous system, the presence of immune markers, and neuroendocrine system disturbances.Secondary factors may include sleep problems, depression or other psychological variables, medications, and lack of exercise [12].
Owing to the paucity of information on the pathogenesis of fatigue and its bearing on an individual with MS, it is important to investigate the associations between high levels of fatigue and other MS-related impairments, functional performance, and community participation.The associations between fatigue and other MS-related impairments, activity, and participation limitations need to be further examined.The current literature is ambiguous regarding the relationship between fatigue and disability status [13][14][15][16] as well as fatigue and physical activity [17][18][19] therefore warranting further investigation.In addition, associations between fatigue and other MS-related impairments, such as dynamic balance, walking ability, lesion of main symptoms of nervous system are still unknown.

Aim
To define a prognostic assessment of fatigue development accompanying lesions of certain functional systems and degree of disability.

Material and methods
A total of 96 patients (34 male and 62 female) aged 15 to 58 years (mean age 38.45±1.04)with a diagnosis of MS were examined.Among the examined patients, 83 showed the signs of fatigue (88 % of the total number of patients that were included in the study).
MS was diagnosed based on conventional clinical neurological and paraclinical examination using McDonald W.I. et al. (2010) criteria.
Duration of the disease ranged from 11 months to 29 years.According to the EDSS, the degree of disability ranged 1.5-6.5 scores, on average -3.8±0.3 scores.
Among the examined patients with fatigue symptom, the stage of MS exacerbation was observed in 34 people (35 %), the stage of remission -in 62 people (65 %).
For prognostic assessment of fatigue development, the relative risk of detection of this symptom higher than 4 scores was defined, depending on the degree of disability according to the EDSS (risk assessment in terms of odds ratios -OR and 95% CI).So statistically significant risk of fatigue was found at EDSS˃4 scores (OR=6.6 (1.6-37.9)),(p<0.05).
Fatigue was detected in 49.1 % of patients with a degree of disability lower than 4 EDSS scores and in 90.4 % of patients with disability higher than 4 EDSS scores (p=0.0027).
MS patients were examined with the same protocol, using formalized scales.To detect fatigue and determine the degree of its severity, Fatigue Severity Scale -FSS (Krupp et al., 1989) was used.The degree of disability in patients was assessed by Kurtzke EDSS (Expanded Disability Status Scale).
Data analysis statistical methods were also used, including methods of descriptive statistics, probability assessment and prognostic significance of obtained data using odds ratio (OR).

Results
Given the variety of complaints and neurological disorders in patients with MS, fluctuations of their severity and impairments in different functional systems of nervous system, the relationship between the initial symptoms of the disease and its clinical manifestations at the time of examination was observed.The onset of MS in the form of sensory impairment was found in 21 patients (25 %), optic nerve lesion -in 17 patients (21 %), pyramidal tract lesion -in 16 patients (19 %), impaired motor coordination -in 15 patients (18 %), cranial nerve disorders -in 10 patients (12 %), general weakness -in 4 patients (5 %) (Fig. 1).

Fig. 2. Distribution of the main symptoms of nervous system lesion in MS patients with fatigue at the time of examination, in %
For prognostic assessment of fatigue development, accompanied by impairment in different functional systems, the relative risk of detection of this symptom higher than 4 scores was defined, depending on presence or absence of functional system lesions (risk assessment in terms of odds ratios -OR and 95 % CI).
Lesion of the pyramidal and coordination systems at the onset of the disease may increase the risk for detection of fatigue higher than 4 scores in the follow-up observation (lesion of pyramidal system -OR=1.62(0.5-5.25), coordination disorders OR=1.41 (0.58-5.16)).Generally, the whole range of initial manifestations does not result in statistically significant prognostic assessment for high rates of fatigue (p>0.05) (Fig. 3).The analysis of the relationship between lesion of functional systems and development of fatigue symptoms showed that lesions of pyramidal and coordination systems at the onset of the disease affect development of fatigue higher than 4 points during the follow-up observation.Lesions of pyramidal, coordination systems or cranial nerves at the time of examination had accurate prognostic assessment for the development of moderate and severe fatigue.

Discussion
The results of our investigation showed that the symptom of fatigue is observed in almost 90 % of MS patients with different types of demyelinating process course and on different stages of the disease.This symptom occurs in patients of all ages, even at the very onset of the disease.
Our data also confirm the role of disability in fatigue development: 90.4 % of respondents with a degree of disability of 4 points on the EDSS scale reported this symptom, unlike patients with mild disability among whom only 49.1 % patients showed fatigue symptoms.
The analysis of the relationship between lesion of functional systems and development of fatigue symptoms showed that lesions of pyramidal and coordination systems at the onset of the disease affect development of fatigue higher than 4 points during the follow-up observation.Le- The results of our research coincide with ones of other investigators [19][20][21][22][23].The major limitation of our work was retrospective character of the study, not allowing correct identification of prognostic factors.
Our future studies will be targeted at the prospective analysis of the relationship between lesions of certain functional systems and development of fatigue in patients with MS.

Conclusions
1.The results of our investigation showed that the symptom of fatigue is observed in almost 90 % of MS patients.
2. Fatigue in MS patients depends on degree of disability on the EDSS scale.
3. The analysis of the relationship between lesion of functional systems and development of fatigue symptoms showed that lesions of pyramidal and coordination systems at the onset of the disease affect development of fatigue higher than 4 points during the follow-up observation.
4. Lesions of pyramidal, coordination systems or cranial nerves at the time of examination had accurate prognostic assessment for the development of moderate and severe fatigue.

Fig. 3 .Fig. 4 .
Fig. 3. Prognostic assessment of fatigue development higher than 4 FSS scores in case of lesion of particular functional systems at the onset of the disease (estimated odds ratio OR) , coordination systems or cranial nerves at the time of examination had accurate prognostic assessment for the development of moderate and severe fatigue.