Clinical, Psychological, and Behavioral Factors Associated with Fatigue in Multiple Sclerosis

Background/Objectives: Fatigue is one of the most common and disabling symptoms of multiple sclerosis (MS) and is associated with clinical, psychological, and behavioral factors. This study aimed to identify factors independently associated with fatigue severity in patients with MS and assess their relative contribution to fatigue variability. Methods: This cross-sectional study included 148 patients with MS in Slovakia (105 women and 43 men; mean age 42.21 ± 9.84 years). Neurological disability and fatigue were assessed using the Expanded Disability Status Scale (EDSS) and Modified Fatigue Impact Scale (MFIS), respectively. Pain was assessed using the SF-36 Bodily Pain domain. Depressive symptoms, anxiety, kinesiophobia, and physical activity were assessed using the Zung Self-Rating Depression Scale (SDS), Beck Anxiety Inventory (BAI), Tampa Scale for Kinesiophobia (TSK), and Godin Leisure-Time Exercise Questionnaire (GLTEQ), respectively. Hierarchical linear regression was used to identify factors independently associated with fatigue. Results: The final model explained 50.7% of MFIS variance (R2 = 0.507; adjusted R2 = 0.463). Lower SF-36 Bodily Pain scores, indicating greater pain and pain-related interference (β = −0.412; p < 0.001), more severe depressive symptoms (SDS; β = 0.266; p < 0.001), and lower physical activity (GLTEQ; β = −0.151; p = 0.027), were independently associated with greater fatigue. The association between EDSS and fatigue was not statistically significant after adjustment (p = 0.162). SDS, BAI, and GLTEQ jointly increased the explained variance by 9.1 percentage points (ΔR2 = 0.091; p < 0.001). Kinesiophobia did not explain statistically significant additional variance (ΔR2 = 0.001; p = 0.539). The estimated indirect association between depressive symptoms and fatigue through kinesiophobia was not statistically significant (B = −0.010; 95% bootstrap CI −0.063 to 0.025). Conclusions: Fatigue in MS is multifactorial. Pain, depressive symptoms, and physical activity were independently associated with fatigue. These findings suggest the relevance of considering these factors in multidisciplinary fatigue assessment in MS. Evidence of an additional independent association involving kinesiophobia was insufficient, but a clinically relevant association cannot be excluded.