Multidimensional Determinants of Sexual Dysfunction in Multiple Sclerosis: Incremental Insights from a Hierarchical...

Background/Objectives: Sexual dysfunction (SD) is a common yet underrecognized consequence of multiple sclerosis (MS) with multidimensional determinants spanning neurological, physical, and psychosocial domains. However, the relative and incremental contribution of fatigue compared with disability and psychological factors remains insufficiently clarified. This study aimed to evaluate the prevalence and severity of sexual dysfunction in MS and to identify independent and incremental predictors using a hierarchical analytical framework. Methods: In this cross-sectional case-control study, 140 patients with MS and 140 age- and sex-matched healthy controls were assessed. Sexual functioning was evaluated using the Arizona Sexual Experience Scale (ASEX) and the Multiple Sclerosis Intimacy and Sexuality Questionnaire-19 (MSISQ-19). Fatigue severity, anxiety, depression, body image, self-esteem, disability (EDSS), and quality of life were measured using validated instruments. Hierarchical multiple linear regression analyses were conducted within the MS cohort to determine independent predictors of MSISQ-19 domain and total scores and to evaluate the incremental contribution of fatigue. Results: Sexual dysfunction was significantly more prevalent in the MS group compared with controls (70.7% vs. 13.6%, p < 0.001). Patients with MS demonstrated higher fatigue, anxiety, depression, and poorer body image, self-esteem, and quality of life (all p < 0.001). Within the MS cohort, individuals with sexual dysfunction exhibited greater symptom burden and disability. Hierarchical regression analyses showed that fatigue produced the largest increase in explained variance across all MSISQ-19 domains (ΔR² range: 0.11-0.19) and remained the strongest independent predictor (β range: 0.29-0.42; p ≤ 0.001). Anxiety retained independent associations with selected domains, whereas disability indices did not remain independently significant after adjustment. Conclusions: Sexual dysfunction in MS reflects a multidimensional burden extending beyond neurological impairment. Fatigue demonstrated the most consistent associations across sexual dysfunction domains, with anxiety contributing to selected aspects of functioning. Given the cross-sectional design, these findings should be interpreted as associations rather than causal relationships. Multidimensional assessment incorporating fatigue and psychological factors may improve the identification of clinically relevant and potentially modifiable determinants within comprehensive MS care.