Background: While clinical factors such as higher Expanded Disability Status Scale (EDSS) score, progressive disease subtype, older age, polysymptomatic onset, and depression have been shown to predict fatigue severity in people with multiple sclerosis (PwMS), their influences have not been evaluated simultaneously while controlling for broader MS severity risk factors and potential confounders.

Objective: To concurrently assess which previously established MS fatigue risk factors affect fatigue severity after adjusting for MS severity, obstructive sleep apnea (OSA), and stimulant use, and to validate these findings using a second fatigue scale.

Methods: We used multivariable linear regression to determine relationships between MS clinical data and MS-related fatigue as measured by the Modified Fatigue Impact Scale (MFIS) and the Fatigue Severity Scale (FSS), controlling for OSA and stimulant use.

Results: Polysymptomatic MS onset (MFIS β = 9.22, p = 0.027; FSS β = 5.90, p = 0.032), depression (MFIS β = 22.01, p < 0.001; FSS β = 13.51, p = 0.003), and higher Expanded Disability Status Scale (EDSS) scores (MFIS β = 2.32, p = 0.028) were associated with more severe fatigue in PwMS.

Conclusions: Polysymptomatic MS onset, comorbid depression, and higher EDSS score remain independently associated with MS fatigue severity even when evaluated together adjusting for relevant controls. PwMS with these characteristics, especially those with all three, should be screened for fatigue and offered symptomatic treatment.