To evaluate independent contributions of sleep, depression, physical disability, and BMI to fatigue in patients with multiple sclerosis (PwMS). 

Fatigue affects about 75% of PwMS and is among the most debilitating symptoms. Nonetheless, it remains poorly understood despite efforts by multiple disciplines to better evaluate and treat it. Understanding separable causes of fatigue is crucial to guide individualized treatment, especially when the evidence supporting the use of medications like stimulants is minimal and conflicting. 

Retrospective chart review captured demographics, disease course (relapsing, progressive), BMI (health proxy), patient-reported fatigue (Fatigue Severity Scale, FSS), depression (Hospital Anxiety and Depression Scale, HADS-D), sleep disturbance (Insomnia Severity Index, ISI), and physical disability (MS Impact Scale, MSIS-phys) for consecutive patients with MS aged 18 to 65 years seen for baseline cognitive screenings. We acquired these same data from a sample of matched controls. For patients, multiple regression predicted FSS with age, sex, disease course, BMI, HADS-D, ISI, and MSIS-phys to identify independent contributors to fatigue. Then, parallel mediation assessed whether these predictors explain differences in fatigue between patients and controls. 

Data were captured for 1240 patients (mean[sd] age: 43.5[11.3]; 863 women; 225 progressive; median[IQR] 7[2,14] years diagnosed). Regression identified female sex (rp=0.08, p=0.008), higher BMI (rp=0.08, p=0.008), and higher MSIS-phys (rp=0.36), HADS-D (rp=0.23), and ISI (rp=0.17; Ps<0.001) as independent predictors of worse fatigue. Relative to controls, patients had higher FSS, HADS-D, MSIS-phys, ISI (Ps<0.001), and BMI (p=0.002). Mediation analyses identified HADS-D, MSIS-phys, ISI, and BMI as independent mediators of fatigue differences between patients and controls (explaining 65.0% of MS-related fatigue).

Poor sleep, depression, physical disability, and higher BMI independently contribute to fatigue severity. Findings highlight the impact of secondary modifiable causes of fatigue in PwMS which should be assessed clinically to better tailor treatment for the individual patient.