Physical Disability, Reduced Brain Volumes Predict Worsening Fatigue in MS

Worsening fatigue in multiple sclerosis (MS) is linked to higher physical disability, depression, lower cognitive performance, and reduced brain volumes. These study results were presented at the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Congress 2025, held in Barcelona, Spain from September 24 to 26, 2025.

Worsening fatigue affects up to 60% of patients with MS. To identify clinical and magnetic resonance imaging (MRI) predictors of worsening fatigue, researchers evaluated 197 patients with MS enrolled in the Predicting Optimal INdividualised Treatment response in MS (POINT-MS) study, a prospective study including patients planning to initiate disease modifying treatment (DMT) within 3 months. Patients were assessed using the Expanded Disability Status Scale (EDSS), Modified Fatigue Impact Scale (MFIS), Symbol Digit Modality Test (SDMT), and brain and spinal cord MRI at baseline, 6, and 18 months. A cohort of 113 healthy controls was used as reference.

Patients and controls were aged mean (SD) 39.8 (11) and 42.3 (11.8) years, and 70% and 61.9% were women, respectively. Patients with MS had a mean (SD) EDSS score of 2.4 (1.6) and a median global MFIS score of 28 (95% CI, 23-32).

Patients with MS had a significant exacerbation in fatigue during the 18-month follow-up period (Cohen’s d, -0.14; 95% CI, -3.41 to -0.20; P <.05). Worsening fatigue was associated with higher EDSS at baseline (b. 3.3; 95% CI, 2.6-4.0), lower SDMT score (b, -0.9; 95% CI, -1.5 to -0.3), and diagnosed depression (b, 5.3; 95% CI, 2.8-7.7).

Decreased brain volume Z-scores in somatosensory, reward-related, cognitive, and emotional regions predicted worsening fatigue, specifically reduced volumes in the bilateral thalamus (Z, -0.63; 95% CI, -0.96 to -0.47), bilateral nucleus accumbens (Z, -0.5; 95% CI,-0.66 to -0.27), right medial orbital gyrus (Z, -0.3; 95% CI, -0.42 to -0.1), left entorhinal cortex (Z, -0.33; 95% CI, -0.44 to -0.16), bilateral middle cingulate gyri (Z, -0.24; 95% CI, -0.4 to -0.1), and white matter (Z, -0.36; 95% CI, -0.5 to -0.16).

The study authors concluded, “Fatigue worsening was associated with cognitive and physical disability and depression before or soon after starting a DMT for MS. Reduced volumes in somatosensory, cognitive, and emotional regions predict future fatigue worsening, implicating subjective perception and related emotional responses as key pathophysiological drivers.”

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.