Data-Driven Fatigue Trajectories in Multiple Sclerosis and Their Predictors

Background and Objectives – Fatigue is one of the most disabling symptoms of multiple sclerosis (MS), yet its longitudinal trajectories and determinants remain poorly characterized. We aimed to identify trajectories of cognitive and physical fatigue in relapsing-remitting MS (RRMS) and to determine baseline clinical and MRI predictors of worsening fatigue. Methods – We conducted a prospective, single-center cohort study embedded in the Predicting Optimal INdividualised Treatment response in MS (POINT-MS) program at the Queen Square MS Centre (London, United Kingdom). Adults with RRMS initiating a new disease-modifying therapy within 3 months of baseline were enrolled and underwent clinical and MRI assessments at baseline, 6 months, and 18 months. Key inclusion criteria were a diagnosis of RRMS, availability of baseline brain and cervical spinal cord MRI, and completion of at least 3 Modified Fatigue Impact Scale (MFIS) assessments. The primary outcome was the longitudinal change in MFIS cognitive and physical subscale scores. Fatigue trajectories were identified using growth mixture modeling. Baseline predictors included demographic factors, disability, cognitive performance, depression diagnosis, proportion of disease duration on disease-modifying treatments (DMTs), and MRI-derived measures of cervical spinal cord cross-sectional area (C-CSA) and regional brain volumes standardized to healthy-control norms. Predictor importance was assessed with conditional random forests, followed by multivariable modeling. Results – We enrolled 225 participants. Three distinct fatigue trajectories emerged for both cognitive and physical MFIS subscales, including improving, stable/mild-worsening, and worsening classes. Worsening trajectories showed annualized increases of +3.32 points/year (cognitive) and +3.37 points/year (physical). Smaller baseline C-CSA was the strongest MRI predictor of worsening trajectories. Clinically, the proportion of disease duration spent on DMTs was the most influential predictor. Discussion – Fatigue in RRMS follows heterogeneous trajectories over short-term follow-up. Smaller cervical spinal cord area was the strongest MRI predictor of worsening fatigue. Damage to ascending somatosensory axons within the cervical cord may reduce afferent input to the thalamus and diminish thalamocortical drive, contributing to both the motor and the cognitive-arousal dimensions of fatigue. These findings support incorporating cervical cord MRI into prognostic models and future fatigue research.