Vertical saccadic slowing is associated with fatigue in multiple sclerosis

Background Fatigue is one of the most prevalent and disabling symptoms of multiple sclerosis (MS), frequently showing weak correlation with physical disability or MRI lesion burden. Central activation models link fatigue to dysfunction of brainstem arousal pathways, particularly the Ascending Reticular Activating System (ARAS). Because vertical saccades are generated in the mesencephalon and interact with these arousal networks, they may provide an objective marker of central fatigue.Objectives To examine the relationship between vertical saccadic parameters and fatigue severity in MS, adjusting for cognitive impairment and affective symptoms.Results Forty-four patients were included (61.4% women; mean age 49.0 ± 9.9 years; median EDSS 2.0). Fatigue severity was inversely associated with vertical saccadic peak velocity, most prominently for upward movements (r = −0.45, p < 0.01). In multivariable models adjusted for age, sex, cognition, lesion burden, depression, and anxiety, slower upward vertical peak velocity independently predicted greater fatigue severity (β = −0.0068; 95% CI −0.0129 to −0.0008; p = 0.028). This association remained statistically significant after additional adjustment for disease phenotype (p = 0.037), infratentorial lesion involvement (p = 0.030), and in a sensitivity analysis excluding interferon-β-treated patients (p = 0.036).Conclusions Higher fatigue severity was independently associated with slower upward vertical saccadic peak velocity, across all sensitivity analyses. These findings suggest that vertical saccadic dynamics may represent a promising objective correlate of central fatigue and support a pathophysiological link with mesencephalic arousal network dysfunction in MS.