Fatigue, cognitive impairment, depression, and pain are highly prevalent symptoms that often co-occur in multiple sclerosis (MS); therefore, these symptoms may be explained by a common etiology.

By reviewing existing literature, we aimed to identify potential underlying biological processes implicated in the interconnectivity among fatigue, cognitive impairment, depression, and pain symptoms in MS.

We found that the co-occurrence of fatigue, cognitive impairment, depression, and pain in MS appears to be associated with a common set of underlying etiological factors, namely neuroanatomical changes, pro-inflammatory cytokines, dysregulation of monoaminergic pathways, and a hyperactive hypothalamic-pituitary-adrenal axis.

These findings have important implications for pharmacological and non-pharmacological disease management strategies as well as for future research activities in MS.