Symptom Interconnectivity in Multiple Sclerosis: A Narrative Review of Potential Underlying Biological Disease Processes

INTRODUCTION: Fatigue, cognitive impairment, depression, and pain are highly prevalent symptoms in multiple sclerosis (MS). These often co-occur and may be explained by a common etiology. By reviewing existing literature, we aimed to identify potential underlying biological processes implicated in the interconnectivity between these symptoms. METHODS: A literature search was conducted to identify articles reporting research into the biological mechanisms responsible for the manifestation of fatigue, cognitive impairment, depression, and pain in MS. PubMed was used to search for articles published from July 2011 to July 2021. We reviewed and assessed findings from the literature to identify biological processes common to the symptoms of interest. RESULTS: Of 693 articles identified from the search, 252 were selected following screening of titles and abstracts and assessing reference lists of review articles. Four biological processes linked with two or more of the symptoms of interest were frequently identified from the literature: (1) direct neuroanatomical changes to brain regions linked with symptoms of interest (e.g., thalamic injury associated with cognitive impairment, fatigue, and depression), (2) pro-inflammatory cytokines associated with so-called ‘sickness behavior,’ including manifestation of fatigue, transient cognitive impairment, depression, and pain, (3) dysregulation of monoaminergic pathways leading to depressive symptoms and fatigue, and (4) hyperactivity of the hypothalamic–pituitary-adrenal (HPA) axis as a result of pro-inflammatory cytokines promoting the release of brain noradrenaline, serotonin, and tryptophan, which is associated with symptoms of depression and cognitive impairment. CONCLUSION: The co-occurrence of fatigue, cognitive impairment, depression, and pain in MS appears to be associated with a common set of etiological factors, namely neuroanatomical changes, pro-inflammatory cytokines, dysregulation of monoaminergic pathways, and a hyperactive HPA axis. This association of symptoms and biological processes has important implications for disease management strategies and, eventually, could help find a common therapeutic pathway that will impact both inflammation and neuroprotection. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40120-022-00368-2.