Unraveling the pathophysiology of restless legs syndrome from multimodal MRI techniques: A systematic review

Background: Restless Legs Syndrome (RLS) is a common neurological disorder currently diagnosed based on clinical features only, and characterized by a compulsive urge to move the legs triggered by rest or diminished arousal. This systematic review aimed at integrating all current brain magnetic resonance imaging (MRI) modalities for a convergent pathophysiological understanding of RLS phenomenology. Methods: We performed a MEDLINE (PubMed)-based systematic review for research articles in patients with primary RLS published in English from 2010 till November 2023. Studies meeting the inclusion criteria according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria were systematically assessed for quality using modality-specific checklists, bias using AXIS tool and a narrative synthesis of the results was conducted. Results: A total of 49 studies (22 structural, 12 DTI, 7 iron-imaging, 4 spectroscopy with 10 datasets combining multiple approaches) involving 1273 patients (414 males) and 1333 healthy controls (478 males) met the eligibility criteria. Despite participant, technical/device-related and statistical heterogeneity, most agree that patients with primary RLS have structural and metabolite alterations, changes in multiple white matter tract architectures, and disrupted functional connectivity within multiple brain areas. Most of the studies (n = 43, 88 %) have a low-risk of bias on the AXIS scale. Scores on the modality-specific checklist ranged from 46 to 92 %, 70–93 % and 54–92 % for structural MRI, DTI and MRS Datasets, respectively. Conclusions: Notwithstanding the large heterogeneity in the methods employed, global connectivity alterations suggest the utility of casting RLS within a system-level perspective rather than viewing it as related to the dysfunction of a single or particular brain region. A holistic approach and its integration within the framework of molecular vulnerability and neurotransmitter alterations are warranted to disentangle the complex pathophysiology of RLS and to identify new therapeutic targets.