Cerebral small vessel disease and glymphatic system dysfunction in Multiple Sclerosis: a narrative review

As the multiple sclerosis (MS) population ages, the prevalence of vascular comorbidities increases, potentially accelerating disease progression and brain atrophy. Recent studies highlight the prevalence of cerebral small vessel disease (CSVD) in MS, suggesting a potential link between vascular comorbidities and accelerated disability. CSVD affects the brain's small vessels, often leading to identifiable markers on MRI such as enlarged perivascular spaces (EPVS). EPVS are increasingly recognized also in MS and have been associated with vascular comorbidities, lower percentage of MS-specific perivenular lesions, brain atrophy and aging. The exact sequence of event leading to MRI visible EPVS is yet to be determined, but an impaired perivascular brain fluid drainage appears a possible physiopathological explanation for EPVS in both CSVD and MS. In this context, a dysfunction of the brain fluid clearance system - also known as "glymphatic system" - appears associated in MS to aging, neuroinflammation, and vascular dysfunction. Advanced imaging techniques show an impaired glymphatic function in both MS and CSVD. Additionally, lifestyle factors such as physical exercise, diet, and sleep quality appear to influence glymphatic function, potentially revealing novel therapeutic strategies to mitigate microangiopathy and neuroinflammation in MS. This review underscores the potential role of glymphatic dysfunction in the complex and not-yet elucidated interplay between neuroinflammation and CSVD in MS.