Perivascular spaces in multiple sclerosis: Markers of neuroinflammation or footprints of vascular pathology?

Perivascular spaces (PVS) are interstitial fluid-filled structures that surround penetrating cerebral vessels and play critical roles in brain waste clearance, immune surveillance, and vascular health. When enlarged (ePVS), they are detectable on magnetic resonance imaging (MRI) and have been implicated in various neurological diseases, including multiple sclerosis (MS). Patients with MS consistently show higher PVS and ePVS number, size, and volume than healthy controls (HC), often in brain regions such as the centrum semiovale and midbrain. Age and male sex are frequently associated with greater ePVS burden, and vascular risk factors-especially hypertension-emerge as consistent contributors. Despite this, associations between ePVS and clinical outcomes like disability and cognitive impairment as well as MRI measures of structural damage such as focal T2-hyperintense white matter lesion volume and brain volumetric measures, remain inconsistent. Histopathological studies are challenging the traditional view of PVS and ePVS as inflammation-driven; instead, most MRI-visible ePVS in MS appear to follow arterioles and exhibit features of small vessel disease, including arteriolar wall thickening, hemosiderin leakage, and extracellular matrix remodeling. These abnormalities are largely independent of demyelination or immune infiltration, suggesting ePVS reflect microangiopathic processes rather than primary inflammatory activity. Accordingly, PVS and ePVS in MS may serve as imaging markers of comorbid vascular pathology and glymphatic dysfunction. However, standardized imaging protocols and longitudinal studies are needed to clarify their diagnostic utility and mechanistic relevance in MS.