(i) to evaluate the impact of risk factors (RFs) for Small Vessel Disease (SVD) and migraine on the percentage of Central Vein Sign (CVS) CVS+/- lesions (%CVS+/-) detected on whole brain and its subregions in multiple sclerosis (MS) patients; (ii) to investigate whether Spherical Mean Technique (SMT) may differentiate CVS+ from CVS- lesions.

The impact of comorbidities on  %CVS+/- in MS diagnosis and monitoring has been poorly investigated.

120 MS patients (female 55%, RRMS 70%), stratified in 4 age groups [Group 1 (18-30 years), Group 2 (31-45 years), Group 3 (46-56 years), Group 4 (57-77 years), n=30 in each group] performed brain 3T-MRI scan with a protocol including 3DEPI-T2*-weighted and multishell diffusion images. CVS assessment was performed on FLAIR* images. Generalized Estimating Equation (GEE) model was used to compare SMT metrics between CVS+ and CVS- lesions.

A total 5303 white matter (WM) lesions were selected for CVS assessment (median: 38 lesions/patient). 3645 (68.7%) were CVS+. Lesion volume was different between CVS+ and CVS− lesions both in whole brain (median:1292 mm³ vs 224 mm³ respectively; p<0.001) and in all the 4 brain subregions [deep/subcortical WM, periventricular, juxtacortical and infratentorial; (p<0.001 for all]. The median %CVS+ decreased from Group 1 to Group 4 (from 79.1% to 57.7%). Deep/subcortical WM was the only subregion in which CVS+ lesion number was not significantly higher than CVS- counterpart. Age and migraine were predictors of a lower %CVS+. CVS+ showed higher SMT-EXTRAMD (p=0.001), higher SMT-EXTRATRANS (p=0.001) and lower SMT-INTRA (p=0.02) than CVS- lesions.

Age was the strongest predictor of %CVS+. CVS+ lesions were characterized by a more severe degree of inflammation, demyelination and fiber disruption. A careful evaluation of comorbidities during CVS assessment for MS diagnosis and monitoring should be mandatory, to avoid misleading interpretations and inappropriate therapeutic strategies.