Background Multiple sclerosis (MS) can cause retinal thinning among persons with MS with optic neuritis (MS-ON). Macular xanthophylls are carotenoids that comprise the macular pigment, filtering blue light and countering photo-oxidation. However, macular xanthophyll status and its implications for markers of neuroaxonal degeneration have not been examined in MS. Objectives This study characterized differences in macular and serum xanthophylls, and retinal morphometry [retinal nerve fiber layer thickness at the macular (mRNFL) and optic disc (odRNFL) and total macular volume (TMV)] in individuals with MS and healthy controls (HC). Associations between macular pigment optical density (MPOD) and retinal morphometry were also examined. Methods Adults aged 45–64 y (HC, n = 42; MS, n = 40) participated in a cross-sectional study. MPOD was measured via heterochromatic flicker photometry. Retinal morphometry was measured via optical coherence tomography (OCT). Serum carotenoids were quantified using HPLC. Dietary carotenoids were collected using 7-d records. One-factor ANOVA was conducted to determine group effects on macular, serum, and dietary carotenoids. Partial correlations examined the relations between MPOD, retinal morphometry, diet, and serum carotenoids. Results Relative to HC, persons with MS-ON had lower MPOD (Cohen's d = 0.84, P = 0.014), lower odRNFL (Cohen's d = 2.16, P <0.001), lower mRNFL (Cohen's d = 0.57, P = 0.028), and lower TMV (Cohen's d = 0.95, P = 0.011). MS without ON (MS) had lower odRNFL (Cohen's d = 0.93, P = 0.001) than HC and lower serum lutein than MS-ON subjects (Cohen's d = 0.65, P = 0.014). Among MS, MPOD was positively correlated with odRNFL thickness (ρ = 0.43, P = 0.049) and TMV (ρ = 0.45, P = 0.039), whereas odRNFL was negatively correlated with serum lutein (ρ = −0.68, P = 0.016) and zeaxanthin (ρ = –0.62, P = 0.028). Conclusions Persons with MS-ON exhibited poorer xanthophyll status in the macula and serum. MPOD was associated with beneficial anatomical features in the MS group. These findings warrant confirmation with larger cohorts and prospective trials to evaluate xanthophyll effects on the anterior visual pathway in MS.

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