Background: Previous investigations on optical coherence tomography (OCT) in multiple sclerosis (MS) focused on generalizable macular and peri-papillary regions without considering the anatomic variations of the retinal layer thickness.

Objective: This study aimed to assess the utility of parafoveal retinal layer thickness measured by OCT, underscoring its relationships with clinical outcomes in MS.

Methods: In this cross-sectional study, 214 people with MS (pwMS) and 57 age- and sex-matched healthy controls (HCs) were enrolled. Spectral domain OCT evaluation using 1, 3, 6 mm Early Treatment Diabetic Retinopathy Study grid were conducted. The macular and parafoveal thickness (excluding the 1 mm foveal/umbo contribution) of the retinal nerve fiber layer (RNFL), ganglion cell-inner plexiform layer (GCIPL), ganglion cell layer (GCL), inner plexiform layer (IPL), and the peri-papillary RNFL (pRNFL) were measured. Multivariable step-wise logistic, linear and generalized estimating equation (GEE) regression models were used to assess the association between the OCT parameters and clinical MS outcomes.

Results: The parafoveal RNFL thickness (d = 0.27, p = 0.023), GCL (d = 0.87, p < 0.001), IPL (d = 0.82, p < 0.001), and GCIPL (d = 0.85, p < 0.001) were all significantly lower in pwMS than HCs. Optic neuritis history [odds ratio (OR) = 0.84, p < 0.001] and progressive MS (PMS) status (OR = 0.92, p < 0.001) were both best predicted by parafoveal GCL. The Expanded Disability Status Scale (EDSS) was associated with the parafoveal thickness of GCL (standardized β = -0.472, p < 0.001) and pRNFL (standardized β = 0.187, p = 0.021). The parafoveal GCL thickness as predictor of MS disability was also confirmed by the GEE models.

Conclusions: This investigation supports the potential use of parafoveal OCT segmentation as an alternative assessment method in detecting neuroinflammatory and neurodegenerative processes in MS. Averaging of the parafoveal retinal layer thickness into the OCT measures may increase the sensitivity of the standard macular OCT segmentation outcomes. Further studies should aim at exploring the reproducibility of this OCT outcome and its longitudinal responsiveness.