Background: The retinal vasculature may be altered in multiple sclerosis (MS), potentially acting as a biomarker of disease processes. Objective: To compare retinal vascular plexus densities in people with MS (PwMS) and healthy controls (HCs), and examine correlations with visual function and global disability. Methods: In this cross-sectional study, 111 PwMS (201 eyes) and 50 HCs (97 eyes) underwent optical coherence tomography angiography (OCTA). Macular superficial vascular plexus (SVP) and deep vascular plexus (DVP) densities were quantified, and poor quality images were excluded according to an artifact-rating protocol. Results: Mean SVP density was 24.1% (SD = 5.5) in MS eyes (26.0% (SD = 4.7) in non-optic neuritis (ON) eyes vs. 21.7% (SD = 5.5) in ON eyes, p < 0.001), as compared to 29.2% (SD = 3.3) in HC eyes ( p < 0.001 for all MS eyes and multiple sclerosis optic neuritis (MSON) eyes vs. HC eyes, p = 0.03 for MS non-ON eyes vs. HC eyes). DVP density did not differ between groups. In PwMS, lower SVP density was associated with higher levels of disability (expanded disability status scale (EDSS): R2 = 0.26, p = 0.004; multiple sclerosis functional composite (MSFC): R2 = 0.27, p = 0.03) and lower letter acuity scores (100% contrast: R2 = 0.29; 2.5% contrast: R2 = 0.40; 1.25% contrast: R2 = 0.31; p < 0.001 for all). Conclusions: Retinal SVP density measured by OCTA is reduced across MS eyes, and correlates with visual function, EDSS, and MSFC scores.

Objective: Therapeutic development in progressive multiple sclerosis (PMS) has been hampered by a lack of reliable biomarkers to monitor neurodegeneration. Optical coherence tomography (OCT)-derived retinal measures have been proposed as promising biomarkers to fulfill this role. However, it is unclear whether retinal atrophy persists in PMS, exceeds normal aging, or can be distinguished from relapsing-remitting multiple sclerosis (RRMS). Methods: 178 RRMS, 186 PMS, and 66 control participants were followed with serial OCT for a median follow-up of 3.7 years. Results: The estimated proportion of peripapillary retinal nerve fiber layer (pRNFL) and macular ganglion cell + inner plexiform layer (GCIPL) thinning in multiple sclerosis (MS) attributable to normal aging increased from 42.7% and 16.7% respectively at age 25 years, to 83.7% and 81.1% at age 65 years. However, independent of age, PMS was associated with faster pRNFL (−0.34 AE 0.09%/yr, p < 0.001) and GCIPL (−0.27 AE 0.07%/yr, p < 0.001) thinning, as compared to RRMS. In both MS and controls, higher baseline age was associated with faster inner nuclear layer (INL) and outer nuclear layer (ONL) thinning. INL and ONL thinning were independently faster in PMS, as compared to controls (INL:−0.09 AE 0.04%/yr, p = 0.03; ONL:−0.12 AE 0.06%/yr, p = 0.04), and RRMS (INL:−0.10 AE 0.04%/yr, p = 0.01; ONL: −0.13 AE 0.05%/yr, p = 0.01), whereas they were similar in RRMS and controls. Unlike RRMS, disease-modifying therapies (DMTs) did not impact rates of retinal layer atrophy in PMS. Interpretation: PMS is associated with faster retinal atrophy independent of age. INL and ONL measures may be novel biomarkers of neurodegeneration in PMS that appear to be unaffected by conventional DMTs. The effects of aging on rates of retinal layer atrophy should be considered in clinical trials incorporating OCT outcomes.

Objective:To evaluate whether a retinal spectral-domain optical coherence tomography (SD-OCT) assessment at baseline is associated with long-term disability worsening in people with multiple sclerosis (PwMS), we performed SD-OCT and Expanded Disability Status Scale (EDSS) assessments among 132 PwMS at baseline and at a median of 10 years later.Methods:In this prospective, longitudinal study, participants underwent SD-OCT, EDSS, and visual acuity (VA) assessments at baseline and at follow-up. Statistical analyses were performed using generalized linear regression models, adjusted for age, sex, race, MS subtype, and baseline disability. We defined clinically meaningful EDSS worsening as an increase of ≥2.0 if baseline EDSS score was <6.0, or an increase of ≥1.0 if baseline EDSS score was ≥6.0.Results:132 PwMS (mean age: 43 years; n=106 patients with relapsing remitting MS) were included in analyses. Median duration of follow-up was 10.4 years. In multivariable models excluding eyes with prior optic neuritis, relative to patients with an average baseline ganglion cell+inner plexiform layer (GCIPL) thickness ≥70µm (the mean GCIPL thickness of all eyes at baseline), an average baseline GCIPL thickness <70µm was associated with a 4-fold increased odds of meaningful EDSS worsening (adjusted odds ratio: 3.97; 95% CI: 1.24-12.70; p=0.02), and an almost 3-fold increased odds of low-contrast VA worsening (adjusted odds ratio: 2.93; 95% CI: 1.40-6.13; p=0.04).Conclusions:Lower baseline GCIPL thickness on SD-OCT is independently associated with long-term disability worsening in MS. Accordingly, SD-OCT at a single time-point may help to guide therapeutic decision making among individual PwMS.Classification of Evidence:This study provides Class I evidence that lower baseline GCIPL thickness on SD-OCT is independently associated with long-term disability worsening in MS.

Optical coherence tomography (OCT) has emerged as a fast, non-invasive, inexpensive, high-resolution imaging technique in multiple sclerosis (MS). Retinal layer quantification by OCT facilitates a ‘window’ into not only local retinal pathology but also global neurodegenerative processes, recognised to be the principal substrates of disability accumulation in MS. While OCT measures in MS have been demonstrated to reflect visual function, inflammatory activity outside of the visual pathways, disability measures including the prediction of disability progression, whole brain atrophy, and the differential neuroprotective effects of disease-modifying therapies, debate continues regarding the clinical utility of OCT in everyday practice. This review presents an overview of the evidence supporting OCT, with particular focus on its application in the MS clinic. We will also discuss the role of OCT in MS clinical trials to develop novel neuroprotective and potential remyelinating therapies.