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Objective: To explore longitudinal changes in brain volumetric measures and retinal layer thicknesses following acute optic neuritis (AON) in people with multiple sclerosis (PwMS), to investigate the process of trans‐synaptic degeneration, and determine its clinical relevance. Methods: PwMS were recruited within 40 days of AON onset (n = 49), and underwent baseline retinal optical coherence tomography and brain magnetic resonance imaging followed by longitudinal tracking for up to 5 years. A comparator cohort of PwMS without a recent episode of AON were similarly tracked (n = 73). Mixed‐effects linear regression models were used. Results: Accelerated atrophy of the occipital gray matter (GM), calcarine GM, and thalamus was seen in the AON cohort, as compared with the non‐AON cohort (−0.76% vs −0.22% per year [p = 0.01] for occipital GM, −1.83% vs −0.32% per year [p = 0.008] for calcarine GM, −1.17% vs −0.67% per year [p = 0.02] for thalamus), whereas rates of whole‐brain, cortical GM, non‐occipital cortical GM atrophy, and T2 lesion accumulation did not differ significantly between the cohorts. In the AON cohort, greater AON‐induced reduction in ganglion cell+inner plexiform layer thickness over the first year was associated with faster rates of whole‐brain (r = 0.32, p = 0.04), white matter (r = 0.32, p = 0.04), and thalamic (r = 0.36, p = 0.02) atrophy over the study period. Significant relationships were identified between faster atrophy of the subcortical GM and thalamus, with worse visual function outcomes after AON. Interpretation: These results provide in‐vivo evidence for anterograde trans‐synaptic degeneration following AON in PwMS, and suggest that trans‐synaptic degeneration may be related to clinically‐relevant visual outcomes. ANN NEUROL 2023;93:76–87 [ABSTRACT FROM AUTHOR]

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 ± 0.09%/yr, p < 0.001) and GCIPL (-0.27 ± 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 ± 0.04%/yr, p = 0.03; ONL:-0.12 ± 0.06%/yr, p = 0.04), and RRMS (INL:-0.10 ± 0.04%/yr, p = 0.01; ONL:-0.13 ± 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. ANN NEUROL 2020;87:885-896. [ABSTRACT FROM AUTHOR]