Trans-Synaptic Degeneration Following Acute Optic Neuritis in Multiple Sclerosis

Abstract

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.

Figure 1. Longitudinal change in retinal layer thicknesses in AON eyes of the AON cohort over the first year.

In the AON eyes of the AON cohort (n=49), changes in retinal layer thicknesses over the course of the first year post-AON are shown here in panels A-D, with each line representing an individual patient. Since pRNFL tends to be swollen at the time of acute optic neuritis (therefore masking a ‘true’ baseline value), the differences in pRNFL between the AON eye and fellow eye at baseline and 1 year are illustrated in panels E and F. Figure was generated using STATA version 16 (StataCorp, College Station, TX). pRNFL=peripapillary retinal nerve fiber layer, GCIPL=ganglion cell + inner plexiform layer, INL=inner nuclear layer, ONL=outer nuclear layer.

Figure 2. Rates of atrophy of brain and brain substructure volumes in the AON cohort versus the non-AON cohort.

Longitudinal changes in brain and brain substructure volumes are demonstrated here in the AON cohort versus the non-AON cohort. Brain and brain substructure volumes were expressed as a fraction of intracranial volume and logarithmically transformed for longitudinal analyses, and direct comparisons in the atrophy rates between the cohorts were made using mixed-effects linear regression including time, cohort and interaction between time and cohort, age, sex and time since disease onset. The AON cohort exhibited significantly faster atrophy of the occipital GM (p=0.01), calcarine GM (p=0.008), and thalamus (p=0.02). There were no significant differences in the rate of whole brain, white matter, cortical GM, non-occipital cortical GM, or subcortical GM between the cohorts. Additionally, the rate of T2 lesion volume accumulation did not differ between the cohorts (+5.6% per year [95% CI 1.6 to 9.7] in the AON cohort versus +5.8% per year [95% CI 3.6 to 7.9] in the non-AON cohort, p=0.78, datapoints not demonstrated on this figure). Figure was generated using GraphPad Prism version 9 (GraphPad Software, La Jolla, CA). GM=gray matter.

Figure 3. Relationships between reduction in GCIPL thickness in the AON eye over the first year, and rates of brain and brain substructure atrophy over the study period, in the AON cohort.

Scatterplots demonstrate relationships between change in GCIPL thickness in the AON eyes over the first year, and rates of brain and brain substructure atrophy, in the AON cohort. R-values and P-values were calculated with Pearson’s correlation, using percentage change in GCIPL thickness in the AON eye over the first year, and participant-specific brain substructure atrophy rates generated from mixed-effects linear regression models. In AON eyes, significant relationships were seen between greater reductions in GCIPL thickness over the first year, and faster whole brain (A), white matter (B), and thalamic (C) atrophy over the study period. Figure was generated using STATA version 16 (StataCorp, College Station, TX).

Figure 4. Relationships between visual outcomes and rates of brain and brain substructure atrophy over the study period, in AON eyes of the AON cohort.

Scatterplots demonstrate relationships between monocular letter acuity at the final study visit, and rates of brain and brain substructure atrophy, in AON eyes of the AON cohort. R-values and P-values were calculated with Pearson’s correlation, using participant-specific brain and brain substructure atrophy rates generated from mixed-effects linear regression models, and letter acuity scores recorded at the final study visit. In AON eyes, significant relationships were seen between worse 100% contrast letter acuity outcomes and faster atrophy of subcortical GM (A), and between worse 1.25% contrast letter acuity and faster thalamic atrophy (B). By comparison, in the fellow eye, there were no significant relationships between letter acuity scores and atrophy of brain or brain substructures. Figure was generated using STATA version 16 (StataCorp, College Station, TX). GM=gray matter.