Using Acute Optic Neuritis Trials to Assess Neuroprotective and Remyelinating Therapies in Multiple Sclerosis

Abstract

Importance: Neuroprotective and remyelinating therapies are required for multiple sclerosis (MS), and acute optic neuritis (AON) is a potential condition to evaluate such treatments.

Objective: To comprehensively assess key biological and methodological aspects of AON trials for testing neuroprotection and remyelination in MS.

Design, setting, and participants: The AON-VisualPath prospective cohort study was conducted from February 2011 to November 2018 at the Hospital Clinic of University of Barcelona, Barcelona, Spain. Consecutive patients with AON were prospectively enrolled in the cohort and followed up for 18 months. Data analyses occurred from November 2018 to February 2019.

Exposures: Participants were followed up for 18 months using optical coherence tomography, visual acuity tests, and in a subset of 25 participants, multifocal visual evoked potentials.

Main outcomes and measures: Dynamic models of retinal changes and nerve conduction and their associations with visual end points; and eligibility criteria, stratification, and sample-size estimation for future trials.

Results: A total of 60 patients (50 women [83%]; median age, 34 years) with AON were included. The patients studied displayed early and intense inner retinal thinning, with a thinning rate of approximately 2.38 μm per week in the ganglion cell plus inner plexiform layer (GCIPL) during the first 4 weeks. Eyes with AON displayed a 6-month change in latency of about 20 milliseconds, while the expected change in the eyes of healthy participants by random variability was 0.13 (95% CI, -0.80 to 1.06) milliseconds. The strongest associations with visual end points were for the 6-month intereye difference in 2.5% low-contrast letter acuity, which was correlated with the peripapillary retinal nerve fiber layer thinning (adjusted R2, 0.57), GCIPL thinning (adjusted R2, 0.50), and changes in mfVEP latency (adjusted R2, 0.26). A 5-letter increment in high-contrast visual acuity at presentation (but not sex or age) was associated with 6-month retinal thinning (1.41 [95% CI, 0.60-2.23] μm less peripapillary retinal nerve fiber layer thinning thinning; P = .001; adjusted R2, 0.20; 0.86 [95% CI, 0.35-1.37] μm less GCIPL thinning; P = .001; adjusted R2, 0.19) but not any change in multifocal visual evoked potential latency. To demonstrate 50% efficacy in GCIPL thinning or change in multifocal visual evoked potential latency, a 6-month, 2-arm, parallel-group trial would need 37 or 50 participants per group to test a neuroprotective or remyelinating drug, respectively (power, 80%; α, .05).

Conclusions and relevance: Acute optic neuritis is a suitable condition to test neuroprotective and remyelinating therapies after acute inflammation, providing sensitive markers to assess the effects on both processes and prospective visual recovery within a manageable timeframe and with a relatively small sample size.

Figure 1.. Models of the Change in Retinal Layer Thicknesses During the 6-Month Follow-up Period

The black points joined by dashed lines represent the individual trajectories of the changes in retinal thickness, the thicker curves represent the individual fit of the model, and the dark red line represents the population model. A, Peripapillary retinal nerve fiber layer (pRNFL); B, macular retinal nerve fiber layer (RNFL); C, ganglion cells plus inner plexiform layer (GCIPL); D, inner nuclear layer (INL); E, outer nuclear layer (ONL); and F, photoreceptors (PRL). The y-axis represents the absolute change (follow-up visit minus baseline) in the affected eye, except for the pRNFL, for which the intereye asymmetry refers to the baseline value in the unaffected eye. The x-axis represents the time in days from clinical onset. A and C, Linear spline mixed-effect models with 2 knots (A, 45 and 85 days) and 1 knot (C, 45 days); B and D-F, mixed-effect, third-order polynomials with all coefficients set as fixed and random effects. All models were fit using the lme4 package in R version 3.5.2 (R Foundation for Statistical Computing).

Figure 2.. Standarized (z Score) Amplitudes and Latencies in the 56 Segments of the Multifocal Visual Evoked Potentials in Affected and Unaffected Eyes

A heatmap display developed in house to visualize the normalized (z score) latencies and amplitudes in the multifocal visual evoked potentials segments. Each segment represents the mean amplitude or latency of a patient’s eyes, with the data available from each visit normalized using the mean (SD) of the values obtained in a sex-matched and age-matched population of healthy volunteers (n = 22) to create a z score. A, Results for the affected eye; B, Results for the unaffected eye. A color scale is used to represent the magnitude and direction of the changes. The latencies and amplitude are adimensional, and the numbers represent the SD from the healthy population. Green represents improvement (normalized z scores in amplitude of more than zero and z scores of latency less than zero), while red represents worsening. In addition, the symbol + denotes all segments greater than 1.96 SD more than the mean; the symbol − was designated for all segments at least 1.96 SD less than the mean, but this was not applicable to any segment. I indicates inferior; N, nasal; S, superior; and T, temporal.

Figure 3.. Change Over 6 Months and 18 Months in the Amplitude and Latency in the 56 Segments of the Multifocal Visual Evoked Potentials in Affected and Unaffected Eyes

A heatmap developed by the authors to visualize the changes in latency and amplitude in the multifocal visual evoked potentials segments. Each segment represents the mean change (6-month and 18-month) relative to the baseline value of each participant and eye, except the latency in the affected eye, for which the baseline value of the unaffected eye was a reference. A, Results for the affected eye; B, Results for the unaffected eye. A color scale is used to represent the magnitude and direction of the changes. Amplitudes were measured in nanovolts and latencies as milliseconds. The numbers represent the 6-month and 18-month changes; green represents improvement (increase in amplitude and decrease in latency relative to the baseline), while red represents worsening. I indicates inferior; N, nasal; S, superior; and T, temporal.

Figure 4.. Assessment of 6-Month Visual Outcomes Based on the Change in Retinal Thickness and Latency During the Follow-up

The different scatterplots represent the changes in the 3 surrogate markers and visual function tests at 6 months. The visual function tests include 2.5% low-contrast letter acuity (LCLA) (A-F), 1.25% low-contrast letter acuity (G-L), and color vision (M-R). Visual recovery is evaluated as the 6-month performance in affected eye (triangles) and the intereye differences, calculated as the affected eye value minus unaffected eye value (dots). The surrogate markers are the 6-month changes in peripapillary retinal nerve fiber layer thickness (orange), ganglion cells plus inner plexiform layer thickness (blue), and latency (brown). Each scatterplot includes the fit of a regression model, and where the model was significant, the adjusted R² and P values of the model are displayed. The models are a linear regression models for LCLA, and a linear spline model with 1 knot each at 20 μm for peripapillary retinal nerve fiber layer (pRNFL) thinning and 15 μm for ganglion cells plus inner plexiform layer (GCIPL) thinning. HRR indicates Hardy-Rand-Rittler plates.