Combining inter-eye differences enhances detection of optic nerve involvement in multiple sclerosis

The 2024 revised McDonald criteria for multiple sclerosis recognize the optic nerve as a topography for dissemination in space. Optical coherence tomography-derived inter-eye differences in peri-papillary retinal nerve fibre layer or ganglion cell-inner plexiform layer thicknesses (≥6 μm or ≥4 μm, respectively) are proposed for identifying unilateral optic nerve involvement. However, the value of combining inter-eye difference measures and optimal temporal- quadrant peri-papillary retinal nerve fibre layer inter-eye differences remains unclear. We investigated the diagnostic performance of combined inter-eye differences, optimal temporal-quadrant peri-papillary retinal nerve fibre layer inter-eye differences, and examined the effects of time, prior optic neuritis frequency, sex, and race on inter-eye differences. Retinal optical coherence tomography images from all study participants underwent rigorous quality control. Receiver operating characteristic analyses and area under the receiver operating characteristic curves (AUC) were used to determine optimal inter-eye differences of individual and combined measures to distinguish eyes with, from without, prior optic neuritis in people with multiple sclerosis. Mixed-effects models were used to assess the impact of time, prior optic neuritis events, sex, and race on inter-eye differences. An independent multiple sclerosis cohort from a second centre was examined for external validation. Among 1854 people with multiple sclerosis, optimal inter-eye difference thresholds for identifying unilateral optic nerve involvement were 6 μm for peri-papillary retinal nerve fibre layer (AUC = 0.80), 4 μm for ganglion cell-inner plexiform layer (AUC = 0.83), and 8 μm for temporal-quadrant peri-papillary retinal nerve fibre layer (AUC = 0.71) thicknesses. Peri-papillary retinal nerve fibre layer inter-eye differences ≥6 μm or ganglion cell-inner plexiform layer inter-eye differences ≥4 μm yielded 87.6% sensitivity, 70.0% specificity, and 64.0% positive predictive value. Concurrent inter-eye differences at lower thresholds (≥5 μm peri-papillary retinal nerve fibre layer, ≥3 μm ganglion cell-inner plexiform layer) reduced sensitivity to 72.5%, but improved specificity (86.6%) and positive predictive value (76.7%), while maintaining accuracy and negative predictive value. Temporal-quadrant peri-papillary retinal nerve fibre layer inter-eye differences did not improve diagnostic performance. Over a median of 5.1 years, ganglion cell- inner plexiform layer and peri-papillary retinal nerve fibre layer inter-eye differences remained stable. Prior optic neuritis counts and sex did not affect inter-eye differences. Although Black Americans had higher inter-eye differences than White Americans, optimal thresholds were comparable across races. The validation cohort comprising 254 people with multiple sclerosis confirmed these findings. In conclusion, concurrent peri-papillary retinal nerve fibre layer (≥5 μm) and ganglion cell-inner plexiform layer inter- eye differences (≥3 μm) improve unilateral optic nerve involvement detection versus either alone (≥6 μm or ≥4 μm, respectively). In contrast, temporal-quadrant peri-papillary retinal nerve fibre layer inter-eye differences offer limited benefit. Inter-eye differences remain stable longitudinally and unaffected by prior optic neuritis frequency.