Optical coherence tomography with voxel-based morphometry: a new tool to unveil focal retinal neurodegeneration in multiple sclerosis

Abstract Neurodegeneration is the main contributor to disability accumulation in multiple sclerosis. Previous studies in neuro-ophthalmology have revealed that neurodegeneration in multiple sclerosis also affects the neuro-retina. Optical coherence tomography (OCT) has been used to measure thinning of retinal layers, which correlates with several other markers for axonal/neuronal loss in multiple sclerosis. However, the existing analytical tools have limitations in terms of sensitivity and do not provide topographical information. In this study, we aim to evaluate whether voxel-based morphometry (VBM) can increase sensitivity in detecting neuroaxonal degeneration in the retina and offer topographical information. A total of 131 people with multiple sclerosis (41 clinically isolated syndrome, 53 relapsing-remitting, and 37 progressive multiple sclerosis) and 50 healthy subjects were included. Only eyes with normal global peripapillary retinal nerve fiber layer thickness (RNFL) and no history of optic neuritis were considered. VBM and voxel-wise statistical comparisons were performed on: 1) patients at different disease stages. 2) patients experienced the first demyelination attack without subclinical optic neuritis, assessed by visual evoked potentials. Standard parameters failed to discern any differences; however, VBM-OCT successfully detected focal macular atrophy of RNFL and ganglion cell/inner plexiform layer, along with thickening of inner nuclear layer in patients who experienced the first demyelination attack (disease duration = 4.2 months). Notably, the atrophy pattern of the ganglion cell/inner plexiform layer was comparable across disease phenotypes. In contrast, the RNFL atrophy spread from the optic nerve head to the fovea as the disease evolved toward the progressive phase. Furthermore, for patients who experienced the first neurological episode, the severity of RNFL atrophy at entry could predict a second attack. Our results demonstrate that VBM-OCT exhibits greater sensitivity than standard parameters in detecting focal retinal atrophy, even at clinical presentation, in eyes with no history of optic neuritis and with normal latency of visual evoked potentials. Thinning of ganglion cell/inner plexiform layer primarily concentrated in nasal perifovea in all disease phenotypes, indicating selective vulnerability of retinal ganglion cells and their perifoveal axons. Conversely, the degree of RNFL thinning seems to be related to the clinical course of multiple sclerosis. The findings suggest bidirectional neurodegeneration in the visual pathway. VBM-OCT shows potential as a valuable tool for monitoring neurodegeneration on a patient level and evaluating the efficacy of novel neuroprotective treatments.