Silent Retinal Neurodegeneration in Multiple Sclerosis: Structural Evidence from Clinically Unaffected Eyes Using Swept-Source OCT and OCT Angiography-A Cross-Sectional, Observational Study.

Background/

Objectives

Retinal optical coherence tomography (OCT) has emerged as a sensitive biomarker of neurodegeneration in multiple sclerosis (MS), yet eyes without overt optic neuritis (ON) are routinely pooled as "clinically unaffected" despite their heterogeneous histories. We evaluated whether never-ON eyes and fellow eyes after unilateral ON differ structurally and microvascularly using swept-source OCT (SS-OCT) and OCT angiography (OCTA).

Methods

In this cross-sectional, single-center study, 126 clinically unaffected MS eyes-96 never-ON eyes and 30 fellow eyes after unilateral ON-were compared with 118 healthy control eyes. SS-OCT quantified ganglion cell-inner plexiform layer (GCIPL), peripapillary retinal nerve fiber layer (pRNFL), and macular RNFL (mRNFL) thickness, while OCTA measured superficial vascular plexus (SVP) vessel density. Between-group differences were assessed using generalized estimating equations with participant-level clustering, empirical (sandwich) standard errors, adjustment for age and sex, and false discovery rate correction.

Results

Despite preserved visual acuity, both never-ON and fellow eyes showed structural retinal thinning relative to controls. GCIPL thickness followed a stepwise gradient-66.14 ± 4.31, 62.08 ± 7.03, and 58.03 ± 7.71 µm in controls, never-ON eyes, and fellow eyes, respectively (FDR-adjusted q = 0.020 for fellow vs. never-ON eyes)-and pRNFL and mRNFL showed a similar overall pattern. After false discovery rate correction, OCTA parameters did not differ significantly between groups.

Conclusions

Clinically unaffected eyes in MS are not structurally normal, and fellow eyes after unilateral ON carry a greater burden of silent retinal damage than never-ON eyes. These two phenotypes should be analyzed separately in MS imaging research. Structural OCT measures, particularly GCIPL thickness, appear more sensitive than microvascular indices for detecting subclinical retinal involvement.