Multiple sclerosis involves progressive axonal loss and neurodegeneration within the central nervous system. In recent years, clinicians have sought reliable non-invasive biomarkers to monitor neurodegenerative progression in secondary progressive multiple sclerosis. The anterior visual pathway offers an accessible window into central pathology. Consequently, quantitative assessment using optical coherence tomography has emerged as a key monitoring tool. Utilizing OCT in progressive MS allows clinicians to measure inner retinal layer thickness with high precision. Specifically, peripapillary retinal nerve fibre layer and macular ganglion cell-inner plexiform layer thicknesses reflect unmyelinated axonal and neuronal soma loss. Data from the multi-arm MS-SMART trial substudy recently highlighted how these ocular metrics correlate with functional and structural disease parameters. Investigators tracked two hundred twelve secondary progressive multiple sclerosis patients over ninety-six weeks. Their findings demonstrate that retinal thinning aligns with cognitive processing speed, deep grey matter loss, gait impairment, and global brain atrophy over time.

Evaluating Retinal Biomarkers and OCT in Progressive MS

Evaluating neuroprotection in secondary progressive multiple sclerosis requires sensitive biomarkers reflecting ongoing central neurodegeneration. In this context, utilizing OCT in progressive MS offers distinct advantages because the retina lacks myelin. Thus, retinal imaging directly captures axonal injury and neuronal soma loss without confounding remyelination signals. The MS-SMART randomised controlled trial substudy evaluated two primary retinal layers: the peripapillary retinal nerve fibre layer and the macular ganglion cell-inner plexiform layer. Investigators enrolled two hundred twelve individuals with secondary progressive multiple sclerosis at baseline, with one hundred ninety-two completing ninety-six weeks of follow-up. Researchers systematically evaluated magnetic resonance imaging scans, clinical disability scales, and structural retinal scans at both time points. Statistical modeling included multivariable linear regressions and mixed-effects models. Ultimately, the trial design allowed researchers to explore cross-sectional correlations and prospective longitudinal associations. By establishing structural links between retinal metrics and brain atrophy, this research validates optical coherence tomography as an effective biomarker in progressive disease cohorts.

Baseline Findings on pRNFL and GCIPL Thickness

At baseline, structural optical coherence tomography metrics demonstrated robust correlations with both cognitive speed and subcortical brain architecture. The Symbol Digit Modalities Test served as the primary measure for cognitive processing speed. Thicker baseline peripapillary retinal nerve fibre layer values significantly correlated with higher cognitive performance scores. Similarly, macular ganglion cell-inner plexiform layer thickness showed an even stronger positive correlation with cognitive processing speed. In addition to cognitive metrics, baseline retinal layer thicknesses correlated with deep grey matter volume measured on magnetic resonance imaging scans. Both peripapillary retinal nerve fibre layer thickness and ganglion cell-inner plexiform layer volume exhibited positive associations with deep grey matter structures. Because deep grey matter atrophy drives long-term physical and cognitive disability in progressive multiple sclerosis, these baseline findings are clinically significant. Therefore, initial retinal structural scans reflect central brain pathology and underlying subcortical neurodegenerative burden.

Longitudinal Changes in Retinal Layer Thinning

Over ninety-six weeks, longitudinal optical coherence tomography measurements demonstrated continuous retinal neurodegeneration among trial participants. The annualised thinning rate for the peripapillary retinal nerve fibre layer was calculated at minus zero point eight three micrometres per year. Meanwhile, the annualised thinning rate for the macular ganglion cell-inner plexiform layer reached minus zero point three seven micrometres per year. These measurable rates confirm ongoing axonal and neuronal loss in secondary progressive multiple sclerosis despite long disease duration. Importantly, baseline retinal thickness significantly predicted future disability accumulation. Participants with thicker baseline peripapillary retinal nerve fibre layers experienced smaller adverse changes in their Expanded Disability Status Scale scores over ninety-six weeks. Furthermore, higher baseline values for both retinal metrics significantly associated with better preservation of walking speed, measured via the Timed 25-Foot Walk test. These prospective associations demonstrate that preserved retinal architecture at baseline predicts milder functional decline.

Correlating Ocular Biomarkers with Brain Atrophy

A key objective of the trial substudy was investigating whether ocular structural changes reflect global central nervous system neurodegeneration over time. Longitudinal MRI assessments revealed a clear relationship between baseline retinal status and overall percentage brain volume change across ninety-six weeks. Higher baseline peripapillary retinal nerve fibre layer thickness significantly associated with reduced rates of whole brain volume loss. Likewise, thicker baseline macular ganglion cell-inner plexiform layers correlated strongly with preserved total brain volume. These structural alignments confirm that retinal thinning mirrors diffuse neurodegenerative processes taking place throughout the central nervous system. Because cerebral atrophy correlates with permanent disability accumulation, having an easily accessible ocular biomarker enhances monitoring capabilities. Furthermore, these findings demonstrate that retinal thinning rates capture neurodegenerative processes occurring independently of acute optic neuritis. Consequently, serial optical coherence tomography scans provide an accessible substitute for serial volumetric MRI scans.

Clinical Implications for Monitoring Secondary Progressive MS

The findings from the MS-SMART substudy hold substantial clinical significance for clinicians managing secondary progressive multiple sclerosis. Tracking disease progression in progressive cohorts remains challenging due to insidious clinical decline and standard disability scale limitations. Integrating quantitative retinal imaging into clinical workflows fills this critical gap. Retinal metrics offer objective, highly reproducible quantitative endpoints that correlate with cognitive processing, motor function, deep grey matter atrophy, and whole-brain volume loss. Furthermore, the high sensitivity of optical coherence tomography makes it a valuable exploratory outcome measure for future clinical trials testing candidate neuroprotective agents. Preserved retinal thickness indicates greater underlying tissue reserve and predicts lower risk of rapid functional deterioration. Clinicians can utilize these measurements to stratify patient risk, tailor monitoring schedules, and counsel patients regarding disease trajectory. Routine optical coherence tomography promises to transform neurodegenerative monitoring into precise structural measurement.

Frequently Asked Questions

What is the clinical significance of OCT in progressive MS?

Optical coherence tomography provides non-invasive, objective measurements of inner retinal layers that reflect central neurodegeneration. In secondary progressive multiple sclerosis, retinal metrics correlate with cognitive processing speed, deep grey matter volume, walking speed, and overall brain atrophy, aiding clinicians in tracking disease progression accurately.

Which retinal layers are routinely measured using OCT in progressive MS?

Clinicians primarily assess the peripapillary retinal nerve fibre layer and the macular ganglion cell-inner plexiform layer. The peripapillary retinal nerve fibre layer contains unmyelinated axons, while the ganglion cell layer contains neuronal cell bodies. Both layers thin progressively as neurodegeneration advances in multiple sclerosis.

How does baseline retinal thickness predict functional decline in SPMS?

Studies show that patients with thicker baseline retinal layers experience less worsening on disability scales and retain better walking speed over two years. Thicker initial retinal layers indicate greater neuroaxonal reserve, which correlates with slower whole-brain volume loss and better functional preservation over time.

Disclaimer: This content is for informational and educational purposes only and does not constitute professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Refer to the latest local and national guidelines for clinical practice.

References

1. De Angelis F et al. Optical coherence tomography in secondary progressive multiple sclerosis: cross-sectional and longitudinal exploratory analysis from the MS-SMART randomised controlled trial. J Neurol Neurosurg Psychiatry. 2025 Jun 12. doi: 10.1136/jnnp-2024-334801. PMID: 39694820.
2. Petzold A et al. Optical coherence tomography in multiple sclerosis: a review. Lancet Neurol. 2010;9(9):921-932.
3. Balk LJ et al. Timing of retinal neuronal and axonal loss in multiple sclerosis: a longitudinal OCT study. J Neurol Neurosurg Psychiatry. 2016;87(8):882-887.