Secondary progressive multiple sclerosis (SPMS) represents a challenging stage of multiple sclerosis characterized by steady neurodegeneration and cumulative disability. Consequently, clinicians urgently need reliable, non-invasive biomarkers to monitor central nervous system loss and predict patient outcomes. Recent findings from the landmark MS-SMART study highlight the clinical value of OCT in progressive MS as a surrogate marker for neuroaxonal damage. Optical coherence tomography provides rapid, high-resolution imaging of inner retinal layers. Specifically, peripapillary retinal nerve fibre layer (pRNFL) and macular ganglion cell-inner plexiform layer (GCIPL) metrics reflect neurodegeneration. By measuring these unmyelinated axons and neuronal cell bodies in the retina, clinicians obtain a direct window into brain pathology. In this trial analysis, researchers evaluated whether structural retinal changes correlate with physical disability, cognitive processing speed, and whole-brain atrophy over a 96-week follow-up period. Furthermore, the findings offer vital insights into how non-invasive ocular imaging can enhance clinical monitoring and therapeutic trials in progressive neurodegenerative diseases.

Evaluating Retinal Metrics with OCT in Progressive MS

The MS-SMART trial sub-study investigated 212 patients diagnosed with secondary progressive multiple sclerosis at baseline. Out of this initial cohort, 192 individuals successfully completed the 96-week longitudinal evaluation. Researchers collected brain magnetic resonance imaging scans, detailed clinical assessments, and optical coherence tomography measurements at baseline and follow-up. Specifically, the study quantified pRNFL and GCIPL thicknesses to evaluate structural neurodegeneration. Most importantly, participants had long disease duration and were not receiving disease-modifying therapies, providing an unconfounded view of natural disease progression. Statistical analyses utilized rigorous multivariable linear regression models and mixed-effects models to track structural changes over time. Consequently, this study represents one of the largest longitudinal OCT evaluations in secondary progressive multiple sclerosis. The investigators assessed how baseline retinal metrics correlated with clinical disability scores, cognitive performance tests, and structural brain volumes. Furthermore, they measured the annual rate of retinal layer loss to establish clear benchmarks for progressive neuroaxonal thinning.

Baseline Correlations with Cognitive Function and Deep Grey Matter

At baseline, structural retinal measurements demonstrated clear correlations with key neurological parameters. Higher pRNFL thickness correlated significantly with better cognitive processing speed, as measured by the Symbol Digit Modalities Test. Similarly, GCIPL thickness showed an even stronger positive correlation with cognitive score performance. Cognitive impairment heavily impacts patient independence and quality of life in secondary progressive disease. Therefore, finding an accessible biomarker for cognitive decline holds immense clinical utility. Additionally, both pRNFL and GCIPL measurements correlated with deep grey matter volume on brain MRI scans. Specifically, pRNFL correlated with deep grey matter volume, while GCIPL displayed a parallel association. Deep grey matter atrophy represents a hallmark of neurodegeneration in progressive multiple sclerosis. Consequently, these robust baseline correlations confirm that inner retinal layer thickness directly reflects the underlying integrity of deep brain structures and cognitive capacity. Overall, retinal imaging offers a sensitive window into central nervous system pathology.

Predicting Physical Disability and Ambulatory Progression

Beyond baseline correlations, inner retinal metrics predicted physical disability progression over 96 weeks. Specifically, baseline pRNFL thickness showed a significant negative association with changes in the Expanded Disability Status Scale score. Patients with thicker pRNFL at baseline experienced less disability accumulation over time. Moreover, both pRNFL and GCIPL thickness predicted changes in mobility measured by the Timed 25-Foot Walk test. Baseline pRNFL associated inversely with walk time deterioration. Similarly, baseline GCIPL thickness showed a robust negative association with mobility decline. Walk speed represents a vital clinical indicator of functional independence in progressive disease. Therefore, these results indicate that thinner retinal layers signal a higher risk of imminent physical decline. Consequently, clinicians can utilize retinal thickness measurements to stratify patients based on their risk for rapid disability progression. In summary, baseline ocular assessments provide critical prognostic information regarding long-term ambulatory decline.

Longitudinal Retinal Thinning and Percentage Brain Volume Change

Longitudinal analysis over 96 weeks revealed measurable, ongoing loss of inner retinal layer thickness in progressive disease. Specifically, the annualized rate of pRNFL thinning reached -0.83 micrometres per year. Simultaneously, GCIPL exhibited an annualized thinning rate of -0.37 micrometres per year. This persistent tissue loss reflects continuous axonal degradation and neuronal soma loss over time. Furthermore, baseline retinal metrics strongly predicted whole-brain structural loss at follow-up. Baseline pRNFL associated significantly with 96-week percentage brain volume change. Likewise, GCIPL thickness displayed a strong positive association with percentage brain volume change. Patients with preserved retinal layers experienced significantly less whole-brain atrophy over two years. In contrast, individuals with advanced retinal thinning exhibited accelerated central neurodegeneration. Consequently, longitudinal OCT metrics provide a sensitive, parallel measure of global cerebral tissue loss in secondary progressive multiple sclerosis. Ultimately, tracking retinal changes helps quantify ongoing neurodegenerative disease activity.

Clinical Implementation and Future Trial Applications

The findings from this trial sub-study carry substantial implications for daily neurological practice and future neuroprotective drug trials. Currently, evaluating neuroprotective agents in progressive multiple sclerosis requires expensive, time-consuming brain MRI protocols. However, optical coherence tomography offers a fast, inexpensive, non-invasive alternative that patients tolerate exceptionally well. Because inner retinal layers lack myelin, optical coherence tomography directly measures unmyelinated axons and neuronal cell bodies without interference from demyelination or remyelination. Consequently, changes in retinal thickness provide a pure reflection of neuroaxonal survival. Clinicians can integrate optical coherence tomography into routine monitoring to identify patients at high risk of rapid cognitive and physical worsening. Furthermore, clinical trials can utilize retinal metrics as sensitive secondary endpoints to evaluate novel neuroprotective therapies. Ultimately, incorporating retinal imaging into comprehensive care protocols enhances clinical precision and accelerates therapeutic discovery in progressive neurodegenerative conditions.

Frequently Asked Questions

How does OCT help monitor secondary progressive multiple sclerosis?

Optical coherence tomography measures inner retinal layer thickness, specifically the peripapillary retinal nerve fibre layer and ganglion cell-inner plexiform layer. Because retinal nerve fibers are unmyelinated, thinning directly reflects neuroaxonal loss in the central nervous system. Consequently, retinal metrics correlate with cognitive processing speed, brain volume loss, and physical disability progression over time.

What were the main longitudinal findings from the MS-SMART trial OCT sub-study?

The MS-SMART sub-study demonstrated significant annualized thinning rates for pRNFL (-0.83 µm/year) and GCIPL (-0.37 µm/year) over 96 weeks. Additionally, baseline retinal thickness significantly predicted percentage brain volume change, mobility decline on the Timed 25-Foot Walk, and disability changes on the Expanded Disability Status Scale in patients with SPMS.

Can OCT replace MRI in progressive multiple sclerosis clinical trials?

While OCT cannot entirely replace brain magnetic resonance imaging, it serves as a highly valuable, cost-effective, and non-invasive complementary biomarker. Retinal layer measurements provide a sensitive primary or secondary endpoint for neuroprotective clinical trials, offering direct structural assessment of neurodegeneration without the high costs and logistical complexity associated with frequent MRI scans.

Disclaimer: This content is for informational and educational purposes only, targeted at healthcare professionals. It does not constitute medical advice or establish a doctor-patient relationship. 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. Chataway J et al. Efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis (MS-SMART): a multi-arm, randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Neurol. 2020 Apr;19(4):214-225.
3. Paul F et al. Optical coherence tomography in multiple sclerosis: a review of current clinical applications and future perspectives. Nat Rev Neurol. 2022;18(5):271-285.