The Evolution of Monitoring in Relapsing Multiple Sclerosis

Managing relapsing multiple sclerosis requires precise monitoring tools to prevent irreversible neurological disability. Clinicians have traditionally relied on the No Evidence of Disease Activity metric, known as NEDA-3, to gauge treatment response. This conventional standard encompasses three parameters: freedom from clinical relapses, absence of confirmed disability progression, and lack of new magnetic resonance imaging lesions. However, standard NEDA-3 fails to capture insidious, subclinical neuroaxonal loss occurring beneath apparent clinical stability. Consequently, many patients who achieve NEDA-3 still experience silent disease progression and delayed functional decline.

Recent advances in non-invasive retinal imaging have established optical coherence tomography as a valuable modality in neuroimmunology. Specifically, tracking retinal layer thinning provides a direct window into central nervous system neurodegeneration. Because the anterior visual pathway shares developmental features with the brain, retinal axonal loss mirrors global cerebral atrophy. Therefore, integrating optical coherence tomography into treatment assessment represents a crucial advancement. By quantifying ongoing axonal loss, clinicians can identify therapeutic failure early and adjust disease-modifying therapies before extensive functional impairment manifests.

Quantifying Retinal Layer Thinning as an Objective Biomarker

Optical coherence tomography measures microstructural retinal architecture down to individual micrometer resolutions. In multiple sclerosis surveillance, two primary anatomical structures serve as critical endpoints: the peripapillary retinal nerve fiber layer and the macular ganglion cell-inner plexiform layer. The peripapillary retinal nerve fiber layer consists predominantly of unmyelinated axons originating from retinal ganglion cells. Meanwhile, the ganglion cell-inner plexiform layer contains the corresponding neuronal cell bodies and dendritic synaptic networks.

Pathophysiologically, inflammation along the optic pathway causes anterograde and retrograde neuroaxonal loss. Additionally, widespread cerebral neurodegeneration produces trans-synaptic axonal degeneration across visual pathways. Standard optical coherence tomography protocols define clinically significant retinal layer thinning as an annualized reduction of at least 1.0 micrometer per year in the peripapillary layer or 0.5 micrometers per year in the ganglion cell-inner plexiform layer. Consequently, these metrics provide sensitive markers of neurodegeneration independent of acute optic neuritis episodes. Measuring these subtle structural alterations empowers clinicians to identify silent disease activity effectively.

Study Design and Longitudinal Cohort Analysis

A pivotal multi-center study evaluated how integrating optical coherence tomography metrics into traditional response definitions affects prognostic accuracy. Researchers analyzed two prospective observational cohorts comprising 124 patients with relapsing multiple sclerosis newly initiating disease-modifying therapies. At baseline and at twelve months, all participants underwent comprehensive clinical evaluations, brain magnetic resonance imaging, and spectral-domain optical coherence tomography scans.

Investigators classified patients at twelve months into conventional NEDA-3 or evidence of disease activity (EDA-3), as well as augmented composite definitions incorporating optical coherence tomography parameters (NEDA-3 plus OCT versus EDA-3 plus OCT). The researchers followed these cohorts over a median duration of 3.4 years to detect confirmed disability progression. Furthermore, the analysis accounted for therapy variations by incorporating treatment efficacy classes as covariates in multivariable models. Female participants accounted for 72 percent of the cohort, with a mean baseline age of 33.1 years. Disability progression ultimately occurred in 28 individuals, providing a robust dataset for prognostic evaluation.

Predictive Superiority of the NEDA-3 Plus OCT Composite

The longitudinal findings revealed striking differences between traditional NEDA-3 and the expanded OCT-inclusive criteria. Conventional NEDA-3 status at twelve months failed to predict future disability progression reliably. Specifically, the time to progression and overall risk showed no statistically significant difference between patients meeting EDA-3 and those achieving NEDA-3 (restricted mean survival time of 43.4 months versus 48.1 months; adjusted hazard ratio 1.52, p = 0.173).

In stark contrast, integrating retinal layer thinning into the assessment framework dramatically enhanced risk stratification. Patients categorized as EDA-3 plus OCT demonstrated a 6.59-fold increased hazard of subsequent confirmed disability progression compared with those achieving NEDA-3 plus OCT (adjusted hazard ratio 6.59, 95 percent lower limit confidence interval 2.38, p = 0.005). Furthermore, individuals with disease activity on the composite metric experienced a significantly shorter time to disability progression (restricted mean survival time of 41.9 months versus 51.9 months, p < 0.001). Therefore, omitting retinal metrics overlooks patients harboring active, silent neuroaxonal destruction.

Pathological Insights into Relapse-Independent Progression

These findings illuminate the complex biological mechanisms driving long-term disability in multiple sclerosis. Traditionally, clinicians viewed relapsing disease primarily through the lens of focal, gadolinium-enhancing inflammatory events. However, contemporary neuroimmunology recognizes that progression independent of relapse activity occurs concurrently from the earliest disease stages. This smoldering neurodegenerative process involves compartmentalized meningeal inflammation, chronic microglial activation, and progressive mitochondrial dysfunction.

Standard magnetic resonance imaging often fails to capture this diffuse, low-grade neurodegeneration because cortical lesion detection and brain volume measurement remain challenging in routine practice. Conversely, spectral-domain optical coherence tomography directly registers insidious axonal drop-out in the anterior visual pathway. Because retinal ganglion cell axons lack myelin within the retina, structural loss directly reflects pure neuroaxonal injury without confounding edema. Consequently, progressive retinal thinning serves as an accessible surrogate for widespread central nervous system atrophy. Identifying ongoing neuroaxonal loss enables clinicians to recognize subclinical treatment failure early and intervene aggressively.

Translating Retinal Biomarkers into Indian Clinical Practice

The implementation of retinal surveillance offers substantial practical advantages for clinical practice in India and resource-diverse settings. While advanced neuroimaging techniques, such as volumetric brain atrophy software, require expensive infrastructure and specialized neuro-radiological expertise, optical coherence tomography is widely accessible across ophthalmology centers. Therefore, fostering multidisciplinary collaboration between neurologists and ophthalmologists can facilitate cost-effective, high-yield longitudinal monitoring.

Clinicians should establish baseline retinal layer measurements upon diagnosing relapsing multiple sclerosis or when initiating disease-modifying therapies. Subsequently, performing repeat scans at twelve months establishes the trajectory of neuroaxonal loss. If a patient exhibits peripapillary or ganglion cell layer thinning above established thresholds, clinicians should critically re-evaluate therapeutic efficacy. This objective indicator of subclinical progression warrants considering escalation to high-efficacy therapies, such as anti-CD20 monoclonal antibodies, even without new radiological lesions. Ultimately, incorporating retinal biomarkers democratizes access to precision medicine, ensuring timely therapeutic adjustments that optimize patient autonomy.

Frequently Asked Questions

How does optical coherence tomography assist in monitoring multiple sclerosis?

Optical coherence tomography provides rapid, high-resolution measurements of the retinal nerve fiber layer and ganglion cell complex. Because retinal neurons lack myelin, structural thinning directly reflects central nervous system neuroaxonal injury. Consequently, tracking these microstructural changes helps clinicians detect subclinical disease progression that standard clinical evaluations and magnetic resonance imaging frequently miss.

What cutoff values define significant retinal thinning in multiple sclerosis?

Clinical studies define meaningful retinal thinning as an annualized loss of at least 1.0 micrometer in the peripapillary retinal nerve fiber layer or 0.5 micrometers in the ganglion cell-inner plexiform layer. Rates exceeding these physiological thresholds indicate ongoing neurodegeneration, signaling a heightened risk of subsequent disability progression despite apparent clinical stability.

How should clinicians respond when retinal thinning occurs despite NEDA-3 status?

When patients demonstrate accelerated retinal layer thinning despite achieving conventional NEDA-3, clinicians should recognize ongoing subclinical neuroaxonal loss. Consequently, physicians should comprehensively re-evaluate therapeutic efficacy, consider switching to high-efficacy disease-modifying therapies, and perform closer longitudinal clinical monitoring to prevent long-term physical and cognitive disability progression.

Disclaimer: This content is for informational and educational purposes only and is not intended as medical advice. Always consult a qualified healthcare provider for diagnosis and treatment decisions. Refer to the latest local and national guidelines for clinical practice.

References

1. Föttinger F et al. Integration of retinal layer thinning into NEDA-3 predicts disability progression in multiple sclerosis. J Neurol. 2026 Jun 09. doi: 10.1007/s00415-026-13909-8. PMID: 42262609.


2. Bsteh G et al. Retinal layer thinning is reflecting disability progression independent of relapse activity in multiple sclerosis. Mult Scler. 2021;27(10):1514-1524.


3. Rothman A et al. Retinal measurements predict 10-year disability in multiple sclerosis. Ann Clin Transl Neurol. 2019;6(2):222-232.


4. Al-Louzi O et al. Retinal Optical Coherence Tomography Longitudinal Measures as Prognostic Biomarkers in Multiple Sclerosis. Neurol Neuroimmunol Neuroinflamm. 2025;12(4):e200388.