Delayed Visual Signals in the Eye Track Hidden Brain Shrinkage in Multiple Sclerosis

For decades, neurologists have relied on a deceptively simple test to probe the health of the visual system in people with multiple sclerosis: the visual evoked potential, or VEP. By recording the electrical activity that travels from the retina to the visual cortex in response to a flickering checkerboard pattern, clinicians can measure precisely how long the brain takes to register what the eye sees. When the protective myelin sheath around the optic nerve is stripped away by inflammation, that signal arrives late. The delay in the so-called P100 wave, the positive deflection that appears roughly one hundred milliseconds after stimulation, has long served as a sensitive marker of optic nerve demyelination. But a lingering question has shadowed the test: does a slowed P100 latency tell us only about the eye, or does it whisper something far more consequential about the brain itself?

A new study published in the Journal of Neurology by Dejan Jakimovski of the University of Rochester and the University at Buffalo, together with an international team of collaborators, tackles that question head-on, and its answer is striking. The researchers found that prolonged P100 latency is directly and independently associated with hallmark MRI signatures of neurodegeneration in multiple sclerosis, including reduced whole brain volume, reduced gray matter volume, and a heavier burden of T2-FLAIR lesions. Critically, these associations persisted even after the team statistically accounted for retinal structural damage and for age, two factors that could otherwise explain the link. The work suggests that a humble electrophysiological measurement of visual processing speed may function as a window onto the diffuse neurodegenerative processes quietly reshaping the brain.

The central methodological challenge the investigators faced was one of disentanglement. Shifts in P100 latency could, in principle, arise from changes anywhere along the visual pathway. Upstream, at the level of the retina, loss of retinal ganglion cell axons, measurable as thinning of the peripapillary retinal nerve fiber layer, could plausibly slow the signal before it even reaches the optic nerve. Downstream, widespread damage within the brain, including demyelination of visual radiations and atrophy of cortical and subcortical structures, could equally delay the arrival of the evoked response. Without a way to separate these possibilities, the interpretation of a delayed P100 wave remained ambiguous. A delayed signal might simply be a retinal story told in milliseconds.

To resolve this ambiguity, the team enrolled 64 people with multiple sclerosis and subjected each participant to a trio of complementary assessments. Spectral domain optical coherence tomography, performed on Heidelberg Spectralis hardware, provided precise measurements of peripapillary retinal nerve fiber layer thickness, an established structural proxy for retinal axonal integrity. Standardized VEP testing yielded monocular P100 latency values for each eye, capturing the functional speed of signal conduction through the visual system. Finally, magnetic resonance imaging delivered quantitative measures of whole brain volume, gray matter volume, and T2-FLAIR lesion volume, the canonical MRI outcomes that neurologists use to gauge tissue destruction and disease progression.

The analytical centerpiece of the study was a series of mediation analyses, a statistical framework that allows researchers to ask whether the relationship between two variables persists after accounting for a third variable that might lie on the causal path between them. In this case, the investigators modeled whether the association between P100 latency and MRI outcomes was mediated by retinal nerve fiber layer thickness, while also adjusting for the well-known effect of age on brain volume. If retinal thinning were the true driver, then once it was held constant, the connection between VEP latency and brain atrophy should have evaporated. It did not.

The results were unambiguous. P100 latency was significantly associated with lower whole brain volume, with a p-value of 0.0037, and remarkably, 87.8 percent of that total effect proved to be direct and independent of both retinal nerve fiber layer measures and the significant age-related covariate effect on brain volume. In other words, nearly nine-tenths of the relationship between slowed visual conduction and brain shrinkage could not be explained by retinal damage or the passage of time. The pattern extended to the other MRI outcomes as well: greater P100 latency directly and independently predicted lower gray matter volume, with p equal to 0.015, and greater T2-FLAIR lesion volume, with p equal to 0.0036, after adjustment for the mediating effects of retinal thickness and age.

These findings carry weight because they reposition the VEP from a narrow diagnostic tool to something approaching a whole-nervous-system barometer. The P100 latency, long appreciated for its role in detecting subclinical optic nerve involvement and in supporting diagnosis under frameworks such as the McDonald criteria, now shows age- and retinal-independent associations with the very imaging outcomes that define neurodegeneration in multiple sclerosis. The authors suggest that, in addition to their established diagnostic utility, VEP measures may provide an objective neurophysiological metric for assessing neurodegeneration itself, a prospect with obvious appeal for clinical trials of remyelinating and neuroprotective agents, where sensitive, repeatable, and inexpensive outcome measures are perpetually in demand.

The study did not emerge from a vacuum. Prior work by overlapping teams had already hinted that VEP latency carries prognostic significance beyond the optic nerve. Earlier investigations linked prolonged latency to longitudinal worsening of fatigue in people with multiple sclerosis and to variance in cognitive performance, while other analyses associated VEP latency measures with brain tissue volume differences and with cortical thinning attributed to trans-synaptic degeneration following optic neuritis. Longitudinal cohort studies had likewise proposed VEP as a prognostic biomarker for neuroaxonal damage, and historical analyses had explored its potential as an outcome measure for remyelination trials, building on observations that latency can recover slowly over years as remyelination proceeds after optic neuritis. The new mediation analysis strengthens this literature by rigorously excluding retinal structural change as an alternative explanation for the latency-brain association.

The interplay between optical coherence tomography and VEP is itself a story of complementary technologies converging on the same biology. OCT offers a structural readout, quantifying the physical thinning of the nerve fiber layer as axons are lost, and has been incorporated into the 2024 McDonald diagnostic criteria for multiple sclerosis alongside VEP. VEP offers a functional readout, capturing conduction speed through myelinated pathways, which can be prolonged by demyelination even when axonal architecture remains partially intact. By combining both modalities in a single cohort and formally testing mediation, the researchers could demonstrate that the functional signal conveys information about global brain health that the structural measurement alone does not capture, a distinction with real consequences for how clinicians and trialists interpret these tests.

Certain caveats temper the enthusiasm. The study was a retrospective analysis of de-identified clinical data, approved under exemption criteria with a waiver of informed consent, and its sample of 64 participants, while adequate for the mediation analyses performed, is modest by the standards of biomarker validation. The datasets are not publicly available due to institutional restrictions, though de-identified data may be shared with qualified researchers upon reasonable request. The cross-sectional design, relating latency to MRI outcomes measured at the same time, cannot establish the temporal precedence needed to declare VEP latency a true predictive biomarker of future atrophy rather than a concurrent correlate. Longitudinal confirmation in larger, independent cohorts will be essential before P100 latency earns a place alongside MRI volumetry in monitoring algorithms. Nevertheless, the prospect is tantalizing: a noninvasive, relatively inexpensive electrophysiological test, already available in most neurology departments, may offer a real-time readout of neurodegenerative processes that MRI can only capture after tissue has been lost. For a disease in which the earliest and most consequential damage often unfolds invisibly, a millisecond-scale signal from the eye may prove to be one of the most informative messages the brain ever sends.

Subject of Research: The association between visual evoked potential latency delays and MRI-based neurodegeneration measures in multiple sclerosis.

Article Title: VEP latency delays predicts MRI neurodegenerative outcomes in multiple sclerosis

Article References: Jakimovski, D., Weller, J., Zivadinov, R., Weinstock-Guttman, B., Golan, D., Zarif, M., Costello, F., Sergott, R. C., Galetta, S. L., Kenney, R., Balcer, L. J., Van Hecke, W., Smeets, D., Dhakal, B., Morrow, S. A., Covey, T. J., & Gudesblatt, M. (2026). VEP latency delays predicts MRI neurodegenerative outcomes in multiple sclerosis. Journal of Neurology, 273(10), Article 621. https://doi.org/10.1007/s00415-026-14151-y

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14151-y

Keywords: multiple sclerosis, visual evoked potentials, P100 latency, optical coherence tomography, retinal nerve fiber layer, brain volume, gray matter atrophy, T2-FLAIR lesion volume, neurodegeneration, MRI biomarkers, optic nerve, neurophysiology