The research, led by Luca Bollo and Angela Vidal-Jordana at the Multiple Sclerosis Centre of Catalonia in collaboration with Vall d’Hebron University Hospital and published in the Journal of Neurology, prospectively followed 46 patients experiencing their first episode of unilateral subacute optic neuritis. Each participant underwent a comprehensive workup: detailed clinical examination, orbital and brain magnetic resonance imaging, optical coherence tomography of the retinal nerve fiber layer, laboratory testing including serum antibodies against aquaporin-4 and myelin oligodendrocyte glycoprotein, and visual evoked potentials, a neurophysiological test that measures how efficiently the visual pathway conducts signals from the retina to the visual cortex. The investigators then applied the original ICON 2022 criteria and compared the results with two modified versions of the framework.

The headline finding is stark. Under the original ICON 2022 criteria, only 20 of the 46 patients, or 43.5 percent, reached the category of definite optic neuritis. When the researchers loosened the clinical requirements, allowing a diagnosis with incomplete clinical features, and required two abnormal paraclinical tests among MRI, optical coherence tomography, and laboratory findings, the proportion of definite cases rose to 32 patients, or 69.6 percent, a difference that was highly statistically significant. When visual evoked potentials were added to the paraclinical toolkit alongside the less stringent clinical definitions, the figure climbed further still, to 39 patients, or 84.8 percent, nearly double the yield of the original criteria.

To understand why this matters, it helps to unpack what each test actually measures. Magnetic resonance imaging with orbital sequences can reveal T2-hyperintense signal and gadolinium enhancement along the optic nerve, direct evidence of inflammation and blood-nerve barrier disruption. Optical coherence tomography quantifies the thickness of the retinal nerve fiber layer and the ganglion cell complex, detecting the axonal loss that follows an inflammatory attack. Visual evoked potentials, by contrast, probe function rather than structure: a flashing or pattern-reversing checkerboard stimulus is presented to each eye while electrodes over the occipital cortex record the timing and amplitude of the brain’s response. Demyelination delays the P100 latency, the characteristic peak of the response, often before structural thinning becomes measurable on scans.

This functional sensitivity is precisely why the addition of VEPs proved so powerful in the study. Patients with incomplete clinical presentations, for example those without the classic combination of pain, visual acuity loss, color vision impairment, and a relative afferent pupillary defect, could still be classified as definite optic neuritis when their paraclinical workup was typical. The effect was most pronounced in exactly this subgroup: individuals whose symptoms did not tick every clinical box but whose MRI, OCT, and electrophysiology told an unambiguous story of optic nerve inflammation. In clinical terms, the modified criteria rescued a substantial fraction of patients who would otherwise have been left in diagnostic limbo, a category with real consequences for treatment decisions, follow-up intensity, and counseling about the risk of future demyelinating events such as multiple sclerosis.

The Barcelona group’s work does not stand in isolation. Since the ICON criteria appeared in The Lancet Neurology in 2022, several groups have tested them against independent cohorts and reported similar concerns about stringency. Correspondence in the same journal questioned how the criteria performed in atypical presentations, and the Acute Optic Neuritis Network published an application of the criteria in 2024 that highlighted classification gaps. Meanwhile, the field of demyelinating disease diagnostics has been moving rapidly toward incorporating the optic nerve more broadly. The 2024 revisions of the McDonald criteria for multiple sclerosis, the most consequential diagnostic framework in the field, now allow optic nerve involvement, demonstrated by MRI or by visual evoked potentials, to contribute to the demonstration of dissemination in space, a change that formally elevates VEPs from a niche neurophysiological tool to a first-line diagnostic instrument.

Against that backdrop, the new study offers prospective, patient-level evidence that the optic neuritis criteria should evolve in the same direction. The authors’ proposed modification is conceptually simple: rather than demanding a complete clinical syndrome, the framework would accept a less strict clinical category and then require corroboration from two abnormal paraclinical tests, with VEPs counted alongside MRI, OCT, and serology. This modular architecture mirrors how modern neurology increasingly thinks about diagnosis, as a Bayesian exercise in which each test contributes independent information about the probability of disease. A delayed P100 latency on VEPs carries information that is partly independent of a normal-appearing retinal nerve fiber layer on OCT, and both can be informative when the MRI shows only subtle optic nerve signal change.

There are important caveats. The cohort of 46 patients is modest, and all participants were recruited at specialized centers in Catalonia with access to expert neuroradiology, neuro-ophthalmology, and neurophysiology, so the modified criteria will need validation in larger and more diverse populations, including settings where antibody testing and VEP recording are less readily available. The study also focused on first-episode unilateral optic neuritis, leaving open the question of how the modified framework performs in bilateral, recurrent, or pediatric disease, where differential diagnoses such as neuromyelitis optica spectrum disorder and MOG antibody-associated disease loom larger and where serological markers carry decisive weight. The researchers themselves frame their findings as supporting revisions aimed at broader clinical applicability rather than as a finished replacement for the 2022 consensus.

Even so, the implications for patients are tangible. A person who wakes with a sore, blurry eye but whose examination findings are incomplete currently risks being labeled with uncertain optic neuropathy, delaying disease-modifying therapy if multiple sclerosis is the underlying cause, or delaying plasma exchange and immunosuppression if aquaporin-4 antibody disease is suspected. By formally recognizing that paraclinical evidence, especially electrophysiological evidence from visual evoked potentials, can compensate for an atypical clinical picture, the modified criteria promise faster, more confident classification and, downstream, better-targeted treatment. The study was funded by the Instituto de Salud Carlos III, and its datasets are available from the corresponding authors, an invitation for other centers to stress-test the approach.

The broader lesson reaches beyond one disease. Diagnostic criteria in neurology have historically leaned heavily on clinical acumen, with imaging and laboratory tests playing supporting roles. The trajectory now visible across multiple sclerosis, neuromyelitis optica, MOG antibody disease, and optic neuritis points toward criteria that fuse clinical features with structural imaging, retinal layer quantification, serology, and neurophysiology in a single probabilistic framework. The Barcelona study demonstrates concretely what that fusion can achieve: the proportion of patients confidently classified as having definite optic neuritis nearly doubled, from 43.5 to 84.8 percent, simply by trusting the objective signals that modern technology can already deliver. If subsequent multicenter validation confirms these results, the humble visual evoked potential, a test first described decades ago, may finally take its place at the center of optic nerve diagnostics, and fewer patients will be left waiting in the gray zone between suspicion and certainty.

Subject of Research: Prospective evaluation of the 2022 international consensus criteria for optic neuritis and the diagnostic value of visual evoked potentials

Article Title: Evaluation of the 2022 international consensus criteria for optic neuritis: the role of clinical features and visual evoked potentials

Article References: Bollo, L., Vidal-Jordana, A., Rodríguez-Acevedo, B., Sceppacuercia, S., Mongay-Ochoa, N., Zancan, V., Ajdinaj, P., Braga, N., Cabello, S., Alberich, M., Corral, J., Auger, C., Tintoré, M., Montalban, X., Pareto, D., Moncho, D., Rovira, À., & Sastre-Garriga, J. (2026). Evaluation of the 2022 international consensus criteria for optic neuritis: the role of clinical features and visual evoked potentials. Journal of Neurology, 273(10), Article 561. https://doi.org/10.1007/s00415-026-13972-1

Image Credits: AI Generated

DOI: 10.1007/s00415-026-13972-1

Keywords: optic neuritis, diagnostic criteria, visual evoked potentials, ICON criteria, MRI, optical coherence tomography, multiple sclerosis, demyelination, neurology, optic nerve, MOG antibodies, prospective study

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

The study, conducted in a mouse model of glaucoma, demonstrates that administration of rhNGF protects retinal ganglion cells from degeneration and preserves visual function. Crucially, the investigators did not stop at showing that the treatment worked; they dissected the mechanisms underlying the benefit, revealing that rhNGF counteracts two intertwined drivers of glaucomatous damage—oxidative stress and neuroinflammation. This dual action positions nerve growth factor not merely as a survival signal for ailing neurons, but as a molecular shield against the hostile retinal environment that develops as the disease progresses.

Nerve growth factor was the first neurotrophin ever discovered, identified more than seventy years ago by Rita Levi-Montalcini and Stanley Cohen, work that earned the Nobel Prize in Physiology or Medicine in 1986. NGF is best known for its role in the development and maintenance of sympathetic and sensory neurons, but it also acts on the central nervous system, including the retina, where its receptors—TrkA and p75NTR—are expressed by retinal ganglion cells and by glial cells such as Müller cells and astrocytes. Over the years, evidence has accumulated that NGF signaling can promote neuronal survival, yet translating that biology into a practical therapy has been difficult, in part because delivering protein drugs to target tissues is challenging and because earlier clinical efforts were hampered by formulation and delivery limitations.

In the glaucoma model used in the study, elevated intraocular pressure triggers a cascade of degenerative events in the retina. Pressure insult compromises axonal transport at the optic nerve head, deprives ganglion cells of trophic support, and sets off a vicious cycle in which stressed neurons release damage signals that activate glial cells. Activated microglia and macroglia, in turn, release pro-inflammatory cytokines such as TNF-alpha and interleukin-1 beta and generate reactive oxygen species, further injuring neurons and perpetuating the inflammatory loop. The result is progressive loss of retinal ganglion cells, thinning of the nerve fiber layer, and deterioration of the visual responses that these cells convey to the brain.

When the researchers administered rhNGF to the glaucomatous mice, they observed a marked preservation of retinal structure and function compared with untreated animals. Histological analysis revealed significantly higher survival of retinal ganglion cells, and functional assessments of the visual pathway confirmed that the anatomical protection translated into preserved vision-related output. The magnitude of the effect indicates that rhNGF does not merely delay degeneration marginally but provides substantive neuroprotection in this experimental setting.

The mechanistic findings are arguably the most significant contribution of the work. Molecular analyses of treated retinas showed a pronounced reduction in markers of oxidative stress. Levels of reactive oxygen species and lipid peroxidation products fell, while endogenous antioxidant defenses were bolstered. This matters because oxidative damage is now recognized as a central pillar of glaucoma pathobiology: the retina is one of the most oxygen-demanding tissues in the body, its ganglion cell mitochondria are exceptionally vulnerable, and oxidative modifications to proteins, lipids, and DNA accumulate early in the disease and correlate with neuronal loss. By damping oxidative injury, rhNGF appears to interrupt one of the key upstream triggers of the degenerative cascade.

Equally important was the effect on neuroinflammation. In untreated glaucomatous retinas, the researchers documented robust activation of microglia—the resident immune cells of the retina and optic nerve—along with elevated expression of inflammatory cytokines. In rhNGF-treated animals, microglial activation was substantially attenuated and the inflammatory signature was blunted. This anti-inflammatory action is notable because it suggests that NGF signaling, in addition to its classical trophic role, actively reprograms the glial response to injury. The TrkA receptor, when engaged by NGF, can activate survival pathways such as PI3K-Akt and MAPK signaling in neurons, while modulating the reactivity of glial cells that would otherwise amplify tissue damage. The study’s data indicate that both dimensions of NGF biology—direct neuronal support and immunomodulation—contribute to the observed protection.

The interplay between oxidative stress and inflammation is what makes these findings particularly compelling. These two processes are not independent; reactive oxygen species can activate inflammatory signaling pathways, including the NF-kappaB and inflammasome pathways, and inflammatory cells are themselves major producers of free radicals. In glaucoma, this creates a self-reinforcing spiral in which each process feeds the other. A therapy that targets only one arm of the spiral may achieve limited benefit, whereas an intervention that simultaneously reduces oxidative damage and suppresses neuroinflammation can potentially break the cycle. The rhNGF results suggest that the molecule does precisely that, which may explain why the neuroprotection achieved in the mouse model was so robust.

The therapeutic implications extend beyond the laboratory. Recombinant human NGF has already navigated part of the translational path: a topical ocular formulation of rhNGF has been approved in Europe for the treatment of neurotrophic keratitis, a disease of corneal nerve degeneration, providing clinical precedent for the safety and feasibility of delivering this protein to the eye. The new findings raise the prospect of repurposing or reformulating rhNGF for glaucoma, potentially as an adjunct to pressure-lowering therapy. Such a combination would address both sides of the disease: intraocular pressure as the major modifiable risk factor, and the downstream neurodegenerative processes that pressure control alone cannot fully halt. For the millions of patients who continue to progress despite adequate pressure management, a neuroprotective add-on would represent a genuine paradigm shift.

Significant work remains before rhNGF can be considered a glaucoma therapy. The current evidence comes from an animal model, and mouse glaucoma models, while informative, do not capture every feature of the human disease, which unfolds over decades rather than weeks. Questions of dosing, delivery route, treatment timing, and long-term safety will need to be answered, and results will need to be replicated in additional models and ultimately in clinical trials. Nevertheless, the study provides a rigorous mechanistic foundation for the idea that nerve growth factor can protect the optic nerve in glaucoma, and it identifies oxidative stress and neuroinflammation as tractable, druggable targets. If the neuroprotective efficacy observed in mice can be reproduced in patients, rhNGF could become one of the first treatments in ophthalmology to preserve vision not by lowering pressure, but by directly defending the neurons that make sight possible.

Subject of Research: Neuroprotective efficacy of recombinant human nerve growth factor in a mouse model of glaucoma

Article Title: rhNGF shows neuroprotective efficacy by counteracting oxidative stress and neuroinflammation in a glaucoma mouse model

Article References: Vecchiotti, D., Di Vito Nolfi, M., Compagnoni, C., Miscione, M. S., Verzella, D., D’Andrea, D., Flati, I., Galli, F., d’Angelo, M., Angelucci, A., Cattani, F., Cimini, A., Tessitore, A., Capece, D., Alesse, E., Allegretti, M., & Zazzeroni, F. (2026). rhNGF shows neuroprotective efficacy by counteracting oxidative stress and neuroinflammation in a glaucoma mouse model. Cell Death Discovery. https://doi.org/10.1038/s41420-026-03345-y

Image Credits: AI Generated

DOI: 10.1038/s41420-026-03345-y

Keywords: glaucoma, rhNGF, nerve growth factor, neuroprotection, oxidative stress, neuroinflammation, retinal ganglion cells, intraocular pressure, microglia, optic nerve, TrkA receptor, Cell Death Discovery