The optic nerve has become the fifth anatomical location in the 2024 revisions of the McDonald criteria for multiple sclerosis (MS). Its involvement can be demonstrated through both structural tools – magnetic resonance imaging (MRI) and optical coherence tomography (OCT) – and functional measures such as visual evoked potentials (VEPs), provided that no alternative aetiological explanation is identified [1].
Why is the optic nerve of particular interest? We asked Professor Shiv Saidha from Johns Hopkins University and Professor Jeffrey Cohen from the Cleveland Clinic’s Mellen Center for MS Treatment and Research.
Professor Saidha tells us, “Acute inflammation of the optic nerve, known as acute optic neuritis, is the initial manifestation of MS in about 25% of people. Data suggest that up to 50 to 70% of people with MS will experience an episode of acute optic neuritis at some point during their disease course [2]. This indicates that clinical involvement of the optic nerve is very common. Even more interestingly, post-mortem studies show that – regardless of whether a person has a clinical history of optic neuritis – most individuals with MS exhibit demyelinating plaques within their optic nerves [3]. In other words, the optic nerve is almost virtually universally affected in MS, making it an ideal model for studying disease mechanisms and a valuable anatomical site for demonstrating dissemination in space.”
In MS inflammation, demyelination, and neurodegeneration all contribute to damage in the visual system [4].
Professor Cohen explains, “The visual system is frequently affected in MS. Both the afferent and efferent visual pathways are involved in the disease process. The afferent pathways transmit sensory information from the eyes to the brain, whereas the efferent pathways control eye movements. Vision plays a crucial role in daily functioning, and its impairment can have a profound impact on an individual’s ability to work and overall quality of life.”
The 25-Item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) and a 10-Item Neuro-Ophthalmic Supplement comprehensively assess the key visual symptoms associated with MS. Commonly reported deficits include reduced visual acuity and contrast sensitivity, binocular vision disturbances and visual field defects, as well as impaired color discrimination, blurred vision, and diplopia – also known as double vision [4].
Imaging the Visual System
During ECTRIMS 2025, Dr. Angela Vidal-Jordana from CEMCAT outlined several key reasons to assess the optic nerve in the diagnostic evaluation of MS. Optic nerve assessment is crucial to rule out alternative diagnoses, particularly ophthalmic conditions; to identify retinal damage resulting from optic nerve lesions, thereby supporting the establishment of an MS diagnosis; and to inform the differential diagnosis of optic neuritis (session available at https://ectrims-congress.virtual-meeting.org/programme/session/67945.)
How do we assess the optic nerve? “Almost everybody is familiar with magnetic resonance imaging (MRI).” Professor Saidha tells us, “There is perhaps less familiarity with OCT. OCT is a highly reproducible, high-resolution, and well-tolerated imaging technique. It is quick, inexpensive, and easy to repeat. With a resolution of approximately 3–5 microns, it provides an almost virtual biopsy of the retina. It is about a thousand times the resolution of a conventional MRI scan. It is a very reliable method when scan quality is ensured. And there are international consensus criteria on how to assess the quality of OCT scans, known as the Oscar-IB criteria, which evaluate Obvious errors, Signal strength, Centration of scan, Algorithm failure, Retinal pathology, Illumination, and Beam placement [5]. The OSCAR-IB quality control criteria help identify suboptimal OCT scans that could otherwise very likely lead to erroneous identification of optic nerve involvement [6].”
Ensuring rigorous quality control is essential when employing OCT and VEPs for the assessment of optic nerve involvement [7].
Professor Saidha continues, “It is essential that results from MRI, OCT and VEPs are always interpreted within the clinical context. No alternative better explanation should account for the abnormalities observed on these paraclinical tests. Numerous inflammatory and non-inflammatory conditions other than MS can affect the optic nerve. Various retinal disorders, such as macular degeneration, may interfere with measurements. Therefore, findings must be carefully contextualised. The paraclinical tools, proposed to demonstrate optic nerve involvement and support dissemination in space, should only be applied in centres that adhere to established quality-control criteria.”
Optic Nerve and Myelin Regeneration
Building upon the pivotal role of the optic nerve in assessing demyelination and neurodegeneration, recent research has also positioned it as a valuable model for studying myelin repair. Many clinical trials of myelin regeneration have focused on individuals with optic neuritis. The optic nerve represents an attractive target for evaluating myelin repair, as VEP latency provides a functional measure of remyelination – shorter latency suggesting restored conduction – and OCT enables quantitative assessment of retinal neuronal loss [8].
Professor Jeffrey Cohen tells us, “The anterior visual system has been the most used model for testing repair-promoting strategies, including both remyelination and neuroprotection approaches. This is an area of great activity, and I believe we will see an increasing number of studies focusing on the optic nerve.”
References
[1] Montalban X et al. Lancet Neurol. 2025; 24.10: 850-865.
[2] Balcer LJ. N. Engl. J. Med. 2006; 354: 1273-80.
[3] Ikuta F, Zimmerman HM. Neurology 1976; 26-28.
[4] Balcer LJ et al. Brain 2015; 138.1: 11-27.
[5] Tewarie P et al. PloS one 2012; 7.4: e34823.
[6] Bacchetti A et al. NNN 2025; 12.6: e200458.
[7] Saidha S et al. Lancet Neurol. 2025; 24.10: 880-892.
[8] Lubetzki C et al. Lancet Neurol. 2020; 19.8: 678-688.
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Written by Stefania de Vito
Special thanks to Professor Shiv Saidha (Johns Hopkins University) and Professor Jeffrey Cohen (Cleveland Clinic’s Mellen Center for Multiple Sclerosis Treatment and Research) for their insights.