Predicting visual outcomes in acute optic neuritis: insights from clinical trial data in an era of diagnostic heterogeneity

Introduction

Optic neuritis (ON) is an inflammatory optic neuropathy with diverse etiologies. Multiple sclerosis (MS) remains the most common cause in many populations, with other atypical causes such as neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) gaining recognition over the past two decades (1). Aquaporin-4 (AQP4) antibodies were discovered in 2004 with international diagnostic criteria for NMOSD published in 2015 (2). More recently, MOGAD gained increasing recognition around 2015 with international diagnostic criteria published in 2023 (3). Atypical causes of ON can present with more severe vision loss at onset, greater optic disc edema, and bilateral simultaneous or sequential involvement (1). Additionally, visual outcomes can be poorer, especially if not recognized and treated early and appropriately. The acute treatment of ON typically involves high-dose corticosteroids, which can be administered intravenously or with a bioequivalent oral dose for 3–5 days. In atypical causes of ON such as MOGAD or NMOSD, this is followed by a steroid taper (1). For ON with severe vision loss, especially in cases which are not steroid responsive, plasma exchange (PLEX) should be considered, though optimal timing of integration into the treatment plan remains unclear (1). Therefore, prospective studies evaluating predictive risk factors for visual outcome after ON are important.

Editorial

In a study by Küchlin et al., predictors of visual outcomes 6 months following ON were assessed using pooled data from the TONE (Treatment of Optic Neuritis with Erythropoietin) study, which spanned from 2014–2017 (4,5). The patient cohort included 103 patients who presented within 10 days onset of unilateral ON without known MS and excluded patients with positive AQP4 antibodies. Patients had a Snellen visual acuity of less than or equal to 20/40. They were treated with a 3-day course of 1 gram intravenous methylprednisolone and were randomized to receive either placebo or erythropoietin. As erythropoietin had no effect on the visual system, pooled treatment-agnostic data from all 103 participants were used for all analyses (4). Several possible predictors including sex, time to steroid treatment, baseline optical coherence tomography (OCT) peripapillary retinal nerve fiber layer (RNFL) thickness, optic disc edema (diagnosed based on OCT), and baseline visual function were considered. Markers of visual function consisted of high and low contrast acuity, contrast sensitivity, visual field mean deviation, and visual evoked potential (VEP) P100. The authors found that male sex, older age (greater than or equal to 40 years), and worse baseline visual function were associated with poorer outcomes at 6 months (4).

Of these factors, baseline visual acuity has the strongest prior validation, established in the original Optic Neuritis Treatment Trial (ONTT) and replicated in modern ON cohorts (6-11). The ONTT also found older age to be statistically associated with slightly worse outcomes, a finding replicated in studies of antibody-mediated ON (7,11). The sex finding has prior structural support from Costello et al., who showed significantly greater RNFL thinning in men than women at 6 months after acute ON (12). Additionally, a large Chinese cohort study of antibody-mediated ON found male sex to be independently associated with higher prevalence of severe vision loss (11). However, the relationship between sex and outcomes may be subtype-specific, as female sex predicted poor recovery specifically in MOGAD-associated ON in one multicenter analysis, underscoring the importance of complete diagnostic workup (8).

An important consideration when interpreting the results of the TONE study is recognizing the patient demographics and heterogeneity of the study population. Notably, all 103 patients were recruited from 12 German academic tertiary centers, which likely see a different ON case mix, racial and ethnic distribution, and referral pattern than community practices or centers in North America or Asia (5). This limits the generalizability of the predictor findings. Importantly, patients with AQP4 positive NMOSD were explicitly excluded from the TONE study by design, and therefore the predictor findings reported here do not apply to this population, which carries a substantially worse visual prognosis than other forms of ON (1).

Although the study attempted to enroll patients with isolated, acute, typical ON, it is possible that some patients in the cohort had alternative diagnoses such as seronegative NMOSD or MOGAD. The International Panel for NMOSD Diagnosis criteria published in 2015 established a more standardized framework to diagnose seronegative NMOSD patients (2). Of note, these guidelines were published around the same time of recruitment of the TONE study population. Perhaps even more importantly, the cohort almost certainly included unrecognized MOGAD cases, as MOG antibody testing was not required for exclusion and formal diagnostic criteria did not exist until 2023 (3). The authors acknowledge that MOGAD is a consideration but noted that these patients generally have swollen optic discs and ultimately have good visual recovery (4). In a recent study which used OCT, approximately 73% of patients with MOGAD have optic disc edema at onset, but the recovery of these patients can be variable (13). Additionally, rebound inflammation can occur after treatment with a short steroid course (as was done in this study), with a steroid taper suggested instead (1). If patients with MOGAD were inadvertently included in the study cohort, this has the potential to skew data regarding outcomes post steroids in the absence of a taper. Furthermore, such cases would be overrepresented among patients with disc edema and worse baseline visual function, potentially confounding both of these predictor findings. Moreover, unlike MS and NMOSD where women are preferentially affected, MOGAD shows no strong sex bias, which could confound the sex-based predictor finding (14).

Other than atypical ON, non-arteritic anterior ischemic optic neuropathy (NAION) is another optic neuropathy that is relatively common and can be misdiagnosed as ON. The authors felt there was one patient whose clinical trajectory was suggestive of NAION, which was described as disc edema at onset with severe vision loss and without subsequent recovery (4). However, an MRI confirmed optic nerve enhancement, which raises the question of whether this may have in fact been MOGAD or some other atypical form of ON. NAION exists on a clinical spectrum and can present with mild vision loss, making differentiation from ON challenging in some cases. Appropriate diagnosis relies on a thorough history and complete eye exam, including assessment of a contralateral disc at risk, with further confirmation using MRI in challenging cases.

The use of OCT in this study can also be more closely examined. The reliance on OCT alone to ascertain disc edema, without clinical correlation or fundus photography, introduces meaningful diagnostic uncertainty. For instance, a physiologically thick RNFL in a patient may be misclassified as disc edema on OCT. Conversely, a small or myopic disc can have true optic disc edema yet an RNFL thickness within normal limits compared to age-matched emmetropes due to having a physiologically thin RNFL at baseline (15). As the authors suggest, future correlation with clinical examination or fundus photography would be beneficial. Additionally, the authors acknowledge that a limitation involved including patients with a baseline abnormal RNFL and ganglion cell layer (GCL) thickness (4). This may have been indicative of unrelated pathology, artifact, physiologic thinning, or possible prior subclinical or undiagnosed ON. Depending on the degree of RNFL or GCL thinning, it is also possible to get a floor effect, whereby no further thinning is possible, hence limiting OCT ability to help detect further ON related RNFL or GCL thinning (15). As well, with a multi-center study, inter-device variability including lack of consistency in OCT protocols and acquisition methods should be considered. However, this would be less relevant for internal visit-to-visit data comparison for a single patient at a given center over time.

A patient’s OCT GCL post ON can be relatively thin, with the patient still having a normal high contrast visual acuity and overall relatively well-preserved visual function (12,16). Thus, composite scores accounting for overall trends in multiple measures of visual function are most helpful in understanding visual outcomes. A related consideration not addressed in this paper is vision-related quality of life. Even when high-contrast visual acuity recovers to near-normal levels following ON, patients frequently report persistent subjective dysfunction including impaired contrast sensitivity, color desaturation, glare, and visual fatigue, which are poorly captured by standard acuity testing alone. Incorporating patient-reported outcome measures such as the NEI-VFQ-25, which was collected in the TONE study, into future predictor analyses would provide a more complete and patient-centered picture of visual recovery (17).

With respect to the VEP findings, the authors appropriately address their paradoxical finding that earlier steroid treatment predicted worse conduction delay at 6 months (4). Firstly, performing and interpreting VEP requires significant training, and it can be difficult to standardize especially across multiple institutions. Additionally, as suggested by the authors, patients with more severe vision loss may have presented earlier (4). Related to this, those who may have alternate diagnoses and atypical causes of ON or other conditions such as NAION may have fallen into this category. The study acknowledges that earlier time to treatment with steroids is associated with improved outcomes in MOGAD and NMOSD related ON. Overall, visual outcomes in AQP4 positive NMOSD are much poorer compared to MOGAD and MS related ON, regardless of timing of steroid initiation (1). From a practical standpoint, the clinical significance of an isolated VEP conduction delay at 6 months is unclear, especially given that this association was not seen with respect to VEP amplitude. While conduction delay may be helpful in supporting the diagnosis of demyelination (in the correct clinical context), its relevance with respect to predicting ultimate visual outcome is unclear. Overall, this emphasizes the importance of considering multiple markers of visual function together when trying to understand a more holistic picture of a patient’s visual outcome.

Overall, in an era of increasing recognition of diagnostic heterogeneity in ON, recognizing atypical features and predictors of poor outcome (within typical and atypical cases) is of great importance. Further understanding these predictors may inform when to escalate treatments for ON. In cases of ON with atypical features, it would be prudent to consider empiric steroid taper post pulse, even before a formal etiology is established, with escalation of therapy considered if there is limited steroid response. Treatments such as PLEX for severe inflammatory ON are thought to have a role based on retrospective studies, though timing of introducing this into care remains unclear, with randomized clinical trials underway (18). Combining our knowledge of markers of worse outcomes with expanding understanding of new treatments will allow for improved delivery of timely and appropriate treatment to patients who would otherwise be left with significant permanent visual impairment.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Eye Science. The article has undergone external peer review.

Peer Review File: Available at https://aes.amegroups.com/article/view/10.21037/aes-2026-0027/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://aes.amegroups.com/article/view/10.21037/aes-2026-0027/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Bennett JL, Costello F, Chen JJ, et al. Optic neuritis and autoimmune optic neuropathies: advances in diagnosis and treatment. Lancet Neurol 2023;22:89-100. [Crossref] [PubMed]
2. Wingerchuk DM, Banwell B, Bennett JL, et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology 2015;85:177-89. [Crossref] [PubMed]
3. Banwell B, Bennett JL, Marignier R, et al. Diagnosis of myelin oligodendrocyte glycoprotein antibody-associated disease: International MOGAD Panel proposed criteria. Lancet Neurol 2023;22:268-82. [Crossref] [PubMed]
4. Küchlin S, Ihorst G, Heinrich SP, et al. Clinical Predictors in Acute Optic Neuritis: Analysis Based on Clinical Trial Data. Ophthalmology 2025;132:631-43. [Crossref] [PubMed]
5. Lagrèze WA, Küchlin S, Ihorst G, et al. Safety and efficacy of erythropoietin for the treatment of patients with optic neuritis (TONE): a randomised, double-blind, multicentre, placebo-controlled study. Lancet Neurol 2021;20:991-1000. [Crossref] [PubMed]
6. The clinical profile of optic neuritis. Experience of the Optic Neuritis Treatment Trial. Optic Neuritis Study Group. Arch Ophthalmol 1991;109:1673-8. [Crossref] [PubMed]
7. Beck RW, Cleary PA, Backlund JC. The course of visual recovery after optic neuritis. Experience of the Optic Neuritis Treatment Trial. Ophthalmology 1994;101:1771-8. [Crossref] [PubMed]
8. Min YG, Moon Y, Kwon YN, et al. Prognostic factors of first-onset optic neuritis based on diagnostic criteria and antibody status: a multicentre analysis of 427 eyes. J Neurol Neurosurg Psychiatry 2024;95:753-60. [Crossref] [PubMed]
9. De Lott LB, Burke JF, Andrews CA, et al. Association of Individual-Level Factors With Visual Outcomes in Optic Neuritis: Secondary Analysis of a Randomized Clinical Trial. JAMA Netw Open 2020;3:e204339. [Crossref] [PubMed]
10. Jarocki A, Benard-Seguin E, Gonzalez LA, et al. Predictors of Long-Term Visual Acuity in a Modern Cohort of Patients With Acute Idiopathic and Multiple Sclerosis-Associated Optic Neuritis. J Neuroophthalmol 2023;43:475-80. [Crossref] [PubMed]
11. Yang M, Wu Y, Song H, et al. Vision Prognosis and Associated Factors of Optic Neuritis in Dependence of Glial Autoimmune Antibodies. Am J Ophthalmol 2022;239:11-25. [Crossref] [PubMed]
12. Costello F, Hodge W, Pan YI, et al. Sex-specific differences in retinal nerve fiber layer thinning after acute optic neuritis. Neurology 2012;79:1866-72. [Crossref] [PubMed]
13. Pakeerathan T, Davis J, Henderson AD, et al. OCT-Based Differentiation of First Acute Optic Neuritis: An International Study of 111 Patients With NMOSD and MOGAD. Neurol Neuroimmunol Neuroinflamm 2026;13:e200531. [Crossref] [PubMed]
14. Voase S, Waters P, Jolles S, et al. MOGAD in South Wales: Diagnostic Evolution and Disease Epidemiology. Eur J Neurol 2026;33:e70502. [Crossref] [PubMed]
15. Chen JJ, Kardon RH. Avoiding Clinical Misinterpretation and Artifacts of Optical Coherence Tomography Analysis of the Optic Nerve, Retinal Nerve Fiber Layer, and Ganglion Cell Layer. J Neuroophthalmol 2016;36:417-38. [Crossref] [PubMed]
16. Fisher JB, Jacobs DA, Markowitz CE, et al. Relation of visual function to retinal nerve fiber layer thickness in multiple sclerosis. Ophthalmology 2006;113:324-32. [Crossref] [PubMed]
17. Mangione CM, Lee PP, Gutierrez PR, et al. Development of the 25-item National Eye Institute Visual Function Questionnaire. Arch Ophthalmol 2001;119:1050-8. [Crossref] [PubMed]
18. Chen JJ, Sotirchos ES, Flanagan EP, et al. Treatment of inflammatory myelitis and optic neuritis with early vs rescue plasma exchange (TIMELY-PLEX). ClinicalTrials.gov. Identifier: NCT07100990. 2025. Available online: https://clinicaltrials.gov/study/NCT07100990.