What TONE trial reveals: a prognostic framework for optic neuritis

Identifying predictive factors in optic neuritis (ON) at presentation is essential for anticipating both visual and structural recovery. Such information guides individualized early interventions, ranging from corticosteroids within the first 48 hours to timely initiation of plasma exchange. Despite therapeutic advances established more than three decades ago by the Optic Neuritis Treatment Trial (1), prognostication in ON has long relied primarily on baseline visual function.

In contrast, the contemporary study by Küchlin et al. (2) represents a paradigm shift by integrating functional testing with structural optical coherence tomography (OCT) metrics and visual evoked potentials (VEP). This multidimensional approach allows the identification of prognostic factors that were previously inaccessible, including the independent impact of sex and age on both functional and structural outcomes. Moreover, rather than focusing solely on treatment effects on recovery speed, their work provides a framework for early risk stratification aimed at supporting time-critical, mechanism-based therapeutic decisions.

The Treatment of Optic Neuritis with Erythropoietin (TONE) study was a multicenter, randomized, double-blind, placebo-controlled phase 3 trial evaluating intravenous erythropoietin as an adjunct to high-dose methylprednisolone in patients with acute unilateral ON. A total of 108 patients without prior multiple sclerosis (MS) were followed for six months. The co-primary outcomes were peripapillary retinal nerve fiber layer atrophy measured by OCT and low-contrast letter acuity (LCLA). The study found no significant differences between the erythropoietin and placebo groups in either structural or functional visual outcomes, including visual acuity, visual fields, contrast sensitivity, visually evoked potentials, or macular retinal layer thickness. Although erythropoietin was generally well tolerated, one thrombotic event occurred. Overall, the TONE trial provides class I evidence that erythropoietin does not confer neuroprotection in acute ON.

Using data from the TONE randomized, double-blind trial cohort, Küchlin et al. (2) investigated clinical predictors of visual and structural outcomes after acute ON. In this context, their analysis represents an important advance, as it integrates standardized measures of visual function, including high-contrast visual acuity (HCVA) [Early Treatment Diabetic Retinopathy Study (ETDRS)] and 2.5% Sloan LCLA, with neurophysiological assessment using P100 VEP latencies and detailed retinal structural evaluation by OCT of the macular ganglion cell-inner plexiform layer (mGCIPL) and peripapillary retinal nerve fiber layer (pRNFL). All parameters were collected with systematic 6-month follow-up, together with additional clinically relevant variables such as visual field mean deviation (MD), enabling a comprehensive multimodal characterization of visual pathway damage and recovery. While these findings provide important advances, several aspects of the study remain controversial and warrant focused discussion.

The analysis included patients with a first unilateral episode of ON, presenting within 10 days of symptom onset and with an HCVA of ≤20/40 in the affected eye at baseline. Although the TONE cohort consisted mainly of isolated ON or probable MS-related ON, systematic screening for myelin oligodendrocyte glycoprotein immunoglobulin (MOG-IgG) antibodies was not performed, meaning that a small number of MOGAD-ON cases may have been included. This is relevant because MOG-ON often presents with prominent optic disc edema yet typically shows excellent visual recovery, potentially attenuating observed associations. Because the trial did not show any drug efficacy, treated and placebo arms were pooled for this analysis.

The TONE analysis identified several independent predictors of 6-month visual and structural recovery. Older age, male sex, and worse baseline visual function were consistently associated with poorer outcomes in both HCVA and LCLA, as well as with reduced retinal thickness in pRNFL and mGCIPL. In addition, significant peripapillary edema (pRNFL swelling >20%) was associated with lesser HCVA recovery.

The study by Küchlin et al. (2) adds value by demonstrating the relationship between HCVA and OCT-derived structural outcomes and, importantly, by detailing how demographic factors influence this predictive relationship. Few prior studies have explored these interactions. Costello et al. (3) found male sex to be independently associated with greater RNFL loss, while Deschamps et al. (4) did not identify independent predictors of visual or retinal outcomes. Both Küchlin et al. (2) and Villoslada et al. (5) emphasize the role of the ganglion cell layer as a predictor of visual function; however, Villoslada et al. focused on early GCIPL thinning as a predictor, whereas Küchlin et al. (2) treated GCIPL as an outcome measure, identifying baseline HCVA and sex as its principal predictors.

A first methodological point of controversy concerns the use of baseline LCLA. Despite its known sensitivity to optic nerve damage, a pronounced floor effect occurred at baseline, as most patients were unable to read any low-contrast letters at presentation, necessitating dichotomization of this variable. Nevertheless, baseline LCLA retained independent predictive value for pRNFL and mGCIPL thinning at six months, suggesting that even minimal residual performance at presentation may reflect underlying risk of optic nerve atrophy.

Another debated aspect is the relationship between visual field function and structural damage after ON. Previous analyses from the ONTT and more recent OCT-based cohorts, such as Szanto et al. (6), demonstrated that MD correlates with pRNFL and GCIPL thinning. Küchlin et al. (2) confirm this association and further show, through multivariable analysis, that baseline MD predicts 6-month structural damage with accuracy comparable to HCVA, supporting its potential role as a global prognostic functional marker.

Age represents another important prognostic variable. Küchlin et al. (2) contextualize worse recovery in older patients within a biologically plausible framework, as remyelination capacity declines with aging. Experimental and clinical studies have shown that aging oligodendrocyte progenitor cells and a less supportive inflammatory microenvironment reduce remyelination efficiency, translating into poorer functional recovery after demyelinating injury (7,8).

The association between male sex and poorer outcomes constitutes another point of controversy. Prospective studies have shown greater pRNFL thinning in men (3), and cohort analyses indicate worse functional recovery in multivariable models (9). Normative VEP studies also demonstrate sex-related differences in latency and amplitude (10). Given that LCLA correlates closely with pRNFL and mGCIPL thinning and is more sensitive than HCVA for detecting residual deficits, the pattern observed by Küchlin et al. (2)—worse LCLA, RNFL, and VEP outcomes in men, but less pronounced differences in HCVA—aligns with prior literature and suggests that high-contrast vision may recover relatively well while structural and contrast-sensitive deficits persist, particularly in men (11,12).

The prognostic role of optic disc edema in ON has historically been controversial. Some clinical series, including bilateral ON cohorts (13), have associated disc swelling with faster short-term visual improvement, whereas physiological studies have linked more pronounced edema with reduced peripapillary perfusion and worse acute vision (14). Heterogeneity among ON subtypes, particularly the inclusion of MOG-associated disease, likely contributes to these discrepancies. As systematic MOG-IgG testing was not performed in the Küchlin et al.'s cohort (2), this confounder cannot be fully excluded.

The most controversial finding from Küchlin et al. (2) is the association between earlier corticosteroid initiation and greater VEP conduction delay at six months. This association was significant only in univariate analysis and not in multivariate models, suggesting the presence of confounding factors. Although causal human data are lacking, the observation is biologically plausible, as experimental models have shown that corticosteroids may delay remyelination through effects on oligodendrocytes and their microenvironment (15,16). In the absence of prospective human evidence, this finding should be interpreted cautiously and regarded as hypothesis-generating.

Several methodological limitations further support a cautious interpretation. The relatively small sample size compared with historical reference cohorts such as the ONTT limits statistical power for subgroup and interaction analyses. The secondary nature of the analysis and pooling of treatment arms introduce additional sources of residual confounding. Incomplete antibody characterization may also have influenced recovery patterns.

The study by Küchlin et al. (2) brings new clarity to prognostication in ON by integrating functional, structural, and neurophysiological measures using a quantitative approach rarely applied in prior literature. Their findings reopen classical debates such as the role of optic disc edema and the influence of sex and age and show that, when evaluated with OCT and adjusted models, some historically inconsistent variables emerge as robust predictors. The most provocative result arises from the neurophysiological analysis, where the association between early steroid treatment and delayed conduction suggests new hypotheses on mechanisms of repair plausible from experimental biology but not yet confirmed in humans. Future prospective studies are therefore required to validate these findings, to clarify the optimal timing of immunomodulatory therapies, and to determine whether high-risk phenotypes may benefit from alternative strategies such as early plasma exchange.

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-2025-1-72/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-2025-1-72/coif). P.V. received grants from the European Commission (101136991); Instituto de Salud Carlos III (ICI24/00028, PI24_00136, RD24/0007/0039); La Caixa Foundation (CI24-20305); Focused Ultrasound Foundation and ALS Foundation (FUSF-RAPS-23-00096); Start2cure Foundation. P.V. also holds patents for “Use of 5’-methylthioadenosine in the prevention and/or treatment of autoimmune diseases and/or transplant rejection” (PCT/ES2005/000139); “Methods for the diagnosis and prognosis of demyelinating diseases and for development of new therapies for demyelinating diseases” (PCT/ES2005/01248); “Genetic markers for predicting the clinical course of Multiple sclerosis” (PCT/P200703415); “Prevention of auto immune diseases and transplant rejection comprises application of 5'-methylthioadenosine and its salts” (ES2259552A1); “Synergic activity of methyltioadenosine and Glatiramer acetate for the treatment of Multiple Sclerosis” (PCT/ES200800806); “Neuroprotective properties of 5'- methylthioadenosine” (PCT/ES200930298; US20120083464A1); “New 3-oxopiperazinium derivatives agonists of nerve growth factor and their use as medicaments” (PCT WO2011/024078A1); “New peptoids agonists of nerve growth factor and their use as medicaments” (PCT WO 2011/024079A1); “Agonists of Nerve Growth Factor Receptor and Their Use as Medicament” (PCT WO2012/028959); “Combination therapy methods, compositions and kits” (WO2021001464A1); “New treatment regimen for the treatment of neurological diseases or conditions” (EP19382950.4); “Systems and methods for improved tractography images” (US20180098700A1); “Kv7 Modulators for Treating Sleep or Anxiety Disorders” (US63011198); “Devices and Associated Systems and Methods for Modulating Brain Activity using Ultrasound Stimulation” (US63030850); “Head-wearable devices for positioning ultrasound transducers for brain stimulation” (US20230166129A1); “Ultrasound Systems and Associated Devices and Methods for Modulating Brain Activity” (US20210370064A1); “Methods for treating or preventing insulin resistance associated disorders” (EP24170667.0); “Adjustable stretcher and system for spinal treatment and method for optimally configuring said system” (WO2025219450); “OCS-05 treating optic neuropathies” (PCT/EP2026/050017); “Treatment of relapsing forms of Multiple Sclerosis” (EP25170494). P.V. received royalties from Oculis SA and Consulting fees from Oculis SA and Telara SL. P.V. received support for attending meetings from Roche and holds stock of Bionure Therapeutics SL, Spiral Therapeutics Inc., Attune Neurosciences Inc., QMENTA SL, Adhera Health Inc and Clarity technologies SL. The other author has no conflicts of interest to declare.

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