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Temporal evolution and factors influencing visual function and RNFL thickness in ethambutol-associated optic neuropathy

European Journal of Medical Research volume 30, Article number: 321 (2025) Cite this article

Abstract

Purpose

This study aimed to investigate the temporal evolution and influencing factors of visual function and optic nerve structure in ethambutol-associated optic neuropathy (EON).

Methods

In this single-center retrospective observational study, we analyzed data from 48 EON patients (26 males and 22 females) with a 12-month follow-up. Comprehensive ophthalmologic assessments, including best corrected visual acuity (BCVA), visual field (VF), optical coherence tomography (OCT), and magnetic resonance imaging (MRI), were conducted to evaluate visual function and optic nerve structure. Statistical analyses including multiple linear regression and comparative analyses (independent t-tests/Mann–Whitney U tests) were performed to identify factors influencing recovery, with effect sizes calculated using Cohen’s d.

Results

Significant improvements in best corrected visual acuity and visual field were observed between 3 and 6 months. The mean improvement in BCVA was 0.25 logMAR (from 1.28 ± 0.64 at 3 months to 0.82 ± 0.60 at 6 months, p < 0.0001, Cohen’s d = 0.74, 95% CI [0.33, 1.15]), and the mean improvement in VF mean deviation was 2.5 dB (from − 13.85 ± 9.23 dB at 3 months to − 10.33 ± 7.58 dB at 6 months, p = 0.037, Cohen’s d = 0.42, 95% CI [0.11, 6.93]), indicating a critical recovery window. Peripapillary retinal nerve fiber layer (pRNFL) thinning was most pronounced between 3 and 9 months, with the temporal quadrant showing the earliest thinning (40.21% reduction by 3 months). Macular ganglion cell-inner plexiform layer (mGCIPL) thickness showed a decreasing trend (73.20 ± 4.76 μm to 55.33 ± 4.16 μm) from 1 month post-onset. Multivariate analysis revealed that disease course was the primary factor influencing VF recovery (β = − 0.31, p = 0.001), while peripapillary retinal nerve fiber layer thinning was associated with gender, ethambutol dosage, and disease duration. Female patients exhibited slower peripapillary retinal nerve fiber layer thinning compared to males.

Conclusions

This study identifies a critical recovery window for visual function in EON between 3 and 6 months, with peripapillary retinal nerve fiber layer thinning progressing significantly between 3 and 9 months. The temporal quadrant of the peripapillary retinal nerve fiber layer may serve as an early marker for disease progression. These findings provide valuable insights for optimizing monitoring and intervention strategies in EON patients, highlighting that early therapeutic interventions—particularly for patients showing temporal RNFL thinning or high-risk features—may maximize visual recovery potential.

Background

Ethambutol-induced optic neuropathy (EON) is a type of optic nerve damage caused by the use of ethambutol (EMB) [1, 2]; a medication commonly used to treat tuberculosis [1]. EON can cause vision loss, color vision changes, and other visual disturbances [3]. The prevalence of EON is 1%–2% among patients using EMB [1]. It is a rare but serious adverse effect of EMB therapy and requires immediate medical attention [4]. The risk factors for EON included high doses of ethambutol, long-term use of ethambutol, renal or liver impairment, older age, pre-existing optic nerve disease or gene abnormal (e.g., Optic Atrophy 1, Leber hereditary optic neuropathy), alcoholism, nutritional deficiencies (vitamin B6 deficiency) and combined use of other neurotoxic drugs [5, 6].

Previous studies about the clinical characteristics of EON were mostly cross-sectional studies [3, 5, 7, 8]. And the assessments of visual function and optic nerve damage were relatively crude [9,10,11,12,13], with visual acuity (VA) and visual evoked potential (VEP) as the only visual function indicators. Recently, with the emergence of high-resolution ophthalmic examination methods such as visual field (VF), macular microperimetry, and optical coherence tomography (OCT), the assessment of optic nerve damage can now be more precise. However, there are few longitudinal cohort studies on EON using these advanced indicators on optic nerve damage of EON.

The goal of this study is to explore the temporal evolution and the factors that influence visual function and peripapillary retinal nerve fiber layer (pRNFL) thickness in EON. By retrospectively analyzing detailed clinical data, including visual acuity, visual field, peripapillary retinal nerve fiber layer, ganglion cell layer (GCL), visual evoked potential, and magnetic resonance imaging (MRI), from 48 EON patients with 12-month follow-up, our aim is to investigate factors that influence EON prognosis, recovery pattern, and pinpoint the time window for recovery, as well as provide relevant reference data to future assessment for EON treatment.

Method

In this single-center, retrospective observational study, data were collected from electronic medical records, the principles of the Declaration of Helsinki, the International Conference on Harmonization, and the Good Clinical Practice Guidelines were followed. The diagnosis criteria for EON were based on previous guidelines [14, 15]. Firstly, vision loss happened only after taking EMB or within 2 months of EMB withdrawal. Secondly, there was evidence of optic nerve damage including: (1) abnormal color vision; (2) central, paracentric scotoma or temporal hemianopia; and (3) optic disc hyperemia or pallor on color fundus photography. Patients were excluded if they had other macular or retinal diseases, cataracts, or any other optic neuropathies, such as glaucoma. Inclusion criteria were patients diagnosed with EON between 2011 and 2021 at Zhongshan Ophthalmic Center with complete follow-up data for at least 6 months, while exclusion criteria included patients with other macular or retinal diseases, cataracts, or any other optic neuropathies, such as glaucoma; this study did not include a control group, as the focus was on the natural recovery patterns in EON patients. This study adhered to the tenets of the Declaration of Helsinki and was approved by the Clinical Research Ethics Board at the Zhongshan Ophthalmic Center of Sun Yat-sen University (2014 meky049) and registered on ClinicalTrial.gov (NCT02886377). Informed consent was obtained from all patients included in the study.

48 EON patients (26 males and 22 females) diagnosed with EON between 2011 and 2021 in Zhongshan Ophthalmic Center were included. Patients were discontinued from EMB treatment immediately and given neuro-nutritional support therapy.

Basic clinical material includes gender, age, duration, dosage, and course of ethambutol treatment, as well as overall health status. Examination data results including logMAR_BCVA, optical coherence tomography, visual field, visual evoked potential, microperimetry, as well as other ophthalmic data: e.g., slit lamp, fundus examination, in the 12 m follow-up were collected. Best corrected visual acuity was presented in the form of logarithm of the minimum angle of resolution visual acuity (logMAR_BCVA). The measurements of peripapillary retinal nerve fiber layer and macular ganglion cell-inner plexiform layer (mGCIPL) values were done by the optical coherence tomography, a SD-OCT machine of Carl Zeiss Meditec, Dublin, CA, USA [16]. The visual field was assessed using the Humphrey Field Analyzer (STATPAC, Allergan Humphrey, San Leandro.CA, USA), and the mean deviation (MD) of the central 30–2 SITA program was used to quantify the visual field detects. The required false-negative and false-positive rates were < 15%, respectively, and that fixation loss was < 30%. The visual field was not assessed when the best corrected visual acuity was < 0.05. Pattern visual evoked potential amplitude and latency data were gained by the machine made in Espion, Diagnosys, America. Threshold data from microperimetry (Macular Integrity Assessment, MAIA, Centervue, Italy) were collected.

The disease course was defined based on the time from symptom onset and categorized into specific intervals for statistical analysis: within 15 days of symptom onset as course “0” (baseline stage), 0.5–1.5 months as course 1 m, 1.5–4.5 months as course 3 m, 4.5–7.5 months as course 6 m, 7.5–10.5 months as course 9 m, and 10.5–13.5 months as course 12 m. Additionally, the disease course was further classified into three clinical phases for temporal analysis: acute phase (0–3 months), subacute phase (3–6 months), and chronic phase (> 6 months). Visual field improvement or deterioration was defined as + 3 dB or − 3 dB change in MD, respectively.

All statistical analyses were performed using SPSS 26.0 (SPSS Inc, Chicago, IL, USA). One eye was randomly selected for analysis in bilateral EON patients. All data were presented as mean ± standard deviation (MEAN ± SD). To compare the differences between data set of adjacent time points, independent t-tests were used for normally distributed continuous variables, Mann–Whitney U tests for non-normally distributed continuous variables, and Fisher’s exact tests were used for expected counts less than 5. Multiple linear regression analysis was conducted to determine independent factors influencing best corrected visual acuity, visual field, and peripapillary retinal nerve fiber layer thickness. Effect sizes for significant differences were calculated using Cohen’s d. p value < 0.05 was considered statistically significant.

Results

Demographic features

48 eyes of 48 patients were collected, including 26 males and 22 females. The mean age was 47.21 ± 16.08 years. The mean treatment course of ethambutol intake was 5.59 ± 3.28 months, the mean daily dose of EMB was 14.35 ± 4.50 mg/(kg*d), and the cumulative dose of EMB was 102,785.7 ± 71,194.9 mg, distributed as shown in Fig. 1. Average time of onset was 5.41 ± 4.58 m (1.3 m–30 m) after first EMB intake, with the earliest visual acuity decreased happened at 1.3 m after EMB intake. The mean EMB withdrawal time was 3.67 ± 1.74 m (0–6 m) after visual symptom. Renal dysfunction was the most common complication (10/48, 20.83%). Among them, 5 of 10 patients with renal dysfunction had a daily dose of less than 15 mg/kg/day. The mean daily dose was 10.72 ± 3.46 mg/kg/d and the mean age was 49.60 ± 4.10 years. No patients had liver dysfunction. Two of the 48 patients had gene abnormalities, one with mtDNA mutation at 11,778 locus and one with nuclear gene OPA1 mutation whose EMB dosage was 14.71 mg/kg/d and 16.67 mg/kg/d, respectively (Table 1).

Fig. 1
figure 1

Distribution of EMB dosage: a daily dosage of EMB, b daily EMB dosage by weight, and c cumulative dosage of EMB (*: p < 0.05, **: p < 0.01)

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Table 1 Demographic and clinical characteristics of 48 patients with EON
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Ophthalmic characteristics

Visual functional features

Best corrected visual acuity

The mean logMAR-VA was 0.86 ± 0.73 at 2 weeks after onset, ranging from 2.5 to 0, significantly higher than that at 3 m (1.28 ± 0.64) (p < 0.001, Cohen’s d = − 0.61, 95% CI [− 0.70, − 0.14], Fig. 2A). At 6 m, visual acuity was 0.82 ± 0.60, significantly higher than that at 3 m (p < 0.0001, Cohen’s d = 0.74, 95% CI [0.33, 1.15]). Visual acuity at 12 m (0.78 ± 0.45) was significantly higher than that at 9 m (0.96 ± 0.43) (p < 0.05, Cohen’s d = − 0.41, 95% CI [− 0.36, 0], Fig. 2A). The final logMAR-VA at 12 m ranged from 1.52 for the lowest, to 0.2 for the highest.

Fig. 2
figure 2

Longitudinal visual function change in EON: A VA increased gradually with significant change between 3 m–6 m and 9 m–12 m; B VF improved gradually significantly from 3 to 6 m; C microperimetry showed gradual improvement without statistically significant change; D PVEP amplitude, E PVEP latency (*: p < 0.05, **: p < 0.01, **: p < 0.001)

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Visual field

The MD of visual field at onset was − 8.92 ± 7.48 dB. The visual field within 3 m deteriorated. However, there was no significant difference in MD at 3 m compared with onset [17]. The MD at 6 m (− 10.33 ± 7.58 dB) recovered significantly compared with 3 m (− 13.85 ± 9.23 dB) (p = 0.037, Cohen’s d = 0.42, 95% CI [0.11, 6.93]), and then remained stable, suggesting a recovery time window between 3 and 6 m (Fig. 2B). Among 18 patients with full course of visual field data, 14 patients (77.78%) had visual field recovery, 1 patient (5.55%) had no significant change, 3 patients (16.67%) had deterioration. Among the three patients with visual field deterioration, 2 of them were complicated with gene mutation (1 with 11,778 mutation, 1 with OPA1 nuclear gene mutation) (Fig. 3).

Fig. 3
figure 3

A VF pattern evolvement: A an EON patient without genetic abnormality showed gradual bilateral VF improvement; B an EON patient with OPA1 gene mutation who showed that VF continued to deteriorate even after EMB withdrawal

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Visual field pattern

In the acute phase (0–3 m), central visual field defects (62.30%) were the most common defect pattern, followed by full-quadrant visual field defects (31.15%) and blind spot enlargement (4.92%). Bilateral horizontal visual field defect (3.28%) and bitemporal visual field defect (3.28%) were also observed. In the chronic phrase (6–12 m), central visual field defect (70.83%) and paracentric scotoma (20.83%) were the most common (Table 2). When considering gender, no differences were found in visual field defect patterns during acute (0–3 m) or chronic (6–12 m) phases.

Table 2 Visual field pattern in EON patients at onset (0–3 m) vs final stable phase (12 m)
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Microperimetry

A trend of recovery was shown in the course of disease (Fig. 2C), increasing gradually from 13.17 ± 12.73 dB to 16.88 ± 6.91 dB, but with no significant difference (p > 0.05).

Pattern visual evoked potential

The variation range of P100 amplitude (Fig. 2D) and latency (Fig. 2E) was wide. Although the pattern visual evoked potential amplitude showed an upward trend, but due to the limited number of patients cases with complete examination results at some time points, there was no significant statistical difference (Fig. 2D, E).

Structural analysis of the optic nerve

The average peripapillary retinal nerve fiber layer thickness observed by the Zeiss optical coherence tomography was 100.80 ± 14.79 μm at 2w and 119.19 ± 26.74 μm at 1 m, suggesting there was mild optic disc edema at the onset. There was no significant peripapillary retinal nerve fiber layer difference between patients with EON and healthy control in the acute phrase, which might be due to the small number of patients who were able to get early OCT examination. The average peripapillary retinal nerve fiber layer thickness showed gradually thinning trend (Fig. 4A) whose decline window was mainly between 3 m (116.29 ± 23.92 μm), 6 m (100.73 ± 27.43 μm) and 9 m (85.75 ± 11.42 μm) (6 m Vs 3 m, p < 0.0001, Cohen’s d = − 0.60, 95% CI [− 25.96, − 5.16]; 9 m Vs 6 m, p = 0.016, Cohen’s d = − 0.71, 95% CI [− 23.47, − 6.49], respectively). There was no significant statistical difference between 12 m (77.25 ± 28.50 μm) and 9 m (85.75 ± 11.42 μm) (p = 0.353, Cohen’s d = − 0.39, 95% CI [− 17.27, 0.27]). The average peripapillary retinal nerve fiber layer thickness was stable at 12 m (77.25 ± 28.50 μm).

Fig. 4
figure 4

A pRNFL showed gradual thinning with significant change between 3–9 m; B GCL showed gradual thinning without statistically significant change (*: p < 0.05, * *: p < 0.01, * * *: p < 0.001)

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Comparison of peripapillary retinal nerve fiber layer thickness in different quadrants: The temporal peripapillary retinal nerve fiber layer (the papillomacular bundle) thickness showed the earliest thinning at 3 m (91.36 ± 22.43 μm) compared to 1 m (92.00 ± 40.01 μm) (p = 0.015, Cohen’s d = − 0.02, 95% CI [− 13.1, 11.82]), and then significantly declined at 6 m (73.80 ± 20.20 μm) compared to 3 m (p = 0.009, Cohen’s d = − 0.82, 95% CI [− 26.1, − 8.99]), after 6 m, it showed stable. The inferior quadrant of peripapillary retinal nerve fiber layer thickness also showed significant thinning later at 6 m (132.90 ± 24.01 μm) compared with 3 m (165.36 ± 34.75 μm) (p = 0.011, Cohen’s d = − 1.09, 95% CI [− 44.04, − 20.88]), while the nasal and superior quadrants did not show any significant difference between adjacent time points, and the trend of change was more moderate (Fig. 5).

Fig. 5
figure 5

Longitudinal quadrant pRNFL thickness change A superior, B temporal, C nasal, D inferior. (*: p < 0.05, * *: p < 0.01, * *: p < 0.001)

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The macular ganglion cell-inner plexiform layer thickness showed gradually thinning trend (Fig. 4B) (from 73.20 ± 4.76 to 55.33 ± 4.16 μm) with no statistical significance which might be due to the small quantity of real-world data (5 patients followed the ganglion cell-inner plexiform layer exam actually). Although this trend did not reach statistical significance in our cohort, the temporal pattern of mGCIPL thinning may potentially correlate with visual function deterioration, warranting further investigation in larger studies. At 1 m, extensive and significant thinning of mGCLIP was found in 4 patients, among them, peripapillary retinal nerve fiber layer was swelling in 2 patients, normal in 1, and another 1 patient had localized macular ganglion cell-inner plexiform layer thinning in the nasal quadrant. The remaining 1 patient had no thinning trend of peripapillary retinal nerve fiber layer or mGCLIPL.

Gender difference analysis of retinal nerve fiber layer and macular ganglion cell-inner plexiform layer: By multivariate regression analysis, the declining trend of retinal nerve fiber layer thickness in female was smaller than that in man (p = 0.007). No significant difference was detected in other indexes between male and female.

Magnetic resonance imaging

16 of 48 patients had brain and optic nerve magnetic resonance imaging exam with contrast enhancement in the acute phase, most of them showed normal magnetic resonance imaging findings. Only 4 patients had abnormal findings, among them, 1 had suspicious mild enhancement of optic chiasm, 1 had bilateral T2 WI signal intensity enhancement, and 2 had local cerebral ischemia (multiple lacunar infarcts and small frontal lobe ischemic foci).

Factors affecting severeness and prognosis

Through multivariate regression and correlation analysis between multi-variables and visual function indexes (such as logMAR_VA, visual field and peripapillary retinal nerve fiber layer) in EON patients were analyzed. No independent factors affecting logMAR_VA were found. The course of disease was the only factor affecting the visual field (p = 0.001), while the average peripapillary retinal nerve fiber layer thickness was related to multiple factors, including gender, average daily dose, average daily dose based on body weight, cumulative dose, duration of EMB intake and disease course. Among all these factors, female was the only one positive factor associated with peripapillary retinal nerve fiber layer, indicating the average peripapillary retinal nerve fiber layer thickness of women was always thicker than in men EON patients (Table 3).

Table 3 Multivariate regression analysis and correlation analysis between EON visual function and RNFL
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Discussion

This study included 48 patients who had detailed follow-up data at multiple time points during a follow-up period of up to 12 months. The follow-up data included visual acuity, visual field, Zeiss optical coherence tomography of the peripapillary retinal nerve fiber layer and the macular ganglion cell inner plexiform layer, magnetic resonance imaging, and microperimetry. To the best of our knowledge, this is the first study on the recovery and its influence factors in visual function and optic nerve structure in EON patients.

Risk factors and dosage considerations in ethambutol

The prevalence of EON ranges from 0.3 to 2% among patients used EMB dose of 15–20 mg/kg/day [15, 18,19,20,21,22]. However, when the dose reached 25 mg/kg/day, the incidence of EON increased to 5%–6%, and it can reach as high as 18% with a dose of 35 mg/kg/day [20, 23, 24]. Therefore, the American Thoracic Society consensus in 2007 recommended a safe daily dose of less than 15 mg/kg/day [25]. Besides the EMB daily dosage, risk factors for EON included long-term intake of ethambutol, renal or liver impairment, older age, pre-existing optic nerve disease or gene abnormalities (e.g., OPA1, LHON), alcoholism, nutritional deficiencies (e.g., vitamin B6, B12 deficiency), and concomitant use of other mitochondria toxic medications [26,27,28,29]. In this study, the average dose of ethambutol was 14.35 ± 4.50 mg/kg/day, with the majority was within the range of [10–15) mg/kg/day (38.10%) and [15–20) mg/kg/day (42.86%), which are considered relatively safe. However, both the daily dose and the long intake of EMB usage were both recognized as definite risk factors for EON. Some studies suggested that even using the daily safety dose, the duration of EMB intake duration should preferably not exceed 4–6 m [20, 23, 24, 30]. Therefore, cumulative dosage (daily dose*duration of medication) might be a better indicator for EON prognosis. Srithawatpong et al. found no statistical significant difference in visual acuity prognosis between two different EMB groups: cumulative dosage of ethambutol (4736.6 ± 3407.9 mg) group and average daily dosage (19.3 ± 3.2 mg/kg/day) compared to the (4332.0 ± 1406.1 mg; 18.3 ± 3.7 mg/kg/day) group [4]. In this study, the cumulative dosage of ethambutol was much higher (102,785.7 ± 71,194.9 mg) and a significant correlation between cumulative dosage and retinal nerve fiber layer thinning was found, indicating that higher cumulative EMB dosage intake did result in a thinner retinal nerve fiber layer. To the best of our knowledge, there have been no established safe range data for cumulative dosage which needed further investigation.

When EON occurred within the safe dosage range, it was necessary to explore the other risk factors [28, 29]. In this study, one patient had OPA1 gene mutation and one had 11,778 mitochondrial gene mutation. The range daily dosage was both within the safe range (14.71 mg/kg/d and 16.67 mg/kg/d, respectively). Among the 10 patients with very low daily EMB dosage intake (less than 15 mg/kg/day), 50% (5 cases) had renal function abnormalities. This suggested that when there were metabolic or genetic abnormalities, it was necessary to reduce the daily dosage and closely monitor the early signs of EON. However, for the remaining five cases, the etiology for EON were unclear. Age might be a factor, since 3 patients were over 50 years old.

Visual function recovery and patterns

Visual acuity

Regarding visual function damage at onset, central visual acuity damage was found in EON, usually > 20/20 (logMAR_VA = 0), which is similar to what we found in this study, with logMAR_VA at onset being 0.86 ± 0.73 (ranging from 0 to 2.5) [31]. Final visual acuity recovery was good (ranging from 1.5 to 0.2) and mainly occurred between 3 to 6 months or 9 months, indicating a long-term observation time window (9–12 months) for visual acuity was warranted in this study.

Visual field and damage patterns

Visual field damage was moderate (− 8.92 ± 7.48 dB) at onset in this study. Chai et al. reported that 50% of patients showed improvement in mean deviation (MD) of the visual field, while the other 50% had worsening. Lee et al. reported a visual field reversibility rate of up to 77.7%. In this study, 77.78% patients experienced some degrees of visual field recovery [32, 33] with 1 (5.55%) unchanged and 3 (16.6% worsen, 2 of whom had preexisting gene mutation). The final MD of visual field was − 9.16 ± 7.12 dB. There was a significant visual field improvement at 6 months compared to 3 months (p = 0.037), indicating a visual field recovery time window between 3 and 6 months endpoint (Fig. 2B). Previous studies on EON visual field recovery have primarily been cross-sectional [25, 34]. The main visual field damage pattern reported in EON was primarily bilateral central and paracentral damage (65.4%), consistent with papillomacular bundle involvement in EON [35, 36]. Hemifield defects and peripheral visual field constriction have also been reported [1]. In our study, the predominant pattern of acute-stage damage was also central scotoma (62.30%), which aligned with the findings reported in Taiwan [19, 37] and higher compared to the findings in South Korea [15, 32], where central scotoma was observed in 35.7% and peripheral constriction in 14.3% of EON cases at onset. There was no preexisting clinical data on visual field contrast between Asian and white EON patients. Notably, no hemifield defects, such as inferior or bitemporal defects was found in this study. Possible reasons for this discrepancy might include variations in patient demographics, disease severity, treatment protocols, or differences in visual field assessment, e.g., [5, 28]. More comprehensive studies with larger samples and diverse patient populations are needed to elucidate the reasons for this variability in visual field damage patterns in EON.

Pattern visual evoked potential

Studies specifically focusing on pattern visual evoked potential in EON are rare [16]. Due to the high individual of visual evoked potential amplitudes to variance, the latency of visual evoked potential _P100 appears to be a reliable measurement for EON prognosis [1, 38, 39]. There is a significant disparity about the reversibility of visual evoked potential amplitude in EON [12]. Menon et al. reported that within 2 months of treatment, 14.4% of eyes showed an increase shortening in pattern visual evoked potential latency, and approximately 80% of eyes demonstrated visual evoked potential amplitude improvement within 1 m after EMB discontinuation [11]. In another study, after 1–3 months EMB usage, as much as 65.4% of eyes may experience delayed P100 latency, and these changes could all be reversed upon discontinuation of EMB [12, 40]. In this study, although there appeared to be some degree of recovery trend in pattern visual evoked potential amplitude during the 12-month follow-up, no statistical comparison could be made due to the limited data available. Further research with larger sample size is necessary to better understand the reversibility of pattern visual evoked potential and its potential as a useful diagnostic and monitoring tool in EON.

Microperimetry

Microperimetry features in EON have not been thoroughly studied [1, 5, 25] which has the potential to be a more sensitive index for central visual function. In our study, we observed a steady increase in microperimetry photopic sensitivity during the 12-month follow-up period, rising from 13.17 ± 12.73 to 16.88 ± 6.91. However, due to the limited clinical utilization of this examination and the small sample size, statistical significance could not be achieved. Further study was needed for its potential as a valuable tool in assessing visual function and follow-up in EON patients.

Optic nerve structural changes

Peripapillary retinal nerve fiber layer

In this study, peripapillary retinal nerve fiber layer swelling within 1–3 months after the onset of symptoms, was observed in the majority of EON patients (51.52%, 17/33), followed by gradual thinning. We found that the retinal nerve fiber layer kept swelling until 1 month, with an obvious thickening of approximately 20 µm at 1 m compared to 2 weeks, although no significant difference was observed. The most significant retinal nerve fiber layer thinning occurred at 6 months. The thinning of the temporal quadrant appeared earliest (at 3 months), which is consistent with previous reports [13, 33], suggesting that the optic-macular bundle is particularly vulnerable and might serve as a sensitive indicator. Menon et al. even observed subclinical EON with selective thinning of the temporal retinal nerve fiber layer [11].

The progressive RNFL thinning observed in EON, particularly in the temporal quadrant, underscores the optic nerve’s (CN II) susceptibility to both toxic and mechanical injury. This vulnerability is critically relevant to neurosurgical approaches targeting the sellar/parasellar region. As demonstrated by Ay et al., the optic nerve’s proximity to the supraclinoid internal carotid artery (ICA) and variations in chiasm position define the “safety window” for transcranial corridors (e.g., opticocarotid triangle). In EON patients, RNFL atrophy may further narrow this window, increasing the risk of iatrogenic injury during dissection. Preoperative OCT assessment of RNFL thickness—especially if temporal quadrant thinning exceeds 40%—could inform approach selection (e.g., favoring endoscopic endonasal over transcranial routes for coexisting pituitary lesions). Moreover, the diaphragma sellae morphology may influence suprasellar tumor extension patterns, warranting high-resolution MRI in EON patients with visual field deterioration [41].

Ganglion cell layer

Additionally, in this study, ganglion cell layer thinning was observed even earlier, 1 month after onset. Previous studies rarely observed earlier changes in the ganglion cell layer compared to the retinal nerve fiber layer [33]. Ganglion cell layer reflected damage to retinal ganglion cell soma of the optic-macular bundle. Han et al. found ganglion cell layer thinning concurrent with temporal retinal nerve fiber layer edema in EON patients [42]. In our study, patients exhibited widespread and pronounced macular ganglion cell-inner plexiform layer thinning, except for one patient who had no significant thinning in both peripapillary retinal nerve fiber layer and macular ganglion cell-inner plexiform layer. It has been reported a correlation between the initial loss of 10 µm thickness in the temporal inner GCIPL and a decrease of 0.5 logMAR visual acuity at 12 m in mitochondrial optic nerve neuropathy [43]. Respectively, macular ganglion cell-inner plexiform layer was not found to be significantly related to the prognosis of EON due to the limited sample size, GCIPL and temporal retinal nerve fiber layer could still be considered as potential biomarkers for subclinical EON and vision prognosis.

Overall, these findings emphasized the importance of early detection and monitoring of changes in the optic nerve and ganglion cell layer to better understand the progression and prognosis of EON. Further studies with larger sample sizes are warranted to confirm and explore the potential of these biomarkers in clinical practice.

Gender differences in EON progression

Previous studies have not identified a gender bias in EON patients [27, 43, 44]. However, in this study, female patients exhibited a significant thicker retinal nerve fiber layer compared to males, but not VA/VF [33]. This result was consistent to the Srithawatpong et al.’s study involving 23 patients and found that female gender was significantly associated with good visual acuity recovery, with an odds ratio of 12.0 (95% confidence interval 1.56, 92.29; p = 0.02) [5]. A similar phenomenon has been reported in other optic nerve disorders such as LHON [45, 46] or glaucoma [47, 48]. Estrogen has been shown to act as a protective factor on astrocytes in the optic disc under oxidative stress, promoting neural regeneration and neuronal survival [48, 49]. Female EON patients might have a better prognosis than males [5].

Magnetic resonance imaging findings

There has been very little research on the magnetic resonance imaging manifestations of EON patients. Kho et al. mentioned that in 19 EON cases with bilateral temporal visual field damage, no magnetic resonance imaging abnormalities was observed in the optic chiasm [35]. However, since no information was provided about the stage of EON in their study due to pre-existing limited EON magnetic resonance imaging data, it is difficult to comprehensively assess the disease progression. Only three case reports have described acute phase magnetic resonance imaging presentations with increased T2 signal or enhancement in the optic chiasm and optic tract [7, 50,51,52,53,54].

In our study, among the 16 patients, only two revealed optic nerve abnormalities: one showed an increased T2 WI signal of the optic nerve, and the other had suspected mild enhancement in the optic chiasm during the acute phase. This limited detection of optic nerve abnormalities could be attributed to the relatively low resolution of some 1.5 T magnetic resonance imaging machines, which have only 3 mm in diameter and can easily miss smaller abnormalities, even with a higher field strength like 3.0 T magnetic resonance imaging. With the advancements in high-resolution magnetic resonance imaging technology, there is potential for improved visualization of optic nerve abnormalities behind the eyeball in cases of EON. As such, future studies with higher-resolution magnetic resonance imaging may provide more detailed insights into the magnetic resonance imaging manifestations of EON patients [55].

Prognostic factors and clinical implications

There were currently limited established predictive biomarkers for EON prognosis [56]. Furthermore, there have been no studies investigating the influencing factors of visual field and retinal nerve fiber layer through multivariate analysis. In a study by Srithawatpong et al., it was found that the initial visual acuity at onset was the only factor associated with visual acuity recovery [5], 9 out of 46 eyes of patients with an initial visual acuity greater than 20/200 achieved significantly better visual acuity prognosis [5].

No independent risk factors could be identified for visual acuity prognosis of EON through multivariate analysis. The disease course was found to be the only factor significantly influencing the visual field prognosis (p = 0.001). As for the prognosis of peripapillary retinal nerve fiber layer, multiple factors such as gender, daily dosage, average weight daily dosage, cumulative medication dosage, total duration of medication, and disease duration were found to have an impact. Our conclusions are consistent with previous reports in the literature [33].

All this information indicated EMB had a dose-effective relationship with optic nerve damage, therefore warranting a prompt diagnosis of EON to minimize damage. The identification of a critical recovery window between 3 to 6 months post-diagnosis highlights the importance of this period as a therapeutic window for intervention. Ophthalmologists should prioritize close monitoring and aggressive treatment during this period, as it represents a key opportunity to optimize visual outcomes in EON patients. Regular assessments of visual acuity, visual field, and optical coherence tomography to monitor retinal nerve fiber layer thickness are recommended during this critical window. Early discontinuation of ethambutol and initiation of neuroprotective therapies. Additionally, efforts should be made to avoid other factors that may exacerbate visual impairment, such as uncontrolled systemic diseases (e.g., diabetes or hypertension), nutritional deficiencies (e.g., vitamin B12 or folate deficiency), or concomitant use of other neurotoxic medications. Personalized management strategies, tailored to factors such as disease course, ethambutol dosage, and gender, should be considered to minimize long-term visual impairment. These findings emphasize the importance of early diagnosis, timely intervention, and individualized treatment plans to improve prognosis in EON patients.

Limitation

This study’s limitation was its design and small sample size when patients did not adhere to follow-up visits, incomplete follow-up data results. Therefore, to obtain a more accurate analysis of the prognosis of this rare optic neuropathy, further research with larger sample sizes and a well-designed prospective randomized clinical trial is necessary.

Conclusion

This study identifies critical recovery windows in ethambutol-associated optic neuropathy, with significant improvements in visual function observed between 3 to 6 months, and retinal nerve fiber layer thinning continuing from 3 to 9 months. The temporal quadrant of the peripapillary retinal nerve fiber layer shows early thinning, suggesting its potential as an early marker for EON progression. Disease course was found to significantly affect visual function recovery, while factors such as ethambutol dosage, gender, and disease duration influenced retinal nerve fiber layer thinning. These findings highlight the critical importance of early diagnosis and intervention, along with personalized management, to preserve visual function in EON patients. Further studies with larger sample sizes are needed to validate these results and refine clinical strategies for EON.

Availability of data and materials

No datasets were generated or analysed during the current study.

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Funding

This clinical research was supported by grants from the National Natural Science Foundation of China to H.Y. (Grant No. 81870656).

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  1. Taimin Guo and Yue Fu contributed equally to this paper.

Authors and Affiliations

  1. State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, 510060, China

    Taimin Guo, Yue Fu, Xiaoyu Xu, Xiaoning Liu, Yurong Zhang & Hui Yang

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Contributions

T.G. collected clinical data and wrote the manuscript. Y.F. contributed to the research ideas and participated in writing the manuscript. X.X., X.L., and Y.Z. were responsible for collecting clinical data. H.Y. contributed to the research ideas and was involved in writing the manuscript. All authors reviewed and approved the final manuscript.

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Correspondence to Hui Yang.

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Guo, T., Fu, Y., Xu, X. et al. Temporal evolution and factors influencing visual function and RNFL thickness in ethambutol-associated optic neuropathy. Eur J Med Res 30, 321 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s40001-025-02573-9

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