Factors Affecting Visual Outcome in Ethambutol-Induced Optic Neuropathy

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OPEN
Factors affecting visual outcome
in patients with toxic optic
neuropathy caused by ethambutol
Kwang Eon Han1, Heejin Yoon1, Heeyoung Choi2, Ji-Eun Lee1 & Su-Jin Kim1,3
This study aims to investigate prognostic factors for visual recovery in patients with ethambutolinduced toxic optic neuropathy (EON) by analyzing visual field (VF) tests, retinal nerve fiber layer
(RNFL) thickness on optical coherence tomography (OCT), and other variables. We retrospectively
reviewed 46 eyes of 23 patients with EON who had been followed up for more than six months.
Patients were categorized into recovery (n = 12) and non-recovery (n = 11) groups based on visual
recovery at six months after discontinuation of ethambutol. In the recovery group, initial bestcorrected visual acuity (BCVA) and VF tests were better (p < 0.001), body weight (p = 0.04) was higher
and the number of patient with diabetes (p = 0.007) was lower than in the non-recovery group. Baseline
BCVA, VF tests, inferior and nasal RNFL thickness were correlated with visual outcomes. Univariate
analysis showed that younger age (p = 0.024), higher body weight (p = 0.033), better initial BCVA
(p < 0.001), better VF tests (p = 0.007), no hypertension (p = 0.044) and no diabetes (p = 0.009) were
significant associated with a good visual outcomes. Multivariate analysis confirmed baseline BCVA
as the only significant prognostic factor. Better BCVA at baseline are associated with favorable visual
outcomes in EON patients. VF parameters, age, hypertension, diabetes, and body weight could also
be considered possible predictors. Although RNFL thickness has significant correlation with visual
outcomes, it does not appear to be a reliable factor to predict visual recovery.
Keywords Ethambutol-induced optic neuropathy, Optical coherence tomography (OCT), Retinal nerve fiber
layer (RNFL) thickness, Visual recovery prognostic factors
Background
Ethambutol, an oral chemotherapeutic agent, was first introduced in 1961 and has since been used as the
primary treatment for tuberculosis, along with isoniazid, rifampin, and pyrazinamide. It works by inhibiting the
biosynthesis of the mycobacterial cell wall, leading to the death of the tuberculosis bacteria1. Ethambutol plays
a vital role in treating tuberculosis, including in strains resistant to other antitubercular drugs. However, 1–5%
of patients who receive the appropriate dose experience drug-induced toxicity, which affects the optic nerve
within days to months of starting the medication, leading to symptoms such as vision impairment, visual field
constriction, and color vision deficits2,3.
Ethambutol should be discontinued immediately if a patient develops visual impairment. Even after
drug discontinuation, vision impairments, and field defects persist or worsen in two-thirds or more of cases.
Therefore, early detection of ethambutol toxicity is critical for preventing permanent visual loss4–6. Many studies
have investigated the structural changes and indicated that the thickness of the retinal nerve fiber layer (RNFL)
on optical coherence tomography (OCT) is effective for the early detection of toxic optic neuropathy7,8.
However, comprehensive studies on the correlation between RNFL thickness, visual field (VF) test results,
visual recovery, and prognostic factors that influence visual recovery are lacking. Therefore, this study aimed
1Department of Ophthalmology, Pusan National University School of Medicine, Research Institute for Convergence
of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Korea. 2Department
of Ophthalmology, School of Medicine, Pusan National University, Biomedical Research Institute, Pusan
National University Hospital, Busan, Korea. 3Department of Ophthalmology, Pusan National University School of
Medicine, Research Institute for Convergence of Biomedical Science and Technology, Pusan National University
Yangsan Hospital, 20-Geumo-ro, Mulgeum-eup, Yangsan 50612, Gyeongsangnam-do, South Korea. email:
[email protected]
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to evaluate the clinical efficacy of VF tests and RNFL thickness in predicting visual recovery in patients who
developed optic neuropathy following ethambutol use.
Materials and methods
We retrospectively analyzed the medical records of 23 patients diagnosed with ethambutol-related toxic optic
neuropathy at Yangsan Pusan National University Hospital between January 2020 and December 2022. The
study adhered to the principles outlined in the Declaration of Helsinki and was approved by the Institutional
Review Board of Pusan National University Yangsan Hospital (IRB number: 55–2024-050). Because this was
a retrospective study, the requirement for informed consent was waived by the Institutional Review Board of
Pusan National University Yangsan Hospital.
Patients were eligible for inclusion if they had been diagnosed with ethambutol-induced toxic optic neuropathy
and had documented follow-up for more than 6 months. Only patients who had undergone assessments of visual
acuity, dilated fundus examination, automated perimetry using a VF analyzer (Humphrey Field Analyzer; Carl
Zeiss-Meditec, Dublin, CA, USA), and Cirrus HD OCT® (Carl Zeiss-Meditec, Oberkochen, Germany) of the
peripapillary RNFL and macular ganglion cell-inner plexiform layer (GC-IPL) were included in the analysis. The
visual field (VF) tests were conducted using the 30 − 2 testing protocol, which evaluates a broad central visual
field including areas most likely affected in ethambutol-related toxic optic neuropathy. Only reliable data from
the VF test results, which included false-positive error rates of less than 20%, false-negative error rates of less
than 20%, and fixation loss rates of less than 20%, were considered for the analysis.
The exclusion criteria for this analysis were as follows: presence of any ophthalmological abnormalities
other than optic nerve disease, including glaucoma; any history of neurologic diseases leading to visual field
defects; and specific conditions such as meningitis or central nervous system (CNS) tuberculosis. We analyzed
the average peripapillary RNFL thickness and the thickness in each quadrant (superior, inferior, temporal, and
nasal). The recovery group was defined as visual recovery 2 lines or more or final visual acuity 0.4 or more.
The patients were divided into two groups based on their recovery states. Six months after the diagnosis, we
evaluated the best-corrected visual acuity (BCVA), VF, RNFL thickness, and GC-IPL thickness of each patient.
Statistical analyses were performed using SPSS for Windows version 23.0 (SPSS Inc Corp., Armonk, NY).
Descriptive statistics, including age, sex, visual acuity (logarithm of the minimum angle of resolution [logMAR]),
duration from neurological symptom onset to surgery, pattern of VF defect, and presence of a central VF
defect were calculated for all patients. Patient characteristics were compared using t-tests or chi-square tests.
Pearson’s correlation coefficient was used to analyze the correlation between VF test results and RNFL thickness.
Univariate and multivariate analyses were conducted for each variable to investigate factors associated with VF
recovery. Statistical significance was defined as p < 0.05.
Results
The study included 23 patients (46 eyes). Of these patients, 14 were male (28 eyes) and 9 were female (18 eyes).
The mean age of the patients was 64.0 ± 18.0 years, and their body weight was 53.4 ± 7.9 kg. The BCVA at baseline
was 0.78 ± 0.71 log MAR. The daily dose of ethambutol was 18.2 ± 4.0 mg, administered over 4.6 ± 3.0 months.
The comorbidities were hypertension in nine patients, diabetes mellitus (DM) in six patients, dyslipidemia
in two patients, and chronic kidney disease (CKD) in three patients (Table 1). All 23 patients in this study
were treated for pulmonary tuberculosis. No cases of extrapulmonary tuberculosis, such as meningitis or CNS
tuberculosis, were included.
Of the 23 patients, 12 were assigned to the recovery group and 11 to the non-recovery group. In the recovery
group, there was a statistically significant increase in body weight and a better initial BCVA (p = 0.038 and
p < 0.001, respectively). The daily dose, usage duration, and total dose of ethambutol did not differ between the
two groups. The mean deviation (MD), pattern standard deviation (PSD), and visual field index (VFI) in the VF
revealed significantly greater impairments in the non-recovery group (all p < 0.001). However, RNFL thickness
did not differ between the two groups. Significantly more patients had DM in the non-recovery group (p = 0.007)
(Table 2).
Pearson correlation analysis was used to examine the relationship between BCVA, VF tests, and RNFL
thickness at baseline and BCVA at 1, 3, and 6 months after discontinuation of ethambutol. The initial BCVA
had a strong positive correlation with BCVA at 1, 3, and 6 months, with correlation coefficients of 0.879, 0.886,
and 0.711, respectively (all p < 0.001). The PSD showed positive correlations of 0.422 at one month and 0.365 at
three months, with each being statistically significant (p = 0.016 and p = 0.047, respectively). The VFI exhibited
negative correlations of −0.539 at one month and − 0.556 at three months(p = 0.001 and p = 0.002, respectively).
RNFL thickness showed a statistically significant negative correlation in the inferior quadrant, with a correlation
coefficient of −0.536 (p = 0.006) one month after discontinuation of ethambutol. Additionally, in the nasal
quadrant, the correlation coefficients were − 0.451 at one month and − 0.555 at three months, both showing
statistically significant negative correlations (p = 0.024 and p = 0.011, respectively) (Table 3).
The univariate logistic regression analysis indicated associations between poor vision recovery and several
factors: old age (Odds Ratio [OR], 1.05; p = 0.024), low body weight (OR, 0.913; p = 0.033), good visual acuity
(OR, 135.3; p < 0.001), low MD (OR, 0.882; p = 0.007), high PSD (OR, 1.419; p = 0.008), low VFI (OR, 0.93;
p = 0.006), as well as hypertension (OR, 3.6; p = 0.044) and diabetes (OR, 9.167; p = 0.009). However, multivariate
analysis revealed that baseline BCVA was the only significant factor affecting visual recovery (Table 4).
Discussion
The exact mechanism of ethambutol-induced optic neuropathy (EON) is not clearly defined; however,
ethambutol toxicity inhibits mitochondrial metabolism, affecting ganglion cells that require high mitochondrial
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Variable
Value
Eyes / Patients
46/23
Sex (male / female)
14/9
Age (years)
64.0 ± 18.0
Body weight (kg)
53.4 ± 7.9
BCVA (logMAR) at first visit
0.78 ± 0.71
Duration of symptoms (weeks)
30.7 ± 12.3
Ethambutol, daily dose (mg)
18.2 ± 4.0
Ethambutol usage duration (months)
4.6 ± 3.0
Ethambutol, total dose (mg)
128970.2 ± 95153.7
Visual field test at the first visit
MD (dB)
−8.8 ± 10.4
PSD (dB)
5.1 ± 3.3
VFI (%)
76.4 ± 29.0
RNFL thickness (µm) at the first visit
Average
99.7 ± 14.3
Superior quadrant
122.9 ± 26.5
Temporal quadrant
76.1 ± 18.5
Inferior quadrant
129.5 ± 21.6
Nasal quadrant
67.0 ± 12.6
Accompanying systemic disease, n(%)
Hypertension, n (%)
9 (39.1%)
Diabetes Mellitus, n (%)
6 (26.1%)
Dyslipidemia, n (%)
2 (8.7%)
CKD, n (%)
3 (13.0%)
Table 1. Baseline characteristics of the patients. Values are presented as mean ± standard deviation, number, or
number (%) unless otherwise indicated. BCVA = best-corrected visual acuity; CKD = chronic kidney disease;
logMAR = logarithm of the minimum angle of resolution; MD = mean deviation; PSD = pattern standard
deviation; RNFL = retinal nerve fiber layer; VFI = visual field index.
respiratory activity9,10. Ethambutol toxicity is traditionally described as reversible upon discontinuation of the
drug, and vision is believed to gradually recover over weeks to months. However, recovery is often incomplete,
even in patients who report visual impairment after the cessation of ethambutol treatment3,11.
Some studies have investigated the prognostic factors for visual recovery in patients with EON. Older age has
been associated with a higher risk of EON occurrence and poorer visual recovery2,12. In our study, older patients
exhibited worse visual recovery rates in univariate analysis, suggesting that age-related vulnerability of the optic
nerve might contribute to less favorable outcomes.
According to Kyncl et al.13, the dosage of ethambutol significantly affects the visual prognosis in patients
with optic neuropathy. Their study highlighted that higher dose of ethambutol were associated with an increased
risk of developing optic neuropathy and poorer visual recovery outcomes. On the other hand, Sadun and Wang
demonstrated that even at recommended doses, ethambutol can cause optic neuropathy without a clear doseresponse relationship14. In this study, daily dosage did not show a significant correlation with visual recovery,
likely because most patients in our study were prescribed the same dosage. This implies that factors other than
dosage, such as individual susceptibility and concurrent medical conditions, may play a substantial role in the
development of EON and its prognosis.
Body weight is a potential prognostic factor. Some studies have indicated that ethambutol toxicity is more
pronounced in individuals with lower body weight due to higher drug concentration relative to body mass2. In
this study, patients with lower body weight showed poorer visual recovery.
Studies by Menon et al.5 and Jin et al.15. have highlighted that these comorbidities can adversely affect the
visual prognosis in optic neuropathy. Hypertension and diabetes can lead to microvascular damage, exacerbating
the effects of EON on the optic nerve and hindering recovery. In this study, hypertension and diabetes were more
prevalent in the non-recovery group, supporting their role as risk factors for poor outcomes.
Our findings also emphasize the importance of initial BCVA and VF tests as significant predictors of
visual recovery. Previous studies have consistently demonstrated that initial visual acuity is a critical factor in
determining the prognosis of optic neuropathies. Menon et al.5 indicated that a better initial visual acuity is
strongly associated with favorable visual outcomes in patients with optic neuropathy. Additionally, Chen et
al.2 and Sivakumaran et al.3 emphasized the importance of VF assessments, highlighting that VF deterioration
is associated with poorer visual recovery. Our study aligns with these findings, showing a strong correlation
between initial BCVA and visual recovery, and between the initial VF and visual recovery, thus highlighting their
importance as prognostic indicators. Furthermore, multivariate analysis confirmed that the initial BCVA was the
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Variable
Recovery
(n = 12)
Non-recovery
(n = 11)
p-value
Eyes
24
22
N/A
Sex (male / female)†
7/5
7/4
0.77
Age (years)*
57.8 ± 19.9
70.82 ± 13.08
0.25
Body weight (kg)*
55.9 ± 4.7
50.75 ± 9.78
0.04
BCVA (logMAR)*
0.2 ± 0.4
1.4 ± 0.5
< 0.001
Duration of symptoms (weeks)*
32.0 ± 12.7
29.4 ± 11.8
0.89
Ethambutol, daily dose (mg)*
18.6 ± 3.0
17.73 ± 4.9
0.08
Ethambutol usage duration (months)*
4.3 ± 3.2
4.9 ± 3.0
0.40
Ethambutol total dose (mg)*
13,198 ± 94906.4
125960.36 ± 97768.5
0.45
MD (dB)
−4.3 ± 4.6
−14.3 ± 12.8
< 0.001
PSD (dB)
3.7 ± 3.3
6.8 ± 2.5
< 0.001
VFI
91.8 ± 13.7
55.3 ± 31.4
< 0.001
Average
102.3 ± 15.4
98.0 ± 13.8
0.63
Superior quadrant
126.4 ± 28.6
120.6 ± 25.7
0.82
Temporal quadrant
72.0 ± 11.0
78.6 ± 21.8
0.35
Inferior quadrant
136.8 ± 23.9
124.9 ± 19.3
0.17
Nasal quadrant
73.2 ± 13.5
68.0 ± 12.0
0.48
Final BCVA*
0.1 ± 0.1
1.4 ± 0.5
< 0.001
MD (dB)
−2.2 ± 2.7
−13.56 ± 7.68
< 0.001
PSD (dB)
2.8 ± 1.8
8.2 ± 2.7
< 0.001
VFI
95.8 ± 6.3
58.6 ± 22.2
< 0.001
Hypertension, n (%)
3(25%)
6(54.55%)
0.07
Diabetes Mellitus, n (%)
1(8.33%)
5(45.45%)
0.007
Dyslipidemia
2(16.67%)
0
0.11
CKD
1(8.33%)
2(18.18%)
0.41
Visual field test at the first visit*
RNFL thickness (µm) at the first visit*
Final Visual field test*
Accompanying systemic disease, n(%)†
Table 2. Comparison between the recovery and non-recovery groups. Values are presented as mean ± standard
deviation, number, or number (%) unless otherwise indicated. N/A = not applicable; BCVA = best-corrected
visual acuity; CKD = chronic kidney disease; logMAR = logarithm of the minimum angle of resolution;
MD = mean deviation; PSD = pattern standard deviation; RNFL = retinal nerve fiber layer; VFI = visual field
index. *Comparison between groups by the Mann–Whitney U test. †Comparison between groups by Fisher’s
exact test.
Variable
Poststop 1 m BCVA
Poststop 3 m BCVA
Poststop 6 m BCVA
R
p-value*
R
p-value*
R
p-value*
0.879
< 0.001
0.886
< 0.001
0.711
< 0.001
MD (dB)
−0.229
0.208
−0.343
0.064
−0.354
0.126
PSD (dB)
0.422
0.016
0.365
0.047
0.225
0.34
VFI (%)
−0.539
0.001
−0.556
0.002
−0.429
0.059
Average
−0.345
0.092
−0.046
0.848
0.009
0.971
Superior quadrant
−0.141
0.501
−0.025
0.918
−0.067
0.791
Temporal quadrant
−0.111
0.599
0.292
0.212
0.15
0.552
Inferior quadrant
−0.536
0.006
−0.067
0.778
−0.077
0.763
Nasal quadrant
−0.451
0.024
−0.555
0.011
−0.002
0.995
BCVA at baseline
Visual field test
at baseline
RNFL thickness (µm)
Table 3. Relationship between baseline BCVA, VF and RNFL thickness and post-stop BCVA. BCVA = bestcorrected visual acuity; MD = mean deviation; PSD = pattern standard deviation; RNFL = retinal nerve fiber
layer; VFI = visual field index.
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Univariate analysis
Multivariate analysis
Variable
OR
95% CI
p-value*
OR
95% CI
p-value*
Age (years)
1.05
1.006–1.096
0.024
1.048
0.963–1.141
0.274
Sex (male)
0.8
0.244–2.626
0.713
Body weight (kg)
0.913
0.839–0.993
0.033
0.952
0.798–1.135
0.58
BCVA (logMAR)
135.3
9.211–1987.33
< 0.001
91.15
6.818–1218.6
< 0.001
Duration of symptoms
(weeks)
0.952
0.738–1.228
0.705
Daily dose (mg)
0.998
0.996–1.001
0.14
Usage duration (months)
1.07
0.867–1.321
0.528
MD (dB)
0.882
0.804–0.967
0.007
1.163
0.748–1.809
0.503
PSD (dB)
1.419
1.096–1.838
0.008
0.7
0.284–1.722
0.437
VFI (%)
0.93
0.883–0.979
0.006
0.827
0.657–1.042
0.107
Average
0.978
0.928–1.031
0.41
Superior quadrant
0.991
0.964–1.02
0.55
Temporal quadrant
1.021
0.979–1.065
0.33
Inferior quadrant
0.973
0.938–1.009
0.14
Nasal quadrant
0.966
0.91–1.026
0.265
Hypertension
3.6
1.033–12.542
0.044
1.907
0.163–22.35
0.607
Diabetes Mellitus
9.167
1.72–48.851
0.009
4.906
0.263–91.57
0.287
2.444
0.401–14.908
0.333
Ethambutol
Visual field test
RNFL thickness (µm)
Accompanying systemic
disease
Dyslipidemia
CKD
Table 4. Predictive factors for Visual Field Recovery. Values are presented as mean ± standard deviation,
number, or number (%) unless otherwise indicated. BCVA = best-corrected visual acuity; CKD = chronic
kidney disease; CI = confidence interval; logMAR = logarithm of the minimum angle of resolution; MD = mean
deviation; OR = odds ratio; PSD = pattern standard deviation; RNFL = retinal nerve fiber layer; VFI = visual field
index. *Logistic regression analysis.
most significant factor affecting visual recovery, underscoring its role as the most reliable predictor. Initial VF
tests also provide crucial information that complements visual acuity in predicting long-term visual outcomes.
Ethambutol-induced toxic optic neuropathy results from mitochondrial dysfunction leading to defects in the
papillomacular bundle. Therefore, temporal RNFL thickness is significantly diminished compared to other areas
of the optic disc nerve fiber layer16. Ambika et al.17 reported that a reduction in temporal RNFL thickness strongly
correlates with poor visual recovery. Lee et al.18. reported that a reduction in the temporal GC-IPL thickness was
negatively correlated with the degree of vision recovery. However, we found no significant correlation between
temporal RNFL thickness and visual recovery. Nevertheless, the inferior and nasal RNFL thicknesses showed a
significant correlation with recovery. In a previous longitudinal analysis, initial RNFL swelling occurred within
three months after symptom onset and then decreased overtime18–20. These observations suggest changes in
RNFL thickness over the disease course, wherein swelling and thinning occur as part of the natural progression
of optic neuropathy. We believe that these results occurred because patients in the recovery group were tested
at a stage where the temporal RNFL was already thin, whereas those in the non-recovery group were examined
during a phase when their temporal RNFL was still thick. These studies suggest that temporal RNFL thinning is
not always the most reliable indicator at all stages of optic neuropathy as its profile varies across different clinical
stages of the disease.
Our regression analysis showed that the RNFL thickness was not significantly associated with visual recovery.
This finding can be attributed to the variability in RNFL thickness at different stages of the disease. Longitudinal
changes in the initial swelling following thinning could lead to inconsistent results when using RNFL thickness
as a predictive measure.
This study has certain limitations. First, its retrospective design inherently limits control over data collection
and introduces potential bias. Second, the small sample size may constrain the interpretation of results. Third,
this study did not include macular ganglion cell layer thickness analysis due to limitations in available data.
Fourth, while the 30 − 2 visual field test was used to assess visual field changes in this study, it has limitations in
detecting a central or cecocentral scotoma. Although the 30 − 2 test provided clinically meaningful data, future
studies should consider incorporating 10 − 2 testing for a more comprehensive evaluation of central visual field
defects. Additionally, data about the accessibility of healthcare, general health and nutritional status which may
have influence the visual outcomes were not included in this study. These contextual differences make direct
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comparisons with other populations or countries challenging. Furthermore, there is a possibility that cases
of toxic optic neuropathy in patients who were not referred from internal medicine to ophthalmology were
missed, which may have affected the overall findings. Future studies with prospective designs, larger cohorts,
and ganglion cell layer thickness analysis are needed to strengthen and expand upon these findings.
In conclusion, the BCVA at baseline is the only significant prognostic factor for visual recovery in patients
with EON. Additionally, VF results, age, hypertension, diabetes, and body weight could be considered possible
factors in predicting visual outcomes. Although RNFL thickness has significant correlation with visual outcomes,
it might not appear to be a reliable factor to predict visual recovery. Therefore, caution should be exercised when
using OCT findings in isolation to predict visual prognosis.
Data availability
The datasets generated and analyzed in the current study are available from the corresponding author on reasonable request.
Received: 30 July 2024; Accepted: 14 February 2025
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Acknowledgements
This manuscript has not been published or presented elsewhere in part or its entirety and is not under consideration by another journal.
Author contributions
K.S.J and C.H.Y. were responsible for the study design and acquisition of clinical information. H.K.E. and K.S.J.
prepared the manuscript. H.K.E. and Y.H.J. were responsible for data analysis. L.J.E. and C.H.Y. reviewed the
manuscript. All the authors have read and approved the final version of the manuscript.
Funding
This study was supported by Research institute for Convergence of biomedical science and technology, Pusan
National University Yangsan Hospital (30-2024-004).
Declarations
Competing interests
The authors declare no competing interests.
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