Natural Course and Prognostic Factors of Ethambutol Toxic Optic Neuropathy

Background: To investigate the natural course and prognostic factors of ethambutol toxic optic neuropathy (ETON). Methods: Medical charts of 87 patients diagnosed with ETON were reviewed retrospectively, and the visual acuity and history of ethambutol medication were analyzed. Based on the nal visual acuity, patients were divided into two groups: recovery and no-recovery groups. We investigated the prognostic factors, including the sex, age, duration of medication, initial visual acuity, and systemic diseases (diabetes mellitus, hypertension, renal disorders, etc.). Results: In this study, 37 men and 50 women, with ages ranging from 22 to 91 years, were included. Although a poor initial visual acuity was noted in the old patients, a short duration of medication had a weak negative correlation with the initial visual acuity. Follow-up of over 1 year could be performed for 28 out of 87 patients, including nine men and 19 women, with a mean age of 70.0 ± 8.2 years. Ten eyes of seven (25%) patients, including three men and four women, did not recover vision after discontinuation of ethambutol. Patients were signicantly older in the no-recovery group than in the recovery group (73.9 ± 8.3 and 68.7 ± 8.1 years, respectively). The poor initial visual acuity and presence of systemic diseases affected the prognosis of ETON. Conclusion: Three-fourth of patients with ETON had visual recovery after discontinuation of ethambutol. High-risk patients with poor prognostic factors, including old age, presence of systemic diseases, and poor initial visual acuity, should be screened in early stages of ETON.


Introduction
Tuberculosis is a serious infectious disease worldwide, and the elderly population is particularly at a high risk. 1,2 Although ethambutol (EMB) hydrochloride is the rst-line agent for treating tuberculosis, it has been associated with side effects. 3 Among these side effects, EMB toxic optic neuropathy (ETON) commonly occurs during the course of the medication. 4 However, only a few studies have investigated the natural course of ETON or response to discontinuation of EMB hydrochloride. 5,6 Chen et al. analyzed 16 patients with ETON and reported that 50% of them had visual impairment without recovery, with only the younger patients showing a favorable outcome. 7 However, another Korean study analyzed 13 patients with ETON and reported that only one-third of them had visual improvement after discontinuation.
Therefore, the aim of this study was to analyze a large number of patients with ETON in terms of visual recovery in a follow-up period of over 1 year after discontinuation of EMB hydrochloride, focusing on the prognostic factors of ETON.

Methods
This study was a retrospective review of the medical records of patients diagnosed with ETON at Kim's Eye Hospital from May 2008 to June 2018 for the analysis of bilateral visual loss after EMB medication.
The study protocol was approved by the Institutional Review Board of Kim's Eye Hospital, and the study was conducted in accordance with the tenets of the Declaration of Helsinki. In order to analyze the recovery of visual function after discontinuation of the medication, patients with a history of optic neuropathy or ocular disorders that could induce progressive visual loss, such as age-related macular degeneration, dense cataract, and retinitis pigmentosa, were excluded. Furthermore, patients who underwent ocular surgery during the follow-up period were excluded.
We reviewed the visual acuity at the rst and nal visits and details of the EMB administration, including the duration and dosage. By comparing the nal and initial visual acuities, the no-recovery group comprised patients with worsening or no improvement of visual acuity. We analyzed prognostic factors, including the sex, age, duration of medication, initial visual acuity, and systemic diseases (diabetes mellitus, hypertension, renal disorders, etc.).
Data were analyzed using SPSS, version 24.0 (IBM Corporation, Armonk, NY, USA), for Windows (Corporation, Redmond, WA, USA). Spearman's correlation coe cient was used to analyze correlations.
Differences between the groups were investigated with the Mann-Whitney U and chi-square tests.
Statistical signi cance was set at p < 0.05.

Results
A total of 87 patients, including 37 men and 50 women, were enrolled in this study. The mean patient age was 66.9 years (range: 22 to 91 years). The dosage information was acquired for 21 patients, and the mean EMB dosage was 14.5 mg/kg/day (range: 13.3 to 15.0 mg/kg/day). The duration of medication before the onset of ETON was acquired for 72 patients, and the mean duration was 5.97 ± 3.16 months.
Although a poor initial visual acuity was noted in the old patients, a short duration of medication had a weak negative correlation with the initial visual acuity (Fig. 1). The initial visual acuity did not differ between the sexes (men, 1.37 ± 0.40; women, 1.48 ± 0.65, p = 0.47) Follow-up of over 1 year could be performed for 28 out of 87 patients, including nine men and 19 women, with a mean age of 70 ± 8.2 years. Of the 28 patients, ten eyes of seven patients did not recover vision after discontinuation of EMB (Fig. 2). The nal visual acuity was lower compared to the initial visual acuity in three of 56 (5.4%) eyes (two men; mean age: 69.5 years). The visual acuity in the remaining seven eyes recovered after discontinuation of EMB (one man and four women; mean age: 71.6 years). Patients were signi cantly older in the no-recovery group than in the recovery group (73.9 ± 8.3 and 68.7 ± 8.1 years, respectively). The poor initial visual acuity and presence of systemic diseases affected the prognosis of ETON (Table 1). The visual acuity recovered up to 0.8 on a decimal scale in 18 eyes of nine patients. All patients in the no-recovery group had a visual acuity worse than or equal to 0.1 on a decimal scale ( Table 2). Gender difference was not found in the two groups (6 men and 15 women in the recovery group and 3 men and 4 women in the no-recovery group, p = .058)

Discussion
In the present study, 75% of patients with ETON had visual recovery after discontinuation of EMB, and old age, presence of systemic diseases, and a poor initial visual acuity were indicators of poor prognosis of ETON. The recovery rate was slightly higher in this study compared to previous studies (30-64%). 3,5,7,8 This could be attributed to the different de nitions of visual improvement used. In a previous study, although the visual acuity improved in some patients, other visual functions, including color vision, visual eld, and electrophysiology, showed dysfunctions. 9 The occurrence of ETON depends on the dosage of EMB 10,11 and can also be induced by a relatively low dosage (10 mg/kg/day). We could not analyze the effects of dosage of EMB because the number of patients whose medical records had detailed information on the dosage was too small to draw meaningful results. However, the toxic dosage of EMB can be estimated considering that an initial dosage of 15 mg/kg/day is most widely used in Korea and that the average dosage of 14.5 mg/kg/day was used in this study. The mean interval between the start of medication and the onset of ETON was 3 to 5 months in a previous study 12 and 5.97 ± 3.16 months in this study, showing similar results. The duration of medication did not affect the recovery from ETON. In addition, the initial visual acuity was worse in patients with a long duration of medication than in those with a short duration of medication, as previously reported in a Taiwanese study. 7 Therefore, further investigations of the correlation between the duration of medication and the severity of visual loss are required.
Several other risk factors, such as the age, sex, initial visual acuity, smoking habit, alcohol consumption, and presence of systemic diseases, including renal failure, have been associated with ETON. 13,14 In the present study, old patients had a poor initial visual acuity and worse prognosis of ETON. Although the correlation between patient age and occurrence of ETON is debated, 7, 15 the positive correlation in this study could be attributed to the decline in renal function with age. 16 The presence of systemic diseases can affect not only the occurrence of ETON but also the deterioration of visual acuity. 17 Women showed a tendency for favorable visual outcome but without statistical signi cance. In Leber's hereditary optic neuropathy, which is a mitochondrial disorder, 18 male predominance is a unique feature, possibly attributable to the neuroprotective effect of the higher estrogen levels in women. 19 Among systemic diseases, we analyzed hypertension, diabetes mellitus, and renal disorders, and their presence affected the visual recovery, consistent with previous studies. 7,14 The exact mechanism underlying the occurrence of ETON after EMB administration is unclear, and several pathways have been suggested. First, EMB is particularly toxic to the retinal ganglion cells through the mechanism of glutamate excitotoxicity. 20,21 Second, it is a zinc-chelating agent, which affects caspase-3 and caspase-6 pathways. 22 If the exact mechanism is identi ed, the association between prognostic factors and EMB could be better understood. -Acknowledgements