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ORIGINAL ARTICLE
Year : 2020  |  Volume : 12  |  Issue : 1  |  Page : 12-16

A prospective evaluation of ocular toxicity in patients receiving ethambutol as anti-tubercular therapy


1 Department of Ophthalmology, R. G. Kar Medical College and Hospital, Kolkata, West Bengal, India
2 Department of Ophthalmology, General Duty Medical Officer, Barasat 2 Block Government Hospital, Kolkata, West Bengal, India
3 Department of Ophthalmology, NRS Medical College and Hospital, Kolkata, West Bengal, India

Date of Submission20-Feb-2020
Date of Acceptance02-Jul-2020
Date of Web Publication27-Aug-2020

Correspondence Address:
Dr Sambit Banerjee
General Duty Medical Officer, Barasat 2 Block Government Hospital, Kolkata – 700 129, West Bengal
India
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DOI: 10.4103/sjopthal.sjopthal_4_20

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  Abstract 

Purpose: The purpose of this study was to detect the early ocular toxicity of ethambutol in tuberculosis patients. Materials and Methods: This was a prospective, nonrandomized noncomparative cross-sectional cohort study of consecutive 93 patients (186 eyes) getting anti-tubercular therapy, including ethambutol (15–20 mg/kg/day) along with isoniazid, rifampicin, and pyrazinamide. The duration of the study was 1 year from June 1, 2018 to May 31, 2019. Best-corrected visual acuity (BCVA), color vision, visual field, contrast sensitivity, pattern-reversal visual evoked responses (VER), and retinal nerve fiber layer (RNFL) thickness measurements were done in both eyes of each patient at baseline and thereafter at 1st, 2nd, and 6th months of therapy. Results: Mean age of the patients was 29.38 ± 8.43 years (range 11–58 years). Among them, 53 were male and 40 were female. All the visual parameters were normal at baseline and 1st month of therapy. Mean BCVA was significantly decreased at the 2nd month but improved at the 6th month. In the 2nd month of treatment, abnormal color vision was detected in 8 patients (16 eyes; 8.6%). Three patients developed bilateral central scotoma, which persisted in two patients even after 6 months of follow-up. The mean latency in VER was significantly increased from baseline at 2nd and 6th months of therapy. The mean contrast sensitivity in both eyes was significantly decreased from baseline at the 2nd month of therapy but improved at 6th month. Mean temporal RNFL thickness was significantly reduced from baseline assessment after 2 and 6 months of treatment. Conclusion: The assessment of BCVA, Colour vision, Visual field, Contrast sensitivity, VER, and RNFL thickness measurements are essential at baseline and thereafter at monthly intervals to detect early ocular ethambutol toxicity.

Keywords: Colour vision, ethambutol, optic neuropathy, retinal nerve fiber layer, tuberculosis


How to cite this article:
Bandyopadhyay S, Banerjee S, Bandyopadhyay SK, Shamantha M C, Biswas S. A prospective evaluation of ocular toxicity in patients receiving ethambutol as anti-tubercular therapy. Sudanese J Ophthalmol 2020;12:12-6

How to cite this URL:
Bandyopadhyay S, Banerjee S, Bandyopadhyay SK, Shamantha M C, Biswas S. A prospective evaluation of ocular toxicity in patients receiving ethambutol as anti-tubercular therapy. Sudanese J Ophthalmol [serial online] 2020 [cited 2020 Oct 28];12:12-6. Available from: https://www.sjopthal.net/text.asp?2020/12/1/12/293635


  Introduction Top


Tuberculosis is a major disease all over the world, accounting for 2.5% of the global disease burden.[1] It is caused by Mycobacterium tuberculosis and can be pulmonary or extrapulmonary.[2],[3] Ethambutol hydrochloride is one of the first-line antitubercular drugs given in the intensive initial phase in categories I and II of tuberculosis as per the World Health Organization guideline.[4] It has been documented to cause optic neuropathy in various studies ranging from 0.5% to 63% of cases.[5] The toxicity of ethambutol is usually dose related and duration related. The incidence varies from 18% in higher doses (>35 mg/kg/day), 5%–6% in moderate doses (25 mg/kg/day) to <1% in lower doses (15 mg/kg/day) with a duration of treatment for at least 2 months.[6] The toxicity has been reported to be reversible following early detection and discontinuation of therapy,[7],[8] but in some studies, the visual damage was permanent.[9],[10] The clinical features of ethambutol-induced toxic optic neuropathy are characterized by subacute painless loss of central vision, centro-cecal scotoma, and dyschromatopsia.[2] Visual acuity, color vision, visual fields, visually evoked responses (VER) and retinal nerve fiber layer (RNFL) thickness assessment by optical coherence tomography (OCT) are the usual tests to detect early and subclinical toxicity.[6]

India is a country known to be endemic for tuberculosis and there had been reports of ethambutol-induced ocular toxicity from north India.[5],[6],[11] As the corresponding data from eastern India is lacking, we had planned to do the above-mentioned study on tuberculosis patients receiving ethambutol under the revised National Tuberculosis Control Programme (RNTCP) in our tertiary care hospital in Kolkata, eastern India.


  Materials and Methods Top


This was a prospective, nonrandomized noncomparative cross-sectional cohort study of consecutive 93 patients (186 eyes) getting anti-tubercular therapy including ethambutol (15–20 mg/kg/day) along with isoniazid, rifampicin, and pyrazinamide. The study was done in the Ophthalmology department, R G Kar Medical College and Hospital in Kolkata, eastern India. The duration of the study was 1 year from June 1, 2018 to May 31, 2019. There were 53 males and 40 females. The patients were enrolled from the Directly Observed Treatment Strategy (DOTS) center in R G Kar Medical College and Hospital in Kolkata, eastern India, under RNTCP of the Government of India. These newly diagnosed patients with tuberculosis (category I) were sent from the DOTS center to the ophthalmology outpatient department for ophthalmologic evaluation at baseline before starting the treatment and follow-up at the 1st, 2nd and 6th months of therapy. The study was approved by the institutional ethics committee, and informed consent was obtained from the patients/parents in case of minors <18 years of age, after explaining the nature of the study. The study protocol was adhered to the tenets of the Declaration of Helsinki on research involving human subjects.

Exclusion criteria

Patients on any other drugs (except first-line anti-tubercular drugs) known to cause optic neuropathy or with any other disease (multiple sclerosis, syphilis, measles, etc.) which can cause optic neuropathy, history of anti-tubercular therapy, preexisting color vision abnormalities, any ocular disease (e.g., glaucoma, diabetic, and hypertensive retinopathy) which can affect output parameters were excluded from the study. Diabetics without ocular manifestations were included.

After taking a detailed clinical history, a complete general and systemic examination was done. Ophthalmological examinations included best-corrected visual acuity (BCVA), Amsler's grid testing, Applanation tonometry, slit-lamp biomicroscopy, fundus examination with +90D lens in slit lamp and indirect ophthalmoscopy. Color vision was assessed with Ishihara pseudoisochromatic plates. The visual field was analyzed by Humphrey field analyzer after full refractive correction. Contrast sensitivity testing was done by the Pelli-Robson chart. Pattern-reversal VER were obtained by Nicolet Bravo EP with 1015 visual stimulator and monitor (Nicolet Biomedical, Madison, Wisconsin, USA). RNFL thickness was measured by OCT (Zeiss Optical Coherence Tomographer, Model 3000°CT-3; Carl Zeiss Meditec, Dublin, California, USA). The first examination was done at baseline before starting the treatment and thereafter at 1st, 2nd, and 6th months of therapy.

Statistical analysis was performed using SPSS (Version 20.0 IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp). Student's paired t-test was done to compare the visual parameters. A value of P < 0.05 was considered statistically significant.


  Results Top


Overall, 93 patients (186 eyes) were included in this study. Among them, 53 were male and 40 were female. The mean age of the patients was 29.38 ± 8.43 years (range 11–58 years). At baseline, all the visual parameters were normal in both eyes of each patient. At the 1st month of therapy, none of the patients complained of any visual disturbances and ocular examinations also revealed no abnormality.

At baseline, BCVA in the Log MAR unit was normal in both eyes of all patients. However, at 2nd month of study, there was a statistically significant decrease in BCVA in both the right and left eyes of the patients [Table 1]. However, BCVA improved in both eyes at 6 months follow-up, and there were no statistically significant differences compared to baseline.
Table 1: Best corrected visual acuity in log minimum angle of resolution unit at baseline, at 2 months and at 6months of starting ethambutol therapy

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In the 2nd month of treatment, abnormal color vision was detected in 8 patients (16 eyes; 8.6%). The blue defect was the most common (6 eyes of 3 patients) followed by Red-Blue-Green defect (4 eyes of 2 patients). Among them, 3 patients also developed bilateral central scotoma with reduced visual acuity and two patients had peripheral field defects. Ethambutol was immediately stopped in these three patients. Visual acuity was improved in one patient after 2 months of stopping the drug, but it did not improve in the other two patients even after 4 months of stoppage of ethambutol therapy (i.e., at 6 months follow-up). Both of them had gross dimness of vision (BCVA hand movement close to face in both eyes) with poor fixation. The patients with peripheral visual field defects showed improvement after cessation of therapy with ethambutol. In overall visual field assessment, the mean deviation was slightly depressed after 2 months and 6 months follow-up but it was not statistically significant [Table 2].
Table 2: Visual field analysis at baseline, at 2 months and at 6months of starting ethambutol therapy (n=186 eyes)

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In pattern VER, the mean latency of the P100 wave component was significantly increased after 2 months compared to baseline (P < 0.001), but there was no significant change in mean amplitude. Although, there was a marginal improvement in the mean latency at 6 months follow-up that was still significantly increased compared to baseline (P < 0.05). The mean amplitude at 6 months follow-up showed no significant change with respect to baseline data [Table 3].
Table 3: Pattern visual evoked response at baseline, at 2 months, and at 6months of starting ethambutol therapy (n=186 eyes)

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Contrast sensitivity has been tested by the Pelli–Robson chart, which is relatively unaffected by the ambient lighting conditions. The contrast sensitivity score is presented as a log value where the maximum score is 2 and value <1.5 indicates visual impairment. Mean contrast sensitivity in both eyes was significantly decreased from baseline at the 2nd month of therapy (P < 0.05 for both the eyes). Thereafter, mean contrast sensitivity increases at 6 months follow-up in both the eyes without any significant change from baseline [Table 4].
Table 4: Contrast sensitivity at baseline, at 2 months, and at 6months of starting ethambutol therapy

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There were no significant changes in mean average RNFL thickness as well as in superior, nasal, and inferior quadrants after 2 months and 6 months of ethambutol therapy. However, mean temporal RNFL thickness was significantly reduced after 2 months from baseline assessment, and this reduction persisted significantly also at 6 months follow-up [Table 5].
Table 5: Retinal nerve fiber layer thickness on optical coherence tomography at baseline, at 2 months, and at 6 months of starting ethambutol therapy (n=186 eyes)

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  Discussion Top


Ethambutol-induced ocular toxicity has been found to be dose related and duration related to many cases remaining subclinical.[6] In our observation, all the visual parameters at baseline and after 1 month of therapy with ethambutol were normal. Although, there are no definite risk factors for permanent visual damage due to toxic effects of ethambutol, old age smoking and renal insufficiency tend to increase the chances of irreversible toxicity.[6]

Acquired abnormal color vision is the most common and early side effect of ethambutol.[12] We have observed abnormalities in color vision in 16/186 (8.6%) eyes after 2 months of therapy with ethambutol. Blue defect was the most common in 6/16 eyes (37.5%) followed by red-blue-green defect in 4/16 eyes (25%). This was much less than Mahrukh and Bhat (2017) who reported 23.23% eyes with altered color vision in patients receiving ethambutol for 2 months.[5] Blue (42%) and blue-yellow (42%) were the leading color vision defect in their observation. Garg et al. have found color vision abnormality in 12.6% of patients getting ethambutol for 2 months.[11] However, Menon et al. did not find any abnormality in visual acuity and color vision in their study of 104 eyes of 52 patients treated with ethambutol under DOTS.[6]

There are variable incidences of visual field defects in ethambutol toxicity, which can be central, peripheral, or both. We had central field defects in 6 eyes of 3 patients (3.23%) and peripheral visual field defects in 4 eyes of 2 patients (2.15%). Central field defect also persisted in 4 eyes of 2 patients even after 4 months of stoppage of ethambutol therapy. Garg et al. and Mahrukh and Bhat had also observed visual field changes following 2 months of ethambutol therapy in 6.3% and 13.63% of eyes, respectively.[5],[11] Menon et al. found peripheral isopter contraction and point defects in 7.69% of eyes, but central fields were normal.[6] However, Kandel et al. did not observe any change in visual field parameters in a study of 44 patients getting ethambutol for 2 months.[4]

In our observation of pattern VER, the mean latency was significantly increased after 2 months without significant change in mean amplitude. This was in agreement with Menon et al., Seth et al., and Srivastava et al., who also used VER as a tool to detect ethambutol-induced optic neuropathy.[6],[13],[14]

We have tested contrast sensitivity by Pelli–Robson chart, which has a high test–retest reliability and is relatively unaffected by the ambient lighting conditions.[15] In our study, mean contrast sensitivity in both eyes was significantly decreased from baseline at the 2nd month of therapy which was similar to Kandel et al.[4] However, Menon et al. had reported no change in contrast sensitivity in their study.[6]

In our observation, there were no significant changes in average as well as superior, inferior, and nasal quadrants RNFL thickness done by OCT. However, there was significant thinning of RNFL in the temporal quadrant after 2 months of therapy with ethambutol. These findings were similar to Chai and Foroozan, Menon et al. and Zoumalan et al.[2],[6],[16] Chai and Foroozan had further observed that a decrease in RNFL thickness is proportional to the severity of the visual function defect.[2] These studies indicate that smaller papillo-macular bundles are most susceptible to ethambutol toxicity like other mitochondrial optic neuropathies.

Although, the exact mechanism of ethambutol-induced optic neuropathy is not known, Heng et al. in a rodent model had observed that ethambutol is toxic to retinal ganglion cells (RGC) bothin vivo and vitro.[17] RGCs became sensitive to normally tolerated levels of extracellular glutamate associated with mitochondrial dysfunction and decreased ATPase activity. They suggested that glutamate antagonists or derivatives of ethambutol which does not cross blood-retinal barrier may be useful in preventing ocular side effects of ethambutol. Yoon et al. also supported this observation of ethambutol toxicity in RGCs of the rodents.[18] The full field electroretinogram (ERG) had been found to be abnormal in presumed ethambutol optic neuropathy by many investigators.[4],[19],[20],[21] It was evident from their observations that cone-driven bipolar cells can also be abnormal in ethambutol toxicity. In an ERG study of the experimental model with fish, ethambutol had been found to have altered the synaptic connections between horizontal cells and cones in a dose-related manner.[22]

Kim and Park in a study of 31 patients had showed that average RNFL thickness increased 5 months after ethambutol treatment (P = 0.032), and P100 latency in pattern VEP was delayed in 2 and 4 months after ethambutol treatment (P = 0.001; P < 0.001, respectively). These early changes in RNFL OCT and pattern VEP progressed 6 months after ethambutol stoppage in 21 patients.[23]

Yang et al., in a large cohort of 415 patients in the Korean population, had observed the incidence of ethambutol-induced optic neuropathy to be 0.7%. The incidence of optic neuropathy was 0.3% in lower doses of ethambutol (≤15 mg/kg/day).[24]

Lee et al. performed OCT of peripapillary and macular RNFL as well as ganglion cell layer plus inner plexus layer (GCIPL) thickness using Early Treatment Diabetic Retinopathy Study circles in ethambutol-induced optic neuropathy. They have observed a 10-μm thickness loss in inner temporal GCIPL in the initial OCT associated with a 0.5 decrease in the amount of logMAR visual acuity recovery at 12 months. They suggested temporal GCIPL as a predictive tool for vision recovery at 12 months after the stoppage of ethambutol.[25]

Jin et al. found subclinical ethambutol-induced optic neuropathy was found in 13% of 168 eyes (84 patients) in the forms of VF index decrease, quadrant RNFL thickness increase and VF pattern defect. Most (73%) of the patients showed recovery to the baseline at 1-month poststoppage of ethambutol.[26]

One limitation of this study is that in rare cases, ocular toxicity can also be contributed by isoniazid, as shown by Şahin et al., which has not been considered here.[27]


  Conclusion Top


It is evident from this study that estimation of visual acuity, color vision, visual field, RNFL thickness, VER and contrast sensitivity at baseline and monthly follow-ups at least up to 6 months of therapy with ethambutol are essential to detect early ocular toxicity. Thereby permanent visual damage can be prevented in most of the cases on the immediate cessation of therapy with ethambutol particularly when the drug is taken for >2 months.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

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2.
Chai SJ, Foroozan R. Decreased retinal nerve fibre layer thickness detected by optical coherence tomography in patients with ethambutol-induced optic neuropathy. Br J Ophthalmol 2007;91:895-7.  Back to cited text no. 2
    
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Kumar V, Abbas AK, Fausto N, Mitchel R. Robbins Basic Pathology. 18th ed. Philadelphia, PA : Saunders/Elsevier; 2007.  Back to cited text no. 3
    
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Kandel H, Adhikari P, Shrestha GS, Ruokonen EL, Shah DN. Visual function in patients on ethambutol therapy for tuberculosis. J Ocul Pharmacol Ther 2012;28:174-8.  Back to cited text no. 4
    
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Mahrukh AA, Bhat MA. Visual field changes in patient receiving antitubercular drug therapy at tertiary care hospital: An analytical observational study. Int J Contemp Med Res 2017;4:346-9.  Back to cited text no. 5
    
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Menon V, Jain D, Saxena R, Sood R. Prospective evaluation of visual function for early detection of ethambutol toxicity. Br J Ophthalmol 2009;93:1251-4.  Back to cited text no. 6
    
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Polak BC, Leys M, van Lith GH. Blue-yellow colour vision changes as early symptoms of ethambutol oculotoxicity. Ophthalmologica 1985;191:223-6.  Back to cited text no. 12
    
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Seth V, Khosla PK, Semwal OP, D'Monty V. Visual evoked responses in tuberculous children on ethambutol therapy. Indian Pediatr 1991;28:713-7.  Back to cited text no. 13
    
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Srivastava AK, Goel UC, Bajaj S, Singh KJ, Dwivedi NC, Tandon MP. Visual evoked responses in ethambutol induced optic neuritis. J Assoc Physicians India 1997;45:847-9.  Back to cited text no. 14
    
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Zoumalan CI, Agarwal M, Sadun AA. Optical coherence tomography can measure axonal loss in patients with ethambutol-induced optic neuropathy. Graefes Arch Clin Exp Ophthalmol 2005;243:410-6.  Back to cited text no. 16
    
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Heng JE, Vorwerk CK, Lessell E, Zurakowski D, Levin LA, Dreyer EB. Ethambutol is toxic to retinal ganglion cells via an excitotoxic pathway. Invest Ophthalmol Vis Sci 1999;40:190-6.  Back to cited text no. 17
    
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Yoon YH, Jung KH, Sadun AA, Shin HC, Koh JY. Ethambutol-induced vacuolar changes and neuronal loss in rat retinal cell culture: Mediation by endogenous zinc. Toxicol Appl Pharmacol 2000;162:107-14.  Back to cited text no. 18
    
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Hennekes R. Clinical ERG findings in ethambutol intoxication. Graefes Arch Clin Exp Ophthalmol 1982;218:319-21.  Back to cited text no. 19
    
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Kakisu Y, Adachi-Usami E, Mizota A. Pattern electroretinogram and visual evoked cortical potential in ethambutol optic neuropathy. Doc Ophthalmol 1987;67:327-34.  Back to cited text no. 20
    
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Kim KL, Park SP. Visual function test for early detection of ethambutol induced ocular toxicity at the subclinical level. Cutan Ocul Toxicol 2016;35:228-32.  Back to cited text no. 23
    
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Yang HK, Park MJ, Lee JH, Lee CT, Park JS, Hwang JM. Incidence of toxic optic neuropathy with lowdose ethambutol. Int J Tuberc Lung. Dis 2016;20:261-4.  Back to cited text no. 24
    
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Lee JY, Choi JH, Park KA, Oh SY. Ganglion cell layer and inner plexiform layer as predictors of vision recovery in ethambutol-induced optic neuropathy: A longitudinal OCT analysis. Invest Ophthalmol Vis Sci 2018;59:2104-9.  Back to cited text no. 25
    
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27.
Şahin A, Kürşat Cingü A, Kaya S, Türkcü G, Arı Ş, Evliyaoǧlu O, et al. The protective effects of caffeic acid phenethyl ester in isoniazid and ethambutol-induced ocular toxicity of rats. Cutan Ocul Toxicol 2013;32:228-33.  Back to cited text no. 27
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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