Visual Function in Patients on Ethambutol Therapy for Tuberculosis

Abstract

Purpose:

Aim of the study was to evaluate the effects of ethambutol therapy in visual functions.

Methods:

Prospective evaluation of 88 eyes of 44 patients on ethambutol therapy under Directly Observed Treatment Short-course (category I) for primary tuberculosis was done before start of ethambutol therapy and after 2 months of starting the therapy. Parameters evaluated were visual acuity with Bailey Lovie Log-MAR chart, contrast sensitivity with Pelli-Robson contrast sensitivity chart, color vision with Farnsworth D15 test, visual fields with Octopus automated perimetry, and multifocal electroretinography (ERG) with Roland-RETI scan along with anterior and posterior segments evaluation.

Results:

No visual functional defect was noted at baseline. On follow-up, color vision, visual field parameters, and anterior and posterior segment findings were not affected in any patients. Mean visual acuity before starting therapy was 0.00±0.08 Log-MAR and after therapy was 0.08±0.18 Log-MAR. Change in visual acuity was statistically significant (p=0.004). Difference between contrast sensitivity before and after therapy was statistically highly significant both monocularly and binocularly (p<0.005 in both cases). P1 amplitudes (in terms of nV/deg² and μV) of ERG waves were significantly reduced and their P1 latencies were significantly increased in all the rings after ethambutol therapy (p<0.05). There was no significant change in N1 amplitudes and N1 latencies after therapy in any of the rings.

Conclusions:

Visual acuity, contrast sensitivity, and multifocal ERG are sensitive tests to detect ethambutol toxicity in subclinical stages and hence very useful tools for monitoring patients under ethambutol therapy for ocular toxicity.

Introduction

Tuberculosis is one of the major diseases of public health importance in the world. It accounts for 2.5% of the global burden of disease.¹ Ethambutol hydrochloride, one of the first-line drugs employed in the treatment of this devastating disease, is used in the initial intensive phase of categories I and II of Tuberculosis. It has the potential to cause toxic optic neuropathy² with a reported incidence that varies widely in different studies ranging from 0.5% to more than 35%.^3–5 There are several reports of permanent visual damage due to ethambutol.^6,7 Reversibility of the toxicity depends on early detection. Visual acuity, color vision, and visual fields that are the usual tests recommended to evaluate ocular effects may not detect cases of early and subclinical toxicity.² Early detection and immediate therapy discontinuation are the only effective management that can halt the progression of vision loss and allow recovery of vision.⁸ Cases of toxicity occurring a few days after initiation of the therapy have been reported.^9,10 No study has reported onset after withdrawal of ethambutol. No “safe dose” of ethambutol has been reported,¹¹ with toxicity observed at doses as low as 12.3 mg/kg per day.¹² In Nepal, the usual daily dose is 15–20 mg/kg for adults whereas it is usually not prescribed to children.

There are many unresolved issues related to ocular toxicity of ethambutol and screening. International guidelines on prevention and early detection of ethambutol-induced ocular toxicity have been published, but views on the use of regular vision tests for early toxicity detection are still divided.^2,6 To our knowledge, no study on the effects of ethambutol therapy in the eye has been done in Nepal. There is a lack of proper referral for regular eye evaluation for patients under ethambutol therapy in Nepal and patients usually visit the eye practitioners when it is too late. Since many clinical tests are performed in this study, it will also help to determine the efficacy of the tests in the detection of subclinical changes induced by ethambutol. Furthermore, this study aims to be helpful in detecting the toxicity in the subclinical stages and hence may prove to be an important step toward its management.

Methods and Tools

This was a prospective study of 44 patients (88 eyes) on ethambutol therapy at a dose of 15–20 mg/kg/day for 2 months under Directly Observed Treatment Strategy (category I) for primary tuberculosis. Examinations were done before start of ethambutol therapy and after 2 months of starting the therapy.

All the cases diagnosed with tuberculosis from the medical outpatient department of Tribhuvan University Teaching Hospital (TUTH) were referred to Directly Observed Treatment Short-course (DOTS) center of TUTH. Among them, the subjects who would receive medications from the DOTS center were referred to the outpatient department of BP Koirala Lions Center for Ophthalmic Studies for detailed ophthalmic evaluation.

Prior to ocular examination, informed consent was obtained from the subjects after the nature of the study was explained to them. The tenets of the Declaration of Helsinki were followed. Detailed ophthalmic evaluation included anterior segment evaluation, visual acuity assessment, refraction, contrast sensitivity assessment, color vision assessment, visual field examination, multifocal electroretinography (ERG), and posterior segment evaluation.

Exclusion criteria included any other ocular or systemic diseases that may have affected the parameters being evaluated. Subjects with best corrected vision less than 0.18 Log-MAR (equivalent to Snellen's 6/9), with preexisting color vision defects, or taking any other drugs known to cause optic neuropathy/maculopathy were excluded from the study. Children below 15 years of age, patients not willing to participate, and subjects lost to follow-up were excluded from the study.

Unaided, pinhole and best corrected visual acuity were recorded using the Bailey Lovie Log-MAR chart. Contrast sensitivity was assessed using the Pelli-Robson CS chart at 1 m distance monocularly and binocularly. Objective refraction was done by using a streak retinoscope (Heine, Beta 200). The final refraction was done by subjective means. Color vision was tested using Farnsworth D15 test under monocular viewing conditions in the same room under similar lighting conditions in both visits. Visual field examination was done using Octopus automated perimetry after measuring the intraocular pressure with Goldmann applanation tonometry. The pupils were dilated with 1% tropicamide. The fundus was examined by direct ophthalmoscopy (Heine, Beta 200) and with a Haag-Streit Slit Lamp with a 90D Volk lens. Any abnormalities in the anterior and posterior segments were noted and the findings were confirmed by a consultant ophthalmologist.

Multifocal ERG was performed using Roland-RETI scan system (Roland Consult, Brandenburg, Germany) under the guidelines given by the International Society for Clinical Electrophysiology for Vision wherever possible.¹³ The patient was properly refracted and the pupils were dilated. Following instillation of 4% xylocaine (AstraZeneca) for topical anesthesia, DTL-thread electrodes (Roland Consult) were placed in both eyes just touching the limbus or nearby bulbar conjunctiva as the active electrode. The points on the skin where the electrodes would be placed were cleaned by a cleaning gel (Electrode PeeNu-Prep; Roland Consult) specific for the purpose. The reference electrodes were kept in the temporal part of the eyes, in the orbital rim. A ground electrode was then placed on the forehead. Conductive glue (TEN 20 conductive EEG-paste; Roland Consult) was used to attach the electrodes on skin. Less than 5 kΩ impedance was achieved in all cases.

Stimulation¹⁴ source used was CRT monitor (17′′ color monitor, luminance 80 cd/m², high contrast; Roland Consult) with frame frequency of 75 Hz. Stimulation calibrations were done as provided by the RETI-scan software (Roland Consult). The high-pass cutoff was 10 Hz and low was 100 Hz. The artifact level was 10%. The records obtained were analyzed in terms of the grouped data, as group averages. The averages were taken in terms of the concentric rings. Duration of the test time was 8 cycles. Fixation was meticulously monitored during the testing duration to prevent abnormal multifocal ERG findings (mERG) due to voluntary eccentric fixation.

Data were analyzed using Statistical Package for the Social Sciences Version 14 (SPSS-14) software and Microsoft Excel 2007. p value less than 0.05 or confidence interval of 95% was regarded as significant.

Results

Mean age of the 44 subjects (88 eyes) included in the study was 26.48±9.50 years. Most of them (82%) were in the age group 15–30. Among them 50% (22) were men and 50% (22) were women. Most of the cases (70.45%) were Indo-Nepalese whereas 29.55% were Tibeto-Nepalese. However, there was no significant difference between Indo-Nepalese and Tibeto-Nepalese races in the visual functions before and after therapy. Most of the cases (56.82%) had pulmonary tuberculosis and 43.18% had extrapulmonary tuberculosis. There was no significant difference in the findings before and after the therapy between the subjects with pulmonary tuberculosis and the subjects with extrapulmonary tuberculosis.

Anterior and posterior segment findings were similar pre- and posttherapy. Mean visual acuity before starting therapy was 0.00±0.08 Log-MAR. Mean visual acuity after therapy was 0.08±0.18 Log-MAR. Change in visual acuity was statistically significant (paired t test; p=0.004). There was a significant difference between contrast sensitivity scores before and after the therapy in both eyes as shown in Table 1. Color vision was normal in every subject.

Table 1.

Contrast Sensitivity

	Before therapy	After therapy	p value
Mean contrast sensitivity—right eye (n=44)	1.83±0.03	1.75±0.08	<0.005
Mean contrast sensitivity—left eye (n=44)	1.84±0.03	1.75±0.07	<0.005
Mean monocular contrast sensitivity (n=88)	1.80±0.26	1.75±0.08	<0.005
Mean binocular contrast sensitivity (n=44)	1.96±0.02	1.88±0.06	<0.005

We considered 3 parameters of automated visual field, namely, mean sensitivity, mean deviation, and loss variance. There was no statistically significant change in the visual field parameters after the therapy (Table 2).

Table 2.

Visual Field Parameters

	Before therapy	After therapy	p value
Mean sensitivity (dB)	28.33±1.62	27.84±1.84	0.485
Mean deviation (dB)	0.90±1.64	1.37±1.78	0.475
Loss variance (dB²)	3.71±2.40	4.88±4.85	0.445

As shown in Table 3, P1 amplitudes (in terms of nV/deg² and μV) were significantly reduced and P1 latencies were significantly increased in all the rings after ethambutol therapy. There was no significant change in N1 amplitudes and N1 latencies in any of the rings after the therapy.

Table 3.

Comparison of Multifocal-Electroretinography Parameters Before and After Therapy

	P1 Amp nV/deg ²			P1 Amp (μV)			N1 Amp (μV)			Implicit time P1 (ms)			Implicit time N1 (ms)
	Before therapy	After therapy	p value	Before therapy	After therapy	p value	Before therapy	After therapy	p value	Before therapy	After therapy	p value	Before therapy	After therapy	p value
Ring 1	94.75±38.53	76.23±35.40	0.02	0.77±0.30	0.61±0.28	0.01	0.28±0.17	0.25±0.18	0.44	45.24±7.22	47.52±3.91	0.05	20.94±6.52	22.46±8.80	0.11
Ring 2	51.99±19.05	41.19±17.05	0.03	0.55±0.19	0.50±0.16	0.03	0.24±0.15	0.22±0.14	0.09	43.29±1.81	43.91±1.75	0.02	23.88±2.50	23.44±5.17	0.95
Ring 3	34.26±7.64	31.14±8.23	0.01	0.51±0.11	0.47±0.12	0.01	0.17±0.08	0.16±0.07	0.82	41.45±1.52	41.85±1.11	0	23.77±1.52	23.88±3.68	0.37
Ring 4	22.86±4.37	20.97±5.24	0.02	0.46±0.08	0.42±0.10	0.03	0.17±0.06	0.16±0.06	0.08	41.08±1.33	41.47±1.26	0	23.05±1.28	23.09±3.12	0.16
Ring 5	15.57±3.58	13.13±4.46	0.01	0.41±0.09	0.35±0.11	0	0.13±0.06	0.12±0.09	0.08	40.71±1.56	41.57±1.40	0	22.39±2.78	23.35±3.12	0.11
Ring 6	12.50±3.39	11.16±3.00	0.03	0.43±0.12	0.38±0.10	0.03	0.14±0.06	0.13±0.06	0.51	41.47±1.65	42.58±1.24	0.04	23.74±1.56	23.92±3.58	0.12

Discussion

The recognition of ocular toxicity as a side effect of ethambutol dates back to 1962 when Carr and Henkind first reported it.¹⁵ The incidence of the toxicity is variably reported in the literature and it appears to be below 1% at the presently used dose of 15–20 mg/kg/day. In our study none of the patients developed clinical symptoms as reported in a prospective study done by Menon et al.² Subclinical toxicity was seen in the form of visual acuity loss, contrast sensitivity loss, and reduction of P1 amplitude with increased latency of ERG waves.

There are no clear risk factors for irreversible visual damage due to the drug, but old age, renal insufficiency, and chronic smoking are said to increase the risk of toxicity.² None of these risk factors were found in the present subjects with the observed subclinical defects.

All the patients recruited obtained the drug from a single source, the DOTS center, which provides free antitubercular drugs, under the revised National Tuberculosis Control Program of the Government of Nepal. This ensured that the drug given to all the patients was of the same potency, thereby avoiding manufacturer-related bias. As per the DOTS requirement all the patients had to take the medicines in front of the DOTS center personnel, which ensured 100% compliance with the therapy.

Contrast sensitivity as measured with the Pelli-Robson chart was affected in most of the patients, unlike earlier reports.⁵ The difference between contrast sensitivity before and after therapy was highly significant both monocularly and binocularly. Arden plates are affected by the ambient lighting conditions, are observer dependent, and are also known to show a high false positive rate.¹⁶ In contrast, the Pelli-Robson chart is relatively unaffected by the ambient lighting conditions, and also has high test-retest reliability.¹⁷

In our study, no color vision defect was detected in any of the patients. However, according to Polak et al.,¹⁸ color vision disturbances are probably the most sensitive indicator of early ethambutol optic neuropathy. Similarly, several previous studies have demonstrated blue-yellow errors in the early stage of intoxication and blue or red-green defects in a later stage of intoxication in patients treated with ethambutol. According to them, these changes in color vision can occur even before visual acuity and visual fields are affected. The degree of recovery depends largely on the extent to which ethambutol has compromised optic nerve function. If the ocular toxicity is not recognized early, the drug can cause permanent loss of vision.¹⁹

The incidence of visual field defects is highly variable among the various studies and the defects were found to be central, peripheral, or both. In general, visual field defects tend to appear with the use of higher dosages of the drug especially in cases with obvious visual deficits.^6,20 There was no change in visual field parameters in this study. Our study supports the view given by Citron, K.M., that visual field evaluation during the treatment serves no useful purpose as it fails to detect ocular toxicity before the symptoms appear.²¹

Previous studies have found abnormalities in the visual evoked potentials,²⁰ full field ERG, and electrooculography in patients with presumed ethambutol optic neuropathy.^22–24 In experiments on fish, ethambutol altered synaptic connections between horizontal cells and cones in a dose-related fashion, resulting in degeneration of the cone pedicles.²⁵ In our study, the P1 amplitudes were found to be significantly lower and P1 latencies were significantly increased in the ethambutol-treated patients compared with their baseline data. The source of the multifocal ERG signals, as in full field ERG, is thought to be from the outer retina with very little contribution from the inner retina (ganglion cell layer).^26,27 Therefore, for a disease to decrease the amplitude of the mERG, the cone-driven bipolar cells must be abnormal. Although there was a statistically significant difference only between the P1 amplitude of the patients before and after the therapy, it is possible that our patient group comprised patients in various stages of ethambutol toxicity.

Because of the small sample size of this study, it is difficult to reach a definite conclusion about our observations. We believe our ERG findings support re-examining the widely accepted notion that ethambutol causes primarily optic neuropathy. In conclusion, our study also suggests that ethambutol usage is associated with a real risk of toxicity.

The patient, the physician, and the ophthalmologist/optometrist must work closely together to make ethambutol a safer drug. The physicians prescribing the drug should be aware of its potential for ocular toxicity, and all patients treated with ethambutol should be educated on its potential side effects. All patients commencing treatment with ethambutol should have a baseline (pretreatment) visual acuity assessment, contrast sensitivity assessment, and multifocal ERG done. These parameters are usually monitored periodically (every 1–3 months) during the treatment of asymptomatic patients. No consensus currently exists regarding the specific visual test and testing intervals appropriate for monitoring asymptomatic patients during treatment,⁹ demanding that the medical personnel makes these decisions at the start of therapy.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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