Ethambutol-Induced Optic Neuropathy : A Case Series

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Ethambutol-Induced Optic Neuropathy: A Case Series

Muhammad Rizqy Abdullah, MD (Neuro-Ophthalmology Unit Fellowship)

Has been reviewed and approved by Supervisor of Neuro-Ophthalmology Unit

Antonia Kartika, MD Rusti Hanindya Sari, MD

NATIONAL EYE CENTER CICENDO EYE HOSPITAL BANDUNG

2023

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Ethambutol-Induced Optic Neuropathy: A Case Series

Abstract

Introduction: Tuberculosis remains a global health problem, with the use of ethambutol as primary drug could resulted in toxic optic neuropathy with variety of presentation.

Purpose: The purpose of this study is to report cases of toxic optic neuropathy caused by ethambutol use.

Case Report:

Case 1: A 46-year-old female with three-week symptoms of blurred vision on both eyes with a history of ethambutol use for six months for pulmonary tuberculosis. Her visual field examination revealed bitemporal hemianopia. The patient regained her vision after discontinuation of ethambutol after five-month evaluation.

Case 2: A 45-year-old female with blurred vision on both eyes for two weeks with a history of five months use of ethambutol due to pulmonary tuberculosis. Patient had systemic hypertension. Examination showed generalized depression visual field defect on both eyes.

However, despite drug cessation she had poor visual prognosis with optic atrophy on both eyes.

Case 3: A 33-year-old male with one month blurred vision with the history of tuberculosis and ethambutol use for eight months. Visual field examination showed central scotoma on both eyes. After discontinuation of ethambutol, patient regained his visual acuity in two-months follow-up.

Case 4: A 46-year-old female with gradual painless visual loss in both eyes for 3 months. She had received ethambutol as tuberculosis therapy for seven months. There was central scotoma on her visual field. Within 3 months after discontinue ethambutol, there was increased visual acuity.

Conclusion: Ethambutol could cause toxic optic neuropathy with variety of presentation and prognosis thus regular screening is important in patients with anti-tubercular therapy.

Keywords: Ethambutol, Tuberculosis, Toxic optic neuropathy, Ethambutol optic neuropathy, Toxicity

I. Introduction

Tuberculosis remains a global health problem with an estimate 10 million total incidence and 1.4 million deaths. The majority of cases are in developing countries, with Indonesia has the second largest tuberculosis burden globally, with an estimate 969,000 total incidence and prevalence rate 354/100,000 population [1]. Ethambutol had been used widely as the first-line drug, associated with other drugs, for the treatment of tuberculosis. The drug is generally well-tolerated, but however the adverse effects of this drug has been documented since its original use, with the most severe being toxic optic neuropathy. The reported incidence varies in different studies, ranging from 0.5 to more than 35%, with another study in 22.5 cases per 1,000 patients [2-5].

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Clinical presentation of ethambutol-induced optic neuropathy is usually bilateral and can be asymmetric, with reduced contrast sensitivity, painless loss of central vision, and dyschromatopsia. Visual field defect is usually a central or cecocentral scotoma, but bitemporal hemianopia have also been described [6]. Symptoms usually appear between four and twelve months after the use of ethambutol [7]. A study describes a dose-related incidence of ocular side effects with the higher dose resulting in higher incidence of optic neuropathy [8]. It is also apparent that ethambutol-induced optic neuropathy can occur despite close ophthalmologic monitoring and the ocular toxicity can be irreversible, permanent, and cause blindness [3].

The purpose of this study is to report cases of ethambutol-induced optic neuropathy.

These cases present with variety of clinical presentation and different visual prognosis.

II. Case Series Case 1

Patient 1 is a 46-year-old female weighing 62 kg with gradual painless visual loss in both eyes for 3 weeks. She had received treatment of anti-tuberculosis drug including isoniazid, rifampicin, pyrazinamide, and ethambutol (1500 mg/day or 25 mg/kg/day) since 6 months prior due to pulmonary tuberculosis. Patient had finished her anti-tubercular therapy two days before initial visit. Patient had no history of any ocular disease previously. There was no history of diabetes, systemic hypertension, renal diseases, alcohol intake, and smoking. Her vital signs were normal. Her best-corrected visual acuity (BCVA) was 0.63 for right eye and 0.8 for left eye. Her color vision using Ishihara plates was 8/38 for right eye and 20/38 for left eye, and Roth 28 hue test showed no abnormality. Her contrast sensitivity using Mars contrast sensitivity book (Mars Perceptrix, Chappaqua, NY, USA) were 1.25% for both eyes. The slit- lamp microscope examination of anterior segments indicated no abnormality. The pupils were normal with no relative afferent pupillary defect (RAPD). The fundus examination revealed normal optic nerve head for right eye and inferior optic nerve head swelling with peripapillary hemorrhage for left eye (Fig.1A). Optical Coherence Tomography (OCT, Carl-Zeiss Meditec, Inc, Dublin, CA) demonstrated inferior retinal nerve fiber layer thickening with nasal layer had the least thickness for left eye (Fig 1B). Automated Perimetry examination (Humphrey Field Analyzer, Carl Zeiss Meditec, Inc, Dublin, CA) indicated bitemporal hemianopia visual field defects (Fig.1C). Her head and orbital CT-scan result revealed no abnormalities. Based on the ocular examinations listed above, the patient was diagnosed as ethambutol-induced optic

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neuropathy. The patient already discontinued the ethambutol and given neurotrophic agents (Q10 coenzyme 30 mg three times daily, methylcobalamin 500 mcg once daily, zinc 20 mg once daily). One-month follow-up, patient came with visual acuity 0.63 both eyes with better result in color vision test (Ishihara plate 37/38 for both eyes) and contrast sensitivity test (1.25%

for both eyes). There was progress on her visual field defect at follow-up (Fig.1D). Within five- months evaluation, her BCVA was 1.0 for both eyes with recovery of dyschromatopsia (Ishihara plate 38/38 for both eyes) and good contrast sensitivity.

Fig. 1A. Fundus photograph at initial visit of case 1. Fundus photography of left eye showed inferior swelling with peripapillary hemorrhage.(LE=Left Eye;RE=Right Eye)

Fig 1B. OCT result at initial visit of case 1. There was inferior inferior retinal nerve fiber layer thickening of left eye.

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Fig 1C. Automated perimetry at initial visit shown bitemporal hemianopia defect

LE RE

Fig.1D. Follow-up 1 month after discontinuation of ethambutol at case 1. Note there was progress on visual field defect compared to initial examination.

Case 2

Patient 2 is a 45-year-old female weighing 54 kg with progressive visual loss in both eyes for 2 weeks. She had received treatment of anti-tuberculosis drug including ethambutol (1000 mg/ day or 18,5 mg/kg/day) since 5 months prior due to pulmonary tuberculosis. Patient had no history of any ocular disease previously. Patient had history of systemic hypertension.

There was no history of diabetes, renal diseases, alcohol intake, and smoking. Her vital sign was normal except for blood pressure which is 145/90. Her BCVA was 0.2 for right eye and 0.125 for left eye. Her color vision using the Ishihara plates was 1/38 (demoplate only) for right eye and 0/38 for left eye. Her Farnsworth test result was unspecific for both eyes. Contrast sensitivity examination using Mars contrast sensitivity book were >25% for both eyes. Ocular examination revealed decreased light reflex on both eyes with grade II RAPD on left eye and minimal lens opacity both eyes. The fundus examination revealed superior and inferior optic nerve head swelling both eyes. Automated Perimetry (Humphrey Field Analyzer, Carl Zeiss Meditec, Inc, Dublin, CA) indicated complete loss of visual field defects both eyes (Fig 2A).

Optical Coherence Tomography (OCT, Carl-Zeiss Meditec, Inc, Dublin, CA) demonstrated superior and inferior thickening of retinal nerve fiber layer both eyes with nasal nerve fiber layer had the least thickness (Fig 2B). Her CT-scan result revealed no abnormalities and HIV test was negative. Based on examinations above, patient was diagnosed as ethambutol-induced

Patient: ELIS SURYANI, NY

Date of Birth: Apr 14, 1975 Gender: Female Patient ID: 951390

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6 optic neuropathy. The ethambutol was not discontinued yet at initial visit but we advised the internist to stop the ethambutol. The patient was given neurotrophic agents (Q10 coenzyme 30 mg three times daily, methylcobalamin 500 mcg once daily, zinc 20 mg once daily) and amlodipine 10 mg. However, two weeks after initial visit, her visual acuity already decreased to 1/60 for right eye and counting finger for left eye. The internist discontinued the ethambutol.

After two-month evaluation, her visual acuity was 1/60 for right eye and counting finger for left eye. Patient finished her anti-tuberculosis therapy for nine months with the exception of ethambutol discontinuation after five month-use. Within seven-month evaluation after initial visit, her BCVA was 1/60 for right eye and increased visual acuity on left eye with 2/60. Patient was later consulted to low vision division, with monofocal glasses and spectacle magnifier.

Papil OCT(Fig.2C) at follow-up showed decreased retinal nerve fiber layer both eyes, with macular OCT (Fig.2D) shown decreased of internal limiting membrane layer both eyes. One- year follow-up patient came with 1/60 both eyes, color vision using Ishihara was unable to evaluate, contrast sensitivity result >25%, and optic atrophy at both eyes (Fig 2E).

LE RE

Fig 2A. Automated perimetry at initial visit at case 1 shown complete loss of visual field.

RE LE

Fig 2B. OCT examination at initial visit at case 2. There was increased thickness of superior and inferior retinal nerve fiber layer at both eyes.

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Date of Birth: Jun 12, 1976 Gender: Female Patient ID: 964036

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RE LE

Fig 2C. OCT examination at follow-up (9 month) at case 2. There was decreased thickness at retinal nerve fiber layer of both eyes.

RE LE

Fig 2D. Macular OCT at follow-up examination (9 month) at case 2. There was decreased thickness of Internal Limiting Membrane at both eyes.

Fig 2E. Fundus Examination at one-year follow-up showed optic atrophy at both eyes.

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8 Case 3

Patient 3 is a 33-year-old male weighing 69 kg with gradual visual loss in both eyes for 1 month. He had received treatment of anti-tuberculosis drug including ethambutol (1500 mg/day or 21 kg/mg/day) 8 months prior due to pulmonary tuberculosis. There was no history of hypertension, renal diseases, alcohol intake, and smoking. Patient had history of metformin use for diabetes mellitus. Her BCVA was 3/60 for right eye and 0.2 for left eye. His color vision using the thirty-eight plate Ishihara Color was 4/38 for right eye and 7/38 for left eye.

Farnsworth test showed no abnormality. Contrast sensitivity were 25% for right eye and 1.25%

for left eye. There was decreased light reflex on both eyes without any RAPD. The fundus examination revealed superior and inferior optic nerve head swelling both eyes. Optical Coherence Tomography (OCT, Carl-Zeiss Meditec, Inc, Dublin, CA) demonstrated increased superior and inferior retinal nerve fiber layer thickness on both eyes (Fig 3A). Automated Perimetry (Humphrey Field Analyzer, Carl Zeiss Meditec, Inc, Dublin, CA) indicated central scotoma on both eyes (Fig 3B). His CT-scan result revealed no abnormalities. His ureum and creatinine function were normal (16 and 0.92 respectively). Based on the ocular examinations listed above, this patient was diagnosed as ethambutol-induced optic neuropathy. The patient discontinued the ethambutol and given neurotrophic agents (Q10 coenzyme 30 mg three times daily, methylcobalamin 500 mcg once daily, zinc 20 mg once daily). Two weeks after, patient came with OD 0.2 and OS 0.2 with enlarged central scotoma on both eyes (Fig 3C), Ishihara plates 8/38 for right eye and 9/38 for left eye, with contrast sensitivity 1.25% both eyes.

However, within two-month follow up, the visual acuity increased to 0.63 for right eye and 0.5 for left eye, Ishihara was 17/38 for right eye and 19/38 for left eye, and good contrast.

RE LE

Fig 3A. OCT examinaton at initial visit for case 3 showed increased thickness of superior and inferior retinal nerve fiber layer both eyes.

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Name:

6/10 11:08 AM 6/14/2022

ASEP SUDRAJAT, TN

11:08 AM 8/10

OD OS

Serial Number: 5000-6298 5000-6298

RNFL Deviation Map

RNFL Quadrants

RNFL Clock Hours

RNFL Thickness

6/14/2022 CZMI

OS OD

Signal Strength:

Exam Time:

Exam Date:

Technician:

Gender:

DOB:

ID:

Name:

6/10 11:08 AM 6/14/2022

ASEP SUDRAJAT, TN

11:08 AM 8/10

OD OS

Serial Number: 5000-6298 5000-6298

RNFL Deviation Map

RNFL Quadrants

RNFL Clock Hours

RNFL Thickness

(9)

LE RE

Fig 3B. Automated perimetry at initial visit for case 3 showed central scotoma both eyes.

LE RE

Fig 3C. Automated perimetry at two-weeks follow-up for case 3 showed increased central scotoma both eyes.

Case 4

Patient 4 is a 46-year-old female weighing 41 kg with gradual painless visual loss in both eyes 3 months prior initial visit. She had received treatment of anti-tuberculosis drug for 14 months, including cycloserine 250 mg/day, pyrazinamide 1500 mg/day, and ethambutol (1000 mg/day or <25 mg/kg/day) since 7 months ago prior due to pulmonary tuberculosis.

Patient had discontinued ethambutol and replaced with levofloxacin 750 mg/day from her internist one month before initial visit. Patient had no history of any ocular disease previously.

There was no history of diabetes, systemic hypertension, renal diseases, alcohol intake, and smoking. Her vital signs were normal. BCVA was 2/60 for right eye and 0.05 for left eye. Her color vision using Ishihara plates was 1/38 (demoplate only) both eyes. Roth 28 Hue Test according to Farnsworth showed unspecified. Contrast sensitivity using Mars Contrast Sensitivity book were 2.5% both eyes. The slit-lamp microscope examination of bilateral anterior segments showed decreased light reflex with no RAPD and others were unremarkable.

The fundus examination revealed hyperemic with blurry edge optic nerve head both eyes.

Patient: ASEP SUDRAJAT, TN

Date of Birth: Mar 25, 1989 Gender: Male Patient ID: 964766

Fixation Monitor:

Fixation Target:

Fixation Losses:

False POS Errors:

False NEG Errors:

Test Duration:

Fovea:

Blind Spot Central 8/21 XX 2%5%

07:51 26 dB

Stimulus:

Background:

Strategy:

Pupil Diameter:

Visual Acuity:

Rx:

III, White 31.5 asb SITA Standard +1.00 DS

Date:

Time:

Age:

Jul 01, 2022 12:33 PM 33

10° 10° 10°

29 28 27 25 27 21 20 26 27 29 24 28 16 21 23 28 28 28 24 26 17 14 13 21 28 29 27 25 16 6 16 12 0 21 28 29 28 25 14 14 27 25 27 16

29 29 28 26 28 27 29 26 29 31 29 28 30 29 30 28

27 31 31 30 29 29 29 30 -3 -4

-6 -8 -6 -12-13 -7 -6 -5 -10 -6 -18-13-10 -4 -6 -6 -10 -9 -17-20-21-13 -5 -5 -7 -10-19-29-19-23-33-12 -5 -5 -7 -10-21-22 -8 -10 -7 -17

-5 -5 -6 -9 -7 -8 -6 -7 -4 -3 -4 -6 -4 -5 -4 -6 -6 -2 -3 -4 -4 -4

-4 -3

1 0 -2 -4 -2 -8 -9 -3 -2 -1 -6 -2 -14 -9 -6 0 -2 -2 -6 -5 -13-16-17 -9 -1 -1 -3 -6 -15-25-15-19-29 -8 -1 -1 -3 -6 -17-18 -4 -6 -3 -13 -1 -1 -2 -5 -3 -4 -2 -3 0 1 0 -2 0 -1 0 -2

-2 2 1 0 0 0 0 1

MD10-2: -9.04 dB P < 1%

PSD10-2: 6.67 dB P < 1%

*** Low Test Reliability ***

P < 5% P < 2% P < 1%

Comments

Patient: ASEP SUDRAJAT, TN

Date of Birth: Mar 25, 1989 Gender: Male Patient ID: 964766

Fixation Monitor:

Fixation Target:

Fixation Losses:

False POS Errors:

False NEG Errors:

Test Duration:

Fovea:

1%05:50 24 dB

Stimulus:

Background:

Strategy:

Pupil Diameter:

Visual Acuity:

Rx:

III, White 31.5 asb SITA Standard +1.00 DS

Date:

Time:

Age:

Jul 01, 2022 12:44 PM 33

10° 10° 10°

29 27

29 29 29 28 30 29

28 30 30 29 26 29 29 30

30 29 29 32 28 27 29 28

30 30 29 29 28 22 23 26 28 23

29 30 29 29 28 24 23 24 29 28

30 31 28 29 28 25 27 29

30 29 29 31 30 29 29 32

30 30 32 31 32 30

30 -3 30

-5 -4 -3 -3 -5 -3 -3

-5 -3 -4 -4 -7 -4 -4 -3

-4 -5 -5 -3 -7 -7 -5 -5

-3 -4 -6 -6 -8 -13 -12 -9 -6 -10

-4 -4 -5 -6 -7 -11 -13 -11 -5 -5

-4 -4 -6 -6 -7 -10 -7 -5

-4 -4 -5 -3 -4 -5 -4 -2

-3 -4 -1 -2 -1 -3

-2 -3

0 -2

-1 0 -1 -2 0 0

-2 0 -1 -1 -4 -1 -1 0

-1 -2 -3 0 -4 -4 -2 -2

0 -1 -3 -3 -5 -10 -9 -6 -3 -7

-1 -1 -2 -3 -4 -8 -10 -8 -2 -2

-1 -1 -4 -3 -4 -7 -4 -2

-1 -1 -2 0 -1 -2 -1 1

-1 -1 2 0 2 0

1 0

MD10-2: -5.13 dB P < 1%

PSD10-2: 2.60 dB P < 1%

P < 5%

P < 2%

P < 1%

Comments