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 Table of Contents  
CASE SERIES
Year : 2022  |  Volume : 34  |  Issue : 1  |  Page : 55-61

Ethambutol-induced optic neuropathy: A case series


Department of Ophthalmology, Giridhar Eye Institute, Kochi, Kerala, India

Date of Submission16-May-2021
Date of Acceptance09-Jun-2021
Date of Web Publication21-Apr-2022

Correspondence Address:
Dr. Anna Elias
Department of Ophthalmology, Giridhar Eye Institute, Kadavanthra, Kochi, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/kjo.kjo_114_21

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  Abstract 


In this observational case series, we describe the clinical features and investigations of three patients with ethambutol-induced optic neuropathy (EION). All three patients had a significant visual loss within 3 months to 1 year of starting antitubercular treatment. Visual field examination revealed bitemporal hemianopia in one patient and central scotomas in another. Optical coherence tomography showed significant global thinning of the ganglion cell layer and thinning of the temporal quadrants of the retinal nerve fiber layer. Visual evoked potential revealed prolonged P1 or P2 latency and reduced amplitude in all three patients. Ethambutol was stopped in all three patients. The visual acuity continued to deteriorate even after stopping the drug but showed gradual improvement over a period of one and a half years. However, the visual recovery was not full in all three patients. Considering the severity and partially irreversible nature of the loss of vision caused by EION, it is imperative to detect it at an early and subclinical stage.

Keywords: Antitubercular treatment, bitemporal hemianopia, ethambutol induced optic neuropathy, ganglion cell layer, humphrey field analyzer, optical coherence tomography, retinal nerve fiber layer, visual evoked potential


How to cite this article:
Elias A, Neena R, Giridhar A. Ethambutol-induced optic neuropathy: A case series. Kerala J Ophthalmol 2022;34:55-61

How to cite this URL:
Elias A, Neena R, Giridhar A. Ethambutol-induced optic neuropathy: A case series. Kerala J Ophthalmol [serial online] 2022 [cited 2022 May 16];34:55-61. Available from: http://www.kjophthal.com/text.asp?2022/34/1/55/343668




  Introduction Top


Tuberculosis caused by Mycobacterium Tuberculosis is one of the major systemic infections in the world.[1] In India, diagnosis and treatment of tuberculosis is based on Revised National Tuberculosis Control Programme (RNTCP) guidelines.[2] According to the updated RNTCP guidelines, all new cases of tuberculosis are treated with an intensive phase, consisting of 2 months of Rifampicin, Isoniazid, Ethambutol and Pyrazinamide on daily dosages as per four weight band categories, followed by a continuation phase in which Pyrazinamide is stopped and Rifampicin, Isoniazid and Ethambutol are continued for 4 months.[3],[4]

Ethambutol was introduced in 1961 as a bacteriostatic agent for Mycobacterium Tuberculosis. In 1962, Carr and Henkind first reported Ethambutol-induced optic neuropathy (EION). The exact mechanism of ocular toxicity remains to be established. It might result from decreased levels of copper in the mitochondria or from the accumulation of zinc in the lysosomes of the retinal ganglion cells.[5] EION is related to dose and duration. The standard daily dose of Ethambutol is 15 mg/kg of body weight given as a single dose. Higher dose, prolonged duration, diabetes mellitus, hypertension, older age, tobacco smoking, alcohol consumption, and poor renal function are risk factors for EION.[6] Toxic optic neuritis may be of early or late-onset, reversible or irreversible and axial or periaxial. Ethambutol can cause visual impairment as a result of retrobulbar neuritis which is related to the dose and duration of treatment.

In this case series, we discuss three patients who presented with EION with a similar spectrum of clinical features.


  Case Reports Top


Case 1

A 45-year-old female patient presented with defective vision in both eyes for the past 2 weeks. She had been started on antitubercular medication 5 months earlier for tuberculous lymphadenitis. She was on Rifampicin, Isoniazid, Ethambutol, and Pyrazinamide. Her best-corrected visual acuity (BCVA) at presentation was 6/9, N6 (RE) and 6/18, N18 (LE). Within 2 days, her visual acuity dropped to 6/18, N8 (RE) and counting finger 2 m, N36 (LE). She was a known diabetic for the past 15 years and a hypertensive for 3 years, on treatment. Anterior segment examination was normal. Pupils were reacting normally to light. Fundus examination was normal in both eyes.

She underwent visual field examination (Central 30–2 threshold test, SITA standard) which revealed bitemporal hemianopia [Figure 1]a,[Figure 1]b,[Figure 1]c,[Figure 1]d. Color vision was defective in both eyes. Ishihara color plates were used to test color vision. She could identify 9/21 (RE) and 5/21 (LE) plates. Full-field flash Visual evoked potential (VEP) revealed delayed P2 latency and reduced amplitude in both eyes. A magnetic resonance imaging (MRI) of the brain and orbit was normal. Optical coherence tomography (OCT) done revealed thinning of the ganglion cell layer (GCL) in both eyes and normal thickness of the retinal nerve fiber layer (RNFL) in the right eye and thinning of the temporal quadrant of the RNFL in the left eye [Figure 1]e,[Figure 1]f,[Figure 1]g. A diagnosis of ethambutol induced optic neuropathy (EION) was made. Ethambutol and Isoniazid were stopped initially. A month later, the patient stopped all antitubercular medication. She was started on multivitamin and mineral supplements. Her vision continued to deteriorate. Six weeks later her visual acuity had plummeted to counting finger 2 m, <N36 (RE) and counting finger 1 m, <N36 (LE).
Figure 1: (a) OD humphrey field analyser 30–2.5.13.18, (b) OS humphrey field analyser 30-2.5.3.18, (c) OD Macula 5.3.18, (d) OS Macula 5.3.18, (e) OD ganglion cell layer 23.5.18, (f) OS ganglion cell layer 23.5.18, (g) OU RNFL 5.3.18, (h) OD humphrey field analyser 30-2 2.5.19, Size 5 stimulus, (i) OS humphrey field analyser 30-2 2.5.19, size 5 stimulus, (j) OU MC 2.5.19, (k) OU ganglion cell layer 2.5.19, (l) OD RNFL FU 2.5.19, (m) OS RNFL FU 2.5.19. (MC – Muliticolour photo, FU – Follow up)

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She was lost to follow-up for a year. When she returned, her visual acuity had improved to 6/60, N36 (RE) and 6/60, N18 (LE). She was continued on multivitamin and mineral supplements. In her last follow up at 20 months after stopping Ethambutol and Isoniazid, her BCVA was 6/24, N8 (RE) and 6/18, N6 (LE). Humphrey field analyzer (HFA) 30–2 using size V stimulus showed normal visual fields [Figure 1]h and [Figure 1]i. Full-field Flash VEP showed normal P2 latency and normal amplitude. Fundus examination did not show disc pallor [Figure 1]j. OCT done showed extensive thinning of the GCL in all quadrants and thinning of the RNFL in the superior, inferior and temporal quadrants in both eyes [Figure 1]k,[Figure 1]l,[Figure 1]m.

To summarize, a 45-year-old female patient was diagnosed to have EION after 5 months of antitubercular medication. Ethambutol and Isoniazid were stopped. She was put on multivitamin and mineral supplements. Her visual acuity continued to drop despite stopping all antitubercular treatment (ATT), but she had partial recovery of vision after one and a half years.

Case 2

A 69-year-old female was referred to our hospital with a history of defective vision in both eyes for the past 3 months. She was diagnosed to have pulmonary tuberculosis and was started on ATT 3 months earlier. She was also a known case of rheumatoid arthritis on tab Hydroxychloroquine (HCQ). Her initial BCVA was 6/6, N6 (RE) and 6/12, N6 (LE). Anterior segment examination showed posterior synechiae in the right eye and pseudophakia. She had an immature senile cataract in the left eye. Intraocular pressure measured by Goldmann Applanation Tonometer was 14 mmHg in the right eye and 13 mmHg in the left eye. Pupillary reaction was slightly sluggish in the right eye and normal in the left eye. Fundus examination revealed small discs with slightly blurred margins and a dull foveal reflex in both eyes [Figure 2]a. Visual field examination (HFA 30–2) revealed central scotomas in both eyes and peripheral constriction in the left eye [Figure 2]b and [Figure 2]c. OCT showed normal GCL and RNFL values [Figure 2]d and [Figure 2]e. Color vision was defective in the left eye (11/21) and almost normal in the right eye (20/21). Multifocal ERG revealed grossly reduced foveal, parafoveal, and perifoveal ring responses in the right eye and a reduced foveal peak in the left eye [Figure 2]f and [Figure 2]g. However, the ellipsoid zone was intact in both eyes signifying that there was no significant retinal toxicity due to HCQ.
Figure 2: (a) CP 2.12.21, (b) OD humphrey field analyser 30-2 12.11.19, (c) OS humphrey field analyser 30-2 12.1119, (d) OU ganglion cell layer 13.12.19, (e) OU Cirrus OCT ONH and RNFL, (f) OD MFERG 14.11.21, (g) OS MFERG 14.11.21, (h) OD humphrey field analyser 30-2 12.2.21, (j) OD ganglion cell layer FU 12.2.21, (k) OS ganglion cell layer FU 12.2.21, (l) OD RNFL FU 12.2.21, (m) OS RNFL FU 12.2.21. (CP – Colour photo, MFERG – Multifocal ERG)

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Pattern VEP showed borderline P1 latency for both checker sizes and reduced amplitude for 1° and 15 min checker size for both eyes, the left eye being more affected. MRI of the brain was normal. She was diagnosed to have EION. Ethambutol and Isoniazid were stopped. She was supplemented with multivitamins. Her rheumatologist stopped HCQ also.

She reported a month later with a significant drop in vision in both eyes CF3 m, N36 (RE) and CF2 m, N36 (LE)]. A repeat HFA 30–2 using size V stimulus showed a central scotoma in both eyes. OCT showed normal GCL and RNFL values.

Six months later, her vision showed significant improvement in the right eye. BCVA was 6/9, N6 (RE) and 6/60, N18 (LE). Color vision also improved to 21/21 (RE) and 14/21 (LE). Fundus examination was unremarkable. OCT showed generalized thinning of the GCL in both eyes. RNFL values were normal in both eyes.

At the 10th month visit, her BCVA was 6/9, N6 (RE) and 6/60, N18 (LE). HFA 30–2 showed improvement in both eyes [Figure 2]h and [Figure 2]i. OCT revealed further deterioration of GCL and temporal thinning of RNFL in both eyes.

She was reviewed 1 year after stopping Ethambutol and Isoniazid. Her BCVA had improved significantly in the left eye also 6/6, N6 (RE), 6/12, N6 (LE)]. GCL and RNFL showed thinning in both eyes. The right eye showed thinning of RNFL in the inferotemporal quadrant and the left eye showed thinning of the temporal and inferotemporal quadrants, corresponding to worse visual acuity in the left eye [Figure 2]j and [Figure 2]k. HFA 30–2 showed significant improvement in the visual fields in both eyes [Figure 2]l and [Figure 2]m.

To summarize, a 69-year-old female was diagnosed to have EION 3 months after starting ATT. Ethambutol and Isoniazid were stopped. She was put on multivitamin and mineral supplements. Visual acuity continued to drop despite stopping Ethambutol and Isoniazid, but she had a significant and slow recovery of vision a year after stopping Ethambutol.

Case 3

A 24-year old, malnourished young female presented with defective vision in both eyes for the past 2 weeks. She had been diagnosed to have tuberculosis of the ankle bones and was started on ATT 5 months earlier. She was on Rifampicin, Isoniazid, Pyrazinamide and Ethambutol. She had no systemic illness. She had ulcers on both feet. Her initial visual acuity was CF2 m in the right eye and CF1 m in the left eye. She was illiterate, hence near vision, recorded as reduced Snellen, was 6/24 in the right eye and 6/45 in the left eye. Ethambutol had been stopped 2 weeks earlier. Pupils were reacting normally to light. Fundus examination showed a normal disc and macula in both eyes [Figure 3]a. Visual fields and color vision could not be assessed due to her poor visual acuity. Standard deviation (SD)-OCT revealed normal thickness of RNFL and marginal thinning of GCL in both eyes [Figure 3]b,[Figure 3]c,[Figure 3]d.
Figure 3: (a) Disc macula wide field image OU 16.12.20, (b) RNFL OD FU 16.12.20 to 17.3 21, (c) OS RNFL FU 16.12.20 to 17.3.21, (d) OU ganglion cell layer FU 16.12.20, 28.1.21, (e) OU ganglion cell layer FU 17.3.21, (f) OU F VEP 24.12.20. (FU – follow up, F VEP – Flash visual evoked potential)

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She was started on multivitamin supplements. Full-field flash VEP revealed delayed P2 latency in both eyes and reduced amplitude in the left eye [Figure 3]f. Six weeks later, her visual acuity was CF1 m in both eyes. Fundus examination showed mild temporal pallor in both eyes. A repeat SD-OCT showed progressive thinning of both GCL and RNFL in both eyes [Figure 3]b,[Figure 3]c,[Figure 3]d,[Figure 3]e. RNFL thinning was visible in the inferotemporal quadrants in both eyes and in temporal quadrants also in the left eye. As her vision was worsening, Isoniazid was also discontinued. The patient stopped ATT on her own a month later. She was reviewed 6 weeks later. Her visual acuity had improved to 6/18, N18 in the right eye. However, the vision in the left eye remained the same at CF1 m, <N36. She was on levofloxacin for her leg ulcers.

To summarize, a young female patient was diagnosed to have EION after 5 months of ATT. Ethambutol and Isoniazid were stopped and she was put on multivitamin supplements. RNFL and GCL showed progressive thinning, the left eye being more involved. Her visual acuity in the right eye showed significant improvement. However, the vision in the left eye remained the same.


  Discussion Top


In this observational case series, we describe the clinical features and investigations of three patients with EION. All three patients were women with ages ranging from 24 to 69 years. All three presented with defective vision, 3 months to 1 year after starting ATT. The deterioration of vision was rapid and significant, reaching levels such as counting finger 1 m, <N36, and continued to progress despite cessation of ATT. Visual field examination showed bitemporal hemianopia in one patient and central scotomas in another. VEP in all three patients revealed prolonged P1 or P2 latency and reduced amplitude. All three patients showed significant thinning of the GCL in all quadrants and thinning of the RNFL mainly in the inferotemporal and temporal quadrants.

Ethambutol and Isoniazid were stopped. Initially, the vision continued to deteriorate even after stopping the drugs. There was a gradual recovery of visual acuity within a time period of one and a half years. The 24–year-old patient showed a faster recovery of visual acuity compared to the two older patients. The patients were started on multivitamins. There was a significant improvement in the visual fields one to one and a half years after stopping Ethambutol. However, the visual recovery was not complete in all three patients. The improvement in vision was not parallel in both eyes.

EION is one of the most common drug-induced optic neuropathies. It is one of the most important first-line drugs used in the treatment of tuberculosis. The incidence of optic neuropathy is dose-dependent. The incidence is reported to be 5% for patients on 25 mg/kg/day and <1% in patients treated with 15 mg/kg/day.[7]

EION usually presents between 3 and 5 months of starting ATT, though toxicity as early as one and a half months and as late as 12 months of starting therapy have been reported.[8] Our three patients presented between 3 and 5 months of starting ATT.

Considering the severity of the visual loss caused by EION, it is imperative to detect it at an early and subclinical stage to prevent permanent visual loss. The screening modalities used are visual field examination, OCT, and VEP.

Fundus examination in the initial stages is normal, but in the later stages as optic atrophy progresses, disc pallor is noted more specifically temporal pallor.

Visual field examination reveals central, centrocecal scotoma or bitemporal hemianopia. In a case series of six patients reported by Mendel et al., four patients presented with bitemporal hemianopia.[9] The temporal field was most commonly affected and the superotemporal quadrant was involved in all their patients. It appears that the retinal ganglion cells and their axons located in an inferior and nasal distribution are more susceptible to EION, causing superotemporal field defects.

OCT provides an objective and quantitative measures of retinal damage. Studies have shown gradual thinning of the RNFL, more significantly in the temporal quadrant of the peripapillary RNFL.[10] Lee et al. have shown that loss of ganglion cell inner plexiform layer (GCIPL) thickness indicated early neuronal loss (earlier than RNFL).[11] An important finding in their study was that the amount of reduction in temporal GCIPL thickness negatively correlated with the degree of vision recovery. In their results as the thickness of the remaining GCIPL increased and damage to the GCIPL decreased during follow-up, the possibility of visual recovery before permanent retinal ganglion cell death increased. Therefore, the measurement of GCIPL thickness could predict visual recovery after stopping Ethambutol.

Lee et al. noted that temporal GCIPL thinning could be related to poorer visual acuity and become a reflection of the severity of EION. Early GCIPL thinning that is present at the onset of symptoms precedes cpRNFL changes that increase at symptom onset and later normalize at 6 months. They recommend using temporal GCIPL over cpRNFL or macular RNFL as an anatomic marker to predict visual acuity improvement in early phase EION. Although color vision, visual fields, and pattern VEP are sensitive diagnostic tools for EION, they can be performed only in patients with reasonably good vision. OCT is the only diagnostic tool that can be performed, irrespective of the quality of vision.

Pattern VEP is a sensitive and early indicator of Ethambutol toxicity.[12],[13] Subclinical toxicity in the form of increased latency of P100 wave of pattern VEP was associated with consumption of a higher daily dose of Ethambutol (18 mg/kg/day).[14]

In our case series, multiple investigations were performed including color photo, visual fields, SD-OCT, VEP, and ERG. Two of the patients showed defective color vision at the initial visit. One of them showed normal GCL and RNFL values on OCT. Though we have presented a small number of patients in our case series, we could infer, which investigations could indicate EION in the subclinical stage. When a suspected case of EION is referred by a physician to the general ophthalmologist, it would be prudent to check color vision as most ophthalmologists would have Ishihara's Charts. Characteristic visual field defects could also point to EION. Our series also showed GCL thinning in the early stages and RNFL thinning, mainly in the inferotemporal and temporal quadrants in the later stage.

VEP proved to be a sensitive indicator of EION. All three patients showed delayed P2 or P1 latency and reduced amplitude in the early stages of EION. Referring a patient for VEP could be worthwhile if one does not have the machine.

Our case series underscores the need to perform a regular ophthalmic evaluation in patients started on Ethambutol. All patients who are newly diagnosed to have tuberculosis should have a baseline ophthalmic examination before commencing treatment with ethambutol. Patients started on ATT should be educated on the potential side effects of the drug. They should be advised to consult an ophthalmologist if they experience any visual symptoms. If the dose taken is more than 15 mg/kg/day, monthly evaluation is warranted.

Once EION is recognized, Ethambutol should be stopped immediately to prevent further visual deterioration. The toxicity is considered reversible on discontinuation of Ethambutol. However, permanent visual impairment has been reported within a follow-up period ranging from 6 months to 3 years, in spite of prompt discontinuation of the drug.[12]

When ocular toxicity is severe, both Ethambutol and Isoniazid should be stopped immediately. About 30% to 50% of patients show recovery to a variable extent after 6–9 months of stopping Ethambutol.[15] In all our three patients, visual acuity continued to deteriorate, despite stopping Ethambutol. This could be due to the cumulative toxicity of Ethambutol and the time taken for the elimination of the drug. However, there was a gradual recovery of vision over a period of three to 14 months. It is important to inform the patient that the improvement of vision, on stopping Ethambutol is not dramatic, but gradual. This information will be a source of encouragement to the patient and may deter the patient from turning to dubious alternative therapies.


  Conclusion Top


EION can result in significant loss of vision. If diagnosed early and the drug stopped, reversal of the toxic effects is possible. The treating doctor, the ophthalmologist and the patient should work closely to prevent irreversible visual loss. Early diagnosis using a sensitive indicator is mandatory to prevent irreversible loss of vision. It is important to formulate guidelines for mandatory ophthalmic evaluation in patients on treatment with Ethambutol.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initial s will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Varma D, Anand S, Reddy AR, Das A, Watson JP, Currie DC, et al. Tuberculosis: An under-diagnosed aetiological agent in uveitis with an effective treatment. Eye (Lond) 2006;20:1068-73.  Back to cited text no. 1
    
2.
Chaudhari A. Recent changes in technical and operational guidelines for tuberculosis control programme in India-2016. A paradigm shift in tuberculosis control. J Assoc Chest Phys 2017;5:1.  Back to cited text no. 2
    
3.
Central TB Division. RNTCP Updated TB Guidelines 2019. New Delhi: Ministry of Health and Family Welfare; 2019.  Back to cited text no. 3
    
4.
Carr RE, Henkind P. Ocular manifestations of ethambutol, Toxic amblyopia after administration of an experimental antituberculous drug. Arch Ophthalmol 1962;67:566-71.  Back to cited text no. 4
    
5.
Chung H, Yoon YH, Hwang JJ, Cho KS, Koh JY, Kim JG. Ethambutol-induced toxicity is mediated by zinc and lysosomal membrane permeabilization in cultured retinal cells. Toxicol Appl Pharmacol 2009;235:163-70.  Back to cited text no. 5
    
6.
Talbert Estlin KA, Sadun AA. Risk factors for ethambutol optic toxicity. Int Ophthalmol 2010;30:63-72.  Back to cited text no. 6
    
7.
Goodman BL, Knollmann BC. Goodman and Gilman's the Pharmacological Basis of Therapeutics. 13th ed. New York: McGraw-Hill Medical; 2018. p. 1074.  Back to cited text no. 7
    
8.
Sivakumaran P, Harrison AC, Marschner J, Martin P. Ocular toxicity from ethambutol, a review of 4 cases and recommended precautions. NZ Med J 1998;111:428-30.  Back to cited text no. 8
    
9.
Mendel T, Fleischman D, Allingham RR, Tseng H, Chesnutt DA. Spectrum and clinical course of visual field abnormalities in ethambutol toxicity. Neuroophthalmology 2016;40:139-45.  Back to cited text no. 9
    
10.
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. 10
    
11.
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. 11
    
12.
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. 12
    
13.
Kumar A, Dada T. Visual evoked response (VER) in ocular ethambutol toxicity. Natl Med J India 1999;12:193-4.  Back to cited text no. 13
    
14.
Mandal S, Saxena R, Dhiman R, Mohan A, Padhy SK, Phuljhele S, et al. Prospective study to evaluate incidence and indicators for early detection of ethambutol toxicity. Br J Ophthalmol. 2021;105:1024-8. [doi: 10.1136/bjophthalmol-2020-316897]. Epub 2020 Jul 26. PMID: 32713840.  Back to cited text no. 14
    
15.
Kumar A, Sandramouli S, Verma L, Tewari HK, Khosla PK. Ocular ethambutol toxicity: Is it reversible? J Clin Neurophthalmol 1993;13:15-7.  Back to cited text no. 15
    


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