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 Table of Contents  
CASE REPORT
Year : 2022  |  Volume : 60  |  Issue : 1  |  Page : 83-85

Ethambutol-induced optic neuritis in a case of pulmonary tuberculosis


1 Department of Clinical and Experimental Pharmacology, School of Tropical Medicine, Kolkata, West Bengal, India
2 Department of Pharmacology, MGM Medical College and Hospital, Kishanganj, Bihar, India
3 Department of Ophthalmology, MGM Medical College and Hospital, Kishanganj, Bihar, India
4 Department of Pathology, MGM Medical College and Hospital, Kishanganj, Bihar, India

Date of Submission12-Jun-2021
Date of Acceptance27-Dec-2021
Date of Web Publication22-Mar-2022

Correspondence Address:
Dr. Shatavisa Mukherjee
Department of Clinical and Experimental Pharmacology, School of Tropical Medicine, Kolkata - 700 073, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/tjosr.tjosr_82_21

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  Abstract 


Ethambutol hydrochloride (EMB) is one of the integral first-line antitubercular agents used in both intensive and continuation phase as per Revised National Tuberculosis Control Programme guidelines. Although usually well tolerated, reports of ocular toxicity secondary to ethambutol have not been rare. The toxicity is dose and duration dependent, and is reported to be usually reversible if detected early, followed by drug stoppage. The present case discusses ethambutol-induced optic neuritis in a male patient diagnosed with pulmonary tuberculosis.

Keywords: Ethambutol, ocular toxicity, optic neuritis, tuberculosis


How to cite this article:
Mukherjee S, Era N, Chatterjee M, Mukherjee M. Ethambutol-induced optic neuritis in a case of pulmonary tuberculosis. TNOA J Ophthalmic Sci Res 2022;60:83-5

How to cite this URL:
Mukherjee S, Era N, Chatterjee M, Mukherjee M. Ethambutol-induced optic neuritis in a case of pulmonary tuberculosis. TNOA J Ophthalmic Sci Res [serial online] 2022 [cited 2022 Jun 29];60:83-5. Available from: https://www.tnoajosr.com/text.asp?2022/60/1/83/340374




  Introduction Top


Tuberculosis, one of the leading causes of death from a single infectious pathogen, is caused by Mycobacterium tuberculosis and can be pulmonary or extrapulmonary in nature. Among other approved drugs, ethambutol hydrochloride (EMB) is one of the first-line chemotherapeutic agents used in the treatment of tuberculosis used both in the intensive and continuation phase according to the new Revised National Tuberculosis Control Program guidelines. Although usually well tolerated, reports of ocular toxicity secondary to ethambutol has not been rare and overall incidence is reported to be ~ 1% correlated to drug dosage.[1] The toxicity is also duration dependent and is reported to be reversible if detected early, followed by drug stoppage. However, few studies have even reported permanent visual damage.[2],[3]

Optic neuritis is the most potential and serious side effect of EMB therapy. EMB-induced optic neuritis is typically characterized by pain in eye movement, loss of central vision, cecocentral scotoma, and dyschromatopsia.[4] The present case discusses EMB-induced optic neuritis in a male patient diagnosed with pulmonary tuberculosis.


  Case Report Top


A 44-year-old nonhypertensive male presented with chief complaints of marked diminution of vision for the past 14 days. The patient complained of pain during eye movements. On being diagnosed with pulmonary tuberculosis, he was started on category I anti-tubercular treatment for the past 4 months. The dosage of ethambutol given to him for initial 2 months was 15 mg/kg. He was not having any family history of neuropathy. Before treatment initiation, the detailed ophthalmological examination was conducted, which showed visual acuity of 6/6 in both eyes. His present examination revealed best-corrected visual acuity in the right eye as 6/18 with no improvement with pinhole and 6/6 in the left eye. Color vision (Ishihara) at presentation was severely impaired in the right eye [Figure 1] and normal in the left eye with greater impairment of red/green hue discrimination. Intraocular pressure was 12 mmHg in the right eye and 14 mmHg in the left eye by Goldmann Applanation Tonometry. The slit-lamp microscope examination of bilateral anterior segments was absolutely within the normal limits. The pupillary check revealed normalcy with no relative afferent pupillary defect. Automated perimetry indicated typical cecocentral visual field defects in both eyes.
Figure 1: Fundus imaging of the right eye showing mild papilledema, a typical sign of optic neuritis

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A diagnosis of suspected case of ethambutol-induced optic neuritis was made. Ethambutol was stopped immediately, though he was continued on other drugs such as isoniazid, rifampicin, and pyrazinamide. The patient was further treated with neurotropic drugs. There was a progressive but slow improvement in his vision. On further review after 3 weeks, his visual acuity was improved, and color vision was also found to be normal. On perimetry assessment, no scotoma was observed. By the next 3 months, his visual acuity improved with 6/12 being in the right eye and 6/9 in the left eye. The patient is on regular follow-up and is improving.

Causality assessment using both Naranjo's algorithm[5] and WHO UMC causality assessment scale[6] conferred it to be under “probable” category. Severity analysis using Hartwig Seigel's scale[7] conferred the case to be “moderate” (level 3). The event was reported under the Pharmacovigilance Programme of India.


  Discussion Top


EMB induced optic neuritis is a well-known complication arising from the use of ethambutol, the severity of which is in a dose-dependent manner. The incidence varies with dose ranges, 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.[2] Various related predisposing factors include increased age, prolonged EMB therapy, higher dosage regime, compromised renal, and/or cardiovascular functions. Comorbidities such as hypertension, diabetes, concurrent optic neuritis due to alcohol and tobacco use also stands out to be important risk factors.[2]

The exact pathophysiology for this complication has not yet been identified. However, mitochondrial disturbance, the zinc-chelating effect of EMB and its metabolite on various mitochondrial metal-containing enzymes are postulated as possible underlying mechanisms.[8] The onset time of EMB-induced ocular toxicity is not predictable. In general, symptoms have been seen to develop within few days to 2 years of drug initiation in the affected individuals. Speaking of clinical presentation, retrobulbar neuritis is the most common form with involvement of either axial (central) fibers or less commonly paraxial (peripheral) fibers. Involvement of central fibers of the optic nerve is usually associated with blurred vision, decreased visual acuity, central scotomas, and often impairment of red/green hue discrimination. On the contrary, peripheral nerve involvement is markedly associated with peripheral constriction of the visual fields, here visual acuity and color vision may not be much affected. Dyschromatopsia is a classical feature and one of the earliest signs of toxicity, where blue-yellow color changes are the most common one encountered. Most patients have subtle pulmonary abnormalities with central or centrocecal scotoma as a common visual field defect. Color vision, visual acuity, visual fields, visually evoked responses, and retinal nerve fiber layer thickness assessment using optical coherence tomography are some usual tests aiding in the detection of early and subclinical toxicity.[4]

As a part of treatment, the only line of action reported is drug stoppage. For those who stopped drug for more than a month, reported a recovery rate of around 50%.[9] However, there exists marked controversy regarding the reversibility of this ocular toxicity. While early studies state visual field defects and contrast sensitivity deterioration as irreversible damages of this adverse event, many studies have also demonstrated toxicity reversal in the majority of patients after 1 month of drug cessation. Thus, prompt identification remains the mainstay.

There are a number of gray areas in the recommendation of preventive measures against drug-induced ocular toxicity during tuberculosis management. Apart from the ocular effects of EMB as discussed, isoniazid can also rarely cause retrobulbar neuritis. Rifampicin can produce orangish tinge in tear secretion along with staining of contact lenses, if any. Thus, in pulmonary or extrapulmonary tuberculosis cases, prompt noting of optic neuritis necessitates immediate discontinuation of EMB. If no improvement is noted within 6 months of EMB stopping, then isoniazid should also be stopped. Pyridoxine at a dosage of 25–100 mg/day may be considered in cases of isoniazid-induced toxic neuropathy.[10]


  Conclusion Top


Although classically labeled as dose and duration dependent and reversible on drug cessation, reversibility of optic neuritis always remains controversial with stray reports of permanent visual defects. This mandates cautious use of the implicating drugs and strict vigilance of adverse outcomes. Patient education regarding safety issues in therapy can further help in prompt patient-initiated safety reporting, identifying and expedited management, thereby ensuring safer patient outcomes at large.

Declaration of patient consent

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

Acknowledgments

We acknowledge and support the untiring efforts and the contribution of the Pharmacovigilance Programme of India toward ensuring better patient safety nationwide.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Song W, Si S. The rare ethambutol-induced optic neuropathy: A case-report and literature review. Medicine (Baltimore) 2017;96:e5889.  Back to cited text no. 1
    
2.
Koul PA. Ocular toxicity with ethambutol therapy: Timely recaution. Lung India 2015;32:1-3.  Back to cited text no. 2
[PUBMED]  [Full text]  
3.
Shayakhmetova GM, Bondarenko LB, Voronina AK, Matvienko AV, Kitam V, Kovalenko VM. Repeated administration of ethambutol in therapeutic dose causes testes alteration and spermatogenesis disruption in Wistar rats. Hum Exp Toxicol 2017;36:520-33.  Back to cited text no. 3
    
4.
Behbehani R. Clinical approach to optic neuropathies. Clin Ophthalmol 2007;1:233-46.  Back to cited text no. 4
    
5.
Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-45.  Back to cited text no. 5
    
6.
The Use of the WHO-UMC System for Standardised Case Causality Assessment. Available from: http://www.who-umc.org/Graphics/24734.pdf. [Last accessed on 2021 May 14].  Back to cited text no. 6
    
7.
Hartwig SC, Siegel J, Schneider PJ. Preventability and severity assessment in reporting adverse drug reactions. Am J Hosp Pharm 1992;49:2229-32.  Back to cited text no. 7
    
8.
Makunyane P, Mathebula S. Update on ocular toxicity of ethambutol. Afr Vision Eye Health 2016;75:a353.  Back to cited text no. 8
    
9.
Kumar A, Sandramouli S, Verma L, Tewari HK, Khosla PK. Ocular ethambutol toxicity: Is it reversible? J Clin Neuroophthalmol 1993;13:15-7.  Back to cited text no. 9
    
10.
Solu TM, Panchal K. Ocular side effects of anti-tubercular drugs in patients receiving anti-Tb treatment at tertiary care center. IP Int J Ocul Oncol Oculoplasty 2020;6:187-91.  Back to cited text no. 10
    


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