Table of Contents  
CASE REPORT
Year : 2014  |  Volume : 16  |  Issue : 1  |  Page : 32-34

Ethambutol induced acute ocular toxicity: A rare case report!


Department of Medicine, Kasturba Medical College, Attavar, Mangalore, Karnataka, India

Date of Web Publication15-May-2014

Correspondence Address:
Dr. Parul Kodan
Department of Medicine, Kasturba Medical College, Manipal University, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2276-7096.132575

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  Abstract 

Ethambutol is a widely used first line agent against tuberculosis, which still remains a disease of significant morbidity and mortality in the developing world. We hereby present a rare case of ethambutol induced acute blindness. Even though, it is a rare incidence of severe form of toxicity of this widely used drug the possible consequences can be alarming for the medical fraternity who is rampantly using this drug.

Keywords: Ethambutol, ocular toxicity, tuberculosis


How to cite this article:
Kodan P, Kariappa A, Hejamady MI. Ethambutol induced acute ocular toxicity: A rare case report!. J Med Trop 2014;16:32-4

How to cite this URL:
Kodan P, Kariappa A, Hejamady MI. Ethambutol induced acute ocular toxicity: A rare case report!. J Med Trop [serial online] 2014 [cited 2019 Mar 19];16:32-4. Available from: http://www.jmedtropics.org/text.asp?2014/16/1/32/132575


  Introduction Top


Tuberculosis is a widely prevalent disease in Indian and African subcontinent. Anti-tubercular drugs should be used with caution as they can cause severe adverse effects. [1],[2] Ethambutol is a first line agent against tuberculosis. It is generally well-tolerated, but known to cause optic neuritis, more specifically retro bulbar neuritis causing blurred vision, decreased visual acuity, central scotomas and loss of red-green color vision. [3] However incidence of it causing complete blindness with its recommended dose within <2 weeks is <1%. [4],[5],[6] We hereby report a case of a young gentleman whose world turns completely dark after <2 weeks of starting this anti-tubercular drug.

The rarity and alarming consequences of this case prompted us to report the case with review of existing literature.


  Case Report Top


This was a case report of a young male patient presented to us in state of altered sensorium with a history of intermittent low grade fever for 2 months. On examination patient was agitated, Glasgow Coma Scale was 14/15 and examination revealed neck rigidity. No cranial nerve deficit was found. Patient had a history of L1 compression fracture because of which he was bedridden for the last 1 year. 2 days later fundus examination revealed mild papilledema on the right side. MRI brain showed mild hydrocephalus with basal meningeal enhancement. Although cerebrospinal fluid analysis could not be done in the patient due to patients firm refusal to get it done in background of L1 compression fracture. Mantoux test was strongly positive. Blood analysis revealed high erythrocyte sedimentation rate. Provisional diagnosis of tubercular meningitis was considered and patient was started on anti-tubercular therapy (ATT). He was started on isoniazid 5 mg/kg, rifampicin10 mg/kg, ethambutol 15 mg/kg and pyrazinamide 25 mg/kg respectively.

With symptomatic treatment and anti-tubercular drugs, patient's general condition improved. Detailed neurological examination 1 week after starting of ATT revealed no new significant finding. Fundus examination revealed no papilledema and normal fundus bilaterally.

However 12 days after starting ATT the patient complained of complete bilateral loss of vision. On examination perception of light was bilaterally absent. Fundus examination was normal.

Probable diagnosis of ethambutol induced ocular toxicity was considered and ethambutol and isoniazid were withdrawn. [6] Hydroxycobalamin was supplemented as recommended.

Within 5 days of stopping the treatment and starting of hydroxycobalamin patient could appreciate hand movement. Follow-up after 1 month of withdrawal of allegedly offending drug, visual acuity of 6/60 was noted.

Although the possibility of any other diagnosis for sudden vision loss could not be ruled out but following the sequence of events, the most probable diagnosis was ethambutol induced ocular toxicity, which is now in the state of resolution after withdrawal of drug.


  Discussion Top


Tuberculosis is the widespread silent killer in our country and isoniazid, rifampicin, ethambutol and pyrazinamide are the frontline armamentarium used against it. Although we know the possible adverse effects of these drugs some of these adverse reactions can present in very rampant form with devastating consequences.

Ethambutol is a bacteriostatic agent active against slow growing mycobacteria. It disrupts the arabinogalactan synthesis and inhibits the formation of mycolyl-arabinogalactan-peptidoglycan complex in the cell wall. And thereby leads to increased permeability of cell wall. [7],[8]

Ocular toxicity in the form of optic neuritis (most commonly retro bulbar neuritis) has been well-documented. Early reports of the same can be traced back to the 1960s. [6],[9] Classically this toxicity is described as dose- and duration-related and usually regarded to be reversible on therapy discontinuation, although reversibility of optic neuritis remains a possibility, many irreversible cases have been described. [10],[11] This complication of ethambutol in form of severe ocular toxicity has been sporadically reported. [12],[13]

The traditionally, most important side-effect of this drug is optic neuritis, resulting in decreased visual acuity and color blindness. This reaction is proportional to the dose of ethambutol and is observed in 15% of patients receiving 50 mg/kg/day, in 5-6% of patients receiving 25 mg/kg/day and in <1% of patients receiving daily doses of 15 mg/kg. [4],[5] In one study, 13 patients developed optic neuritis between 1 and 6 (mean = 2.9) months after receiving ethambutol at a dose ranging from 13 to 20 mg/kg/day (mean = 17 mg/kg/day) for pulmonary tuberculosis or of the lymph nodes. However, in our case the patient developed severe ocular toxicity with a daily dose of 15 mg/kg and that too within than 2 weeks of starting the drug. The possibility of such toxicity according to literature is <1%. [4],[5] A rare case report of idiosyncratic reaction with ethambutol has been described by Karnik et al. [13] Rapid development of optic neuritis in our patients could possibly be due to idiosyncratic reaction to the drug.

Factors which may predispose to toxicity include altered renal function. Furthermore, history of ethanol and tobacco consumption may predispose to ocular toxicity. [6],[14] In our case, the patient had a history of heavy ethanol and tobacco consumption though renal functions were normal.

The exact mechanism of this ocular neurotoxic effect has not been identified. Animal studies have demonstrated ethambutol toxicity in the retinal ganglion neurons of rodents. One of the principal theories for its toxicity has been the zinc-chelating effect of ethambutol and its metabolite. [15],[16],[17] Postulated biochemical pathways that mediate the toxic damage include downstream effector caspase-3 and caspase-6,815 and an excitotoxic pathway. [18]

Karnik et al. in their article reported rapidly progressive deterioration of vision after only 3 days of treatment with ethambutol. [13] In conclusion; ethambutol could cause an optic neuritis after a few doses. Mechanism of injury is probably different from the common optic neuritis secondary to ethambutol. Early detection of these cases and withdrawal of ethambutol along with initiation of hydroxycobalamin may be associated with good prognosis in such cases. [13]

In many studies treatments of sudden severe acute toxicity caused by ethambutol includes withdrawal of the drugs. It is recommended to stop isoniazid also in severe cases, as the drug itself has been implicated in probable ocular toxicity. Isoniazid should also be stopped if less severe optic neuritis does not improve within 6 weeks after stopping ethambutol. [6],[19] Hydroxycobalamin should be supplemented. [13] Regular ophthalmological check-up is advised for all patients (especially those at risk) on ethambutol. [6],[20],[21]


  Conclusion Top


Anti-tubercular drugs like ethambutol can cause potentially dangerous adverse effects. Measures to ensure a high level of awareness in medical staff and patients of these potential adverse effects appear to be the best current preventive method. Although rare, ethambutol induced acute vision loss is an alarming complication, which needs timely withdrawal of anti-tubercular drugs (both isoniazid and ethambutol in severe cases) and initiation of hydroxycobalamin.


  Acknowledgments Top


The authors are thankful to Dr. Raghavendra Bhat, HOD, Department of Medicine, KMC, Mangalore for his valuable guidance and Department of Ophthalmology for their valuable inputs.

 
  References Top

1.Shi R, Itagaki N, Sugawara I. Overview of anti-tuberculosis (TB) drugs and their resistance mechanisms. Mini Rev Med Chem 2007;7:1177-85.  Back to cited text no. 1
    
2.Addington WW. The side effects and interactions of antituberculosis drugs. Chest 1979;76:782-4.  Back to cited text no. 2
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3.Kokkada SB, Barthakur R, Natarajan M, Palaian S, Chhetri AK, Mishra P. Ocular side effects of antitubercular drugs-a focus on prevention, early detection and management. Kathmandu Univ Med J (KUMJ) 2005;3:438-41.  Back to cited text no. 3
    
4.Citron KM, Thomas GO. Ocular toxicity from ethambutol. Thorax 1986;41:737-9.  Back to cited text no. 4
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5.Leibold JE. The ocular toxicity of ethambutol and its relation to dose. Ann N Y Acad Sci 1966;135:904-9.  Back to cited text no. 5
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6.Chan RY, Kwok AK. Ocular toxicity of ethambutol. Hong Kong Med J 2006;12:56-60.  Back to cited text no. 6
    
7.Jankute M, Grover S, Rana AK, Besra GS. Arabinogalactan and lipoarabinomannan biosynthesis: Structure, biogenesis and their potential as drug targets. Future Microbiol 2012;7:129-47.  Back to cited text no. 7
    
8.Mikusová K, Slayden RA, Besra GS, Brennan PJ. Biogenesis of the mycobacterial cell wall and the site of action of ethambutol. Antimicrob Agents Chemother 1995;39:2484-9.  Back to cited text no. 8
    
9.Aouam K, Chaabane A, Loussaïef C, Ben Romdhane F, Boughattas NA, Chakroun M. Adverse effects of antitubercular drugs: Epidemiology, mechanisms, and patient management. Med Mal Infect 2007;37:253-61.  Back to cited text no. 9
    
10.Tsai RK, Lee YH. Reversibility of ethambutol optic neuropathy. J Ocul Pharmacol Ther 1997;13:473-7.  Back to cited text no. 10
    
11.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. 11
    
12.Melamud A, Kosmorsky GS, Lee MS. Ocular ethambutol toxicity. Mayo Clin Proc 2003;78:1409-11.  Back to cited text no. 12
    
13.Karnik AM, Al-Shamali MA, Fenech FF. A case of ocular toxicity to ethambutol - An idiosyncratic reaction? Postgrad Med J 1985;61:811-3.  Back to cited text no. 13
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14.Murray FJ. US Public Health Service experience with ethambutol. Proceedings of the International Congress of Chemotherapy; 1967 Jun26-Jul 1; Vienna, Austria. Vienna: Vienna Medical Academy Publishing House; 1967. p. 339.  Back to cited text no. 14
    
15.Shindler KS, Zurakowski D, Dreyer EB. Caspase inhibitors block zinc-chelator induced death of retinal ganglion cells. Neuroreport 2000;11:2299-302.  Back to cited text no. 15
    
16.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. 16
    
17.Kahana LM. Toxic ocular effects of ethambutol. CMAJ 1987;137:213-6.  Back to cited text no. 17
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18.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. 18
    
19.Sivakumaran P, Harrison AC, Marschner J, Martin P. Ocular toxicity from ethambutol: A review of four cases and recommended precautions. N Z Med J 1998;111:428-30.  Back to cited text no. 19
    
20.Chuenkongkaew W, Samsen P, Thanasombatsakul N. Ethambutol and optic neuropathy. J Med Assoc Thai 2003;86:622-5.  Back to cited text no. 20
    
21.Chatterjee VK, Buchanan DR, Friedmann AI, Green M. Ocular toxicity following ethambutol in standard dosage. Br J Dis Chest 1986;80:288-91.  Back to cited text no. 21
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  In this article
Abstract
Introduction
Case Report
Discussion
Conclusion
Acknowledgments
References

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