Ethambutol Optic Neuropathy

Paul D. Chamberlain; Ama Sadaka; Shauna Berry; Andrew G. Lee


Curr Opin Ophthalmol. 2017;28(6):545-551. 

In This Article


Recent estimates suggest that the prevalence of EON in patients treated for Mycobacterium tuberculosis is around 1–2%.[4–6,7**] Combined with the WHO estimates of the prevalence of M. tuberculosis, EON could affect approximately 100 000 people worldwide each year.[8] In one of the largest epidemiologic studies regarding EON to date, Chen et al.[7] in 2015 reported on the incidence of EON in 4 803 patients diagnosed with tuberculosis over a 10-year period in Southern Taiwan. They found the incidence of EON to be 1.29%, with an average ethambutol dose in these patients of 16 mg/kg per day. The study noted that ophthalmologic examinations were only available for approximately one-fourth of patients, so the true incidence may be higher. Another recent study from 2016[9] reporting on 415 nonimmunocompromised patients taking ethambutol for tuberculosis or Mycobacterium avium complex lung disease found an incidence of 0.7%. In this study, the average daily ethambutol dose was 14.5 mg/kg per day, and in patients who were taking less than 15 mg/kg per day of ethambutol, the incidence was low at 0.3% but not zero. Although these studies showed a relatively small risk of EON, the risk varies greatly with ethambutol dose.

The WHO treatment guidelines for M. tuberculosis therapy initiation include an ethambutol starting dose of 15–20 mg/kg per day.[10] Although ethambutol is often associated with tuberculosis, nontubercular mycobacterial infections are also treated with ethambutol and have different dosing. The two most commonly encountered nontubercular mycobacterial infections are M. avium complex and Mycobacterium kansasii.[11] Initial dosing recommendations from the American Thoracic Society for the treatment of these infections range from 15 mg/kg per day for M. kansasii to 25 mg/kg per day for macrolide-resistant M. avium complex.[11] The variability in initial dosing is important as EON is a dose-dependent toxicity. At doses of ethambutol as less as 15 mg/kg per day the risk of EON is less than 1%.[9] With higher doses of 20, 25, and more than 35 mg/kg per day the risk estimates increase to 3, 5–6, and 18–33%, respectively.[9,12–14] Table 1 shows recommended starting doses for the most common mycobacterial infections and Table 2 shows the estimated prevalence of EON at several different doses. Ophthalmologists following patients on ethambutol should be aware of these dose-dependent differences as patients with nontubercular mycobacterial infections may be at greater risk for EON due to higher dosing of ethambutol.

Other risk factors other than dose for the development of EON have also been identified. A 2012 case-control study with a sample of 231 patients found that age greater than 65 years, hypertension, and the presence of renal disease were associated with a greater risk of developing EON.[6] Other studies have also identified renal dysfunction as a major risk factor for development of EON.[4,15] As ethambutol is excreted by the kidneys, prescribers of ethambutol and those monitoring for vision changes should be especially vigilant with patients who have renal disease. In addition, concomitant isoniazid therapy, that has been independently associated with a similar optic neuropathy in several case reports,[16–18] in combination with ethambutol for treatment of Mycobacterium spp. may put patients at greater risk for development of optic neuropathy.[19–21] Many authors recommend discontinuing the isoniazid if patients do not respond or continue to progress after discontinuation of the ethambutol in suspected cases of EON.