Journal of Neuro-Ophthalmology, March 1993, Volume 13, Issue 1

Ocular ethambutol toxicity: is it reversible?

Delayed onset ocular ethambutol toxicity is usually considered to be reversible following prompt withdrawal of the drug. However, in a series of seven consecutive patients with severe visual deficit due to ethambutol toxicity, only 42.2% (3 of the 7 patients) achieved a visual recovery of better than 20/200 after an average follow-up of 8.3 +/- 2.1 months after stoppage of the drug. On fluorescein angiography, three cases (42.2%) progressed to optic atrophy during the follow-up with permanent visual damage. There were no predisposing or risk factors to contribute toward the poor visual gain. In this background, we recommend discontinuation of ethambutol from the antituberculous regimen. As an additional sidelight, the value of visually evoked potential in the monitoring of patients on ethambutol, especially in cases with early periaxial neuritis, has been emphasised.

Joumal of Clinical Neuro-ophlhalmology 13(1); 15-17, 1993. © 1993 Raven Press, Ltd., New York Ocular Ethambutol Toxicity: Is It Reversible? Atul Kumar, M.D., S. Sandramouli, M.D., Lalit Verma, M.D., H. K. Tewari, M.D., and P. K. Khosla, M.S. Delayed onset ocular ethambutol toxicity is usually con­sidered to be reversible follOWing prompt withdrawal of the drug. However, in a series of seven consecutive pa­tients with severe visual deficit due to ethambutol tox­icity, only 42.2% (3 of the 7 patients) achieved a visual recovery of better than 20/200 after an average follow-up of 8.3 :!: 2.1 months after stoppage of the drug. On flu­orescein angiography, three cases (42.2%) progressed to optic atrophy during the follow-up with permanent vi­sual damage. There were no predisposing or risk factors to contribute toward the poor visual gain. In this back­ground, we recommend discontinuation of ethambutol from the antituberculous regimen. As an additional side­light, the value of visually evoked potential in the mon­itoring of patients on ethambutol, especially in cases with early periaxial neuritis, has been emphasised. Key Words: Ethambutol-Visually evoked potential­Optic neuropathy-Toxicity. From the Dr. Rajendra Prasad Centre for Ophthalmic Sci­ences, All India Institute of Medical Sciences, Ansan Nagar, New Delhi 110029, India. Address correspondence and reprint requests to Dr. Atul Ku­mar, Dr. Rajendra Prasad Centre for OphthalmIC SCIences, All India Institute of Medical Sciences, Ansan Nagar, New DelhI 110029, India. 15 Ethambutol hydrochloride, a bacteriostatic anti­tuberculous drug, was developed in 1962. Since then, mild to severe toxic amblyopia due to etham­butol have been reported by several authors (1-6). The toxic optic neuritis may be early or late onset, may be reversible or irreversible and axial or peri­axial (2,5,7-10). Generally, the early-onset toxicity is believed to be irreversible (4,9,11) and due to idiosyncratic reaction (12), though exception exists (7). On the contrary, delayed-onset optic neurop­athy is considered reversible (5,8,13,14) and is probably related to the drug's antimycobacterial mechanism of action as a chelating agent possibly brought about by depleting the eye of zinc (10). Presently, there are several controversial reports in the medical literature regarding the safety of ethambutol use as a routine antituberculous drug. Our experience with this questionably safe drug was highly discouraging. The present communica­tion highlights the invariably poor visual outcome of the eyes afflicted with ethambutol toxicity. MATERIALS AND METHODS Eight consecutive patients who were diagnosed and confirmed to have ethambutol ocular toxicity, on the basis of the clinical features, color vision deficits, visual evoked response (VER), and Gold­mann field charting, were included for the study. Ethambutol was stopped immediately after the clinical diagnosis of ethambutol toxicity was made. All the patients were followed up to a minimum period of 6 months with the parameters of clinical examination, including vision recording, color vi­sion, VER, and field charting. All the patients were under treatment with neurovitamins, following the stoppage of the ethambutol. Medical consulta­tion was obtained for ruling out any other systemic problems in all the patients. 16 RESULTS A. KUMAR ET AL. DISCUSSION The average age of the study group was 39.3 years (range 16-65 years), with equal number of males and females (4 each). All the patients re­ceived ethambutol (25 mg/kg body weight) along with isoniazid (300 mg daily), rifampicin (600 mg daily), and B-complex capsules. All the cases ex­cept Case 8 presented to us with a sudden dimi­nution of vision of recent onset. The average du­ration of ethambutol treatment prior to the onset of symptoms was 3.4 ± 2.6 months (range 50 days to 8 months). The average period of follow-up for the first seven cases was 8.3 ± 2.1 months (range 6-12 months). Initially all the patients had an increased latency and decreased amplitude in VER with blue-yellow color vision defects. Central scotoma with or without blind spot enlargement was no­ticed in the first seven cases. All the first seven cases had a severe reduction in visual acuity as shown in Table 1. At the end of the follow-up, only 3 of the 7 cases (42.2%) had a documented gain in their visual acuity of better than 6/60 (Table 1). Case 8 presented to us for a routine examination with nonspecific symptoms of itching and had a visual acuity of 6/6 in both her eyes. However, on VER recording, she was observed to have a pro­longed latency period with normal amplitude. Her color vision and field charting results were within normal limits. She was followed up for the next month with no further change in her follow-up parameters. There was no definite correlation of the extent of visual deficit with the period of onset of symptoms following the ethambutol therapy nor with the de­gree of visual recovery. During the follow-up, on fluorescein angiography, Cases 2, 3, and 7 were documented to have hypoperfusion of the disc, suggestive of optic atrophy in both the eyes. In India, tuberculosis is a highly prevalent dis­order, and ethambutol is one of the routinely used drugs as the first line of antituberculous agents along with isoniazid. The usually prescribed dose of ethambutol is 25 mg/kg body weight. The study group was chosen from a multitude of patients who visited our hospital for eye examination with or without symptoms, following ethambutol ther­apy. The exact statistics are, however, not available. Delayed-onset optic neuropathy caused by the toxic effect of ethambutol has been known to be dose-related and usually reversible (5,8-10,15). Ir­reversible ocular toxicity at the dose of 15 mg/kg has also been reported (2). Bouzas and coworkers (3) recorded only one of 14 patients with etham­butol toxicity who suffered from permanently re­duced vision. Similar results were published by Orou et a!. (16) and Pahlitzsch & Tiburtius (17). In a report by Kakisu et a!. (14), 3 of 6 cases had permanently reduced vision, but the drop in vision could be explained in all three cases by risk factors such as diabetes, alcohol abuse, and reduced kid­ney function. DeVita et a!. (18) suggested discon­tinuation of ethambutol in cases of renal tubercu­losis, due to compromise of renal excretion of the drug. Their report highlighted renal dysfunction as a potential risk factor with ethambutol therapy. Smith (19) suggested barring of ethambutol from the antituberculous regime in view of its severe and capricious nature of toxicity. The author's con­clusion was based upon his observation of irre­versible ocular toxicity despite proper dosage and prompt withdrawal of the drug in four of his pa­tients. Our report of seven cases uniformly pre­sented with severe reduction in visual acuity and showed poor visual recovery in 4 of the 7 cases without any detectable risk factors. Even the visual TABLE 1. Details of patients with ethambutol ocular toxicity Time interval between Best corrected vision onset of therapy & Initial Final Case no., toxic effects Follow-up age, sex Diagnosis (months) (months) RE LE RE LE 1: 45 M Pulmonary 2 8 CF CF 20/40 20/200 2: 24 F Pulmonary 1.5 9 CF CF FC FC 3: 33 M Pulmonary 1.5 9 CF CF CF CF 4: 65 M Pulmonary 3 12 20/120 20/120 20/80 20/80 5: 16 F Lymphadenitis 8 8 20/120 20/120 20/30 20/60 6: 35 M Pulmonary 6 6 FC FC 20/200 20/200 7: 51 F Pulmonary 2 6 20/200 20/120 20/200 20/120 Mean 3.4 ± 2.6 8.3 ± 2.1 8: 45 F Spinal 10 20/20 20/20 20/20 20/20 CF, Hand movements close to face; FC, Finger counting at one meter. I Clin Neuro-ophthalmol, Vol. 13, No.1, 1993 OCULAR ETHAMBUTOL TOXICITY 17 recovery observed in the three cases was never 100% in any of the cases. Stoppage of ethambutol and the neurovitamins had no obvious beneficial effects on the recovery of the patients. Kakisu et a1. (14) observed the initial drop in visual acuity following intoxication as the most re­liable prognostic factor concerning visual recovery. However, our study revealed a poor correlation with the initial drop in visual acuity. There was overall poor visual recovery in the series, and even in the cases that recovered partially, no reliable parameter could be used as a useful predictor of good visual recovery. Isoniazid has been documented as a cause of bilateral optic neuritis, especially when used in combination with ethambutol (11). All our cases were continuing to receive isoniazid even when ethambutol was stopped. Isoniazid is presumed to be responsible for the optic neuritis if visual abnor­malities persist for 3 months after the discontinu­ation of ethambutol (11). In this context, whether our cases had irreversible ethambutol toxicity or isoniazid nerve damage remains to be proved. The mechanism behind the interesting observa­tion of an asymmetrical recovery between the two eyes of Cases 1 and 5 remains unexplained, de­spite an extensive review of the literature. Simi­larly, though sporadic incidence of optic atrophy has been reported in the literature, following ethambutol intoxication (20), the documented progress of three cases toward optic atrophy strongly underscores the use of this drug in rou­tine antituberculous regimen. As mentioned in the literature (9), the central type of optic neuritis following ethambutol ther­apy was the most commonly observed type of neu­ritis in our series (7 of 8 cases, 87.5%). Case 8 with good visual acuity and normal color vision, but prolonged latency in VER, perhaps sustained a periaxial optic neuritis. The abnormal VER ob­served in the case indicates a definite role for mon­itoring the patients on ethambutol therapy with VER. The case benefited well from cessation of therapy after the detection of the toxicity, although the follow-up was short. Although ethambutol is claimed to be a potent antituberculous agent (21), despite 30 years of use the safety of the drug is still in dispute (21,22). Incidence of ocular toxicity has been described to be about 5% with dosage of 25 mg/kg, which is the usually prescribed initial dosage for the first 2 months of antituberculous therapy (23). We, how­ever, observed sudden-onset blindness despite proper dosing of ethambutol, careful ophthalmo­logic follow-up, and prompt discontinuation of ethambutol in initial visual dysfunction. Consider­ing that the role of ethambutol in antituberculous regimen is still arguable (24) and that the drug is a potentially blinding agent as observed in this se­ries, we recommend reconsideration regarding the use of ethambutol as one of the first-line antituber­culous drugs. 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