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Ocular Toxicity from Ethambutol
OCULAR TOXICITY FROM ETHAMBUTOL G. J. BARRON, M.D.,
LEO TEPPER, M.D.,
AND GINO IOVINE,
M.D.
Sylmar, California Since its introduction in 1961, ethambutol (Lederle), has received wide clinical applica tion as an oral agent specifically effective against Mycobacterium tuberculosis. Early toxicologic studies on dogs showed that pro longed usage at relatively high dosages pro duced deep pigmentation of the tapetum lucidum in the eye. In 1962, Carr and Henkind 1 first reported a high incidence of reversible toxic amblyopia in the original group of pa tients treated with the drug. Additional stud ies have cited further incidence of ocular toxicity that was dose-related.2"9 This ocular toxicity has been manifested by the follow ing findings: (1) a loss of central vision as sociated with a central scotoma, and a marked decrease in color discrimination, which Leibold8 calls an axial type of optic neuritis; (2) a paraxial type that manifests itself by defects in the peripheral visual field isopters; and (3) no retinal lesions in all but one study.10 Leibold8 recommended that all patients on ethambutol receive complete ocu lar examinations before treatment, and follow-up examinations on a monthly basis, primarily to test visual acuity. He considered studies in visual fields unnecessary when a patient was taking less than 30 mg of etham butol per day. Roussos and Tsolkas10 found, in contrast to other reported results, a 2% incidence of ocular toxicity in 250 patients receiving 15 mg of ethambutol daily for four to eight months. Their findings differed in that color perception was unaltered; edema and hyperemia occurred in the posterior pole, with one case showing dotted hemorrhages in the deeper layers of the retina; visual acuity reFrom the Los Angeles County-Olive View Medi cal Center, Sylmar, California, and the UCLA School of Medicine, Los Angeles, California. Reprint requests to G. J. Barron, M.D., Los An geles County-Olive View Medical Center, Sylmar, CA 91342.
turned to normal in only one of the four cases; and pigment disturbances occurred in all cases. In other studies,1"9 ophthalmoscopic abnormalities occurred only once,1 in a diabetic patient. In these studies, 19 vision returned to normal with cessation of etham butol. Because no other studies reported ophthalmoscopic changes, those reported by Roussos and Tsolkas10 may be cases of pathologic processes rather than ethambutol intoxication. MATERIALS AND METHODS
In a study at Olive View Medical Center, 304 patients received ethambutol in a double or triple chemotherapy regimen used rou tinely to treat tuberculosis. If a patient ex hibited intolerance to aminosalicylic acid, ethambutol was substituted. Patients with a history of treatment with streptomycin, isoniazid aminosalicylic acid, and considered upon admission to be a patient with tu berculosis reactivation or treatment failure received ethambutol and one or two addi tional secondary drugs until results of tests for susceptibility to antituberculosis drugs were reported. Such patients received etham butol daily in a single dose of 25 mg/kg for a period of 60 days, then reduced to 15 mg/ kgBefore treatment with ethambutol, all pa tients received a complete ophthalmic exami nation. Any abnormality in the optic disk was diagrammed. Patients were excluded whose visual acuity could not be determined due to cloudy media or to inability to per form either the E game or other visual acu ity tests. Patients who needed them received spectacles. The initial examination was followed by monthly tests for visual acuity and color discrimination and by HarringtonFlocks visual field test. Any changes were investigated promptly. If visual acuity de creased more than one line, the patients were
256
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rerefracted promptly. If refraction failed to improve the visual acuity, and if there was no change in clarity of the refracting media, ethambutol was discontinued. Changes in color vision perception and visual field de fects were indications for discontinuing treatment. Patients with adverse reactions were examined weekly. CASE REPORTS Case 1—A 23-year-old-Mexican woman was admitted to Olive View Medical Center on Nov. 29, 1968, with a sputum culture positive for M. tuber culosis; she had been treated with streptomycin, isoniazid, and amino salicylic acid at another insti tution. The patient denied any history of night sweats, chills, fever, cough, weight loss, or fatigue. She had no known allergies, and her medical his tory showed no hospitalizations or medical prob lems. Because of extensive disease and slow clinical response, her therapeutic regimen was modified. On Jan. 17, 1969, after ophthalmic evaluation, she was given 5 g of ethambutol daily (15 m g / k g ) and 1 g twice a week of viomycin sulfate. At initial examination, the patient's visual acuity was 20/25 in the right eye and 20/30 in the left eye. On Jan. 9, visual acuity was 20/20 in both eyes, and color vision and visual fields were within normal limits. On Feb. 10, visual acuity and color were still normal, but on March 10, signs of constriction of visual fields appeared (Fig. 1), and one week later, further visual field loss (Fig. 2 ) . Visual acuity re mained at. 20/20. On March 26, further constriction
was noted, and although a complete ophthalmic ex amination revealed no changes in the media or in the optic disk, ethambutol was discontinued immedi ately. On April 2, visual fields were unchanged, but nine days later the fields again were markedly con stricted despite the discontinuance of ethambutol. Quantitative field tests were performed, and there was a fairly steep visual field loss (Fig. 3 ) . Be cause of the constricted fields and lack of improve ment, the patient had x-ray film examination of the skull and neurologic consultation on April 25; all results were normal. Approximately six weeks after the discontinuation of ethambutol, there was im provement in both the 2-mm and 10-mm isopters. Visual fields improved henceforth. During the course of visual field impairment, the patient con tinued to receive isoniazid and viomycin. By May 23, the visual fields showed definite constriction in volving the blind spot in both eyes; approximately three months after discontinuation of the drug, the 2-mm isopter had improved remarkably (Fig. 4 ) , and improvement was rapid thereafter. By July 14, visual fields were normal with the 2-mm Lumiwand. This patient seemed to exhibit a clear case of toxic amblyopia secondary to ethambutol adminis tration. There was no history of alcoholism or dia betes, and no neurologic indications or x-ray results to suggest any other cause. T h e patient continued on other antituberculous drugs throughout her hospitalization. She did not show the decreased visual acuity, central scotoma, or change in color vision noted by other investigators. Case 2—A 21-year-old Korean woman was ad mitted to a private hospital for hemoptysis in De cember 1969. After chest x-ray revealed pulmonary infiltrates suggestive of tuberculosis, she was admit ted to Olive View Medical Center on Dec. 9, where
345
240
255
270
LEFT
285
300
240
255
270
285
300
RIGHT
Fig. 1 (Barron, Tepper, and Iovine). First visual field that showed a detectable abnormality while patient was on ethambutol (2 mm w/1000).
258
AMERICAN JOURNAL OF OPHTHALMOLOGY
FEBRUARY, 1974
345
Fig. 2 (Barron, Tepper, and Iovine). Visual field six days later showing marked constriction of the field; patient still on ethambutol (2 mm w/1000). M. tuberculosis was isolated on sputum culture. Ini tial therapy consisted of streptomycin, isoniazid, and aminosalicylic acid resin (Rezipas), but Rezipas was discontinued because of gastrointestinal in tolerance, and a daily dosage of 800 mg ethambutol (IS mg/kg) was substituted. Initial ophthalmic examination on Jan. 6, 1970, revealed a visual acuity of 20/20—2 in the right eye
and 20/25—2 in the left eye. Results of complete ophthalmic examination were normal. One month later, visual acuity in the right eye was 20/25—2 and 20/30—2 in the left eye. Visual acuity was unchanged on March 5, but by April 2, it had decreased to 20/40 in the right eye and 20/50—1 in the left eye. Results of color vision and Harrington-Flocks tests were within normal limits. On April 16, visual acuity was
'345
. 2 MM
w//ooo
L 5 MM
Fig. 3 (Barron, Tepper, and Iovine). Progression of visual field loss despite discontinuation of etham butol.
VOL. 77, NO. 2
ETHAMBUTOL TOXICITY
259
WL
1801-
wsr
'345
225> 240
255
270
LEFT
285
300
240
255
270
285
300
RIGHT
Fig. 4 (Barron, Tepper, and Iovine). Improved visual field, three months after discontinuation of ethambutol (2 mm w/1000). 20/30-1 in the right eye and 20/50 in the left eye. was decreased to 15 mg/kg. On Dec. 18, 1970, visual Again, results of color vision and Harrington-Flocks acuity was 20/25 in the right eye and 20/20 in the left tests were normal. Complete ophthalmic examination eye, with no significant refraction error, and results revealed no ocular abnormality. Because of the of a complete ophthalmic examination were essenti greater-than-2 line change in the visual acuity, ally negative. No change was noted until April 20, ethambutol was stopped. On May 3, visual acuity 1971, when visual acuity had decreased to 20/25 in was 20/30 in the right eye and 20/70 in the left eye. the right eye and 20/40—1 letter in the left eye. He Eleven days later, visual acuity had improved to failed the color vision test. Small abnormalities of 20/30 in the right eye and 20/40 in the left eye, and both maculae did not constitute a cause for the de in another two weeks to 20/25 in both eyes. The pa creased visual acuity. Ethambutol was discontinued, tient, at subsequent biweekly follow-ups, has re and the patient's visual acuity returned to 20/25 in ported visual improvement, and her visual acuity at the left eye within eight days, but his color vision re present is 20/25 in both eyes. mained defective. Three weeks after discontinuation Although this patient represents a case of of ethambutol, visual acuity was 20/40 in both eyes; toxic amblyopia due to ethambutol administration, by July 3, 1971, it was 20/30 in the right eye and the fact that color vision was good throughout the 20/50 in the left eye, with poor color discrimination. treatment and no scotoma could be elicited made us Examination of the posterior pole showed a large question the validity of the decreased visual acuity. white exudative type of material in the macula of the The possibility remains that the patient could have right eye; the left macula had multiple small drubeen malingering; her history reveals episodes of sen, a granular appearance, and no light reflex. Eth failing to take medication as prescribed and of sign ambutol was prescribed, once again, with no fur ing out of hospitals against medical advice. ther deterioration of vision. Case 3—A 57-year-old man was admitted to Ol Whether the visual acuity of this patient was de ive View Medical Center on June 11, 1969, with a creased by ethambutol alone, or whether macular history of chronic far-advanced pulmonary tubercu degeneration or chronic brain syndrome were con losis, chronic alcoholism, hypertensive encephalop- tributing causes was unclear. athy, and chronic brain syndrome. Streptomycin, aminosalicylic acid, and isoniazid were adminis DISCUSSION tered until Dec. 26, when 25 mg/kg ethambutol was Cases 1 and 2 exhibited changes in visual prescribed because of his chronicity and intolerance to aminosalicylic acid. Until April 21, 1970, the pa acuity not attributable to any causes other tient received isoniazid, pyridoxine hydrochloride. than ethambutol administration and re ethionamide, and ethambutol. During this time, he was also given chlorpromazine (Thorazine) hydro- versible when ethambutol was discontinued. chloride and prochlorperazine (Compazine). After Fundus examination with the direct and in the first month, the original 25 mg/kg ethambutol direct ophthalmoscope and with the contact
260
AMERICAN JOURNAL OF OPHTHALMOLOGY
lens did not demonstrate changes in the disk, the macula, or the vitreous. Results of fluorescein studies on Case 1 were normal. Early reports 2-9 indicate that toxicity from ethambutol is dose related. Diabetes and decreased renal clearance increase the toxicity, but a daily dosage of 15 mg/kg is relatively safe. Our study of over 300 pa tients indicates that a dosage of 25 mg/kg for 60 days, followed by 15 mg/kg for an indefinite period of time is exceedingly safe. However, due to the periaxial neuritis at the lower dosage, documented in Case 1, we rec ommend that examinations for visual acuity be followed by monthly visual field studies to find the rare, early periaxial defects. Realiz ing this would be a time-consuming and ex pensive method of follow-up, we suggest the rapid and inexpensive Harrington-Flocks test as sufficient for detecting significant field defects. SUMMARY
A total of 304 patients being treated with ethambutol, 25 mg/kg daily for a period of 60 days, followed by a maintenance dose of 15 mg/kg per day, were followed for two years. Three cases (1.03%) of reversible op tic nerve toxicity occurred. Monthly followup examinations were essential, but ophthal mic parameters were measured safely by the Medical Pulmonary Clinic. Ethambutol was a possible etiologic agent in optic nerve neu ritis.
FEBRUARY, 1974
ACKNOWLEDGMENTS
We wish to acknowledge the assistance of Betty Stout, ophthalmic technician, and Seymour Froman, M.D., in the preparation of this manuscript. Verona Pettyjohn, Jules Stein Eye Institute, provided edi torial assistance.
REFERENCES
1. Carr, R. E., and Henkind, P.: Ocular manifes tations of ethambutol. Arch. Ophthalmol. 67 :S66, 1962. 2. Pyle, M. M., Pfuetze, K. H., Pearlman, M. D., de la Huerga, J., and Hubble, R. H.: A four-year clinical investigation of ethambutol in initial and retreatment cases of tuberculosis. Ann. N. Y. Acad. Sci. 13S :428, 1966. 3. Place, V. A., Peets, E. A., Buyske, D. A., and Little, R. R.: Metabolic and special studies of eth ambutol in normal volunteers and tuberculosis pa tients. Ann. N. Y. Acad. Sci. 135 :775, 1966. 4. Bobrowitz, I. D.: Ethambutol in the retreatment of pulmonary tuberculosis. Ann. N. Y. Acad. Sci. 135 :796, 1966. 5. Corpe. R. F., and Blalock, F. A.: Multi-drug therapy including ethambutol in retreatment of pul monary tuberculosis. Ann. N. Y. Acad. Sci. 135: 823, 1966. 6. Pyle, M. M.: Ethambutol in the retreatment and primary treatment of tuberculosis. A four-year clinical investigation. Ann. N. Y. Acad. Sci. 135: 835, 1966. 7. Donomae, I., and Yamamoto, K.: Clinical evaluation of ethambutol in pulmonary tuberculosis. Ann. N. Y. Acad. Sci. 135 :849, 1966. 8. Leibold, J. E.: The ocular toxicity of etham butol and its relation to dose. Ann. N. Y. Acad. Sci. 135 :904, 1966. 9. Bobrowitz, I. D.: Comparison of ethambutolINH vs. INH-PAS in the original treatment of tu berculosis. Ann. N. Y. Acad. Sci. 135 :921, 1966. 10. Roussos, T., and Tsolkas, A.: Toxicity of myambutol on human eye. Ann. Ophthalmol. 2:578, 1970.
LEO TEPPER, M.D.,
AND GINO IOVINE,
M.D.
Sylmar, California Since its introduction in 1961, ethambutol (Lederle), has received wide clinical applica tion as an oral agent specifically effective against Mycobacterium tuberculosis. Early toxicologic studies on dogs showed that pro longed usage at relatively high dosages pro duced deep pigmentation of the tapetum lucidum in the eye. In 1962, Carr and Henkind 1 first reported a high incidence of reversible toxic amblyopia in the original group of pa tients treated with the drug. Additional stud ies have cited further incidence of ocular toxicity that was dose-related.2"9 This ocular toxicity has been manifested by the follow ing findings: (1) a loss of central vision as sociated with a central scotoma, and a marked decrease in color discrimination, which Leibold8 calls an axial type of optic neuritis; (2) a paraxial type that manifests itself by defects in the peripheral visual field isopters; and (3) no retinal lesions in all but one study.10 Leibold8 recommended that all patients on ethambutol receive complete ocu lar examinations before treatment, and follow-up examinations on a monthly basis, primarily to test visual acuity. He considered studies in visual fields unnecessary when a patient was taking less than 30 mg of etham butol per day. Roussos and Tsolkas10 found, in contrast to other reported results, a 2% incidence of ocular toxicity in 250 patients receiving 15 mg of ethambutol daily for four to eight months. Their findings differed in that color perception was unaltered; edema and hyperemia occurred in the posterior pole, with one case showing dotted hemorrhages in the deeper layers of the retina; visual acuity reFrom the Los Angeles County-Olive View Medi cal Center, Sylmar, California, and the UCLA School of Medicine, Los Angeles, California. Reprint requests to G. J. Barron, M.D., Los An geles County-Olive View Medical Center, Sylmar, CA 91342.
turned to normal in only one of the four cases; and pigment disturbances occurred in all cases. In other studies,1"9 ophthalmoscopic abnormalities occurred only once,1 in a diabetic patient. In these studies, 19 vision returned to normal with cessation of etham butol. Because no other studies reported ophthalmoscopic changes, those reported by Roussos and Tsolkas10 may be cases of pathologic processes rather than ethambutol intoxication. MATERIALS AND METHODS
In a study at Olive View Medical Center, 304 patients received ethambutol in a double or triple chemotherapy regimen used rou tinely to treat tuberculosis. If a patient ex hibited intolerance to aminosalicylic acid, ethambutol was substituted. Patients with a history of treatment with streptomycin, isoniazid aminosalicylic acid, and considered upon admission to be a patient with tu berculosis reactivation or treatment failure received ethambutol and one or two addi tional secondary drugs until results of tests for susceptibility to antituberculosis drugs were reported. Such patients received etham butol daily in a single dose of 25 mg/kg for a period of 60 days, then reduced to 15 mg/ kgBefore treatment with ethambutol, all pa tients received a complete ophthalmic exami nation. Any abnormality in the optic disk was diagrammed. Patients were excluded whose visual acuity could not be determined due to cloudy media or to inability to per form either the E game or other visual acu ity tests. Patients who needed them received spectacles. The initial examination was followed by monthly tests for visual acuity and color discrimination and by HarringtonFlocks visual field test. Any changes were investigated promptly. If visual acuity de creased more than one line, the patients were
256
257
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VOL. 77, N O . 2
rerefracted promptly. If refraction failed to improve the visual acuity, and if there was no change in clarity of the refracting media, ethambutol was discontinued. Changes in color vision perception and visual field de fects were indications for discontinuing treatment. Patients with adverse reactions were examined weekly. CASE REPORTS Case 1—A 23-year-old-Mexican woman was admitted to Olive View Medical Center on Nov. 29, 1968, with a sputum culture positive for M. tuber culosis; she had been treated with streptomycin, isoniazid, and amino salicylic acid at another insti tution. The patient denied any history of night sweats, chills, fever, cough, weight loss, or fatigue. She had no known allergies, and her medical his tory showed no hospitalizations or medical prob lems. Because of extensive disease and slow clinical response, her therapeutic regimen was modified. On Jan. 17, 1969, after ophthalmic evaluation, she was given 5 g of ethambutol daily (15 m g / k g ) and 1 g twice a week of viomycin sulfate. At initial examination, the patient's visual acuity was 20/25 in the right eye and 20/30 in the left eye. On Jan. 9, visual acuity was 20/20 in both eyes, and color vision and visual fields were within normal limits. On Feb. 10, visual acuity and color were still normal, but on March 10, signs of constriction of visual fields appeared (Fig. 1), and one week later, further visual field loss (Fig. 2 ) . Visual acuity re mained at. 20/20. On March 26, further constriction
was noted, and although a complete ophthalmic ex amination revealed no changes in the media or in the optic disk, ethambutol was discontinued immedi ately. On April 2, visual fields were unchanged, but nine days later the fields again were markedly con stricted despite the discontinuance of ethambutol. Quantitative field tests were performed, and there was a fairly steep visual field loss (Fig. 3 ) . Be cause of the constricted fields and lack of improve ment, the patient had x-ray film examination of the skull and neurologic consultation on April 25; all results were normal. Approximately six weeks after the discontinuation of ethambutol, there was im provement in both the 2-mm and 10-mm isopters. Visual fields improved henceforth. During the course of visual field impairment, the patient con tinued to receive isoniazid and viomycin. By May 23, the visual fields showed definite constriction in volving the blind spot in both eyes; approximately three months after discontinuation of the drug, the 2-mm isopter had improved remarkably (Fig. 4 ) , and improvement was rapid thereafter. By July 14, visual fields were normal with the 2-mm Lumiwand. This patient seemed to exhibit a clear case of toxic amblyopia secondary to ethambutol adminis tration. There was no history of alcoholism or dia betes, and no neurologic indications or x-ray results to suggest any other cause. T h e patient continued on other antituberculous drugs throughout her hospitalization. She did not show the decreased visual acuity, central scotoma, or change in color vision noted by other investigators. Case 2—A 21-year-old Korean woman was ad mitted to a private hospital for hemoptysis in De cember 1969. After chest x-ray revealed pulmonary infiltrates suggestive of tuberculosis, she was admit ted to Olive View Medical Center on Dec. 9, where
345
240
255
270
LEFT
285
300
240
255
270
285
300
RIGHT
Fig. 1 (Barron, Tepper, and Iovine). First visual field that showed a detectable abnormality while patient was on ethambutol (2 mm w/1000).
258
AMERICAN JOURNAL OF OPHTHALMOLOGY
FEBRUARY, 1974
345
Fig. 2 (Barron, Tepper, and Iovine). Visual field six days later showing marked constriction of the field; patient still on ethambutol (2 mm w/1000). M. tuberculosis was isolated on sputum culture. Ini tial therapy consisted of streptomycin, isoniazid, and aminosalicylic acid resin (Rezipas), but Rezipas was discontinued because of gastrointestinal in tolerance, and a daily dosage of 800 mg ethambutol (IS mg/kg) was substituted. Initial ophthalmic examination on Jan. 6, 1970, revealed a visual acuity of 20/20—2 in the right eye
and 20/25—2 in the left eye. Results of complete ophthalmic examination were normal. One month later, visual acuity in the right eye was 20/25—2 and 20/30—2 in the left eye. Visual acuity was unchanged on March 5, but by April 2, it had decreased to 20/40 in the right eye and 20/50—1 in the left eye. Results of color vision and Harrington-Flocks tests were within normal limits. On April 16, visual acuity was
'345
. 2 MM
w//ooo
L 5 MM
Fig. 3 (Barron, Tepper, and Iovine). Progression of visual field loss despite discontinuation of etham butol.
VOL. 77, NO. 2
ETHAMBUTOL TOXICITY
259
WL
1801-
wsr
'345
225> 240
255
270
LEFT
285
300
240
255
270
285
300
RIGHT
Fig. 4 (Barron, Tepper, and Iovine). Improved visual field, three months after discontinuation of ethambutol (2 mm w/1000). 20/30-1 in the right eye and 20/50 in the left eye. was decreased to 15 mg/kg. On Dec. 18, 1970, visual Again, results of color vision and Harrington-Flocks acuity was 20/25 in the right eye and 20/20 in the left tests were normal. Complete ophthalmic examination eye, with no significant refraction error, and results revealed no ocular abnormality. Because of the of a complete ophthalmic examination were essenti greater-than-2 line change in the visual acuity, ally negative. No change was noted until April 20, ethambutol was stopped. On May 3, visual acuity 1971, when visual acuity had decreased to 20/25 in was 20/30 in the right eye and 20/70 in the left eye. the right eye and 20/40—1 letter in the left eye. He Eleven days later, visual acuity had improved to failed the color vision test. Small abnormalities of 20/30 in the right eye and 20/40 in the left eye, and both maculae did not constitute a cause for the de in another two weeks to 20/25 in both eyes. The pa creased visual acuity. Ethambutol was discontinued, tient, at subsequent biweekly follow-ups, has re and the patient's visual acuity returned to 20/25 in ported visual improvement, and her visual acuity at the left eye within eight days, but his color vision re present is 20/25 in both eyes. mained defective. Three weeks after discontinuation Although this patient represents a case of of ethambutol, visual acuity was 20/40 in both eyes; toxic amblyopia due to ethambutol administration, by July 3, 1971, it was 20/30 in the right eye and the fact that color vision was good throughout the 20/50 in the left eye, with poor color discrimination. treatment and no scotoma could be elicited made us Examination of the posterior pole showed a large question the validity of the decreased visual acuity. white exudative type of material in the macula of the The possibility remains that the patient could have right eye; the left macula had multiple small drubeen malingering; her history reveals episodes of sen, a granular appearance, and no light reflex. Eth failing to take medication as prescribed and of sign ambutol was prescribed, once again, with no fur ing out of hospitals against medical advice. ther deterioration of vision. Case 3—A 57-year-old man was admitted to Ol Whether the visual acuity of this patient was de ive View Medical Center on June 11, 1969, with a creased by ethambutol alone, or whether macular history of chronic far-advanced pulmonary tubercu degeneration or chronic brain syndrome were con losis, chronic alcoholism, hypertensive encephalop- tributing causes was unclear. athy, and chronic brain syndrome. Streptomycin, aminosalicylic acid, and isoniazid were adminis DISCUSSION tered until Dec. 26, when 25 mg/kg ethambutol was Cases 1 and 2 exhibited changes in visual prescribed because of his chronicity and intolerance to aminosalicylic acid. Until April 21, 1970, the pa acuity not attributable to any causes other tient received isoniazid, pyridoxine hydrochloride. than ethambutol administration and re ethionamide, and ethambutol. During this time, he was also given chlorpromazine (Thorazine) hydro- versible when ethambutol was discontinued. chloride and prochlorperazine (Compazine). After Fundus examination with the direct and in the first month, the original 25 mg/kg ethambutol direct ophthalmoscope and with the contact
260
AMERICAN JOURNAL OF OPHTHALMOLOGY
lens did not demonstrate changes in the disk, the macula, or the vitreous. Results of fluorescein studies on Case 1 were normal. Early reports 2-9 indicate that toxicity from ethambutol is dose related. Diabetes and decreased renal clearance increase the toxicity, but a daily dosage of 15 mg/kg is relatively safe. Our study of over 300 pa tients indicates that a dosage of 25 mg/kg for 60 days, followed by 15 mg/kg for an indefinite period of time is exceedingly safe. However, due to the periaxial neuritis at the lower dosage, documented in Case 1, we rec ommend that examinations for visual acuity be followed by monthly visual field studies to find the rare, early periaxial defects. Realiz ing this would be a time-consuming and ex pensive method of follow-up, we suggest the rapid and inexpensive Harrington-Flocks test as sufficient for detecting significant field defects. SUMMARY
A total of 304 patients being treated with ethambutol, 25 mg/kg daily for a period of 60 days, followed by a maintenance dose of 15 mg/kg per day, were followed for two years. Three cases (1.03%) of reversible op tic nerve toxicity occurred. Monthly followup examinations were essential, but ophthal mic parameters were measured safely by the Medical Pulmonary Clinic. Ethambutol was a possible etiologic agent in optic nerve neu ritis.
FEBRUARY, 1974
ACKNOWLEDGMENTS
We wish to acknowledge the assistance of Betty Stout, ophthalmic technician, and Seymour Froman, M.D., in the preparation of this manuscript. Verona Pettyjohn, Jules Stein Eye Institute, provided edi torial assistance.
REFERENCES
1. Carr, R. E., and Henkind, P.: Ocular manifes tations of ethambutol. Arch. Ophthalmol. 67 :S66, 1962. 2. Pyle, M. M., Pfuetze, K. H., Pearlman, M. D., de la Huerga, J., and Hubble, R. H.: A four-year clinical investigation of ethambutol in initial and retreatment cases of tuberculosis. Ann. N. Y. Acad. Sci. 13S :428, 1966. 3. Place, V. A., Peets, E. A., Buyske, D. A., and Little, R. R.: Metabolic and special studies of eth ambutol in normal volunteers and tuberculosis pa tients. Ann. N. Y. Acad. Sci. 135 :775, 1966. 4. Bobrowitz, I. D.: Ethambutol in the retreatment of pulmonary tuberculosis. Ann. N. Y. Acad. Sci. 135 :796, 1966. 5. Corpe. R. F., and Blalock, F. A.: Multi-drug therapy including ethambutol in retreatment of pul monary tuberculosis. Ann. N. Y. Acad. Sci. 135: 823, 1966. 6. Pyle, M. M.: Ethambutol in the retreatment and primary treatment of tuberculosis. A four-year clinical investigation. Ann. N. Y. Acad. Sci. 135: 835, 1966. 7. Donomae, I., and Yamamoto, K.: Clinical evaluation of ethambutol in pulmonary tuberculosis. Ann. N. Y. Acad. Sci. 135 :849, 1966. 8. Leibold, J. E.: The ocular toxicity of etham butol and its relation to dose. Ann. N. Y. Acad. Sci. 135 :904, 1966. 9. Bobrowitz, I. D.: Comparison of ethambutolINH vs. INH-PAS in the original treatment of tu berculosis. Ann. N. Y. Acad. Sci. 135 :921, 1966. 10. Roussos, T., and Tsolkas, A.: Toxicity of myambutol on human eye. Ann. Ophthalmol. 2:578, 1970.