Journal of Neuro-Ophthalmology, June 1987, Volume 7, Issue 2

Optic neuropathy in ethambutol-treated renal tuberculosis.

Ethambutol is frequently used in the treatment of tuberculosis, and, although optic neuropathies have been reported with the use of ethambutol, this adverse side effect has been considered to be rare and generally reversible with discontinuation of the medication. However, we recently saw two patients with renal tuberculosis treated with ethambutol in whom visual loss from toxic optic neuropathies was severe and irreversible despite careful ophthalmological monitoring and prompt discontinuation of the agent at the first sign of impaired visual function. While ethambutol treatment is most commonly instituted for pulmonary tuberculosis, it is interesting to note that both of these patients had renal tuberculosis. Since ethambutol is actively excreted via the renal system, compromise of renal function such as due to renal tuberculosis may lead to serum concentration elevations of ethambutol sufficient to produce optic neuropathy.

JOUTnIlI of ClinicalNeuro-ophthalmology 7(2): 77-$3, 1987. Optic Neuropathy in Ethambutol-Treated Renal Tuberculosis Edward G. DeVita, M.D., Michael Miao, B.S., Alfredo A. Sadun, M.D., Ph.D. © 1987 Raven Press, New York Ethambutol is frequently used in the treatment of tuber­culosis, and, although optic neuropathies have been re­ported with the use of ethambutol, this adverse side ef­fect has been considered to be rare and generally revers­ible with discontinuation of the medication. However, we recently saw two patients with renal tuberculosis treated with ethambutol in whom visual loss from toxic optic neuropathies was severe and irreversible despite careful ophthalmolOgical monitoring and prompt dis­continuation of the agent at the first sign of impaired visual function. While ethambutol treatment is most commonly insti­tuted for pulmonary tuberculosis, it is interesting to note that both of these patients had renal tuberculosis. Since ethambutol is actively excreted via the renal system, compromise of renal function such as due to renal tuberculosis may lead to serum concentration ele­vations of ethambutol sufficient to produce optic neu­ropathy. Key Words: Ethambutol-OptiC Neuropathy-Optic Neuritis-Renal tuberculosis. From the Departments of Ophthalmology and Neurosur­gery, University of Southern California School of Medicine, and the Estelle Doheny Eye Foundation, 1355 San Pablo Street, Los Angeles, California. Address correspondence and reprint requests to Alfredo A. Sadun, M.D., Ph.D., Estelle Doheny Eye Foundation, 1355 San Pablo Street, Los Angeles, CA 90033, U.S.A. 77 The last 3 decades have seen an increasing number of agents becoming available for the treat­ment of tuberculosis (1). Ethambutol is one of the more widely chosen medications, often given in conjunction with isoniazid (INH), rifampin, or streptomycin as a third agent in the triple-dose regimen. Although ethambutol may be toxic, the adverse side effects have been considered rare and controllable (2-8); further, ophthalmic complica­tions have been regarded as very uncommon and reversible (1,2,9-11). Although ethambutol is usually administered in the treatment of primary pulmonary tuberculosis (TB), it has also been used in the treatment of renal TB. However, the risks and benefits of ethambutol treatment of renal TB may not be similar to those of pulmonary TB. A difference in the risk of ethambutol toxicity may be due to the fact that ethambutol is excreted pri­marily via the renal system (12). Compromise of renal function might therefore increase the serum concentration of ethambutol, and thus the likeli­hood of adverse toxic effects. Herein, we present two cases of secondary renal TB in which treat­ment with ethambutol led to severe and nonrever­sible visual loss from bilateral toxic optic neuropa­thies. CASE REPORTS Case 1 A 52-year-old white man was seen March 6, 1985, for ophthalmologic consultation with a com­plaint of painless, bilateral loss of vision, worse in the right eye than in the left. In the 2-week period prior to examination the patient also noticed a loss of color vision. Past medical history included a 78 E. G. DEVITA ET AL. diagnosis of renal tuberculosis in September 1984, for which the patient was started on ethambutol, 1,200 mg/day (13.6 mglkg); INH, 300 mg/day; and prophylactic vitamin B6• Hospital records at the time of diagnosis of renal TB showed that the patient was admitted initially for fever of unknown origin. Laboratory examina­tion demonstrated a urine analysis with greater than 100 white blood cells; stains and cultures for acid fast bacilli and bacteria were negative. A com­plete blood count revealed a slight elevation of the white blood cells; electrolytes were within normal limits. The blood urea nitrogen was 25 mg/dl and serum creatinine 2.3 mg/dl. A creatinine clearance was performed and was moderately depressed at 65.9 mlImin (low normal range down to 75.0 mlI min). Computerized tomographic scan of the ab­domen and kidneys was normal. The skin test for TB (PPO) was strongly positive. The patient had done well following initiation of anti-tuberculin therapy and was discharged shortly thereafter. Additional past medical history was negative for ophthalmologic disorders and was positive for in­fectious hepatitis in 1972. The patient has no his­tory of smoking or alcohol abuse. On ophthalmologic examination (approximately 6 months after ethambutol therapy initiation), the patient was noted to have visual acuities of 20/20 in the right eye and 20/20 in the left eye; color vi­sion testing showed that the patient was able to discern 19 of 20 Ishihara color plates with both the right and left eyes. Tangent screen visual field testing, with both white and red objects, was without deficit, and contrast sensitivity showed a mild decrease in all spatial frequencies; no abnor­malities of the optic discs were found. The patient was seen 2 weeks later, at which time there was further deterioration, with visual acuities of 20/60 - 2 in the right eye, 20/25 - 3 in the left eye, and color vision of 15/20 in the right eye and 16/20 in the left eye. Because of the deficit in color vision, ethambutol and INH were discon­tinued. Neuro-ophthalmologic consultation was then obtained (approximately 6th months after be­ginning ethambutol therapy and 2 weeks after dis­continuance of ethambutol). The visual acuities were 20/100 +2 in the right eye and 20/50 - 2 in the left eye; the patient could perceive five of eight Ishihara color test plates in the right eye and four of eight in the left eye. Tangent screen evaluation of the visual fields demonstrated depression of the superior temporal fields in both eyes. To rule out a chiasmal lesion, a computerized tomographic Scan was performed and was normal. On funduscopic examination the optic discs did not show any evi- . """"'i,!,I!",lmnl, Vol, 7, No.2. 1987 dence of atrophy. A trial dose of prednisone therapy was started but was not beneficial.. The patient was seen again 3 months after eth­ambutol discontinuation, and the visual acuities had deteriorated further to 20/200 in the right eye and 20/300 in the left eye. Color vision was further impaired since the patient could perceive 4 of 20 Ishihara test plates in the right eye and 3 of 20 in the left eye. Octopus visual field testing showed cecocentral scotomas in both the right (Fig. 1a and b) and left eyes (Fig. 1c and d). The patient devel­oped hematuria, and urine cultures grew out acid fast bacilli. The patient was started on strepto­mycin and rifampin; follow-up cultures were neg­ative. Four months after ethambutol discontinuation, visual acuities were impaired to a best-corrected level of 20/200 in the right eye and 20/400 in the left eye; color vision impairment had also stabilized to perception of 5 of 20 test plates in the right eye and 2 of 20 plates in the left eye. Threshold Amsler grid (TAG) testing was performed (13), which demonstrated a large scotoma in the right eye that began at the blind spot and almost reached fixa­tion. In the left eye, TAG showed a similarceco­central scotoma that extended from the blind spot to fixation. Funduscopic examination revealed marked bilateral optic atrophy (worse temporally) (Fig. 2a and b), and contrast sensitivity tests dem­onstrated slight impairment in the lower spatial frequencies and severe impairment of contrast sensitivity in the higher spatial frequencies. In summary, the patient developed bilateral optic neuropathies, first noted about 6 months after initiation of ethambutol. Visual impairment progressed slowly and stabilized at approximately 10 months, despite cessation of therapy 2 weeks after the first signs of visual loss. Visual acuities 1 year later were 20/200 in the right eye and 20/400 in the left eye, and were associated with classic ce­cocentral visual field defects. Case 2 A 41-year-old white man went to his private physician on May 28, 1981, complaining of fre­quency and urgency of urination and nocturia. A diagnosis of urethritis was made, and after an un"' successful trial of Bactrim, the patient was ad­mitted to the hospit~ for further evaluation. Past medical history was lsignificant for pulmonary 1'8 at age 8 (treated wiQ\ INH from 1953 to 1956) ana:. infectious hepatitis /rtt age 18. The patient had nQ; history of alcohol abuse. On physical exa~nation, the patient was noteW OPTIC NEUROPATHY IN RENAL TUBERCULOSIS 79 u +o + o 1 I) +0+00 + 0 + + -0"'-------, + + + I]) ++@OO +OO€J€J +000+ O-_-i]) @ • +.l.oo@ ++++0+ + + + + + + + + + + + + 0+0 + + + 0+ + + 1 -::;il) -40 -20 o 20 40 1b .JII-.~ ...- _ _.- __ . ....•.:..:..:..:.:._:.:..:..:..:..:..:..:..:...:..:..:..:..:..:.:3:fiE:-:--:=--=--=_=::::-:::::..• H ..·...•...•.._._•....•.•....•....-..-.__......._..•.....•........•......•.......•.........•......•.....•.......•........•.....•....•......1...•.1...•.1......~.....-...t:......:•_.......•..._•._.•..•._.._._.._..•...•...•._..•..•_..•..•.•..•..•..•....•.....•..... 1 ••••••••••••••••••• ::::::::::::::::::::!ft.:::!t ::::::::::::::::::: .:::.:.=..=_:::::::::::::::::::::::::::::::::::::::::. 5:::::::::::::::::::::::::::::::::::::::::::::- ::S~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~H~~~' ·:iii§ii5~gg~~~~iiiiiisiiiis5::- W ·...·...·.·..·...·...·...·...·...·...·...·...·...·...·...·...·...·...·...·...·...·...·...·...·...·...·..·..·.· It·..i.·...·..·.__·.·...·.._·__·.·__··.__-.··_·._···.· -60 1a + + + + 0 1]:1 + + + 0 + +0+ I:H.-+ + 1:1 + + + + + 1 +30 + + + + + + + + + + + + + + + + + + + + 0+ 0+ I) +0+ + + 0+ +00 + + + + + lit + + 0 0++ + 1 -:31) ld -40 -20 o 20 40 60 o .0 1 I co 2? -40 -:0 -60 lc FIG. 1. Octopus perimetry 60° around fixation. Cecocentral visual field defects are noted in the right eye (a and b) and the left eye (c and d). Strategy 31 Octopus perimetry (central 30°) shows the extent of cecocentral depression in the right eye (b) and the left eye (d). Difference table: +. deviation < 4 dB; O. deviation 5-9 dB;€J. deviation 10-19 dB; lit. deviation> 19 dB; •. absolute defect. to have right costavertebral angle tenderness. The remainder of the physical examination, including abdominal and genitourinary examinations, was within normal limits. Complete blood count and electrolytes were within normal limits and the blood urea nitrogen was 10 mgldl. No serum creat­inine or creatinine clearance testing was done. Uri­nalysis showed 50-60 white blood cells. Routine urine culture was negative, but both urine and sputum smears and cultures revealed acid fast ba­cilli. Thirty-six-hour skin testing for TB (PPD) was strongly positive, and chest x-ray showed apical capping of the right lobe and a calcified granuloma in the left upper lobe. The patient was further evaluated with an intra­venous pyelogram, renal sonogram, computerized JClin Neuro-ophthalmol, Vol. 7, No.2, 1987 80 E. G. DEVITA ET AL. FIG. 2. a: Right fundus. Severe pallor of the entire optic disc. b: Left fundus. Marked pallor of the optic disc, most pronounced temporally. tomographic scan of the kidneys, and cystoscopy with bladder biopsy, all of which were consistent with active secondary renal TB. The patient was then started on INH, 300 mg/day; rifampin, 600 mg/day; and pyridoxine, 50 mg/day. A complete ophthalmic examination revealed best visual acuities of 20/25 in the right eye and 20/25 in the left eye. The remainder of the oph­thalmic examination was normal except that the fundus examination showed mild temporal pallor of the optic discs. Optic nerve functions, however, were normal as shown by color vision and pupil­lary testing. The patient was started on a third antituberculin agent, ethambutol, 2,000 mg/day (20.95 mg/kg); after 60 days, this was decreased to 1,200 mg/day (12.5 mglkg). Thirty days after ethambutol initia­tion, visual acuity was 20/30 in the right eye and 20/30 in the left eye, and color vision remained near normal (the patient perceived 11 of 12 Ishi­hara test plates in both eyes). However, 3 months after ethambutol initiation, the patient noted marked loss of vision: visual acuity had decreased to 20/60 - 2 in the right eye, 20/60 - 3 in the left eye, and the color vision was impaired to percep­tion of 8 of 12 plates in the right eye and 5 of 12 in the left eye. Although ethambutol was discon­tinued at this time, visual acuity continued to de­teriorate. Two months after discontinuation of ethambutol, visual acuity was 20/300 in the right eye and counting fingers in the left eye; color vi­sion was also further impaired to 2 of 12 in the right eye and 0 of 12 in the left eye. Examination of the optic discs showed marked optic atrophy (Fig. 3a and b), and Octopus visual field testing re­vealed large cecocentral scotomas in both eyes (Fig. 4a and b). hi I'Jovember 1982, the patient was readmitted to the ho~pital for evaluation. Amipaque cisterno­grnm and computerized tomographic scanning ] Clin Nellfo-ophlhalmol, Vol. 7, No.2, 1987 were normal except that the optic nerves, optic chiasm, and optic tracts were somewhat small, in­dicating mild optic atrophy. Laboratory studies, including acid fast bacilli smears and cultures, were negative. In summary, the patient developed bilateral optic neuropathies approximately 30 days after ethambutol initiation; visual acuity progressively deteriorated after 5 months to about 20/400 in both eyes, and showed no improvement despite prompt discontinuation of ethambutol. DISCUSSION The preceding two case reports describe severe and irreversible ethambutol-induced optic neurop­athies associated with the treatment of renal TB. Previous reports of optic nerve ethambutol toxicity described deficits in visual acuity, color vision, and visual fields (1,4,9). However, the literature suggests that these manifestations are not common, and are less severe and usually revers­ible in patients treated with ethambutol for pulmo­nary TB. In the doses commonly used to treat pulmonary TB (25 mglkg/day or less), ethambutol can cause a bilateral retrobulbar optic neuropathy (4,14) [In the initial treatment of pulmonary TB, ethambutol is usually administered in a dose of 15 mglkg/day; in the retreatment of pulmonary TB, ethambutol is usually given in a dose of 25 mglkg/day for 60 days followed by 15 mg/kg/day for the remainder of the therapy (10).] Initial manifestations of ethambutol neuropathy occur as early as 4 months and as late as 12 months after the start of therapy (15). Retro­bulbar neuropathy secondary to ethambutol occurs in an axial, periaxial, or combined axial­periaxial distribution (12,15). Axial neuropathies most commonly demonstrate deficits in visual acuity, color vision, and visual fields (in a classic OPTIC NEUROPATHY IN RENAL TUBERCULOSIS 81 FIG. 3. a: Right fundus. b: Left fundus. Marked pallor of both optic discs. most pronounced temporally. cecocentral pattern), whereas periaxial neuropa­thies, usually seen with higher doses of medica­tion, result in defects in the peripheral visual fields (11,12,15). Papillitis is rarely seen in ethambutol toxicity, and is more commonly found in the optic neuropathy caused by INH (2,9). Isoniazid in itself causes an optic neuropathy that at times may be difficult to distinguish from that caused by ethambutol, which is often admin­istered concurrently (14). INH may produce a moderate, reversible, bilateral papillitis occurring 10-60 days after initiation of therapy (16). Deficits may occur in visual acuity and color vision, and the visual fields may show defects suggesting chiasmal involvement (16). DIFFgKENCE +------'-G------t- 00000 0 •• 0000 00.000000 008000+00 C~ e _ • 0 0 + a 0 a c~ 000 •• 0+00 00 •• +000+ 0000000 00000 - il----+I---~ -30 0 +3C 4a Our patients demonstrated axial retrobulbar neuropathies with an onset 30 days-six months after beginning ethambutol and INH therapy. The marked impairments of visual acuity and color vi­sion and the cecocentral scotoma were most con­sistent with ethambutol optic neuropathy. Fur­thermore, papillitis was not detected prior to the development of optic atrophy. Ethambutol is bacteriostatic (and not bacterio­cidal) against Mycobacterium tuberculosis (17). Sev­eral hypotheses have been advanced to explain the mechanisms of ethambutol action on the ac­tively dividing Mycobacterium tuberculosis. Etham­butol probably inhibits RNA synthesis in the nu­cleus of an actively dividing cell by chelating one DIFFERENCE o 0000. +000 •• a 0++00a ••• aao+a •••• 0+000.a.0 +0+0 ••••• +00000aaa +000000 00003 1----t-1-----l~ -30 0 +30 ·4b FIG. 4. Strategy 31 Octopus perimetry (central 30°) shows cecocentral defects in the left eye (a) and the right eye (b). Difference table: +. deviation < 4 dB;O. deviation 5-9 dB; e. deviation 10-19 dB; e. deviation> 19 dB; •• absolute defect. JClin NeuTo-ophthalmol, Vol. 7, No.2, 1987 82 E. G. DEVITA ET AI. or several metal-containing enzyme systems in the nucleic acid structures of the mycobacterium (18). Spermidine and magnesium have been found to counteract the effect of ethambutol, possibly by competing for chelation (17). Alternatively, since formic acid is a known metabolite of ethambutol, it may be the basis for the toxic optic neuropathy (6). A recent theory suggests that ethambutol inhibits phosphorylation by cyclic AMP-dependent pro­tein kinase-A (19). The myelin basic proteins re­quired for optic nerve fiber function and integrity are phosphorylated by this mechanism. Further speculation on the mechanism of eth­ambutol toxic neuropathy delves into the one sim­ilarity between actively dividing mycobacteria and the nonproliferating neurons of the central nervous system. In the Mycobacterium tuber­culosis, microtubules guide chromosomes in the actively dividing nucleus; in contrast, in neurons the microtubules provide structural integrity as well as assistance in axonal transport. Ethambutol may inhibit mycobacterial duplication as well as impair optic nerve axons, via microtubular disrup­tion. Most patients treated with ethambutol have pul­monary TB, while both of the patients reported herein developed optic neuropathies following treatment for renal TB. It is likely that in patients with renal TB there is decreased excretion of eth­ambutol secondary to compromised renal func­tion, thus resulting in elevated levels of etham­butol in serum. The renal system is a major deter­minant of serum ethambutol levels since ethambutol is excreted 70% via the kidneys and 25% via gastrointestinal loss; 5% is metabolized in the liver (12,20). Renal excretion of ethambutol approaches 7 cc/kg/min (6). However, because normal creatinine excretion is only about 2 cclkglmin (21), tubular se­cretion accounts for most ethambutol excretion. Creatinine excretion is an estimate of glomerular filtration but not of ethambutol tubular secretion. Hence, serum creatinine levels and creatinine clearance measurements will not accurately esti­mate ethambutol clearance. Malfunction of tubular secretion consequent to renal tuberculosis may lead to increased serum levels of ethambutol even in patients with normal blood urea nitrogen and serum creatinine levels, and it may therefore be difficult to regulate appropriate serum ethambutol levels in patients with renal tuberculosis. Further­more, serum ethambutol levels are not obtained in most institutions. We (.()Tic1ude that ethambutol be contraindicated in such patients or used only if ethambutol serum levels can be adequately monitored. In the cases reported here, renal function was not adequately assessed nor were levels of serum ethambutol. Though documented elevated serum ethambutol levels would have been desirable, they were not obtained. Nonetheless, the association between optic neuropathy and ethambutol toxicity is strongly suggested by this and similar studies. In summary, we present two cases of severe, nonreversible optic neuropathies resulting from the treatment of renal TB with ethambutol at stan­dard doses. Our results would suggest that the pa­tient with renal TB is at risk to develop bilateral severe and irreversible toxic optic neuropathies, such as those presently reported. We thus recom­mend that ethambutol not be used in the treat­ment of renal TB or in any patient with decreased renal function until further studies delineating the serum levels of ethambutol in renal TB are re­ported. Acknowledgment: The authors thank Ann Dawson for her assistance with the manuscript. REFERENCES 1. Roussos T, Tsolkas A. Toxicity of myambutol on human eyes. Ann Ophtha/mo/1970;2:678. 2. Bronte-Stewart J, Pettigrew AH, Foulds WS. Toxic optic neuropathy and its experimental production. Trans Oph­thalmol Soc UK 1976;96:355. 3. American Thoracic Society. Ethambutol in the treatment of tuberculosis. A statement by the committee on therapy. Am Rev Resp Dis 1968;98:320. 4. Citron K. Ethambutol: a review with special reference to ocular toxicity. Tubercle 1969;50:32. 5. Barron G, Tepper L, Iovine G. Ocular toxicity from etham­butol. Am JOphtha/moI1974;77:256. 6. Goodman L, Gilman A. Pharmacological basis of therapeutics. 7th ed. New York: Macmillan, 1985:1199-212. 7. Addington W. The side effects and interactions of anti tu­berculosis drugs. Chest 1979;76(suppl):782. 8. Yoshikawa T, Nagami P. Adverse drug reactions in TB therapy: risks and recommendations. Geriatrics 1982;37:6l. 9. Carr R, Henkind P. Ocular manifestations of ethambutol. Arch OphthalmoI1962;67:566. 10. Bobrowitz I. Ethambutol in the retreatment of pulmonary tuberculosis. Ann NY Acad Sci 1966;135:796. 11. Leibold J. The ocular toxicity of ethambutol and its relation to dose. Ann NY Acad Sci 1966;135:904. 12. Roberts S. A review of the papers on the ocular toxicity of ethambutol hydrochloride: myambutol an anti-tuberculosis drug. Am JOptom Physiol Opt 1974;51:987. 13. W~ll.M, Sadun A. Threshold Amsler grid testing: cross-po­lanzmg lenses enhance yield. Arch Ophthalmol 1986;104: 520. 14. Duane T, Jaeger E. Biomedical foundations of Ophthalmology. Ph.iladelphia: Harper & Row, vol 3, chap 16. 1985:1-25. 15. LeIbold J. Drugs having a toxic effect on the optic nerve. Int Ophthalmol Clin 1971;11:137. OPTIC NEUROPATHY IN RENAL TUBERCULOSIS 83 16. I<ass I, Mandel W, Cohen H, Dressler S. Isoniazid as a cause of optic neuritis and atrophy. JAMA 1957;164:1740. 17. Forbes M, Peets E, Kuck N. Effect of ethambutol on myco­bacteria. Ann NY Acad Sci 1966;135:726. 18. Shepherd R, Baughn C, Cantrall M, Goodstein B, Thomas J, Wilkinson R. Structure-activity studies leading to etham­butol, a new type of anti-tuberculous compound. Ann NY Acad Sci 1966;135:686. 19. Inoue M, Iga T. Effect of Chlorpromazine and ethambutol on phosphorylation of myelin basic protein. Proc Int Con­gress Neuro-ophthalmol, in press. 20. Peets E, Sweeney W, Place V, Buyske 0, The absorption, excretion, and metabolic fate of ethambutol in man. Am Rev Resp Dis 1965;91:51. 21. Hamburger J, Crosnier J. Nephrology, 1st ed. New York: John Wiley &: Sons, 1979:63-5. JClin Neuro-ophthalmol, Vol. 7, No.2, 1987