Re-Treatment With Ethambutol After Toxic Optic Neuropathy.

There are no data in the literature regarding the safety of re-treatment with ethambutol for recurrent mycobacterial infection after prior ethambutol-induced optic neuropathy. We describe a patient who developed optic neuropathy attributed to ethambutol, recovered fully after drug withdrawal, and tolerated a 14-month long re-treatment 10 years later without developing recurrent optic neuropathy.

Original Contribution Re-Treatment With Ethambutol After Toxic Optic Neuropathy Marc A. Bouffard, MD, Ruvandhi R. Nathavitharana, MD, David S. Yassa, MD, MPH, Nurhan Torun, MD, FRCS(C) Abstract: There are no data in the literature regarding the safety of re-treatment with ethambutol for recurrent mycobacterial infection after prior ethambutol-induced optic neuropathy. We describe a patient who developed optic neuropathy attributed to ethambutol, recovered fully after drug withdrawal, and tolerated a 14-month long re-treatment 10 years later without developing recurrent optic neuropathy. Journal of Neuro-Ophthalmology 2017;37:40-42 doi: 10.1097/WNO.0000000000000445 © 2016 by North American Neuro-Ophthalmology Society E thambutol is an important component of the treatment for mycobacterial infections. Toxic optic neuropathy is a dose-dependent side effect of ethambutol treatment, occurring in approximately 5%-6% of patients at a dosage of 25 mg/kg/day, and 1% at 15 mg/kg/day or less (1). Approximately 10% of affected patients have permanent visual impairment (2). Some individuals require retreatment for mycobacterial infections, but the safety of a full course of ethambutol re-treatment in a patient who previously developed and recovered from ethambutolinduced optic neuropathy has not been established (3). CASE REPORT A 49-year-old woman with cough, wheeze, chest tightness, fatigue, and anorexia was diagnosed with Mycobacterium avium complex (MAC) infection. The diagnosis was made Department of Neurology (MAB, NT), Beth Israel Deaconess Medical Center, Boston, Massachusetts; Division of Infectious Disease (RRN, DY), Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts; and Division of Ophthalmology (NT), Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts. The authors report no conflicts of interest. Address correspondence to Marc A. Bouffard, MD, 608 Massachusetts Avenue #1, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard University School of Medicine, Boston, MA 02118; E-mail: [e-mail] 40 based on 3 positive sputum cultures and characteristic radiographic findings of a right upper lobe cavitary lesion, bilateral bronchiectasis, and tree-in-bud inflammatory changes. Her treatment regimen included rifampin, clarithromycin, and ethambutol at a dose of 22 mg/kg/day. Seven months into treatment, she developed dyschromatopsia, difficulty reading books, and her computer screen which progressed to difficulty recognizing faces. At another institution, visual acuity was 20/80 bilaterally with decreased color vision. She was referred to a neuro-ophthalmologist and diagnosed with ethambutol-induced optic neuropathy. After ethambutol cessation, her visual acuity color vision recovered over several months, and the patient did not notice any persistent deficit. She continued on rifampin, clarithromycin, and ciprofloxacin to complete a 14-month course of treatment without any further ocular complications. Ten years later, the patient developed malaise, fatigue, cough, and night sweats. She was initially treated with steroids, azithromycin, and then a course of ciprofloxacin without improvement. Computed tomography of the chest revealed tree-in-bud opacities and a right lower lobe cavitary lesion consistent with recurrent pulmonary MAC infection. This was confirmed through sputum culture. At the time of our evaluation, visual acuity was 20/20 in each eye, and the patient recognized the Ishihara plates correctly. Pupillary reactions, automated visual fields, and ophthalmoscopy were unremarkable. Optical coherence tomography (OCT) showed thinning of the temporal retinal nerve fiber layer bilaterally (Fig. 1). She was subsequently treated with rifampin, clarithromycin, and ethambutol. Rather than re-treatment with daily ethambutol therapy, this medication was dosed at 25 mg/kg/day 3 d/wk in accordance with American Thoracic Society/International Disease Society of America guidelines and the little data which exist in the literature regarding ethambutol rechallenge after prior toxic optic neuropathy (3-5). On initiation of therapy, the patient's blood urea nitrogen and creatinine were normal and did Bouffard et al: J Neuro-Ophthalmol 2017; 37: 40-42 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 1. Optical coherence tomography (OCT) prior to re-treatment with ethambutol. A repeat OCT after re-treatment was unchanged from above. not change significantly over her 14-month course of ethambutol. She also received copper supplementation (2 mg daily), given for its possible protective role in the prevention of ethambutol-induced optic neuropathy (6,7). Automated visual fields (Humphrey 30-2) were repeated monthly and remained unremarkable. The patient tolerated a 14-month course of 3 times weekly ethambutol dosing. OCT at the end of treatment showed no significant change compared with the OCT obtained before re-treatment. Bouffard et al: J Neuro-Ophthalmol 2017; 37: 40-42 DISCUSSION Recurrent mycobacterial disease remains a major problem worldwide (5). Although a wealth of data exists regarding the development of optic neuropathy while on ethambutol, we know of only 1 report that has made mention of re-treatment after ethambutol-induced toxic optic neuropathy. Griffith et al (3) reviewed 229 patients treated with ethambutol for MAC infections. Eight of the 139 patients on daily therapy 41 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution had ocular toxicity, either manifest primarily as a marked decrease in acuity or color vision. All recovered after cessation of ethambutol. However, 4 patients re-initiated ethambutol 3 times per week at a dosing schedule at 25 mg/kg. None sustained recurrent optic neuropathy, although the duration for which each patient remained on this regimen was not reported. Choosing an appropriate weight-based dose may be critical to safely re-treating patients with ethambutol. Previous studies have shown a clear correlation between weight-based dosing and the risk of ethambutol-induced ocular toxicity. However, there are no data to suggest that ethambutol-induced optic neuropathy at a supratherapeutic or high-normal dose will recur at a lower dose. The cohort described by Griffith et al (3) was dosed at 25 mg/kg/dose daily for 2 months and then decreased to 15 mg/kg/dose daily for the remainder of their course. Changing patients from the 15 mg/kg/dose daily to 25 mg/kg/dose at a frequency of 3 times per week lower the total weekly dose from 105 to 75 mg/kg. Attention to renal dosing of ethambutol is another important factor. In their combined retrospective analysis of 16 of their own cases of ethambutol-induced optic neuropathy and 54 from the literature, Estlin and Sadun (8) noted that 88% of patients had either known renal disease or significant risk factors for renal disease. Yet renal function was reported in only 3 of the 70 patients. There were no reports of a reduction in dosing frequency based on low glomerular filtration rate. Of the cases reviewed which did include a medical history, the authors did not identify any cases of ethambutol-mediated optic neuropathy that occurred without risk factors for renal disease, a prolonged course (greater than 2 months), or a high ethambutol dose (greater than 21.4 mg/kg/day). Modification of copper and zinc intake may further influence the safety of ethambutol rechallenge. Ethambutol is known to be a copper chelator. Copper is required for the function of cytochrome oxidase and the electron transport chain. Lack of copper may result in energy deprivation to metabolically active cells. Kozak et al (9) showed that copper supplementation does not seem to decrease mycobacterial susceptibility to ethambutol. Re-treatment of mycobacterial infections with ethambutol after prior ethambutol-induced optic neuropathy is 42 a controversial topic with very little data to guide clinical decision making. Our case suggests that recurrent toxicity can be avoided when less frequent dosing is used and close attention is paid to maintaining an appropriate dose based on weight and renal function. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: M. A. Bouffard and N. Torun; b. Acquisition of data: N. Torun, D. A. Yassa, and R. R. Nathavitharana; c. Analysis and interpretation of data: M. A. Bouffard, N. Torun, D. A. Yassa, and R. R. Nathavitharana. Category 2: a. Drafting the manuscript: M. A. Bouffard, N. Torun, D. A. Yassa, and R. R. Nathavitharana; b. Revising it for intellectual content: M. A. Bouffard, N. Torun, D. A. Yassa, and R. R. Nathavitharana. Category 3: a. Final approval of the completed manuscript: M. A. Bouffard, N. Torun, D. A. Yassa, and R. R. Nathavitharana. REFERENCES 1. Sadun AA, Wang MY. Drug-related mitochondrial optic neuropathies. J Neuroophthalmol. 2013;33:172-178. 2. Ezer N, Benedetti A, Darvish-Zargar M, Menzies D. Incidence of ethambutol-related visual impairment during treatment of active tuberculosis. Int J Tuberc Lung Dis. 2013;7: 447-455. 3. Griffith DE, Brown-Elliott BA, Shepherd S, McLarty J, Griffith L, Wallace RJ Jr. Ethambutol ocular toxicity in treatment regimens for Mycobacterium avium complex lung disease. Am J Resp Crit Care Med. 2005;172:250-253. 4. Griffith DE, Aksamit T, Brown-Elliott BA, Catanzaro A, Daley C, Gordin F, Holland SM, Horsburgh R, Huitt G, Iademarco MF, Iseman M, Olivier K, Ruoss S, von Reyn CF, Wallace RJ Jr, Winthrop K. ATS Mycobacterial Diseases Subcommittee, American Thoracic Society, Infectious Disease Society of America. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med. 2007;175:367-416. 5. Lee BY, Kim S, Hong Y, Lee SD, Kim WS, Kim DS, Shim TS, Jo KW. Risk factors for recurrence after successful treatment of Mycobacterium avium complex lung disease. Antimicrob Agents Chemother. 2015;59:2972-2987. 6. Pineles SL, Wilson CA, Balcer LJ, Slater R, Galetta SL. Combined optic neuropathy and myelopathy secondary to copper deficiency. Surv Ophthalmol. 2010;55:386-392. 7. Schleper B, Stuerenburg HJ. Copper deficiency-associated myelopathy in a 46-year-old woman. J Neurol. 2001;248:705- 706. 8. Estlin KAT, Sadun AA. Risk factors for ethambutol optic neuropathy. Int Ophthalmol. 2010;30:63-72. 9. Kozak SF, Inderlied CB, Hsu HY, Heller KB, Sadun AA. The role of copper on ethambutol's antimicrobial action and implications for ethambutol-induced optic neuropathy. Diagn Microb Inf Dis. 1998;30:83-87. Bouffard et al: J Neuro-Ophthalmol 2017; 37: 40-42 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.