Clinical characteristics and prognostic factors analysis of ethambutol-induced optic neuropathy_Chinese Journal of Ocular Fundus Diseases

Authors：

Xiao Qing , Sun Chuanbin , Sun Mingming , Xu Quangang , Wei Shihui ,  Zhou Huanfen

Department of Ophthalmology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China;
Xiao Qing and Sun Chuanbin are working on the Eye center, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China;

Corresponding author：

Zhou Huanfen, Email: zhouzhoueye@163.com

Keywords：

Ethambutol/adverse effects; Optic nerve diseases; Disease attributes; Prognosis; Root cause analysis

DOI：

10.3760/cma.j.cn511434-20190401-00123

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Objective To observe the clinical features and visual prognostic factors of ethambutol-induced optic neuropathy (EON).Methods A cohort study. Twenty-four inpatients (46 eyes) identified as EON in Neuro-Ophthalmology Department of Chinese PLA General Hospital from January 2014 to December 2017 were enrolled, including 14 males (26 eyes) and 10 females (20 eyes) with a ratio of 1.4/1 male/female. The average age was 42.79±15.12 years and the average weight was 62.46±12.31 kg. The average time duration between oral administration of ethambutol and occurrence of EON was 9.94±16.49 months. The average time of ethambutol duration was 7.06±11.68 months, with an average accumulative dose of 156.7±1 779.0 g and the average daily dose of 15.07±8.95 mg/(kg·d). All patients were tested with visual acuity, fundus photos, colour vision, OCT, visual field, VEP, orbital MRI and the gene of OPA1 and mitochondrial deoxyribonucleic acid (mtDNA). All the patients accepted drug withdrawal immediately after diagnosis, and were given the treatment of systemic nerve nutrition and improvement of microcirculation for 2 weeks. The time of follow-up was more than 12 months. According to whether the visual acuity (VA) in any of eyes was over than 0.1 at the last follow-up, all the patients were divided into two groups: the bad VA group (VA less than or equal to 0.1) and the better VA group (VA over than 0.1) group. The χ² test and Fisher's exact probabilistic method test were used to compare the counting data between groups, and the Wlincox rank sum test was used to compare the measurement data. Multiple factors of VA outcome between the patients with bad or better va were analyzed by logistic regression.Results Thirty eyes (65.2%) had VA less than or equal to 0.1 and 5 eyes (10.9%) had VA over than 0.5 at EON onset. The VA of the rest 11 eyes (23.9%) was higher than 0.1 and lower than 0.5. At the last follow-up, 20 eyes (43.5%) had VA less than or equal to 0.1 and 9 eyes (19.6%) had VA over than 0.5, the VA of the rest 17 eyes (36.9%) was higher than 0.1 and lower than 0.5. Fundus examination revealed 7 eyes (15.3%) with optic disc edema. OCT revealed significant loss of the retinal nerve fiber layer (RNFL) in the affected eyes, mainly in the temporal RNFL of the optic disc. All patients had dyschromasia, mainly in distinguishing the color of red and green. The types of visual field defect was as following: central dark spot (52.2%), diffuse visual acuity decreased (30.4%), temporal hemianopsia (17.4%). Orbital MRI revealed that 12/24 (50.0%) patients had T2 lesions with T1 enhancement in 6/24 patients (25.0%). Genetic test showed that 4 patients (16.7%) had gene mutation. Among them, there were 2 patients with OPA1 mutation, 1 with mtDNA 14340 point mutation and 1 with the mtDNA 11778 point mutation. Thirteen patients showed better VA outcomes (over than 0.1) while 11 showed bad VA outcomes after discontinuation of ethambutol. Between the better VA group and the bad VA group, there were statistically significant differences in the daily dose of ethambutol and gene mutation (P=0.031, 0.023). The daily dose was related to visual prognosis of EON while only the daily dose of more than 18 mg/(kg·d) may lead to bad VA outcomes according to the logistic analysis (95% CI 0.007-0.736, OR=0.069, P=0.027).Conclusions EON may have OPA1 and mtDNA mutation with more bilateral eyes involved and less optic edema, which about 43.5% of the patients showed irreversible visual impact. The daily dose of ethambutol is related to the vision recovery.

Citation： Xiao Qing, Sun Chuanbin, Sun Mingming, Xu Quangang, Wei Shihui, Zhou Huanfen. Clinical characteristics and prognostic factors analysis of ethambutol-induced optic neuropathy. Chinese Journal of Ocular Fundus Diseases, 2020, 36(4): 269-274. doi: 10.3760/cma.j.cn511434-20190401-00123 Copy

1.	Jayanetti V, Rossiter-Thornton M, Azar D, et al. Sibling ethambutol optic chiasmopathy[J]. Neuroophthalmology, 2017, 42(1): 40-43. DOI: 10.1080/01658107.2017.1322616.
2.	刘子豪, 李红阳, 姜兆财, 等. 乙胺丁醇视神经病变临床特征分析[J]. 眼科, 2014, 23(1): 43-46. DOI: 10.13281/j.cnki.issn.1004-4469.2014.01.011.Liu ZH, Li HY, Jiang ZC, et al. Clinical characteristics of ethambutol optic neuropathy: 17 cases report[J]. Ophthalmol CHN, 2014, 23(1): 43-46. DOI: 10.13281/j.cnki.issn.1004-4469.2014.01.011.
3.	曹珊珊, 彭春霞, 李晓明, 等. 18例乙胺丁醇中毒性视神经病变的临床特点[J]. 眼科, 2016, 25(2): 123-126. DOI: 10.13281/j.cnki.issn.1004-4469.2016.02.013.Cao SS, Peng CX, Li XM, et al. Clinical characteritics of ethambutol optic neuropathy in eighteen cases[J]. Ophthalmol CHN, 2016, 25(2): 123-126. DOI: 10.13281/j.cnki.issn.1004-4469.2016.02.013.
4.	王伟, 杨晖, 张秀兰. 乙胺丁醇中毒性视神经病变的研究现状[J]. 中华眼科杂志, 2012, 48(2): 184-188. DOI: 10.3760/cma.j.issn.0412-4081.2012.02.021.Wang W, Yang H, Zhang XL. Present status of ethambutol-induced optic neuropathy[J]. Chin J Ophthalmol, 2012, 48(2): 184-188. DOI: 10.3760/cma.j.issn.0412-4081.2012.02.021.
5.	左海红. 乙胺丁醇中毒性视神经病变的研究现状[J]. 继续医学教育, 2012, 48(2): 97-100. DOI: 10.3969/j.issn.1004-6763.2017.03.051.Zuo HH. Present status of ethambutol-induced optic neuropathy[J]. Continuing Med Edu, 2012, 48(2): 97-100. DOI: 10.3969/j.issn.1004-6763.2017.03.051.
6.	Lim SA. Ethambutol associated optic neuropathy[J]. Ann Acad Med Singapore, 2006, 35(4): 274-278. DOI: 10.1097/00000441-200604000-00010.
7.	Guillet V, Chevrollier A, Cassereau J, et al. Ethambutol-induced optic neuropathy linked to OPA1 mutation and mitochondrial toxicity[J]. Mitochondrion, 2010, 10(2): 115-124. DOI: 10.1016/j.mito.2009.11.004.
8.	Pradhan M, Sharp D, Best S, et al. Drug-induced optic neuropathy--TB or not TB[J]. Surv Ophthalmol, 2010, 55(4): 378-385. DOI: 10.1016/j.survophthal.2009.10.005.
9.	Blanc C, Heran F, Habas C, et al. MRI of the optic nerves and chiasm in patients with leber hereditary optic neuropathy[J]. J Neuroophthalmol, 2018, 38(4): 434-437. DOI: 10.1097/WNO.0000000000000621.
10.	Osaguona VB, Sharpe JA, Awaji SA, et al. Optic chiasm involvement on MRI with ethambutol-induced bitemporal hemianopia[J]. J Neuroophthalmol, 2014, 34(2): 155-158. DOI: 10.1097/WNO.0000000000000095.
11.	陈冬军, 陈建华, 王伟, 等. OCT在乙胺丁醇所导致的视神经病变早期诊断中的应用[J]. 中国地方病防治杂志, 2017, 32(5): 545-546.Chen DJ, Chen JH, Wang W, et al. The application of optic coherence tomography in the early diagnosis of ethambutol-induced optic neuropathy[J]. Chin J Ctrl Endem Dis, 2017, 32(5): 545-546.
12.	Peng CX, Zhang AD, Chen B, et al. Macular thickness as a predictor of loss of visual sensitivity in ethambutol-induced optic neuropathy[J]. Neural Regen Res, 2016, 11(3): 469-475. DOI: 10.4103/1673-5374.179061.
13.	Lee JY, Choi JH, Park KA, et al. Ganglion cell layer and inner plexiform layer as predictors of vision recovery in ethambutol-induced optic neuropathy: a longitudinal OCT analysis[J]. Invest Opth Vis Sci, 2018, 59(5): 2104-2109. DOI: 10.1167/iovs.17-22988.
14.	Zoumalan CI, Sadun AA. Optical coherence tomography can monitor reversible nerve-fibre layer changes in a patient with ethambutol-induced optic neuropathy[J]. Br J Ophthalmol, 2007, 91(6): 839-840. DOI: 10.1136/bjo.2006.107326.
15.	Kumar A, Sandramouli S, Verma L, et al. Ocular ethambutol toxicity: is it reversible?[J]. J Clin Neuroophthalmol, 1993, 13(1): 15-17. DOI: 10.1016/0891-0618(93)90031-X.
16.	Tsai RK, Lee YH. Reversibility of ethambutol optic neuropathy[J]. J Ocul Pharmacol Ther, 1997, 13(5): 473-477. DOI: 10.1089/jop.1997.13.473.
17.	Lee EJ, Kim SJ, Choung HK, et al. Incidence and clinical features of ethambutol-induced optic neuropathy in Korea[J]. J Neuroophthalmol, 2008, 28(4): 269-277. DOI: 10.1097/WNO.0b013e31818e3c6b.
18.	Vashist P, Senjam SS, Gupta V, et al. Definition of blindness under National Programme for Control of Blindness: do we need to revise it?[J]. Indian J Ophthalmol, 2017, 65(2): 92-96. DOI: 10.4103/ijo.IJO_869_16.
19.	Zhou H, Wang W, Xu Q, et al. Clinical features and visual outcomes of optic neuritis in Chinese children[J/OL]. J Ophthalmol, 2016, 2016: 9167361[2016-09-20]. https://doi.org/10.1155/2016/9167361. DOI: 10.1155/2016/9167361.
20.	陈进波, 丘少杰. 乙胺丁醇中毒性视神经病变21例临床分析[J]. 中国实用眼科杂志, 2006, 24(8): 822-824. DOI: 10.3760/cma.j.issn.1006-4443.2006.08.016.Chen JB, Qiu SJ. Clinical characteristics of ethambutol optic neuropathy: 21 cases report[J]. Chin J Pract Ophthalmol, 2006, 24(8): 822-824. DOI: 10.3760/cma.j.issn.1006-4443.2006.08.016.
21.	Chen SC, Lin MC, Sheu SJ. Incidence and prognostic factor of ethambutol-related optic neuropathy: 10-year experience in southern Taiwan[J]. Kaohsiung J Med Sci, 2015, 31(7): 358-362. DOI: 10.1016/j.kjms.2015.05.004.
22.	Talbert EK, Sadun AA. Risk factors for ethambutol optic toxicity[J]. Int Ophthalmol, 2010, 30(1): 63-72. DOI: 10.1007/s10792-009-9293-z.
23.	Ikeda A, Ikeda T, Ikeda N, et al. Leber’s hereditary optic neuropathy precipitated by ethambutol[J]. Jpn J Ophthalmol, 2006, 50(3): 280-283. DOI: 10.1007/s10384-005-0308-7.
24.	Seo JH, Hwang JM, Park SS. Antituberculosis medication as a possible epigenetic factor of Leber’s hereditary optic neuropathy[J]. Clin Exp Ophthalmol, 2010, 38(4): 363-366. DOI: 10.1111/j.1442-9071.2010.02240.x.
25.	Pommer R, Schoeler S, Mawrin C, et al. The G11778A LHON mutation does not enhance ethambutol cytotoxicity in a cybrid model[J]. Clin Neuropathol, 2008, 27(6): 414-423. DOI: 10.5414/NPP27414.

1. Jayanetti V, Rossiter-Thornton M, Azar D, et al. Sibling ethambutol optic chiasmopathy[J]. Neuroophthalmology, 2017, 42(1): 40-43. DOI: 10.1080/01658107.2017.1322616.
2. 刘子豪, 李红阳, 姜兆财, 等. 乙胺丁醇视神经病变临床特征分析[J]. 眼科, 2014, 23(1): 43-46. DOI: 10.13281/j.cnki.issn.1004-4469.2014.01.011.Liu ZH, Li HY, Jiang ZC, et al. Clinical characteristics of ethambutol optic neuropathy: 17 cases report[J]. Ophthalmol CHN, 2014, 23(1): 43-46. DOI: 10.13281/j.cnki.issn.1004-4469.2014.01.011.
3. 曹珊珊, 彭春霞, 李晓明, 等. 18例乙胺丁醇中毒性视神经病变的临床特点[J]. 眼科, 2016, 25(2): 123-126. DOI: 10.13281/j.cnki.issn.1004-4469.2016.02.013.Cao SS, Peng CX, Li XM, et al. Clinical characteritics of ethambutol optic neuropathy in eighteen cases[J]. Ophthalmol CHN, 2016, 25(2): 123-126. DOI: 10.13281/j.cnki.issn.1004-4469.2016.02.013.
4. 王伟, 杨晖, 张秀兰. 乙胺丁醇中毒性视神经病变的研究现状[J]. 中华眼科杂志, 2012, 48(2): 184-188. DOI: 10.3760/cma.j.issn.0412-4081.2012.02.021.Wang W, Yang H, Zhang XL. Present status of ethambutol-induced optic neuropathy[J]. Chin J Ophthalmol, 2012, 48(2): 184-188. DOI: 10.3760/cma.j.issn.0412-4081.2012.02.021.
5. 左海红. 乙胺丁醇中毒性视神经病变的研究现状[J]. 继续医学教育, 2012, 48(2): 97-100. DOI: 10.3969/j.issn.1004-6763.2017.03.051.Zuo HH. Present status of ethambutol-induced optic neuropathy[J]. Continuing Med Edu, 2012, 48(2): 97-100. DOI: 10.3969/j.issn.1004-6763.2017.03.051.
6. Lim SA. Ethambutol associated optic neuropathy[J]. Ann Acad Med Singapore, 2006, 35(4): 274-278. DOI: 10.1097/00000441-200604000-00010.
7. Guillet V, Chevrollier A, Cassereau J, et al. Ethambutol-induced optic neuropathy linked to OPA1 mutation and mitochondrial toxicity[J]. Mitochondrion, 2010, 10(2): 115-124. DOI: 10.1016/j.mito.2009.11.004.
8. Pradhan M, Sharp D, Best S, et al. Drug-induced optic neuropathy--TB or not TB[J]. Surv Ophthalmol, 2010, 55(4): 378-385. DOI: 10.1016/j.survophthal.2009.10.005.
9. Blanc C, Heran F, Habas C, et al. MRI of the optic nerves and chiasm in patients with leber hereditary optic neuropathy[J]. J Neuroophthalmol, 2018, 38(4): 434-437. DOI: 10.1097/WNO.0000000000000621.
10. Osaguona VB, Sharpe JA, Awaji SA, et al. Optic chiasm involvement on MRI with ethambutol-induced bitemporal hemianopia[J]. J Neuroophthalmol, 2014, 34(2): 155-158. DOI: 10.1097/WNO.0000000000000095.
11. 陈冬军, 陈建华, 王伟, 等. OCT在乙胺丁醇所导致的视神经病变早期诊断中的应用[J]. 中国地方病防治杂志, 2017, 32(5): 545-546.Chen DJ, Chen JH, Wang W, et al. The application of optic coherence tomography in the early diagnosis of ethambutol-induced optic neuropathy[J]. Chin J Ctrl Endem Dis, 2017, 32(5): 545-546.
12. Peng CX, Zhang AD, Chen B, et al. Macular thickness as a predictor of loss of visual sensitivity in ethambutol-induced optic neuropathy[J]. Neural Regen Res, 2016, 11(3): 469-475. DOI: 10.4103/1673-5374.179061.
13. Lee JY, Choi JH, Park KA, et al. Ganglion cell layer and inner plexiform layer as predictors of vision recovery in ethambutol-induced optic neuropathy: a longitudinal OCT analysis[J]. Invest Opth Vis Sci, 2018, 59(5): 2104-2109. DOI: 10.1167/iovs.17-22988.
14. Zoumalan CI, Sadun AA. Optical coherence tomography can monitor reversible nerve-fibre layer changes in a patient with ethambutol-induced optic neuropathy[J]. Br J Ophthalmol, 2007, 91(6): 839-840. DOI: 10.1136/bjo.2006.107326.
15. Kumar A, Sandramouli S, Verma L, et al. Ocular ethambutol toxicity: is it reversible?[J]. J Clin Neuroophthalmol, 1993, 13(1): 15-17. DOI: 10.1016/0891-0618(93)90031-X.
16. Tsai RK, Lee YH. Reversibility of ethambutol optic neuropathy[J]. J Ocul Pharmacol Ther, 1997, 13(5): 473-477. DOI: 10.1089/jop.1997.13.473.
17. Lee EJ, Kim SJ, Choung HK, et al. Incidence and clinical features of ethambutol-induced optic neuropathy in Korea[J]. J Neuroophthalmol, 2008, 28(4): 269-277. DOI: 10.1097/WNO.0b013e31818e3c6b.
18. Vashist P, Senjam SS, Gupta V, et al. Definition of blindness under National Programme for Control of Blindness: do we need to revise it?[J]. Indian J Ophthalmol, 2017, 65(2): 92-96. DOI: 10.4103/ijo.IJO_869_16.
19. Zhou H, Wang W, Xu Q, et al. Clinical features and visual outcomes of optic neuritis in Chinese children[J/OL]. J Ophthalmol, 2016, 2016: 9167361[2016-09-20]. https://doi.org/10.1155/2016/9167361. DOI: 10.1155/2016/9167361.
20. 陈进波, 丘少杰. 乙胺丁醇中毒性视神经病变21例临床分析[J]. 中国实用眼科杂志, 2006, 24(8): 822-824. DOI: 10.3760/cma.j.issn.1006-4443.2006.08.016.Chen JB, Qiu SJ. Clinical characteristics of ethambutol optic neuropathy: 21 cases report[J]. Chin J Pract Ophthalmol, 2006, 24(8): 822-824. DOI: 10.3760/cma.j.issn.1006-4443.2006.08.016.
21. Chen SC, Lin MC, Sheu SJ. Incidence and prognostic factor of ethambutol-related optic neuropathy: 10-year experience in southern Taiwan[J]. Kaohsiung J Med Sci, 2015, 31(7): 358-362. DOI: 10.1016/j.kjms.2015.05.004.
22. Talbert EK, Sadun AA. Risk factors for ethambutol optic toxicity[J]. Int Ophthalmol, 2010, 30(1): 63-72. DOI: 10.1007/s10792-009-9293-z.
23. Ikeda A, Ikeda T, Ikeda N, et al. Leber’s hereditary optic neuropathy precipitated by ethambutol[J]. Jpn J Ophthalmol, 2006, 50(3): 280-283. DOI: 10.1007/s10384-005-0308-7.
24. Seo JH, Hwang JM, Park SS. Antituberculosis medication as a possible epigenetic factor of Leber’s hereditary optic neuropathy[J]. Clin Exp Ophthalmol, 2010, 38(4): 363-366. DOI: 10.1111/j.1442-9071.2010.02240.x.
25. Pommer R, Schoeler S, Mawrin C, et al. The G11778A LHON mutation does not enhance ethambutol cytotoxicity in a cybrid model[J]. Clin Neuropathol, 2008, 27(6): 414-423. DOI: 10.5414/NPP27414.

Chinese Journal of Ocular Fundus Diseases

Clinical characteristics and prognostic factors analysis of ethambutol-induced optic neuropathy

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