Ethambutol: friend or foe?

Editorial

Ethambutol: friend or foe? Expert Rev. Ophthalmol. 9(2), 59–61 (2014)

Expert Review of Ophthalmology Downloaded from informahealthcare.com by 149.255.255.242 on 05/20/14 For personal use only.

Rosa A Tang Author for correspondence: University Eye Institute at University of Houston – Neuroophthalmology, 4901 Calhoun Street, Houston, TX 77204, USA [email protected]

Jade Schiffman University Eye Institute at University of Houston – Neuroophthalmology, 4901 Calhoun Street, Houston, TX 77204, USA

Roberto Alejandro Cruz Neuro-ophthalmology of Texas, 2501 West Holcombe, Houston, TX 77030, USA and Neuro-ophthalmology of Texas, PLLC – Neuro-Ophthalmology, 2617 C West Holcombe Blvd, Houston, TX 77025, USA

Gabriela Corsi Neuro-ophthalmology of Texas, PLLC – Neuro-Ophthalmology, 2617 C West Holcombe Blvd, Houston, TX 77025, USA

Ethambutol (EMB) is one of the first-line antimycobacterial drugs used to treat tuberculosis and is also used to treat atypical mycobacterium infections. It is almost always used in combination with other antimycobacterial drugs. Ever since the drug’s introduction in the 1960s, there have been descriptions of optic neuropathy associated with EMB. Despite a clear association of EMB-induced optic neuropathy, many questions remain unanswered, namely, which tests are more accurate to monitor toxicity, how often should they be performed and once the optic neuropathy is present, how much of it is reversible?

In 2011, there were an estimated 8.7 million new cases of tuberculosis (TB) worldwide (13% co-infected with HIV) and 1.4 million people died from TB, including almost 1 million deaths among HIV-negative individuals [1]. Ethambutol (EMB) is one of the firstline antimycobacterial drugs used to treat TB and it is also used to treat atypical mycobacterium infections. It is used to prevent or delay the emergence of drug resistance. It is almost always used in combination with other antimycobacterial drugs. Ever since the drug’s introduction in the 1960s, there have been descriptions of optic neuropathy (ON) associated with EMB [2]. Sadun and Wang estimated that about 100,000 acquired cases of blindness each year can be attributed iatrogenically to EMB [3]. Despite a clear association of EMBinduced ON (EON), many questions remain unanswered, namely, which tests are more accurate to monitor toxicity, how often should they be performed and once the ON is present, how much of it is reversible. EON most commonly affects the central ON fibers resulting in progressive loss of visual acuity with central or cecocentral scotomas, dyschromatopsia and loss of high spatial frequency contrast sensitivity [3,4]. Although the pathophysiology of EON is not fully understood, the proposed mechanisms involve the chelating effect of the drug on metal ions, most notably zinc and copper

contained in prokaryotic ribosomes [4]. Due to the similarity of bacterial and mammalian mitochondrial DNA, EMB disrupts oxidative phosphorylation at the level of iron-containing complex I and copper-containing complex IV of the electron-transporting chain [5]. EMB decreases the levels of copper available for cytochrome oxidase c, causing a sustained impairment in energy production that eventually leads to accumulation of oxygen reactive species and subsequent apoptosis and resultant ON degeneration [3,6]. Another mechanism proposed is that EMB toxicity results in cellular vacuoles of acidic composition, becomes permeable causing the release of proapoptotic factors into the cytosol of retinal ganglion cells (RGCs), through a zinc-mediated mechanism [7,8]. The clinical findings of EON may be explained by the compromised axonal transport in RGCs, which may be particularly vulnerable to EMB toxicity in the papillomacular bundle, perhaps due to the narrow caliber axons of long length [3,8]. EMB also has affinity for the optic chiasm and bitemporal visual fields defects manifest with toxicity [6]. The visual loss in EON is typically relatively symmetrical, with a subacute onset, usually commencing 2–8 months after initiation of therapy [6]. There is variability at the onset of EON as reported in a meta-analysis of 70 cases by Talbert and Sadun, where the shortest duration of therapy prior to onset of

KEYWORDS: antimycobacterial drugs • ethambutol • ethambutol-induced optic neuropathy • mycobacterium • optic neuropathy

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10.1586/17469899.2014.898564

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Tang, Schiffman, Cruz & Corsi

symptoms was 3 days and the longest was 18 months [9]. Lee et al. has described EON to be dose- and duration-related, though other studies like the one by Chen et al. contradict this [10]. Typically, once the drug is discontinued the vision loss is reversible to some degree; however, permanent visual impairment without recovery occurs and the vision loss may continue to progress after the drug is stopped for many weeks and then progression stops followed by potential improvement [11–13]. Vision could return to normal but often there is some degree of permanent vision loss with optic atrophy, especially if the drug is not stopped early. There are different dosing regimens with EMB for the different mycobacterial infections. ON develops in 50% of patients taking EMB with doses of 60–100 mg/kg/day, while EON develops in 6% of patients at 25 mg/kg/day and in only 1% for those using £15 mg/kg/day [5,13]. Therefore, we prefer the dose of £15 mg/kg/day. However, sometimes the dose is not given daily and in higher amounts. Risk factors other than dose exist for the development of EON including increased age, renal impairment, arterial hypertension, diabetes and ON due to alcohol/tobacco abuse. In a report of 16 cases of EON, Talbert and Sadun conclude that the correlation between increasing age and risk for EON is due to the fact that renal function decreases with age [4,9,10]. Since almost 70% of each EMB dose is cleared renally, almost any disease of the kidney could impair removal of EMB from the serum [6]. Obesity can also influence distribution and elimination of EMB and if the ideal body weight is not used instead of total body weight in calculations for obese patients, there is a risk for drug overdose [4,11]. Therefore, it is important for ophthalmologist and internal medicine physicians to be aware of these risk factors. Another rare yet important point to remember is that any preexisting genetic conditions affecting the mitochondrial metabolism such as Leber hereditary ON, and autosomal dominant optic atrophy likely make patients more vulnerable to EON. Drug–drug interaction could also add an additional risk factor, medications that block oxidative phosphorylation including chloramphenicol, linezolid, erythromycin, streptomycin and antiretroviral drugs can further contribute to the development of EON, other medications such as infliximab, amiodarone, clioquinol, dapsone, quinine, pheniprazine, suramin and isoniazid have also been associated with ON, even though their mechanism of action is less strongly associated with mitochondrial dysfunction. Once EON is recognized, EMB must be immediately discontinued. This remains the only way to eventually stop progression of visual loss and possibly allow recovery of vision [14]. Several guidelines have been suggested to detect EON at its early stages; however, there is no consensus on specific screening and monitoring on asymptomatic patients [11]. A baseline exam prior to initiation of EMB is best performed at which time educating the patient about EON and how to monitor this. Santaella and Fraunfelder also recommend, and we agree with obtaining informed consent prior to assuming care for patients taking EMB [15]. Patients should report any vision or 60

color vision loss as soon as possible and stop the medication should this occur and visit their eye doctors promptly. Regularly scheduled follow-up visits are advisable, and as to its frequency, The Physician’s Desk Reference recommends monthly ophthalmic examinations for patients taking EMB doses >15 mg/kg/day, however, there is no agreement on how often to see patients when the dose exceeds 15 mg/kg/day [15]. An examination schedule dependent on the patients risk factors should be made. However, should vision loss ensue between visits, it is extremely important to educate the patient on reporting this change in vision to their ophthalmologist, who should then arrange to see the patient rapidly. Once vision loss is confirmed to be due to EMB, this information should be given to the physician who is dispensing the medication, and the patient should withhold further doses of EMB and be sure they connect with their treating doctor who will determine what treatment strategy should be taken at this point. It is also critical for all doctors involved to spot changes in risk factors while on therapy including weight loss or worsening renal function and alerting the treating physicians (usually infectious disease and/or pulmonary) to have them relook at these parameters and consider if the drug dosages require adjustment in order to prevent irreversible visual sequelae. As to the examination itself evaluating the visual acuity, color vision, Amsler grid and visual fields are the key tests to perform [5]. The visual field test to consider is 10-2 Humphrey Visual Field testing size III with best visual acuity. Unfortunately, the clinical evaluation of the optic nerve in the early stages of EON may be normal as optic disk pallor doesn’t develop until months after the retinal nerve fibers are lost [12]. Color vision defects might provide the earliest indication for detection of early toxicity. Blue-yellow errors are found in the early stage of intoxication and blue- or red-green defects are found in later stages [14]. Retinal nerve fiber optical coherence tomography (OCT) is another tool. There are variable reports both of retinal nerve fiber layer (RNFL) thickening as well as thinning. It is not unreasonable to get baseline OCT retinal nerve fiber thickness measurements. Some literature suggests OCT can be useful to monitor the RNFL for early reversible axonal swelling in EON cases. One author observed a concurrent improvement in a patient’s visual field defects as the thickness of the RNFL decreased in the involved quadrant, attributing this to resolution of axonal swelling in RGCs after cessation of EMB therapy with recovery of such cells [16]. Similarly, Chai and Foroozan found improvement of visual fields in the majority of patients they studied, but either a decrease or no change in the RNFL thickness was found [17]. Fraunfelder et al. consider that OCT could detect early EMB toxicity that is not detected with the baseline clinical subjective exam [6]. However, Masvidal et al. describe a structural–functional dissociation during the recovery phase of EON, in which the patient’s vision gradually improved despite progressive bilateral optic disk cupping, disk pallor and progressive RNFL loss on OCT. The authors emphasize the need for careful interpretation of OCT findings Expert Rev. Ophthalmol. 9(2), (2014)


Ethambutol

when predicting visual outcomes [8]. The study by Kim and Hwang showed that RNFL decreased as time progressed, but that was not obvious on initial presentation. The authors state that RNFL OCT may be useful in identifying serial changes in RNFL as time passes, but it may not be useful to detect the problem initially [2]. In general, by the time there is retinal nerve fiber drop out in patients with EON, there is already significant and irreversible toxicity. So this test may show an initial mild thickening of RNFL with early toxicity, followed by severe thinning in late toxicity. However, this test has not been studied enough to make recommendations. The new OCT ganglion cell analysis software may show findings of EON prior to the retinal nerve fiber loss. Although EON can produce changes in electrophysiological tests including visual evoked potentials, full-field electroretinogram (ERG), electro-oculograms and multifocal ERG, they all seem impractical for common use and not ready for prime time [6,14,18]. However, the abnormalities in ERGs suggest that EMB may cause retinal toxicity too. In fish, EMB altered synaptic connections between the horizontal and cone cells. EMB ON must be anticipated in all patients on EMB. We propose the following algorithm: • Do a full eye exam before treatment or within the first 2 weeks of treatment. Perform vision, color vision, Amsler grid, 10-2 visual fields. Perform an RNFL OCT and if available ganglion cell analysis. Also do fundus photography, if available. • Have the patient sign an informed consent about taking this drug and the fact that there may be serious vision loss and References 1.

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WHO. Global Tuberculosis report 2012. WHO/HTM/TB/2012.6. WHO; Geneva, Switzerland: 2012 Kim Y, Hwang J. Serial retinal nerve fiber layer changes in patients with toxic optic neuropathy associated with antituberculosis pharmacotherapy. J Ocul Pharmacol Ther 2009;25:6 Sadun A, Wang M. Ethambutol optic neuropathy: how we can prevent 100,000 new cases of blindness each year. J Neuro-Ophthalmol 2008;28:4 Hasenbosch R, Alffenaar J, Koopmans S, et al. Ethambutol-induced optical neuropathy: risk of overdosing in obese subjects. Int J Tuberc Lung Dis 2008;12(8): 967-71 Wang M, Sadun A. Drug-related mitochondrial optic neuropathies. J Neuroophthalmol 2013;33:172-8 Fraunfelder F, Sadun A, Wood T. Update on ethambutol optic neuropathy. Expert Opin Drug Saf 2006;5(5):615-18

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they must agree with an examination schedule in that informed consent. • Prior to the patient leaving the eye doctor, we suggest to train the patient on how to use vision tests, review these tests with the patient so they know how to use the visual acuity chart, Amsler grid and color vision charts. The patient must report changes immediately in any of those tests and they should perform the tests daily. Nowadays, the use of smart phones facilitates these tools to the patients. • Regarding how often patients should be seen, healthy, young patients without renal disease or prior optic nerve disease can be evaluated every 2 months if on 15 mg/kg/day or less and every 6 weeks if on 20 mg/kg/day doses. Elderly patients or those patients with renal issues should be seen monthly. • EMB dosage must be adjusted if the presence of any of the previously mentioned risk factors is encountered or suspected, in this case the eye care provider should connect with the treating doctors in order to have them consider lowering the dose of EMB. Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript.

Guillet V, Chevrollier A, Cassereau J, et al. Ethambutol-induced optic neuropathy linked to OPA1 mutation and mitochondrial toxicity. Mitochondrion 2010;10(2):115-24 Masvidal D, Parrish R, Lam B. Structural-functional dissociation in presumed ethambutol optic neuropathy. J Neuroophthalmol 2010;30:305-10 Talbert K, Sadun A. Risks factors for ethambutol optic toxicity. Int Ophthalmol 2010;30:63-72

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Chen H, Lai S, Muo C, et al. Ethambutol-induced optic neuropathy: a nationwide population-based study from Taiwan. Br J Ophthalmol 2012;96:1368-71

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Chan R, Kwok A. Ocular toxicity of ethambutol. Hong Kong med J 2006;12(1): 56-60

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Lee E, Kim S, Choung H, et al. Incidence and clinical features of ethambutol-induced optic neuropathy in Korea. J Neuroophthalmol 2008;28(4):269-77

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Lim S. Ethambutol-associated optic neuropathy. Ann Acad Med Singapore 2006;35:274-8

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Kandel H, Adhikari P, Shrestha G, et al. Visual function on patients on ethambutol therapy for tuberculosis. J Ocul Pharmacol Ther 2012;28(2):174-8

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Santaella R, Fraunfelder F. Ocular adverse effects associated with systemic medications. Drugs 2007;67(1):75-9

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Zoumalan C, Sadun A. Optical coherence tomography can monitor reversible nerve-fibre layer changes in a patient with ethambutol-induced optic neuropathy. Br J Ophthalmol 2007;91(6):839-40

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Chai S, Foroozan C. Decreased retinal nerve fibre layer thickness detected by optical coherence tomography in patients with ethambutol-induced optic neuropathy. Br J Ophthalmol 2007;91:895-7

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Menon V, Jain D, Saxena R, Sood R. Prospective evaluation of visual function for early detection of ethambutol toxicity. Br J Ophthalmol 2009;93:1251-4

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