Regular visual assessment required for patients on TB therapy

Ethambutol is the first-line treatment for tuberculosis, but the most severe side effect is optic neuritis.

Antituberculosis treatment consists of a multidrug therapy and a 6-month regimen of isoniazid, rifampin, ethambutol HCl and pyrazinamide, with ethambutol being the first-line treatment used for tuberculous and nontuberculous mycobacteria.

Tuberculosis incidence in the U.S. has decreased; however, it has been suggested that the decrease in tuberculosis may be related to the increased prevalence of nontuberculous mycobacteria (NTM) due to antimycobacterial immunity from former TB infections (Horsburgh et al.). NTM are ubiquitous and quite resistant, and there has been an 8.2% increase in prevalence from 1997 to 2007 (estimating from 20 to 47 cases per 100,000 per year), according to Adjemian and colleagues.

Side effects, risk factors

Ethambutol’s side effects include gastrointestinal upset, nausea, dizziness, fever, pruritis, rash, thrombocytopenia, hepatitis, “stocking-and-glove” peripheral neuropathy and, the most severe, optic neuritis.

Retrobulbar optic neuritis most commonly damages the central, or axial, fibers of the optic nerve, leading to decreased vision, central scotomas and dyschromatopsia. In the case of peripheral or periaxial fiber involvement, peripheral visual field constriction occurs.

Ethambutol-induced optic toxicity is classified as mitochondrial optic neuropathy, clinically resembling other toxic optic neuropathies, nutritional deficiencies and even genetic causes such as Leber’s hereditary optic neuropathy and dominant optic atrophy.

The proposed mechanism involves insult to mitochondrial oxidative phosphorylation due to ethambutol’s metal chelation property leading to the selective damage of papillomacular fibers. The papillomacular bundle (PMB) is the preferential site of damage because of its high-energy demand, long unmyelinated course from the macula to the optic nerve anterior to the lamina cribrosa and its narrow caliber (Sadun).

The risk factors associated with ethambutol-induced optic toxicity include dosing, duration, renal disease and age. Toxicity has been reported in 50% of those taking 60 mg/kg/d to 100 mg/kg/d, 18.6% of those taking more than 30 mg/kg/d, 5% to 6% of those taking 25 mg/kg/d, 3% of those taking 20 mg/kg/d and 1% of those taking 15 mg/kg/d (Leiboid and Santaella et al.) No safe dose has been determined, as toxicity has been reported with dosing as low as 12.3 mg/kg/d (Choi et al.).

Management guidelines

Some management guidelines for prescribing ethambutol suggested by Estlin and Sadun include maintaining a dose of close to 15 mg/kg/d or 15 mg/kg three times weekly in the case of low glomerular filtration rate, checking patient’s weight monthly, screening for visual changes monthly in the case of prolonged therapy and educating the patient to report visual changes immediately.

The American Thoracic Society, CDC and Infectious Diseases Society of America jointly developed guidelines for patients treated with ethambutol, recommending baseline visual acuity using Snellen testing and color discrimination testing prior to treatment, followed by monthly subjective visual symptom assessment and monthly color discrimination test (Nahid et al.).

Clinical features of optic neuropathy

Ethambutol-induced optic neuropathy is typically characterized as bilateral, subacute, progressive and painless central vision loss. Other clinical features include dyschromatopsia, decreased high-spatial contrast sensitivity, bilateral central or cecocentral scotomas with rare cases of bitemporal scotomas and peripheral constriction, and bilateral sluggish pupillary response without relative afferent pupillary defect.

Funduscopic examination is typically normal given retrobulbar involvement; however, there may be a slight hyperemic optic swelling and later-stage temporal pallor development. Ocular involvement and onset of symptoms described by different studies can vary from a few days to a few months and even up to 2 years after the initiation of treatment (Schild et al. and Chatterjee et al.).

Clinical exam

The eye examination should include visual acuity assessment, pupil check, color vision testing, contrast sensitivity, visual field, dilation, OCT, electroretinography and visual-evoked potential (VEP). Visual acuity with ethambutol-induced optic neuropathy varies from minimally decreased to no light perception. Pupils may be normal to sluggish, but a relative afferent pupillary defect is not present due to the neuropathy being bilateral and symmetric.

Dyschromatopsia is known to be the most sensitive indicator of early toxicity and occurs before visual acuity and visual field changes. Blue-yellow defects are noticed in the early stages, while red-green changes will be seen in the later stage of toxicity. Ishihara plates cannot detect blue-yellow defects; therefore, the use of Farnsworth-Munsell D-15 or, even better, Lanthony desaturated panel D-15 is indicated. Subclinical toxicity can be detected with contrast sensitivity measurement. Kandel and colleagues reported Pelli-Robson contrast sensitivity to be clinically significantly reduced both monocularly and binocularly before and after ethambutol use.

Another useful tool is visual field testing, with hallmark findings of bilateral central-cecocentral defects. However, visual field testing fails to detect toxicity subclinically. Central scotomas can be explained by injury to the papillomacular axial fibers. Rare visual field defects include bitemporal defects or peripheral field constriction.

Imaging, lab studies

Ethambutol-induced optic neuropathy is a diagnosis of exclusion; therefore, certain lab testing and imaging studies are necessary. Laboratory testing includes complete blood cell count, urinalysis for heavy metal screening, serum B12 and red blood cell folate levels to rule out nutritional deficiencies. Liver function profile including aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma glutamyltransferase (GGT) with mean corpuscular volume (MCV) tests for alcoholism. In the case of bitemporal visual field defect, MRI of the optic nerve and chiasm with/without contrast to rule out compressive lesions and orbital view with fat suppression to exclude any demyelinating lesions should be ordered.

OCT is also an important ancillary test for detecting subclinical toxicity. Thinning of the retinal nerve fiber layer has been shown and is first noticed inferotemporally, supporting involvement of the PMB (Chai et al.). Furthermore, Vieira and colleagues analyzed the role of retinal ganglion cell layer thickness and volume using spectral domain OCT in toxic and nutritional optic neuropathy. They reported a statistically significant decrease in the retinal ganglion cell thickness and volume, with the greatest decrease noted inferior nasally, consistent with the proposed mechanism of selective damage to retinal ganglion cells in PMB. Visual-evoked potential showed significantly reduced P100 amplitude and is also useful in differentiating demyelinating disease from optic neuropathy (Sharma et al.).

Monitoring schedule

Currently, there is no consensus on standard ocular screening or appropriate follow-up interval for asymptomatic patients. However, it is suggested that during treatment, patients with increased risk factors (dosing, duration, renal disease and age) should be monitored monthly due to increased risk of toxicity, and asymptomatic patients should be monitored every 1 to 3 months (Cornblath et al., Kandel et al. and Makunyane et al.). Visual recovery largely depends on the duration of optic nerve damage, and complete recovery may not be achieved, resulting in partial or permanent visual impairment. Some studies have reported progressive visual loss even after ethambutol cessation (Sivakumaran et al., Kumar et al. and Tsai et al.). Few studies have reported an estimated 50% visual recovery rate at 6-month follow-up after ethambutol cessation (Kumar et al., Tsai et al. and Chen et al.).

Mitochondrial dysregulation and damage to ganglion cell axons is a slow process; therefore, prompt recognition and immediate cessation of ethambutol use is fundamental for improved visual outcome and recovery. The clinical course of optic toxicity is unpredictable, so a multidisciplinary team approach involving the physician, optometrist/ophthalmologist, neuro-ophthalmologist and the patient should be considered to ensure safety during the treatment. The patient must be extensively educated on the ocular side effects by the prescribing physician and the importance of seeking care if any new visual symptoms occur. Early detection is the key to reversing the toxicity and recovering vision.

References:

• Adjemian J, et al. Am J Respir Crit Care Med. 2012;doi.org/10.1164/rccm.201111-2016OC.
• Chai SJ, et al. Br J Ophthalmol. 2007;doi.org/10.1136/bjo.2006.113118.
• Chatterjee VKK, et al. Br J Dis Chest. 1986;doi.org/10.1016/0007-0971(86)90066-5.
• Chen SC, et al. Kaohsiung J Med Sci. 2015;doi:10.1016/j.kjms.2015.05.004.
• Choi SY, et al. Korean J Ophthalmol. 1997;11:106-110.
• Cornblath WT, et al. J Neuroophthalmol. 2002;22:124–125.
• Fraunfelder FW, et al. Expert Opin Drug Saf. 2006;doi:10.1517/14740338.5.5.615.
• Grzybowski A, et al. Acta Ophthalmol. 2015;doi:10.1111/aos.12515.
• Horsburgh CR, et al. J Infect Dis. 1996;174:1212–1217.
• Kandel H, et al. J Ocul Pharmacol Ther. 2012;doi:10.1089/jop.2011.0095.
• Kumar A, et al. J Clin Neuroophthalmol. 1993;13:15-17.
• Leiboid JE. Ann New York Acad Sci. 1966;135:904-909.
• Levin L, Arnold A. Neuro-ophthalmology: The Practical Guide. NY:Thieme Medical Publishers; 2005. Chapter 25.
• Makunyane, P, et al. African Vision and Eye Health. 2016;75(1)4.
• Nahid P, et al. Clin Infect Dis. 2016; doi:10.1093/cid/ciw376.
• Polak BC, et al. Ophthalmologica. 1985;doi:10.1159/000309592.
• Sadun A. Trans Am Ophthalmol Soc. 1998;96:881-923.
• Santaella RM, et al. Drugs. 2007;67:75-93.
• Schild HS, et al. Am J Med. 1991;doi.org/10.1016/0002-9343(91)80028-K.
• Sharma P, et al. Indian J Ophthalmol. 2011;doi:10.4103/0301-4738.77035.
• Sivakumaran P, et al. NZ Med J. 1998;111:428-430.
• Talbert Estlin KA, et al. Int Ophthalmol. 2010;doi:10.1007/s10792-009-9293-z.
• Tsai RK, et al. J Ocul Pharmacol Ther. 1997;doi:10.1089/jop.1997.13.473.
• Vieira LM, et al. J Neuroophthalmol. 2015;doi:10.1097/WNO.0000000000000229.
• World Health Organization. Global Tuberculosis Report: 2016. www.WHO/HTM/TB/2016.13.

For more information:

• Charlene Singh, OD, completed a residency in primary eye care/ocular disease in the Optometry Service at the W.G. “Bill” Hefner VA Healthcare System (HCS) based in Salisbury, N.C. She is currently a consultant optometrist at the Salisbury HCS Charlotte VA Healthcare Center and can be reached at: dr.charlenesingh@gmail.com.

Source: Healio