Ocular toxicity with ethambutol therapy: Timely recaution

Ethambutol (EMB) is a widely used agent in the treatment of tubercular and non-tubercular mycobacterial disease. The drug is regarded as the least toxic of the first-line antituberculosis drugs, with a low incidence of ocular toxicity.[1,2] However, in this issue of Lung India, Garg et al.[3] caution against the continued threat of ocular side effects of the drug among patients on the commonly employed directly observed short course (DOTS) regimen for treatment of tuberculosis, which argues for an active surveillance for detection and management of ocular toxicity during EMB therapy. The incidence of EMB ocular toxicity has been reported in various ways. In a recent systematic review, the pooled cumulative incidence of any visual impairment in patients of active tuberculosis, receiving EMB, was 22.5 per 1000 persons treated with EMB, with permanent impairment in 4.3/1000 persons. However, after restricting the analyses to those in whom the average dose was 27.5 mg/kg/day or less and treatment duration was for two to nine months, the incidence of any visual impairment was 19.2/1000, and permanent impairment was 2.3/1000 persons treated. The majority of the episodes were reversible, with resolution of the impairment after an average of three months.[4] The incidence of toxicity among various previously reported Indian studies ranged from 0.6 to 3% among those receiving antitubercular medication,[5,6,7] whereas, Garg et al., from a carefully planned evaluation, reported loss of visual acuity in 9.4% (n = 12) eyes, visual field defects in 6.3% (n = 8), optic disc abnormalities in 4.7% (n = 6), and color vision abnormalities in 12.3% (n = 16) eyes.[3]

Although uncommon at standard doses, optic neuritis is the most important potential side effect of EMB. Retrobulbar neuritis is the most common, with involvement of either the axial fibers or less commonly periaxial fibers, and a mixed pattern on occasion.[2,8] Mitochondrial dysfunction leading to optic neuropathies is getting recognized a lot more as a spectrum of conditions that reach a similar end point.[9] EMB toxicity has been identified as being dose-related, with a reported incidence of 18% in patients receiving >35 mg/kg/day, 5-6% with 25 mg/kg/day, and <1% with 15 mg/kg/day of EMB, for more than two months.[2,10]

Clinically, EMB optic neuropathy presents with simultaneous bilateral involvement. However, the onset may be unilateral, but eventually both eyes are involved. If the visual loss is unilateral, or if a significant difference in the visual acuity is present between the two eyes, other diagnoses must be considered. Symptoms generally appear between four and twelve months after initiating EMB, but rarely have been reported within few days of the start of therapy.[11] There are no reports of optic neuropathy following stoppage of EMB therapy. The onset may be sooner in patients with concurrent renal disease as a result of higher serum levels in the face of impaired excretion. Patients gradually become aware of a painless blur in the center of their reading vision, which continues to progress slowly. The insidious onset and slow progression of the symptoms often delay early detection, and hence, there is a consequent delay in its management. Central scotoma is the most common visual field defect, but bitemporal defects[12,13] or peripheral field constriction have also been reported.[14] Dyschromatopsia (abnormal color perception) can be the initial symptom in some patients.[15] Some investigators have reported that patients have, in particular, a red-green dyschromatopsia, but others have found a predominantly blue-yellow one.[16] Formal visual field evaluation, whether it is static (Humphrey) or kinetic (Goldmann), and color vision testing are thus important to unravel the underlying visual defects. Even as commonly used Ishihara charts and Farsworth-Mussel D-15 test, used by Garg et al.,[3] elicit the usual color perception defect; the subtle blue-yellow defect can only be detected with the use of the generally unavailable desaturated panel of Lanthony.[14] Optical coherence tomography (OCT), which is commonly used to measure nerve fiber layer thickness in patients with glaucoma, can also be used to quantify such changes caused by EMB, in patients with optic neuropathy.[17,18] As early changes are not clinically apparent, OCT can clearly quantify the loss of retinal nerve fibers from the optic nerves of these patients as a sign of early toxicity from the drug, which would not be apparent on funduscopy. Therefore, in conjunction with visual field testing, it is an additional objective test available to monitor patients on EMB.[19]

The exact mechanism of the ocular neurotoxic effect of EMB is yet to be identified. Animal studies have demonstrated EMB toxicity on the retinal ganglion neurons in rodents. Hypotheses for its toxicity have been made, including the zinc chelating effect of EMB and its metabolite on various mitochondrial metal-containing enzymes[9,20,21] and the excitotoxic pathway.[22] Ethambutol is a metal chelator and its anti-mycobacterial properties are related to the inhibition of arabinosyltransferase, an important enzyme for mycobacterial cell-wall synthesis.[9] Ethambutol also disrupts oxidative phosphorylation and mitochondrial function by interfering with the iron-containing complex I and copper containing complex IV. The resultant effect is the generation of a reactive oxygen species and a cascade of events resulting in tissue injury and cellular apoptosis.[4,9] Retinal ganglion cells (RGC) were markedly damaged in monkeys with EMB-induced optic neuropathy, both functionally and morphologically, indicating that RGCs are predominantly affected in the retina of patients with EMB-induced optic neuropathy.[23] The feature of temporal pallor seen commonly in toxic optic neuropathy is due to the high mitochondrial content of the papillomacular bundle, and hence, the ganglion cells in this area are most affected by mitochondrial disturbance.[9]

Various risk factors identified in different studies as predisposing to the ocular toxicity of EMB include increasing age, prolonged duration of EMB, a higher dose, hypertension, poor renal function, diabetes, and concurrent optic neuritis, related to tobacco and alcohol.[24,25,26,27] HIV-positive patients on antiretroviral therapy may be especially vulnerable to the toxic effects of EMB, via a multiple hit effect.[28]

Other than stopping the drug, no specific treatment is available for the optic neuropathy caused by EMB. Most patients will recover after stopping the drug,[4] but this may take weeks to months. However, there are reports that vision may continue to decline or fail to recover even after the drug is stopped.[29] Fortunately, in the study by Garg et al., all the patients had an improvement in their visual disturbances. In mice models, caffeic acid phenethyl ester was found to significantly decrease the oxidative stress in the retina and optic nerve of INH- and ETM-treated rats and could prevent retinal ganglion cell loss.[30]

The usual confusion regarding the etiology of ocular toxicity in patients receiving EMB is because of the concurrent administration of isoniazid. This was also acknowledged by Garg et al.[3]. However, their concern was offset by the recovery of visual impairment upon stoppage of isoniazid. If visual impairment persists after stoppage of EMB, stoppage of INH can be considered.

Recommendation of various preventive strategies for the prevention of EMB toxicity is difficult. Patients with risk factors need the drug to be prescribed only after careful thought is given to the pros and cons. As abnormal color perception may be an early and sensitive indicator of toxicity, prescribing EMB for those with baseline color vision abnormality will need more careful monitoring. A high degree of awareness of this potential ocular side effect of EMB is crucial for both the healthcare staff as well as the patient.

Another important facet brought forth by the study of Garg et al.[3] is the recognition that EMB ocular toxicity can occur during intermittent DOTS therapy. EMB toxicity with intermittent dosing was recently reported in another study also,[31] which was in contravention to the commonly held belief of a less toxic potential of intermittent dosing of EMB, in comparison to daily dosing.[32] Thus the study by Garg et al. is a timely caution that complacency in monitoring ocular toxicity in intermittent, standard dose DOTS, is fraught with significant ocular toxicity, which if undetected, can result in disastrous visual defects. Physicians treating patients with EMB need to be wary of this and must adopt appropriate strategies for early detection and management of the potential toxicity.