The purpose of this review is to update clinicians on available literature on the ocular toxicity of ethambutol and the type of eye care to be provided to patients treated with these medications. Ethambutol is a commonly used first-line anti-tuberculosis drug. Since its first use in the 1960s, ocular toxicity is described as related to dose and duration, and it is reversible on therapy discontinuation. However, the reversibility of the toxic optic neuropathy remains controversial. The mechanism of ocular toxicity owing to ethambutol is still under investigation. Other than discontinuing the drug, no specific treatment is available for the optic neuropathy caused by ethambutol. Doctors prescribing ethambutol should be aware of the ocular toxicity, and the drug should be used with proper patient education and ophthalmic monitoring.
Tuberculosis (TB) has been present since 460 BC, as the most widespread disease of the time, and it was fatal. The causative organism of TB is
Ethambutol is one of the first-line anti-TB medications. The other medications or drugs in the treatment regimen include isoniazid, rifampicin and pyrazinamide. Ethambutol is a bacteriostatic drug,
The purpose of this paper is to give an update of published literature on ethambutol-induced ocular toxicity. Ophthalmologists should be aware of the ocular features and management strategies so that they can control the toxicity effectively.
We performed a literature search for publications from 1950 to January 2016, using the search ‘toxic or adverse effects of ethambutol in the eye or the ocular’. All relevant English language publications were included.
The most commonly reported side-effect of ethambutol is optic neuritis; however, it is uncommon in patients prescribed standard doses.
The literature describes a dose-related incidence of ethambutol-related ocular side-effects, with 50% of patients taking 60 mg/kg/day – 100 mg/kg/day and 1% with dosage less than 15 mg/kg/day.
The exact pathophysiology and pathobiology of ethambutol optic neuropathy has not yet been identified. Authors have postulated that mitochondrial disturbance, the zinc-chelating effect and its metabolite are the possible underlying mechanisms.
Ethambutol disrupts oxidative phosphorylation and mitochondrial function by interfering with iron-containing complex I and copper-containing complex IV. The resultant effect is the generation of reactive oxygen species and a cascade of events, resulting in tissue injury and cellular apoptosis. Another theory is the zinc-chelating effect of ethambutol and its metabolite (ethylenediiminodibutyric acid) in the retinal ganglion.
The metabolite of ethambutol is a strong chelator of copper, which is required as a cofactor for cytochrome
The onset of ocular symptoms is usually delayed and may occur months after the commencement of the therapy. However, rare cases of idiosyncratic reaction presenting days after the commencement of a standard dose have been reported.
The results of clinical examination are likely to vary. Both eyes are usually equally affected but can be asymmetric if any disorder is detected.
The incidence of visual field defects vary among studies. In general, visual field defects tend to appear with the use of higher dosages of the drug. Central scotoma is the most reported visual field defect but bitemporal defects or peripheral field constriction can also occur. Colour vision abnormality (dyschromatopsia) may be one of the first detectable signs of ocular toxicity owing to ethambutol.
The toxicity of ethambutol is considered reversible on discontinuation of the therapy; however, views are divided.
Isoniazid is frequently prescribed concurrently with ethambutol. Isoniazid therapy has also been associated with optic neuropathy,
Once ethambutol-induced ocular toxicity is recognised, the drug should be immediately stopped and the patient referred to an ophthalmologist for further evaluation. Presently, therapy discontinuation is the only effective management strategy that can stop the progression of vision loss and allow recovery of vision. Clinicians should consider OCT and contrast sensitivity testing as these tests could detect subclinical optic neuropathy not detected with baseline examination.
Clinicians should obtain baseline examination which should include visual acuity testing, anterior segment examination, pupillary testing, colour vision and contrast sensitivity testing, fundus and optic nerve examination and OCT testing. Health education should be provided to patients on visual side-effects. Patients should be advised that if any visual symptoms occur, they should see an ophthalmologist. Treatment includes discontinuation of the drug. Check-up should be done monthly for patients taking more than 15 mg/kg/day. The prognosis depends on the dosage and duration of being on the ethambutol drug.
The patient, the prescribing doctor and the ophthalmologist or optometrist should work closely together to make ethambutol a safe drug. TB is a public health problem and it would be difficult to eradicate the disease, and the use of ethambutol is most likely to continue. All newly diagnosed TB patients should have an ophthalmological examination before commencing treatment with ethambutol. The doctor prescribing ethambutol should be aware of its potential for ocular toxicity, and all patients treated with this drug should be educated on its potential side-effects (loss of visual acuity, contrast sensitivity, colour vision and visual fields). When the side-effects are noticed, ethambutol should be immediately discontinued. When ocular toxicity is severe, both ethambutol and isoniazid should be immediately stopped. However, it is crucial to consult the prescribing doctor and other managing doctors before discontinuing any medication to prevent harm to the patient’s overall health.
The authors declare that they have no financial interest or personal relationships which might have inappropriately influenced them in writing this article.
The authors, P.M. and S.M., were equally responsible and contributed equally to the preparation and the writing of this article.