Drug Toxicities

AMINOGLYCOSIDE TOXICITY

The aminoglycoside antibiotics include gentamicin, amikacin, and tobramycin. These drugs are used for the treatment and prophylaxis of endophthalmitis. They are toxic to the retina when they enter the vitreous or posterior chamber in high enough concentrations. Toxicity occurs most commonly through inadvertent leakage into the eye from subconjunctival injections or direct injection into the vitreous of inappropriately diluted mixtures.

Symptoms

Aminoglycoside toxicity causes an acute and severe loss of vision.

Clinical Features

Following exposure to a toxic level of these agents, the retina exhibits significant whitening. The area of ischemic retinal whitening can have distinct borders that are irregular in contour. The involved area is typically centered near the macula. Frequently, small retinal hemorrhages are present. Findings that occur weeks to months later include optic atrophy, pigmentary irregularity, and neovascular glaucoma secondary to severe retinal ischemia.

Ancillary Testing

The fluorescein angiogram shows hypofluorescence as a result of nonperfusion of the retinal arterioles. The hypofluorescence tends to be localized to the area of retinal whitening, but can be widespread. The earlyand middle-phase angiograms show hypofluorescence of the affected area. The late phases of the angiogram can demonstrate staining of the edges of the area. The electroretinogram shows a marked reduction and can become extinguished in severe cases.

Pathology/Pathogenesis

In high concentrations, the aminoglycoside drugs appear to cause a direct chemical injury to the retina and nerve fiber layer. Each of the drugs has a different dose that is toxic.

Treatment/Prognosis

Immediate pars plana vitrectomy with a washout of the posterior chamber has been suggested as treatment, if the unintended administration of the drug is recognized quickly. This may reduce the extent and severity of retinal toxicity. Other than this, there is no known treatment. The prognosis is generally poor, with loss of central visual acuity.

Systemic Evaluation

There is no systemic evaluation indicated in aminoglycoside toxicity.

Acute gentamicin toxicity has occurred after subconjunctival injection following cataract surgery. Note the ischemic retinal whitening and intraretinal hemorrhages.

This patient developed retinal toxicity following intravitreal injection of amikacin for infectious endophthalmitis. The fundus examination revealed ischemic retinal whitening.

The fluorescein angiogram of the same patient reveals widespread closure of the retinal arterioles and loss of capillary perfusion.

The fluorescein angiogram of the same patient revealed enlargement of the foveal avascular zone with capillary nonperfusion.

Chloroquine and hydroxychloroquine are used for the treatment of malaria and a variety of collagen vascular diseases including systemic lupus erythematosus.

Irreversible retinal damage has been observed in some patients who have received long-term or high-dose therapy. Patients with collagen vascular diseases taking chloroquine or hydroxychloroquine must be monitored regularly to facilitate early detection of retinal toxicity and discontinuation of treatment.

Symptoms

Pathology/Pathogenesis

Toxicity with chloroquine is more likely with daily doses greater than 250 mg. The drug can be found in both blood and urine up to 5 years after discontinuation of the drug, hence the reports of progressive toxicity even after the drug is stopped. Toxicity with hydroxychloroquine is unusual if the daily dose is kept below 6.5 mg/kg per day. Both of these chemicals have an affinity for melanin and cause lysosomal damage in the ganglion cell layer and degeneration of the photoreceptor outer segments.

Early symptoms of toxicity are paracentral scotomas. As toxicity progresses, patients report loss of acuity and nyctalopia. Dyschromatopsia can occur as well.

Clinical Features

Patients may describe paracentral scotomas and distortion on Amsler grid testing. Early in the course of retinal toxicity, no funduscopic abnormalities or mild stippling of the retinal pigment epithelium (RPE) may be visible. In the later stages, granularity of the RPE is observed in a bull’s eye pattern of retinal pigment epithelial atrophy. Arteriolar narrowing, optic disc pallor, and peripheral RPE degeneration may develop as well. Poliosis, subepithelial corneal deposits, decreased corneal sensitivity, and even sixth cranial nerve palsies may be observed.

Ancillary Testing

How to monitor patients for the early signs of toxicity is still controversial. Central visual field testing with a red test object, Amsler grid monitoring, color vision testing, and electroretinographic studies have all been proposed. Fundus photographs may be obtained for future comparison.

Fluorescein angiography may demonstrate more prominent retinal pigment epithelial alterations than suspected by clinical examination. The classic finding is a bull’s eye pattern of hypoand hyperfluorescence related to the pigmentary alterations. The hyperfluorescence is an example of a transmission or “window” defect. The electroretinogram may be reduced or extinguished in advanced cases.

Treatment/Prognosis

Chloroquine appears to be more toxic than hydroxychloroquine. Nevertheless, patients taking either medication should be monitored regularly for toxicity. The drug should be discontinued immediately if any signs or symptoms of retinal disease occur. Unfortunately, retinal toxicity may progress despite discontinuation of the medication.

Systemic Evaluation

Systemic toxicity related to chloroquine and hydroxychloroquine is uncommon. Systemic side effects include central nervous system reactions such as tinnitus, gastrointestinal disturbances, blood dyscrasias, dermatologic reactions, and rare reports of neuromyotoxicity. It is important to establish and maintain good communication with the treating rheumatologist or primary physician regarding the patient’s ocular status.

The characteristic retinal finding in chloroquine toxicity is a bull’s eye maculopathy. A central region of hyperpigmentation is surrounded by a zone of hypopigmentation.

Advanced cases of chloroquine toxicity may reveal optic disc pallor, retinal vascular narrowing, and peripheral retinal pigmentary alterations in addition to the bull’s eye maculopathy.

Fluorescein angiography demonstrates a transmission or “window” defect corresponding to the zone of retinal pigment epithelial atrophy.

Peripheral retinal pigmentary alterations range from mild stippling of the retinal pigment epithelium to widespread retinal pigment epithelial derangement.

Chloroquine toxicity may progress even after cessation of the medication. This is related to the slow excretion of chloroquine from the body. This patient was found to have a bull’s eye maculopathy after years of chloroquine therapy.

Note the progression of the bull’s eye maculopathy in the same patient 1 year following discontinuation of chloroquine. The patient reported reduced vision with paracentral scotomas.