Summary

Various topical, intravitreal and systemic medications can cause retinal toxicity. Despite the presence of the blood-ocular barrier, the retina is still susceptible to the toxic effects of certain drugs, leading to dysfunction and degeneration of the retina . In most cases, retinal toxicity can be reversed by discontinuing the causative agent. However, sometimes progressive or permanent visual loss can occur. Here, we provide a summary of the patterns of retinal injury caused by different drugs.

Patterns of retinal toxicity

Below we summarise the different patterns of drug-induced retinal toxicity. For many drugs, the precise mechanisms by which they cause toxicity is yet to be elucidated.

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Since numerous drugs can produce a variety of toxic effects on the retina, it is always important to include medications in your differential diagnosis for retinopathy. This also highlights the importance of taking a thorough drug history.

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Disruption of the retina and retinal pigment epithelium

Medications that induce a pigmentary maculopathy:

• Chloroquine and its derivatives (e.g. hydroxychloroquine) - initially used as antimalarial prophylaxis, these drugs are now used to treat various autoimmune conditions e.g. rheumatoid arthritis, systemic lupus erythematous. Early toxicity may be asymptomatic, but eventual patients develop paracentral scotoma, decreased visual acuity (when the fovea is involved), metamorphopsia and photophobia. The first sign is often loss of the foveal light reflex. The classic sign is a “bull’s eye maculopathy” appearance, where the fovea is surrounded by a ring of depigmentation inside a ring of hyperpigmentation. In severe toxicity, the peripheral retina can be involved, with optic disc pallor, bone spicules and retinal vessel attenuation. Hydroxychloroquine is generally considered to be safer than chloroquine. Patients taking these medications should have ****a baseline assessment of visual acuity and an OCT scan of the macula before commencing treatment, with subsequent screening for retinopathy. Significant damage can occur without being visible on funduscopy, hence OCT now plays an important role in screening these patients.

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Loss of the outer retinal layer in a parafoveal distribution on the OCT scan has high sensitivity for detecting hydroxychloroquine toxicity.

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• Phenothiazines (e.g. chlorpromazine, thioridazine) - typically used as antipsychotics to treat schizophrenia and other psychiatric disorders. Symptoms include blurred vision, dyschromatopsia, nyctalopia and visual field scotomas. Funduscopic changes include mild granular pigment stippling (in early stages) - described as a “salt and pepper” pigmentary disturbance, circumscribed areas of RPE loss (intermediate stages), and widespread areas of depigmentation, hyperpigmented plaques, vascular attenuation and optic atrophy (in late stages). Even if a patient discontinues the drug, the early fundus changes often progress.
• Alkylating agents (e.g. cisplatin)
• Deferrioxamine - a chelating agent used to treat iron toxicity. Patients can experience rapid visual loss. The fund initially appear normal or mild greying of the macula, but within weeks, mottled pigmentary changes appear.

Bull’s eye maculopathy in a 55-year-old patient who had been taking hydroxychloroquine for 10 years. (A) Colour fundus photographs showing the bull’s eye maculopathy, (B) fundus autofluorescence with central hypo autofluorescence surrounding by a rim of hyper autofluorescence, (C) SD-OCT shows marked parafoveal thinning of the retina, especially the outer photoreceptor layers. Image courtesy of Geamănu Pancă et al.

Medications causing serous retinal detachments:

• MEK (mitogen-activated protein kinase) inhibitors - a new class of chemotherapy agents used to treat metastatic melanoma. MEK inhibitors are thought to cause RPE-induced dysfunction, with subsequent accumulation of subretinal fluid, leading to bilateral multifocal serous retinal detachment with ≥1 focus involving the fovea.
• FGFR (fibroblast growth factor receptor) inhibitors - another new class of chemotherapy drugs

Medications causing retinal oedema and atrophy: