Every ophthalmologist should be familiar with medication-induced ocular side effects. Many drugs can have adverse effects on the eye: the agents are as varied as bisphosphonates, tamoxifen, sildenafil, hydroxychloroquine, Thioridazine and amiodarone.¹

These systemic medications do not cause events considered rare, but are well described, even when used at “safe” daily dosages. In fact, health professionals at poison control centers² look for ocular reactions, such as mydriasis and nystagmus, to help determine which toxin the patient ingested.

A handful of common exam findings should alert a clinician to possible medication toxicities. These conditions include cystoid macular edema (CME), retinal crystal deposition and dry eye.

COMMON MEDICATIONS CAUSING TOXICITY

First, the medications that should catch your eye if listed in your patient’s chart:

Hydroxychloroquine

Hydroxychloroquine (Plaquenil, Sanofi-Synthelabo Inc.) is prescribed to treat connective tissue and autoimmune diseases. Known risk factors for the development of hydroxychloroquine retinopathy include daily dosage, age greater than 60 years, liver or renal disease, concomitant maculopathy, concurrent tamoxifen use, treatment duration greater than five years and obesity. Current guidelines recommend basing daily dosage on actual body weight (less than 5 mg/kg/day) rather than ideal body weight. AAO guidelines suggest that a dilated fundus examination be performed at the initiation of therapy. Annual optical coherence tomography (OCT), fundus autofluorescence (FAF), and perimetry (10-2 Humphrey visual field) is recommended starting at the fifth year of treatment or earlier.³

Clinical examination classically demonstrates a bull’s eye maculopathy in more advanced cases. However, modern imaging should reveal minor structural alterations before gross abnormalities are apparent on fundus examination. Early OCT changes may include thinning of the outer nuclear layer, while later stages demonstrate a distinct parafoveal atrophy of the outer retina with attenuation of the ellipsoid segment (Figure 1).⁴ Autofluorescence may demonstrate paracentral hyper- or hypoautofluorescence, depending on the stage. Any visual field defect should be closely analyzed. Multifocal electroretinography can be particularly helpful for confirming early toxicity and monitoring recovery (Figure 2). In Asian patients, retinal toxicity may occur in a more perifoveal than parafoveal distribution. If hydroxychloroquine toxicity is suspected, medication discontinuation is typically recommended. Retinal changes, however, may persist or even worsen after cessation of drug therapy.⁵

Thioridazine

Thioridazine is an antipsychotic drug that physicians once widely prescribed but now prescribe less frequently because of concern over significant retinal toxicity. Initial symptoms may include central vision loss, dyschromatopsia, and nyctalopia in the acute phase. Retinal findings mostly involve retinal pigment epithelial (RPE) and choriocapillaris loss, which evolves from a stippled appearance to a classic nummular pattern.⁶ Fluorescein angiography demonstrates the loss of RPE initially, followed by severe atrophy of the choriocapillaris in the late stage of disease. Electroretinography and electro-oculography may be diminished, but they are not good screening tools as they may not demonstrate significant abnormality until the retinopathy is advanced. Although there is no consensus on appropriate screening, routine dilated fundus examination with OCT and possible FAF or fluorescein angiography may be indicated. If evidence of toxicity is diagnosed, thioridazine must be discontinued. Progressive retinal changes may continue to occur since the medication is stored in the eye.⁵

Tamoxifen

Tamoxifen (Nolvadex, Genox, Tamifen, among others), an estrogen antagonist, is a chemotherapeutic agent commonly used in the management of breast adenocarcinoma. Toxicity generally does not occur in dosages of 20 mg/day or less, although crystals may still be seen in up to 4% of patients on chronic treatment. Visual symptoms may include dyschromatopsia and mild visual deficits. Parafoveal yellowish-white crystals may be seen in the retina.⁷ Macular pigmentary changes and cystoid edema may accompany the crystals. OCT may demonstrate hyper-reflective inner plexiform deposits, ellipsoid segment loss, and CME. Often crystalline deposition has no associated retinal dysfunction, and these situations are often monitored closely.⁴ However, if there is confirmed retinal dysfunction, it may be prudent to discuss with the oncologist the possibility of switching medications.

Sildenafil

Sildenafil (Viagra, Pfizer), and other selective phosphodiesterase-5 inhibitors, are first-line agents for male erectile dysfunction. Bluish visual hues are a typical complaint, which may last up to hours after ingestion. Visual symptoms are more common at higher doses.

A variety of diagnoses have been associated with sildenafil, albeit rarely, including retinal hemorrhages, vascular occlusion, oculomotor nerve palsy, central serous chorioretinopathy and nonarteritic anterior ischemic optic neuropathy (NAION).⁸ There is currently no indication for routine screening of asymptomatic patients.⁵

COMMON EXAM FINDINGS THAT MAY BE ASSOCIATED WITH MEDICATION TOXICITY

Cystoid macular edema

Unexplained or persistent CME is a common retina referral. In the setting of CME without a known cause or persistent edema despite typical management, a thorough medication history review should be performed.

The use of topical epinephrine in the management of glaucoma has declined in recent years. This medication has been shown to be associated with CME, particularly in aphakic patients. Discontinuation of treatment is typically adequate to reduce the macular edema.

In rare instances, CME without leakage on fluorescein angiography has been reported in patients ingesting high doses of nicotinic acid. OCT findings and vision usually normalize with termination of niacin.⁹

Similarly, paclitaxel (Taxol, Bristol-Myers) and docetaxel (Taxotere, Sanofi-Aventis) are antimicrotubule agents that are typically used for treatment of systemic cancers. The associated CME classically does not show leakage on fluorescein angiography.¹⁰ The management of this macular edema may require cessation of treatment, topical or systemic carbonic anhydrase inhibitors, or intravitreal injections of antivascular endothelial growth factor (anti-VEGF) medications.

Latanoprost (Xalatan, Pfizer), a prostaglandin analogue commonly used as a first-line agent in the treatment of glaucoma, has been implicated in the development of CME in up to 5% of patients. These patients may also exhibit anterior uveitis.¹¹ Cessation of treatment may improve the edema and help clinch the diagnosis.

Fingolimod (Gilenya, Novartis) is an immunomodulatory agent targeting the sphingosine-1-phosphate receptor for the treatment of multiple sclerosis. This medication has been associated with the development of CME in approximately 1% of patients, typically in the first few weeks of the treatment course.^12,13 Discontinuation of treatment and/or topical anti-inflammatory drops may be required to manage the condition.

Retinal crystals

Crystal deposition in the retina can be a striking and intriguing exam finding. These crystals are frequently due to medication toxicities.

Tamoxifen, as described above, may cause inner retinal crystal deposition, which would be most dense in the paramacular region. Punctate pigmentary changes and CME may also be seen. Intravitreal anti-VEGF therapy may improve associated macular edema.

Canthaxanthin is a carotenoid used for the treatment of vitiligo, erythropoietic protoporphyria, psoriasis and photosensitive eczema. It has been historically used as an over-the-counter oral tanning agent. Classic retinopathy exhibits a ring-shaped deposition of yellow-orange crystals in the superficial retina with high-dose therapy. Patients are frequently asymptomatic.

Methoxyflurane (formerly Penthrane, Abbott), an inhalation anesthetic, is typically no longer used in the US. Extended use can lead to renal failure due to calcium oxalate crystals in the kidney, as well as numerous yellow-white punctate peri-arterial deposits in the posterior pole.

Talc retinopathy may exhibit characteristic small, white crystals in the end arterioles of the posterior pole. The condition arises when substances such as methylphenidate (Ritalin) or methadone are crushed and then injected intravenously.

SUMMARY

Although there are thousands of systemic medications, only a small number of them produce retinal changes. With many new drugs reaching the market annually, ophthalmologists must maintain a high index of suspicion that patients’ clinical findings and visual symptoms may be related to their systemic medications. OM

REFERENCES

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9. Gass JDM. Nicotinic acid maculopathy. Am J Ophthalmol. 1973;76:500-510.
10. Joshi MM, Garretson BR. Paclitaxel maculopathy. Arch Ophthalmol. 2007;125:709-710.
11. Warwar RE, Bullock JD, Ballal D. Cystoid macular edema and anterior uveitis associated with latanoprost use. Experience and incidence in a retrospective review of 94 patients. Ophthalmology. Feb 1998;105:263-268.
12. Zarbin MA, Jampol LM, Jager RD, et al. Ophthalmic evaluations in clinical studies of fingolimod (FTY720) in multiple sclerosis. Ophthalmology. 2013;120:1432-1439.
13. Afshar AR, Fernandes JK, Patel RD, et al. Cystoid macular edema associated with fingolimod use for multiple sclerosis. JAMA Ophthalmol. 2013;131:103-107.

About the Authors

William F. Mieler, MD, is vice chairman, Department of Ophthalmology, Cless Family Professor of Ophthalmology, University of Illinois at Chicago.

Michael T. Andreoli, MD, completed his ophthalmology residency and vitreoretinal surgery fellowship at University of Illinois at Chicago. He plans to continue research and clinical practice in vitreoretinal surgery and ocular oncology.