Corneal manifestations of systemic disease have long been on the radar of anterior segment specialists, but keep in mind that some slit-lamp findings can be caused by the medications our patients are prescribed, and may mimic the changes associated with the disease itself. Systemic medications reach the cornea through the tear film, aqueous humor and limbal vasculature. Access from the tear film leads to deposition in the epithelium, from the limbal vasculature into the stroma, and from the aqueous into the endothelium, epithelium and stroma.¹

Fortunately, these corneal abnormalities usually are not visually debilitating or permanent. It is, however, important to recognize these associations and to openly communicate your concerns with the primary care physician or specialist who prescribed the systemic drug, as they can be a precursor to lens, optic nerve or retinal changes that can cause permanent and serious vision impairment. A thorough case history that elicits all medical conditions and medications—dosage and length of treatment—is essential to identify the genesis of the abnormal slit-lamp findings.

In the January/February column, we introduced Cystaran 0.44% (cysteamine ophthalmic solution, Sigma-Tau Pharmaceuticals), a topical ophthalmic drop for the treatment of patients suffering from corneal cystine crystal accumulation secondary to cystinosis. This medication is expressly intended to treat an ocular side effect of a systemic disease. It is rare to have such a remedy at hand; more often, careful monitoring and judicious use of the systemic agent is the best approach.

Here are a just a few examples of medications that are associated with corneal changes.

Epithelium
• Vortex keratopathy, or corneal verticillata, is a common side effect of a number of systemic medications—e.g., amiodarone, aminoquinolones, indomethacin, tamoxifen, atovaquone and tilorone—and results from the intralysosomal accumulation of lipids. This condition presents with golden-brown deposits in a whorl-like pattern normally seen in the inferior corneal epithelium. This configuration is a result of the corneal epithelium’s growth and repair process.² Patients who present with this finding are typically asymptomatic, though they may report photophobia or halos around lights. Vortex keratopathy as a side effect is indistinguishable from what we see in Fabry’s disease, an inherited lysosomal storage disease.

• Amiodarone, an anti-arrhythmic agent, is strongly linked to the development of corneal verticillata. In fact, it is present in 69% to 100% of patients taking 200mg to 2,400mg daily, and is detectable within four to six months. It is concentrated in the tears and appears to be more severe in contact lens wearers.³ Discontinuation of the drug typically allows for resolution of the keratopathy within three to 20 months.^4-6

John Dovie, OD, and Andrew Gurwood, OD, reported on a case of amiodarone-induced keratopathy with acute onset of bilateral corneal edema and subepithelial cysts that caused decreased acuity, glare and halos, which persisted for two months after discontinuation of the medication.⁷ Mesut Erdurmus, MD, and colleagues reported a rare case of amiodarone-associated endothelial deposition, seen with a confocal laser scanning microscope, in a patient taking 200mg daily for six years.⁸ Amiodarone has also been linked to lenticular opacities and optic neuropathy.^9,10

• Chloroquine (Aralen, Sanofi Aventis) and hydroxychloroquine (Plaquenil, Sanofi Aventis) are antimalarial agents used in the management of rheumatoid arthritis and lupus. Corneal manifestations include vortex keratopathy and decreased corneal sensation. The corneal findings are benign, but the retinal toxicity is concerning, as it is irreversible (even with discontinuation of the drug) and can lead to permanent central and peripheral vision loss.¹¹

While corneal findings had been thought to have no correlation with the development of retinal toxicity, Aljoscha Neubauer, MD, and colleagues conducted a screening of 93 patients with marked corneal deposits who were taking either chloroquine or hydroxychloroquine, and using electro-oculogram and computerized color vision testing, found a 50% sensitivity and 90% specificity for retinopathy.^12,13

• Tamoxifen, an estrogen antagonist used in the long-term treatment of breast cancer, creates bilateral, white or multi-colored, whorl-like, central subepithelial opacities that can cause reduced visual acuity.¹⁴ Tamoxifen retinopathy is rare, but has been detected at even low levels of treatment. After tamoxifen cessation, almost all of the ocular abnormalities are reversible—except for the retinal opacities, which can include bilateral macular edema, and yellow-white dots in the paramacular and foveal areas.¹⁵

Stroma /Endothelium
• Chlorpromazine (Thorazine, GlaxoSmithKline) is a phenothiazine antipsychotic associated with pigmentary deposition in multiple ocular tissues—including the eyelid, cornea, conjunctiva and lens—when taken at high doses for prolonged periods.¹⁶ Chlorpromazine has been noted to cause dramatic skin discoloration and multiple corneal crystalline deposits.¹⁷ White deposits have been detected in deeper layers of the cornea—including subepithelial stroma, Descemet’s and endothelium—via HRT II cornea module and confocal microscopy.^18,19

• Amantadine (Symmetrel, Endo Pharmaceuticals) is prescribed to reduce tremors associated with Parkinson’s disease and treat fatigue associated with multiple sclerosis. It has been implicated as the cause for otherwise unexplainable corneal edema that begins several months after institution of therapy and is usually reversible after cessation.^20-22

• Gold. Arun D. Singh, MD, reported a case of an asymptomatic patient receiving regular intramuscular injections of colloidal gold for rheumatoid arthritis who had fine, diffuse yellow-brown deposits in the central corneal epithelium and confluent deposits in the deep central corneal stroma. Discontinuation of the medication is not required.²³

Though not nearly a comprehensive list, this column should serve as a reminder to the eye care practitioner that a thorough medical case history that includes all medications, dosage and duration of treatment is incredibly important. While corneal manifestations of systemic medications are typically benign and generally require no treatment, artificial tears in some cases may help minimize corneal deposition, especially from the tear film.

Sometimes these manifestations can be linked to more serious lenticular, optic nerve or retinal findings, and this should be reported to the patient’s primary care physician in a timely manner. Report ocular side effects to the National Registry of Drug-Induced Ocular Side Effects at www.eyedrugregistry.com. 

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23. Singh AD, Puri P, Amos RS. Deposition of gold in ocular structures, although known, is rare. A case of ocular chrysiasis in a patient of rheumatoid arthritis on gold treatment is presented. Eye. 2004 Apr;18(4):443-44.