The ocular side effects of systemic drugs

An update on the evidence of how Plaquenil, Fosamax and other common systemic drugs affect the eyes.

By Leonid Skorin, Jr, DO, OD, MS

About the Author
	Leonid Skorin, Jr., DO, OD, MS, practices at the Mayo Clinic Health System in Albert Lea, Minn. He is an assistant professor of ophthalmology at Mayo Clinic College of Medicine. His e-mail is skorin.leonid@mayo.edu Disclosure: Dr. Skorin has no relationships to disclose.

The American Academy of Ophthalmology's 2011 release of revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy highlights the actuality that some systemic medications can be hazardous to our patients' vision. Knowing which systemic medications can cause damage to the visual system and knowing when and how to evaluate patients to prevent this damage must be within the purview of every ophthalmologist.

This article reviews the latest evidence on the ocular side effects of systemic drugs and explores how we should address them in the clinic.

HCQ AND CQ

Affinity for the RPE

Hydroxychloroquine (HCQ) and chloroquine (CQ) are anti-malarial drugs commonly used in the treatment of rheumatoid arthritis, systemic lupus erythematosus, Sjögrens syndrome and dermatologic and other inflammatory conditions. HCQ (Plaquenil and other brand names) has largely replaced CQ because it has fewer side effects and patients tolerate it better.

These medications have an affinity for the retinal pigment epithelium (RPE), causing RPE depigmentation and additionally damaging the rod and cone receptors within the macula. This results in the classic funduscopic presentation of bull's-eye maculopathy (Figure 1). Even with prompt discontinuation of these medications, vision often deteriorates further for up to several years.¹

Figure 1. Ultra-widefield fluorescein angiography exhibits hydroxychloroquine toxicity with “bull's eye” maculopathy.

COURTESY: JOHN W. KITCHENS, MD

Patients taking one of these two drugs for longer than five to seven years or a cumulative dose of 1,000 g HCQ or 460 g CQ are at risk of retinopathy.² Patients of short stature or who are obese need their daily dose of these drugs adjusted.^2,3

Managing HCQ, CQ patients

Patients on HCQ or CQ therapy should have a baseline examination within the first year of starting therapy. The new AAO guidelines include a 10-2 visual field test and at least one objective measure: spectral-domain OCT (SD-OCT), multifocal electroretinogram (mf-ERG) or fundus autofluorescence (FAF).² The ophthalmologist can obtain fundus photography to document a healthy retina or any pre-existing retinal changes at her or his discretion.

After five years of HCQ or CQ use, the AAO guidelines recommend yearly examinations with 10-2 visual field and objective testing.² Screen high-risk patients (older age, pre-existing retinal disease, underlying hepatic or renal disease) earlier and possibly more often.^2,4

The AAO guidelines indicate a shift toward more objective testing, yet the subjective white 10-2 visual field is still an integral part of the screening process. Paracentral scotomas typically manifest first with central scotomas, and a decrease in visual acuity occurring later as the toxicity spreads toward the fovea.³

SD-OCT will exhibit a disruption of the photoreceptor integrity line (inner-outer segment layer)⁵ first seen in the parafoveal retina. The mf-ERG will show a depression or blunting of the perifoveal wave amplitudes and has been found to be a suitable alternative to visual field testing in those who cannot perform the subjective test.² FAF will exhibit absent RPE (hypofluorescence) or stressed photoreceptors (hyperfluorescence) in patients with HCQ- or CQ-induced retinopathy.²

ETHAMBUTOL

Toxic optic neuropathy

Ethambutol has been a mainstay of tuberculosis therapy for several decades. Even today, tuberculosis is still the most common infectious disease, infecting millions of people worldwide.⁶ More recently, ethambutol has become an important component, second only to marcolides, in current multidrug treatment regimens for patients with pulmonary and disseminated Mycobacterium avium complex disease.⁷

Ethambutol is an antimicrobial agent and acts only on proliferating cells. It inhibits synthesis of RNA by preventing mycolic acid from incorporating into the mycobacterial cell wall. The most serious potential adverse effect of ethambutol is toxic optic neuropathy.

In the treatment of tuberculosis, the reported incidence of optic neuropathy when ethambutol is taken for more than two months is 18% in subjects receiving more than 35 mg/kg/day, 5% to 6% with 25 mg/kg/day and less than 1% with 15 mg/kg/day.⁷ The onset of toxic optic neuropathy may occur sooner if the patient has concurrent renal disease, which results in reduced excretion of the medication.⁸

Managing ethambutol-induced disease

Patients who develop ethambutol-induced toxic optic neuropathy present with decreased visual acuity in the setting of a normal-appearing ocular examination. Visual fields typically show a cecocentral or bitemporal defect. Dyschromatopsia may be the earliest sign of toxicity and blue-yellow color changes are the most common color defect.⁹

The standard evaluation for patients taking this drug includes visual acuity, threshold visual fields, ophthalmoscopy and color vision testing with either Farnsworth Panel D-15 test or the Farnsworth-Munsell 100-Hue test, both of which are effective for detecting subtle color vision changes associated with early ethambutol toxicity.

In a recent study, contrast sensitivity using the Pelli-Robson contrast sensitivity chart and mf-ERG have been shown to be sensitive tests to detect ethambutol toxicity in subclinical stages.¹⁰ Early detection is important because vision loss is not always reversible even after discontinuation of the medication.⁹

AMIODARONE

Keratopathy and neuropathy

The most frequent ocular finding in patients taking the anti-arrhythmic medication amiodarone is verticillate or whorl keratopathy. This keratopathy may occasionally produce symptoms of glare, halos or blurred vision and is reversible. Amiodarone is known by the brand names Cordarone (Pfizer, New York) and Pacerone (Upsher-Smith Laboratories, Maple Grove, Minn.).

More visually significant is amiodarone-induced optic neuropathy. Its presentation has been described as insidious at onset, simultaneous and bilateral with visual field loss, and with visual acuity ranging from 20/20 to 20/200.¹¹ Alternatively, the presentation may be acute in onset or the localization retrobulbar.¹²

Questions over incidence

The incidence of amiodarone-related optic neuropathy has been estimated at 1.76% over a 10-year period vs. 0.3% in an age-matched population not using the drug.¹³ Some have challenged this incidence as overestimated because the original study included patients with more tenuous clinical presentations or those having comorbid diseases such as diabetes or hypertension, both of which are also risk factors for non-arteritic anterior ischemic optic neuropathy (NAION).¹⁴

The commonality and overlap of patients who take amiodarone and are at risk for NAION can be so great that it may be difficult to tease out those whose optic neuropathy is a direct result of their amiodarone use. Authors have suggested amiodarone is a potential risk factor for optic neuropathy rather than a direct cause of it, so no specific recommendations exist for periodic ophthalmic screenings of patients on amiodarone.¹⁴

FINGOLIMOD

Risk of CME

Fingolimod (Gilenya, Novartis, Basel, Switzerland) is an oral sphingosine-1-phosphate (S1P) receptor modulator used to prevent exacerbations of relapsing-remitting multiple sclerosis.¹⁵ This immunosuppressive agent can cause cystoid macular edema (CME) (Figure 2). The occurrence of macular edema appears to be dose-dependent with an incidence of approximately 0.5% when patients take the currently approved oral dose of 0.5 mg.¹⁵

Figure 2. The MS agent fingolimod has been associated with angiographic CME, as imaged on fundus photography (A) and confirmed on OCT (B).

COURTESY: KEITH A. WARREN, MD

In addition, one study showed overall macular volume increased in up to 74% of eyes in a fingolimod-treated group of patients vs. 37% of control eyes.¹⁶ The examiners in this study used SD-OCT to identify the modest macular volume increase that occurred relatively rapidly (five months from initiation of therapy).¹⁶

Although the exact mechanism causing the macular edema is not known, some have speculated that fingolimod induces degradation of the S1P receptor that helps maintain vascular endothelial integrity, resulting in the breakdown of the inner blood-retinal barrier.¹⁷

Managing fingolimod-induced CME

If CME occurs, the fingolimod should be stopped, which would ultimately resolve the edema.¹⁸ However, complete resolution can take from one to six months.¹⁹ Topical steroid and non-steroidal anti-inflammatory medication may help accelerate recovery.

Recommendations for patients taking this medication include a baseline ophthalmic evaluation before treatment and at three or four months after the first dose.¹⁵ Patients should monitor their own vision daily with an Amsler grid chart and report to their ophthalmologist if they experience any painless reduction in vision. Ophthalmoscopy and SD-OCT are indicated for monitoring the macula.

BISPHOSPHONATES

Uveitis, scleritis, episcleritis

Bisphosphonates such as alendronate (Fosamax, Merck, Whitehouse Station, N.J.) aid in inhibiting osteoporosis in postmenopausal women and manage hypercalcemia of malignancy.²⁰ Numerous case reports and case series have described an association between oral bisphosphonates and ocular inflammation, such as uveitis, scleritis and episcleritis. In most cases, symptoms of inflammation start within days of starting bisphosphonate therapy.

A recent retrospective cohort study confirmed that first-time users of bisphosphonates were at an increased risk of developing uveitis and scleritis compared to people with no bisphosphonate use.²¹ The release of inflammatory mediators is believed to be the possible mechanism for bisphosphonate-induced inflammatory events.²²

Because uveitis and scleritis can be associated with significant morbidity, all patients starting these medications should be counseled to return to their physician immediately at the first signs and symptoms of ocular inflammation. They should be directed to discontinue the bisphosphonate agent and start appropriate anti-inflammatory therapy.

AMANTADINE

Corneal edema

Amantadine (Symmetrel, Endo Pharmaceuticals, Malvern, Pa.) is an antiviral agent used to treat influenza. It has also been found beneficial in controlling the fatigue associated with multiple sclerosis and treating the dyskinesia and motor fluctuations in Parkinson's disease associated with the decarboxylase inhibitor levodopa.²³

Amantadine can cause corneal edema that begins a few months to several years after starting therapy and can occur even in a corneal graft.²⁴ Although some authors have found the corneal edema resolves when patients discontinued the amantadine and initiated topical steroid therapy, others have found the corneal edema can be potentially irreversible.

Histopathological analysis of corneal buttons in patients with amantadine-induced corneal edema has shown significant loss of endothelial cells.²⁴ Analysis of the corneal endothelium of patients on amantadine but not exhibiting corneal edema has shown these patients have lower endothelial cell density and lower cell hexagonality, and the higher the cumulative dose of amantadine therapy, the greater the reduction in endothelial cell density.²⁵

Managing amantadine-induced corneal edema

Treatment of amantadine-induced corneal edema includes stopping the drug and topical steroid treatment. If the edema persists and causes significant visual disability, then either a full-thickness corneal transplantation or Descemet's stripping automated endothelial keratoplasty may be indicated.^24,26 OM

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