`
`Common Medications That May Be Toxic to the Retina
`
`Clinical advice you can trust
`
`Omar Abbasi, MD, and Asheesh Tewari, MD, Detroit
`
`PUBLISHED 11 JUNE 2009
`
`Common Medications That May Be Toxic to the Retina
`The side effects are often reversible, but it’s important that clinicians be able to recognize the signs.
`
`A variety of pharmacologic agents can cause toxicity to the retina. While many of these can be grouped by anatomic location or
`type of toxicity, there are also individual medications with characteristic effects. In this article, we will describe several major
`categories of pharmacologic retinal toxicity and discuss examples of individual medications.
`
`
`Pigmentary Retinopathy
`
` • Quinolines. Chloroquine (Aralen) and hydroxychloroquine (Plaquenil) are traditional antimalarial agents now used in the
`treatment of autoimmune diseases, including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Both
`medications have been shown to bind melanin and to concentrate in the iris, ciliary body and retinal pigment epithelium, altering
`normal physiologic function.
`1
`
`Early on, patients may be entirely asymptomatic, with only blunting of the foveal reflex and RPE granular pigmentary changes.
`With progression, symptoms can include blurred vision, decreased vision, scotomas and photopsias.
`
`As RPE degeneration continues, the classic fundus pattern of bilateral bulls-eye maculopathy can be identified on both clinical and
`fluorescein angiography exam. In late-stage disease, optic disc pallor and arteriovenous narrowing may also develop.
`
`Retinal toxicity has been shown in patients taking greater than 3 mg/kg/day of chloroquine or 6.5 mg/kg/day of
`hydroxychloroquine. While most cases of toxicity have been reported for chloroquine, hydroxychloroquine has supplanted it as
`2
`the more commonly used treatment agent for both RA and SLE.
`
`The American Academy of Ophthalmology has suggested guidelines in order to monitor patients on hydroxychloroquine therapy,
`recommending a baseline dilated fundus exam, automated macular perimetry and Amsler grid testing. Patients should be
`3
`monitored annually, as toxicity can be irreversible and even progress after drug cessation.
`
` • Thioridazine. Thioridazine (Mellaril) is a piperadine antipsychotic agent that has seen a decrease in use with the advent of
`atypical antipsychotic agents. Ocular toxicity was first described in 1980 and has been shown in both short- and long-term
`4
`treatment.
`
`Symptoms of toxicity include decreased vision and dyschromatopsia. On clinical exam, macular pigmentary changes can develop
`into a salt-and-pepper pattern. Long-term use can cause significant optic nerve atrophy and destruction of both the RPE and
`choriocapillaris.
`
`Once signs or symptoms are noted, the medication should be discontinued. Unfortunately, complete visual recovery is rare, and
`visual dysfunction often persists and may even progress after cessation.
`
` • Deferoxamine. Deferoxamine (Desferal) is an iron-chelating agent used to treat conditions with excessive serum iron levels,
`including hemochromatosis. Given in both subcutaneous and intravenous forms, it can also be used to treat aluminum toxicity.
`Ocular signs of toxicity include vision loss, scotomas, dyschromatopsia, and nyctalopia.
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`Fundus examination is often normal; however, RPE mottling may develop over time. Studies have suggested that deferoxamine
`5
`toxicity may cause diminished ERG amplitudes and late-phase vascular leakage on FA.
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`Deferoxamine toxicity is reversible with drug cessation, with full recovery of visual function. However, the medication is often used
`for chronic conditions, such as thalassemia, that require regular therapy. In these patients, monitoring with frequent ophthalmic
`exams is essential to detect early vision loss.
`
`
`Choroidal Toxicity
`
` • Topiramate. Topiramate (Topamax) is a sulfamate-substituted monosaccharide oral anticonvulsant used for the treatment of
`seizures, prophylaxis for migraine, as well as off-label in the treatment of bipolar disorder. Since 2001, several case reports have
`described induced myopia and bilateral angle-closure glaucoma associated with topiramate use.
`6
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`Patients often present within one month of treatment onset, complaining of blurred vision, eye pain and headache. Signs include
`diffuse corneal edema, shallowing of the anterior chamber and significantly raised intraocular pressure. Retinal striae on fundus
`exam may also be noted.
`
`It has been suggested that uveal effusion or ciliary edema leads to forward displacement of the lens-iris diaphragm and
`thickening of the lens by relaxation of zonules. This, in turn, causes anterior chamber shallowing and induced myopia, while
`retinal striae are caused by vitreoretinal traction.
`7
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`While all of the changes are reversible with prompt cessation of the drug, it is often necessary to use cycloplegic agents to reverse
`the anterior displacement of the lens-iris diaphragm. Laser peripheral iridotomy is not useful in lowering IOP as the mechanism of
`angle-closure is not pupillary block. Instead, a combination of topical anti-glaucoma agents can be used for IOP control.
`
` • Metronidazole. Other sulfa-containing medications can cause a similar pattern of symptoms. Metronidazole (Flagyl) is a
`nitroimadazole sulfa agent used to treat anaerobic and protozoal infections, such as Clostridium and Trichomonas,
`8
`respectively. It, along with sulfa analogs such as sulfanilamide (AVC), acetazolamide (Diamox) and hydrochlorothiazide (Oretic),
`9
`has been shown to cause induced bilateral myopia and anterior chamber shallowing from ciliochoroidal swelling. As with
`topiramate, stopping each medication will lead to resolution of ocular changes.
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`Macular Edema
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`Figure 1a. Cystoid macular edema with latanoprost use.
`
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`Figure 1b. Cystoid macular edema with latanoprost use: petalloid pattern of foveal hyperfluorescence on fluorescein angiography.
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` • Latanoprost. Latanoprost (Xalatan) is a prostaglandin analog used to lower IOP by increasing uveoscleral outflow. Patients
`may present with ocular side effects including conjunctival hyperemia, darkening of eyelashes and iris heterochromia. In addition,
`latanoprost is a factor in the development of reversible cystoid macular edema (See Figures 1a & b).
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`The risk has been shown to be particularly high in patients with a prior history of complicated intraocular surgery, epiretinal
`membrane, anterior uveitis, or diabetes mellitus.10 The CME is reversible on discontinuation of the latanoprost but resolution can
`be expedited with the use of topical steroidal and non-steroidal agents.
`
` • Epinephrine. The sympathomimetic agent epinephrine, and its prodrug dipivefrin, is no longer used as primary therapy for the
`treatment of glaucoma in the United States. It acts to lower IOP by decreasing aqueous production but has been shown to induce
`11
`cystoid macular edema in glaucomatous aphakic or pseudophakic patients.
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`Patients complain of blurred or decreased vision within weeks to months of initiating therapy. CME can be documented by FA and
`ocular coherence tomography and will resolve with drug cessation. Consequently, epinephrine and dipivefrin should be avoided
`as first-line therapy for treatment of elevated IOP in patients with previous intraocular surgery.
`
` • Niacin. Niacin, or vitamin B3, is used to treat pellagra, hyperlipidemia and hypercholesterolemia. While facial flushing is the
`most common systemic side effect, patients may have visual complaints including blurred vision, decreased vision and
`metamorphopsia.
`
`On clinical exam, the macula appears edematous. However, niacin-induced macular edema has the unique characteristic of being
`angiographically silent. While OCT imaging exhibits classic cystic intraretinal edema, FA is silent without leakage, which is thought
`12
`to indicate that the edema is secondary to fluid accumulation inside retinal cells, as opposed to an extracellular location.
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`The discontinuation of niacin will gradually reduce CME and improve visual acuity.
`
` • Rosiglitazone. Rosiglitazone (Avandia) is a thiazolidinedione oral agent used to decrease insulin resistance in type 2 diabetes.
`In 2005, a case report described worsening diabetic macular edema with rosiglitazone use.13
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`While congestive heart failure and renal disease are known to worsen DME, systemic fluid retention and peripheral edema have
`also been described in up to 15 percent of patients on therapy.14,15 Rosiglitazone may independently increase retinal endothelial
`16
`cell permeability and increase vascular endothelial growth factor, leading to intraretinal edema and blurred vision.
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`Drug cessation may lead to rapid resolution of both the DME and peripheral edema, however, most cases resolve slowly and may
`require focal laser photocoagulation as adjunctive therapy.
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`Crystalline Retinopathy
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`Crystalline retinopathy has been observed in several systemic and inherited renal diseases including cystinosis and oxalosis. The
`appearance of refractile crystals in the subretinal, intraretinal or preretinal spaces has also been associated with medication use.
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`Common Medications That May Be Toxic to the Retina
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`Figure 2a. Crystalline retinopathy with tamoxifen use: Refractile crystals are noted in the perifoveal area.
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`Figure 2b. Crystalline retinopathy with tamoxifen use: Foveal cystic changes on optical coherence tomography.
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`Figure 2c. Crystalline retinopathy with tamoxifen use: Perifoveal leakage on fluorescein angiography. (Figure 2a, b and c images provided courtesy David Sarraf,
`
`MD.)
`
` • Tamoxifen. Tamoxifen is a selective estrogen receptor modulator used in the management of breast cancer. It is an
`amphiphilic agent that can accumulate in lysosomes and cause oxidative damage.
`
`Patients may be asymptomatic at onset but may complain of decreased vision and dyschromatopsia. Ocular symptoms have been
`noted most often with doses greater than 120 mg twice per day, while therapeutic doses are much lower. Current anti-
`17
`neoplastic regimens start at 20 mg per day and increase to 40 mg per day as needed.
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`Clinically, fundus examination will show refractile intraretinal crystalline deposits concentrated primarily in the perifoveal macula
`(See Figure 2a). Both OCT and FA are used to confirm the presence of CME (See Figures 2b & c).
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`While the current therapeutic dosing levels are less than those shown to cause crystal deposition, annual ophthalmologic exams
`are recommended. Cessation of tamoxifen is recommended if crystals are seen. However, even if visual function recovers as the
`CME resolves, intraretinal crystalline deposits often persist over time.
`
` • Canthaxanthine. Canthaxanthine is a vitamin A derivative used in the treatment of psoriasis and eczema, and had been used
`18
`previously as an oral tanning agent. Toxicity has been shown after high-dose oral therapy of greater than 0.5 mg/kg/day.
`Patients are primarily asymptomatic and diagnosis of toxicity is based on both clinical exam and a history of ingestion.
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`On fundus exam, a doughnut-shaped ring of golden intraretinal deposits surrounds the fovea. FA, ERG and color vision are
`typically normal; however OCT demonstrates crystalline deposition within the inner retinal layers. Visual field testing shows a
`dose-dependent decrease in retinal sensitivity and may be helpful in detecting toxicity.
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`Patients should be monitored with regular ophthalmologic exams. With drug cessation, the retinal crystals may take years to
`disappear, while patients often remain asymptomatic.
`
` • Talc. Talc retinopathy inevitably indicates a history of intravenous drug abuse. Talc, an inert filler used in oral powdered
`medications, deposits in the arterial system of the lungs and liver when injected systemically. It may also lodge in the macular
`19
`arterial vasculature, causing a granulomatous reaction with focal occlusion, leading to eventual macular ischemia.
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`The talc deposits range from 5 to 10 µm in size and are visualized as refractile yellow opacities in the macula. Ischemic sequelae
`include peripheral retinal or optic disk neovascularization, vitreous hemorrhage and arteriovenous anastomosis. Patients often
`present complaining of severe, progressive vision loss.
`
`FA imaging will show capillary nonperfusion, enlargement of the foveal avascular zone and vascular leakage. Treatment of the
`peripheral neovascularization with panretinal photocoagulation is essential, however there is no effective treatment for macular
`ischemia once present.
`
`
`Miscellaneous Medications
`
` • Digoxin. Digoxin (Lanoxin) is a cardiac glycoside used in the treatment of atrial fibrillation, atrial flutter and congestive heart
`failure. It has a narrow therapeutic window, but systemic toxicity is rare when plasma digoxin concentration is less than 0.8 µg/L.
`
`Ocular side effects are common with high doses, with symptoms ranging from decreased vision to photopsias, xanthopsia and
`scotomas. Digoxin acts on retinal cells by inhibiting the sodium-potassium ATPase pump and altering potassium levels. The
`disturbance is primarily electrical and fundus examination is unremarkable. ERG studies may show prolonged b-waves reflecting
`bipolar and Müller cell dysfunction.
`20
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`When digoxin is stopped, both the visual symptoms and prolonged ERG b-wave will resolve over weeks as the medication is
`metabolized.
`
` • Sildenafil. Sildenafil (Viagra) is a selective inhibitor of cGMP-specific phosphodiesterase type 5 (PDE5) that causes smooth
`muscle relaxation and vasodilation in the treatment of erectile dysfunction. While it is selective for PDE5, sildenafil also acts on the
`retina to alter cGMP levels by inhibiting retina-specific PDE6.
`21
`
`Patients may present with visual disturbances, complaining of cyanopsia, photophobia and blurred vision. Typically, visual acuity
`is unchanged and there are no fundoscopic changes on exam. Symptoms resolve over four to six hours after medication
`ingestion.
`
`
`Figure 3. Interferon retinopathy: Scattered cotton wool spots are noted in the nasal macula.
`Recent case reports have also described nonarteritic, anterior ischemic optic neuropathy with sildenafil use.
` However, a recent
`22
`review of pooled data from PDE5-inhibitor clinical trials did not find any direct evidence of an increased risk of NAION.
` It is still
`23
`advisable, however, to inform patients of the need to seek immediate medical attention if sudden vision loss develops.
`
` • Interferon. Interferon (Betaseron) is a recombinant DNA-based protein used in the treatment of several conditions, including
`hepatitis C, leukemia, lymphoma and multiple sclerosis.
`
`Retinopathy is a well-characterized side effect of treatment and includes cotton-wool spots, intraretinal and pre-retinal
`hemorrhage, and macular edema (See Figure 3). A wide incidence range of 18 percent to 86 percent has been reported for
`24
`interferon retinopathy.
` Signs develop within two weeks to three months of treatment onset; patients may complain of blurred
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`vision or be entirely asymptomatic. Vision loss, though rare, can occur and be irreversible. Patients with diabetes mellitus and/or
`hypertension are more likely to show clinical signs of interferon retinopathy and must be followed closely.
`
`Clinical findings usually resolve spontaneously when interferon is discontinued, however the benefit of completing treatment
`must be weighed against the risk of permanent vision loss and discussed with the prescribing physician. At baseline, a full
`fundoscopic exam with photos is helpful to monitor the patient both pre- and post-treatment.
`
`We have summarized above several classes of medications, as well as individual agents, that cause both ocular and retinal
`toxicity. The specific constellation of signs and symptoms for each medication is important to recognize in order to identify and
`detect toxicity, especially as many adverse effects are reversible with medication cessation.
`
`
`Dr. Abbasi is an ophthalmology resident at the Kresge Eye Institute, Wayne State University Department of Ophthalmology. Dr. Tewari is a
`vitreoretinal surgeon at Kresge and is an assistant professor in the same department. Contact Dr. Tewari at the Kresge Eye Institute, 4717
`St. Antoine Blvd., Detroit, Mich., 48201. Phone: (313) 993-0871, fax: (313) 577-2905, e-mail: atewari@med.wayne.edu.
`
`
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