Ophthalmic Pearls

RETINA

Hydroxychloroquine-Induced Retinal Toxicity

by mark s. hansen, md, and stefanie g. schuman, md edited by ingrid u. scott, md, mph, sharon fekrat, md, and michael f. marmor, md

any systemic medica- 1 tions may cause retinal toxicity. One such com- monly used medication for dermatologic and Mrheumatologic inflammatory condi- tions is hydroxychloroquine (Plaque- nil), a chloroquine derivative. It is used to treat many diseases including malaria, and sys- temic erythematosus. Retinal toxicity from hydroxy- 2 chloroquine is rare, but even if the medication is discontinued, vision loss may be irreversible and may continue to progress. It is imperative that pa- tients and physicians are aware of and watch for this drug’s ocular side ef- fects. And before treatment is initiated with hydroxychloroquine, a complete ophthalmic examination should be performed to determine any baseline 3 maculopathy. Ophthalmologists should also fol- low the most current screening guide- lines established by the Academy,1 recently revised in light of new find- ings. (For a broader look at drugs with ocular side effects, see last month’s Clinical Update, “Rx Side Effects: New ADVANCED BULL’S-EYE . A 55-year-old female who had been tak- Plaquenil Guidelines and More.”) ing hydroxychloroquine for 10 years before the onset of symptoms. Color fundus photos showing bull’s-eye maculopathy (1). Fundus autofluorescence with central Symptoms and Signs mottled hypo­autofluorescence with surrounding rim of hyperautofluorescence (2). Symptoms. Patients in earlier stages of SD-OCT shows marked parafoveal thinning of the retina (arrows), especially of the hydroxychloroquine retinal toxicity outer photoreceptor layers (3). usually do not experience symptoms, though the rare patient may note a usually notice symptoms only after up to three visual functions: acuity, paracentral that causes trou- have become severe. When peripheral vision and night vision. ble with reading as well as diminished allowed to advance, hydroxychloro- Signs. On examination, a telltale color vision. However, most patients quine retinal toxicity leads to loss of sign of hydroxychloroquine toxicity

eyenet 33 Ophthalmic Pearls is a bilateral change in the retinal pig- Medication Dosage ment epithelium of the macula that Several factors have been associated Systemic Medications That gives the commonly described appear- with the risk of developing hydroxy- Can Cause Retinal Toxicity ance of a bull’s-eye (Fig. 1). This is a chloroquine retinopathy. One of the Canthaxanthine Isotretinoin late finding, however, and too late for most important appears to be dos- screening to be useful. age—with debate over whether daily Chlorpromazine Methoxyflurane In early toxicity there are no vis- intake vs. cumulative dosage is most Deferoxamine Rifabutin ible signs, but field, OCT and mfERG significant. Recent studies indicate Digoxin Sildenafil changes can be detected. If abnor- that cumulative dosage may be a more Ethambutol Tamoxifen malities are present only unilater- important consideration than daily Ethylene glycol Thioridazine ally, investigate other causes besides dosage.2 However, since higher daily hydroxychloroquine toxicity (see dosage will obviously lead to the toxic “Differential Diagnosis of Bull’s-Eye cumulative dose more rapidly, daily age for most indications is 200 mg to Maculopathy”). dosage is still important to consider. 400 mg per day. Daily dosage is recom- Higher daily dosage also leads to mended not to exceed 400 mg. Mechanism of Toxicity higher concentration of the drug in the The mechanism of hydroxychloro- RPE, which could lead to more aggres- Risk for Toxicity quine retinal toxicity has yet to be sive tissue damage. Previous reports Although it is not possible to predict fully elucidated. Studies have shown indicate that toxicity is rare if dosing which patients will develop retinal tox- that the drug affects the metabolism of is less than 6.5 mg/kg/day.2 To avoid icity, high-risk characteristics include retinal cells and also binds to melanin overdosage, especially in obese patients the following: in the RPE, which could explain the or those of short stature, dose should • daily dose greater than 400 mg (or, persistent toxicity after discontinua- be based on height, which allows for an in people of short stature, a daily dos- tion of the medication. However, these estimation of ideal body weight. (The age over 6.5 mg/kg ideal body weight) findings do not explain the clinical drug clears slowly from the blood, so or total cumulative dose of more than pigmentary changes causing a bull’s- basing dosage on weight puts obese 1,000 g eye maculopathy. patients at risk.) The typical daily dos- • medication use longer than five years • concomitant renal or liver disease Watching for Plaquenil Toxicity (because the drug is cleared by both routes) BASELINE EXAM ANNUALLY AFTER 5 YEARS • underlying retinal disease or macu- • Ocular exam NORMAL • Ocular exam lopathy • Automated visual • Automated visual • age greater than 60 years. fields with white fields with white 10-2 protocol 10-2 protocol Monitoring Guidelines • One or more of • One or more of these Guidelines on screening for retinopa- these objective objective tests: ABNORMAL thy associated with hydroxychloro- tests: FAF quine toxicity were initially published FAF mfERG by the Academy in 2002. These guide- mfERG SD-OCT lines were updated in February of this SD-OCT TOXICITY SUSPECTED year, given the emergence of more Optional: Fundus • Repeat visual fields sensitive diagnostic techniques and the photography • Perform more of the recognition that risk of toxicity from objective tests above years of hydroxychloroquine use is • Perform more frequent greater than previously believed. exams The updated guidelines state that due to sensitivity, specificity and reli- TOXICITY CONFIRMED ability issues, it is not recommended that Amsler grid testing, color vision testing, fundus examination and full- • Refer to prescribing field electroretinogram or electroocu- physician logram be used for toxicity screening. • Discontinue medication Fluorescein angiography may assist in • Examine at 3 months, visualizing early subtle changes in the then annually until stable RPE, but it is not considered a screen-

34 june 2011 Ophthalmic Pearls

Differential Diagnosis of abnormalities are noted on baseline examination. However, earlier, more Coming in the next Bull’s-Eye Maculopathy frequent screening may be prudent for Age-related macular degeneration those at higher risk for toxicity. After five years of treatment, perform an- Benign concentric annular dystrophy nual screenings, including an ocular Central areolar choroidal dystrophy examination, 10-2 threshold field Chloroquine/hydroxychloroquine retinal testing, and one of the objective tests. Feature toxicity In practical terms, SD-OCT is most DALK, DSEK and DMEK widely available, and is very sensitive, Chronic macular hole Explained so practitioners should look for subtle Cone and cone-rod dystrophies parafoveal abnormalities. Understand the rationale Stargardt disease Toxicity: suspected and confirmed. behind each approach, the Whenever you note abnormalities, criteria for patient selection ing tool for retinal toxicity. obtain additional testing. Repeat vi- and the concerns to watch for It is critical to counsel patients sual fields promptly if you see central peri- and postoperatively. about the benefits and limitations of or parafoveal changes, even if these screening, underscoring that it can appear to be nonspecific. If these catch toxicity at early stages and mini- findings are reproducible, follow up Clinical Update mize vision loss but cannot necessarily with objective testing. If toxicity is Cornea: New guidelines from prevent all toxicity and vision loss. suspected, perform more frequent and the Blepharitis Working Group. Baseline examination. At the detailed examinations. Once toxicity is Glaucoma: Managing initiation of treatment with hydroxy- confirmed, the prescribing physician advanced disease. chloroquine, the prescribing physi- should be notified and hydroxychloro- cian should refer the patient to an quine discontinued unless it is medi- Pediatrics: Surgical treatment ophthalmologist. During the initial cally critical and the patient has been for children with uveitis. examination, it is recommended that informed of the visual risk. Before dis- the patient receive: continuation, inform the patient that 1) a thorough ocular examination doc- the drug clears slowly from the body Destination umenting any preexisting conditions, and therefore visual function may con- Orlando 2) a Humphrey visual field central 10-2 tinue to slowly deteriorate. Preview some highlights of white-on-white pattern, and Subspecialty Day. 3) at least one of the following objec- Conclusion tive tests, if available: Patients and their physicians prescrib- • fundus autofluorescence (FAF) ing hydroxychloroquine need to be Blink • multifocal electroretinogram keenly aware of retinal toxicity risks Take a guess at the next (mfERG) or and the importance of regular screen- issue’s mystery image. • spectral domain OCT (SD-OCT). ing, and ophthalmologists who see In fact, mfERG—a test that is these patients should keep retinal typically available in large clinical toxicity in the front of their minds. Products & Services Check out EyeNet ’s centers—objectively evaluates func- Adhering to the Academy’s guidelines tion and can be used in place of visual will help achieve the goal of identify- marketplace. fields. It’s also worth considering the ing abnormalities with screenings and use of color fundus photographs to examination prior to the patient’s vi- assist in documenting changes over sual complaints. For Your Convenience time, especially if there is preexisting These stories also will be retinal pathology. However, the dilated 1 Marmor, M. F. et al. Ophthalmology 2011; available online at fundus exam should not be considered 118:415–422. www.eyenetmagazine.org. a screening tool, as it only picks up 2 Mieler, W. F. New Monitoring Guidelines relatively late toxic changes. for Hydroxychloroquine. Presented at Retina Ongoing monitoring. Encourage Subspecialty Day, Oct. 16, 2010, Chicago. FOR ADVERTISING INFORMATION the patient to obtain an annual oph- Mark Mrvica or Kelly Miller thalmic examination as part of the Dr. Hansen is a first-year ophthalmology resi- M. J. Mrvica Associates Inc. screening process. Since toxicity is rare dent, and Dr. Schuman is assistant professor 856-768-9360 within the first five years of treatment, of ophthalmology. Both are at Duke University [email protected] ancillary testing is not necessary unless Eye Center in Durham, N.C.

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