OPTICAL COHERENCE TOMOGRAPHY FINDINGS IN HYDROXYCHLOROQUINE AND CHLOROQUINE–ASSOCIATED MACULOPATHY Anne E. Fung, MD,* Chander N. Samy, MD, FACS,† Philip J. Rosenfeld, MD, PHD*
Background: Vision loss and maculopathy associated with hydroxychloroquine and chloroquine use are infrequent but significant adverse effects. Bull’s eye maculopathy related to these drugs, including peripheral and macular pigment changes, has been described; however, to our knowledge, optical coherence tomography (OCT) findings of the associated retinal pigment epithelium (RPE) atrophy have not yet been reported. Methods: Single case report. Results: A 48-year-old woman was treated with hydroxychloroquine (7.8 mg/[kg 䡠 d]) for 8 years followed by chloroquine (3.9 mg/[kg 䡠 d]) for 5 months for systemic lupus erythematosus. Fundus examinations for toxicity were conducted every 6 months. These medications were discontinued when the patient developed photopsias. Nine years after discontinuation, the patient further developed new scotomas and a bull’s eye pattern RPE atrophy. The photographic and OCT findings of hydroxychloroquine- and chloroquineassociated maculopathy are presented along with guidelines on dosing and screening. Conclusion: The ophthalmologist’s awareness of dosing guidelines and communication with prescribing physicians are important in preventing ocular toxicities associated with hydroxychloroquine and chloroquine. Current guidelines suggest the following maximal dosages: hydroxychloroquine, 6.5 mg/(kg 䡠 d); and chloroquine, 3 mg/(kg 䡠 d). A patient weighing ⬍135 lb should not receive ⬎400 mg of hydroxychloroquine daily. RETINAL CASES & BRIEF REPORTS 1:128 –130, 2007
From *Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, Florida; and †Ocala Eye, Ocala, Florida.
Our patient was treated with both drugs at levels above the currently accepted range of safety. We present the optical coherence tomography (OCT) findings of hydroxychloroquine and chloroquine–associated maculopathy.
V
ision loss and maculopathy associated with hydroxychloroquine and chloroquine use are infrequent but significant adverse effects.1 These drugs have been used to treat malaria and rheumatologic diseases since the 1940s. In 1959, Hobbs et al2 first described chloroquine-associated maculopathy, including peripheral and macular pigment changes, macular edema, and narrowing of the retinal vessels associated with scotomas and visual field changes.
Case Report A 48-year-old 112-lb woman with systemic lupus erythematosus was treated with hydroxychloroquine (400 mg daily for 8 years [7.8 mg/kg/d]) followed by chloroquine (200 mg daily for 5 months [3.9 mg/kg/d]). Fundus examinations for toxicity were performed every 6 months. Chloroquine administration was discontinued in 1995 when the patient noted shimmering halos around lights. Macular examination showed mild bull’s eye maculopathy. After discontinuation of treatment, her visual symptoms stabilized. In 2004, 9 years after chloroquine administration was discontinued, the patient had new scotomas and difficulty reading. Fundus examination revealed progression of the bull’s eye maculopathy
The authors have no competing interests in this report. Reprint requests: Philip J. Rosenfeld, MD, PhD, Bascom Palmer Eye Institute, 900 NW 17th Street, Miami, FL 33136; e-mail: [email protected]
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Fig. 1. Right eye of a patient with hydroxychloroquine and chloroquine–associated maculopathy. A, Color photograph showing bull’s eye maculopathy. B, Yellow arrow indicates horizontal direction of optical coherence tomographic cross section revealing thinned retinal layers. Increased choroidal reflectivity (blue arrows) likely corresponds to the area of retinal pigment epithelium and choriocapillaris atrophy that results in the bull’s eye appearance. A decreased foveal thickness of 117 m, most likely due to diffuse photoreceptor loss, is demonstrated on the macular thickness map (above left) as well as topographically (above right).
Fig. 2. Left eye of a patient with hydroxychloroquine and chloroquine–associated maculopathy. A, Color photograph showing bull’s eye maculopathy. B, Optical coherence tomographic cross section showing decreased retinal thickness (foveal thickness, 124 m) and increased choroidal reflectivity likely corresponding to the areas of retinal pigment epithelium and choriocapillaris atrophy that constitute the bull’s eye maculopathy (blue arrows).
bilaterally. Vision was 20/30 in the right eye and 20/20 in the left eye. In 2004, OCT (Stratus OCT III, Software version 4.02; Carl Zeiss, Dublin, CA) revealed bilateral diffuse atrophy of the neurosensory retina with central retinal thicknesses of 117 m and 124 m (Figs. 1 and 2). The foveal contours were mildly blunted, and perifoveal patterns of increased choroidal reflectivity were present symmetrically. This pattern of increased reflectivity appeared to correspond to the area of retinal pigment epithelium atrophy responsible for the bull’s eye appearance.
Discussion Pigmentary maculopathy and vision loss are rare but serious drug-related adverse events from hydroxychloroquine or chloroquine use.1 OCT for our patient clearly and reproducibly demonstrated the diffuse retinal atrophy and increased choroidal reflectivity that results from the drug-induced loss of the retinal pigment epithelium and choriocapillaris, which causes the bull’s eye appearance in the macula. Unfortunately, the mechanisms whereby the drugs cause damage to the retina, retinal pigment epithelium, and choriocapillaris are still inconclusive. Several theories exist including lysosomal dysfunction causing phos-
pholipid accumulation, reduction of glutathione levels causing increased susceptibility to oxidative stress, and toxic accumulations in the retinal pigment epithelium due to melanin binding.1,3,4 Manifestations of toxicity may include a paracentral scotoma, impaired peripheral and night vision, bull’s eye maculopathy, and, in the late stages, diffuse retinal pigment epithelium atrophy with loss of central acuity. As seen in this case, cessation of the drug does not usually reverse these findings, prevent progression of disease, or prevent the onset of the maculopathy. The continued progression of disease is thought to be caused by either the accumulation of drug in adipose tissue or the continued decline of already injured cells.5 The ophthalmologist’s awareness of dosing guidelines and communication with prescribing physicians are important in preventing ocular toxicities associated with hydroxychloroquine and chloroquine. Current guidelines suggest maximal dosages of hydroxychloroquine and chloroquine of 6.5 mg/kg/d and 3 mg/kg/d, respectively. A hydroxychloroquine daily
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dose of 400 mg should not be given to patients weighing ⬍135 lb, and a chloroquine daily dose of 250 mg should not be given to those weighing ⬍183 lb. Our 112-lb patient was taking the drugs at doses exceeding the current guidelines. Current AAO recommendations suggest a baseline screening evaluation within the first year of initiating therapy, which includes dilated biomicroscopic fundus examination and Amsler grid or Humphrey 10-2 visual field testing. Most importantly, patients should be encouraged to monitor themselves at home with an Amsler grid to recognize visual changes even before a visible maculopathy develops.1 Should a patient present with new visual changes associated with these high-risk drugs, OCT may be a useful, noninvasive addition to the clinical evaluation. The discovery of diffuse retinal atrophy or increased reflectance in a perifoveal pattern by OCT could sup-
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2007
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VOLUME 1
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NUMBER 3
port a suspected diagnosis of hydroxychloroquine- or chloroquine-associated retinal toxicity. Key words: hydroxychloroquine and chloroquine– associated maculopathy, optical coherence tomography. References 1.
2. 3.
4.
5.
Marmor MF, Carr RE, Easterbrook M, et al. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy. Ophthalmology 2002;109:1377–1382. Hobbs HE, Sorsby A, Freedman A. Retinopathy following chloroquine therapy. Lancet 1959;2:478–480. Mahon GJ, Anderson HR, Gardiner TA, et al. Chloroquine causes lysosomal dysfunction in neural retina and RPE: implications for retinopathy. Curr Eye Res 2004;28:277–284. Toler SM. Oxidative stress plays an important role in the pathogenesis of drug-induced retinopathy. Exp Biol Med 2004;229:607–615. Ehrenfeld M, Nesher R, Merin S. Delayed-onset chloroquine retinopathy. Br J Ophthalmol 1986;70:280–283.
Background: Vision loss and maculopathy associated with hydroxychloroquine and chloroquine use are infrequent but significant adverse effects. Bull’s eye maculopathy related to these drugs, including peripheral and macular pigment changes, has been described; however, to our knowledge, optical coherence tomography (OCT) findings of the associated retinal pigment epithelium (RPE) atrophy have not yet been reported. Methods: Single case report. Results: A 48-year-old woman was treated with hydroxychloroquine (7.8 mg/[kg 䡠 d]) for 8 years followed by chloroquine (3.9 mg/[kg 䡠 d]) for 5 months for systemic lupus erythematosus. Fundus examinations for toxicity were conducted every 6 months. These medications were discontinued when the patient developed photopsias. Nine years after discontinuation, the patient further developed new scotomas and a bull’s eye pattern RPE atrophy. The photographic and OCT findings of hydroxychloroquine- and chloroquineassociated maculopathy are presented along with guidelines on dosing and screening. Conclusion: The ophthalmologist’s awareness of dosing guidelines and communication with prescribing physicians are important in preventing ocular toxicities associated with hydroxychloroquine and chloroquine. Current guidelines suggest the following maximal dosages: hydroxychloroquine, 6.5 mg/(kg 䡠 d); and chloroquine, 3 mg/(kg 䡠 d). A patient weighing ⬍135 lb should not receive ⬎400 mg of hydroxychloroquine daily. RETINAL CASES & BRIEF REPORTS 1:128 –130, 2007
From *Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, Florida; and †Ocala Eye, Ocala, Florida.
Our patient was treated with both drugs at levels above the currently accepted range of safety. We present the optical coherence tomography (OCT) findings of hydroxychloroquine and chloroquine–associated maculopathy.
V
ision loss and maculopathy associated with hydroxychloroquine and chloroquine use are infrequent but significant adverse effects.1 These drugs have been used to treat malaria and rheumatologic diseases since the 1940s. In 1959, Hobbs et al2 first described chloroquine-associated maculopathy, including peripheral and macular pigment changes, macular edema, and narrowing of the retinal vessels associated with scotomas and visual field changes.
Case Report A 48-year-old 112-lb woman with systemic lupus erythematosus was treated with hydroxychloroquine (400 mg daily for 8 years [7.8 mg/kg/d]) followed by chloroquine (200 mg daily for 5 months [3.9 mg/kg/d]). Fundus examinations for toxicity were performed every 6 months. Chloroquine administration was discontinued in 1995 when the patient noted shimmering halos around lights. Macular examination showed mild bull’s eye maculopathy. After discontinuation of treatment, her visual symptoms stabilized. In 2004, 9 years after chloroquine administration was discontinued, the patient had new scotomas and difficulty reading. Fundus examination revealed progression of the bull’s eye maculopathy
The authors have no competing interests in this report. Reprint requests: Philip J. Rosenfeld, MD, PhD, Bascom Palmer Eye Institute, 900 NW 17th Street, Miami, FL 33136; e-mail: [email protected]
128
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Fig. 1. Right eye of a patient with hydroxychloroquine and chloroquine–associated maculopathy. A, Color photograph showing bull’s eye maculopathy. B, Yellow arrow indicates horizontal direction of optical coherence tomographic cross section revealing thinned retinal layers. Increased choroidal reflectivity (blue arrows) likely corresponds to the area of retinal pigment epithelium and choriocapillaris atrophy that results in the bull’s eye appearance. A decreased foveal thickness of 117 m, most likely due to diffuse photoreceptor loss, is demonstrated on the macular thickness map (above left) as well as topographically (above right).
Fig. 2. Left eye of a patient with hydroxychloroquine and chloroquine–associated maculopathy. A, Color photograph showing bull’s eye maculopathy. B, Optical coherence tomographic cross section showing decreased retinal thickness (foveal thickness, 124 m) and increased choroidal reflectivity likely corresponding to the areas of retinal pigment epithelium and choriocapillaris atrophy that constitute the bull’s eye maculopathy (blue arrows).
bilaterally. Vision was 20/30 in the right eye and 20/20 in the left eye. In 2004, OCT (Stratus OCT III, Software version 4.02; Carl Zeiss, Dublin, CA) revealed bilateral diffuse atrophy of the neurosensory retina with central retinal thicknesses of 117 m and 124 m (Figs. 1 and 2). The foveal contours were mildly blunted, and perifoveal patterns of increased choroidal reflectivity were present symmetrically. This pattern of increased reflectivity appeared to correspond to the area of retinal pigment epithelium atrophy responsible for the bull’s eye appearance.
Discussion Pigmentary maculopathy and vision loss are rare but serious drug-related adverse events from hydroxychloroquine or chloroquine use.1 OCT for our patient clearly and reproducibly demonstrated the diffuse retinal atrophy and increased choroidal reflectivity that results from the drug-induced loss of the retinal pigment epithelium and choriocapillaris, which causes the bull’s eye appearance in the macula. Unfortunately, the mechanisms whereby the drugs cause damage to the retina, retinal pigment epithelium, and choriocapillaris are still inconclusive. Several theories exist including lysosomal dysfunction causing phos-
pholipid accumulation, reduction of glutathione levels causing increased susceptibility to oxidative stress, and toxic accumulations in the retinal pigment epithelium due to melanin binding.1,3,4 Manifestations of toxicity may include a paracentral scotoma, impaired peripheral and night vision, bull’s eye maculopathy, and, in the late stages, diffuse retinal pigment epithelium atrophy with loss of central acuity. As seen in this case, cessation of the drug does not usually reverse these findings, prevent progression of disease, or prevent the onset of the maculopathy. The continued progression of disease is thought to be caused by either the accumulation of drug in adipose tissue or the continued decline of already injured cells.5 The ophthalmologist’s awareness of dosing guidelines and communication with prescribing physicians are important in preventing ocular toxicities associated with hydroxychloroquine and chloroquine. Current guidelines suggest maximal dosages of hydroxychloroquine and chloroquine of 6.5 mg/kg/d and 3 mg/kg/d, respectively. A hydroxychloroquine daily
130
RETINAL CASES & BRIEF REPORTSℜ
dose of 400 mg should not be given to patients weighing ⬍135 lb, and a chloroquine daily dose of 250 mg should not be given to those weighing ⬍183 lb. Our 112-lb patient was taking the drugs at doses exceeding the current guidelines. Current AAO recommendations suggest a baseline screening evaluation within the first year of initiating therapy, which includes dilated biomicroscopic fundus examination and Amsler grid or Humphrey 10-2 visual field testing. Most importantly, patients should be encouraged to monitor themselves at home with an Amsler grid to recognize visual changes even before a visible maculopathy develops.1 Should a patient present with new visual changes associated with these high-risk drugs, OCT may be a useful, noninvasive addition to the clinical evaluation. The discovery of diffuse retinal atrophy or increased reflectance in a perifoveal pattern by OCT could sup-
●
2007
●
VOLUME 1
●
NUMBER 3
port a suspected diagnosis of hydroxychloroquine- or chloroquine-associated retinal toxicity. Key words: hydroxychloroquine and chloroquine– associated maculopathy, optical coherence tomography. References 1.
2. 3.
4.
5.
Marmor MF, Carr RE, Easterbrook M, et al. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy. Ophthalmology 2002;109:1377–1382. Hobbs HE, Sorsby A, Freedman A. Retinopathy following chloroquine therapy. Lancet 1959;2:478–480. Mahon GJ, Anderson HR, Gardiner TA, et al. Chloroquine causes lysosomal dysfunction in neural retina and RPE: implications for retinopathy. Curr Eye Res 2004;28:277–284. Toler SM. Oxidative stress plays an important role in the pathogenesis of drug-induced retinopathy. Exp Biol Med 2004;229:607–615. Ehrenfeld M, Nesher R, Merin S. Delayed-onset chloroquine retinopathy. Br J Ophthalmol 1986;70:280–283.
