AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

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• Follow-up
• Miscellaneous
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INTRODUCTION

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Background

Chloroquine and hydroxychloroquine belong to the quinolone family. They are related drugs with different therapeutic and toxic doses with similar clinical indications for use and manifestations of retinal toxicity.

Initially, chloroquine was given for malaria prophylaxis and treatment, and, later, it was used by rheumatologists for treating rheumatoid arthritis, systemic/discoid lupus erythematosus, and other connective tissue disorders. Dermatologists use these drugs for cutaneous lupus. Since it is far less toxic to the retina, hydroxychloroquine has replaced chloroquine, except for individuals who travel in areas endemic with malaria.

Expanded use of these drugs for nonmalarial disease entities has resulted in prolonged duration of therapy and higher daily dosages leading to cumulative doses greater than those used in antimalarial therapy. The first reports of retinal toxicity attributed to chloroquine appeared during the late 1950s. In 1958, Cambiaggi first described the classic retinal pigment changes in a patient receiving chloroquine for systemic lupus erythematous (SLE) treatment. In 1959, Hobbs established a definite link between long-term use of chloroquine and subsequent development of retinal pathology. In 1962, J Lawton Smith coined the term bull's eye maculopathy, regarded as the classic finding of macular toxicity. Many reports on chloroquine retinopathy exist. In contrast, only a few cases of hydroxychloroquine toxicity have been reported.

Internists, rheumatologists, or dermatologists who usually give chloroquine and hydroxychloroquine may not be fully aware of the potential ophthalmic implications. Patients and primary care physicians should understand that screening helps to identify toxicity early, prior to severe damage, but cannot prevent toxicity or guarantee that no visual loss will occur.

Pathophysiology

Chloroquine has an affinity for pigmented (melanin-containing) structures, which may explain its toxic properties in the eye. Melanin serves as a free-radical stabilizer and as an agent that can bind toxins. Although it binds potentially retinotoxic drugs, it is unclear whether the effect is beneficial or harmful. Chloroquine and its principal metabolite have been found in the pigmented ocular structures at concentrations much greater than in any other tissue in the body. With more prolonged exposure, the drug accumulates in the retina. The drug is retained in the pigmented structures long after its use is stopped. The kinetics of chloroquine metabolism are complicated, with the half-life increasing as the dosage is increased. In patients with retinopathy, 5 years or more after discontinuation, traces of chloroquine have been found in plasma, erythrocytes, and urine.

Frequency

United States

Two trends are consistent in literature, despite the variability of the statistics; the incidence of retinopathy increased with both the dose and the duration of treatment.

Bernstein estimated an incidence of 10% in unmonitored patients taking 250 mg/d of chloroquine and 3-4% in unmonitored patients taking 400 mg/d of hydroxychloroquine.¹

International

Incidence from 1-28% has been reported.

Mortality/Morbidity

See Clinical for detailed information.

Race

No known racial predilection exists.

Sex

No known sexual predilection exists.

Age

No known age predisposition exists, although older patients are believed to be at a higher risk because of the potential for diseased retinas.

CLINICAL

Section 3 of 11  

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History

• Some patients with retinopathy may be asymptomatic. When they are symptomatic, visual acuity initially remains excellent despite complaints of parafoveal metamorphopsia and difficulty in reading or performing fine visual tasks (due to central or paracentral scotomas).
• Other reported visual symptoms include the following:
• • Dimness
  • Flickering or flashing lights of yellow
  • Green or red haloes
  • Cycloplegia
  • Amblyopia
  • Diplopia
  • Blindness
  • Photophobia
  • Oculogyric crisis
• Systemic complaints include the following:
  
  
  • Nausea, abdominal pain, and vomiting
  • Occasionally, skin conditions, such as rashes, pruritus, and sensitivity to ultraviolet light, may be present.
  • Rarely, neurologic symptoms, such as vertigo, tinnitus, irritability, cranial nerve palsies, and myasthenialike muscle weakness, may manifest.

Physical

All patients undergoing chloroquine and/or hydroxychloroquine therapy should have a baseline ophthalmologic examination within the first year to document any complicating ocular conditions and to establish a record of the fundus appearance and the visual field.

• Complete ophthalmologic examination
• • History (including refraction)
  • Visual acuity (uncorrected visual acuity [UCVA] and best spectacle corrected visual acuity [BSCVA])
  • Slit lamp biomicroscopy
  • Direct and indirect ophthalmoscopy
  • Dilated cornea and retina examination
• Baseline ancillary tests (see Imaging Studies and Other Tests)  
• • Amsler grid and perimetry (Humphrey 10-2)
  • Optional color testing
  • Optional fundus photography
  • Optional specialized tests, such as fluorescein angiography or multifocal electroretinogram (ERG)
• Corneal
• • Corneal deposits, limited to the basal epithelium, are described as tiny white dots that become yellow and then golden brown with continued use of the medication. The deposition pattern ranges from a fine diffuse punctate appearance, to radial or whorl-like lines converging just inferior to the central cornea, to coalesced and darkened lines.
  • Manifestation of these corneal deposits apparently is not related to duration or dose, and it is completely reversible once the medication is discontinued. Chloroquine has been associated with more keratopathy than has hydroxychloroquine.
  • A decrease in corneal sensation has been reported in approximately 50% of patients taking chloroquine.
• Lenticular: Chloroquine, but not hydroxychloroquine, may cause white, flakelike posterior subcapsular lens opacity.
• Uveal (ciliary body): Chloroquine, but not hydroxychloroquine, may decrease accommodation.
• Retinal
  
  
  • The fundus appearance may remain entirely normal, even after scotomas have developed (see Media file 4).
• • Early changes include irregularity (mild stippling or mottling) in the macular pigmentation and blunting (reversible) of the foveal reflex. Examination with a red-free filter may enhance detection of these changes.
  • Later, the central irregular pigmentation may become surrounded by a concentric zone of hypopigmentation, usually oval and more prominent inferiorly to the fovea (see Media file 1). This condition often is bilateral, although asymmetry is not uncommon.
  • If the treatment is not halted and the toxicity progresses, the classic bull's eye maculopathy appears.
• • Further prolonged exposure to the quinolones may lead to more generalized pigmentary changes.
  • End-stage retinopathy presents with peripheral pigment irregularity and bone spicule formation, vascular attenuation, and optic disc pallor. It sometimes is mistaken for retinitis pigmentosa.
• Systemic: The systemic complaints may be observed at consult. Poliosis has been reported.

Causes

• Chloroquine
• • Maintenance dose greater than 3.5 mg/kg/d
  • Duration of treatment greater than 10 years
  • Evidence of renal insufficiency
• Hydroxychloroquine
• • Maintenance dose greater than 6.5 mg/kg/d
  • Duration of treatment greater than 10 years
  • Evidence of renal insufficiency
• In addition to the previous use of chloroquine and/or hydroxychloroquine, risk factors include the following:
• • Obesity
  • Presence of macular degeneration or retinal dystrophy
  • Advanced age
  • Hepatic and/or renal failure

DIFFERENTIALS

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Other Problems to be Considered

Stargardt disease
Dominant cone dystrophy
Fabry disease
Amiodarone therapy

WORKUP

Section 5 of 11  

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Imaging Studies

• Fluorescein angiography  
• • Macular pigmentary changes seen in well-established quinolone maculopathy are highlighted with angiography, but its use as an early method of detection is doubtful.
  • No reported cases of retinopathy detected by fluorescein angiography prior to development of scotomas, macular pigment changes, or loss of acuity.
  • Most patients with relative scotomas had negative angiograms.
  • All patients with absolute scotomas had positive angiograms. Positive angiograms show early hyperfluorescence in the macular area that corresponds to areas of attenuation of the retinal pigment epithelium (RPE) and accentuation of the underlying choroidal fluorescence.
• Angiography should be performed in patients with preexisting macular disease.
• See Retinal examination/photography in Other Tests.

Other Tests

• Amsler grid  
• • An Amsler grid is a sensitive method of detecting paracentral scotomas within 10° of fixation.
  • This is an excellent screening method for early antimalarial retinopathy.
  • This may pick up small defects before they are seen by kinetic and static visual fields.
  • Relative scotomas may be revealed with the red Amsler grid.
  • Dispensing an Amsler grid to the patient for weekly self-monitoring is suggested.
• Perimetry  
• • Baseline central visual field examination may be useful because the earliest macular changes are nonspecific and may be indistinguishable from age-related changes.
  • Humphrey 10-2 program (white target) is recommended for confirming defects found by the Amsler grid.
  • The early scotomas associated with retinal toxicity are subtle and usually within 10° of fixation. They are more commonly manifested superiorly than inferiorly to fixation.
  • The later scotomas attributed to retinotoxicity are enlarged and may involve fixation, which reduces visual acuity.
• Retinal examination/photography 
• • Early fundus changes include the loss of foveal reflex, macular edema, and pigment mottling that is enhanced with the red-free filter.
  • There is poor correlation of the appearance of the macula with visual field testing results.
  • Mottling or stippling of the RPE is similar in appearance to early age-related macular degeneration.
  • A late fundus finding is a bull's eye pattern of maculopathy.
  • Baseline photographs are suggested because the earliest macular changes are nonspecific and may be indistinguishable from age-related changes.
  • Repeat dilated examinations and photography of the perimacular pigmented epithelium are recommended every 6-12 months.
• Color vision  
• • Color vision testing may be helpful in patients with unreliable visual field results.
  • Color vision testing has not been shown to be sensitive for the detection of antimalarial retinopathy.
  • Most patients with color vision defects also have absolute scotomas.
  • Both the Ishihara plates and the Farnsworth D-15 test have been shown to be normal in the presence of early retinopathy. Acquired maculopathies are in general more likely to affect the blue-yellow or tritan axis of confusion than the red-green.
  • Male patients should have a baseline test prior to the use of chloroquine and/or hydroxychloroquine to identify any underlying congenital color deficiency that might be confused later with toxicity.
• Macular dazzle test (photostress test) 
• • One of the methods of subjective evaluation of the macula is to “dazzle” the macula with a light source of an ophthalmoscope or a pen torch and then to measure the length of time that the subject takes to regain the previous level of visual acuity. 
  • A conventional electronic flash from a camera can also be used as a light source.
• Electrophysiologic studies  
• • Electroretinogram (full field, focal, and multifocal): Focal ERG techniques can record an ERG response from the foveal and parafoveal regions. The multifocal ERG seems more appropriate for the evaluation of chloroquine and/or hydroxychloroquine toxicity because it generates local ERG responses topographically across the posterior pole and because it can document a bull's eye distribution of ERG depression. According to a case report, a 53-year-old woman presented with a complaint of something "funny" with her vision. The possibility of hydroxychloroquine toxicity was entertained, although clinical evidence was not found. Findings from color vision testing and a funduscopic examination were normal. The findings from a full-field ERG were normal, but foveal cone ERGs were reduced bilaterally. These findings prompted the question of possible early hydroxychloroquine retinopathy (see Media files 4-5). 
  • Electro-oculogram (EOG): EOG as an objective test of global retinal function ("mass response") shows abnormalities in late chloroquine or hydroxychloroquine toxicity but is not sensitive to early functional changes that are predominant in the macula. This test has little role in the screening of patients for early hydroxychloroquine toxicity, but it remains useful in the evaluation of any patient with manifest toxicity to determine how severe and widespread the damage. 
  • Dark adaptometry: Pupils are dilated, and the retina is dark adapted for 30 minutes. Dark adaptation can be affected in late toxicity but may have no role in screening.
  • Computerized acuity mapping of the macula: The patient fixates on a central cross and is presented with 101 letters flashed in succession to different locations within each macula. Letters not seen or incorrectly named are considered errors, and their locations with respect to fixation are designated with black dots. Patients with vision better than 20/80 are candidates for this test. The patient described above in the case report, with foveal cone ERG reduction, had abnormal computerized acuity mapping of the macula results.

Histologic Findings

Animal studies: First morphologic changes involve ganglion cells manifesting membranous cytoplasmic bodies within 1 week of onset of chloroquine treatment. Other neural cells of the retina later show these changes. Reversible changes are present for up to 5 months of therapy. Prolonged therapy resulted in progressive degeneration of the ganglion cells and photoreceptor cell bodies and nuclei with outer segment involvement. The most severe changes tended to be perifoveal, with relative foveal sparing. Abnormalities of the pigment epithelium and choroid were seen only after degeneration of the ganglion cells and photoreceptors was established. All of the observations described were made before any detectable abnormalities in the fundus or on ERG.

Human studies: Pathologic studies of patients with chloroquine retinopathy are few and are limited to cases with advanced retinopathy. Consistent findings include degeneration of the outer retina, particularly the photoreceptors and the outer nuclear layer, with relative sparing of the photoreceptors in the fovea. Pigment migration into the retina is seen. Pathologic changes in the ganglion cells have been a consistent finding. Sclerosis of the retinal arterioles is variable.

TREATMENT

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Medical Care

• Withdrawal of the medication and shifting to another form of treatment is the standard of care.
• If serious toxic symptoms occur from overdosage or sensitivity, it has been suggested that ammonium chloride (8 g qd in divided doses for adults) be administered orally 3-4 times/wk for several months after therapy has been stopped.
• • Acidification of the urine increases renal excretion of the 4-aminoquinoline compounds by 20-90%.
  • In patients with impaired renal function and/or metabolic acidosis, caution must be taken.

Consultations

Coordination with the rheumatologist or the dermatologist is warranted for comprehensive care of the patient.

MEDICATION

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Withdrawal of the agent is the standard of care for patients who develop toxicity.

Drug Category: Diuretic, Miscellaneous

Acidification of urine increases renal excretion of 4-aminoquinoline compounds by 20-90%.

FOLLOW-UP

Section 8 of 11  

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Further Outpatient Care

• Once retinal toxicity is identified, the drug is discontinued; the patient is administered other immunosuppressive agents. Chloroquine and/or hydroxychloroquine clear very slowly from the body, so the full effects may not manifest for 3–6 months. Slow, continued deterioration of visual function may occur even after the drug is discontinued. The authors recommend that patients be reevaluated 3 months after a diagnosis of toxicity is made, even after discontinuation of drug use. Annual examinations are recommended until the findings are clearly stable.
• • Distance and near acuity
  • Color vision
  • Visual field examination (red pin and red Amsler grid)
  • Slit lamp biomicroscopic examination of the cornea
  • Dilated examination of the retina
  • Electroretinogram (full field and multifocal)
  • Perimetry (Humphrey 10-2)
  • Fundus photography
  • Fluorescein angiography

In/Out Patient Meds

• Discontinue use of quinolones.

Deterrence/Prevention

• The recommended safe threshold dose has been reported as 3.5 mg/kg/d for chloroquine and 6.5 mg/kg/d for hydroxychloroquine.
• • These dosages are based on lean body weight.
  • A body mass index calculator used by endocrinologists is helpful in calculating the recommended dose.

Complications

• See Physical.

Prognosis

• If the maximum daily dosage recommendations are followed, then the likelihood of toxicity is small.
• If diagnosed early, toxicity (eg, corneal epithelial changes, loss of normal foveal reflex) is reversible.
• Once the appearance of a bull's eye maculopathy is noted, disturbances associated with this condition are irreversible.

Patient Education

• Monitor patients on an annual basis. Record visual symptomatology, visual acuity, and Amsler grid testing.
• Advise patients to discontinue treatment and to seek consultation with an ophthalmologist if changes in visual acuity or blurred vision occur while on treatment.
• See Deterrence/Prevention.

MISCELLANEOUS

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Medical/Legal Pitfalls

• The most important factor in avoiding toxicity with long-term therapy appears to be the daily dose. If the daily dose is below the stated threshold levels, then the chance of encountering any retinopathy is small. However, it is essential that the early symptoms of toxicity are discussed with the patient. A high index of suspicion of toxicity would justify the performance of expensive ancillary procedures to detect possible retinopathy.
• In addition to following the guidelines for the safe administration of chloroquine/hydroxychloroquine therapy, dose adjustments should be made in consideration of lean body weight and renal and hepatic insufficiency.

Special Concerns

• Pediatric: Use of quinolones in children should be monitored closely.
• Geriatric: Elderly patients should be considered part of a high-risk group; therefore, they should be monitored closely.
• Renal insufficiency: Dose adjustments should be made in patients with renal impairment.
• Hepatic insufficiency: Dose adjustments should be made in patients with hepatic impairment.

MULTIMEDIA

Section 10 of 11  

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Media file 1:  Fluorescein angiogram of left macula in patient with hydroxychloroquine retinopathy. Reprinted from American Journal of Ophthalmology, Vol 104, Johnson and Vine, Hydroxychloroquine therapy in massive total doses without retinal toxicity, pages 139-144, Copyright 1987, with permission from Elsevier Science.
	View Full Size Image
Media type:  Photo

Media file 2:  Membranous cytoplasmic bodies in ganglion cell of retina. (N=nucleus) (X12,500.) Reprinted from American Journal of Ophthalmology, Vol 67, Gleiser CA, Dukes TW, Lawwill T, Read WK, Bay WW, Brown RS. Ocular changes in swine associated with chloroquine toxicity, pages 399-405, Copyright 1969, with permission from Elsevier Science.
	View Full Size Image
Media type:  Photo

Media file 3:  Swollen ganglion cells with foamy cytoplasm (Hematoxylin-eosin, X500). Reprinted from American Journal of Ophthalmology, Vol 67, Gleiser CA, Dukes TW, Lawwill T, Read WK, Bay WW, Brown RS. Ocular changes in swine associated with chloroquine toxicity, pages 399-405, Copyright 1969, with permission from Elsevier Science.
	View Full Size Image
Media type:  Photo

Media file 4:  A 53-year-old female with a complaint of something "funny" with her vision. The possibility of hydroxychloroquine toxicity was entertained, although clinical evidence was not found. Color vision testing and funduscopic examination were normal. A full field electroretinogram was normal, but foveal cone electroretinograms were reduced bilaterally. These findings prompted the question of possible early hydroxychloroquine retinopathy.
	View Full Size Image
Media type:  Photo

Media file 5:  The same patient as described in Media file 4 (other eye, left eye). The patient (with foveal cone electroretinogram reduction) had abnormal computerized acuity mapping of the macula results.
	View Full Size Image
Media type:  Photo

Media file 6:  An Amsler grid is used to assess the central portion of the macula. This simple test is helpful for patients to monitor their vision at home.
	View Full Size Image
Media type:  Illustration

REFERENCES

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Article Last Updated: Apr 1, 2008