The Fluoroquinolone Toxicity Research Foundation

 
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Authored by Manolette Rangel Roque, MD, Chief of Service, Immunology and Uveitis Service, Consulting Staff, Cornea and Refractive Surgery Service, Q.C. Eye Center, Cavite Eye and ENT Center, Makati Eye Laser Center
Coauthored by C Stephen Foster, MD, FACS, Director of Immunology and Uveitis Service, Professor, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School


Manolette Rangel Roque, MD, is a member of the following medical societies: American Society of Cataract and Refractive Surgery, Association for Research in Vision and Ophthalmology, and International Society of Refractive Surgery
Edited by Kilbourn Gordon III, MD, Scientific Director, Foresight Ventures; Donald S Fong, MD, MPH, Assistant Clinical Professor of Ophthalmology, UCLA School of Medicine; Consulting Physician, Department of Ophthalmology, Southern California Permamente Medical Group; J James Rowsey, MD, Consulting Staff, Department of Corneal and Refractive Surgery, St Luke's Hospital; Lance L Brown, OD, MD, Staff Physician, Department of Ophthalmology, University of Kansas Medical Center; and Hampton Roy, Sr, MD, Clinical Associate Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences


eMedicine Journal, May 25 2001, Volume 2, Number 5

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.
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:
 In the US: 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.
 Internationally: 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.
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:
 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 a 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 Picture 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 Picture 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: Risk factors include the following:
 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
ARMD, Exudative
ARMD, Nonexudative
Best Disease
Chorioretinopathy, Central Serous

Other Problems to be Considered:
Stargardt disease
Dominant cone dystrophy
Fabry disease
Amiodarone therapy
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.
Other Tests:
 Amsler grid
 Sensitive method of detecting paracentral scotomas within 10° of fixation.
 Excellent screening for early antimalarial retinopathy.
 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 more commonly are 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.
 Poor correlation with appearance of the macula and visual field testing results.
 Mottling or stippling of the RPE is similar in appearance to early age-related macular degeneration.
 Late fundus finding of "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
 May be helpful in patients with unreliable visual field result.
 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.
 Macular dazzle test
 Electrophysiologic studies
 Electroretinogram (full field and foveal cone) - Recently, 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. Color vision testing and funduscopic examination were normal. A full field electroretinogram (ERG) was normal, but foveal cone ERGs were reduced bilaterally. These findings prompted the question of possible early hydroxychloroquine retinopathy (see Picture 4, Picture 5).
 Electro-oculogram
 Dark adaptation - Dilated, dark-adapted for 30 minutes
 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 (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.

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.

Further Outpatient Care:
 Annual evaluation should be performed.
 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
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.
 See ETools@NCEMI for the calculator for body mass index.
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.

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 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.
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