eMedicine Specialties > Ophthalmology > Unclassified Disorders

Chloroquine/Hydroxychloroquine Toxicity: Differential Diagnoses & Workup

Author: Manolette R Roque, MD, MBA, DPBO, FPAO, President and CEO, Chief of Service, Ocular Immunology and Uveitis, Consulting Staff, Cornea and Refractive Surgery, Eye Republic Ophthalmology Clinic; General Manager, Ophthalmic Consultants Philippines Co; Consulting Staff, CME Liaison, Section Chief of Ocular Immunology and Uveitis, Department of Ophthalmology, Asian Hospital and Medical Center
Coauthor(s): Barbara L Roque, MD, Full Partner, Ophthalmic Consultants Philippines Co, Chief of Service, Pediatric Ophthalmology and Strabismus, Consulting Staff, Orbit and Eye Plastics, EYE REPUBLIC Ophthalmology Clinic; C Stephen Foster, MD, FACS, FACR, FAAO, Clinical Professor of Ophthalmology, Harvard Medical School; Consulting Staff, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary; Founder and President, Ocular Immunology and Uveitis Foundation, Massachusetts Eye Research and Surgery Institution
Contributor Information and Disclosures

Updated: Apr 1, 2008

Differential Diagnoses

ARMD, Exudative
ARMD, Nonexudative
Best Disease
Chorioretinopathy, Central Serous

Other Problems to Be Considered

Stargardt disease
Dominant cone dystrophy
Fabry disease
Amiodarone therapy

Workup

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.

More on Chloroquine/Hydroxychloroquine Toxicity

Overview: Chloroquine/Hydroxychloroquine Toxicity
Differential Diagnoses & Workup: Chloroquine/Hydroxychloroquine Toxicity
Treatment & Medication: Chloroquine/Hydroxychloroquine Toxicity
Follow-up: Chloroquine/Hydroxychloroquine Toxicity
Multimedia: Chloroquine/Hydroxychloroquine Toxicity
References
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References

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Further Reading

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Keywords

chloroquine, hydroxychloroquine, Aralen, Plaquenil, bull's eye maculopathy, toxicity

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Contributor Information and Disclosures

Author

Manolette R Roque, MD, MBA, DPBO, FPAO, President and CEO, Chief of Service, Ocular Immunology and Uveitis, Consulting Staff, Cornea and Refractive Surgery, Eye Republic Ophthalmology Clinic; General Manager, Ophthalmic Consultants Philippines Co; Consulting Staff, CME Liaison, Section Chief of Ocular Immunology and Uveitis, Department of Ophthalmology, Asian Hospital and Medical Center
Manolette R Roque, MD, MBA, DPBO, FPAO is a member of the following medical societies: American Academy of Ophthalmic Executives, American Society of Cataract and Refractive Surgery, American Society of Ophthalmic Administrators, American Uveitis Society, International Ocular Inflammation Society, Philippine Medical Association, Philippine Ocular Inflammation Society, and Philippine Society of Cataract and Refractive Surgery
Disclosure: Nothing to disclose.

Coauthor(s)

Barbara L Roque, MD, Full Partner, Ophthalmic Consultants Philippines Co, Chief of Service, Pediatric Ophthalmology and Strabismus, Consulting Staff, Orbit and Eye Plastics, EYE REPUBLIC Ophthalmology Clinic
Disclosure: Nothing to disclose.

C Stephen Foster, MD, FACS, FACR, FAAO, Clinical Professor of Ophthalmology, Harvard Medical School; Consulting Staff, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary; Founder and President, Ocular Immunology and Uveitis Foundation, Massachusetts Eye Research and Surgery Institution
C Stephen Foster, MD, FACS, FACR, FAAO is a member of the following medical societies: Alpha Omega Alpha, American Academy of Ophthalmology, American Association of Immunologists, American College of Rheumatology, American College of Surgeons, American Federation for Clinical Research, American Medical Association, American Society for Microbiology, American Uveitis Society, Association for Research in Vision and Ophthalmology, Massachusetts Medical Society, Royal Society of Medicine, and Sigma Xi
Disclosure: Nothing to disclose.

Medical Editor

Kilbourn Gordon III, MD, FACEP, Urgent Care Physician, Primary Medical, Huntington Walk-In and Greenwich Convenient Medical Center
Kilbourn Gordon III, MD, FACEP is a member of the following medical societies: American Academy of Ophthalmology and Wilderness Medical Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

J James Rowsey, MD, Former Director of Corneal Services, St Luke's Cataract and Laser Institute, Florida
J James Rowsey, MD is a member of the following medical societies: American Academy of Ophthalmology, American Association for the Advancement of Science, American Medical Association, Association for Research in Vision and Ophthalmology, Florida Medical Association, Pan-American Association of Ophthalmology, Sigma Xi, and Southern Medical Association
Disclosure: Nothing to disclose.

CME Editor

Lance L Brown, OD, MD, Ophthalmologist, Affiliated With Freeman Hospital and St John's Hospital, Regional Eye Center, Joplin, Missouri
Disclosure: Nothing to disclose.

Chief Editor

Hampton Roy Sr, MD, Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences
Hampton Roy Sr, MD is a member of the following medical societies: American Academy of Ophthalmology, American College of Surgeons, and Pan-American Association of Ophthalmology
Disclosure: Nothing to disclose.

 
 
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