Close
New

Medscape is available in 5 Language Editions – Choose your Edition here.

 

Chloroquine and Hydroxychloroquine Toxicity

  • Author: Manolette R Roque, MD, MBA, FPAO; Chief Editor: Hampton Roy, Sr, MD  more...
 
Updated: Nov 03, 2015
 

Practice Essentials

Chloroquine and hydroxychloroquine belong to the quinolone family. They are related drugs with similar clinical indications for use and similar manifestations of retinal toxicity, although their therapeutic and toxic doses differ. The image below depicts hydroxychloroquine retinopathy.

Fluorescein angiogram of left macula in patient wi 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.

Signs and symptoms

Retinopathy may be asymptomatic or may cause parafoveal metamorphopsia and difficulty in reading or performing fine visual tasks (due to central or paracentral scotomas). Visual acuity initially remains excellent. See the image below.

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
  • Rarely, neurologic symptoms, such as vertigo, tinnitus, irritability, cranial nerve palsies, and myasthenialike muscle weakness

Findings on eye examination include the following:

  • Corneal deposits
  • Posterior subcapsular lens opacity (chloroquine only)
  • Irregularity in the macular pigmentation and blunting of the foveal reflex (early)
  • Bull’s eye maculopathy (classic finding)
  • Peripheral pigment irregularity and bone spicule formation, vascular attenuation, and optic disc pallor (end stage)

See Clinical Presentation for more detail.

Diagnosis

Patients starting treatment with chloroquine/hydroxychloroquine should have a baseline examination by an ophthalmologist that includes the following:

  • History (including refraction)
  • Visual acuity (uncorrected visual acuity [UCVA] and best spectacle-corrected visual acuity [BSCVA])
  • Slit-lamp biomicroscopy
  • Direct and indirect ophthalmoscopy (this is not a screening tool; it picks up relatively late toxic changes only)

The examination should also include a Humphrey visual field central 10-2 white-on-white pattern, and at least one of the following objective tests, if available (see Workup):

  • Spectral domain optical coherence tomography (SD-OCT)
  • Fundus autofluorescence (FAF) test
  • Multifocal electroretinogram (mfERG)

Ancillary tests used in the diagnosis of toxicity include the following:

  • Amsler grid
  • Color vision testing
  • Color fundus photography: documenting changes over time, especially in patients with preexisting retinal pathology
  • Full-field ERG or electro-oculogram
  • Fluorescein angiography: may assist in visualizing early subtle changes in the retinal pigment epithelium

See Workup for more detail.

Management

Withdrawal of the medication and shifting to another form of treatment is the standard of care. Coordination with the rheumatologist or the dermatologist is warranted for comprehensive care of the patient. Patients with serious toxic symptoms may benefit from acidification of the urine with ammonium chloride to increase renal excretion of the drug.

See Treatment and Medication for more detail.

Next

Background

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

Initially, chloroquine was given for malaria prophylaxis and treatment. Subsequently, 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. Expanded use of these drugs for nonmalarial disease entities has resulted in prolonged duration of therapy and higher daily dosages than those used in antimalarial therapy.

Since it is far less toxic to the retina, hydroxychloroquine has replaced chloroquine, except for individuals who travel in areas endemic with malaria. Many reports on chloroquine retinopathy exist. In contrast, only a few cases of hydroxychloroquine toxicity have been reported.

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). 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.

Internists, rheumatologists, or dermatologists may not be fully aware of the potential ophthalmic implications of using chloroquine and hydroxychloroquine. Regular screening, including multifocal electroretinographic assessment, is a required element in the preferred practice pattern of patients treated with these agents. 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.

Previous
Next

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 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 remains in the pigmented structures long after its use is stopped. In patients with retinopathy, traces of chloroquine have been found in plasma, erythrocytes, and urine 5 years or more after discontinuation of the drug.

Previous
Next

Etiology

Chloroquine/hydroxychloroquine retinopathy is most influenced by daily dose, length of use, and cumulative dose. The kinetics of chloroquine metabolism are complicated, with the half-life increasing as the dosage is increased.

Factors associated with hydroxychloroquine toxicity include the following:

  • Daily dose greater than 400 mg
  • Maintenance dose greater than 6.5 mg/kg/d (in people of short stature)
  • Total cumulative dose of more than 1000 g
  • Duration of treatment greater than 5 years
  • Evidence of renal insufficiency
  • Evidence of liver disease
  • Underlying retinal disease or maculopathy (macular degeneration)
  • Age older than 60 years

Factors associated with chloroquine toxicity include the following:

  • Maintenance dose greater than 3.5 mg/kg/d
  • Duration of treatment greater than 5 years
  • Renal insufficiency or liver disease
  • Obesity

A study of chloroquine/hydroxychloroquine retinopathy–related risk factors in a Turkish cohort found no significant difference between affected and nonaffected patients with respect to several risk factors, and found that the cumulative dose of hydroxychloroquine was significantly higher in the nonaffected patients. These findings suggest that the currently widely accepted risk factors may not be applicable to all patients and that there may be risk factors previously not reported that may play a role in the development of toxicity.[1]

Previous
Next

Epidemiology

Two trends are consistent in the literature, despite the variability of the statistics: the incidence of retinopathy from chloroquine/hydroxychloroquine increases with both the dose and the duration of treatment. In the United States, 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.[2] Internationally, incidence rates from 1-28% have been reported.

No known racial or sexual predilection exists for chloroquine/hydroxychloroquine toxicity. No known age predisposition exists, although older patients are believed to be at a higher risk because of the potential for diseased retinas.

Previous
Next

Prognosis

If the maximum daily dosage recommendations are followed, the likelihood of toxicity from chloroquine or hydroxychloroquine 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, however, disturbances associated with chloroquine/hydroxychloroquine retinal toxicity are irreversible.

Previous
Next

Patient Education

When starting patients on chloroquine or hydroxychloroquine, it is imperative for clinicians to counsel them about the benefits and limitations of screening. Patient education must clearly stress the fact that those measures can detect toxicity at early stages and limit vision loss but cannot necessarily prevent all toxicity and vision loss.

Advise patients to discontinue treatment and to seek consultation with an ophthalmologist if changes in visual acuity or blurred vision occur while on treatment.

Previous
 
 
Contributor Information and Disclosures
Author

Manolette R Roque, MD, MBA, FPAO Section Chief, Ocular Immunology and Uveitis, Department of Ophthalmology, Asian Hospital and Medical Center; Section Chief, Ocular Immunology and Uveitis, International Eye Institute, St Luke's Medical Center Global City; Senior Eye Surgeon, The LASIK Surgery Clinic; Director, AMC Eye Center, Alabang Medical Center

Manolette R Roque, MD, MBA, FPAO is a member of the following medical societies: American Academy of Ophthalmology, American Society of Cataract and Refractive Surgery, Philippine Medical Association, American Uveitis Society, International Ocular Inflammation Society, Philippine Ocular Inflammation Society, American Society of Ophthalmic Administrators, American Academy of Ophthalmic Executives, Philippine Society of Cataract and Refractive Surgery

Disclosure: Nothing to disclose.

Coauthor(s)

C Stephen Foster, MD, FACS, FACR, FAAO, FARVO 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, FARVO 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, Sigma Xi

Disclosure: Nothing to disclose.

Barbara L Roque, MD, DPBO, FPAO Senior Partner, Roque Eye Clinic; Chief of Service, Pediatric Ophthalmology and Strabismus Section, Department of Ophthalmology, Asian Hospital and Medical Center; Active Consultant Staff, International Eye Institute, St Luke's Medical Center Global City

Barbara L Roque, MD, DPBO, FPAO is a member of the following medical societies: American Academy of Ophthalmology, American Association for Pediatric Ophthalmology and Strabismus, American Society of Cataract and Refractive Surgery, Philippine Society of Cataract and Refractive Surgery, Philippine Academy of Ophthalmology, Philippine Society of Pediatric Ophthalmolo

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, Pan-American Association of Ophthalmology

Disclosure: Nothing to disclose.

Acknowledgements

Harold H Harsch, MD Program Director of Geropsychiatry, Department of Geriatrics/Gerontology, Associate Professor, Department of Psychiatry and Department of Medicine, Froedtert Hospital, Medical College of Wisconsin

Harold H Harsch, MD is a member of the following medical societies: American Psychiatric Association

Disclosure: lilly Honoraria Speaking and teaching; Forest Labs None None; Pfizer Grant/research funds Speaking and teaching; Northstar None None; Novartis Grant/research funds research; Pfizer Honoraria Speaking and teaching; Sunovion Speaking and teaching; Otsuke Grant/research funds reseach; GlaxoSmithKline Grant/research funds research; Merck Honoraria Speaking and teaching

Alan D Schmetzer, MD Professor Emeritus, Interim Chairman, Vice-Chair for Education, Associate Residency Training Director in General Psychiatry, Fellowship Training Director in Addiction Psychiatry, Department of Psychiatry, Indiana University School of Medicine; Addiction Psychiatrist, Midtown Mental Health Cener at Wishard Health Services

Alan D Schmetzer, MD is a member of the following medical societies: American Academy of Addiction Psychiatry, American Academy of Clinical Psychiatrists, American Academy of Psychiatry and the Law, American College of Physician Executives, American Medical Association, American Neuropsychiatric Association, American Psychiatric Association, and Association for Convulsive Therapy

Disclosure: Eli Lilly & Co. Grant/research funds Other

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

References
  1. Yaylali SA, Sadigov F, Erbil H, Ekinci A, Akcakaya AA. Chloroquine and hydroxychloroquine retinopathy-related risk factors in a Turkish cohort. Int Ophthalmol. 2013 Mar 2. [Medline].

  2. Bernstein HN. Chloroquine ocular toxicity. Surv Ophthalmol. 1967 Oct. 12(5):415-47. [Medline].

  3. [Guideline] Hansen MS, Schuman SG. Hydroxychloroquine-Induced Retinal Toxicity. American Academy of Ophthalmology. Available at http://www.aao.org/publications/eyenet/201106/pearls.cfm?RenderForPrint=1&. Accessed: April 23, 2013.

  4. [Guideline] Karmel M. Rx Side Effects: New Plaquenil Guidelines and More. American Academy of Ophthalmology. Available at http://www.aao.org/aao/publications/eyenet/201105/retina1.cfm?RenderForPrint=1&. Accessed: April 23, 2013.

  5. Cukras C, Huynh N, Vitale S, Wong WT, Ferris FL 3rd, Sieving PA. Subjective and objective screening tests for hydroxychloroquine toxicity. Ophthalmology. 2015 Feb. 122 (2):356-66. [Medline].

  6. Anderson C, Pahk P, Blaha GR, Spindel GP, Alster Y, Rafaeli O, et al. Preferential Hyperacuity Perimetry to detect hydroxychloroquine retinal toxicity. Retina. 2009 Sep. 29(8):1188-92. [Medline].

  7. Angi M, Romano V, Valldeperas X, Romano F, Romano MR. Macular sensitivity changes for detection of chloroquine toxicity in asymptomatic patient. Int Ophthalmol. 2009 Jan 23. [Medline].

  8. Michaelides M, Stover NB, Francis PJ, Weleber RG. Retinal toxicity associated with hydroxychloroquine and chloroquine: risk factors, screening, and progression despite cessation of therapy. Arch Ophthalmol. 2011 Jan. 129(1):30-9. [Medline].

 
Previous
Next
 
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.
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.
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.
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.
The same patient as described in the image above (other eye, left eye). The patient (with foveal cone electroretinogram reduction) had abnormal computerized acuity mapping of the macula results.
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.
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.