Hydroxychloroquine toxicity

From EyeWiki
Original article contributed by: Judy E. Kim, MD
All contributors: Judy E. Kim, MD, Marcus M. Marcet, MD and Theodore Leng, MD, MS
Assigned editor: Theodore Leng, MD, MS
Review: Assigned status Update Pending by Theodore Leng, MD, MS on December 20, 2014.

Hydroxychloroquine is a well tolerated medication for various rheumatologic and dermatologic conditions. Its main side effects are gastrointestinal upset, skin rash, headache, and ocular toxicity[1]. Within the eye, hydroxychloroquine negatively impacts the cornea, ciliary body, and retina[1]

Disease Entity

Hydroxychloroquine (Plaquenil) and chloroquine cause ocular toxicity, including the cornea, ciliary body, and retina [1]. Chloroquine can cause cataract; however, no reports of hydroxychloroquine and cataract have been reported[1]. This article focuses upon hydroxychloroquine retinopathy.


Chloroquine was originally used as an anti-malarial therapeutic. Chloroquine is now uncommonly used in favor of its derivative hydroxychloroquine. In the United States, hydroxychloroquine is most often used for its anti-inflammatory effects in rheumatology and dermatology[2][3]. Its toxic effects on the retina are seen in the macula. While early toxicity may be asymtomatic, patients with more advanced stage of toxicity may complain of color vision changes or paracentral scotomas. Advanced hydroxychloroquine toxicity presents as a bull’s eye maculopathy. Since retinal toxicity is usually irreversible, early detection of retinal toxicity and cessation of the offending agent is the best treatment[2][3]. Corneal toxicity presents as an intraepithelial deposition of the drug into the cornea, which rarely affects vision[1]. Ciliary body dysfunction disturbs accommodation and is rare[1].

Risk Factors

Hydroxychloroquine retinopathy is most influenced by daily dose, length of use, and cumulative dose over time. Risk for toxicity is least with less than 6.5 mg/kg/day for hydroxychloroquine and 3 mg/kg/day for chloroquine[2]. Patients are at low risk during the first 5 years of treatment. Cumulative use in excess of 250 grams increases the risk for toxic retinopathy[3][4]. Other risk factors include obesity, kidney or liver disease, older age, and other retinal disorders[2]. Obesity is a risk factor because the drug does not penetrate lipid rich tissues. The recommended doses are based upon ideal body weight. Therefore, obesity is a risk factor due to improper dosing, rather than a specific risk. Kidney and liver disease predispose to hydroxychloroquine toxicity due to impaired clearance of the drug. Old age is hypothesized to contribute to overall risk due to the natural aging process of the retinal pigment epithelium (RPE), causing the RPE to be more sensitive to toxic drugs. Similarly, concomitant retinal conditions predispose to toxicity due to predamaged cellular elements. These criteria define low and high risk patient populations. A high risk patient is one who receives greater than 6.5 mg/kg/day for more than 5 years with coexisting retinal disease, liver or kidney disease, age greater than 60 years old, and high fat level (unless the dosage is appropriately reduced for ideal body weight)[5]. High risk patients have a 5% chance of developing toxic retinopathy[4]. Keratopathy is rare (<1%) in patients receiving doses below 6.5 mg/kg/day. If keratopathy develops, it is a sign that the patient is over-medicated and macular toxicity needs to be addressed[1]. Ciliary body dysfunction is rare and no risk factors are identified1.

General Pathology

Hydroxychloroquine retinopathy causes destruction of macular rods and cones with sparing of foveal cones. This pattern provides the typical bull’s eye appearance. RPE migrates into the areas of destructed photoreceptors, causing pigment laden cells to be detected in the outer nuclear and outer plexiform layers[1]. Hydroxychloroquine keratopathy is caused by deposition of unmodified hydroxychloroquine salts within the epithelium[1].


Hydroxychloroquine binds to melanin, accumulates in the RPE, and remains there for long periods of time. It is directly toxic to the RPE, causing cellular damage and atrophy[2]. This occurs due to disruption of RPE metabolism, specifically from lysosomal damage[4], and reduced phagocytic activity toward shed photoreceptor outer segments. Accumulation of photoreceptor outer segments leads to RPE degeneration, migration into the outer retina, and finally photoreceptor loss[1].

Primary prevention

A complete ophthalmologic examination is recommended before starting hydroxychloroquine therapy. During this exam, patients should be tested for macular appearance, color vision, Amsler grid, Humphrey 10-2 visual fields, and macular fundus photography for comparison. Use of a red Amsler grid or red visual field test object is recommended for initial use and follow up because it provides earlier detection, at a stage where changes may still be reversible[2]. Follow up examinations are recommended after 5 years of hydroxychloroquine use. High risk patients should be followed yearly and non-high risk patients should be followed every 3 years after the 5 year low risk period[4].



For retinopathy, patients should be asked about poor central vision, change in color vision, central blind spots, difficulty reading, and metamorphopsia. For keratopathy, patients should be asked about halos around light, decreased visual acuity, or photophobia. For ciliary body dysfunction, patients should be asked about difficulty with reading and other activities that require accommodation.

Physical examination

Physical exam should focus upon the condition that required hydroxychloroquine therapy to be initiated. Knowing the status of the primary disease process will be helpful to determine if cessation of treatment or lowering of medication is indicated.


Hydrochloroquine retinopathy is caused by build up of the systemic drug and thus the findings are bilateral and symmetric[3]. The early signs of hydroxychloroquine toxicity are macular edema and/or bilateral granular depigmentation of the RPE in the macula. With continued exposure to the drug, this can progress to an atrophic bull’s eye maculopathy with concentric rings of hypopigmentation and hyperpigmentation surrounding the fovea[2][3]. These changes can progress with additional drug exposure to include other areas of the fundus, causing widespread atrophy[2]. At this point, attenuation of retinal arterioles and optic disc pallor will be evident[6]. Hydroxychloroquine keratopathy presents as an intraepithelial deposit. The deposits may take the form of whirls, linear opacities, or punctate lesions[1]. Ciliary body dysfunction can be detected by poor near vision.


In retinopathy, patients are often asymptomatic. If they do have symptoms they complain of visual color deficits, specifically red objects, missing central vision, difficulty reading, reduced or blurred vision, glare, flashing lights, and metamorphopsia [1][2][3]. The symptoms are often in both eyes. In keratopathy, patients complain of halos around light and photophobia. In ciliary body dysfunction, patients will not be able to read or do other activities requiring accommodation.

Clinical diagnosis

Hydroxychloroquine retinal toxicity is often divided into premaculopathy and true retinopathy. This distinction is important clinically because premaculopathy is reversible and will not progress after drug discontinuation. Conversely, true retinopathy is irreversible and can continue to worsen even after a patient stops hydroxychloroquine therapy. Premaculopathy is when a patient with no visual symptoms, no loss of visual acuity, and only diminished visual fields with a red test object demonstrates macular RPE stippling and diminished foveal light reflex on clinical exam. On the other hand, true retinopathy occurs when a patient does have visual symptoms, diminished visual acuity, reduced visual fields with both white and red test objects, and bull’s eye maculopathy changes as described above[6].

Diagnostic procedures

Fluorescien angiography will demonstrate a hyperfluorescent window defect in a bull’s eye pattern in the area of RPE loss[3]. Humphrey 10-2 visual fields can demonstrate (para)central scotomas[1]. Multifocal electroretinogram may show “moat around a small hill” appearance[4]. Optical coherence tomography (OCT) can detect early retinopathy via RPE and photoreceptor loss in the parafoveal regions Newer technologies such as spectral domain OCT and autofluorescence can detect even earlier retinopathy before visual loss.

Laboratory test

There are no indicated laboratory tests.

Differential diagnosis

Hydroxychloroquine maculopathy shares characteristic with several acquired or congenital diseases of the macula. The differential diagnosis includes age-related macular degeneration, cone dystrophy, rod and cone dystrophy, Startgardt’s disease, neuronal ceroid lipofuscinosis, and fenestrated sheen macular dystophy[1].


General treatment

At the first signs of retinal toxicity, hydroxychloroquine should be stopped to prevent further retinal damage and visual loss[2].

Medical therapy

Premaculopathy is reversible with cessation of therapy. True retinopathy is irreversible. Vision can be stabilized with discontinuation of hydroxychloroquine. However, visual loss can continue to progress in some instances after stopping the drug. Keratopathy is fully reversible with discontinuation of hydroxychloroquine.

Medical follow up

Patients should be examined before starting hydroxychloroquine. Patients should be re-examined at 5 years of therapy. After the 5 year window, high risk patients should be followed yearly and low risk patients every 3 years.

Patients can use hydroxychloroquine tracking app's like Hydroxy Counter to alert them as to when toxic doses may be reached.


There is no surgical therapy.


Premaculopathy is fully reversible[1]. True bull’s eye maculopathy is irreversible. Most patient’s vision remains stable after cessation of treatment. Occasionally, patient’s vision will continue to worsen[1]. This occurs because hydroxychloroquine has a long half-life. In fact, the drug can still be detected in the blood and urine of patients 5 years after cessation of therapy[4]. Keratopathy is fully reversible[1].

Additional Resources


  1. 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 Yam, J.C. & Kwok, A.K. 2006. Ocular toxicity of hydroxychloroquine. Hong Kong Med J 12: 294-304.
  2. 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 AAO. in Basic and Clinical Sciences Course (Lifelong Education for the Ophthalmologist, San Fransisco, CA, 2006).
  3. 3.0 3.1 3.2 3.3 3.4 3.5 3.6 Lang, G.K. Ophthalmology: A Pocket Textbook Atlas (Thieme, Stuttgart, 2007).
  4. 4.0 4.1 4.2 4.3 4.4 4.5 Blodi, D.A.Q.a.B.A. Clinical Retina (AMA Press, 2002).
  5. Marmor, M.F., Carr, R.E., Easterbrook, M., Farjo, A.A. & Mieler, W.F. 2002. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy: a report by the American Academy of Ophthalmology. Ophthalmology 109: 1377-82.
  6. 6.0 6.1 Bernstein, H.N. 1983. Ophthalmologic considerations and testing in patients receiving long-term antimalarial therapy. Am J Med 75: 25-34.