Hydroxychloroquine Toxicity

From EyeWiki

Hydroxychloroquine is a well-tolerated medication for various rheumatologic and dermatologic conditions. It has also been used off-label as a potential therapy for the novel coronavirus, COVID-19, although data to support its efficacy is mixed and primarily anecdotal due to the lack of large controlled trials[1]. Its main side effects are gastrointestinal upset (vomiting, diarrhea, stomach cramps), skin rash, headache, dizziness, and ocular toxicity[2]. However, serious side effects including arrhythmia, bronchospasm, angioedema, and seizures can rarely occur. Within the eye, hydroxychloroquine can adversely impact the cornea, ciliary body, and retina.[2]

Disease Entity

Hydroxychloroquine (Plaquenil) and chloroquine cause ocular toxicity to various parts of the eye such as the cornea, ciliary body, and retina [2]. Chloroquine can also induce cataract formation; however, no reports of hydroxychloroquine and cataract have been reported[2]. 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[3][4]. 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 bullseye maculopathy. Since retinal toxicity is usually irreversible, early detection of retinal toxicity and cessation of the offending agent is the best treatment[3][4]. Corneal toxicity presents as an intraepithelial deposition of the drug into the cornea, which rarely affects vision[2]. Ciliary body dysfunction disturbs accommodation and is rare[2].

Risk Factors

Hydroxychloroquine retinopathy is most influenced by daily dose and duration of use. Risk for toxicity is less with <5.0 mg/kg real weight/day for hydroxychloroquine and <2.3 mg/kg real weight/day for chloroquine[3]. Patients are at low risk during the first 5 years of treatment. Other major risk factors include renal disease (eGFR <60ml/min/1.73m2), concominant drug use (e.g., tamoxifen), and macular disease which is thought to potentially affect screening and susceptibility to hydroxychloroquine and chloroquine. Genetic factors (e.g., polymorphisms in the cytochrome P450 gene which may impact blood concentrations) may be a lesser risk factor associated with toxicity risk, whilst others (e.g. some nonpathogenic ABCA4 polymorphisms) may actually be protective[3][5]. Concomitant retinal conditions predispose to toxicity due to predamaged cellular elements. At recommended doses, the risk of toxicity up to 5 years is under 1% and up to 10 years is under 2%, but rises to nearly 20% after 20 years. However, if a patient has not demonstrated toxicity after the 20-year point, he/she only has a 4% risk of developing toxicity the subsequent year.[3] Keratopathy is rare (<1%) in patients treated with typical doses of hydroxychloroquine. Ciliary body dysfunction is rare and no risk factors are identified.

General Pathology

Hydroxychloroquine retinopathy causes destruction of macular rods and cones with sparing of foveal cones. This pattern provides the typical bullseye appearance. RPE migrates into the areas of destructed photoreceptors, causing pigment laden cells to be detected in the outer nuclear and outer plexiform layers[2]. Hydroxychloroquine keratopathy is caused by deposition of unmodified hydroxychloroquine salts within the epithelium[2].


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[3]. This occurs due to disruption of RPE metabolism, specifically from lysosomal damage[6], 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[2].

Primary prevention

A complete ophthalmologic examination is recommended before starting or within the first year of starting hydroxychloroquine therapy. During this exam, patients should receive a fundus examination; visual fields and spectral-domain optical coherence tomography (SD-OCT) should be added if maculopathy is present. Annual screening should begin after 5 years of drug use for most patients, but should commence sooner in those where major risk factors are present.[3] Annual screening should include both automated visual fields and SD-OCT. Of note, the 10-2 field has high resolution within the macula, but recent data suggests that wider test patterns (24-2 or 30-2) are needed for patient of Asian descent who are more likely to have pathological findings extend beyond the central macula[7][8]. Of note, African-American and Hispanic patients also seem to have a slightly higher predilection for pathological findings to present outside the central macula, but the exact association is still not well-understood in these populations. Additional testing that should be considered include multifocal electroretinography (mfERG), fundus autofluoresence (FAF). Microperimetry and adaptic optics may be helpful in the future, but their potential roles in screening are still being evaluated. Color testing, Amsler grid, time-domain OCT, fluorescein angiography, and full-field ERG are no longer recommended for hydroxychloroquine toxicity screening purposes.



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. To assess risk factors, they should be asked questions such as when they started taking Plaquenil, what their current dosage is, what their current body weight is, whether or not they have had an ophthalmic examination in the past, how often they see their rheumatologist, whether they have liver or kidney disease, and whether they are taking other drugs associated with retinal toxicity, such as tamoxifen.

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[4]. 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 bullseye maculopathy with concentric rings of hypopigmentation and hyperpigmentation surrounding the fovea[3][4]. As mentioned above, these findings may be in the peripheral macula near the arcades in patients of Asian descent.[7][8]These changes can progress with additional drug exposure to include other areas of the fundus, causing widespread atrophy[3]. At this point, attenuation of retinal arterioles and optic disc pallor can also be evident[9]. Hydroxychloroquine keratopathy presents as an intraepithelial deposit. The deposits may take the form of whirls, linear opacities, or punctate lesions[2]. Ciliary body dysfunction can be detected by poor near vision.


In the initial stages of hydroxycloroquine toxicity, 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 [2][3][4]. 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.

Diagnostic procedures

The earliest finding is disruption in the parafoveal ellipsoid zone. In later stages, this may be accompanied by changes affecting the parafoveal outer nuclear layer, inner plexiform layer, and external limiting membrane. Increased thickness of the retinal pigment epithelium-Bruchs' membrane has also been observed in early toxicity. The classic "flying saucer" sign is seen on OCT and describes a preservation of the outer retinal layers subfoveally with perifoveal loss of the ellipsoid zone on both sides of the fovea in a line scan. Ganglion cell complex and peripapillary retinal nerve fiber layer defects have also been reported.

In early cases of toxicity, visual fields will typically reveal a paracentral scotoma. If a 24-2 or 30-2 field is performed, be way of overlooking the 2-degree field of sparing seen on 10-2 fields; in these tests, a small central defect may be seen instead. The area of risk on a 10-2 Humphrey visual field is typically two to six degrees from the center in non-Asian patients, although exceptions of course exist.

Fundus autofluorescence can reveal early parafoveal or extramacular photoreceptor damage as an area of hyper-autofluorescence that may precede thinning on SD-OCT. Later on, this area can be hypo-autofluorescence as the RPE becomes atrophic.[10][11] Multifocal ERG may reveal depression in the parafoveal or extramacular area in early retinopathy.

Laboratory testing

There are no indicated laboratory tests. However, liver and renal function tests can assist in determining a patient's risk profile.

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, Stargardt’s disease, neuronal ceroid lipofuscinosis, and fenestrated sheen macular dystophy[2].


General treatment

At the first signs of retinal toxicity, hydroxychloroquine should be stopped to prevent further retinal damage and visual loss[3].

Medical therapy

There is no diet or medical therapy to prevent or treat this type of retinal toxicity; the best approach is primary prevention. Oftentimes, by the time a true bullseye maculopathy becomes visible on examination, the disease has already been progressing for years. When recommending cessation of the drug, it is important to work with the patient's rheumatologist (or prescriber of drug) so that systemic control of disease is also addressed and optimized.

Medical follow up

Patients should be examined before starting hydroxychloroquine. Patients should be re-examined at 5 years of therapy and annually thereafter, unless risk factors are present for which then annual visits should commence earlier.


There is no surgical therapy.


In general, hydroxychloroquine and chloroquine retinopathy are not reversible, and even following drug cessation, cellular damage appears to continue for a certain period of time. However, the earlier the retinopathy is recognized, the greater the chance of visual preservation. Keratopathy has been reported to be fully reversible[2].


  1. Gbinigie K, Frie K. Should chloroquine and hydroxychloroquine be used to treat COVID-19? A rapid review. BJGP Open 2020. 2020;Epub ahead of press.
  2. 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 Yam, J.C. & Kwok, A.K. 2006. Ocular toxicity of hydroxychloroquine. Hong Kong Med J 12: 294-304.
  3. 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 Marmor MF, Kellner U, Lai TYY, Melles RB, Mieler WF, for the American Academy of Ophthalmology. Recommendations on Screening for Chloroquine and Hydroxychloroquine Retinopathy. Ophthalmology. 2016;123:1386-94.
  4. 4.0 4.1 4.2 4.3 4.4 Lang, G.K. Ophthalmology: A Pocket Textbook Atlas (Thieme, Stuttgart, 2007).
  5. Lee Y, Vinayagamoorthy N, Han K, et al. Association of polymorphisms of cytochrome P450 2D6 with blood hydroxychloroquine levels in patients with systemic lupus erythematosus. Arthritis Rheumatol. 2016;68:184-90.
  6. Blodi, D.A.Q.a.B.A. Clinical Retina (AMA Press, 2002).
  7. 7.0 7.1 Melles RB, Marmor MF. Pericentral retinopathy and racial differences in hydroxychloroquine toxicity. Ophthalmology. 2015;122:110-6.
  8. 8.0 8.1 Lee DH, Meelles RB, Joe SG, et al. Pericentral hydroxychloroquine retinopathy in Korean patients. Ophthalmology. 2015;122:1252-6.
  9. Bernstein, H.N. 1983. Ophthalmologic considerations and testing in patients receiving long-term antimalarial therapy. Am J Med 75: 25-34.
  10. Marmor MF. Comparison of screening procedures in hydroxychloroquine toxicity. Arch Ophthalmol. 2012;130:461-9.
  11. Kellner U, Renner AB, Tillack H. Fundus autofluorescence and mfERG for early detection of retinal alterations in patients using chloroquine/hydroxychloroquine. Invest Ophthalmol Vis Sci. 2006;47:3561-8.
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