Chloroquine and Hydroxychloroquine Toxicity

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Practice Essentials

Coronavirus Disease 2019 (COVID-19) and Chloroquine/Hydroxychloroquine

Chloroquine and hydroxychloroquine have displayed the ability to inhibit replication of multiple coronaviruses in vitro. Publications anew support the hypothesis that both chloroquine and hydroxychloroquine can improve the clinical outcome of patients with coronavirus disease 2019 (COVID-19). Hydroxychloroquine appears to be safer and more potent in inhibiting the causative virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in vitro. The numerous molecular mechanisms by which they can achieve such results remain to be further explored.[1, 2, 3]

Early reports of in vivo use have been promising. However, no randomized clinical trials have been conducted to inform clinical guidance on the use, dosing, and duration of chloroquine/hydroxychloroquine for prophylaxis or treatment of COVID-19.[4] The potential nonjudicious use of chloroquine/hydroxychloroquine is alarming, since it may lead to irreversible vision loss. Although it may appear safe at low doses, chloroquine/hydroxychloroquine retinopathy is influenced most by daily dose, length of use, and cumulative dose.

Background

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



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Fluorescein angiogram of left macula in patient with hydroxychloroquine retinopathy. Reprinted from American Journal of Ophthalmology, Vol 104, Johnso....

Etiology

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

Factors associated with hydroxychloroquine toxicity include the following:

Factors associated with chloroquine toxicity include the following:

Factors associated with toxicity in both drugs include the following:

Signs and symptoms

Retinopathy may be asymptomatic or may cause central or paracentral scotomas leading to difficulty reading or performing fine visual tasks (due to parafoveal metamorphopsia). Visual acuity usually remains intact until advanced disease.

Other reported visual symptoms include the following:

Systemic complaints include the following:

Findings on eye examination include the following:

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:

The examination should also include a Humphrey visual field central 10-2 white-on-white pattern (24-2 or 30-2 in Asian patients) and at least one of the following objective tests, if available (see Workup):

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

See Workup for more detail.

Management

Withdrawal of the medication and shifting to another treatment is the standard of care. Coordination with the rheumatologist or the dermatologist may be warranted for comprehensive care of the patient. No diet or medical therapy has been proven effective to prevent, treat, or reduce risk of retinal toxicity.

See Treatment and Medication for more detail.

Background

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

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.

Hydroxychloroquine has largely replaced chloroquine in the United States, except among patients who travel to areas endemic with malaria. Although the mechanisms of the two agents are presumed to be the same, many reports suggest that chloroquine is more toxic to the retina than hydroxychloroquine. The toxic dosage for chloroquine was derived from hydroxychloroquine retinal toxicity studies, although no definitive data have shown pharmacologic equivalence.[5]

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 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.

Physicians who prescribe chloroquine and hydroxychloroquine may not be fully aware of the potential ophthalmic implications. In the management of patients treated with these agents, the preferred practice is regular screening. Patients and referring physicians should understand that screening helps to identify toxicity early but cannot guarantee prevention of toxicity and vision loss.

Pathophysiology

The mechanism of chloroquine and hydroxychloroquine toxicity is not well understood. 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, including retinotoxic drugs. However, it is unclear whether this binding effect is beneficial or harmful.

Chloroquine and its principal metabolite accumulate in pigmented ocular structures at concentrations higher than other tissues and withdraws more slowly relative to other tissues upon withdrawal of therapy.[6, 7] Prolonged exposure can allow the drug to accumulate in the retina, where it 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.[8] However, progression of retinopathy after discontinuation of therapy may not result from slow clearance but gradual decompensation of cells injured during drug therapy.[5]

Etiology

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

Factors associated with hydroxychloroquine toxicity include the following:

Factors associated with chloroquine toxicity include the following:

Factors associated with toxicity in both drugs include the following:

A study of chloroquine/hydroxychloroquine retinopathy in a Turkish cohort found no significant difference between affected and unaffected patients with respect to several risk factors. Rather, the cumulative dose of hydroxychloroquine was significantly higher in the unaffected 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.[9]

Epidemiology

Despite variability of statistics in published reports, a consistent trend found in the literature is that the incidence of retinopathy from chloroquine/hydroxychloroquine increases with both the daily dose and the duration of treatment. The risk of developing retinal toxicity is less than 2% in patients who use dosages below the recommended threshold for up to 10 years. The risk increases significantly after 20 years of therapy and/or daily dose above the recommended threshold.[10]

Older patients are believed to be at a higher risk because of the higher rate of retinal comorbidities.

Prognosis

If the maximum daily dosage recommendations are followed, the likelihood of toxicity from chloroquine or hydroxychloroquine is less than 1% the first five years of treatment.[5] Corneal epithelial changes are usually reversible, but retinopathy caused by these agents are not. If diagnosed early, before RPE damage, there is mild and limited progression of the disease upon discontinuation of the agents. Once the appearance of a bull's eye maculopathy is noted, which indicates advanced stage of toxicity, disease progression can continue for years after discontinuation of the agents. Risk to vision and disease progression are a function of disease severity at the time of detection.[11, 12]

Patient Education

When starting patients on chloroquine or hydroxychloroquine, clinicians should counsel patients about the benefits and limitations of screening. Patients should be informed that screening can detect toxicity at early stages and limit progression of vision loss but cannot necessarily prevent all toxicity and associated vision risk.

Advise patients to consult their physician and an ophthalmologist if changes in visual acuity or if blurred vision occurs while on treatment, as risk of vision loss may warrant discontinuation of the medication.

History

Patients with hydroxychloroquine retinopathy are usually asymptomatic with unaffected visual acuity until advanced stages. Symptomatic patients report difficulty reading and performing fine visual tasks owing to central or paracentral scotomas.

Other reported visual symptoms include the following:

Systemic complaints include the following:

Physical Examination

In the general physical examination, the systemic complaints in patients with chloroquine/hydroxychloroquine toxicity (see History) may be observed. Ophthalmic examination may disclose corneal deposits, as well as changes in the lens, ciliary body, and retina.

Corneal deposits

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 deposits have varying patterns, such as a fine diffuse punctate appearance, a radial or whorl-like lines converging just inferior to the central cornea (verticillata), or coalesced and darkened lines.

Manifestation of these corneal deposits is not related to duration, dose, or vision loss and is completely reversible upon discontinuation of the medication. Chloroquine has been associated with keratopathy more than hydroxychloroquine. Older studies have shown a decrease in corneal sensation in approximately 50% of patients taking chloroquine.[13]

Lenticular, uveal (ciliary body), and retinal findings

Chloroquine, but not hydroxychloroquine, may cause white, flakelike posterior subcapsular lens opacity, and may decrease accommodation transiently with treatment.[14]

On retinal examination, the fundus appearance may remain entirely normal even after development of scotomas. 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. Patients of African American and Hispanic descent usually show initial photoreceptor damage in the parafoveal pattern as classically described in patients of European descent, but involvement of the macula is more common in these groups. Asian patients show initial damage more peripherally near the arcades.[5]

Later, the central irregular pigmentation may become surrounded by a concentric zone of hypopigmentation, usually oval and more prominent inferiorly to the fovea (see the image below). This condition often is bilateral, although asymmetry is not uncommon.



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Fluorescein angiogram of left macula in patient with hydroxychloroquine retinopathy. Reprinted from American Journal of Ophthalmology, Vol 104, Johnso....

If the treatment is not halted, retinopathy may progress to develop the classic bull's eye maculopathy. The finding is uncommon in patients of Asian heritage and becomes increasingly less common in other demographics with improved early screening. Further prolonged exposure may lead to more generalized pigmentary changes, RPE involvement, and foveal encroachment, leading to loss of visual acuity.[10] End-stage retinopathy presents with peripheral pigment irregularity and bone spicule formation, vascular attenuation, retinal atrophy, and optic disc pallor. It is sometimes mistaken for retinitis pigmentosa. Advanced cases of widespread RPE involvement may be accompanied by cystoid macular edema.[12]

Approach Considerations

Given the emergence of more sensitive diagnostic techniques and the recognition that risk of toxicity from years of hydroxychloroquine use is greater than previously believed, the American Academy of Ophthalmology has released updated guidelines on screening for retinopathy associated with hydroxychloroquine toxicity. The guidelines recommend, that within the first year of treatment with chloroquine and/or hydroxychloroquine, the prescribing physician should refer the patient to an ophthalmologist for a baseline examination.[5]

The ophthalmologist should conduct a complete examination to document any preexisting conditions, the visual field, and the fundus appearance to rule out underlying diseases. The examination should include the following:

The examination should also include a Humphrey visual field central 10-2 white-on-white pattern (24-2 or 30-2 in Asian patients), and at least one of the following objective tests, if available (see Workup):

Cukras et al reported that optical coherence tomography (OCT) retinal thickness and visual field mean deviation (VFMD) are objective measures demonstrating clinically useful sensitivity and specificity for the detection of hydroxychloroquine toxicity as identified by mfERG and thus may be suitable surrogate tests.[15]

Ahn et al reported that 9-mm horizontal- and vertical-line scans and wide-volume SS-OCT scans yielded the highest sensitivity in detecting hydroxychloroquine toxicity in the Asian population.[16]

The following ancillary tests are not recommended for toxicity screening because of low sensitivity, specificity, or reliability but may be used in diagnosing toxicity:

Other studies include the macular dazzle (photostress) test and dark adaptometry. The photostress test is a method of subjective evaluation of the macula in which the clinician "dazzles" the macula with a light source and then measures the length of time that the subject takes to regain the previous level of visual acuity. An ophthalmoscope or a pen torch is customarily used as the light source, but a conventional electronic flash from a camera can also serve this purpose.

In dark adaptometry, the 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.

Retinal Examination and Photography

Fundus photography has low sensitivity for toxicity signs in early stages and is not recommended for regular screening. Baseline retinal photographs may be used in patients starting chloroquine/hydroxychloroquine therapy to document pre-existing age-related macular changes.

When observable, early fundus changes in chloroquine/hydroxychloroquine toxicity include the loss of foveal reflex, macular edema, and pigment mottling that is enhanced with the red-free filter. The appearance of the macula correlates poorly with visual-field testing results.[17]

Mottling or stippling of the retinal pigment epithelium is similar in appearance to early age-related macular degeneration. A bull's eye pattern of maculopathy is a late fundus finding.

Amsler Grid

An Amsler grid may be used to detect paracentral scotomas within 10° of fixation. It is not recommended as a screening method for early antimalarial retinopathy because it is inconsistent in detecting subtle scotomas. However, it may reveal defects before they can be visualized by kinetic and static visual fields. Relative scotomas may be revealed with the red Amsler grid.

Patients may find it helpful to monitor their vision at home with an Amsler grid, shown in the image below.



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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.

Color Vision Testing

Color vision testing may be helpful in patients with unreliable visual field results. However, color vision testing has not been shown to be sensitive or specific for the detection of chloroquine/hydroxychloroquine retinopathy and should not be used for screening.

Male patients can have a baseline test prior to the use of chloroquine and/or hydroxychloroquine to identify any underlying congenital color vision deficiency that might be confused later with toxicity. 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 generally more likely to affect the blue-yellow or tritan axis of confusion than the red-green. Most patients with color vision defects also have absolute scotomas.

Perimetry

Baseline central visual field examination may be useful because early macular changes are nonspecific and may be indistinguishable from age-related changes. The Humphrey 10-2 program (white target) is recommended for confirming defects found by the Amsler grid. Since the pattern of toxicity often extends beyond the macula in Asian patients, 24-2 or 30-2 should be used in these patients.

The early scotomas associated with retinal toxicity are subtle and usually within 10° of fixation. They more commonly manifest as superonasal field defects. The later scotomas attributed to retinotoxicity become enlarged and may involve fixation, which reduces visual acuity. Visual fields can vary considerably between visits; uncertain results and should prompt retesting or evaluation with other objective tests. 

Preferential hyperacuity perimetry (PHP)

A pilot study conducted in 15 patients on chloroquine or hydroxychloroquine therapy found that the 10 patients with known or suspected toxicity—based on standardized visual field testing, fluorescein angiography, or both—all demonstrated significant hyperacuity defects on PHP testing.[18] None of the 5 patients on long-term therapy who had no clinical evidence of toxicity demonstrated a PHP hyperacuity defect. The researchers concluded that PHP has potential benefit as a useful adjunct for testing patients with suspected toxicity.

Microperimetry (MP-1)

Microperimetry (MP-1) has not been proven to be more revealing than automated perimetry and requires different test patterns for Asians and non-Asians.[5] However, a case report from England noted the use of MP-1 in detecting subclinical early retinal toxicity as a result of long-term use of chloroquine and in monitoring the changes in macular sensitivity. Although the patient was asymptomatic with best-corrected visual acuity of 20/20, MP-1 showed bilateral loss of sensitivity in the macular region with a dense scotoma within the central 12°.[19]

Fluorescein Angiography

Angiography may be performed in patients with preexisting macular disease. Angiography highlights the macular pigmentary changes that occur in well-established quinolone maculopathy. Fundus autofluorescence can give a topographic view of damage across the posterior fundus and extramacular patterns in Asian eyes, but the value of angiography as an early method of detection has not been established. Angiography can reveal late changes such as RPE defects and is not recommended for screening.

Most patients with relative scotomas usually have negative angiography findings, while patients with absolute scotomas usually have positive findings. Positive angiography findings 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. Reduced fluorescence is seen with late RPE loss. 

Electroretinography

ERG can be full field, focal, or multifocal. Focal ERG techniques can record an ERG response from the foveal and parafoveal regions. Compared with focal ERG, mfERG is more appropriate for the evaluation of chloroquine and/or hydroxychloroquine toxicity because it generates local ERG responses topographically across the posterior pole and can document a parafoveal or extramacular depression in early retinopathy or bull's eye distribution of ERG depression in late stages. Objective evaluation of visual field can be confirmed with similarly sensitive mfERG.

Electro-oculogram

The 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 is not recommended for screening of early hydroxychloroquine toxicity, but it may be useful in the evaluation of any patient with manifest toxicity to determine severity and geographic extent of the damage.

Computerized Acuity Mapping of the Macula

In this technique, 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 are designated with black dots with respect to fixation. Patients with vision better than 20/80 are candidates for this test. Patients with reduced ERG in the foveal cone may result in abnormal acuity mapping results.

Spectral Domain Optical Coherence Tomography

Pasadhika and Fishman evaluated the peripapillary retinal nerve fiber layer (RNFL) thickness and macular inner and outer retinal thickness using spectral domain optical coherence tomography (SD-OCT) in patients with long-term exposure to hydroxychloroquine or chloroquine. They concluded that OCT is useful for the detection of peripapillary RNFL thinning in clinically evident retinopathy.[20]

Selective photoreceptor loss and macular thinning are strong indicators of toxicity and can be detected in the absence of clinically apparent fundus changes. Non-Asian eyes show localized thinning of photoreceptors in the parafoveal region, while Asian eyes show thinning near the arcades and therefore need wider-angle scans.

SD-OCT may be less sensitive than mfERG but is definitive when the characteristic regional thinning pattern is detected.[5] Uncertain results can be retested using the same or different objective tests for confirmation. 

Histologic Findings

Animal studies have shown that the first morphologic changes become visible within 1 week after initiation of chloroquine treatment and involve ganglion cells manifesting membranous cytoplasmic bodies. Other neural cells of the retina show these changes later. Changes after up to 5 months of therapy were reversible.

Prolonged therapy resulted in progressive degeneration of the ganglion cells, photoreceptor cell bodies and nuclei, and outer segment involvement. The most severe changes tended to be perifoveal, with relative foveal sparing. Abnormalities of the pigment epithelium and choroid were seen after degeneration of the ganglion cells and photoreceptors. These changes were observed before abnormalities in the fundus or on ERG were detectable.

Pathologic studies of patients with chloroquine retinopathy are few and limited to cases with advanced retinopathy. However, consistent findings in literature include degeneration of the outer retina, particularly the photoreceptors and the outer nuclear layer, with relative sparing of the photoreceptors in the fovea. Pathologic changes in the ganglion cells are common, and pigment migration into the retina is also seen. Sclerosis of the retinal arterioles is variable.

Approach Considerations

Withdrawal of the medication and shifting to another form of treatment is the standard of care. No diet or medical therapy has been proven effective to prevent, treat, or reduce risk of retinal toxicity.[5] Coordination with the rheumatologist or the dermatologist may be warranted for comprehensive care of the patient.

Patients with retinal comorbidities such as age-related maculopathy and macular dystrophies are sometimes advised to avoid excessive sun exposure and to maintain intake of lutein and zeaxanthin. However, the value of these recommendations are unknown.[5]

Early reports regarding management of systemic chloroquine toxicity have recommended the use of ammonium chloride to increase renal clearance of the drug through urine acidification, but no recent reports have recommended the same management for chloroquine retinopathy. Case reports of ammonium chloride use in chloroquine retinopathy have not concluded in support of this countermeasure. 

Deterrence/Prevention

During therapy, patients should be monitored on an annual basis starting after the first five years of exposure. Screening should start sooner and more frequently for patients with major risk factors. The clinician should note visual symptoms, visual acuity, and fundus examination results. In addition, physicians should check dosage relative to body weight and changes in systemic status at each visit. Annual screenings should include an ocular examination, 10-2 threshold field testing (wider tests such as 24-2 or 30-2 for patients from Asian descent due to tendency for peripheral involvement), and SD-OCT. An objective test such as SD-OCT, mfERG, or fundus autofluorescence should be used to confirm subjective findings before toxicity is diagnosed.

The most important factor in avoiding toxicity with long-term therapy is high daily dose relative to real body weight. If the daily dose is below the stated threshold levels, then the annual incremental risk of developing toxic retinopathy is less than 1% for the first two decades of use.[5] However, the clinician should discuss the early symptoms of toxicity with the patient. A high index of suspicion of toxicity warrants ancillary procedures to detect possible retinopathy.

Based on 2016 recommendations from the American Academy of Ophthalmology, the recommended safe threshold dose has been reported as 2.3 mg/kg/d for chloroquine and 5 mg/kg/d for hydroxychloroquine. Real weight, not ideal weight, is used for the dosage calculation.

Pediatric and elderly patients may be considered at high risk for toxicity and should be monitored closely. Dose adjustments should be made in patients with renal impairment or hepatic insufficiency.

The National Registry of Drug-Induced Ocular Side Effects offers a resource to retrieve and to contribute information regarding suspected drug toxicities. To access the Registry, go to www.eyedrugregistry.com. 

Long-Term Monitoring

A yearly visual field examination is useful to detect changes from hydroxychloroquine. Multifocal ERG assessment is part of the preferred practice for managing patients on antimalarial agents. When abnormalities are detected, additional testing should be obtained. Humphrey visual field central 10-2 white-on-white pattern (24-2 or 30-2 in Asian patients) should be repeated if central or parafoveal changes are seen, even if these appear to be nonspecific. If the findings are reproducible, objective testing should be performed repeatedly.

If toxicity is suspected, more frequent and detailed examinations should be conducted. Once toxicity is confirmed, the prescribing physician should be informed, and discontinuation of hydroxychloroquine therapy should be assessed against medical indication of the therapy with the patient informed of the visual risk. The agent may be substituted by other immunosuppressive agents.

Chloroquine and/or hydroxychloroquine clear slowly from the body, so the full effects may not manifest for 3-6 months. Slow, continued deterioration of visual function may occur even after the drug is discontinued.

A small case series study revealed evidence of retinal toxicity that included difficulty with reading, variable fundus findings ranging from normal to bull’s eye maculopathy, reduced rod and cone function on electroretinography (ERG), and abnormal visual fields. Six of 16 patients had progressive loss of retinal function despite cessation of the study drug.[21]

The authors recommend that patients be reevaluated 3 months after a diagnosis of retinal toxicity is made, even after discontinuation of drug use. Annual examinations are recommended until the findings have stabilized.

Guidelines Summary

The American Academy of Ophthalmology released revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy in 2016.[22]

All patients must undergo a baseline dilated fundus examination to rule out preexisting maculopathy. Patients on acceptable doses and without major risk factors may undergo annual screening 5 years after initiation of treatment.

The primary screening tests include automated visual field and SD-OCT. Useful additional objective tests include functional multifocal electroretinography (mfERG) and structural fundus autofluorescence (FAF).

Medication Summary

Withdrawal of the agent is the standard of care for patients who develop toxicity from chloroquine or hydroxychloroquine. No diet or medical therapy has been proven effective to prevent, treat, or reduce risk of retinal toxicity. 

Author

Manolette R Roque, MD, MBA, FPAO, Department Chairman and Chief of Section on 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

Disclosure: Nothing to disclose.

Coauthor(s)

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

Disclosure: Nothing to disclose.

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

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Aldeyra Therapeutics (Lexington, MA); Bausch & Lomb Surgical, Inc (Rancho Cucamonga, CA); Eyegate Pharma (Waltham, MA); Novartis (Cambridge, MA); pSivida (Watertown, MA); Xoma (Berkeley, CA); Allakos (Redwood City, CA)<br/>Serve(d) as a speaker or a member of a speakers bureau for: Alcon (Geneva, Switzerland); Allergan (Dublin, Ireland); Mallinckrodt (Staines-upon-Thames, United Kingdom)<br/>Received research grant from: Alcon; Aldeyra Therapeutics; Allakos Pharmaceuticals; Allergan; Bausch & Lomb; Clearside Biomedical; Dompé pharmaceutical; Eyegate Pharma; Mallinckrodt pharmaceuticals; Novartis; pSivida; Santen; Aciont.

Chief Editor

Andrew G Lee, MD, Chair, Department of Ophthalmology, Blanton Eye Institute, Houston Methodist Hospital; Clinical Professor, Associate Program Director, Department of Ophthalmology and Visual Sciences, University of Texas Medical Branch School of Medicine; Clinical Professor, Department of Surgery, Division of Head and Neck Surgery, University of Texas MD Anderson Cancer Center; Professor of Ophthalmology, Neurology, and Neurological Surgery, Weill Medical College of Cornell University; Clinical Associate Professor, University of Buffalo, State University of New York School of Medicine

Disclosure: Received ownership interest from Credential Protection for other.

Additional Contributors

Huy Nguyen, Clinical Researcher, Department of Ophthalmology, Baylor College of Medicine

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. Zhou D, Dai SM, Tong Q. COVID-19: a recommendation to examine the effect of hydroxychloroquine in preventing infection and progression. J Antimicrob Chemother. 2020 Mar 20. [View Abstract]
  2. Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, et al. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clin Infect Dis. 2020 Mar 9. [View Abstract]
  3. Devaux CA, Rolain JM, Colson P, Raoult D. New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19?. Int J Antimicrob Agents. 2020 Mar 11. 105938. [View Abstract]
  4. Information for Clinicians on Therapeutic Options for COVID-19 Patients. Centers for Disease Control and Prevention. Available at https://www.cdc.gov/coronavirus/2019-ncov/hcp/therapeutic-options.html. 2020 March 21; Accessed: 2020 March 22.
  5. Marmor MF, Kellner U, Lai TY, Melles RB, Mieler WF, American Academy of Ophthalmology. Recommendations on Screening for Chloroquine and Hydroxychloroquine Retinopathy (2016 Revision). Ophthalmology. 2016 Jun. 123 (6):1386-94. [View Abstract]
  6. Mason CG. Ocular accumulation and toxicity of certain systemically administered drugs. J Toxicol Environ Health. 1977 May. 2 (5):977-95. [View Abstract]
  7. BERNSTEIN H, ZVAIFLER N, RUBIN M, MANSOUR AM. THE OCULAR DEPOSITION OF CHLOROQUINE. Invest Ophthalmol. 1963 Aug. 2:384-92. [View Abstract]
  8. RUBIN M, BERNSTEIN HN, ZVAIFLER NJ. STUDIES ON THE PHARMACOLOGY OF CHLOROQUINE. RECOMMENDATIONS FOR THE TREATMENT OF CHLOROQUINE RETINOPATHY. Arch Ophthalmol. 1963 Oct. 70:474-81. [View Abstract]
  9. Yaylali SA, Sadigov F, Erbil H, Ekinci A, Akcakaya AA. Chloroquine and hydroxychloroquine retinopathy-related risk factors in a Turkish cohort. Int Ophthalmol. 2013 Dec. 33 (6):627-34. [View Abstract]
  10. Melles RB, Marmor MF. The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy. JAMA Ophthalmol. 2014 Dec. 132 (12):1453-60. [View Abstract]
  11. Marmor MF, Hu J. Effect of disease stage on progression of hydroxychloroquine retinopathy. JAMA Ophthalmol. 2014 Sep. 132 (9):1105-12. [View Abstract]
  12. Kellner S, Weinitz S, Farmand G, Kellner U. Cystoid macular oedema and epiretinal membrane formation during progression of chloroquine retinopathy after drug cessation. Br J Ophthalmol. 2014 Feb. 98 (2):200-6. [View Abstract]
  13. Percival SP, Behrman J. Ophthalmological safety of chloroquine. Br J Ophthalmol. 1969 Feb. 53 (2):101-9. [View Abstract]
  14. Costedoat-Chalumeau N, Dunogué B, Leroux G, Morel N, Jallouli M, Le Guern V, et al. A Critical Review of the Effects of Hydroxychloroquine and Chloroquine on the Eye. Clin Rev Allergy Immunol. 2015 Dec. 49 (3):317-26. [View Abstract]
  15. 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. [View Abstract]
  16. Ahn SJ, Joung J, Lim HW, Lee BR. Optical Coherence Tomography Protocols for Screening of Hydroxychloroquine Retinopathy in Asian Patients. Am J Ophthalmol. 2017 Sep 27. [View Abstract]
  17. Browning DJ. Hydroxychloroquine and chloroquine retinopathy: screening for drug toxicity. Am J Ophthalmol. 2002 May. 133 (5):649-56. [View Abstract]
  18. 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. [View Abstract]
  19. Angi M, Romano V, Valldeperas X, Romano F, Romano MR. Macular sensitivity changes for detection of chloroquine toxicity in asymptomatic patient. Int Ophthalmol. 2010 Apr. 30 (2):195-7. [View Abstract]
  20. Pasadhika S, Fishman GA. Effects of chronic exposure to hydroxychloroquine or chloroquine on inner retinal structures. Eye (Lond). 2010 Feb. 24 (2):340-6. [View Abstract]
  21. 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. [View Abstract]
  22. [Guideline] AAO Quality of Care Secretariat, Hoskins Center for Quality Eye Care. Recommendations on Screening for Chloroquine and Hydroxychloroquine Retinopathy - 2016. American Academy of Ophthalmology. Available at https://www.aao.org/clinical-statement/revised-recommendations-on-screening-chloroquine-h. March 2016; Accessed: March 11, 2019.

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.

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.

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.

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.