What are the effects of Hydroxychloroquine (HCQ) on the eyes?

Hydroxychloroquine Ocular Effects

Hydroxychloroquine causes irreversible retinal toxicity that primarily damages photoreceptors in a dose-dependent manner, with an overall prevalence of 7.5% in long-term users, and this retinopathy can progress even after drug discontinuation, making regular screening essential to prevent permanent vision loss. 1

Primary Retinal Toxicity

Mechanism and Pathophysiology

• The primary damage targets photoreceptors, with secondary disruption of the retinal pigment epithelium (RPE) as the outer nuclear layer degenerates. 1
• The classic "bull's-eye maculopathy" pattern should no longer be seen with proper screening, as modern imaging detects toxicity long before RPE damage becomes visible on fundus examination. 1
• Retinopathy can progress even after stopping the drug, likely representing gradual decompensation of cells injured metabolically during drug exposure, though clearance takes many months. 1

Racial and Ethnic Variations

• European descent patients show initial photoreceptor damage in the classic parafoveal distribution. 1
• Asian descent patients predominantly show initial damage in a more peripheral extramacular distribution near the vascular arcades. 1
• African-Americans and Hispanics show predominantly parafoveal patterns similar to Europeans, but with possibly greater tendency toward extramacular involvement. 1

Clinical Presentation and Progression

Early Stage Findings

• Most patients developing HCQ toxicity have no visual symptoms at all, with visual acuity remaining excellent until severe stages. 1
• A few perceptive patients may notice paracentral scotomas while reading. 1
• Early detection shows subtle OCT abnormalities including attenuation of the parafoveal ellipsoid zone and loss of clear continuous interdigitation zone, which may precede visual field defects. 2

Advanced Stage Complications

• If drug exposure continues, the area of functional disturbance expands, the RPE becomes involved, and maculopathy can encroach on the foveal center with eventual loss of visual acuity. 1
• Cystoid macular edema may develop, and advanced cases show widespread RPE and retinal atrophy with loss of visual acuity, peripheral vision, and night vision. 1
• When retinopathy is not recognized until a bull's-eye appears, the disease can progress for years, often with foveal thinning and eventual loss of visual acuity. 1

Corneal Effects (Reversible)

• Chloroquine, and less frequently HCQ, can cause whorl-like intraepithelial deposits (verticillata) in the cornea. 1
• These corneal changes are NOT a direct marker for retinal damage, are NOT associated with visual loss, and in contrast to retinopathy are usually reversible. 1

Risk Factors and Prevalence

Dose-Dependent Risk

• The overall prevalence of toxicity is 7.5% in patients using HCQ for more than 5 years, though this varies greatly with daily dose and duration. 1
• Daily dose is the most critical determinant of risk, more closely correlated with real weight than ideal weight. 1
• Patients using 4.0-5.0 mg/kg real weight have less than 1% risk in the first 5 years and less than 2% up to 10 years. 1
• Risk increases sharply to approximately 20% after 20 years of use. 1

Major Risk Factors

• High daily dosage relative to body weight (>5.0 mg/kg real weight) dramatically increases both population risk and annual incremental risk. 1
• Renal disease is the greatest additional risk factor, as reduced renal function increases systemic HCQ levels and risk of toxicity. 1
• Concomitant tamoxifen use increases the risk of retinopathy, as tamoxifen itself can be retinotoxic. 1
• High myopia has been associated with increased risk of HCQ retinopathy. 3
• Pre-existing retinal or macular disease may increase risk and interfere with screening test interpretation. 1

Screening Recommendations

Baseline Examination

• A baseline retinal examination should be performed within the first few months of HCQ usage to rule out underlying retinal disease that might compromise retinal function or complicate recognition of retinopathy. 1
• Automated visual fields and SD-OCT should be included during baseline exam in patients with pre-existing macular conditions. 4

Ongoing Screening Schedule

• If no special risk factors exist, screening for retinopathy may be deferred for 5 years after baseline, but thereafter should be performed annually. 1
• Screening should begin sooner if risk is high (high daily dose, kidney disease, or concurrent tamoxifen usage). 1
• For a patient with a normal screening examination in a given year, the risk of developing retinopathy in the ensuing year is low (<5%), even after 20 years of use. 1

Screening Modalities

• The mainstays of early detection are optical coherence tomography (OCT) and automated visual fields. 1
• OCT generates high-resolution cross-sections showing individual retinal layers and potential regions of thinning. 1
• Visual fields should typically focus on the central 10 degrees (10-2 pattern) to detect parafoveal changes. 1
• Fundus autofluorescence (FAF) and multifocal electroretinogram (mfERG) have also been shown to be useful adjunctive tests. 4
• It is critical that screening be performed by practitioners experienced with interpretation of these techniques. 1

Dosage Recommendations

• All patients using HCQ should keep daily dosage <5.0 mg/kg real weight. 1
• Very thin patients are at increased risk when dose is calculated by ideal weight rather than real weight. 1
• There may be rare instances when higher doses are needed to manage life-threatening disease, but this requires careful risk-benefit discussion. 1
• Patients with renal insufficiency may need lower doses and closer monitoring, as the drug is primarily eliminated through the renal route. 1, 5

Critical Clinical Pitfalls

• Do not wait for visible fundus changes or bull's-eye lesions – these represent advanced, irreversible damage that should no longer occur with proper screening. 1
• Do not assume corneal deposits (verticillata) indicate retinal toxicity – these are not correlated and are reversible. 1
• Do not calculate dose based on ideal body weight – real weight is more accurate for risk assessment, particularly in very thin patients. 1
• Do not screen only the central macula in Asian patients – they require testing that reaches beyond the central macula to detect pericentral arcade involvement. 1
• Do not rely solely on visual field testing – OCT abnormalities may precede functional visual field defects in early toxicity. 2
• Toxicity can develop even with "standard" dosing after prolonged use, so there is no truly "safe" dosage for indefinite duration. 1

Patient Counseling (FDA Label Requirements)

• Inform patients that irreversible retinal damage has been observed with hydroxychloroquine use. 6
• Advise patients of the importance of ophthalmology visits for monitoring their eyes. 6
• Instruct patients to seek medical attention promptly if they experience decreased vision or decreased dark adaptation. 6