What are the ocular side effects of hydroxychloroquine and the recommended screening and management?

Ocular Side Effects of Hydroxychloroquine

Primary Ocular Toxicity: Irreversible Retinopathy

Hydroxychloroquine causes irreversible, dose-dependent retinal toxicity that primarily damages photoreceptors and can progress even after drug discontinuation, affecting 7.5% of long-term users overall but rising to approximately 20% after 20 years of use. 1, 2

The retinopathy is not reversible, and cellular damage may continue progressing for years after stopping the medication, particularly when not detected early. 3 When recognized before retinal pigment epithelium (RPE) damage occurs, there is only mild and limited progression after discontinuation, and the fovea is typically preserved. 3 However, once a bull's-eye maculopathy appears, the disease can progress for years with foveal thinning and eventual loss of visual acuity. 3

Mechanism and Progression

• The primary damage targets photoreceptors, with secondary disruption of the RPE as the outer nuclear layer degenerates. 1
• Most patients developing toxicity have no visual symptoms at all, with visual acuity remaining excellent until severe stages. 1
• 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
• Advanced cases show widespread RPE and retinal atrophy with loss of visual acuity, peripheral vision, and night vision. 1

Racial and Ethnic Variations in Presentation

• European descent patients show initial photoreceptor damage in the classic parafoveal distribution (the typical "bull's-eye" pattern). 1
• Asian descent patients predominantly show initial damage in a more peripheral extramacular distribution near the vascular arcades, requiring different screening approaches. 1, 4

Corneal Effects (Benign and Reversible)

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

Other Ocular Effects

• Cystoid macular edema may develop in some cases. 1
• Lens opacities and ciliary body involvement have been reported but are less common. 5

Risk Factors for Retinopathy

Major Risk Factors

Daily dose is the most critical determinant of risk, more closely correlated with real weight than ideal weight. 1

• Dosage >5.0 mg/kg real body weight dramatically increases both population risk and annual incremental risk. 3
• Extreme doses (800-1000 mg/day or up to 20 mg/kg) can be exceedingly dangerous, showing 25-40% incidence of retinopathy with signs of damage within 1-2 years. 3
• Duration of use: Risk remains <2% within the first 10 years at doses of 4.0-5.0 mg/kg, but rises to almost 20% after 20 years. 2

Renal disease effectively increases circulating drug levels since hydroxychloroquine is cleared largely by the kidney, creating unpredictably high blood drug levels. 3, 6

Concomitant tamoxifen use significantly increases risk (odds ratio 4.59). 2

Pre-existing macular disease may increase risk and can interfere with interpretation of screening procedures. 3

Lesser Risk Factors

• Age: No significant association between age and risk of toxicity has been demonstrated. 3
• Liver disease: No clear association with toxicity has been demonstrated despite hepatic metabolism. 3

Screening Recommendations

Baseline Examination

A baseline retinal examination should be performed within the first year of hydroxychloroquine usage to rule out underlying retinal disease that might compromise retinal function or complicate recognition of retinopathy. 1, 6

The baseline exam should include:

• Best corrected distance visual acuity (BCVA) 6
• Automated threshold visual field of the central 10 degrees (with retesting if abnormality noted) 6
• Spectral-domain optical coherence tomography (SD-OCT) 6
• Fundus examination 3

Annual Screening Timing

If no special risk factors exist, screening for retinopathy may be deferred for 5 years after baseline, but thereafter should be performed annually. 1, 3

• Screening should begin sooner if major risk factors are present (high dose, renal disease, tamoxifen use, pre-existing macular disease). 3
• More frequent screening may be considered for patients with major risk factors. 3

Recommended Screening Tests

The primary screening modalities are automated visual fields and spectral-domain OCT, with fundus autofluorescence and multifocal ERG as useful adjuncts. 7

Spectral-Domain OCT Findings

• Look for localized parafoveal thinning of the photoreceptor layers and focal interruption of the ellipsoid zone, as these are the most specific early anatomic markers in patients of European descent. 4
• Focal interruption or loss of the ellipsoid zone in the parafoveal region is often the earliest detectable structural change. 4
• For Asian patients, use wider scanning protocols (30° line scans) as toxicity often manifests peripherally near the arcades rather than parafoveally. 4

Visual Field Testing

• Automated threshold visual fields of the central 10 degrees for non-Asian patients 6
• For Asian patients, visual field testing should be performed in the central 24 degrees instead of the central 10 degrees 6

What NOT to Use for Screening

• Time-domain OCT lacks sufficient resolution to detect early toxic changes and should not be used. 4
• Fundus examination and ophthalmoscopy detect only late-stage disease and should not be relied upon for screening. 4
• Normal visual acuity is maintained until severe stages, so it cannot be used to rule out toxicity. 4

Dosage Recommendations

All patients using hydroxychloroquine should keep daily dosage <5.0 mg/kg real body weight. 1, 6

• Dosing should be based on real body weight, not ideal body weight, as real weight predicts risk better. 2
• Patients with renal insufficiency may need lower doses and closer monitoring. 1
• Check the dosage relative to weight at every visit. 3

Management of Detected Toxicity

If ocular toxicity is suspected, discontinue hydroxychloroquine immediately and monitor the patient closely, as retinal changes and visual disturbances may progress even after cessation of therapy. 6

• When retinopathy is recognized early before RPE damage, there is only mild and limited progression after discontinuing medication (approximately 4 μm/year of foveal thinning). 4
• Verify suspicious findings with more than one test or by repeat testing before making definitive recommendations. 3
• Coordinate decisions with the rheumatologist or physician managing the underlying condition. 5

Important Clinical Pitfalls

• Do not confuse corneal deposits with retinal toxicity—corneal verticillata are benign, reversible, and do not predict retinal damage. 1
• Do not rely on visual acuity or fundus appearance for screening—patients maintain excellent vision until severe stages, and fundoscopic changes appear late. 1, 4
• Do not use ideal body weight for dosing calculations—real body weight correlates better with toxicity risk. 2
• Do not use standard central protocols for Asian patients—broader scanning patterns are needed as toxicity manifests peripherally. 4
• Do not assume safety based on cumulative dose alone—the combination of daily dose and duration determines risk more accurately. 3, 2