Longitudinal Ellipsoid Zone Dynamics During Hydroxychloroquine Use

Background/Objectives: Hydroxychloroquine (HCQ) retinopathy can be underrecognized early, as structural changes in OCT may precede symptoms and are often subtle. Early detection is crucial to prevent irreversible damage. This study evaluated longitudinal OCT changes preceding overt HCQ toxicity using ellipsoid zone (EZ) mapping. Methods: Patients on long-term HCQ underwent two macular cube scans at least one year apart using Cirrus HD-OCT. Scans were analyzed with an EZ-mapping platform and manually validated. Patients with baseline OCT signs of toxicity or co-existing macular disease were excluded based on masked expert review. Results: Three hundred and seventy-three eyes of 373 patients were included. The mean age was 57.0 ± 12.6 years, the mean HCQ dose was 379.4 ± 59.4 mg, the treatment duration was 5.6 ± 3.7 years, and the OCT interval was 3.1 ± 0.9 years. Outer retinal metrics remained stable across the cohort. The mean en face EZ attenuation increased from 3.3% to 3.9% (p = 0.24). Thirty-four eyes (9.1%) experienced an absolute increase of ≥4% (~1.5 mm²) in EZ attenuation. This increase was significantly associated with age at HCQ initiation (p < 0.001), age at the time of the first and second OCT (p < 0.001), and baseline visual acuity (p = 0.01), and demonstrated changes in other outer retinal metrics (p < 0.01). Only 3/34 eyes (8.9%) were diagnosed by the managing clinician with HCQ toxicity at the time of the second OCT. However, 26 of these eyes (76.5%) had signs of HCQ toxicity by expert review, suggesting the overall greater sensitivity of these quantitative outer retinal metrics for detecting toxicity compared with clinician review. Conclusions: Longitudinal OCT assessment revealed overall stability in outer retinal metrics in eyes on HCQ, but a subset showed increased EZ attenuation, which correlated with age at the time of HCQ initiation, baseline visual acuity, and expert OCT review. These changes may help identify at-risk eyes and eyes with early toxicity and warrant further validation as potential screening biomarkers.