Longitudinal Ellipsoid Zone Dynamics During Hydroxychloroquine Use

Abstract

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.

Keywords: automated feature segmentation; ellipsoid zone integrity; hydroxychloroquine retinopathy; optical coherence tomography.

Figure 1

Ellipsoid zone (EZ) mapping and horizontal OCT B-scan image of hydroxychloroquine eye as an illustrative example of mapping and measurements. (A) EZ–retinal pigment epithelium (RPE) en face topographical map. The red line indicates the location of the horizontal B-scan. (B) Macular map sector with an inner circle representing the macular radius of 0.5 mm (corresponds to ‘central subfield’) and an outer circle representing the macular radius of 1.0 mm (corresponds to ‘parafoveal’). (C) Horizontal B-scan crossing the central fovea displaying semi-automatically segmented retinal layer boundaries. Each boundary was reviewed, and segmentation errors were manually corrected. The outer boundaries of the internal limiting membrane (a, blue), outer plexiform layer (b, green), EZ band (c, yellow), and RPE (d, orange). For retinal thickness measurement, three orange lines parallel to the vertical axis of the B-scan image are illustrated at the fovea, 1.0 mm nasal and temporal to the fovea. Orange figures indicate retinal thickness between the neighboring boundaries at each location.

Figure 2

Case example of longitudinal stability while on hydroxychloroquine (HCQ). A 47-year-old woman on HCQ, where daily dosing based on actual body weight was 5.56 mg/kg/day, for 12 years at the time of the first OCT (A,B) and 14 years at the time of the second OCT (C,D). There were no significant changes in ellipsoid zone (EZ)–retinal pigment epithelium (RPE) mapping (A,C) or horizontal B-scan images (B,D). The outer boundaries of the internal limiting membrane (blue), outer plexiform layer (green), EZ band (yellow), and RPE (orange) (B,D).

Figure 3

Case example of progressive en face ellipsoid zone (EZ) attenuation while on hydroxychloroquine (HCQ). A 70-year-old woman on HCQ. The daily dosing based on actual body weight was 5.22 mg/kg/day for 1 year at the time of the first OCT (A,B) and 6 years at the time of the second OCT (C,D). There were subtle areas of partial parafoveal ellipsoid zone (EZ)–retinal pigment epithelium (RPE) attenuation in the EZ-RPE mapping (A) and in the first OCT (B). These areas increased in size and became more confluent with progression to areas of total EZ-RPE attenuation in the EZ-RPE mapping (C) and in the second OCT (D). Subtle EZ attenuation may have been present in OCT at the first OCT (B) but became more apparent by the second OCT (D). The outer boundaries of the internal limiting membrane (blue), outer plexiform layer (green), EZ band (yellow), and RPE (orange) (B,D).