Factors Influencing Retinal Pigment Epithelium-Atrophy Progression Rate in Stargardt Disease

Abstract

Purpose: To evaluate demographic, clinical, imaging, and genetic factors associated with retinal pigment epithelium enlargement in Stargardt disease (STGD1) and to measure the agreement between short-wavelength fundus autofluorescence (SW-FAF) and near-infrared fundus autofluorescence (NIR-FAF).

Methods: Retrospective cohort study of patients with STGD1 with ≥2 gradable SW-FAF images. RPE-atrophy areas were measured on SW-FAF and NIR-FAF at each visit and regressed against time to obtain the rate of RPE-atrophy enlargement. Agreement between SW-FAF and NIR-FAF with regards to baseline atrophic areas and rates of enlargement was evaluated. Baseline factors predictive of faster SW-FAF RPE-atrophy enlargement were investigated with linear mixed models.

Results: Fifty-four eyes of 28 patients (median age: 45 years; 13 males) were included. SW-FAF and NIR-FAF agreed well for slow rates of RPE-atrophy progression, but agreement decreased as the rate increased. Median (interquartile range [IQR]) rate of RPE-atrophy expansion was 0.18 (0.10-0.85) mm²/year on SW-FAF and 0.24 (0.08-0.33) mm²/year on NIR-FAF. Larger baseline RPE-atrophy area (estimate: 0.057 mm²/year, P < 0.001), worse visual acuity (0.305 mm²/year, P = 0.005), multifocal disease (0.401 mm²/year, P = 0.02), and SW-FAF pattern (0.534 mm²/year, P =0 .03) were associated with a faster rate of progression (predictive R²: 0.65).

Conclusions: SW-FAF and NIR-FAF are not interchangeable in the evaluation of RPE-atrophy enlargement, and both imaging modalities may be required for optimal detection of disease progression. A multivariable model based on baseline clinical and imaging information may identify patients at higher risk of fast disease progression.

Translational relevance: The knowledge of the agreement of different FAF modalities, the estimated rates of RPE-atrophy enlargement, and factors predictive of faster anatomic decay in STGD1 may allow tailored clinical management and better clinical trials design.

Keywords: Stargardt disease; best-corrected visual acuity; disease progression; near-infrared autofluorescence; short-wavelength autofluorescence.

Figure 1.

Clinical pattern of STGD1 patients based on SW-FAF. Corresponding NIR-FAF and optical coherence tomography scan passing through the fovea are shown. Pattern 1: Altered speckled hypo-FAF signal at the posterior pole with hyper-FAF flecks at the posterior pole; background FAF is homogeneous. At the end of the follow-up, a small area of definitely decreased autofluorescence enlarges temporally to the fovea. Pattern 2: Altered round central hypo-FAF signal sparing of the fovea; background FAF is homogeneous. A hyper-FAF halo is present. At the end of the follow-up, the area of definitely decreased autofluorescence expands toward the fovea. Pattern 3: Multiple, diffuse hyper-FAF flecks involving the entire macular region and extending beyond the vascular arcades; background FAF is heterogeneous. After 2 years, the area of definitely decreased autofluorescence clearly enlarges and coalesces.

Figure 2.

Comparison between SW-FAF and NIR-FAF. (A) Bland-Altman plot comparing the matched methods in estimating baseline RPE-atrophy area. On the x-axis the mean atrophic area is presented. The 0-horizontal line represents the no-bias line (mean difference = 0), whereas black spots describe the true corresponding measurement among coupled devices. The 95% LOAs are shown as dotted lines. The 95% confidence intervals of the no-bias line (purple), superior (green) and inferior LOA (pink) are shown. The graph shows that baseline area estimated on SW-FAF was smaller than NIR-FAF. (B) Bland-Altman plot comparing the matched methods in estimating the rate of RPE-atrophy enlargement. On the x-axis the mean rate of progression is presented. The 95% confidence intervals of the no-bias line (purple), superior (green) and inferior LOA (pink) are shown. Most of the values clustered around the no-bias line. Limits of agreement were wide; the distribution of biases showed a positive trend for disease rates >0.2 mm²/year. One observation fell outside the 95% confidence bands of the LOA.