Multimodal in-vivo maps as a tool to characterize retinal structural biomarkers for progression in adult-onset Stargardt disease

Abstract

Purpose: To characterize retinal structural biomarkers for progression in adult-onset Stargardt disease from multimodal retinal imaging in-vivo maps.

Methods: Seven adult patients (29-69 years; 3 males) with genetically-confirmed and clinically diagnosed adult-onset Stargardt disease and age-matched healthy controls were imaged with confocal and non-confocal Adaptive Optics Scanning Light Ophthalmoscopy (AOSLO), optical coherence tomography (OCT), fundus infrared (FIR), short wavelength-autofluorescence (FAF) and color fundus photography (CFP). Images from each modality were scaled for differences in lateral magnification before montages of AOSLO images were aligned with en-face FIR, FAF and OCT scans to explore changes in retinal structure across imaging modalities. Photoreceptors, retinal pigment epithelium (RPE) cells, flecks, and other retinal alterations in macular regions were identified, delineated, and correlated across imaging modalities. Retinal layer-thicknesses were extracted from segmented OCT images in areas of normal appearance on clinical imaging and intact outer retinal structure on OCT. Eccentricity dependency in cell density was compared with retinal thickness and outer retinal layer thickness, evaluated across patients, and compared with data from healthy controls.

Results: In patients with Stargardt disease, alterations in retinal structure were visible in different image modalities depending on layer location and structural properties. The patients had highly variable foveal structure, associated with equally variable visual acuity (-0.02 to 0.98 logMAR). Cone and rod photoreceptors, as well as RPE-like structures in some areas, could be quantified on non-confocal split-detection AOSLO images. RPE cells were also visible on dark field AOSLO images close to the foveal center. Hypo-reflective gaps of non-waveguiding cones (dark cones) were seen on confocal AOSLO in regions with clinically normal CFP, FIR, FAF and OCT appearance and an intact cone inner segment mosaic in three patients.

Conclusion: Dark cones were identified as a possible first sign of retinal disease progression in adult-onset Stargardt disease as these are observed in retinal locations with otherwise normal appearance and outer retinal thickness. This corroborates a previous report where dark cones were proposed as a first sign of progression in childhood-onset Stargardt disease. This also supports the hypothesis that, in Stargardt disease, photoreceptor degeneration occurs before RPE cell death.

Keywords: ABCA4; STGD1; Stargardt disease; adaptive optics; adult-onset; multi-modal imaging; photoreceptors; retina.

Figure 1

Kongsberg AOSLO Analysis user interface. The center of the green cross mark the corresponding locations on each of the image modalities. The green square marked on the AOSLO image montage show the location of the displayed confocal, non-confocal (calculated) and darkfield image. The filled yellow square on the AOSLO image montage marks the 100x100 µm region (yellow dotted squares) where reflective cones, cone inner segments and RPE cells are marked.

Figure 2

Multimodal imaging of a 52-year-old female with adult-onset STGD1 (Patient nr. 4). Intact outer retinal layers, referred to as foveal sparing, seen on OCT scan (C) of the foveal center corresponds to an area of residual cone inner-segment mosaic seen in the non-confocal split-detection image of the fovea (E). Cone reflectance is irregular in the confocal image (D). The RPE cell mosaic can be seen in the dark-field image (F). The yellow solid line in (A) marks the OCT scan position (C). The location marked by yellow boxes in (A) and (B) and yellow dotted lines in (C) corresponds to the AOSLO image location in (D–F). The foveal center is marked with an asterisk.

Figure 3

Cone density as a function of distance from the foveal center in regions with non-waveguiding cones in STGD1 patients. The round dots and error bars show the normal mean ± 2SD at the corresponding locations along the superior (dark blue), nasal (purple) or temporal (blue) meridian.

Figure 4

Multimodal imaging of a 29-year-old male with STGD1 (Patient nr. 2) showing regions of dark cones seen on confocal AOSLO (D) in areas with normal fundus infrared (A), autofluorescence (B) and OCT (C) appearance. An intact cone inner segment mosaic can be seen in the corresponding non-confocal split-detection image (E), although the cone density was lower than normal. The yellow solid line in (A) marks the OCT scan position (C). The location marked by yellow boxes in (A) and (B) and yellow dotted lines in (C) corresponds to the AOSLO image location in (D) and (E). The foveal center is marked with an asterisk.

Figure 5

Multimodal imaging of a 52-year-old female with STGD1 (Patient nr. 4) showing regions of dark cones seen on confocal AOSLO (D) in areas with normal fundus infrared (A), autofluorescence (B) and OCT (C) appearance. An intact cone inner segment mosaic can be seen in the corresponding non-confocal split-detection image (E), although the cone density was lower than normal. The yellow solid line in (A) marks the OCT scan position (C). The location marked by yellow boxes in (A) and (B) and yellow dotted lines in (C) corresponds to the AOSLO image location in (D) and (E).

Figure 6

Multimodal imaging of an area near the transition zone between the atrophic and non-atrophic retina region (≈5 degrees temporal of the foveal center, (A–E)]. A small mosaic of polygonal structures, hypothesized to be RPE cells, is seen on the non-confocal split-detection image (E). The corresponding location on the autofluorescence image shows a hyperreflective area (B), whereas hyperreflectivity/thickening at the level of RPE-photoreceptor complex can be seen on OCT (C). The RPE-like structures appear hyperreflective with darker edges on confocal reflectance (D) and dark field (F) images. The location imaged in (D–F) is indicated by yellow boxes in (A) and (B) and by yellow dotted lines in (C).