Adaptive Optics Scanning Laser Ophthalmoscopy in Stargardt Disease Reveals Decreased Cone and Rod Densities

Abstract

Purpose: Stargardt disease (SD) is defined clinically by its ophthalmoscopic features including atrophy and lipofuscin deposition in the retinal pigment epithelium (RPE). The causative ABCA4 gene encodes a protein uniquely expressed in the cone and rod outer segments. The pathologic steps by which mutations in ABCA4 lead to the clinically detectable RPE changes remain unclear. We investigated whether photoreceptor changes precede RPE loss in SD using adaptive optics scanning laser ophthalmoscopy (AOSLO).

Methods: Two brothers with SD, aged 8 and 17 years, underwent a comprehensive eye examination and conventional imaging including fundus photography and optical coherence tomography (OCT). Genetic testing was performed using a combination of allele-specific testing and sequencing of the ABCA4 gene. AOSLO images were obtained at the central fovea and along the inferior and temporal meridians to generate 10x1.5 degree montages. The center of the foveal avascular zone was used as the foveal center. Cones were counted using custom semi-automated cone marking software. Peripheral cones and rods were counted at 100 µm intervals in 100x100 µm and 50x50 µm windows respectively. At the foveal center, cones were counted in a 50x50 µm window.

Results: Genetic testing showed the presence of three likely disease-causing mutations: Gly863Ala, Gly1961Glu, and Arg2030Stop. The older brother had visual acuity 20/150 with a central scotoma and macular RPE atrophy with no peripheral flecks. His brother had visual acuity 20/30 with subtle RPE stippling in the macula. In both brothers, OCT confirmed central retinal thinning. AOSLO revealed that rod density was decreased to ~30% of normal in the peripheral macula; these areas appeared normal by ophthalmoscopy and OCT. Cones in the peripheral macula showed a dark, low reflective appearance with density 30% of normal. No cones were detectable in the foveal center of the older brother. In the younger brother, foveal cones were enlarged with low density.

Conclusions: This study provides the first in vivo images of both rods and cones in SD. Although the primary clinical features of SD are changes in the RPE, AOSLO reveals decreased density of both cones and rods in areas that appear normal by conventional imaging methods. These findings suggest that loss of cone and rod photoreceptors precedes clinically detectable RPE disease in SD.

Keywords: 550 imaging/image analysis: clinical • 648 photoreceptors • 696 retinal degenerations: hereditary