Fundus Flecks in Recessive Stargardt Disease: Understanding the Source of the Autofluorescence

Abstract

Purpose: Fundus flecks in recessive Stargardt disease (STGD1), exhibit increased short-wavelength autofluorescence (SW-AF). We evaluated the apparently incongruous situation whereby flecks in STGD1 exhibit increased SW-AF that is considered to originate from RPE lipofuscin, while near infrared AF (NIR-AF), emitted primarily from RPE melanin, is reduced or absent at fleck positions. NIR-AF and SW-AF patterns and structural integrity in spectral domain optical coherence tomography (SD-OCT) scans, were evaluated.

Methods: We studied 19 STGD1 patients (age 9-54) carrying one or two (expected) disease-causing ABCA4 mutations as determined by direct sequencing. All patients presented with macular and extramacular flecks. SW-AF and NIR-AF images and spectral domain optical coherence tomography (SD-OCT) scans were obtained with the Spectralis and/or HRA2 confocal scanning laser ophthalmoscope.

Results: Flecks observed in SW-AF images typically co-localized with darkened foci in NIR-AF images; the NIR-AF profiles were larger. With serial AF imaging, the decreased NIR-AF signal from flecks could precede apparent changes in SW-AF. Flecks identified in SW-AF images corresponded to hyperreflective deposits traversing photoreceptor-attributable SD-OCT bands. The hyperreflectivity could be limited to the interdigitation zone (Staurenghi et al., Ophthalmology, 2014) or could progressively extend through the ellipsoid zone (EZ) and external limiting membrane (ELM) and impinge on the band attributable to the outer nuclear layer (ONL). The hyperreflective deposits corresponding to flecks did not displace outer retinal layers. Rather, the EZ and/or ELM bands were interrupted at the fleck while being continuous on either side of the fleck. Thinning of ONL at positions of flecks increased with their outer to inner expansion. When exhibiting SW-AF fading, flecks were less reflective in SD-OCT images.

Conclusions: The SD-OCT findings are indicative of photoreceptor cell degeneration. Given that in NIR-AF images, flecks are predominantly hypofluorescent and larger and NIR-AF darkening occurs prior to heightened SW-AF signal, it appears that RPE cells associated with flecks in STGD1 are atrophied or lost. The concurrent brightness of the SW-AF signal likely originates from increased bisretinoid lipofuscin formation in degenerating photoreceptor cell outer segments impaired by the failure of RPE.