Assessing Cone Structure in Achromatopsia With AOSLO and SDOCT

Abstract

Purpose : With gene therapy trials for achromatopsia (ACHM) imminent, it is important to quantify residual cone structure in these retinas. We examined the relationship between foveal cone density as assessed by adaptive optics scanning light ophthalmoscopy (AOSLO) and measurements of photoreceptor structure made with spectral-domain optical coherence tomography (SDOCT) in patients with ACHM.

Methods : Fifty-one subjects with CNGB3-associated ACHM were recruited (mean 22.8 yrs, range = 6-55 yrs). Images were acquired with SDOCT as well as confocal and split-detector AOSLO. Peak cone density was measured by manually marking all cones in the rod-free region of the fovea and sampling these coordinates with a moving 55x55μm window. OCT phenotype was graded on a scale from 1-4 based on integrity of the second hyper-reflective outer retinal band; outer nuclear layer (ONL) thickness was measured using longitudinal reflectivity profiles through the foveola (ONL thickness = distance from the inner boundary of the ONL to the external limiting membrane).

Results : Measureable AOSLO images were obtained for 27 subjects (53%), while OCT grade and ONL thickness were obtained for all 51 subjects. OCT grades 1-4 were assigned to 18, 13, 17 and 3 subjects respectively. The grade 4 subjects were significantly older (mean 38.7 yrs) than the grade 1 subjects (mean 16.4 yrs); there were no other relationships between age and OCT grade. ONL thickness ranged from 47.4-122.3μm (mean = 74.1μm) in grades 1-3, showing no trend with grade or age (The ONL was absent in grade 4 retinas). The OCT grade 1 group had a mean peak density of 39,471 cones/mm² (range = 27,107-53,554), the grade 2 group a mean of 24,463 cones/mm² (range = 12,231-44,958), and the grade 3 group a mean of 14,105 cones/mm² (range = 7,273-26,777). There was a difference only between grade 1 and 3 (p<0.01). No relationship between peak cone density and either age or ONL thickness was observed.

Conclusions : All subjects with grade 1, 2 and 3 retinas had remnant foveal cone inner segment structure, demonstrating at least the anatomical potential to benefit from gene therapy. The significant overlap in the degree of residual cone inner segment structure between subjects with different OCT grades suggests it may not be possible to estimate the “therapeutic potential” of a given ACHM retina using OCT imagery alone.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

 

An example of low and high foveal cone density in ACHM. Scale bars = 100μm (AO)