Longitudinal study of cone photoreceptors during retinal degeneration and in response to ciliary neurotrophic factor treatment

Abstract

Purpose: To study cone photoreceptor structure and function in patients with inherited retinal degenerations treated with sustained-release ciliary neurotrophic factor (CNTF).

Methods: Two patients with retinitis pigmentosa and one with Usher syndrome type 2 who participated in a phase 2 clinical trial received CNTF delivered by an encapsulated cell technology implant in one eye and sham surgery in the contralateral eye. Patients were followed longitudinally over 30 to 35 months. Adaptive optics scanning laser ophthalmoscopy (AOSLO) provided high-resolution images at baseline and at 3, 6, 12, 18, and 24 months. AOSLO measures of cone spacing and density and optical coherence tomography measures of retinal thickness were correlated with visual function, including visual acuity (VA), visual field sensitivity, and full-field electroretinography (ERG).

Results: No significant changes in VA, visual field sensitivity, or ERG responses were observed in either eye of the three patients over 24 months. Outer retinal layers were significantly thicker in CNTF-treated eyes than in sham-treated eyes (P < 0.005). Cone spacing increased by 2.9% more per year in sham-treated eyes than in CNTF-treated eyes (P < 0.001, linear mixed model), and cone density decreased by 9.1%, or 223 cones/degree(2) more per year in sham-treated than in CNTF-treated eyes (P = 0.002, linear mixed model).

Conclusions: AOSLO images provided a sensitive measure of disease progression and treatment response in patients with inherited retinal degenerations. Larger studies of cone structure using high-resolution imaging techniques are urgently needed to evaluate the effect of CNTF treatment in patients with inherited retinal degenerations.

Trial registration: ClinicalTrials.gov NCT00447980.

Figures

Figure 1.

Retinal and AOSLO images. For each patient, fundus photographs are shown with AOSLO images and foveal horizontal spectral-domain optical coherence tomography (OCT) scans superimposed (horizontal lines: OCT scan location; white squares on AOSLO images: ROIs where cone spacing was analyzed in each AOSLO image over 30 months; yellow squares: retinal locations of density examples shown in Fig. 2). (A) Sham-treated and CNTF-treated eyes of patient 1. (B) Sham-treated and CNTF-treated eyes of patient 2. Bilateral epiretinal membranes on OCT images. (C) CNTF-treated and sham-treated eyes of patient 3. No AOSLO images were acquired in the sham-treated eye of patient 3 because of severe cystoid macular edema and vitreous opacities (arrow points to opacity obscuring retinal detail).

Figure 2.

Cone photoreceptor density using AOSLO. Examples of paired AOSLO images at baseline and post-treatment in patient 1 sham (A) and CNTF-treated (B), patient 2 sham (C) and CNTF-treated (D), and patient 3 CNTF-treated (F) eyes in which cone density measurements were made (yellow squares, Fig. 1). Red dots: cones identified for density analysis. (E) Cone density over time in sham (red, n = 9) and CNTF-treated (blue) eyes (n = 12). Solid lines: patient 1; long dashed line: patient 2; short dashed lines: patient 3; gray bar: measurement error (±6.3%).

Figure 3.

Cone photoreceptor tracking using AOSLO. (A) Individual cones (red crosses) are visible within a mosaic in a normal subject at baseline (top) and 53 months later (bottom). Yellow circles: cones (8/1906 or 0.4%) that were not seen 53 months later. (B) Individual cones are visible within a mosaic in the CNTF-treated eye of patient 3 at baseline (top), 20 months (middle), and 32 months (bottom) and show no loss over 32 months.