Adaptive optics imaging of inherited retinal diseases

Abstract

Adaptive optics (AO) ophthalmoscopy allows for non-invasive retinal phenotyping on a microscopic scale, thereby helping to improve our understanding of retinal diseases. An increasing number of natural history studies and ongoing/planned interventional clinical trials exploit AO ophthalmoscopy both for participant selection, stratification and monitoring treatment safety and efficacy. In this review, we briefly discuss the evolution of AO ophthalmoscopy, recent developments and its application to a broad range of inherited retinal diseases, including Stargardt disease, retinitis pigmentosa and achromatopsia. Finally, we describe the impact of this in vivo microscopic imaging on our understanding of disease pathogenesis, clinical trial design and outcome metrics, while recognising the limitation of the small cohorts reported to date.

Keywords: genetics; imaging; retina; vision.

Figure 1

Adaptive optics scanning laser ophthalmoscopy (AOSLO) imaging of a healthy subject and cone quantification. (A) Colour fundus photograph (30°) of a healthy subject (MM_0136), with AOSLO montage superimposed. The white square encompasses the foveal avascular zone (region of interest, ROI), which is magnified in (B). (B) Confocal AOSLO of the ROI, the estimated foveal centre is marked with a white cross and the 55 μm×55 μm area of sampling for cone counting with a white box at 0.35° from the foveal centre. Scale bar=100 μm. (C) Magnified view of the sampled area. (D) The sampled area with cones marked. (E) The sampled area with Voronoi domains. (F) The Voronoi representation coloured according to the number of neighbouring cells. Green represents six-sided bound cones. Scale bar for (C–F)=20 μm.

Figure 2

Adaptive optics scanning laser ophthalmoscopy (AOSLO) imaging of the cone dysfunction syndromes. Column (A) shows the infrared reflectance (IR) fundus photographs for each subject (1, 2, 3, 4). The green arrow represents the section in which the optical coherence tomography (OCT) (Spectralis HRA+OCT, Heidelberg Engineering, Heidelberg, Germany) presented in column (B) is taken; the black square represents the 450 μm×300 μm region of interest imaged with AOSLO which is presented in columns (C) and (D). Column (B) shows OCT horizontal scans through the fovea and the white arrows mark the corresponding AOSLO area (450 μm wide). Column (C) depicts confocal AOSLO (cAOSLO) and column (D) split detection (SD) AOSLO. Subjects (1) and (2) have achromatopsia associated with CNGB3 and CNGA3 gene mutations, respectively. (1C/2C) Dark spaces are observed, due to loss of cone waveguiding properties, which correspond to visible foveal cone inner segments in (1D/2D), respectively, with a substantial difference in cone numerosity between the two subjects. (3) A molecularly confirmed subject with blue cone monochromacy. (3C) Dark foveal centre, with a sparse array of large bright spots, which are believed to be S cones, immediately surrounding it. (3D) Remnant inner segment structure. (4) A molecularly confirmed subject with Bornholm eye disease (LIAVA haplotype). (4C) All cones are resolved in cAOSLO, with a few apparent non-waveguiding cones (dark spaces). (4D) SD-AOSLO does not resolve foveal inner segments due to the better preserved mosaic (smaller cone diameters and tighter packing geometry) compared with the other cone dysfunction syndromes. All AOSLO images were acquired using a custom-built AOSLO housed at University College London/Moorfields Eye Hospital, London. Scale bar=50 μm.

Figure 3

Multimodal imaging of retinitis pigmentosa. (A) Infrared reflectance (IR) fundus photograph of a subject (MM_0205) with X-linked retinitis pigmentosa associated with RPGR gene. The white arrow represents the section of the optical coherence tomography (OCT) presented in (B). (B) Horizontal transfoveal OCT line scan, with the white arrows indicating the width of the corresponding AOSLO imaged area in (D). (C) Fundus autofluorescence imaging, with the confocal AOSLO (cAOSLO) imaged area (D) superimposed over the foveal avascular zone and the white arrow represents the section presented in the OCT scan (B). (D) cAOSLO imaging revealing a disrupted waveguiding mosaic, not as uniform in appearance as in a healthy subject (figure 1). (E) Magnification of cAOSLO over the estimated foveal centre (marked with a white dashed square in (D)) shows irregularly waveguiding cones, which appear dim (some are indicated with white arrows); and (F) the corresponding split detection AOSLO in exact spatial registration showing relatively healthy-appearing cone inner segments, the white arrows indicate the corresponding inner segments for the irregularly waveguiding cones identified with white arrows in (E).