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Adaptive Optics Imaging of Inherited Retinal Diseases Br J Ophthalmol: first published as 10.1136/bjophthalmol-2017-311328 on 15 November 2017. Downloaded from Review Adaptive optics imaging of inherited retinal diseases Michalis Georgiou,1,2 Angelos Kalitzeos,1,2 Emily J Patterson,3 Alfredo Dubra,4 Joseph Carroll,3 Michel Michaelides1,2 ► Additional material is ABSTRact in patients with IRD. By focusing a scanning light published online only. To view Adaptive optics (AO) ophthalmoscopy allows for non- source on the photoreceptor layer and rejecting please visit the journal online (http:// dx. doi. org/ 10. 1136/ invasive retinal phenotyping on a microscopic scale, out-of-focus light through the use of a confocal bjophthalmol- 2017- 311328). thereby helping to improve our understanding of retinal aperture, axial sectioning is achieved, thereby diseases. An increasing number of natural history studies increasing image contrast.8 11 Photoreceptors with 1UCL Institute of and ongoing/planned interventional clinical trials exploit relatively intact outer segments waveguide some Ophthalmology, University AO ophthalmoscopy both for participant selection, College London, London, UK incident light, and backscatter a very small frac- 2Moorfields Eye Hospital NHS stratification and monitoring treatment safety and tion (less than 0.1%), which is used for imaging.12 Foundation Trust, London, UK efficacy. In this review, we briefly discuss the evolution When collecting that light in a confocal detector, 3Department of Ophthalmology of AO ophthalmoscopy, recent developments and its the cone8 13 14 and perifoveal rod8 15 16 mosaics can and Visual Sciences, Medical application to a broad range of inherited retinal diseases, College of Wisconsin, be resolved. Several systems have been developed including Stargardt disease, retinitis pigmentosa and Milwaukee, Wisconsin, USA including both custom-built and commercially 4Department of Ophthalmology, achromatopsia. Finally, we describe the impact of this Stanford University, Palo Alto, in vivo microscopic imaging on our understanding of available devices. California, USA disease pathogenesis, clinical trial design and outcome The non-confocal backscattered light can also metrics, while recognising the limitation of the small be exploited to reveal the photoreceptor inner Correspondence to cohorts reported to date. segment mosaic. For example, the split detection Michel Michaelides, UCL (SD) technique (SD-AOSLO) does so by subtracting Institute of Ophthalmology, University College London, images created by capturing the light to the left of London EC1V 9EL, UK; michel. the confocal aperture with one detector and the michaelides@ ucl. ac. uk INTRODUCTION light to the right of it with a different one.17 This Inherited retinal disease (IRD) is the leading cause recent development was transformational because Received 15 September 2017 of legal blindness in England and Wales among cones with compromised outer segments (as would Revised 23 October 2017 the working age population and the second most Accepted 4 November 2017 1 be anticipated in the majority of IRDs) can now be common in childhood. IRD is a group of clini- Published Online First reliably identified for the first time. This has major 15 November 2017 cally heterogeneous conditions, which can result in diagnostic challenges, often thereby necessitating implications for patient stratification and targeting 18–25 detailed multimodal retinal imaging, as well as of intervention. electrophysiological and psychophysical evalua- Due to light safety restrictions, each individual tion. They are subject to a broad range of research AOSLO raw frame is captured using very low illu- mination power (~100 W at the pupil) and thus avenues and interventions which have been recently µ http://bjo.bmj.com/ reviewed.2 Here, we categorise IRDs on the basis of the resulting images are inherently noisy. There- natural history (stationary or progressive) and the fore, AOSLO image sequences are captured at each primarily affected retinal cell type. retinal location of interest, and used to create a In vivo retinal imaging has been rapidly evolving higher signal-to-noise ratio (SNR) image by aver- over the last decades primarily due to advances in aging a few of these frames after correcting for optics, electronics and computer technology. The eye motion and scanning distortions.26 These high introduction of optical coherence tomography SNR images are then stitched together to create on September 29, 2021 by guest. Protected copyright. (OCT) has revolutionised the clinical investigation a larger montage (figure 1). A range of photore- of retinal diseases.3 4 One of the main limiting factors ceptor metrics have been employed to date, with for in vivo retinal imaging is ocular aberrations, due cone density for a given eccentricity being the most to the optical imperfections of the eye.5 Adaptive widely used, and usually compared with normative optics (AO) can be employed in ophthalmology to 27 13 28 29 6 data from histology or imaging studies. overcome the aforementioned limitation. Other metrics include (1) cone spacing—average distance between cells in a given location, (2) BRIEF OVERVIEW OF AO RETINAL IMAGING Voronoi analysis (figure 1) which involves counting The incorporation of AO to any ophthalmo- the number of neighbouring cells based on the scopic technique, including fundus photography, distance between them, thereby assessing mosaic OCT and scanning laser ophthalmoscopy (SLO), 28 18 provides in vivo microscopic imaging.6–9 AO geometry, (3) reflectivity, and (4) metrics for ophthalmoscopes typically use a wavefront sensor the preferred orientation of cones and local spatial 30 to measure the ocular monochromatic aberra- anisotropy. The combination of OCT and AO (AO-OCT) To cite: Georgiou M, tions and a deformable mirror to correct for 6 9 10 Kalitzeos A, Patterson EJ, the detected aberrations. Herein we will be is an evolving field, aiming for 3D reconstruction et al. Br J Ophthalmol focusing on AOSLO photoreceptor imaging as this and offers greater axial resolution compared with 2018;102:1028–1035. is the modality that has been most extensively used AOSLO.31 1028 Georgiou M, et al. Br J Ophthalmol 2018;102:1028–1035. doi:10.1136/bjophthalmol-2017-311328 Br J Ophthalmol: first published as 10.1136/bjophthalmol-2017-311328 on 15 November 2017. Downloaded from Review IRDS AND AO RETINAL OPHTHALMOSCOPY are needed to evaluate cellular disease progression and poten- The selected conditions below have been prioritised based on the tially identify the most suitable participants for ongoing and ability of published AO ophthalmoscopy studies to demonstrate multiple planned gene therapy and pharmacological interven- clinical, research or trial utility. There are inherent limitations tions.19 33 34 36 AO ophthalmoscopy may be a useful method of due to the often small cohorts reported to date. These are usually monitoring in trials, since ‘classic’ parameters of ophthalmolog- small due to the vast genetic and phenotypic heterogeneity of ical examination including best corrected visual acuity (BCVA) IRDs, the low prevalence of each genotype and due to the diffi- are not sufficiently sensitive outcome measures for conditions culty of establishing multicentre studies given the limited avail- such as STGD1.37 ability of AOSLO. However, similar limitations are often faced by other studies using other modes of high-resolution imaging. Best disease For clarity, we have included the number of subjects in each Normal photoreceptor structure and cone densities in areas study we describe and whether the patients were molecularly adjacent to clinically visible lesions have been reported, with confirmed (online supplementary table 1). persistent photoreceptor structure overlying stage 1 and 2 vitel- liform Best disease lesions, in keeping with relatively intact Macular dystrophies visual acuity (VA).38 Using cAOSLO and SD-AOSLO, variable Stargardt disease photoreceptor architecture has been observed to be associated Stargardt disease (STGD1) is the most common form of hered- with different stages of the disease and the location within the 32 itary macular dystrophy. Confocal AOSLO (cAOSLO) has lesions, including reduced cone density, due to major discontinu- demonstrated abnormal and decreased cone spacing in regions ities/gaps in the mosaic, and cone inner segment enlargement.23 corresponding to areas of reduced and irregular fundus auto- fluorescence (FAF), in predominantly late-onset/foveal sparing X-linked retinoschisis molecularly proven patients (11 of 12 patients).33 Moreover, Duncan et al39 have reported increased and irregular cone foveal retinal pigment epithelium (RPE) cells were imaged in spacing within the foveal schisis characterising X-linked reti- areas where the photoreceptor mosaic appeared disrupted in noschisis. Interestingly, cone spacing was normal and regular confocal reflectance imaging, suggesting photoreceptor loss elsewhere. The preserved waveguiding cones at the fovea and preceding RPE cell loss—although the application of SD-AOSLO eccentric macular regions may indicate increased likelihood of would address whether there are in fact cone inner segments successful rescue with intervention—and could also be helpful present.33 Song et al also reported increased photoreceptor in patient selection. spacing, in genetically proven STGD1 (n=2), in otherwise normal appearing areas on OCT and FAF imaging; also consis- tent with photoreceptor loss preceding clinically detectable RPE Stationary dysfunction syndromes
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