The Cone Dysfunction Syndromes

The cone dysfunction syndromes are a heterogeneous group of inherited, predominantly stationary retinal disorders characterised by reduced central vision, and varying degrees of colour vision abnormalities, nystagmus and photophobia. This review details the following conditions: complete and incomplete achromatopsia, blue-cone monochromatism, oligocone trichromacy, bradyopsia, and Bornholm eye disease. We describe the clinical, psychophysical, electrophysiological and imaging findings that are characteristic to each condition, in order to aid their accurate diagnosis, as well as highlight some classically held notions about these diseases that have come to be challenged over recent years. The latest data regarding the genetic aetiology and pathological changes observed in the cone dysfunction syndromes are discussed, and, where relevant, translational avenues of research, including completed and anticipated interventional clinical trials, for some of the diseases described herein will be presented. Finally, we briefly review the current management of these disorders

Subclinical Photoreceptor Disruption in Response to Severe Head Trauma

Commotio retinae is a transient opacification of the retina due to outer retinal disruption occurring in a contrecoup fashion after blunt trauma.Histological studies in animals and humans after ocular blunt trauma have revealed that disruption occurs at the level of the photoreceptor outer segments and retinal pigment epithelium.Recent reports using optical coherence tomography (OCT) have shown detectable disruption at the level of the photoreceptor inner segment/outer segment junction and retinal pigment epithelium and that these changes may be reversible over time with restoration of normal outer retinal architecture.However, the resolution of existing OCT technology may not be sensitive enough to detect photoreceptor disruption. Adaptive optics (AO) imaging systems enable cellular-resolution imaging of the human retina, and there is a growing number of cases where deficits have been visible on AO images but not on OCT. Herein, we report a case of subclinical photoreceptor disruption after head trauma as seen by an AO scanning ophthalmoscope (AOSO) but not apparent clinically or on spectral-domain OCT (SD-OCT)

Repeatability of \u3cem\u3eIn Vivo\u3c/em\u3e Parafoveal Cone Density and Spacing Measurements

Purpose. To assess the repeatability and measurement error associated with cone density and nearest neighbor distance (NND) estimates in images of the parafoveal cone mosaic obtained with an adaptive optics scanning light ophthalmoscope (AOSLO).Methods. Twenty-one participants with no known ocular pathology were recruited. Four retinal locations, approximately 0.65[degrees] eccentricity from the center of fixation, were imaged 10 times in randomized order with an AOSLO. Cone coordinates in each image were identified using an automated algorithm (with or without manual correction) from which cone density and NND were calculated. Owing to naturally occurring fixational instability, the 10 images recorded from a given location did not overlap entirely. We thus analyzed each image set both before and after alignment.Results. Automated estimates of cone density on the unaligned image sets showed a coefficient of repeatability of 11,769 cones/mm2 (17.1%). The primary reason for this variability appears to be fixational instability, as aligning the 10 images to include the exact same retinal area results in an improved repeatability of 4358 cones/mm2 (6.4%) using completely automated cone identification software. Repeatability improved further by manually identifying cones missed by the automated algorithm, with a coefficient of repeatability of 1967 cones/mm2 (2.7%). NND showed improved repeatability and was generally insensitive to the undersampling by the automated algorithm.Conclusions. As our data were collected in a young, healthy population, this likely represents a best-case estimate for corresponding measurements in patients with retinal disease. Similar studies need to be carried out on other imaging systems (including those using different imaging modalities, wavefront correction technology, and/or image analysis software), as repeatability would be expected to be highly sensitive to initial image quality and the performance of cone identification algorithms. Separate studies addressing intersession repeatability and interobserver reliability are also needed

Relationship Between the Foveal Avascular Zone and Foveal Pit Morphology

Purpose.To assess the relationship between foveal pit morphology and size of the foveal avascular zone (FAZ). Methods. Forty-two subjects were recruited. Volumetric images of the macula were obtained using spectral domain optical coherence tomography. Images of the FAZ were obtained using either a modified fundus camera or an adaptive optics scanning light ophthalmoscope. Foveal pit metrics (depth, diameter, slope, volume, and area) were automatically extracted from retinal thickness data, whereas the FAZ was manually segmented by two observers to extract estimates of FAZ diameter and area. Results. Consistent with previous reports, the authors observed significant variation in foveal pit morphology. The average foveal pit volume was 0.081 mm3 (range, 0.022 to 0.190 mm3). The size of the FAZ was also highly variable between persons, with FAZ area ranging from 0.05 to 1.05 mm2 and FAZ diameter ranging from 0.20 to 1.08 mm. FAZ area was significantly correlated with foveal pit area, depth, and volume; deeper and broader foveal pits were associated with larger FAZs. Conclusions. Although these results are consistent with predictions from existing models of foveal development, more work is needed to confirm the developmental link between the size of the FAZ and the degree of foveal pit excavation. In addition, more work is needed to understand the relationship between these and other anatomic features of the human foveal region, including peak cone density, rod-free zone diameter, and Henle fiber layer

Assessing the Spatial Relationship Between Fixation and Foveal Specializations

Increased cone photoreceptor density, an avascular zone (FAZ), and the displacement of inner retinal neurons to form a pit are distinct features of the human fovea. As the fovea provides the majority of our vision, appreciating how these anatomical specializations are related is important for understanding foveal development, normal visual function, and retinal disease. Here we evaluated the relationship between these specializations and their location relative to the preferred retinal locus of fixation (PRL). We measured foveal pit volume, FAZ area, peak cone density, and location of the PRL in 22 subjects with normal vision using optical coherence tomography and adaptive optics scanning light ophthalmoscopy. Foveal pit volume was positively correlated with FAZ area; however, peak cone density was not correlated with pit volume. In addition, there was no systematic offset of the location of any of these specializations relative to PRL, and there was no correlation between the magnitude of the offset from PRL and the corresponding foveal specialization measurements (pit volume, FAZ area, peak cone density). The standard deviation of our PRL measurements was consistent with previous measurements of fixational stability. These data provide insight into the sequence of events during foveal development and may have implications for visual function and retinal disease

Novel Heterozygous Deletion in Retinol Dehydrogenase 12 (RDH12) Causes Familial Autosomal Dominant Retinitis Pigmentosa.

Mutations in the retinol dehydrogenase 12 (RDH12) gene are primarily associated with Leber congenital amaurosis (LCA) type 13, a severe early onset autosomal recessive retinal dystrophy. Only one family with a heterozygous variant, associated with mild retinitis pigmentosa (RP), has been reported. We report a novel heterozygous variant [(c.759del; p.(Phe254Leufs∗24)], resulting in a frameshift and premature termination identified in two unrelated individuals with familial autosomal dominant RP. Both heterozygous variants are associated with a late onset RP phenotype, suggesting a possible genotype-phenotype correlation

Topographical Choroidal Thickness Change Following PDT for CSC: An OCT Case Report

Purpose. To describe topographical changes in choroidal thickness as measured by optical coherence tomography following photodynamic therapy (PDT) for central serous chorioretinopathy (CSC). Methods. Case report. Results. By 1 month following PDT, mean (SD) choroidal thickness decreased from 562 microns (24) to 424 microns (27) (P < 0.01) at 3 mm temporal to fovea, 483 microns (9) to 341 microns (21) (P < 0.01) at 1.5 mm temporal to fovea, 576 microns (52) to 370 microns (81) (P < 0.01) under the fovea, 442 microns (30) to 331 microns (54) (P < 0.04) at 1.5 mm nasal to fovea, and 274 microns (39) to 171 microns (17) (P < 0.01) at 3 mm nasal to fovea. The Location of greatest choroidal thickness (648 microns) prior to treatment was at point of leakage on fluorescein angiogram (FA). This region decreased to 504 microns following treatment. Conclusion. A decrease in choroidal thickness can be seen following PDT for CSC as far as 3 mm temporal and 3 mm nasal to fovea. The Location of greatest choroidal thickness may be at point of leakage on FA

Effects of Intraframe Distortion on Measures of Cone Mosaic Geometry from Adaptive Optics Scanning Light Ophthalmoscopy

Purpose: To characterize the effects of intraframe distortion due to involuntary eye motion on measures of cone mosaic geometry derived from adaptive optics scanning light ophthalmoscope (AOSLO) images. Methods: We acquired AOSLO image sequences from 20 subjects at 1.0, 2.0, and 5.08 temporal from fixation. An expert grader manually selected 10 minimally distorted reference frames from each 150-frame sequence for subsequent registration. Cone mosaic geometry was measured in all registered images (n ¼ 600) using multiple metrics, and the repeatability of these metrics was used to assess the impact of the distortions from each reference frame. In nine additional subjects, we compared AOSLO-derived measurements to those from adaptive optics (AO)-fundus images, which do not contain system-imposed intraframe distortions. Results: We observed substantial variation across subjects in the repeatability of density (1.2%–8.7%), inter-cell distance (0.8%–4.6%), percentage of six-sided Voronoi cells (0.8%–10.6%), and Voronoi cell area regularity (VCAR) (1.2%–13.2%). The average of all metrics extracted from AOSLO images (with the exception of VCAR) was not significantly different than those derived from AO-fundus images, though there was variability between individual images. Conclusions: Our data demonstrate that the intraframe distortion found in AOSLO images can affect the accuracy and repeatability of cone mosaic metrics. It may be possible to use multiple images from the same retinal area to approximate a ‘‘distortionless’’ image, though more work is needed to evaluate the feasibility of this approach. Translational Relevance: Even in subjects with good fixation, images from AOSLOs contain intraframe distortions due to eye motion during scanning. The existence of these artifacts emphasizes the need for caution when interpreting results derived from scanning instruments

Outer Retinal Structure in Best Vitelliform Macular Dystrophy

Importance Demonstrating the utility of adaptive optics scanning light ophthalmoscopy (AOSLO) to assess outer retinal structure in Best vitelliform macular dystrophy (BVMD). Objective To characterize outer retinal structure in BVMD using spectral-domain optical coherence tomography (SD-OCT) and AOSLO. Design, Setting, and Participants Prospective, observational case series. Four symptomatic members of a family with BVMD with known BEST1 mutation were recruited at the Advanced Ocular Imaging Program research lab at the Medical College of Wisconsin Eye Institute, Milwaukee. Intervention Thickness of 2 outer retinal layers corresponding to photoreceptor inner and outer segments was measured using SD-OCT. Photoreceptor mosaic AOSLO images within and around visible lesions were obtained, and cone density was assessed in 2 subjects. Main Outcome and Measure Photoreceptor structure. Results Each subject was at a different stage of BVMD, with photoreceptor disruption evident by AOSLO at all stages. When comparing SD-OCT and AOSLO images from the same location, AOSLO images allowed for direct assessment of photoreceptor structure. A variable degree of retained photoreceptors was seen within all lesions. The photoreceptor mosaic immediately adjacent to visible lesions appeared contiguous and was of normal density. Fine hyperreflective structures were visualized by AOSLO, and their anatomical orientation and size were consistent with Henle fibers. Conclusions and Relevance The AOSLO findings indicate that substantial photoreceptor structure persists within active lesions, accounting for good visual acuity in these patients. Despite previous reports of diffuse photoreceptor outer segment abnormalities in BVMD, our data reveal normal photoreceptor structure in areas adjacent to clinical lesions. This study demonstrates the utility of AOSLO for understanding the spectrum of cellular changes that occur in inherited degenerations such as BVMD. Photoreceptors are often significantly affected at various stages of inherited degenerations, and these changes may not be readily apparent with current clinical imaging instrumentation

Retinal Architecture in ​\u3cem\u3eRGS9-\u3c/em\u3e and ​\u3cem\u3eR9AP\u3c/em\u3e-Associated Retinal Dysfunction (Bradyopsia)

Purpose To characterize photoreceptor structure and mosaic integrity in subjects with RGS9- and R9AP-associated retinal dysfunction (bradyopsia) and compare to previous observations in other cone dysfunction disorders such as oligocone trichromacy. Design Observational case series. Methods setting: Moorfields Eye Hospital (United Kingdom) and Medical College Wisconsin (USA). study population: Six eyes of 3 subjects with disease-causing variants in RGS9 or R9AP. main outcome measures: Detailed retinal imaging using spectral-domain optical coherence tomography and confocal adaptive-optics scanning light ophthalmoscopy. Results Cone density at 100 μm from foveal center ranged from 123 132 cones/mm2to 140 013 cones/mm2. Cone density ranged from 30 573 to 34 876 cones/mm2 by 600 μm from center and from 15 987 to 16,253 cones/mm2 by 1400 μm from center, in keeping with data from normal subjects. Adaptive-optics imaging identified a small, focal hyporeflective lesion at the foveal center in both eyes of the subject with RGS9-associated disease, corresponding to a discrete outer retinal defect also observed on spectral-domain optical coherence tomography; however, the photoreceptor mosaic remained intact at all other observed eccentricities. Conclusions Bradyopsia and oligocone trichromacy share common clinical symptoms and cannot be discerned on standard clinical findings alone. Adaptive-optics imaging previously demonstrated a sparse mosaic of normal wave-guiding cones remaining at the fovea, with no visible structure outside the central fovea in oligocone trichromacy. In contrast, the subjects presented in this study with molecularly confirmed bradyopsia had a relatively intact and structurally normal photoreceptor mosaic, allowing the distinction between these disorders based on the cellular phenotype and suggesting different pathomechanisms