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

Choroideremia: from genetic and clinical phenotyping to gene therapy and future treatments

Choroideremia is an X-linked inherited chorioretinal dystrophy leading to blindness by late adulthood. Choroideremia is caused by mutations in the CHM gene which encodes Rab escort protein 1 (REP1), an ubiquitously expressed protein involved in intracellular trafficking and prenylation activity. The exact site of pathogenesis remains unclear but results in degeneration of the photoreceptors, retinal pigment epithelium and choroid. Animal and stem cell models have been used to study the molecular defects in choroideremia and test effectiveness of treatment interventions. Natural history studies of choroideremia have provided additional insight into the clinical phenotype of the condition and prepared the way for clinical trials aiming to investigate the safety and efficacy of suitable therapies. In this review, we provide a summary of the current knowledge on the genetics, pathophysiology, clinical features and therapeutic strategies that might become available for choroideremia in the future, including gene therapy, stem cell treatment and small-molecule drugs with nonsense suppression action

Human Factor and Usability Testing of a Binocular Optical Coherence Tomography System

PURPOSE: To perform usability testing of a binocular optical coherence tomography (OCT) prototype to predict its function in a clinical setting, and to identify any potential user errors, especially in an elderly and visually impaired population. METHODS: Forty-five participants with chronic eye disease (mean age 62.7 years) and 15 healthy controls (mean age 53 years) underwent automated eye examination using the prototype. Examination included 'whole-eye' OCT, ocular motility, visual acuity measurement, perimetry, and pupillometry. Interviews were conducted to assess the subjective appeal and ease of use for this cohort of first-time users. RESULTS: All participants completed the full suite of tests. Eighty-one percent of the chronic eye disease group, and 79% of healthy controls, found the prototype easier to use than common technologies, such as smartphones. Overall, 86% described the device to be appealing for use in a clinical setting. There was no statistically significant difference in the total time taken to complete the examination between participants with chronic eye disease (median 702 seconds) and healthy volunteers (median 637 seconds) (P = 0.81). CONCLUSION: On their first use, elderly and visually impaired users completed the automated examination without assistance. Binocular OCT has the potential to perform a comprehensive eye examination in an automated manner, and thus improve the efficiency and quality of eye care. TRANSLATIONAL RELEVANCE: A usable binocular OCT system has been developed that can be administered in an automated manner. We have identified areas that would benefit from further development to guide the translation of this technology into clinical practice

Investigating Biomarkers for USH2A Retinopathy Using Multimodal Retinal Imaging

Pathogenic mutations in USH2A are a leading cause of visual loss secondary to non-syndromic or Usher syndrome-associated retinitis pigmentosa (RP). With an increasing number of RP-targeted clinical trials in progress, we sought to evaluate the photoreceptor topography under-lying patterns of loss observed on clinical retinal imaging to guide surrogate endpoint selection in USH2A retinopathy. In this prospective cross-sectional study, twenty-five patients with molecularly confirmed USH2A-RP underwent fundus autofluorescence (FAF), spectral-domain optical coherence tomography (SD-OCT) and adaptive optics scanning laser ophthalmoscopy (AOSLO) retinal imaging. Analysis comprised measurement of FAF horizontal inner (IR) and outer (OR) hyperautofluorescent ring diameter; SD-OCT ellipsoid zone (EZ) and external limiting membrane (ELM) width, normalised EZ reflectance; AOSLO foveal cone density and intact macular photoreceptor mosaic (IMPM) diam-eter. Thirty-two eyes from 16 patients (mean age ± SD, 36.0 ± 14.2 years) with USH2A-associated Usher syndrome type 2 (n = 14) or non-syndromic RP (n = 2) met the inclusion criteria. Spatial align-ment was observed between IR-EZ and OR-ELM diameters/widths (p <0.001). The IMPM border occurred just lateral to EZ loss (p < 0.001), although sparser intact photoreceptor inner segments were detected until ELM disruption. EZ width and IR diameter displayed a biphasic relationship with cone density whereby slow cone loss occurred until retinal degeneration reached ~1350 µm from the fovea, beyond which greater reduction in cone density followed. Normalised EZ reflectance and cone density were significantly associated (p <0.001). As the strongest correlate of cone density (p < 0.001) and best-corrected visual acuity (p <0.001), EZ width is the most sensitive biomarker of structural and functional decline in USH2A retinopathy, rendering it a promising trial endpoint

Agreement Between Spectral-Domain and Swept-Source Optical Coherence Tomography Retinal Thickness Measurements in Macular and Retinal Disease

INTRODUCTION: To assess inter-device agreement in optical coherence tomography-derived retinal thickness measurements in patients with known macular conditions between spectral-domain and swept-source optical coherence tomography (OCT). METHODS: Two hundred seventy-two subjects were included in the study. They consisted of 91 male (33.5%) and 181 female (66.5%) subjects, and 132 left (48.5%) and 140 right (51.5%) eyes. Each subject underwent spectral-domain OCT (SD-OCT, Spectralis, Heidelberg Engineering; RTVue XR Avanti XR HD, Optovue) and swept-source OCT (SS-OCT; DRI-OCT-1, Atlantis, Topcon) in a single imaging session performed by the same clinical trial-certified technician. The comparison of retinal thickness reproducibility between devices was performed using Bland-Altman analyses and across the entire data set using the intraclass correlation coefficient (ICC). RESULTS: The ICC of the retinal thickness measurements (95% confidence interval) made using all three OCT instruments was 0.81 (0.77-0.84). The mean difference in mean retinal thickness between Spectralis SD-OCT and Topcon SS-OCT was 59.1 μm (95% limit of agreement [LoA] -21.7 to 139.8 μm). The mean difference in mean retinal thickness between Optovue SD-OCT and Topcon SS-OCT was 21.8 μm (95% LoA -34.7  to 78.3 μm). CONCLUSIONS: Retinal layer thickness measurements vary between SS-OCT and SD-OCT devices. We describe inter-device agreement in retinal thickness between SS-OCT and SD-OCT in patients with macular conditions. Clinicians should be aware of the differences in retinal thickness values when imaging patients using different OCT devices and should consider using the same OCT device model in order to monitor clinical change. TRIAL REGISTRATION: ClinicalTrials.gov Identifier (NCT02828215)

Assessing Retinal Structure In Complete Congenital Stationary Night Blindness and Oguchi Disease

Purpose To examine retinal structure and changes in photoreceptor intensity after dark adaptation in patients with complete congenital stationary night blindness and Oguchi disease. Design Prospective, observational case series. Methods We recruited 3 patients with complete congenital stationary night blindness caused by mutations in GRM6, 2 brothers with Oguchi disease caused by mutations in GRK1, and 1 normal control. Retinal thickness was measured from optical coherence tomography images. Integrity of the rod and cone mosaic was assessed using adaptive optics scanning light ophthalmoscopy. We imaged 5 of the patients after a period of dark adaptation and examined layer reflectivity on optical coherence tomography in a patient with Oguchi disease under light- and dark-adapted conditions. Results Retinal thickness was reduced in the parafoveal region in patients with GRM6 mutations as a result of decreased thickness of the inner retinal layers. All patients had normal photoreceptor density at all locations analyzed. On removal from dark adaptation, the intensity of the rods (but not cones) in the patients with Oguchi disease gradually and significantly increased. In 1 Oguchi disease patient, the outer segment layer contrast on optical coherence tomography was 4-fold higher under dark-adapted versus light-adapted conditions. Conclusions The selective thinning of the inner retinal layers in patients with GRM6 mutations suggests either reduced bipolar or ganglion cell numbers or altered synaptic structure in the inner retina. Our finding that rods, but not cones, change intensity after dark adaptation suggests that fundus changes in Oguchi disease are the result of changes within the rods as opposed to changes at a different retinal locus

Relationship Between Foveal Cone Specialization and Pit Morphology in Albinism

Purpose.Albinism is associated with disrupted foveal development, though intersubject variability is becoming appreciated. We sought to quantify this variability, and examine the relationship between foveal cone specialization and pit morphology in patients with a clinical diagnosis of albinism. Methods. We recruited 32 subjects with a clinical diagnosis of albinism. DNA was obtained from 25 subjects, and known albinism genes were analyzed for mutations. Relative inner and outer segment (IS and OS) lengthening (fovea-to-perifovea ratio) was determined from manually segmented spectral domain-optical coherence tomography (SD-OCT) B-scans. Foveal pit morphology was quantified for eight subjects from macular SD-OCT volumes. Ten subjects underwent imaging with adaptive optics scanning light ophthalmoscopy (AOSLO), and cone density was measured. Results. We found mutations in 22 of 25 subjects, including five novel mutations. All subjects lacked complete excavation of inner retinal layers at the fovea, though four subjects had foveal pits with normal diameter and/or volume. Peak cone density and OS lengthening were variable and overlapped with that observed in normal controls. A fifth hyper-reflective band was observed in the outer retina on SD-OCT in the majority of the subjects with albinism. Conclusions. Foveal cone specialization and pit morphology vary greatly in albinism. Normal cone packing was observed in the absence of a foveal pit, suggesting a pit is not required for packing to occur. The degree to which retinal anatomy correlates with genotype or visual function remains unclear, and future examination of larger patient groups will provide important insight on this issue

Dynamic Changes in Schlemm Canal and Iridocorneal Angle Morphology During Accommodation in Children With Healthy Eyes: A Cross-Sectional Cohort Study

PURPOSE: The purpose of this study was to explore changes in Schlemm canal (SC), trabecular meshwork (TM), and iridocorneal angle (ICA) morphology during accommodative effort in children and young adults. METHODS: We acquired anterior segment optical coherence tomography images (AS-OCT) of the ICA and ciliary muscle (CM) of both eyes of 50 children age 4 to 16 years with healthy eyes, at two levels of accommodation: 2.5 and 15 diopters (D). Semiautomated nasal ICA measurements were as follows: angle opening distance at 500/750 μm (AOD-500, -750), trabecular iris space area at 500/750 μm (TISA-500, -750), and trabecular iris angle at 500/750 μm (TIA-500, -750). Manual measurements were as follows: anteroposterior and radial SC diameter (SC-APD, SC-RD), cross-sectional area of SC (SC-CSA) and TM height (TMH), TM length (TML), and TM density (TMD). CM width was measured at 1, 2, and 3 mm from the scleral spur (CM-1, CM-2, CM-3). For each parameter, a three-level random-effects model was fitted to estimate differences between the two levels of accommodation. RESULTS: With accommodative effort, SC diameters and CSA increase significantly, as do TM length and iridocorneal angle parameters. With increasing age, SC dimensions reduce. Angle parameters are smaller in eyes with greater spherical equivalent (hypermetropia). CONCLUSIONS: AS-OCT can be used to visualize dynamic morphologic changes in outflow structures with physiologic accommodation. The increase in SC dimensions with accommodative effort may contribute to the regulation of IOP in children

Cone Photoreceptor Structure in Patients With X-Linked Cone Dysfunction and Red-Green Color Vision Deficiency

Purpose: Mutations in the coding sequence of the L and M opsin genes are often associated with X-linked cone dysfunction (such as Bornholm Eye Disease, BED), though the exact color vision phenotype associated with these disorders is variable. We examined individuals with L/M opsin gene mutations to clarify the link between color vision deficiency and cone dysfunction. Methods: We recruited 17 males for imaging. The thickness and integrity of the photoreceptor layers were evaluated using spectral-domain optical coherence tomography. Cone density was measured using high-resolution images of the cone mosaic obtained with adaptive optics scanning light ophthalmoscopy. The L/M opsin gene array was characterized in 16 subjects, including at least one subject from each family. Results: There were six subjects with the LVAVA haplotype encoded by exon 3, seven with LIAVA, two with the Cys203Arg mutation encoded by exon 4, and two with a novel insertion in exon 2. Foveal cone structure and retinal thickness was disrupted to a variable degree, even among related individuals with the same L/M array. Conclusions: Our findings provide a direct link between disruption of the cone mosaic and L/M opsin variants. We hypothesize that, in addition to large phenotypic differences between different L/M opsin variants, the ratio of expression of first versus downstream genes in the L/M array contributes to phenotypic diversity. While the L/M opsin mutations underlie the cone dysfunction in all of the subjects tested, the color vision defect can be caused either by the same mutation or a gene rearrangement at the same locus

Childhood lensectomy is associated with static and dynamic reduction in Schlemm canal size: a biomechanical hypothesis of post-lensectomy glaucoma

OBJECTIVE: To compare Schlemm canal (SC) and trabecular meshwork (TM) in children with healthy eyes and those with and without glaucoma after lensectomy. DESIGN: Cross-sectional observational study. PARTICIPANTS: Fifty children age 4 to 16 years with healthy eyes and 48 children post lensectomy (124 healthy and 72 post-lensectomy eyes). METHODS: /Interventions: Anterior segment optical coherence tomography (AS-OCT, Tomey Casia) of the nasal iridocorneal angle, at two levels of accommodative effort (2.5D, 15D). For each parameter and state of accommodation, a random-effects model was fitted to estimate differences between healthy eyes and eyes with history of lensectomy. MAIN OUTCOME MEASURES: Dimensions of SC and TM; conventional AS-OCT irido-corneal angle (ICA) measurements. RESULTS: The horizontal diameter of SC and its cross-sectional area (SC-CSA) are significantly smaller in post-lensectomy than in healthy eyes. Accommodative effort increases SC size in healthy, but not in post-lensectomy eyes. CONCLUSIONS: Lensectomy is associated with a reduction in SC size and a loss of physiological SC dilatation during accommodative effort, which may reflect a reduction in outflow facility and contribute to the development of post-lensectomy glaucoma