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

Optical Coherence Tomography Angiography (OCTA) in Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorder

Vascular changes are increasingly recognized as important factors in the pathophysiology of neuroinflammatory disease, especially in multiple sclerosis (MS). The relatively novel technology of optical coherence tomography angiography (OCTA) images the retinal and choroidal vasculature non-invasively and in a depth-resolved manner. OCTA provides an alternative quantitative measure of retinal damage, by measuring vascular density instead of structural atrophy. Preliminary results suggest OCTA is sensitive to retinal damage in early disease stages, while also having less of a "floor-effect" compared with commonly used OCT metrics, meaning it can pick up further damage in a severely atrophied retina in later stages of disease. Furthermore, it may serve as a surrogate marker for vascular pathology in the central nervous system. Data to date consistently reveal lower densities of the retinal microvasculature in both MS and neuromyelitis optica spectrum disorder (NMOSD) compared with healthy controls, even in the absence of prior optic neuritis. Exploring the timing of vascular changes relative to structural atrophy may help answer important questions about the role of hypoperfusion in the pathophysiology of neuroinflammatory disease. Finally, qualitative characteristics of retinal microvasculature may help discriminate between different neuroinflammatory disorders. There are however still issues regarding image quality and development of standardized analysis methods before OCTA can be fully incorporated into clinical practice

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

Directional optical coherence tomography provides accurate outer nuclear layer and Henle fiber layer measurements

Purpose: The outer nuclear layer (ONL) contains photoreceptor nuclei, and its thickness is an important biomarker for retinal degenerations. Accurate ONL thickness measurements are obscured in standard optical coherence tomography (OCT) images because of Henle fiber layer (HFL). Improved differentiation of the ONL and HFL boundary is made possible by using directional OCT, a method that purposefully varies the pupil entrance position of the OCT beam. Methods: Fifty-seven normal eyes were imaged using multiple pupil entry positions with a commercial spectral domain OCT system. Cross-sectional image sets were registered to each other and segmented at the top of HFL, the border of HFL and the ONL and at the external limiting membrane. Thicknesses of the ONL and HFL were measured and analyzed. Results: The true ONL and HFL thicknesses varied substantially by eccentricity and between individuals. The true macular ONL thickness comprised an average of 54.6% of measurements that also included HFL. The ONL and HFL thicknesses at specific retinal eccentricities were poorly correlated. Conclusion: Accurate ONL and HFL thickness measurements are made possible by the optical contrast of directional OCT. Distinguishing these individual layers can improve clinical trial endpoints and assessment of disease progression

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