Derivation of human retinal cell densities using high-density, spatially localized optical coherence tomography data from the human retina.

This study sought to identify demographic variations in retinal thickness measurements from optical coherence tomography (OCT), to enable the calculation of cell density parameters across the neural layers of the healthy human macula. From macular OCTs (n = 247), ganglion cell (GCL), inner nuclear (INL), and inner segment-outer segment (ISOS) layer measurements were extracted using a customized high-density grid. Variations with age, sex, ethnicity, and refractive error were assessed with multiple linear regression analyses, with age-related distributions further assessed using hierarchical cluster analysis and regression models. Models were tested on a naïve healthy cohort (n = 40) with Mann-Whitney tests to determine generalizability. Quantitative cell density data were calculated from histological data from previous human studies. Eccentricity-dependent variations in OCT retinal thickness closely resemble topographic cell density maps from human histological studies. Age was consistently identified as significantly impacting retinal thickness (p = .0006, .0007, and .003 for GCL, INL and ISOS), with gender affecting ISOS only (p < .0001). Regression models demonstrated that age-related changes in the GCL and INL begin in the 30th decade and were linear for the ISOS. Model testing revealed significant differences in INL and ISOS thickness (p = .0008 and .0001; however, differences fell within the OCT's axial resolution. Qualitative comparisons show close alignment between OCT and histological cell densities when using unique, high-resolution OCT data, and correction for demographics-related variability. Overall, this study describes a process to calculate in vivo cell density from OCT for all neural layers of the human retina, providing a framework for basic science and clinical investigations.

Reproducibility and Reliability of Subbasal Corneal Nerve Parameters of the Inferior Whorl in the Neurotoxic and Healthy Cornea.

PURPOSE: The aim of this study was to investigate the reliability of subbasal corneal nerve plexus parameters of the inferior whorl compared with the central cornea with in vivo corneal confocal microscopy and to investigate the impact of inferior whorl pattern complexity on reproducibility. METHODS: Subbasal corneal nerves of healthy controls (n = 10) and patients with chemotherapy-induced peripheral neuropathy (n = 10) were imaged with a laser scanning confocal microscope. Two masked, experienced observers and the original image taker were tasked with selecting representative images of the central cornea and inferior whorl for each participant. This was conducted on 2 occasions 1 week apart. Corneal nerve fiber length (CNFL) and fractal dimension (CNFrD) [central cornea: CNFL and CNFrD; inferior whorl region: inferior whorl length (IWL) and inferior whorl fractal dimension (IWFrD)] were analyzed. Intraclass correlation coefficient (ICC) was analyzed for interobserver and intraobserver reliability. Inferior whorl complexity was classified according to the ease of identification of the center point of convergence. RESULTS: Interobserver ICC was 0.992 for CNFL, 0.994 for CNFrD, 0.980 for IWL, and 0.954 for IWFrD. When analyzed by inferior whorl complexity, the interobserver reliability was similar for simple (0.987 for IWL; 0.960 for IWFrD) and complex patterns (0.967 for IWL; 0.949 for IWFrD). However, intraobserver ICC were reduced for complex (IWL 0.841-0.970; IWFrD 0.830-0.955) compared with simple patterns (IWL 0.931-0.970; IWFrD 0.921-0.969). CONCLUSIONS: Although the overall interobserver reliability was excellent for the central corneal and inferior whorl parameters, there was lower intraobserver reliability for the inferior whorl parameters for complex morphological patterns. To improve reliability, more sophisticated wide-field imaging of the inferior whorl may be needed.

Automated analysis of corneal nerve tortuosity in diabetes: implications for neuropathy detection.

CLINICAL RELEVANCE: There is potential benefit in analysing corneal nerve tortuosity as a marker for assessment and progression of systemic diabetic neuropathy. BACKGROUND: The aim of this work was to determine whether tortuosity significantly differs in participants with type 1 (T1DM) and type 2 (T2DM) diabetes compared to controls and whether tortuosity differed according to neuropathy status. METHODS: Corneal nerves of 164 participants were assessed across T1DM, T2DM and control groups. Images of corneal nerves were captured via in vivo corneal confocal microscopy. Diabetic neuropathy status was examined using the Total Neuropathy Score (TNS). Tortuosity was assessed with Cfibre v0.097. Results were compared between groups with a linear mixed model accounting for location of image and controlling for age, producing Tortuosity Factor (TF), an estimate of the marginal means of each group. RESULTS: Tortuosity was significantly reduced in the T1DM group compared to controls (TF = 0.241, 95%CI = 0.225-0.257 vs. TF = 0.272, 95%CI = 0.252-0.292; mean difference = -0.031, p = 0.02) and in the T2DM group compared to controls (TF = 0.261, 95%CI = 0.244-0.278 vs. TF = 0.289, 95%CI = 0.270-0.308; mean difference = -0.029, p = 0.03). Tortuosity did not significantly differ between participants with T1DM and T2DM accounting for age and TNS (TF = 0.240, 95%CI = 0.215-0.265 vs. 0.269, 95%CI = 0.244-0.293, mean difference = -0.029, p = 0.11). Tortuosity was significantly reduced in participants with neuropathy (TNS≥2) compared to participants with no neuropathy (TNS< 2) (TF = 0.248, 95%CI = 0.231-0.265 vs. TF = 0.272, 95%CI = 0.260-0.283; mean difference = -0.024, p = 0.03). CONCLUSIONS: Tortuosity is significantly reduced in participants with T1DM and T2DM compared to age matched controls and in participants with neuropathy compared to those without neuropathy.

Location-Specific Thickness Patterns in Intermediate Age-Related Macular Degeneration Reveals Anatomical Differences in Multiple Retinal Layers.

Purpose: To examine individual retinal layers' location-specific patterns of thicknesses in intermediate age-related macular degeneration (iAMD) using optical coherence tomography (OCT). Methods: OCT macular cube scans were retrospectively acquired from 84 iAMD eyes of 84 participants and 84 normal eyes of 84 participants propensity-score matched on age, sex, and spherical equivalent refraction. Thicknesses of the retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer + Henle's fiber layer (ONL+HFL), inner- and outer-segment layers (IS/OS), and retinal pigment epithelium to Bruch's membrane (RPE-BM) were calculated across an 8 × 8 grid (total 24° × 24° area). Location-specific analysis was performed using cluster(normal) and grid(iAMD)-to-cluster(normal) comparisons. Results: In iAMD versus normal eyes, the central RPE-BM was thickened (mean difference ± SEM up to 27.45% ± 7.48%, P < 0.001; up to 7.6 SD-from-normal), whereas there was thinned outer (OPL, ONL+HFL, and non-central RPE-BM, up to -6.76% ± 2.47%, P < 0.001; up to -1.6 SD-from-normal) and inner retina (GCL and IPL, up to -4.83% ± 1.56%, P < 0.01; up to -1.7 SD-from-normal) with eccentricity-based effects. Interlayer correlations were greater against the ONL+HFL (mean |r| ± SEM 0.19 ± 0.03, P = 0.14 to < 0.0001) than the RPE-BM (0.09 ± 0, P = 0.72 to < 0.0001). Conclusions: Location-specific analysis suggests altered retinal anatomy between iAMD and normal eyes. These data could direct clinical diagnosis and monitoring of AMD toward targeted locations.

Review of referrals reveal the impact of referral content on the triage and management of ophthalmology wait lists.

OBJECTIVES: Many chronic eye conditions are managed within public hospital ophthalmology clinics resulting in encumbered wait lists. Integrated care schemes can increase system capacity. In order to direct implementation of a public hospital-based integrated eye care model, this study aims to evaluate the quality of referrals for new patients through information content, assess triage decisions of newly referred patients and evaluate the consistency of referral content for new patients referred multiple times. DESIGN: A retrospective and prospective review of all referral forms for new patients referred to a public hospital ophthalmology clinic between January 2016 and September 2017, and September 2017 and August 2018, respectively. SETTING: A referral-only public hospital ophthalmology clinic in metropolitan Sydney, Australia. PARTICIPANTS: 418 new patients on existing non-urgent wait lists waiting to be allocated an initial appointment, and 528 patients who were newly referred. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was the information content of referrals for new patients. The secondary outcomes were triage outcomes for new incoming referrals, and the number of new patients with multiple referrals. RESULTS: Of the wait-listed referrals, 0.2% were complete in referral content compared with 9.8% of new incoming referrals (p<0.001). Of new incoming referrals, 56.7% were triaged to a non-urgent clinic. Multiple referrals were received for 49 patients, with no change in the amount of referral content. CONCLUSIONS: Most referrals were incomplete in content, leading to triage based on limited clinical information. Some new patients were referred multiple times with their second referral containing a similar amount of content as their first. Lengthy wait lists could be prevented by improving administrative processes and communication between the referral centre and referrers. The future implementation of an integrated eye care model at the study setting could sustainably cut wait lists for patients with chronic eye conditions.

Evaluation of the initial implementation of a nationwide diabetic retinopathy screening programme in primary care: a multimethod study.

OBJECTIVES: The Australian Government funded a nationwide diabetic retinopathy screening programme to improve visual outcomes for people with diabetes. This study examined the benefits and barriers of the programme, image interpretation pathways and assessed the characteristics of people who had their fundus photos graded by a telereading service which was available as a part of the programme. DESIGN: Multimethod: survey and retrospective review of referral forms. SETTING: Twenty-two primary healthcare facilities from urban, regional, rural and remote areas of Australia, and one telereading service operated by a referral-only eye clinic in metropolitan Sydney, Australia. PARTICIPANTS: Twenty-seven primary healthcare workers out of 110 contacted completed a survey, and 145 patient referrals were reviewed. RESULTS: Manifest qualitative content analysis showed that primary healthcare workers reported that the benefits of the screening programme included improved patient outcomes and increased awareness and knowledge of diabetic retinopathy. Barriers related to staffing issues and limited referral pathways. Image grading was performed by a variety of primary healthcare workers, with one responder indicating the utilisation of a diabetic retinopathy reading service. Of the people with fundus photos graded by the reading service, 26.2% were reported to have diabetes. Overall, 12.3% of eyes were diagnosed with diabetic retinopathy. Photo quality was rated as excellent in 46.2% of photos. Referral to an optometrist for diabetic retinopathy was recommended in 4.1% of cases, and to an ophthalmologist in 6.9% of cases. CONCLUSIONS: This nationwide diabetic retinopathy screening programme was perceived to increase access to diabetic retinopathy screening in regional, rural and remote areas of Australia. The telereading service has diagnosed diabetic retinopathy and other ocular pathologies in images it has received. Key barriers, such as access to ophthalmologists and optometrists, must be overcome to improve visual outcomes.

Topical Review: Assessment of Binocular Sensory Processes in Low Vision.

SIGNIFICANCE: This article summarizes the evidence for a higher prevalence of binocular vision dysfunctions in individuals with vision impairment. Assessment for and identification of binocular vision dysfunctions can detect individuals experiencing difficulties in activities including reading, object placement tasks, and mobility.Comprehensive vision assessment in low vision populations is necessary to identify the extent of remaining vision and to enable directed rehabilitation efforts. In patients with vision impairment, little attention is typically paid to assessments of binocular vision, including ocular vergence, stereopsis, and binocular summation characteristics. In addition, binocular measurements of threshold automated visual fields are not routinely performed in clinical practice, leading to an incomplete understanding of individuals' binocular visual field and may affect rehabilitation outcomes.First, this review summarizes the prevalence of dysfunctions in ocular vergence, stereopsis, and binocular summation characteristics across a variety of ocular pathologies causing vision impairment. Second, this review examines the links between clinical measurements of binocular visual functions and outcome measures including quality of life and performance in functional tasks. There is an increased prevalence of dysfunctions in ocular alignment, stereopsis, and binocular summation across low vision cohorts compared with those with normal vision. The identification of binocular vision dysfunctions during routine low vision assessments is especially important in patients experiencing difficulties in activities of daily living, including but not limited to reading, object placement tasks, and mobility. However, further research is required to determine whether addressing the identified deficits in binocular vision in low vision rehabilitative efforts directly impacts patient outcomes.

Modelling normal age-related changes in individual retinal layers using location-specific OCT analysis.

Current descriptions of retinal thickness across normal age cohorts are mostly limited to global analyses, thus overlooking spatial variation across the retina and limiting spatial analyses of retinal and optic nerve disease. This retrospective cross-sectional study uses location-specific cluster analysis of 8 × 8 macular average grid-wise thicknesses to quantify topographical patterns and rates of normal, age-related changes in all individual retinal layers of 253 eyes of 253 participants across various age cohorts (n = 23-69 eyes per decade). Most retinal layers had concentric spatial cluster patterns except the retinal nerve fibre layer (RNFL) which displayed a nasal, asymmetric radial pattern. Age-related thickness decline mostly occurred after the late 4th decade, described by quadratic regression models. The ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), and outer nuclear layer + Henle's fibre layer (ONL+HFL) were significantly associated with age (p < 0.0001 to < 0.05), demonstrating similar rates of thickness decline (mean pooled slope = - 0.07 µm/year), while the IS/OS had lesser mean pooled thickness slopes for all clusters (- 0.04 µm/year). The RNFL, OPL, and RPE exhibited no significant age-related thickness change, and the RNFL were significantly associated with sex. Analysis using spatial clusters compared to the ETDRS sectors revealed more extensive spatial definition and less variability in the former method. These spatially defined, clustered normative data and age-correction functions provide an accessible method of retinal thickness analysis with more spatial detail and less variability than the ETDRS sectors, potentially aiding the diagnosis and monitoring of retinal and optic nerve disease.

Remote Grading of the Anterior Chamber Angle Using Goniophotographs and Optical Coherence Tomography: Implications for Telemedicine or Virtual Clinics.

PURPOSE: To evaluate the agreement and accuracy of grading goniophotographs and anterior segment optical coherence tomography (AS-OCT) results for assessment of the anterior chamber angle, and elicit factors driving concordance between perceived grade and ground truth. METHODS: Three clinicians evaluated the goniophotographs and AS-OCT results of 75 patients. Graders' impressions of the angle grade, trabecular pigmentation, and iris contour were compared with the ground truth gonioscopic examination result when physically performed by a senior optometrist. Percentage agreement and kappa statistics were calculated. Binary logistic regression was used to elicit factors for accurate grading. RESULTS: Exact angle matches and binary (open or closed) evaluations were above guessing rate for all graders. There was a systematic bias toward underestimating the angle structure across all graders, especially at the superior angle, by approximately 1 ordinal unit. Kappa statistics showed fair-moderate agreement for exact (0.387-0.520) and binary (0.347-0.520) angle evaluations. Agreement was unchanged when using a multimodal approach (0.373-0.523). Factors driving concordance were primarily related to the extremes of the anterior chamber angle configuration (shallow or deep structures, and iris contour). However, prediction models did not fully explain the levels of concordance with the ground truth (maximum R 2 amongst models 0.177). CONCLUSIONS: Although moderate agreement between graders and ground truth could be obtained under binary evaluations, angle grades were generally underestimated. Factors affecting concordance were primarily the extremes of the ground truth angle and iris contour. TRANSLATIONAL RELEVANCE: We highlight factors affecting accuracy of grading goniophotography and AS-OCT images of the anterior chamber angle.