Defining the structure-function relationship of specific lesions in early and advanced age-related macular degeneration.

The objective of this study is to define structure-function relationships of pathological lesions related to age-related macular degeneration (AMD) using microperimetry and multimodal retinal imaging. We conducted a cross-sectional study of 87 patients with AMD (30 eyes with early and intermediate AMD and 110 eyes with advanced AMD), compared to 33 normal controls (66 eyes) recruited from a single tertiary center. All participants had enface and cross-sectional optical coherence tomography (Heidelberg HRA-2), OCT angiography, color and infra-red (IR) fundus and microperimetry (MP) (Nidek MP-3) performed. Multimodal images were graded for specific AMD pathological lesions. A custom marking tool was used to demarcate lesion boundaries on corresponding enface IR images, and subsequently superimposed onto MP color fundus photographs with retinal sensitivity points (RSP). The resulting overlay was used to correlate pathological structural changes to zonal functional changes. Mean age of patients with early/intermediate AMD, advanced AMD and controls were 73(SD = 8.2), 70.8(SD = 8), and 65.4(SD = 7.7) years respectively. Mean retinal sensitivity (MRS) of both early/intermediate (23.1 dB; SD = 5.5) and advanced AMD (18.1 dB; SD = 7.8) eyes were significantly worse than controls (27.8 dB, SD = 4.3) (p < 0.01). Advanced AMD eyes had significantly more unstable fixation (70%; SD = 63.6), larger mean fixation area (3.9 mm2; SD = 3.0), and focal fixation point further away from the fovea (0.7 mm; SD = 0.8), than controls (29%; SD = 43.9; 2.6 mm2; SD = 1.9; 0.4 mm; SD = 0.3) (p ≤ 0.01). Notably, 22 fellow eyes of AMD eyes (25.7 dB; SD = 3.0), with no AMD lesions, still had lower MRS than controls (p = 0.04). For specific AMD-related lesions, end-stage changes such as fibrosis (5.5 dB, SD = 5.4 dB) and atrophy (6.2 dB, SD = 7.0 dB) had the lowest MRS; while drusen and pigment epithelial detachment (17.7 dB, SD = 8.0 dB) had the highest MRS. Peri-lesional areas (20.2 dB, SD = 7.6 dB) and surrounding structurally normal areas (22.2 dB, SD = 6.9 dB) of the retina with no AMD lesions still had lower MRS compared to controls (27.8 dB, SD = 4.3 dB) (p < 0.01). Our detailed topographic structure-function correlation identified specific AMD pathological changes associated with a poorer visual function. This can provide an added value to the assessment of visual function to optimize treatment outcomes to existing and potentially future novel therapies.

Relationship Between Retinal Layer Thickness and Genetic Susceptibility to Age-Related Macular Degeneration in Asian Populations.

Purpose: For OCT retinal thickness measurements to be used as a prodromal age-related macular degeneration (AMD) risk marker, the 3-dimensional (3D) topographic variation of the relationship between genetic susceptibility to AMD and retinal thickness needs to be assessed. We aimed to evaluate individual retinal layer thickness changes and topography at the macula that are associated with AMD genetic susceptibility. Design: Genetic association study. Participants: A total of 1579 healthy participants (782 Chinese, 353 Malays, and 444 Indians) from the multiethnic Singapore Epidemiology of Eye Diseases study were included. Methods: Spectral-domain OCT and automatic segmentation of individual retinal layers were performed to produce 10 retinal layer thickness measurements at each ETDRS subfield, producing 3D topographic information. Age-related macular degeneration genetic susceptibility was represented via single nucleotide polymorphisms (SNPs) and aggregated via whole genome (overall) and pathway-specific age-related macular degeneration polygenic risk score (PRSAMD). Main Outcome Measures: Associations of individual SNPs, overall PRSAMD, and pathway-specific PRSAMD with retinal thickness were analyzed by individual retinal layer and ETDRS subfield. Results: CFH rs10922109, ARMS2-HTRA1 rs3750846, and LIPC rs2043085 were the top AMD susceptibility SNPs associated with retinal thickness of individual layers (P < 1.67 × 10-3), all at the central subfield. The overall PRSAMD was most associated with thinner L9 (outer segment photoreceptor/retinal pigment epithelium complex) thickness at the central subfield (ß = -0.63 µm; P = 5.45 × 10-9). Pathway-specific PRSAMD for the complement cascade (ß = -0.53 µm; P = 9.42 × 10-7) and lipoprotein metabolism (ß = -0.05 µm; P = 0.0061) were associated with thinner photoreceptor layers (L9 and L7 [photoreceptor inner/outer segments], respectively) at the central subfield. The mean PRSAMD score was larger among Indians compared with that of the Chinese and had the thinnest thickness at the L9 central subfield (ß = -1.00 µm; P = 2.91 × 10-7; R2 = 5.5%). Associations at other retinal layers and ETDRS regions were more heterogeneous. Conclusions: Overall genetic susceptibility to AMD and the aggregate effects of the complement cascade and lipoprotein metabolism pathway are associated most significantly with L7 and L9 photoreceptor thinning at the central macula in healthy individuals. Photoreceptor thinning has potential to be a prodromal AMD risk marker, and topographic variation should be considered. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Normative Data and Associations of OCT Angiography Measurements of the Macula: The Singapore Malay Eye Study.

OBJECTIVE: To describe the normative quantitative parameters of the macular retinal vasculature, as well as their systemic and ocular associations using OCT angiography (OCTA). DESIGN: Population-based, cross-sectional study. SUBJECTS: Adults aged > 50 years were recruited from the third examination of the population-based Singapore Malay Eye Study. METHODS: All participants underwent a standardized comprehensive examination and spectral-domain OCTA (Optovue) of the macula. OCT angiography scans that revealed pre-existing retinal disease, revealed macular pathology, and had poor quality were excluded. MAIN OUTCOME MEASURES: The normative quantitative vessel densities of the superficial layer, deep layer, and foveal avascular zone (FAZ) were evaluated. Ocular and systemic associations with macular retinal vasculature parameters were also evaluated in a multivariable analysis using linear regression models with generalized estimating equation models. RESULTS: We included 1184 scans (1184 eyes) of 749 participants. The mean macular superficial vessel density (SVD) and deep vessel density (DVD) were 45.1 ± 4.2% (95% confidence interval [CI], 37.8%-51.4%) and 44.4 ± 5.2% (95% CI, 36.9%-53.2%), respectively. The mean SVD and DVD were highest in the superior quadrant (48.7 ± 5.9%) and nasal quadrant (52.7 ± 4.6%), respectively. The mean FAZ area and perimeter were 0.32 ± 0.11 mm2 (95% CI, 0.17-0.51 mm) and 2.14 ± 0.38 mm (95% CI, 1.54-2.75 mm), respectively. In the multivariable regression analysis, female sex was associated with higher SVD (ß = 1.25, P ≤ 0.001) and DVD (ß = 0.75, P = 0.021). Older age (ß = -0.67, P < 0.001) was associated with lower SVD, whereas longer axial length (ß = -0.42, P = 0.003) was associated with lower DVD. Female sex, shorter axial length, and worse best-corrected distance visual acuity were associated with a larger FAZ area. No association of a range of systemic parameters with vessel density was found. CONCLUSIONS: This study provided normative macular vasculature parameters in an adult Asian population, which may serve as reference values for quantitative interpretation of OCTA data in normal and disease states.

Retinal neural dysfunction in diabetes revealed with handheld chromatic pupillometry.

BACKGROUND: To evaluate the ability of handheld chromatic pupillometry to reveal and localise retinal neural dysfunction in diabetic patients with and without diabetic retinopathy (DR). METHODS: This cross-sectional study included 82 diabetics (DM) and 93 controls (60.4 ± 8.4 years, 44.1% males). DM patients included those without (n = 25, 64.7 ± 6.3 years, 44.0% males) and with DR (n = 57, 60.3 ± 8.5 years, 64.9% males). Changes in horizontal pupil radius in response to blue (469 nm) and red (640 nm) light stimuli were assessed monocularly, in clinics, using a custom-built handheld pupillometer. Pupillometric parameters (phasic constriction amplitudes [predominantly from the outer retina], maximal constriction amplitudes [from the inner and outer retina] and post-illumination pupillary responses [PIPRs; predominantly from the inner retina]) were extracted from baseline-adjusted pupillary light response traces and compared between controls, DM without DR, and DR. Net PIPR was defined as the difference between blue and red PIPRs. RESULTS: Phasic constriction amplitudes to blue and red lights were decreased in DR compared to controls (p < 0.001; p < 0.001). Maximal constriction amplitudes to blue and red lights were decreased in DR compared to DM without DR (p < 0.001; p = 0.02), and in DM without DR compared to controls (p < 0.001; p = 0.005). Net PIPR was decreased in both DR and DM without DR compared to controls (p = 0.02; p = 0.03), suggesting a wavelength-dependent (and hence retinal) pupillometric dysfunction in diabetic patients with or without DR. CONCLUSIONS: Handheld chromatic pupillometry can reveal retinal neural dysfunction in diabetes, even without DR. Patients with DM but no DR displayed primarily inner retinal dysfunction, while patients with DR showed both inner and outer retinal dysfunction.

Three-dimensional modelling of the choroidal angioarchitecture in a multi-ethnic Asian population.

This study aimed to describe the topographic variation of the macula's choroidal angioarchitecture using three-dimensional (3D) choroidal vascularity index (CVI) of healthy eyes from an Asian population and to investigate the associations of CVI. 50 participants were recruited via stratified randomisation based on subfoveal choroidal thickness from the Singapore Epidemiology of Eye Diseases Study. Macular volume scans were acquired using spectral-domain optical coherence tomography with enhanced depth imaging. CVI was assessed based on B-scan binarisation and choroid segmentation. The 3D CVI of the whole, superior, central, and inferior macula were 62.92 ± 1.57%, 62.75 ± 1.93%, 63.35 ± 1.72%, and 62.66 ± 1.70%, respectively, pairwise comparisons P all > 0.05). 3D CVI (Whole Macula) and 2D CVI (Subfoveal) were associated only with each other and not with other ocular and systemic factors. 2D CVI (Subfoveal) had a moderate agreement with 3D CVI (Central Macula) [intraclass corelation coefficient (ICC) = 0.719], and had poorer agreement with 3D CVI of the whole macula, superior, and inferior macula (ICC = 0.591, 0.483, and 0.394, respectively). Scanning volume did not influence 3D CVI measurements. In conclusion, 3D CVI demonstrated no significant topographic variation. CVI was not correlated with demographic or ocular structural features. 2D CVI of the fovea is partially representative of 3D CVI of the macula.

Novel volumetric imaging biomarkers for assessing disease activity in eyes with PCV.

The aim of this study was to evaluate influence of baseline imaging features on visual and anatomical outcomes in eyes with PCV treated with anti-VEGF monotherapy. In this prospective study we enrolled participants with treatment-naïve PCV who followed a treat-and-extend protocol using intravitreal aflibercept (IVA) monotherapy. Baseline clinical features evaluatedincluded best corrected visual acuity (BCVA), traditional features such as lesion size, fluid-related OCT parameters and novel parameters using automated software. This included quantitative and qualitative pigment epithelium detachment (PED) parameters [height, volume]; and choroidal parameters. [choroidal thickness (CT), choroidal volume (CV) and choroidal vascularity index (CVI). We evaluated the predictive value of each parameter on visual and anatomical outcome at month 12. We additionally evaluated initial treatment response after 3 monthly injections with respect to month 12 outcomes. Fifty-two eyes from 52 participants were included in the study. The BCVA increased from 61.1 ± 13.2 to 69.6 ± 13.2 early treatment diabetic retinopathy study (ETDRS) letters (p < 0.01) and CRT reduced from 455.7 ± 182.4 µm to 272.7 ± 86.2 (p < 0.01) from baseline to month 12. The proportion of eyes with PED decreased significant from 100% at baseline to 80% at month 12 (p < 0.01). Reduction in the mean maximum height of PED (from 381.3 ± 236.3 µm to 206.8 vs ± 146.4 µm) and PED volume (from 1322 ± 853 nl to 686 ± 593 nl) (p < 0.01) was also noted from baseline to month12. Baseline features associated with better month 12 BCVA included baseline BCVA (ß = - 0.98, 95%CI - 3.38 to - 1.61, p = 0.02) and baseline CRT (ß = - 0.98, 95%CI - 1.56 to - 0.40, p = 0.04) while the disease activity at month12 was significantly associated with lower baseline CRT (366.0 ± 129.5 vs 612.0 ± 188.0 , p < 0.001), lower baseline PED height (242.0 ± 150.0 vs 542.0 ± 298.0 µm, p < 0.01), lower baseline PED volume (0.6 ± 0.3 mm3 vs 2.2 ± 1.3 mm3 vs, p < 0.01), lower proportion with marked CVH (17.9% vs 46.2%, p = 0.02) and lower mean CVI (61.8 ± 1.4 vs 63.0 ± 1.4, p < 0.02). Additionally, a larger decrease in CRT (per 100 nm) and larger PED volume reduction (per 100 nl) at month 3 from baseline were associated with greater BCVA gain and inactive disease. PED-related volumetric parameters have an additional predictive value to traditional biomarkers of disease activity in eyes with PCV undergoing anti-VEGF monotherapy. With increasingly precise quantification, PEDs can be a crucial biomarker in addition to traditional parameters and may aid in retreatment decisions.

New digital models of care in ophthalmology, during and beyond the COVID-19 pandemic.

COVID-19 has led to massive disruptions in societal, economic and healthcare systems globally. While COVID-19 has sparked a surge and expansion of new digital business models in different industries, healthcare has been slower to adapt to digital solutions. The majority of ophthalmology clinical practices are still operating through a traditional model of 'brick-and-mortar' facilities and 'face-to-face' patient-physician interaction. In the current climate of COVID-19, there is a need to fuel implementation of digital health models for ophthalmology. In this article, we highlight the current limitations in traditional clinical models as we confront COVID-19, review the current lack of digital initiatives in ophthalmology sphere despite the presence of COVID-19, propose new digital models of care for ophthalmology and discuss potential barriers that need to be considered for sustainable transformation to take place.

Digital Technology for AMD Management in the Post-COVID-19 New Normal.

PURPOSE: The COVID-19 pandemic has put strain on healthcare systems and the availability and allocation of healthcare manpower, resources and infrastructure. With immediate priorities to protect the health and safety of both patients and healthcare service providers, ophthalmologists globally were advised to defer nonurgent cases, while at the same time managing sight-threatening conditions such as neovascular Age-related Macular Degeneration (AMD). The management of AMD patients both from a monitoring and treatment perspective presents a particular challenge for ophthalmologists. This review looks at how these pressures have encouraged the acceptance and speed of adoption of digitalization. DESIGN AND METHODS: A literature review was conducted on the use of digital technology during COVID-19 pandemic, and on the transformation of medicine, ophthalmology and AMD screening through digitalization. RESULTS: In the management of AMD, the implementation of artificial intelligence and "virtual clinics" have provided assistance in screening, diagnosis, monitoring of the progression and the treatment of AMD. In addition, hardware and software developments in home monitoring devices has assisted in self-monitoring approaches. CONCLUSIONS: Digitalization strategies and developments are currently ongoing and underway to ensure early detection, stability and visual improvement in patients suffering from AMD in this COVID-19 era. This may set a precedence for the post COVID-19 new normal where digital platforms may be routine, standard and expected in healthcare delivery.

POLYPOIDAL CHOROIDAL VASCULOPATHY FEATURES VARY ACCORDING TO SUBFOVEAL CHOROIDAL THICKNESS.

PURPOSE: To evaluate associations between choroidal thickness and features of polypoidal choroidal vasculopathy (PCV) lesions based on multimodal imaging. METHODS: This cross-sectional analysis included treatment-naive PCV eyes from a prospectively recruited observational cohort. Associations between of subfoveal choroidal thickness (SFCT) and qualitative and quantitative morphologic features of PCV lesions on color fundus photographs, indocyanine green and fluorescein angiography, and spectral-domain optical coherence tomography were evaluated. RESULTS: We included 100 eyes with indocyanine green angiography-proven PCV. Subfoveal choroidal thickness showed a bimodal distribution with peaks at 170 µm and 350 µm. There was a significant linear increase in the total lesion area (P-trend = 0.028) and the polypoidal lesion area (P-trend = 0.030 and P-continuous = 0.037) with increasing SFCT. Pairwise comparisons between quartiles showed that the total lesion area (4.20 ± 2.61 vs. 2.89 ± 1.43 mm2, P = 0.024) and the polypoidal lesion area (1.03 ± 1.01 vs. 0.59 ± 0.45 mm2, P = 0.042) are significantly larger in eyes in Q4 (SFCT ≥ 350 µm) than eyes in Q1 (SFCT ≤ 170 µm). Although there was no significant linear trend relating SFCT to best-corrected visual acuity, pairwise comparisons showed that eyes in Q4 (SFCT ≥ 350 µm) have significantly worse vision (0.85 ± 0.63 vs. 0.55 ± 0.27 logMAR, P = 0.030) than eyes in Q2 (SFCT 170-260 µm). CONCLUSION: Total lesion areas and polypoidal lesion areas tend to be larger in eyes with increasing SFCT. Choroidal background may influence the phenotype or progression pattern of PCV.

Intravitreal Injection with a Conjunctival Injection Device: A Single-Center Experience.

Purpose: To evaluate the clinical performance of the intravitreal injection assistant device (InVitria) compared with the conventional freehand technique for delivering intravitreal injections. Methods: Seventy patients were randomized to receive intravitreal injections via the conventional freehand technique while 70 received injections using the InVitria. Half of all procedures in each group were performed by junior surgeons, while the rest were performed by senior surgeons. Results: Mean injections times were 90.0 ± 23.3 seconds and 64.9 ± 26.8 seconds for conventional versus InVitria (P < 0.001). Mean injection times with the conventional technique were 85.5 ± 23.0 seconds vs. 94.2 ± 23.0 seconds for senior versus junior surgeons (P = 0.120). Mean injection times with the InVitria were 56.1 ± 26.1 seconds vs. 66.3 ± 26.9 seconds (P = 0.211) for senior versus junior surgeons. There were no significant differences in pain scores regardless of technique (conventional versus In Vitria: 2.03 ± 1.73 vs. 2.13 ± 2.20, P = 0.770). Conclusions: In our experience, the InVitria is a comparable alternative to the conventional freehand technique of delivering intravitreal injections, with the potential for faster injection times and without compromising on patient comfort. Translational Relevance: The study provides evidence to suggest that the InVitria may be deployed effectively in clinical practice.

Choroidal Thickness Changes in Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy: A 12-Month Prospective Study.

PURPOSE: To describe 12-month changes in choroidal thickness after anti-vascular endothelial growth factor (anti-VEGF) therapy for typical age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV). DESIGN: Prospective, consecutive, noninterventional, longitudinal case series. METHODS: This study included patients with typical AMD and PCV who received anti-VEGF therapy over a 12-month period. We used spectral-domain optical coherence tomography with enhanced depth imaging mode to measure choroidal thickness. RESULTS: Of the 163 patients, 77 had typical AMD and 86 had PCV. Patients with PCV were younger (67.6 vs 72.5 years, P < .01) and received fewer anti-VEGF injections (3.9 vs 5.6, P = .02) than patients with typical AMD. Baseline subfoveal choroidal thickness was not significantly different between PCV and typical AMD eyes, and was thicker in the study eye compared to fellow eye in the typical AMD group (223.1 vs 208.8 µm, P < .01). Subfoveal choroidal thickness decreased significantly in both typical AMD (213.7 µm to 190.3 µm, P < .001) and PCV (240.8 µm to 213.4 µm, P < .01) eyes, but no significant change was noted in fellow unaffected eyes. Reduction in choroidal thickness was associated with elevated C-reactive protein (odds ratio [OR]: 1.4, P = .04) and smoking (OR: 7.6, P = .03) at baseline, but not with age, refractive error, diagnosis of typical AMD or PCV, number or type of anti-VEGF injections, PDT therapy, or baseline choroidal thickness. CONCLUSIONS: A significant reduction in subfoveal choroidal thickness was noted after anti-VEGF therapy in typical AMD and PCV. Choroidal thickness changes were similar despite differences in number of anti-VEGF treatment.

The outcomes of primary pediatric keratoplasty in Singapore.

PURPOSE: To evaluate the long-term corneal graft survival and risk factors for graft failure in pediatric eyes. DESIGN: Retrospective, interventional consecutive case series. METHODS: Unilateral eyes of 105 patients aged 16 years and below were included from the Singapore Corneal Transplant Study between April 4, 1991 and April 4, 2011. Corneal graft survival was calculated using Kaplan-Meier survival analysis, and survival distributions were compared using log-rank test. RESULTS: Mean recipient age was 8.38 ± 5.63 years (range 0.18-15.92 years). Mean follow-up time was 34.16 ± 39.10 months. Main diagnoses were corneal scar (22.9%), limbal dermoid (21.9%), anterior segment dysgenesis (15.2%), and keratoconus (14.3%). Forty-four eyes (41.9%) underwent penetrating keratoplasty (PK), 37 (35.2%) underwent anterior lamellar keratoplasty (ALK), 22 (21.0%) underwent lamellar corneal patch graft, and 2 (1.9%) underwent Descemet stripping automated endothelial keratoplasty (DSAEK). Kaplan-Meier survival rates for PK were 92.8% at 1 year, 88.9% at 2-4 years, and 80.9% at 5-16 years; survival rates for ALK were 88.0% at 1 year and 84.3% at 2-7 years; survival rates for corneal patch graft were 100% at 1-3 years and 90% at 4-10 years; these were not statistically significant (P = .362). Deep corneal vascularization (P = .012), preexisting active inflammation (P = .023), preexisting glaucoma drainage device (P = .023), and preexisting ocular surface disease (P = .037) were associated with reduced graft survival in a univariate analysis. CONCLUSIONS: We report good long-term graft survival following pediatric keratoplasty for various indications. Lamellar keratoplasty, when indicated, should be the procedure of choice in high-risk keratoplasties.