HYPERREFLECTIVE FOCI NOT SEEN AS HYPERPIGMENTARY ABNORMALITIES ON COLOR FUNDUS PHOTOGRAPHS IN AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To investigate the prognostic value of quantifying optical coherence tomography (OCT)-defined hyperreflective foci (HRF) that do not correspond to hyperpigmentary abnormalities (HPAs) on color fundus photographs (CFPs)-HRF (OCT+/CFP-) -when considered in addition to HPA extent, for predicting late age-related macular degeneration development. This study sought to understand the impact of HRF (OCT+/CFP-) extent on visual sensitivity. METHODS: Two hundred eighty eyes from 140 participants with bilateral large drusen underwent imaging and microperimetry at baseline, and then 6-monthly for 3-years. The extent of HPAs on CFPs and HRF (OCT+/CFP-) on OCT was quantified at baseline. Predictive models for progression to late age-related macular degeneration, accounting for drusen volume and age, were developed using HPA extent, with and without HRF (OCT+/CFP-) extent. The association between HPA and HRF (OCT+/CFP-) extent with sector-based visual sensitivity was also evaluated. RESULTS: Incorporating HRF (OCT+/CFP-) extent did not improve the predictive performance for late age-related macular degeneration development ( P ≥ 0.32). Increasing HPA and HRF (OCT+/CFP-) extent in each sector were independently and significantly associated with reduced sector-based visual sensitivity ( P ≤ 0.004). CONCLUSION: The addition of HRF (OCT+/CFP-) extent to HPA extent did not improve the prediction of late age-related macular degeneration development. HRF (OCT+/CFP-) extent was also independently associated with local reductions in visual sensitivity, after accounting for HPAs.

A semi-automated pipeline for quantifying drusen-like deposits in human induced pluripotent stem cell-derived retinal pigment epithelium cells.

Age-Related Macular Degeneration (AMD) is a highly prevalent form of retinal disease amongst Western communities over 50 years of age. A hallmark of AMD pathogenesis is the accumulation of drusen underneath the retinal pigment epithelium (RPE), a biological process also observable in vitro. The accumulation of drusen has been shown to predict the progression to advanced AMD, making accurate characterisation of drusen in vitro models valuable in disease modelling and drug development. More recently, deposits above the RPE in the subretinal space, called reticular pseudodrusen (RPD) have been recognized as a sub-phenotype of AMD. While in vitro imaging techniques allow for the immunostaining of drusen-like deposits, quantification of these deposits often requires slow, low throughput manual counting of images. This further lends itself to issues including sampling biases, while ignoring critical data parameters including volume and precise localization. To overcome these issues, we developed a semi-automated pipeline for quantifying the presence of drusen-like deposits in vitro, using RPE cultures derived from patient-specific induced pluripotent stem cells (iPSCs). Using high-throughput confocal microscopy, together with three-dimensional reconstruction, we developed an imaging and analysis pipeline that quantifies the number of drusen-like deposits, and accurately and reproducibly provides the location and composition of these deposits. Extending its utility, this pipeline can determine whether the drusen-like deposits locate to the apical or basal surface of RPE cells. Here, we validate the utility of this pipeline in the quantification of drusen-like deposits in six iPSCs lines derived from patients with AMD, following their differentiation into RPE cells. This pipeline provides a valuable tool for the in vitro modelling of AMD and other retinal disease, and is amenable to mid and high throughput screenings.

A Deep Learning Framework for the Detection and Quantification of Reticular Pseudodrusen and Drusen on Optical Coherence Tomography.

Purpose: The purpose of this study was to develop and validate a deep learning (DL) framework for the detection and quantification of reticular pseudodrusen (RPD) and drusen on optical coherence tomography (OCT) scans. Methods: A DL framework was developed consisting of a classification model and an out-of-distribution (OOD) detection model for the identification of ungradable scans; a classification model to identify scans with drusen or RPD; and an image segmentation model to independently segment lesions as RPD or drusen. Data were obtained from 1284 participants in the UK Biobank (UKBB) with a self-reported diagnosis of age-related macular degeneration (AMD) and 250 UKBB controls. Drusen and RPD were manually delineated by five retina specialists. The main outcome measures were sensitivity, specificity, area under the receiver operating characteristic (ROC) curve (AUC), kappa, accuracy, intraclass correlation coefficient (ICC), and free-response receiver operating characteristic (FROC) curves. Results: The classification models performed strongly at their respective tasks (0.95, 0.93, and 0.99 AUC, respectively, for the ungradable scans classifier, the OOD model, and the drusen and RPD classification models). The mean ICC for the drusen and RPD area versus graders was 0.74 and 0.61, respectively, compared with 0.69 and 0.68 for intergrader agreement. FROC curves showed that the model's sensitivity was close to human performance. Conclusions: The models achieved high classification and segmentation performance, similar to human performance. Translational Relevance: Application of this robust framework will further our understanding of RPD as a separate entity from drusen in both research and clinical settings.

Hyperpigmentary abnormalities in age-related macular degeneration: association with progression and impact on visual sensitivity.

BACKGROUND/AIMS: To investigate the additional prognostic value of quantifying the extent of colour fundus photography (CFP)-defined hyperpigmentary abnormalities (HPAs) compared with their presence alone for predicting progression to late-stage age-related macular degeneration (AMD) and to understand their association with visual sensitivity in individuals with intermediate AMD. METHODS: 140 participants with bilateral large drusen underwent multimodal imaging and microperimetry at baseline and then every 6 months for up to 3 years. Baseline CFPs were graded for the presence of HPAs and their extent was quantified. Optical coherence tomography (OCT) scans were used to quantify drusen volume. Predictive models for progression to late AMD (including OCT signs of atrophy) were developed using either HPA presence or extent. The association between HPA extent with mean visual sensitivity (both overall and sector based) was also evaluated. All models were adjusted for the confounders of baseline age and drusen volume. RESULTS: The predictive performance for late AMD development was not significantly different for HPA presence or extent (p=0.92). Increasing HPA extent in each sector, but not its overall extent in an eye, was associated with reduced sector-based visual sensitivity (p<0.001 and p=0.671, respectively). CONCLUSION: In a cohort with bilateral large drusen, quantifying HPA extent did not improve the prediction of late AMD development compared with presence alone. HPA extent was associated with more local, rather than generalised, reductions in visual sensitivity. These findings suggest that quantification of HPA extent adds little to the prediction of AMD progression, but that it provides an imaging biomarker of visual dysfunction.

Exploring Reticular Pseudodrusen Extent and Impact on Mesopic Visual Sensitivity in Intermediate Age-Related Macular Degeneration.

Purpose: To explore the impact of the extent of reticular pseudodrusen (RPD) on mesopic visual sensitivity in individuals with intermediate age-related macular degeneration (AMD). Methods: In total, 570 eyes from 285 participants with bilateral large drusen underwent microperimetry testing to assess the visual sensitivity of the central 3.6-mm region and multimodal imaging to determine the extent of RPD in the central 20° × 20° region (at the eye level). Mean visual sensitivity within five sectors in the central 3.6-mm region sampled on microperimetry and the extent of RPD in these sectors were derived. Linear mixed models were used to examine the association between the extent of RPD on overall mean visual sensitivity and sector-based mean sensitivity. Results: An increasing extent of RPD at the eye level and within sectors was associated with a significant reduction in overall and sector-based mean sensitivity, respectively (P < 0.001 for both). However, when both RPD parameters were considered together in a multivariable model, only an increasing extent of RPD at the eye level (P < 0.001) and not within each sector (P = 0.178) was independently associated with reduced sector-based mean sensitivity. Conclusions: Mesopic visual sensitivity is generally reduced in eyes with large drusen and coexistent RPD compared to eyes without RPD, with greater reductions with an increasing extent of RPD. However, reduced sector-based visual sensitivities are explained by the overall extent of RPD present, rather than their extent within the sector itself. These findings suggest that there are generalized pathogenic changes in eyes with RPD accounting for the observed mesopic visual dysfunction.

Reticular Pseudodrusen on the Risk of Progression in Intermediate Age-Related Macular Degeneration.

PURPOSE: To examine the association between reticular pseudodrusen (RPD) and progression to late age-related macular degeneration (AMD) in individuals with intermediate AMD. DESIGN: Prospective cohort study. METHODS: Two hundred eighty eyes from 140 participants with bilateral large drusen underwent multimodal imaging (MMI), including optical coherence tomography (OCT), near-infrared reflectance (NIR), fundus autofluorescence, and color fundus photography (CFP), at 6-monthly intervals up over a 36-month follow-up period. The presence of RPD per eye was determined based on either a combined MMI criterion, or each individual imaging modality, and their extent measured on combined OCT and NIR imaging. The association between the presence of RPD on different imaging modalities, and their extent, with the development of late AMD (including OCT-defined atrophy) was evaluated. RESULTS: The presence of RPD on MMI, or any of its individual modalities, at baseline was not significantly associated with an increased rate of developing late AMD, with or without adjusting for risk factors for AMD progression (age, drusen volume on OCT, and pigmentary abnormalities on CFP; all P ≥ 0.205). The extent of RPD present was also not significantly associated with an increased rate of developing late AMD, with or without adjustment for risk factors for AMD progression (both P ≥ 0.522). CONCLUSIONS: In this cohort with bilateral large drusen, the presence of RPD was not significantly associated with an increased risk of developing late AMD. Additional longitudinal studies in all stages of AMD are needed to understand the implications of RPD on vision loss in this condition.

A clinical perspective on the expanding role of artificial intelligence in age-related macular degeneration.

In recent years, there has been intense development of artificial intelligence (AI) techniques, which have the potential to improve the clinical management of age-related macular degeneration (AMD) and facilitate the prevention of irreversible vision loss from this condition. Such AI techniques could be used as clinical decision support tools to: (i) improve the detection of AMD by community eye health practitioners, (ii) enhance risk stratification to enable personalised monitoring strategies for those with the early stages of AMD, and (iii) enable early detection of signs indicative of possible choroidal neovascularisation allowing triaging of patients requiring urgent review. This review discusses the latest developments in AI techniques that show promise for these tasks, as well as how they may help in the management of patients being treated for choroidal neovascularisation and in accelerating the discovery of new treatments in AMD.

Reticular pseudodrusen: A critical phenotype in age-related macular degeneration.

Reticular pseudodrusen (RPD), or subretinal drusenoid deposits (SDD), refer to distinct lesions that occur in the subretinal space. Over the past three decades, their presence in association with age-related macular degeneration (AMD) has become increasingly recognized, especially as RPD have become more easily distinguished with newer clinical imaging modalities. There is also an increasing appreciation that RPD appear to be a critical AMD phenotype, where understanding their pathogenesis will provide further insights into the processes driving vision loss in AMD. However, key barriers to understanding the current evidence related to the independent impact of RPD include the heterogeneity in defining their presence, and failure to account for the confounding impact of the concurrent presence and severity of AMD pathology. This review thus critically discusses the current evidence on the prevalence and clinical significance of RPD and proposes a clinical imaging definition of RPD that will help move the field forward in gathering further key knowledge about this critical phenotype. It also proposes a putative mechanism for RPD formation and how they may drive progression to vision loss in AMD, through examining current evidence and presenting novel findings from preclinical and clinical studies.

Idiopathic hypertrophic cranial polyneuropathy: a rare cause of orbital pain.

Hypertrophic cranial polyneuropathy (HCP) is sporadically encountered in clinical practice. Aetiologies of HCP have been classified as autoimmune, infectious and demyelinating. However, an accurate diagnosis remains elusive in some cases despite rigorous investigations. These cases represent idiopathic HCP. Given the high clinical variance in presenting symptoms, HCP often leaves medical practitioners in a diagnostic quandary. Here, we seek to expand current knowledge by reporting the first documented case of idiopathic HCP presenting atypically with unilateral orbital pain and exclusively involving the bilateral trigeminal nerves.

Hypertension, blood pressure control and diabetic retinopathy in a large population-based study.

BACKGROUND: Clinical trials have shown beneficial effects of blood pressure (BP) control in reducing the risk of diabetic retinopathy (DR). However, association between BP control and DR in population-based studies is not clear. We aimed to examine the association of hypertension and BP control with DR. METHODS: We analysed data from a population-based cross-sectional study of Chinese, Malay and Indians adults with diabetes and hypertension (2004-2011, n = 2189, aged 40-80 years) in Singapore. DR severity was assessed from retinal photographs and graded for any- and vision-threatening DR (VTDR) using the modified Airlie House classification. Hypertension status was classified into (1) good control: on treatment (SBP < 130 and DBP < 80 mm Hg), (2) moderate control: on treatment, with BP levels other than group 1 and 3, (3) poor control: on treatment (SBP ≥140 and DBP ≥ 90 mm Hg), (4) untreated hypertension, any BP level. SBP, DBP and pulse pressure (PP) were analyzed as categories and as continuous variables. The association between BP and DR was assessed using multivariable logistic regression models. RESULTS: The prevalence of any-DR and VTDR in the study population was 33.8% and 9.0% respectively. Both poorly controlled and untreated hypertension were significantly associated with any-DR with odds ratio (OR) (95% confidence interval [CI]) of 1.97 (1.39-2.83), and 2.01 [1.34-3.05]. Among BP components, SBP and PP were associated with both any-DR and VTDR with OR (95% CI) of 1.45 (1.28-1.65) and 1.61 (1.41-1.84) for any-DR, and 1.44 (1.19-1.76) and 1.67 (1.37-2.06) for VTDR. CONCLUSION: In a population-based sample of Asian adults with diabetes and hypertension, treated but poorly controlled as well as untreated hypertension were significantly associated with any-DR. Among the BP components, higher SBP and PP levels were associated with both any-DR and VTDR. Further longitudinal studies are necessary to confirm our findings.

Association between Optical Coherence Tomography and Fluorescein Angiography based retinal features in the diagnosis of Macular Edema.

The association between optical coherence tomography (OCT) and the geometrical vascular parameters obtained from the fluorescein angiography (FA) of the eyes with macular edema (ME) was investigated. Data from 82 untreated eyes with ME were studied. Fractal dimension (FD), simple tortuosity, branching angle, total angle count and vessel to background ratio were the five vasculature parameters from FA that were studied. The four OCT features measured were central retinal/foveal thickness, average para-fovea thickness, average peri-fovea thickness and OCT volume. The four OCT parameters showed a significant difference between ME requiring treatment (MERT) and non-MERT eyes with the central retinal thickness (threshold at 300 µm) and average para-fovea thickness (threshold at 338.5 µm) as most significant. The results also indicate that FD from the FA of retinal vessels in the macular region was associated with the changes in retinal thickness and that OCT parameters can potentially be used for directly identifying ME.

Transnational review of visual standards for driving: How Australia compares with the rest of the world.

IMPORTANCE: Driving is a highly visual task and a primary mode of transportation for many people around the world. BACKGROUND: There appears to be little uniformity of vision standards across the world for driving. We reviewed the basic screening visual requirements for obtaining standard private and commercial driving licences for a total of 70 jurisdictions, and reviewed the evidence behind these standards. DESIGN: Systematic review of basic screening vision standards worldwide for driving and literature review. SAMPLES: Published online documentation on visual acuity and field requirements for driving. METHODS: Journal articles, government reports and websites obtained via a Google search were used to review the regulations for driving. This was limited by the comprehensiveness of resources, and countries were excluded if the requirements were unclear or unattainable. A literature review was performed using Medline with keywords vision, driving and visual field. MAIN OUTCOME MEASURES: Visual parameters used for driving assessment. RESULTS: The results suggest significant variations across the world. The visual acuity requirements for a private licence range from a minimum of 6/9 to 6/60. The minimum binocular horizontal field requirement ranges from 110° to 150°. In general, standards for a commercial licence are stricter compared to a private licence. A literature review could not support the current driving standards as evidence-based. CONCLUSIONS AND RELEVANCE: The disunity of driving vision requirements worldwide likely reflects the inconclusive evidence base. Accounting for individual differences and the ability to predict individual risk is important in the context of determining driving licensure.

Bleb-associated endophthalmitis: Proportion, presentation, management and outcomes in Victoria, Australia.

IMPORTANCE: Bleb-associated endophthalmitis is a potentially vision-threatening complication of trabeculectomy. With improvements in surgical technique and changing patterns of intraoperative antimetabolite use, a re-evaluation of the incidence of bleb-associated endophthalmitis is warranted. BACKGROUND: To investigate changes in the incidence, presentation, management and outcomes of bleb-associated endophthalmitis between 1997 and 2015 in Victoria, Australia. DESIGN: A retrospective cohort analysis. PARTICIPANTS: Consecutive cases of bleb-associated endophthalmitis managed at the Royal Victorian Eye and Ear Hospital (RVEEH) between 1997 and 2015. METHODS: Medical record review of consecutive cases of bleb-associated endophthalmitis and statistical analysis were performed. MAIN OUTCOME MEASURES: Visual acuity, including loss of light perception, intraocular pressure, and need for further surgery. RESULTS: Sixty-seven eyes with bleb-associated endophthalmitis (BAE) were identified. Of these, 41 had trabeculectomy performed in Victoria during the study period, over which time 11 129 trabeculectomies were performed. The proportion of BAE was stable over time (0.4%). The mean age at presentation was 73.7 ± 12.1 years old and the majority of patients were Caucasian (79.1%). The mean duration between glaucoma filtration surgery and the development of bleb-associated endophthalmitis was 3 years (Interquartile Range = 0.4-6.0 years). The cultures were positive in 71.6% of cases. Approximately 1 in 8 patients required enucleation. The final visual acuity was poor with a Snellen Visual Acuity (VA) of 6/60 or worse in two-thirds of patients. CONCLUSIONS AND RELEVANCE: Bleb-associated endophthalmitis is an uncommon complication following glaucoma filtration surgery. The proportion has remained stable over time. Visual outcomes remain poor.

Agreement study between color and IR retinal images based on retinal vasculature morphological parameters.

BACKGROUND: Color fundus photography have been extensively used to explore the link between retinal morphology changes associated with various disease i.e. Diabetic Retinopathy, Glaucoma. The development of multimodal imaging system that integrates Infrared Scanning Laser Ophthalmoscope (IR-SLO) and Optical Coherence Tomography (OCT) could help in studying these diseases at an early stage. The aim of this study was to test the agreement between the retinal vasculature parameters from the Infrared images obtained from optical coherence tomography and color fundus imaging. METHODS: The IR and Color retinal images were obtained from 16 volunteer participants and seven retinal vessel parameters, i.e. Fractal Dimension (FD), Average Angle (ABA), Total Angle Count (TAC), Tortuosity (ST), Vessel/Background ratio (VBR), Central Retinal Arteriolar Equivalent (CRAE) and Central Retinal Venular Equivalent (CRVE) were extracted from these retinal images using Retinal Image Vasculature Assessment software (RIVAS) and Integrative Vessel Analysis (IVAN). RESULTS: The Bland Altman plot was used to investigate the agreement between the two modalities. The paired sample t-test was used to assess the presence of fixed bias and the slope of Least Square Regression (LSR) line for the presence of proportional bias. The paired sample t-test showed that there was no statistically significant difference between Color and IR based on retinal vessel features (all p values > 0.05). LSR also revealed no statistically significant difference in the retinal vessel features between Color and IR. CONCLUSION: This study has revealed that there is a fair agreement between Color and IR images based on retinal vessel features. This research has shown that it is possible to use IR images of the retina to measure the retinal vasculature parameters which has the advantage of being flash-less, can be used even if there is opacity due to cataract, and can be performed along with OCT on the same device.

Glaucoma laser and surgical procedure rates in Australia.

AIM: To determine trends in the number of glaucoma laser and surgical procedures performed in Australia between 1994 and 2014. METHODS: Medicare claims were analysed to determine the number of glaucoma-related procedures reimbursed in Australia between 1994 and 2014. Glaucoma procedures were identified by Medicare Benefits Schedule item number and analysed by age range, gender, state, month and year. RESULTS: Laser trabeculoplasty rates declined 60% between 1994 and 2003 before increasing a dramatic 353% between 2003 and 2014. Laser iridotomies increased 281% over the study period while cyclodestructive procedures increased 207%. The number of primary filtering operations for glaucoma fell 68% from a peak in 1996 to a low in 2006 and then remained stable. However, the number of filtering operations in eyes where a previous filtering operation had been performed increased 27%. There was a marked increase in glaucoma drainage device insertion, increasing 234% over the study period. CONCLUSIONS: There has been a substantial increase in laser trabeculoplasty procedures in Australia, following a decline between 1994 and 2003. Primary filtering operations for glaucoma have declined in number while glaucoma drainage devices are playing an increasingly prominent role in the surgical management of glaucoma.