Joint Multimodal Deep Learning-based Automatic Segmentation of Indocyanine Green Angiography and OCT Images for Assessment of Polypoidal Choroidal Vasculopathy Biomarkers.

Purpose: To develop a fully-automatic hybrid algorithm to jointly segment and quantify biomarkers of polypoidal choroidal vasculopathy (PCV) on indocyanine green angiography (ICGA) and spectral domain-OCT (SD-OCT) images. Design: Evaluation of diagnostic test or technology. Participants: Seventy-two participants with PCV enrolled in clinical studies at Singapore National Eye Center. Methods: The dataset consisted of 2-dimensional (2-D) ICGA and 3-dimensional (3-D) SD-OCT images which were spatially registered and manually segmented by clinicians. A deep learning-based hybrid algorithm called PCV-Net was developed for automatic joint segmentation of biomarkers. The PCV-Net consisted of a 2-D segmentation branch for ICGA and 3-D segmentation branch for SD-OCT. We developed fusion attention modules to connect the 2-D and 3-D branches for effective use of the spatial correspondence between the imaging modalities by sharing learned features. We also used self-supervised pretraining and ensembling to further enhance the performance of the algorithm without the need for additional datasets. We compared the proposed PCV-Net to several alternative model variants. Main Outcome Measures: The PCV-Net was evaluated based on the Dice similarity coefficient (DSC) of the segmentations and the Pearson's correlation and absolute difference of the clinical measurements obtained from the segmentations. Manual grading was used as the gold standard. Results: The PCV-Net showed good performance compared to manual grading and alternative model variants based on both quantitative and qualitative analyses. Compared to the baseline variant, PCV-Net improved the DSC by 0.04 to 0.43 across the different biomarkers, increased the correlations, and decreased the absolute differences of clinical measurements of interest. Specifically, the largest average (mean ± standard error) DSC improvement was for intraretinal fluid, from 0.02 ± 0.00 (baseline variant) to 0.45 ± 0.06 (PCV-Net). In general, improving trends were observed across the model variants as more technical specifications were added, demonstrating the importance of each aspect of the proposed method. Conclusion: The PCV-Net has the potential to aid clinicians in disease assessment and research to improve clinical understanding and management of PCV. Financial Disclosures: Proprietary or commercial disclosure may be found after the references.

Analysis of the pachychoroid phenotype in an Asian population: methodology and baseline study population characteristics.

AIM: To describe the clinical characteristics in a cohort of patients with the pachychoroid phenotype and to evaluate the association of ocular and systemic factors with type of complications observed. METHODS: We report baseline findings from a prospective observational study which recruited subjects with subfoveal choroidal thickness (SFCT) of ≥300 µm on spectral-domain optical coherence tomography (OCT). Multimodal imaging was used to classify eyes as uncomplicated pachychoroid (UP) or pachychoroid disease with pachychoroid pigment epitheliopathy (PPE), central serous chorioretinopathy (CSC) or pachychoroid neovasculopathy (PNV) subtypes. RESULTS: Among 181 eyes of 109 participants (mean age 60.6 years, 33 (30.3%) female, 95 (7.2%) Chinese), 38 eyes (21.0%) had UP. Of 143 eyes (79.0%) with pachychoroid disease, 82 (45.3%), 41 (22.7%) and 20 (11.0%) had PPE, CSC and PNV, respectively. Addition of autofluorescence and OCT angiography to structural OCT led to reclassification of 31 eyes to a more severe category. Systemic and ocular factors evaluated, including SFCT, were not associated with disease severity. Comparison of PPE, CSC and PNV eyes showed no significant difference in OCT features of retinal pigment epithelial (RPE) dysfunction, but disruption of the ellipsoid zone (PPE 30.5% vs CSC 70.7% vs PNV 60%, p<0.001) and thinning of inner nuclear/inner plexiform layers (PPE 7.3% vs CSC 36.6% vs PNV 35%, p<0.001) were more frequent in CSC and PNV eyes. CONCLUSIONS: These cross-sectional associations suggest pachychoroid disease manifestations may reflect progressive decompensation from the choroid to the RPE then retinal layers. Planned follow-up of this cohort will be beneficial in clarifying the natural history of the pachychoroid phenotype.

FIVE-YEAR INCIDENCE OF FELLOW EYE NEOVASCULAR INVOLVEMENT IN AGE-RELATED MACULAR DEGENERATION AND POLYPOIDAL CHOROIDAL VASCULOPATHY IN AN ASIAN POPULATION.

PURPOSE: To assess 5-year cumulative incidence and risk factors of fellow eye involvement in Asian neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy. METHODS: In a prospective cohort study of Asian nAMD and polypoidal choroidal vasculopathy, the fellow eyes were evaluated for exudation. The 5-year incidence of exudation was compared between nAMD and polypoidal choroidal vasculopathy. RESULTS: A total of 488 patients were studied. The 5-year incidence of exudation in fellow eyes was 16.2% (95% confidence interval: 12.0-20.2). Polypoidal choroidal vasculopathy compared with nAMD in the first eye was associated with lower fellow eye progression (9.8% [95% confidence interval: 5.1-14.3]) vs. 22.9% [95% confidence interval: 15.8-29.3], P < 0.01). Drusen (hazards ratio 2.11 [95% confidence interval: 1.10-4.06]), shallow irregular retinal pigment epithelium elevation (2.86 [1.58-5.18]), and pigment epithelial detachment (3.01 [1.27-7.17]) were associated with greater progression. A combination of soft drusens and subretinal drusenoid deposits, and specific pigment epithelial detachment subtypes (multilobular, and sharp peaked) were associated with progression. Pigment epithelial detachment, shallow irregular retinal pigment epithelium elevation, and new subretinal hyperreflective material occurred at 10.4 ± 4.2 months, 11.1 ± 6.0 months, and 6.9 ± 4.3 months, respectively, before exudation. CONCLUSION: The 5-year incidence of fellow eye involvement in Asian nAMD is lower than among Caucasians because of a higher polypoidal choroidal vasculopathy prevalence. Drusens, shallow irregular retinal pigment epithelium elevation, and pigment epithelial detachment are risk factors for fellow eye progression.

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.

OPTICAL COHERENCE TOMOGRAPHY FEATURES OF POLYPOIDAL LESION CLOSURE IN POLYPOIDAL CHOROIDAL VASCULOPATHY TREATED WITH AFLIBERCEPT.

PURPOSE: To evaluate whether optical coherence tomography (OCT) can determine polypoidal lesion (PL) perfusion in polypoidal choroidal vasculopathy eyes after 12 months of aflibercept monotherapy. Polypoidal lesion perfusion status, assessed by indocyanine green angiography, is an important anatomical outcome in polypoidal choroidal vasculopathy management. METHODS: Post hoc data from a prospective randomized, open-label, study in eyes with polypoidal choroidal vasculopathy undergoing monotherapy with aflibercept evaluated PL perfusion status based on indocyanine green angiography (gold standard) and OCT features from baseline to 12 months. RESULTS: Individual PLs (110 in total) from 48 eyes (48 patients) showed at 12 months; 57/110 PLs (51.8%) were closed on indocyanine green angiography. At 12 months, eyes with closed PLs were more likely to have the following OCT features: 1) no subretinal fluid (67.1% vs. 32.9%), 2) smaller pigment epithelial detachment height (67.2 [±43.8] vs. 189.2 [±104.9] µm), 3) densely hyperreflective pigment epithelial detachment contents (84.0% vs. 16.0%), 4) an absence of a hyperreflective ring(64.0% vs. 36.0%), and a 5) indistinct overlying retinal pigment epithelial (71.4% vs. 28.6%) (all P < 0.05). The three highest performing OCT features that differentiated perfused from closed PLs were (1), (3), and (4) (area under the receiver operating characteristic curve 0.85, 0.73, and 0.70, respectively). A combination of these three features achieved an area under the receiver operating characteristic curve of 0.90. CONCLUSION: Polypoidal lesion closure, an important anatomical treatment outcome in polypoidal choroidal vasculopathy typically defined by indocyanine green angiography, can be accurately detected by specific OCT features.

Multicentre, randomised clinical trial comparing intravitreal aflibercept monotherapy versus aflibercept combined with reduced-fluence photodynamic therapy (RF-PDT) for the treatment of polypoidal choroidal vasculopathy.

PURPOSE: To compare the efficacy and safety of intravitreal aflibercept (IVA) monotherapy versus aflibercept combined with reduced-fluence photodynamic therapy (RF-PDT) (IVA+RF-PDT) for the treatment of polypoidal choroidal vasculopathy (PCV). METHODS AND ANALYSIS: Multicentred, double-masked, randomised controlled trial to compare the two treatment modalities. The primary outcome of the study is to compare the 52-week visual outcome of IVA versus IVA+RF PDT. One hundred and sixty treatment-naïve patients with macular PCV confirmed on indocyanine green angiography will be recruited from three centres in Singapore. Eligible patients will be randomised (1:1 ratio) into one of the following groups: IVA monotherapy group-aflibercept monotherapy with sham photodynamic therapy (n=80); combination group-aflibercept with RF-PDT (n=80). Following baseline visit, all patients will be monitored at 4 weekly intervals during which disease activity will be assessed based on best-corrected visual acuity (BCVA), ophthalmic examination findings, optical coherence tomography (OCT) and angiography where indicated. Eyes that meet protocol-specified retreatment criteria will receive IVA and sham/RF-PDT according to their randomisation group. Primary endpoint will be assessed as change in BCVA at week 52 from baseline. Secondary endpoints will include anatomical changes based on OCT and dye angiography as well as safety assessment. Additionally, we will be collecting optical coherence tomography angiography data prospectively for exploratory analysis. ETHICS AND DISSEMINATION: This study will be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with the ICH E6 guidelines of Good Clinical Practice and the applicable regulatory requirements. Approval from the SingHealth Centralised Institutional Review Board has been sought prior to commencement of the study. TRIAL REGISTRATION NUMBER: NCT03941587.

Choroidal Haller's and Sattler's Layers Thickness in Normal Indian Eyes.

AIM: This study aims to study normative choroidal thickness (CT) and Haller's and Sattler's layers thickness in normal Indian eyes. MATERIALS AND METHODS: The choroidal imaging of 73 eyes of 43 healthy Indian individuals was done using enhanced depth imaging feature of spectralis optical coherence tomography. Rraster scan protocol centered at fovea was used for imaging separately by two observers. CT was defined as the length of the perpendicular line drown from the outer border of hypereflective RPE-Bruch's complex to inner margin of choroidoscleral junction. Choroidal vessel layer thickness was measured after defining a largest choroidal vessel lumen within 750 µ on either side of the subfoveal CT vector. A perpendicular line was drawn to the innermost border of this lumen, and the distance between the perpendicular line and innermost border of choroidoscleral junction gave large choroidal vessel layer thickness (LCVLT, Haller's layer). Medium choroidal vessel layer thickness (MCVLT, Sattler's layer) was measured as the distance between same perpendicular line and outer border of hypereflective RPE-Bruch's complex. RESULTS: The mean age of individuals was 28.23 ± 15.29 years (range 14-59 years). Overall, the mean subfoveal CT was 331.6 ± 63.9 µ. Mean LCVLT was 227.08 ± 51.24 µ and the mean MCVLT was 95.65 ± 23.62 µ. CT was maximum subfoveally with gradual reduction in the thickness as the distance from the fovea increased. CONCLUSION: This is the first study describing the choroidal sublayer thickness, i.e., Haller's and Sattler's layer thickness along with CT in healthy Indian population.

Age-related Changes in the Foveal Bulge in Healthy Eyes.

BACKGROUND: Intact foveal bulge has been associated with good visual outcome in retinal diseases. The aim of this study was to study the variation in foveal bulge with age. METHODS: It was an observational cross-sectional study conducted between October 2014 and December 2015. Totally, 101 eyes of 101 healthy volunteers were studied in a tertiary care center. All individuals had best corrected visual acuity of 20/20 or better. High myopia (>6 D), high hyperopia (>4 D), unstable fixation, media opacities and retinal disorder like diabetic retinopathy, retinal vein occlusion were the exclusion criteria. Spectral domain optical coherence tomography was used to identify foveal bulge. The height of foveal bulge was measured as the distance between inner border of retinal pigment epithelium and outer border of inner segment - outer segment line (ellipsoid zone) at fovea. Main outcome measures were a correlation between the height of the foveal bulge and age of the participants. RESULTS: Foveal bulge was present in 61 (60.4%) and absent in 40 (39.6%) eyes. Mean age of patients with and without foveal bulge was 33.3 ± 16.2 years and 44.1 ± 20.5 years respectively (P = 0.02). Mean height of foveal bulge was 41.1 ± 6.4 µ (range: 23-51 µ). The height of the foveal bulge showed a negative correlation with the age of the participants (r = -0.15). CONCLUSION: Foveal bulge was more commonly seen in younger individuals and its height decreased with age. Age matching across groups should be undertaken in studies using foveal bulge as prognostic tool.

Comparison of photodynamic therapy, ranibizumab/bevacizumab or combination in the treatment of myopic choroidal neovascularisation: a 9-year-study from a single centre.

AIM: To compare treatment outcomes for myopic choroidal neovascularisation (CNV) managed with verteporfin photodynamic therapy (vPDT), intravitreal antivascular endothelial growth factor (anti-VEGF, bevacizumab/ranibizumab) agents or combination thereof. METHODS: Clinical data of 79 eyes with myopic CNV examined from March 2004 to July 2013 was retrospectively reviewed. Patients were managed with vPDT, intravitreal bevacizumab (1.25 mg/0.05 mL)/ranibizumab (0.5 mg/0.05 mL) or a combination of vPDT and anti-VEGF. Outcome measures included complete regression (scarring) of CNV and best-corrected visual acuity (BCVA). RESULTS: Treatments provided were vPDT (n=23), anti-VEGF (n=25) (ranibizumab, n=12; bevacizumab, n=13), vPDT+anti-VEGF (n=31). Mean logMAR BCVA changed from 0.59±0.44 to 0.49±0.40 at mean follow-up of 54.63±39.46 months. Mean logMAR vision changed from 0.68±0.57, 0.54±0.48 and 0.59±0.39 at presentation to 0.59±0.53, 0.38±0.44 and 0.37±0.37 at last follow-up in PDT (p=0.4), anti-VEGF (p=0.1) and vPDT+anti-VEGF groups (p=0.0002), respectively. CNV was scarred in 64 eyes (81%) at mean 11.03±13.56 months. Most common complication was macular scar (n=64), associated with reduced (n=17) or preserved (n=47) vision. Chorioretinal atrophy attributable to vPDT was seen in five eyes (vPDT, n=3; vPDT+anti-VEGF, n=2). CONCLUSION: Combination of vPDT and intravitreal anti-VEGF (ranibizumab/bevacizumab) was associated with better visual outcomes and higher rates of regression in eyes with myopic CNV as compared with monotherapy with PDT or anti-VEGF. Larger size of CNV, and high refractive error were independent risk factors for poor visual outcomes.