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.

Polypoidal Choroidal Vasculopathy: Consensus Nomenclature and Non-Indocyanine Green Angiograph Diagnostic Criteria from the Asia-Pacific Ocular Imaging Society PCV Workgroup.

PURPOSE: To develop consensus terminology in the setting of polypoidal choroidal vasculopathy (PCV) and to develop and validate a set of diagnostic criteria not requiring indocyanine green angiography (ICGA) for differentiating PCV from typical neovascular age-related macular degeneration (nAMD) based on a combination of OCT and color fundus photography findings. DESIGN: Evaluation of diagnostic test results. PARTICIPANTS: Panel of retina specialists. METHODS: As part of the Asia-Pacific Ocular Imaging Society, an international group of experts surveyed and discussed the published literature regarding the current nomenclature and lesion components for PCV, and proposed an updated consensus nomenclature that reflects our latest understanding based on imaging and histologic reports. The workgroup evaluated a set of diagnostic features based on OCT images and color fundus photographs for PCV that may distinguish it from typical nAMD and assessed the performance of individual and combinations of these non-ICGA features, aiming to propose a new set of diagnostic criteria that does not require the use of ICGA. The final recommendation was validated in 80 eyes from 2 additional cohorts. MAIN OUTCOME MEASURES: Consensus nomenclature system for PCV lesion components and non-ICGA-based criteria to differentiate PCV from typical nAMD. RESULTS: The workgroup recommended the terms polypoidal lesion and branching neovascular network for the 2 key lesion components in PCV. For the diagnosis of PCV, the combination of 3 OCT-based major criteria (sub-retinal pigment epithelium [RPE] ring-like lesion, en face OCT complex RPE elevation, and sharp-peaked PED) achieved an area under the receiver operating characteristic curve of 0.90. Validation of this new scheme in a separate subset 80 eyes achieved an accuracy of 82%. CONCLUSIONS: We propose updated terminology for PCV lesion components that better reflects the nature of these lesions and is based on international consensus. A set of practical diagnostic criteria applied easily to spectral-domain OCT results can be used for diagnosing PCV with high accuracy in clinical settings in which ICGA is not performed routinely.

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.

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.

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.

Efficacy of a novel personalised aflibercept monotherapy regimen based on polypoidal lesion closure in participants with polypoidal choroidal vasculopathy.

PURPOSE: To compare the efficacy of aflibercept using a personalised versus fixed regimen in treatment-naïve participants with polypoidal choroidal vasculopathy (PCV). DESIGN: A 52-week, randomised, open-label, non-inferiority, single-centre study that included participants with symptomatic PCV. Participants were randomised (3:1 ratio) to receive either personalised (n=40) or fixed 8-weekly treatment regimen (n=13). The personalised regimen allowed for either early treat and extend (T&E) after week 12 or late T&E with 3 additional 4-weekly aflibercept injections until week 24 in participants with residual polypoidal lesions (PL) on indocyanine green angiography (ICGA) at week 12. MAIN OUTCOMES AND MEASURES: Non-inferiority of personalised to fixed regimen for mean change in best-corrected visual acuity (BCVA) from baseline to week 52 (non-inferiority margin: -5 letters). The key secondary outcomes include reduction in central subfield thickness (CSFT) on optical coherence tomography and the anatomical closure of PL on ICGA. RESULTS: Of the 53 participants, the mean (SD) age was 69.2 (8.1) years, 19 (35.8 %) were male. Personalised group was non-inferior to fixed for the primary end point (+8.1 vs +7.9 letters at week 52, respectively; difference 0.16, 95% CI -2.8 to 2.4, p=0.79). There was greater reduction in mean CSFT (SD) in the personalised versus fixed group (-248.8 (169.9) vs -164.8 (148.9) µm, p=0.03). Closure of PL occurred in 21 (55.2%) and 5 (41.6%) of study eyes in personalised and fixed groups, respectively at week 52 (p=0.41). CONCLUSIONS: Personalised regimen achieved non-inferior BCVA gain and numerically higher PL closure compared with fixed regimen. TRIAL REGISTRATION NUMBER: NCT03117634.

Diabetic Macular Ischemia: Influence of Optical Coherence Tomography Angiography Parameters on Changes in Functional Outcomes Over One Year.

Purpose: To prospectively evaluate whether diabetic macular ischemia detected with coherence tomography angiography (OCTA) is associated with change in functional outcomes over a period of one year. Methods: This is a one-year prospective, observational study that included 56 eyes with varying levels of diabetic retinopathy. All participants underwent best corrected visual acuity evaluation, swept-source OCTA and microperimetry at baseline and repeated at one year. Parafoveal vessel densities (VD) and foveal avascular zone (FAZ) areas were generated from OCTA in the superficial and deep vascular plexuses. The influence of baseline and change in OCTA parameters on change in visual acuity and retinal sensitivity over one year was evaluated. Results: Over the one-year follow-up period, 16% (9) of eyes had at least one line worsening in BCVA and 7% (4) of eyes had at least 5% decrease in retinal sensitivity compared to baseline. Diabetic retinopathy progressed in 12.5%. Mean superficial vascular plexus (SVP) FAZ area increased (0.32 ± 0.15 to 0.39 ± 0.18 mm2, P = 0.003) and parafoveal VD in deep vascular plexus (DVP) decreased (49.8 ± 3.7% to 48.8 ± 2.9%, P = 0.040) at one year compared to baseline. In the multivariate regression analysis, larger baseline DVP FAZ area was associated with worsening of BCVA over one year (ß = 0.16 logMAR per mm2, 95% CI 0.02 to 0.31, P = 0.032). In addition, larger decreases in SVP VD (ß = -4.18 db per 10% decrease, 95% CI -6.55 to -1.80, P = 0.002) was associated with worsening of retinal sensitivity over one year. Conclusions: Progression of parafoveal microvasculature changes over one year can be detected using OCTA. Larger baseline DVP FAZ area on OCTA is predictive of worsening in visual outcomes, and larger decreases in SVP VD were associated with worsening of retinal sensitivity over a course of one year in diabetic individuals.

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.

T and genetic variations between Asian and Caucasian polypoidal choroidal vasculopathy.

PURPOSE: To compare phenotypic and genetic variations in polypoidal choroidal vasculopathy (PCV) between Caucasian and Asian patients. METHODS: We analysed phenotypic and genotypic data from two sites, Association for Innovation and Biomedical Research on Light and Image, Portugal and Singapore National Eye Centre, Singapore. Baseline fundus photography, spectral domain-optical coherence tomography, indocyanine green and fluorescein angiography scans were analysed by respective reading centres using a standardised grading protocol. Single nucleotide polymorphisms across 8 PCV loci were compared between cases and controls selected from each population. RESULTS: One hundred and forty treatment-naïve PCV participants (35 Portuguese and 105 Singaporean) were included. The Portuguese cohort were older (72.33±8.44 vs 68.71±9.40 years, p=0.043) and were comprised of a lower proportion of males (43% vs 71%, p=0.005) compared with the Singaporean cohort. Differences in imaging features include higher prevalence of soft drusen (66% vs 30%, p=0.004), lower prevalence of subretinal haemorrhage (14% vs 67%, p<0.001), smaller polypoidal lesion (PL) area (0.09±0.09 vs 0.76±0.93 mm2, p<0.001), lower ratio of PL to branching vascular network area (3% vs 38%, p<0.001) and lower central retinal thickness (346.48±93.74 vs 493.16±212.92 µm, p<0.001) in the Portuguese cohort. CETP rs3764261 (OR 2.467; 95% CI 1.282 to 4.745, p=0.006) in the Portuguese population was significantly associated with PCV and CFH rs800292 (OR 1.719; 95% CI 1.139 to 2.596, p=0.010) in the Singaporean population, respectively. CONCLUSION: Among Asian and Caucasian patients with PCV, there are significant differences in the expression of phenotype. We also identified different polymorphisms associated with PCV in the two populations.

Patterns and Determinants of Choroidal Thickness in a Multiethnic Asian Population: The Singapore Epidemiology of Eye Diseases Study.

PURPOSE: To describe the distribution and determinants of choroidal thickness (CT) in participants in a population study based on spectral-domain (SD)-OCT measurements. DESIGN: Population-based, cross-sectional study. PARTICIPANTS: Ethnic Chinese, Indian, and Malay adults aged more than 50 years without any retinal diseases (e.g., diabetic retinopathy, macular edema, age-related macular degeneration, central serous chorioretinopathy) that might affect the CT were recruited from the Singapore Epidemiology of Eye Diseases Study. METHODS: Choroidal imaging was performed by SD-OCT (Spectralis, Heidelberg Engineering, Heidelberg, Germany) in enhanced depth imaging (EDI) mode. Subfoveal choroidal thickness (SFCT) was measured on the foveal line scan by 2 retinal experts independently (YS and KT), and the average was used in the analyses. In Chinese and Indian cohorts in whom macular raster scans were captured, the manufacturer-supplied research software (Heyex SP-X version 6.4.8.116; Heidelberg Engineering) was used to obtain automated segmentation yielding mean choroidal thickness in each of the 9 ETDRS grid sectors. MAIN OUTCOME MEASURES: Subfoveal choroidal thickness and regional CT in the 9 ETDRS grid sectors. RESULTS: For the SFCT analysis, 2794 eyes of 1619 participants (Chinese, Indian, and Malay ) were included. The mean age was 60.9 years (standard deviation, 7.7), and 797 (49.2%) were male. Mean SFCT was 255.2 µm (standard deviation, 102.6). The normal range of SFCT was 106 to 447 µm (corresponding to 5th and 95th percentile limits of SFCT, respectively). In multivariable models, thinner SFCT was associated with older age, female gender, longer axial length, and Malay (vs. Chinese) ethnicity. In the subset of Chinese and Indian eyes (n = 1842) in whom regional variation was evaluated, the choroid was thickest at the superior and temporal sectors and thinner at the inferior and nasal sectors. CONCLUSIONS: Subfoveal choroidal thickness is influenced by age, gender, and ethnicity along with regional differences even within individual eyes. Subfoveal choroidal thickness also shows a wide range in physiologic limits. These data may be used as a reference in future studies.