Rationale and protocol paper for the Asia Pacific Network for inherited eye diseases.

PURPOSE: There are major gaps in our knowledge of hereditary ocular conditions in the Asia-Pacific population, which comprises approximately 60% of the world's population. Therefore, a concerted regional effort is urgently needed to close this critical knowledge gap and apply precision medicine technology to improve the quality of lives of these patients in the Asia-Pacific region. DESIGN: Multi-national, multi-center collaborative network. METHODS: The Research Standing Committee of the Asia-Pacific Academy of Ophthalmology and the Asia-Pacific Society of Eye Genetics fostered this research collaboration, which brings together renowned institutions and experts for inherited eye diseases in the Asia-Pacific region. The immediate priority of the network will be inherited retinal diseases (IRDs), where there is a lack of detailed characterization of these conditions and in the number of established registries. RESULTS: The network comprises 55 members from 35 centers, spanning 12 countries and regions, including Australia, China, India, Indonesia, Japan, South Korea, Malaysia, Nepal, Philippines, Singapore, Taiwan, and Thailand. The steering committee comprises ophthalmologists with experience in consortia for eye diseases in the Asia-Pacific region, leading ophthalmologists and vision scientists in the field of IRDs internationally, and ophthalmic geneticists. CONCLUSIONS: The Asia Pacific Inherited Eye Disease (APIED) network aims to (1) improve genotyping capabilities and expertise to increase early and accurate genetic diagnosis of IRDs, (2) harmonise deep phenotyping practices and utilization of ontological terms, and (3) establish high-quality, multi-user, federated disease registries that will facilitate patient care, genetic counseling, and research of IRDs regionally and internationally.

Diagnostic Challenges in ABCA4-Associated Retinal Degeneration: One Gene, Many Phenotypes.

(1) Purpose: ABCA4-associated retinal degeneration (ABCA4-RD) is a phenotypically diverse disease that often evades diagnosis, even by experienced retinal specialists. This may lead to inappropriate management, delayed genetic testing, or inaccurate interpretation of genetic testing results. Here, we illustrate the phenotypic diversity of ABCA4-RD using a series of representative cases and compare these to other conditions that closely mimic ABCA4-RD. (2) Methods: Genetically confirmed ABCA4-RD cases with representative phenotypes were selected from an inherited retinal disease cohort in Singapore and compared to phenocopies involving other retinal diseases. (3) Results: ABCA4-RD phenotypes in this series included typical adolescent-onset Stargardt disease with flecks, bull's eye maculopathy without flecks, fundus flavimaculatus, late-onset Stargardt disease, and severe early-onset Stargardt disease. Phenocopies of ABCA4-RD in this series included macular dystrophy, pattern dystrophy, cone dystrophy, advanced retinitis pigmentosa, Leber congenital amaurosis, drug toxicity, and age-related macular degeneration. Key distinguishing features that often suggested a diagnosis of ABCA4-RD were the presence of peripapillary sparing, macular involvement and centrifugal distribution, and a recessive pedigree. (4) Conclusions: ABCA4-RD demonstrates a remarkable phenotypic spectrum that makes diagnosis challenging. Awareness of the clinical spectrum of disease can facilitate prompt recognition and accurate diagnostic testing.

RETINITIS PIGMENTOSA ASSOCIATED WITH THE EYS C2139Y VARIANT : An Important Cause of Blindness in East Asian Populations.

PURPOSE: The study aimed to describe the phenotypic features of retinitis pigmentosa (RP) associated with the previously described EYS C2139Y variant in Singaporeans and establish the importance of this variant as a prevalent cause of RP among East Asians. METHODS: A clinical phenotyping and exome-sequencing study was conducted on consecutive patients with nonsyndromic RP. Epidemiological analysis was performed using Singaporean and global population-based genetic data. RESULTS: A study of 150 consecutive unrelated individuals with nonsyndromic RP found that 87 (58%) of cases had plausible genotypes. A previously described missense variant in the EYS gene, 6416G>A (C2139Y), occurred heterozygously or homozygously in 17 of 150 families (11.3%), all with autosomal recessive RP. Symptom onset in EYS C2139Y-related RP ranged from 6 to 45 years, with visual acuity ranging from 20/20 at 21 years to no light perception by 48 years. C2139Y-related RP had typical findings, including sectoral RP in cases with EYS E2703X in trans . The median age at presentation was 45 years and visual fields declined to less than 20° (Goldmann V4e isopter) by age 65 years. Intereye correlation for visual acuity, fields, and ellipsoid band width was high (r 2 = 0.77-0.95). Carrier prevalence was 0.66% (allele frequency of 0.33%) in Singaporean Chinese and 0.34% in East Asians, suggesting a global disease burden exceeding 10,000 individuals. CONCLUSION: The EYS C2139Y variant is common in Singaporean RP patients and other ethnic Chinese populations. Targeted molecular therapy for this single variant could potentially treat a significant proportion of RP cases worldwide.

The economic burden of inherited retinal disease in Singapore: a prevalence-based cost-of-illness study.

OBJECTIVE: To assess the economic impact of inherited retinal disease (IRD) among Singaporeans. METHODS: IRD prevalence was calculated using population-based data. Focused surveys were conducted for sequentially enrolled IRD patients from a tertiary hospital. The IRD cohort was compared to the age- and gender-matched general population. Economic costs were expanded to the national IRD population to estimate productivity and healthcare costs. RESULTS: National IRD caseload was 5202 cases (95% CI, 1734-11273). IRD patients (n = 95) had similar employment rates to the general population (67.4% vs. 70.7%; p = 0.479). Annual income was lower among IRD patients than the general population (SGD 19,500 vs. 27,161; p < 0.0001). Employed IRD patients had lower median income than the general population (SGD 39,000 vs. 52,650; p < 0.0001). Per capita cost of IRD was SGD 9382, with a national burden of SGD 48.8 million per year. Male gender (beta of SGD 6543, p = 0.003) and earlier onset (beta of SGD 150/year, p = 0.009) predicted productivity loss. Treatment of the most economically impacted 10% of IRD patients with an effective IRD therapy required initial treatment cost of less than SGD 250,000 (USD 188,000) for cost savings to be achieved within 20 years. CONCLUSIONS: Employment rates among Singaporean IRD patients were the same as the general population, but patient income was significantly lower. Economic losses were driven in part by male patients with early age of onset. Direct healthcare costs contributed relatively little to the financial burden.

Characterizing the genotypic spectrum of retinitis pigmentosa in East Asian populations: a systematic review.

BACKGROUND: Ongoing trials for retinitis pigmentosa (RP) are genotype-specific, with most trials conducted on European cohorts. Due to genetic differences across diverse ancestries and populations, these therapies may not be efficacious in East Asians. MATERIALS AND METHODS: A literature search was conducted from 1966 to September 2022 for cohort studies on East Asian populations reporting on non-syndromic RP genotypes and variants. Population-weighted prevalence was used to determine the genotypes and individual variants across the entire cohort. The carrier prevalence of common variants was compared against those in Europe. RESULTS: A total of 12 articles describing 2,932 clinically diagnosed East Asian RP probands were included. We identified 876 variants across 54 genes. The most common genotypes included USH2A, EYS, RPGR, ABCA4, PRPF31, RHO, RP1, RP2, PDE6B and SNRNP200, with USH2A as the most common (17.1%). Overall, 60.5% of probands with clinically relevant variants were found to have one of the genotypes above, with 543/876 (62.0%) of the variants occurring in these genes. The most frequently reported variant was USH2A missense variant c.2802T>G/p.C934W (4.9%). Carrier prevalence of these variants was significantly different (p < 0.0001) than in Europe. CONCLUSIONS: USH2A was the most commonly affected RP gene in this East Asian cohort, although sub-population analysis revealed distinct genotype prevalence patterns. While the genotypes are similar between East Asia and European cohorts, variants are specific to East Asia. The identification of several prevalent variants in USH2A and EYS provides an opportunity for the development of therapeutics that are relevant for East Asia patients.

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.

WFS1-Associated Optic Neuropathy: Genotype-Phenotype Correlations and Disease Progression.

OBJECTIVE: To evaluate the pattern of vision loss and genotype-phenotype correlations in WFS1-associated optic neuropathy (WON). DESIGN: Multicenter cohort study. METHODS: The study involved 37 patients with WON carrying pathogenic or candidate pathogenic WFS1 variants. Genetic and clinical data were retrieved from the medical records. Thirteen patients underwent additional comprehensive ophthalmologic assessment. Deep phenotyping involved visual electrophysiology and advanced psychophysical testing with a complementary metabolomic study. MAIN OUTCOME MEASURES: WFS1 variants, functional and structural optic nerve and retinal parameters, and metabolomic profile. RESULTS: Twenty-two recessive and 5 dominant WFS1 variants were identified. Four variants were novel. All WFS1 variants caused loss of macular retinal ganglion cells (RGCs) as assessed by optical coherence tomography (OCT) and visual electrophysiology. Advanced psychophysical testing indicated involvement of the major RGC subpopulations. Modeling of vision loss showed an accelerated rate of deterioration with increasing age. Dominant WFS1 variants were associated with abnormal reflectivity of the outer plexiform layer (OPL) on OCT imaging. The dominant variants tended to cause less severe vision loss compared with recessive WFS1 variants, which resulted in more variable phenotypes ranging from isolated WON to severe multisystem disease depending on the WFS1 alleles. The metabolomic profile included markers seen in other neurodegenerative diseases and type 1 diabetes mellitus. CONCLUSIONS: WFS1 variants result in heterogenous phenotypes influenced by the mode of inheritance and the disease-causing alleles. Biallelic WFS1 variants cause more variable, but generally more severe, vision and RGC loss compared with heterozygous variants. Abnormal cleftlike lamination of the OPL is a distinctive OCT feature that strongly points toward dominant WON.

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.

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.

Deep clinical phenotyping and gene expression analysis in a patient with RCBTB1-associated retinopathy.

Background: Mutations in the RCC1 and BTB domain-containing protein 1 (RCBTB1) gene have been implicated in a rare form of retinal dystrophy. Herein, we report the clinical features of a 45-year-old Singaporean-Chinese female and her presymptomatic sibling, who each possesses compound heterozygous mutations in RCBTB1. Expression of RCBTB1 in patient-derived cells was evaluated.Materials and Methods: The natural history was documented by a series of ophthalmic examinations including electroretinography, fundus autofluorescence imaging, spectral-domain optical coherence tomography, visual field, microperimetry, and adaptive optics retinal imaging. Patient DNA was genetically analysed using a 537-gene Next Generation Sequencing panel and targeted Sanger sequencing. Expression of RCBTB1 in lymphocytes, fibroblasts, and induced pluripotent stem cells (iPSC) derived from the proband and healthy controls was characterized by quantitative PCR, Sanger sequencing, and western blotting.Results: The proband presented with left visual distortion at age 40 due to extrafoveal chorioretinal atrophy. Atrophy expanded at 1.3 (OD) and 1.0 (OS) mm2/year. Total macular volume declined by 0.09 (OD) and 0.13 (OS) mm3/year. Microperimetry demonstrated enlarging scotoma in both eyes. Generalised cone dysfunction was demonstrated by electroretinography. A retinal dystrophy panel testing revealed biallelic frameshifting mutations, c.170delG (p.Gly57Glufs*12) and c.707delA (p.Asn236Thrfs*11) in RCBTB1. The level of RCBTB1 mRNA expression was reduced in patient-derived lymphocytes compared to controls. RCBTB1 protein was detected in control fibroblasts and iPSC but was absent in patient-derived cells.Conclusions: Atrophy expansion rate and macular volume change are feasible endpoints for monitoring RCBTB1-associated retinopathy. We provide further functional evidence of pathogenicity for two disease-causing variants using patient-derived iPSCs.

Gene-Based Therapeutics for Inherited Retinal Diseases.

Inherited retinal diseases (IRDs) are a heterogenous group of orphan eye diseases that typically result from monogenic mutations and are considered attractive targets for gene-based therapeutics. Following the approval of an IRD gene replacement therapy for Leber's congenital amaurosis due to RPE65 mutations, there has been an intensive international research effort to identify the optimal gene therapy approaches for a range of IRDs and many are now undergoing clinical trials. In this review we explore therapeutic challenges posed by IRDs and review current and future approaches that may be applicable to different subsets of IRD mutations. Emphasis is placed on five distinct approaches to gene-based therapy that have potential to treat the full spectrum of IRDs: 1) gene replacement using adeno-associated virus (AAV) and nonviral delivery vectors, 2) genome editing via the CRISPR/Cas9 system, 3) RNA editing by endogenous and exogenous ADAR, 4) mRNA targeting with antisense oligonucleotides for gene knockdown and splicing modification, and 5) optogenetic approaches that aim to replace the function of native retinal photoreceptors by engineering other retinal cell types to become capable of phototransduction.

Quantitative Microvascular Analysis With Wide-Field Optical Coherence Tomography Angiography in Eyes With Diabetic Retinopathy.

Importance: Wide-field optical coherence tomographic angiography (OCTA) may provide insights to peripheral capillary dropout in eyes with diabetic retinopathy (DR). Objective: To describe the diagnostic performance of wide-field OCTA with and without large vessel removal for assessment of DR in persons with diabetes. Design, Setting, and Participants: This case-control study was performed from April 26, 2018, to April 8, 2019, at a single tertiary eye center in Singapore. Case patients were those with type 2 diabetes for more than 5 years and bilateral DR diagnosed by fundus imaging; control participants included those with no self-reported history of diabetes, a fasting glucose level within the normal range in the past year, and no ocular pathologic findings. A wide-field (12 × 12-mm2) fovea-centered scan was performed using a prototype swept source OCTA system. Retinal microvasculature was examined by separating the angiograms into large vessels, capillaries, and capillary dropout regions. Main Outcomes and Measures: Area under the receiver operating characteristic curve (AUC) for DR severity discrimination using wide-field vascular metrics. Retinal perfusion density (RPD), capillary perfusion density (CPD), large vessel density (LVD), and capillary dropout density (CDD) were calculated. Low-contrast regions were excluded from the calculation. Results: A total of 49 eyes in 27 control participants (17 male [63.0%]; mean [SD] age, 59.96 [7.63] years; age range, 44-79 years) and 76 eyes in 47 patients with diabetes (29 male [61.7%]; mean [SD] age, 64.36 [8.08] years; range, 41-79 years) were included. Among eyes in patients with diabetes, 23 were in those with diabetes but no DR, 25 in those with mild nonproliferative DR, and 28 in those with moderate to severe nonproliferative DR. There was no difference in RPD, CPD, LVD, and CDD between the control group and the group with diabetes and no DR. There was a stepwise decrease in RPD, CPD, and CDD in the diabetes with no DR, mild nonproliferative DR, and moderate to severe nonproliferative DR groups, whereas LVD was not associated with DR staging. The nonproliferative DR group had decreased RPD, CPD, and CDD compared with the control group. The CPD had higher AUCs than RPD for discriminating diabetes with nonproliferative DR (combined mild and moderate to severe nonproliferative DR) vs no DM (AUC, 0.92 [95% CI, 0.87-0.98] vs 0.89 [95% CI, 0.83-0.95], P = .01), diabetes with no DR vs mild nonproliferative DR (AUC, 0.81 [95% CI, 0.68-0.94] vs 0.77 [95% CI, 0.64-0.91], P = .18), and mild nonproliferative DR vs moderate to severe nonproliferative DR (AUC, 0.82 [95% CI, 0.71-0.94] vs 0.78 [95% CI, 0.65-0.91], P = .01) but similar AUCs for no DM vs diabetes with no DR. The total perfusion density and CPD in wide-field OCTA had better discriminative power than the central 6 × 6-mm2 field (CPD, 0.89 [95% CI, 0.83-0.95] vs 0.84 [95% CI, 0.77-0.92], P = .06; total perfusion density, 0.93 [95% CI, 0.87-0.98] vs 0.90 [95% CI, 0.83-0.96], P = .06). Conclusions and Relevance: The findings suggest that wide-field OCTA provides information on microvascular perfusion and may be useful for detecting predominant peripheral capillary dropout in eyes with nonproliferative DR. A vascular selectivity approach excluding the large vessels may improve the discriminative power for different stages of DR.

Real-World Treatment Outcomes of Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy in Asians.

PURPOSE: To describe the 12-month outcomes of treatment-naïve eyes with choroidal neovascularization (CNV) resulting from age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) after initiation of intravitreal anti-vascular endothelial growth factor (VEGF) monotherapy or combination therapy with verteporfin photodynamic therapy (PDT). DESIGN: A 12-month single-center, retrospective, comparative, nonrandomized cohort study. PARTICIPANTS: Patients with AMD or PCV who initiated intravitreal anti-VEGF therapy during 2015. METHODS: Demographics, visual outcomes, OCT, and treatment data were collected at baseline and months 1, 3, 6, and 12 after treatment initiation. Multivariate analysis was performed to identify baseline features predictive of visual maintenance and improvement after 12 months of treatment. MAIN OUTCOME MEASURES: Primary end point was visual acuity (VA) change from baseline to month 12. Secondary end points were treatment exposure and change in central subfield thickness on OCT. RESULTS: A total of 364 patients (165 AMD and 199 PCV) were included. Baseline vision was 41 and 43 logarithm of the minimum angle of resolution (logMAR) letters for AMD and PCV patients, respectively. Patients with AMD and PCV received 5.5 and 5.3 injections (5.0 monotherapy vs. 5.6 combination therapy; mean, 1.2 PDT sessions), respectively. Patients with AMD gained 4.7 logMAR letters after 12 months (P = 0.002), whereas PCV patients gained 6.6 logMAR letters (P = 0.001) and 10.8 logMAR letters (P < 0.001) for monotherapy and combination therapy, respectively. Only patients with presenting VA of fewer than 35 letters (Snellen equivalent, 6/60) achieved significant visual improvement (10.4 letters for AMD, 17.1 letters for PCV with monotherapy, and 35.5 letters for PCV with combination therapy). Predictors of VA gain included number of intravitreal injections (AMD and PCV adjusted odds ratio, 12.1 [P = 0.001] and 12.5 [P = 0.004] for ≥7 injections, respectively) and baseline VA of 20 logMAR letters or fewer (adjusted odds ratio, 3.8 and 10.6 for AMD and PCV, respectively). Age, gender, race, use of PDT or focal laser therapy, and central subfield thickness were not predictive of significant visual gain at 12 months. CONCLUSIONS: In Asian patients, treatment of AMD with anti-VEGF therapy yielded 12-month visual outcomes comparable with those of other real-world studies from Western populations but poorer than those of controlled trials. In contrast, for PCV eyes, anti-VEGF monotherapy and combination therapy with PDT yielded comparable outcomes as those of controlled clinical trials.

IMPROVED DETECTION AND DIAGNOSIS OF POLYPOIDAL CHOROIDAL VASCULOPATHY USING A COMBINATION OF OPTICAL COHERENCE TOMOGRAPHY AND OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY.

PURPOSE: To assess the ability of optical coherence tomography (OCT) alone and in combination with OCT angiography (OCTA) to differentiate polypoidal choroidal vasculopathy (PCV) from neovascular age-related macular degeneration, as compared to fluorescein angiography and indocyanine green angiography. METHODS: This is a cross-sectional study. All participants had a standardized history, clinical examination including measurement of best-corrected visual acuity, slit-lamp biomicroscopy, and indirect fundus examination, and underwent standardized imaging (color photography, fluorescein and indocyanine green angiography, OCT, and OCTA) after predefined protocols. We used a 2-step approach (Step 1: spectral domain OCT; Step 2: addition of OCTA) combining structural OCT and OCTA to differentiate 50 treatment-naive eyes with PCV, choroidal neovascularization, and retinal angiomatous proliferation and compared with the diagnosis based on fluorescein angiography and indocyanine green angiography. Spectral domain OCT signs used to diagnose PCV included presence of two out of three of any retinal pigment epithelium detachment (pigment epithelial detachment/double-layer sign), notched or narrow-peaked pigment epithelial detachment, or round subretinal pigment epithelium structure. Optical coherence tomography angiography signs used to diagnose PCV included presence of a localized subretinal pigment epithelium hyperflow signal in the cross-sectional OCTA and/or presence of a focal hyperflow sign in en face OCTA based on outer retina slab. RESULTS: Based on fluorescein angiography and indocyanine green angiography, the diagnosis was choroidal neovascularization in 24 eyes, PCV in 23 eyes, and retinal angiomatous proliferation in 3 eyes. Based on spectral domain OCT signs, PCV was diagnosed in 19/23 (82.6%) eyes; however, specificity of OCT was only 51.9%. Cross-sectional OCTA showed a diffuse hyperflow signal in all 24 (100.0%) eyes with choroidal neovascularization, whereas a localized subretinal pigment epithelium hyperflow signal was detected in 19/23 (82.6%) eyes with PCV. En face OCTA only detected a nodular hyperflow signal in 10/23 eyes (43.5%) with PCV. Combination of OCT and OCTA achieved 82.6% sensitivity and 100.0% specificity for differentiating PCV from choroidal neovascularization/retinal angiomatous proliferation. CONCLUSION: Cross-sectional OCTA is more sensitive than en face OCTA in detecting flow signal in polyps. Combination of structural OCT and OCTA can be used to screen for PCV with a high level of sensitivity and specificity.

Human pharyngeal microbiota in age-related macular degeneration.

BACKGROUND: While the aetiology of age-related macular degeneration (AMD)-a major blinding disease-remains unknown, the disease is strongly associated with variants in the complement factor H (CFH) gene. CFH variants also confer susceptibility to invasive infection with several bacterial colonizers of the nasopharyngeal mucosa. This shared susceptibility locus implicates complement deregulation as a common disease mechanism, and suggests the possibility that microbial interactions with host complement may trigger AMD. In this study, we address this possibility by testing the hypothesis that AMD is associated with specific microbial colonization of the human nasopharynx. RESULTS: High-throughput Illumina sequencing of the V3-V6 region of the microbial 16S ribosomal RNA gene was used to comprehensively and accurately describe the human pharyngeal microbiome, at genus level, in 245 AMD patients and 386 controls. Based on mean and differential microbial abundance analyses, we determined an overview of the pharyngeal microbiota, as well as candidate genera (Prevotella and Gemella) suggesting an association towards AMD health and disease conditions. CONCLUSIONS: Utilizing an extensive study population from Singapore, our results provided an accurate description of the pharyngeal microbiota profiles in AMD health and disease conditions. Through identification of candidate genera that are different between conditions, we provide preliminary evidence for the existence of microbial triggers for AMD. Ethical approval for this study was obtained through the Singapore Health Clinical Institutional Review Board, reference numbers R799/63/2010 and 2010/585/A.

Incidence of Fellow Eye Involvement in Patients With Unilateral Exudative Age-Related Macular Degeneration.

Importance: Since the advent of optical coherence tomography angiography (OCT-A), nonexudative neovascularization has been described in the fellow eyes of unilateral exudative age-related macular degeneration (AMD). However, there is limited literature describing the natural course and optimal management of these lesions. Objective: To determine the incidence of fellow eye involvement in patients presenting with unilateral typical AMD or polypoidal choroidal vasculopathy and to evaluate the patterns of OCT-A changes within 6 months before the onset of exudative changes, especially focusing on nonexudative neovascularization. Design, Setting, and Participants: Data for this study were taken from a prospective, observational cohort study involving Asian patients with exudative AMD in the Asian AMD Phenotyping Study between October 2015 and March 2016. Analyses began in June 2017. Only patients who had gradable OCT-A and indocyanine green angiography (ICGA) scans of the fellow eye at baseline and follow-up at least 6 months apart were included for the analysis. The contralateral eye was evaluated for presence of nonexudative neovascularization based on multimodal imaging, which included ICGA, spectral domain optical coherence tomography, and OCT-A. Main Outcomes and Measures: The difference between the incidence of those with nonexudative choroidal neovascularization and those without as analyzed using log-rank test and qualitative analysis of OCT-A images. Results: We included 95 fellow eyes of 95 patients who presented with unilateral exudative AMD with a mean (SD) age of 68.6 (8.6) years. Nonexudative neovascularization was present in 18 eyes (19%) (8 [22.9%] and 10 [19.0%] fellow eyes with typical AMD and polypoidal choroidal vasculopathy, respectively; 8 [44.4%] on OCT-A; 5 [27.8%] on ICGA; and 5 [27.8%] on both OCT-A and ICGA). Development of exudative changes was noted in 6 fellow eyes (6.3%). Four eyes developed exudation from previously noted nonexudative neovascularization, and 2 eyes arose exudative changes from de novo. The probability of developing exudation within 6 months was significantly higher in eyes with baseline nonexudative neovascularization (0.087; 95% CI, 0.0033-0.210) compared with eyes without (0.010; 95% CI, 0.0026-0.041) (P = .008). In all eyes whose OCT-A images were available immediately before the onset of exudative changes, there was an increase in the size of network vessels compared with baseline. Conclusions and Relevance: The presence of nonexudative neovascularization may predispose to the development of exudative changes.

CHOROIDAL VASCULAR HYPERPERMEABILITY AS A PREDICTOR OF TREATMENT RESPONSE FOR POLYPOIDAL CHOROIDAL VASCULOPATHY.

PURPOSE: To investigate the influence of choroidal vascular hyperpermeability (CVH) and choroidal thickness on treatment outcomes in eyes with polypoidal choroidal vasculopathy (PCV) undergoing anti-vascular endothelial growth factor monotherapy or combination therapy of photodynamic therapy and anti-vascular endothelial growth factor injections. METHODS: The authors performed a prospective, observational cohort study involving 72 eyes of 72 patients with polypoidal choroidal vasculopathy (mean age 68.6 years, 51% men) treated with either monotherapy (n = 41) or combination therapy (n = 31). Each eye was imaged with color fundus photography, fluorescent angiography, indocyanine green angiography, and spectral domain optical coherence tomography. Indocyanine green angiography images were used to evaluate CVH, and spectral domain optical coherence tomography was used to measure central choroidal thickness. Changes in visual acuity over 12 months, and number of anti-vascular endothelial growth factor injections were investigated. RESULTS: Choroidal vascular hyperpermeability was present in 31 eyes (43.1%). Visual acuity change over 12 months was numerically better in the CVH group compared with the CVH (-) group (-0.099 and -0.366 logarithm of the minimal angle of resolution unit in the CVH (-) and CVH (+) groups, respectively, multivariate P = 0.063) and significantly better in a matched pair analysis (P = 0.033). Furthermore, in the combination therapy group, the number of injection was significantly lower in the CVH (+) group compared with the CVH (-) group (4.68 vs. 2.58 injections/year in the CVH (-) and CVH (+) groups; P = 0.0044). There was no significant relationship between treatment response and choroidal thickening. CONCLUSION: The presence of CVH is associated with better visual outcome in eyes with polypoidal choroidal vasculopathy and lower injection number in combination therapy. Thus, CVH, but not choroidal thickness, should be further evaluated as a potential biomarker for selecting patients for combination therapy.

COMPARISON OF OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHIC CHANGES AFTER ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY ALONE OR IN COMBINATION WITH PHOTODYNAMIC THERAPY IN POLYPOIDAL CHOROIDAL VASCULOPATHY.

PURPOSE: To compare changes in optical coherence tomography angiography in eyes with polypoidal choroidal vasculopathy after treatment with anti-vascular endothelial growth factor monotherapy or combined with photodynamic therapy. METHODS: This is a longitudinal case-controlled study. The authors performed optical coherence tomography angiography at baseline and Month 3 in patients with treatment-naive polypoidal choroidal vasculopathy undergoing monotherapy (n = 10) or combination therapy (n = 13). We analyzed flow signal within the outer retina and choriocapillaris using automated segmentation. The authors analyzed the presence of pachyvessels using a 10.4-µm segment through Haller layer. The changes in each layer were compared between treatments. RESULTS: At Month 3, both groups showed similar improvement in best-corrected visual acuity and central retinal thickness. However, flow signal within the polypoidal choroidal vasculopathy complex was decreased in more eyes after combination therapy than after monotherapy (84.6% vs. 40.0%, P = 0.04). Patchy reduction in flow signal within the choriocapillaris layer was noted in 15.4% and 10.0% after combination therapy and monotherapy, respectively (P = 0.61). Significant reduction in pachyvessel caliber was seen only after combination therapy but not after monotherapy (75.0% vs. 0.0%, P = 0.01). CONCLUSION: Longitudinal optical coherence tomography angiography demonstrates more significant reduction in lesion flow and pachyvessels in the short term after combination therapy than after monotherapy, although visual and structural OCT showed similar improvement.

Choroidal Remodeling in Age-related Macular Degeneration and Polypoidal Choroidal Vasculopathy: A 12-month Prospective Study.

Choroid thinning occurs in age-related macular degeneration (AMD). However, it remains unclear whether the reduction is due to reduction in choroidal vessels or shrinkage of choroidal stroma, or both. The purpose of this study was to evaluate the changes of the choroidal vascular and stromal area in 118 patients with typical AMD (t-AMD) and polypoidal choroidal vasculopathy (PCV) over a 12-month period. We used spectral-domain optical coherence tomography (SD-OCT) with enhanced depth imaging (EDI) mode to measure the subfoveal choroidal thickness (CT), central retinal thickness (CRT) and choroidal vascularity index (CVI - ratio of luminal area to total choroidal area). At baseline, PCV eyes had higher CRT (471.6 µm vs 439.1 µm, p = 0.02), but comparable subfoveal CT and CVI, compared to t-AMD. Eyes with high CVI at baseline showed marked reduction in stromal area compared with eyes with average or low CVI. Over 12 months, CRT and subfoveal CT significantly decreased (p < 0.001) in both subtypes. Eyes with high baseline CVI showed significant CVI reduction from baseline to month 12 (p < 0.001), whereas eyes with average to low baseline CVI showed increase in CVI. These differences in choroidal vascularity may reflect different predominant pathogenic processes and remodeling in AMD eyes with varying spectrum.

Prevalence and Risk Factors for Nonexudative Neovascularization in Fellow Eyes of Patients With Unilateral Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy.

Purpose: To determine the prevalence of subclinical nonexudative neovascularization and associated choroidal vascular changes in the fellow eyes of patients presenting with unilateral typical exudative AMD (tAMD) or polypoidal choroidal vasculopathy (PCV) using indocyanine green angiography (ICGA) and swept-source (SS) optical coherence tomography angiography (OCT-A). Methods: We recruited patients presenting with tAMD or PCV in a prospective clinical study. The diagnosis in the presenting eye was determined based on clinical, fluorescein angiography (FA), and ICGA findings. We evaluated the contralateral eye for presence of nonexudative neovascularization, choroidal hyperpermeability, and pachyvessels in the outer choroid, based on multimodal imaging which included ICGA, spectral-domain (SD) OCT and OCT-A. We measured subfoveal choroidal thickness in both eyes for each patient. Results: We included 76 fellow eyes of 76 patients who presented with unilateral tAMD (n = 33) or PCV (n = 43). Nonexudative neovascularization was present in 18% eyes (14 eyes, 8 in tAMD group, 6 in PCV group; 7 on ICGA, 4 on OCT-A, 3 on both ICGA and OCT-A). Pachychoroid pigment epitheliopathy was present in 13 eyes with nonexudative neovascularization, and was the only risk factor associated with nonexudative neovascularization. Conclusions: Approximately one in five fellow eyes with unilateral tAMD and PCV have features of nonexudative neovascularization. The use of multimodal imaging including ICGA and OCT-A can identify these features. The presence of pachychoroid epitheliopathy should alert clinicians to the possibility of underlying neovascularization.