Diagnostic Challenges in Inflammatory Choroidal Neovascularization.

Inflammation plays a key role in the induction of choroidal neovascularization (CNV). Inflammatory choroidal neovascularization (iCNV) is a severe but uncommon complication of both infectious and non-infectious uveitides. It is hypothesized that its pathogenesis is similar to that of wet age-related macular degeneration (AMD), and involves hypoxia as well as the release of vascular endothelial growth factor, stromal cell-derived factor 1-alpha, and other mediators. Inflammatory CNV develops when inflammation or infection directly involves the retinal pigment epithelium (RPE)-Bruch's membrane complex. Inflammation itself can compromise perfusion, generating a gradient of retinal-choroidal hypoxia that additionally promotes the formation of choroidal neovascularization in the course of uveitis. The development of choroidal neovascularization may be a complication, especially in conditions such as punctate inner choroidopathy, multifocal choroiditis, serpiginous choroiditis, and presumed ocular histoplasmosis syndrome. Although the majority of iCNV cases are well defined and appear as the "classic" type (type 2 lesion) on fluorescein angiography, the diagnosis of iCNV is challenging due to difficulties in differentiating between inflammatory choroiditis lesions and choroidal neovascularization. Modern multimodal imaging, particularly the recently introduced technology of optical coherence tomography (OCT) and OCT angiography (noninvasive and rapid imaging modalities), can reveal additional features that aid the diagnosis of iCNV. However, more studies are needed to establish their role in the diagnosis and evaluation of iCNV activity.

Optical coherence tomography biomarkers for myopic choroidal neovascularization treated with anti-vascular endothelial growth factor.

In recent years, optical coherence tomography (OCT) biomarkers for specific retinal diseases have been found to be associated with treatment outcome and disease recurrence. The main purposes of this study were to identify OCT biomarkers for myopic choroidal neovascularization (mCNV) treated with intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF). OCT features in 43 eyes of 39 patients with mCNV treated with anti-VEGF with at least 1 year of follow-up were retrospectively analyzed. Eyes with subretinal hyperreflective material (SHM) in baseline spectral-domain OCT (SD-OCT) had significantly more visual improvement than eyes without SHM at month 6 (p = 0.007) and had a trend of more visual improvement than eyes without SHM (p = 0.058) at month 12. Eyes with subretinal fluid (SRF) at baseline had significantly more central retinal thickness (CRT) decrease than patients without SRF at month 6 and 12 (p = 0.012 and 0.006 respectively). In univariate regression analysis, dome-shaped macula (DSM), SRF in baseline OCT image and fuzzy border of mCNV when entering pro re nata (PRN) injection protocol tended to have higher risk of disease recurrence in 1 year (odds ratio: 14.86 (p = 0.003), 3.75 (p = 0.049) and 22.92 (p < 0.001) respectively). However, they were not significant in multivariate regression analysis. OCT biomarkers at baseline could provide prognostic information for mCNV management.

QUANTIFIED ANASTOMOTIC AREAS OF NEOVASCULARIZATION AS FACTORS ASSOCIATED WITH FREQUENT RECURRENCE IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To investigate the quantitative characteristics of anastomoses of macular neovascularization (MNV) in neovascular age-related macular degeneration using optical coherence tomography angiography according to the frequency of intravitreal injections. METHODS: Eighty-six eyes of 86 patients treated for neovascular age-related macular degeneration were classified into two groups based on the number of intravitreal injections administered over 12 months: stable (<3) and unstable (≥3). Anastomotic areas were defined as areas surrounded by neighboring vessels in the MNV; their total number, mean area, maximal and minimal diameters (i.e., maximal and minimum Feret diameters), and ratio (Feret aspect ratio) were analyzed in the inner and outer areas of the MNV. RESULTS: Forty-four and 42 eyes were classified into the stable and unstable groups, respectively. The eyes in the unstable group had larger anastomotic areas with longer minimum Feret diameters and longer perimeters in the outer MNV. In the logistic regression analysis, instability was associated with a larger anastomotic area and a longer minimum Feret diameter in the outer MNV. Multivariate analysis revealed that a longer minimum Feret diameter in the outer MNV was the most significant factor ( P = 0.03). CONCLUSION: The quantitative characteristics of the anastomotic areas in the MNV might indicate the need for intravitreal injections in patients with neovascular age-related macular degeneration.

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.

HYPERREFLECTIVE FOCI PRECEDE MACULAR NEOVASCULARIZATION FORMATION IN ANGIOID STREAKS.

PURPOSE: To describe the steps leading to the development and progression of macular neovascularization (MNV) in angioid streaks. METHODS: The study was designed as retrospective, longitudinal case series. Patients with angioid streaks were investigated by means of multimodal imaging, including fundus autofluorescence and structural optical coherence tomography. Main outcome measures were hyperreflective foci and MNV progression steps. RESULTS: Overall, 40 eyes (20 patients) affected by angioid streaks were evaluated. Over the follow-up, five eyes of five patients developed MNV. The mean follow-up was of 1.6 years. The mean number of anti-vascular endothelial growth factor injections was 4.35 ± 1.4. Mean best-corrected visual acuity was 0.53 ± 0.38 LogMAR at the MNV onset, improving to 0.42 ± 0.40 LogMAR at the end of the follow-up ( P > 0.05). Intraretinal hyperreflective foci onset and coalescence represented the first alterations occurring before the onset of the MNV. Anti-vascular endothelial growth factor treatment was associated with exudation relapsing and remitting, with still present intraretinal hyperreflective foci and pigment accumulation. The longitudinal analysis of our cohort of eyes outlined the event timeline: 1.2 months to find concentrated hyperreflective foci, 4.5 months to observe pigment organization through the outer nuclear layer, and 1.5 years to detect MNV. CONCLUSION: Hyperreflective foci formation, concentration, and migration represent early alterations occurring before the onset of the MNV in angioid streaks.

Sequential retinal pigment epithelium tears following intravitreal Ranibizumab injections for age-related macular degeneration.

PURPOSE: To report a case of sequential retinal pigment epithelium (RPE) tears following intravitreal Ranibizumab injections for neovascular age-related macular degeneration (AMD). METHODS: Retrospective, observational case. CASE DESCRIPTION: A 75-year-old hypertensive male was diagnosed with active neovascular AMD and pre-existing RPE tear in the left eye. His presenting best-corrected visual acuity was counting finger @ 1 metre,

Long-term outcomes of anti-vascular endothelial growth factor treatment in peripapillary choroidal neovascularisation due to age-related macular degeneration.

OBJECTIVE: To report the long-term outcomes of anti-vascular endothelial growth factor (VEGF) treatment in eyes with peripapillary choroidal neovascularisation (PPCNV) associated with age-related macular degeneration (AMD). METHODS: A retrospective cohort study included patients with AMD-related PPCNV. Eyes were treated with anti-VEGF according to pro re nata regimen. Inactivation index was calculated as the proportion of disease inactivity from the total follow up time. RESULTS: Sixty-seven eyes of 66 consecutive patients were included in the study; mean follow-up time was 53.2 months. Best corrected visual acuity (BCVA) remained stable for the first four years of follow up, with a significant deterioration in BCVA thereafter. Baseline BCVA was a significant predictor of final BCVA (p < 0.001). The mean inactivation index was 0.38 ± 0.23. Subretinal fluid (SRF) at presentation was significantly associated with decreased inactivation index (p < 0.05). Worse baseline BCVA, SRF and pigment epithelium detachment (PED), male sex, and younger patient age were associated with increased risk for recurrence after first inactivation (p < 0.05). CONCLUSION: The use of anti-VEGF agents in the treatment of AMD-related PPCNV managed to preserve BCVA in the first four years of follow-up. Male sex, SRF and PED at presentation and baseline BCVA are associated with increased risk for PPCNV recurrence after the first inactivation, and should prompt careful follow-up in these patients.

Association of HERPUD1 genetic variant rs2217332 with age-related macular degeneration and polypoidal choroidal vasculopathy in an Indian cohort.

PURPOSE: Age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) are sister diseases and have several similar clinical features and still have few genetic differences. The association of HERPUD1 (homocysteine inducible ER protein with ubiquitin like domain 1) gene variant rs2217332 with PCV is known; however, such association with AMD has not been reported in the Indian population. We analyzed the association of rs2217332 with PCV and AMD to identify the preferential association of this variant with these diseases. METHODS: This is a population-based case-control study consisting of 422 patients (129 AMD cases; 101 PCV cases, 192 healthy controls) recruited from the vitreoretinal clinic Sankara Nethralaya. The sample size for the study was calculated using appropriate power calculation methods. Genotype was determined using PCR-based Sanger sequencing. The SPSS V23.0 statistical package tool was used to calculate chi-square and ROC to determine the association of rs2217332 with control, AMD, and PCV. RESULTS: Here, we report for the first time the association of this genetic variant (rs2217332) with AMD and PCV in the Indian population. The case-control study shows a significant association of this SNP with PCV (P value = 0.002); however, this variant is not significantly associated with AMD (P value = 0.602). Comparison between AMD (as control) and PCV (as case) also showed significant association of the SNP with PCV (P value = 0.02). Minor allele A conferred to increase the risk of PCV. CONCLUSIONS: The study concludes that the genetic variant rs2217332 in HERPUD1 gene is highly significantly associated with PCV and not with AMD in Indian populations.

LATE CHOROIDAL NEOVASCULAR COMPLICATIONS IN A PATIENT TREATED FOR RETINOBLASTOMA. A CASE REPORT.

AIM: Case report of choroidal neovascularization (CNV) detection in patient who was treated for bilateral retinoblastoma in early childhood. MATERIAL AND METHODS: Patient at 1.5 years of age treated for endophytic retinoblastoma stage 4 (according to the Reese-Ellsworth classification) bilaterally, with a positive mutation in the Rb1 gene. After undergoing bilateral retinal laser treatment and 6 cycles of systemic chemotherapy, the tumor remained inactive without other complications. At the age of 14, the boy developed visual impairment in his left eye with metamorphosis. Based on a local finding and other auxiliary examinations, he was diagnosed with CNV in the macular area at the interface of the tumor scar and the healthy retina of the left eye. RESULTS: After three applications of anti-VEGF (antibodies blocking vascular endothelial growth factor) substance intravitreally (bevacizumab 1.2 mg), there was a reduction in CNV and also an improvement in visual function.

Predicting Visual Outcomes in Choroidal Osteoma Treated with Anti-vascular Endothelial Growth Factor.

PURPOSE: To determine potential factors associated with the long-term visual prognoses in patients with choroidal osteoma undergoing anti-vascular endothelial growth factor (VEGF) treatment. DESIGN: Retrospective case series. METHODS: Patients diagnosed at tertiary high-volume hospitals between January 2000 and December 2020 were evaluated. The primary outcome measure was visual acuity at 5-year follow-up. The secondary outcome measures included factors associated with favorable vision, defined as loss of <1 line and >20/200 vision. RESULTS: Of 38 eyes from 36 patients (22 female, 61%; mean age 38 years) with choroidal osteoma, 23 eyes (61%) received anti-VEGF treatment (bevacizumab 1.25mg/0.05 cc, monthly or treat-and-extend) and 65% completed the 5 years of follow-up. All treated eyes had associated chorioretinal comorbidities (subretinal fluid 91%; choroidal neovascularization 74%; subretinal hemorrhage 30%). Although there was significant vision loss by 5 years (P = .002), 12 eyes (44%) had favorable outcomes. Only tumor thickness was significantly associated with unfavorable visual outcomes (OR 917.1, 95% CI 1.0-5687.7; P = .049). The optimal cut-off point predictive of visual outcomes was 1.4 mm, and tumor thickness ≥ 1.4 mm was associated with unfavorable vision (OR 27.0, 95% CI 2.0-368.4; P = .013). CONCLUSIONS: Among patients with choroidal osteoma undergoing anti-VEGF therapy, a particular patient subset presented with divergent outcomes with very poor vision. Tumor thickness appeared to be the differentiating factor and is thus a potential prognostic indicator for long-term visual prognoses.

Genome-wide Survival Analysis for Macular Neovascularization Development in Central Serous Chorioretinopathy Revealed Shared Genetic Susceptibility with Polypoidal Choroidal Vasculopathy.

PURPOSE: To identify susceptibility genes for macular neovascularization (MNV) development in central serous chorioretinopathy (CSC). DESIGN: Genome-wide survival analysis using a longitudinal cohort study. PARTICIPANTS: We included 402 and 137 patients with CSC but without MNV at their first visit from the Kyoto CSC Cohort and Kobe CSC dataset, respectively. All patients underwent detailed ophthalmic examinations, including multimodal imaging, such as fundus autofluorescence, spectral-domain OCT, and fluorescein angiography/indocyanine green angiography or OCT angiography. METHODS: We conducted a genome-wide survival analysis using the Kyoto CSC Cohort. We applied the Cox proportional hazard model to adjust for age, sex, and the first principal component. Single nucleotide polymorphisms (SNPs) with P values < 1.0 × 10-5 were carried forward to the replication in the Kobe CSC dataset. Moreover, we evaluated the contribution of previously reported age-related macular degeneration (AMD) susceptibility loci. We used FUMA and ToppFun for the functional enrichment analysis. MAIN OUTCOME MEASURES: The association between SNPs and MNV development in patients with CSC. RESULTS: Rs370974631 near ARMS2 displayed a genome-wide significant association in the meta-analysis of discovery and replication result (hazard ratio [HR]meta, 3.63; Pmeta = 5.76 × 10-9). Among previously reported AMD susceptibility loci, we additionally identified CFH rs800292 (HR, 0.39, P = 2.55 × 10-4), COL4A3 rs4276018 (HR, 0.26, P = 1.56 × 10-3), and B3GALTL rs9564692 (HR, 0.56, P = 8.30 × 10-3) as susceptibility loci for MNV development in CSC. The functional enrichment analysis revealed significant enrichment of 8 pathways (GO:0051561, GO:0036444, GO:0008282, GO:1990246, GO:0015272, GO:0030955, GO:0031420, and GO:0005242) related to ion transport. CONCLUSIONS: ARMS2, CFH, COL4A3, and B3GALTL were identified as susceptibility genes for MNV development in CSC. These 4 genes are known as susceptibility genes for AMD, whereas COL4A3 and B3GALTL were previously reported to be polypoidal choroidal vasculopathy (PCV)-specific susceptibility genes. Our findings revealed the shared genetic susceptibility between PCV and MNV secondary to CSC.

PREDICTING LESION SHRINKAGE IN EYES WITH MYOPIC CHOROIDAL NEOVASCULARIZATION FROM FEATURES ON OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY.

PURPOSE: To identify baseline morphological predictors of lesion shrinkage in eyes with myopic choroidal neovascularization (mCNV) treated with anti-vascular endothelial growth factor. METHODS: This retrospective study included 46 eyes (41 consecutive patients) with active mCNV receiving anti-vascular endothelial growth factor treatment. Optical coherence tomography angiography was performed at baseline and 1 year after treatment. Quantitative features were obtained from optical coherence tomography angiography images using AngioTool software. Eyes were classified as "high shrinkage" or "low shrinkage" according to the median relative change in lesion area. Baseline quantitative morphological features associated with mCNV shrinkage were identified in univariate and multivariate analyses. RESULTS: The mCNV area was significantly smaller after 1 year ( P = 0.013), with a median relative change of -16.5%. The relative change in mCNV area was -48.3% in high-shrinkage eyes (n = 23) and -5.2% in low-shrinkage eyes (n = 23). High-shrinkage eyes had a smaller mCNV area ( P = 0.013), shorter total vessel length ( P = 0.023), and higher end point density ( P < 0.001). Multivariate analysis showed significant associations of high shrinkage with end point density (ß = -0.037, P = 0.043) and previous anti-vascular endothelial growth factor treatment (ß = 0.216, P = 0.029). CONCLUSION: Morphological features of neovascularization detected by optical coherence tomography angiography can predict lesion shrinkage in eyes with mCNV receiving anti-vascular endothelial growth factor therapy. Higher end point density contributed to shrinkage, particularly of treatment-naive lesions.

Predictors of anti-VEGF efficacy in chronic central serous chorioretinopathy based on intraocular cytokine levels and pigment epithelium detachment subtypes.

PURPOSE: The aim of this study was to compare intraocular cytokines among different types of pigment epithelial detachments (PEDs) in patients with chronic central serous chorioretinopathy (CSC) and to investigate the association of cytokine levels and PED types with response to anti-vascular endothelial growth factor (VEGF) therapy. METHODS: We included 88 patients with chronic CSC and 30 controls. The anti-VEGF agent conbercept was given intravitreally to chronic CSC patients. Cytokines VEGF, interleukin-6 (IL-6), IL-8, IL-10, interferon-inducible protein-10 and monocyte chemoattractant protein-1 in aqueous humour were measured. Treatment efficacy, cytokine levels, changes in best-corrected visual acuity (BCVA) and optical coherence tomography parameters were assessed at baseline and 1 month after treatment. RESULTS: Patients were divided into three groups: flat irregular PED (FIPED) with choroidal neovascularization (CNV), FIPED without CNV and focal PED. Vascular endothelial growth factor (VEGF) was the only cytokine significantly higher in chronic CSC FIPED patients. There were no significant differences in VEGF between FIPED patients with or without CNV (p = 0.234). At 1 month after conbercept injection, treatment effective rates in FIPED patients with or without CNV were significantly higher than in patients with focal PED (p < 0.05). Best-corrected visual acuity (BCVA) was improved in both FIPED groups (p < 0.05), but not in the focal PED group (p = 0.180). All three groups had significant decreases in central macular thickness (p < 0.05), and PED heights in FIPED patients were reduced (p < 0.05). CONCLUSIONS: Patients with FIPED in chronic CSC had elevated intraocular VEGF levels and responded favourably to conbercept. Anti-VEGF treatment may be an option for FIPED CSC patients with or without secondary CNV.

Vascular endothelial growth factor inhibitors for predominantly Caucasian myopic choroidal neovascularization: 2-year treatment outcomes in clinical practice: data from the Fight Retinal Blindness! Registry.

PURPOSE: To report the 24-month outcomes of vascular endothelial growth factor (VEGF) inhibitors for myopic choroidal neovascularization (mCNV) in predominantly Caucasian eyes in routine clinical practice. METHODS: Retrospective analysis of treatment-naïve eyes starting intravitreal injection of VEGF inhibitors of either bevacizumab (1.25 mg) or ranibizumab (0.5 mg) for mCNV from 1 January 2006 to 31 May 2018 that were tracked in the Fight Retinal Blindness! registry. RESULTS: We identified 203 eyes (bevacizumab-85 and ranibizumab-118) of 189 patients. The estimated mean (95% CI) change in VA over 24 months for all eyes using longitudinal models was +8 (5, 11) letters with a median (Q1, Q3) of 3 (2, 5) injections given mostly during the first year. The estimated mean change in VA at 24 months was similar between bevacizumab and ranibizumab [+9 (5, 13) letters for bevacizumab versus +9 (6, 13) letters for ranibizumab; p = 0.37]. Both agents were also similar in the mCNV activity outcomes, treatment frequency and visit frequency. CONCLUSIONS: The 24-month treatment outcomes of VEGF inhibitors for mCNV were favourable in this largest series yet reported of predominantly Caucasian eyes in routine clinical practice, with approximately two lines of visual gain and a median of three injections given mostly during the first year. These outcomes are similar to those reported for predominantly Asian eyes. Bevacizumab appeared to be as safe and effective as ranibizumab.

Longitudinal assessment of type 3 macular neovascularization using 3D volume-rendering OCTA.

OBJECTIVE: To investigate the evolution of treatment-naive type 3 macular neovascularization (MNV) undergoing anti-vascular endothelial growth factor (VEGF) treatment through volume rendered three-dimensional (3D) optical coherence tomography angiography (OCTA). DESIGN: Retrospective observational study. PARTICIPANTS: Patients with type 3 MNV and age-related macular degeneration (AMD). METHODS: Included subjects had three loading injections of an anti-VEGF agent. The OCTA volume data at baseline and follow-up were processed with a previously published algorithm in order to obtain a volume-rendered representation of type 3 MNV. Progressive changes in type 3 lesions were analyzed via 3D OCTA volume rendering. RESULTS: A total of 14 treatment-naive eyes with type 3 MNV from 11 AMD patients (7 females) were included. At both baseline and follow-up visits, a type 3 MNV complex was identifiable. Each complex was composed of a mean number of 2.5 ± 0.7 vascular branches at baseline and 1.4 ± 0.6 at the follow-up visit (p < 0.0001). The mean changes in central macular thickness and visual acuity were significantly correlated with modifications in the number of type 3 MNV branches (ρ = -0.533, p = 0.049, and ρ = -0.581, and p = 0.040, respectively). CONCLUSIONS: This study demonstrated that type 3 lesions do not disappear completely after loading treatment, as indicated previously by histopathologic studies. Importantly, quantitative volume changes in type 3 lesions are directly associated with treatment response.

Tilted disc syndrome (TDS): New hypotheses for posterior segment complications and their implications in other retinal diseases.

Tilted disc syndrome (TDS) is considered a congenital anomaly due to a delayed closure of the embryonic fissure. It is characterized by an oblique orientation of the axis of the optic disc, associated with other posterior pole anomalies such as inferior crescent, situs inversus and inferior staphyloma. The aim of this review was to summarize the data supporting the current hypotheses for the pathogenesis of TDS, and its anatomical and functional clinical consequences. Recent imaging techniques, such as magnetic resonance imaging, wide-field fundus imaging, and 2- and 3-D optical coherence tomography have provided a new perspective on TDS and its complications. Different abnormalities have previously been reported, both in the anterior and posterior segments. The focus was on vision-threatening chorioretinal changes or complications, including choroidal neovascularization and serous retinal detachments and their therapeutic options. Based on clinical observations, assumptions were proposed to understand the occurrence of complications such as chorioretinal degenerative changes, choroidal neovascularization and polypoidal choroidal vasculopathy, macular serous retinal detachment, myopic foveoschisis and chorioretinal folds. These hypotheses could be referred to as the curvature "breaking point" hypothesis, the uneven growth "tractional" hypothesis, the "container-content" imbalance hypothesis, and the "choroidal funnel" hypothesis. Because these complications could also occur in other contexts, understanding the pathogenesis of TDS complications could help to understand their pathophysiology.