Importance of optical coherence tomography raster scans in early detection of active fellow-eye neovascularization in unilateral neovascular age-related macular degeneration.

PURPOSE: To investigate the incidence of and risk factors for failure of detection of active fellow-eye neovascularization on optical coherence tomography(OCT) crosshair scans in patients with unilateral neovascular age-related macular degeneration(AMD). METHODS: In this retrospective study, patients who experienced the development of active neovascularization in the fellow eye during the follow-up period were included(n = 75). Cases in which the neovascularization in the fellow eye could be identified solely through crosshair scans were defined as the crosshair scan detection group(n = 63). Cases in which the aforementioned findings could not be identified through crosshair scans but could be identified through raster scans were defined as the raster scan detection group(n = 12). The factors were compared between the two groups. Risk factors related to undetected neovascularization on crosshair scans were additionally identified. RESULTS: Active fellow-eye neovascularization, was not detected on OCT crosshair scans in 12 cases(16.0%) but was identified on raster scans in all cases. There was a significant difference in the proportion of neovascularization types between the crosshair scan detection group and the raster scan detection group(P = 0.023). Among the 35 fellow-eye neovascularization cases in patients with type 3 macular neovascularization(MNV), 10(28.6%) were not detected on crosshair scans. Multivariate analysis revealed a significantly higher risk for undetectable fellow-eye neovascularization on crosshair scans in patients with type 3 MNV than in those with typical neovascular AMD(P = 0.037,ß = 9.600). CONCLUSIONS: Our findings suggest the need for routine OCT raster scans during fellow-eye examinations in patients with unilateral neovascular AMD, particularly when the first-affected eye is diagnosed with type 3 MNV.

Subfoveal choroidal thickness after brolucizumab therapy for neovascular age-related macular degeneration: a short-term multicenter study.

BACKGROUND/PURPOSE: Observation of choroidal thickness after anti-vascular endothelial growth factor (VEGF) therapy may be important for the ideal management of neovascular age-related macular degeneration (AMD). This study investigated changes in subfoveal choroidal thickness (SCT) during loading doses of intravitreal injections of brolucizumab in eyes with neovascular AMD. METHODS: This study included 73 eyes of 72 patients with neovascular AMD at five university hospitals in Japan. All 73 eyes underwent three monthly 6.0 mg intravitreal injections of brolucizumab at baseline, 1 month, and 2 months. The SCT at 3 months was evaluated using optical coherence tomography. RESULTS: The 73 eyes were classified into the treatment-naïve group (43 eyes) and the switched group (30 eyes) that were switched from other anti-VEGF treatments. After three intravitreal injections of brolucizumab, SCT significantly decreased from 236.5 ± 98.8 µm at baseline to 200.4 ± 98.3 µm at 3 months (percent of baseline 84.7%, P < 0.001) in the treatment-naïve group. In the switched group, SCT also significantly decreased from 229.0 ± 113.2 µm at baseline to 216.9 ± 110.2 µm at 3 months (percent of baseline 94.7%, P = 0.039), although the decrease was not as marked compared to that of the treatment-naïve group. CONCLUSION: Intravitreal injections of brolucizumab for neovascular AMD significantly reduced the SCT in both the treatment-naïve and switched groups. Brolucizumab may cause significant anatomic changes in the choroid, particularly in treatment-naïve AMD eyes, possibly more than that previously reported for other anti-VEGF agents.

The RAP study, report 4: morphological and topographical characteristics of multifocal macular neovascularization type 3.

PURPOSE: To report on the morphological characteristics and regional distribution of multifocal macular neovascularization type 3 (mMNV3). METHODS: Twenty-two consecutive eyes of 21 patients with mMNV3 were included using multimodal imaging. The count and stage of lesions of all MNV types and the existence of exudate and hemorrhage were determined. Also, we addressed the regional distribution of MNV3 lesions between the superior-inferior and the nasal-temporal halves of the macula, and the range of the distance of the lesions from the central fovea. Furthermore, we explored the number of feeding vessels including the cilioretinal artery. RESULTS: We found 51 lesions in 22 eyes of 21 patients. They were bifocal in 16 (73%) eyes, trifocal in 5 (23%), and quadrifocal in one (4%). No lesion of MNV1 or 2 was found. Fifteen (68%), 2 (9%), and 16 (73%) eyes were associated with retinal hard exudate, subretinal pigment epithelium exudate, and intraretinal hemorrhage, respectively. Thirty (59%) lesions were located in the temporal half of the macula, whereas 21 (41%) were located nasally (p = 0.07). One (2%) lesion was closer than 500 µm, 49 (96%) between 500 and 1500 µm, and one (2%) between 1500 and 3000 µm. The lesions were supplied by one arteriole in one (4%) eye, two arterioles in 16 (73%) eyes, and 3 arterioles in 5 (23%) eyes. The CRA contributed as a feeding vessel in 5 (23%) eyes. CONCLUSION: The multifocal variant of MNV3 has specific morphological and topographical characteristics. Multimodal imaging allows the understanding of the pathomorphological condition in more detail.

Transcriptional and Distributional Profiling of Microglia in Retinal Angiomatous Proliferation.

Macular neovascularization type 3, formerly known as retinal angiomatous proliferation (RAP), is a hallmark of age-related macular degeneration and is associated with an accumulation of myeloid cells, such as microglia (MG) and infiltrating blood-derived macrophages (MAC). However, the contribution of MG and MAC to the myeloid cell pool at RAP sites and their exact functions remain unknown. In this study, we combined a microglia-specific reporter mouse line with a mouse model for RAP to identify the contribution of MG and MAC to myeloid cell accumulation at RAP and determined the transcriptional profile of MG using RNA sequencing. We found that MG are the most abundant myeloid cell population around RAP, whereas MAC are rarely, if ever, associated with late stages of RAP. RNA sequencing of RAP-associated MG showed that differentially expressed genes mainly contribute to immune-associated processes, including chemotaxis and migration in early RAP and proliferative capacity in late RAP, which was confirmed by immunohistochemistry. Interestingly, MG upregulated only a few angiomodulatory factors, suggesting a rather low angiogenic potential. In summary, we showed that MG are the dominant myeloid cell population at RAP sites. Moreover, MG significantly altered their transcriptional profile during RAP formation, activating immune-associated processes and exhibiting enhanced proliferation, however, without showing substantial upregulation of angiomodulatory factors.

Intraretinal Cysts as a Manifestation of Retinal Angiomatous Proliferation in Optical Coherence Tomography Angiography.

Background and Objectives: Intraretinal cysts are common pathology observed inspectral domain optical coherence tomography (SDOCT) in patients with neovascular form of age-related macular degeneration (AMD). The aim of the study was to determine if the presence of intraretinal cysts is positively correlated with diagnosis of retinal angiomatous proliferation (RAP) in optical coherence tomography angiography (OCTA). Material and Methods: A total of 21 eyes with intraretinal cysts in SDOCT exam (Group1) and 21 eyes with subretinal fluid(Group 2) were enrolled into the study. In each eye, the presence of intraretinal neovascularization (IRN) and chorioretinal anastomosis (CRA) was evaluated in OCTA by two experienced graders. Results: IRN was observed in 20 eyes (95.2%) from Group 1 and 5 eyes (23.8%) from Group 2. Features of CRA were found in 18 eyes (80.95%) and 16 eyes (76.2%) respectively for Group 1 and 2. Patients with cysts are 50 (95% CI: 5.43−460.52) times more likely to have IRN (p < 0.001). Conclusions: The presence of intraretinal cysts on SDOCT retinal sections in eyes with neovascular AMD corresponds to the presence of IRN on OCTA examination. The results indicate that the absence of a cyst does not exclude the presence of IRN and CRA which can be identified on OCTA.

Early OCTA Changes of Type 3 Macular Neovascularization Following Brolucizumab Intravitreal Injections.

BACKGROUND AND OBJECTIVES: Brolucizumab is a novel anti-vascular endothelial growth factor (VEGF), whose efficacy has been shown in the Hawk and Harrier phase 3 clinical studies. The goal of the present case series is to report initial results of brolucizumab intravitreal injections (IVI) on type 3 neovascularization in neovascular age-related macular degeneration (nAMD), evaluated by optical coherence tomography angiography (OCTA). MATERIALS AND METHODS: This is a bicentric retrospective case series. Patients with newly diagnosed type 3 MNV treated with brolucizumab IVI and at least 6 months follow-up were enrolled. OCTA en face images and B-scans were analyzed for lesions at baseline, 1 month, 3 months, and 6 months. Whenever detectable, lesion area on outer retina and choriocapillaris layers was measured. RESULTS: Twelve eyes of 12 patients were included into the study. The most consistent OCTA sign at baseline was the presence of a vascular tuft in the outer retina (100%). The highest response was achieved at 3 months, with statistically significant decrease in lesion detection in the outer retina, in the choriocapillaris, and outer retinal lesion size. At 6 months, 58% of outer retinal lesions had disappeared. CONCLUSIONS: Brolucizumab IVI shows a good short-term efficacy for the treatment of type 3 neovascularizations. Further studies with greater number of patients and longer follow-up are warranted to confirm these findings.

Difference in treatment burden of neovascular age-related macular degeneration among different types of neovascularization.

PURPOSE: To evaluate the difference in the treatment burden among different types of neovascular age-related macular degeneration (AMD). METHODS: This retrospective, observational study included 431 patients who were diagnosed with neovascular AMD. Patients were divided into three groups: type 1 or 2 neovascularization group (n = 167), type 3 neovascularization group (n = 50), and polypoidal choroidal vasculopathy (PCV) group (n = 214). The number of hospital visits per year and the number of anti-vascular endothelial growth factor (VEGF) injections per year were compared among these groups. Furthermore, the incidence of bilateral involvement during the follow-up period was compared among the groups. RESULTS: The mean follow-up period was 50.6 ± 11.3 months. The number of hospital visits per year was significantly higher in the type 1 or 2 neovascularization group (mean: 6.1 ± 1.5) and type 3 neovascularization (6.6 ± 1.6) than in the PCV group (6.0 ± 1.5) (P < 0.001). The number of anti-VEGF injections per year was significantly higher in type 3 neovascularization group (3.1 ± 1.7) than in the type 1 or 2 neovascularization group (2.3 ± 1.5) or the PCV group (2.3 ± 1.2) (P = 0.042). There was a significant difference in the incidence of bilateral involvement among patients in type 1 or 2 neovascularization group (20.4%), type 3 neovascularization group (46.0%), and the PCV group (15.4%) (P < 0.001). CONCLUSIONS: The high frequency of hospital visits and that of anti-VEGF injections in patients with type 3 neovascularization suggests high treatment burden in these patients. The high incidence of bilateral involvement could be one of the primary reasons for high treatment burden in patients with type 3 neovascularization.

Assessing the long-term evolution of type 3 neovascularization in age-related macular degeneration using optical coherence tomography angiography.

PURPOSE: To analyze the evolution of type 3 neovascularization in eyes with age-related macular degeneration during anti-vascular endothelial growth factor (VEGF) treatment using optical coherence tomography angiography (OCTA) analysis. METHODS: Forty-one treatment-naïve eyes (37 patients) with type 3 neovascularization were retrospectively included in the study. The growth and morphological changes in the type 3 lesions, which were recorded using OCTA, were compared across time. RESULTS: The high-flow signal of the lesion on OCTA was significantly increased at the sub-retinal pigment epithelium (RPE) and the choriocapillaris during anti-VEGF treatment. The detection rate of the flow signal in the sub-RPE increased from 50.0% at baseline and 51.2% at 12 months to 65.9% at 24 months (P = 0.013). The flow signal extending into the choriocapillaris was detected in 0% of the eyes at baseline, 9.8% of the eyes at 12 months, and 17.1% of the eyes at 24 months (P = 0.018). The presence of subretinal drusenoid deposits (SDD) was significantly more frequent in the group with extension into the choriocapillaris (100%) than in the group without (61.8%, P = 0.036). For the four eyes with extension into the choroid, the morphological feature of the lesion on en face OCTA evolved into a tangled vascular network, similar to type 1 neovascularization. CONCLUSION: OCTA analysis revealed that type 3 neovascularization gradually extended downward toward the sub-RPE and choroid during anti-VEGF treatment. The extension of the lesion into the choriocapillaris, suggesting retinal-choroidal anastomosis, was significantly more frequent in eyes with SDD.

One-Year Results of Fixed Aflibercept Treatment Regime in Type 3 Neovascularization.

PURPOSE: To evaluate the effect of intravitreal aflibercept injections in treatment-naive type 3 neovascularization using a fixed treatment regime during the first year of therapy. METHODS: Fourteen eyes of 14 patients diagnosed with type 3 neovascularization were studied. All patients were treated with intravitreal aflibercept injections using a fixed treatment regime of 3 consecutive monthly dosages followed by 2-month interval injections. Results were assessed after a 12-month follow-up period. Changes of best corrected visual acuity (BCVA), central retinal thickness (CRT), central macular volume (CMV), and retinal pigment epithelium (RPE) atrophy at fundus autofluorescence and infrared reflectance images were recorded and analyzed. RESULTS: BCVA improved from 60.3 ± 11.7 ETDRS letters at the baseline to 70.9 ± 10.3 ETDRS letters at 12-months follow-up (p = 0.036). Also, CRT and CMV statistically improved after the treatment (from 425 ± 117 to 308 ± 117 µm [p = 0.031] and from 9.52 ± 1.90 to 8.29 ± 0.95 mm3 [p = 0.073], respectively). In 4 patients, development and progression of RPE atrophy were observed, and it was associated with the presence of serous pigment epithelium detachment at the baseline. Furthermore, the development of a fibrotic lesion eccentric to the fovea was observed in 5 patients, without significant impairment of BCVA (p = 0.290). CONCLUSION: Intravitreal aflibercept administered in a fixed treatment regime during the first year of therapy may be effective for the improvement and stabilization of BCVA in eyes with type 3 neovascularization. However, RPE atrophy and subretinal/intraretinal fibrosis can develop during the treatment.

Long-term incidence and timing of reactivation in patients with type 3 neovascularization after initial treatment.

PURPOSE: The purpose of the present study was to evaluate the long-term incidence and timing of reactivation in patients with type 3 neovascularization who were treated with three monthly anti-vascular endothelial growth factor (VEGF) injections. METHODS: A total of 179 patients (179 eyes) diagnosed with type 3 neovascularization with dry macula after three monthly anti-VEGF loading injections were included in this retrospective study. After the initial treatment, patients were followed up without further injection until the first reactivation. The incidence and timing of the first reactivation after the initial treatment were recorded, and factors predictive of early reactivation (≤ 6 months after the third anti-VEGF injection) were investigated. RESULTS: During a mean follow-up of 37.5 ± 18.8 months, the first reactivation was noted in 145 patients (81.0%) at a mean of 6.6 ± 4.1 months after the third injection. In 94 eyes (64.8%), reactivation was noted 2-6 months after the third injection, while in 37 eyes (25.5%) it was noted 7-12 months after the third injection. In the remaining 14 eyes (9.7%), the reactivation was noted after this period. The incidence of early reactivation was higher in women (P = 0.014) and patients with thicker choroid (P = 0.026). CONCLUSIONS: In patients with type 3 neovascularization, almost all reactivation was noted within 15 months of the third anti-VEGF injection, suggesting the need for close follow-up and detailed examination during this period. Female patients with thick choroid should be monitored more frequently during this early period.

Focal retinal pigment epithelium atrophy at the location of type 3 neovascularization lesion: a morphologic feature associated with low reactivation rate and favorable prognosis.

PURPOSE: To investigate the clinical significance of focal retinal pigment epithelium (RPE) atrophy in the eyes with type 3 neovascularization. METHODS: This retrospective study included 184 eyes those were diagnosed with type 3 neovascularization and were treated with antivascular endothelial growth factor (VEGF) therapy. Focal RPE atrophy was defined as a localized RPE atrophy found at the same location as the type 3 lesion. The incidence of reactivation after 3 loading injections and the visual outcomes was compared between a focal RPE atrophy group and a nonfocal RPE atrophy group. In the focal RPE atrophy group, the number of injections was compared between before and after the development of RPE atrophy. RESULTS: The mean follow-up period was 37.6 ± 18.8 months; focal RPE atrophy developed in 24 eyes (13.0%). Reactivation of the lesion after 3 loading injections was significantly less frequent in the focal RPE atrophy group (58.3%) than that in the nonfocal RPE atrophy group (85.0%) (P = 0.004). In the focal RPE atrophy group, the mean best-corrected visual acuity (BCVA) was 0.68 ± 0.28 (Snellen equivalent = 20/95) at diagnosis and 0.70 ± 0.48 (20/100) at the final follow-up. In the nonfocal RPE atrophy group, the values were 0.75 ± 0.34 (20/112) and 1.12 ± 0.68 (20/263), respectively. The BCVA at the final follow-up was significantly better in the focal RPE atrophy group (P < 0.001). The mean number of injections per year was 4.9 ± 1.8 and 1.3 ± 1.6 before and after the development of focal RPE atrophy, respectively (P < 0.001). CONCLUSIONS: Development of focal RPE atrophy was associated with a low incidence of reactivation of type 3 neovascularization and was therefore predictive of a favorable visual prognosis.

Age-related differences in the prevalence of subtypes of Neovascular age-related macular degeneration in the first diagnosed eye.

PURPOSE: To evaluate age-related differences in the prevalence of subtypes of neovascular age-related macular degeneration (AMD) in the first diagnosed eye. METHODS: This retrospective, observational study included 1099 eyes of 1099 patients diagnosed with neovascular AMD. The neovascular AMD cases were classified into three subtypes: typical neovascular AMD, polypoidal choroidal vasculopathy (PCV), and type 3 neovascularization. The patients were divided into four groups, according to age: > 50 and < 60 years, ≥ 60 and < 70 years, ≥ 70 and < 80 years, and ≥ 80 years. Difference in the prevalence of three AMD subtypes was evaluated among the four age groups. RESULTS: In the age group > 50 and < 60 years, 34 (25.0%) and 102 patients (75.0%) were diagnosed with typical neovascular AMD and PCV, respectively. In the age group ≥ 60 and < 70 years, 90 (28.1%), 206 (64.4%), and 24 patients (7.5%) were diagnosed with typical neovascular AMD, PCV, and type 3 neovascularization, respectively. In the age group ≥ 70 and < 80 years, the corresponding numbers were 200 (41.9%), 197 (41.3%), and 80 (16.8%), respectively; in the age group ≥80 years, the corresponding values were 83 (50.0%), 39 (23.5%), and 44 (26.5%), respectively. A significant difference was observed in the prevalence of the subtypes of neovascular AMD among the four age groups (chi-square test, P < 0.001). CONCLUSION: Subtype prevalence in newly diagnosed neovascular AMD differs significantly according to age. This result suggests that different pathophysiology may be involved in the development of different subtypes of neovascular AMD.

Intravitreal Aflibercept for Retinal Angiomatous Proliferation: Results of a Prospective Case Series at 96 Weeks.

INTRODUCTION: Retinal angiomatous proliferation (RAP) is a subtype of neovascular age-related macular degeneration (nAMD). Untreated, the lesions are thought to be aggressive and lead to a poor visual outcome. Despite some limitations, studies reporting the treatment of RAP lesions with the intravitreal anti-VEGF drugs ranibizumab and bevacizumab have demonstrated variable but generally favourable responses. More recently, aflibercept has been licensed for the treatment of nAMD and may offer some advantages over other agents. We present the visual and anatomical outcomes at 96 weeks of patients with RAP lesions who were treated with intravitreal aflibercept, according to the pivotal VIEW study nAMD treatment protocol. METHODS: This is a prospective study of treatment-naïve patients with Reading Centre-graded RAP lesions. The patients received aflibercept every 8 weeks, after 3 initial monthly injections, up to and including week 48. During weeks 52-96, patients received injections at least every 12 weeks, with monthly evaluations for interim injections if they fulfilled the retreatment criteria. At each visit, best-corrected visual acuity (BCVA) and optical coherence tomography (OCT) central macular thickness (CMT) were measured. RESULTS: Forty-six patients reached study completion at week 96. Mean BCVA had improved by 6.0 (standard deviation [SD] 7.9) and 4.8 (SD 7.4) ETDRS letters at 52 (p = 0.003) and 96 (p = 0.02) weeks, respectively, from a baseline of 57.3 (SD 12.0) letters. At 52- and 96-week time points, 45/46 (98%) and 41/46 (89%) of patients, respectively, had maintained their vision (<15 letters of BCVA lost). At the 96-week time point, 13/46 (28%) of patients had gained ≥15 letters and also demonstrated a mean reduction in CMT of 162 µm (SD 106) (p = <0.0001), with 72% of maculae being fluid-free. Using univariate analysis, we found no significant difference between any of the visual outcome measures in this study and the pivotal VIEW study; the mean number of injections required and change in CMT were also similar. CONCLUSIONS: In this study, we present the 96-week results, of the largest series to date, of patients treated prospectively with aflibercept for RAP using the VIEW protocol. We show that they benefited from treatment to a degree similar to those with type 1 and 2 nAMD.

Treatment Effects in Retinal Angiomatous Proliferation Imaged with OCT Angiography.

PURPOSE: This prospective case series is aimed at exploring optical coherence tomographic angiography (OCT-A) as a treatment monitoring tool in patients treated for retinal angiomatous proliferation (RAP). METHODS: Twelve treatment-naïve RAP patients were included, with a median age of 79 years (range 65-90). Patients were imaged with an experimental 1,040-nm swept-source phase-resolved OCT-A instrument before and after treatment. Treatment consisted of either intravitreal bevacizumab or triamcinolone injections with or without photodynamic therapy (PDT). Abnormal blood flow after treatment was graded as increased, unchanged, decreased, or resolved. RESULTS: OCT-A images before and after treatment could be obtained in 9 patients. The median follow-up period was 10 weeks (range 5-19). After various treatments, the RAP lesion resolved in 7 patients, in 1 patient the OCT-A depicted decreased flow in the lesion, and 1 patient showed unchanged abnormal blood flow. Monotherapy with intravitreal bevacizumab injections resolved RAP in 1 out of 2 patients. Combined therapy of bevacizumab with PDT resolved RAP in 6 out of 7 patients. CONCLUSIONS: OCT-A visualized resolution of abnormal blood flow in 7 out of 9 RAP patients after various short-term treatment sequences. OCT-A may become an important noninvasive monitoring tool for optimizing treatment strategies in RAP patients.

Case series of coexistence of polypoidal choroidal vasculopathy with other rare fundus diseases.

PURPOSE: To record the coexistence of polypoidal choroidal vasculopathy (PCV) with other rare fundus diseases in a Chinese population. METHOD: In this retrospective hospital-based study, a chart review of 861 patients with newly diagnosed PCV was performed. The clinical features of rare fundus comorbidities of PCV were recorded. RESULTS: Five eyes of 5 patients aged 63.4 ± 11.22 years (0.58%) had PCV coexisting with other fundus diseases in the same eye. Of the 5 PCV patients, 2 (0.23%) had myelinated nerve fiber, 2 (0.23%) had branch retinal vein occlusion, and 1 (0.12%) had retinal angiomatous proliferation. CONCLUSION: We reported rare fundus comorbidities of PCV in a large Chinese cohort. These comorbidities included myelinated nerve fiber, branch retinal vein occlusion and retinal angiomatous proliferation. The combination might constitute an accidental occurrence.

Long-Term Results of Combination Treatment with Single-Dose Ranibizumab plus Photodynamic Therapy for Retinal Angiomatous Proliferation.

PURPOSE: To present functional and anatomic outcomes of combination therapy with ranibizumab and photodynamic therapy (PDT) in a series of retinal angiomatous proliferation (RAP) cases. METHODS: A total of 17 eyes of 17 patients with RAP were included. Thirteen eyes were treatment naïve and 4 were already on ranibizumab monotherapy. Combined treatment with single-dose ranibizumab and PDT was performed on all treatment-naïve cases. Follow-up was performed every month for 6-38 months, using optical coherence tomography and indocyanine green angiography when necessary. RESULTS: Overall, 6 out of 7 treatment-naïve cases with stage I or II disease manifested complete angiographic resolution of the hot spot with a single injection of ranibizumab plus PDT. In stage III disease, 7 out of 10 eyes showed persistent leakage immediately after the combined treatment. The rate of hot spot occlusion was found to correlate with the stage of disease (p = 0.05). There was a significant improvement in posttreatment BCVA for all patients regardless of disease stage (p = 0.02), which was more evident in the earlier stages. Improvement was also greater for treatment-naïve patients (p = 0.03). The posttreatment improvement in BCVA was strongly correlated with hot spot occlusion (p < 0.001). CONCLUSIONS: Single-dose modified anti-VEGF treatment in combination with PDT may provide long-term regression at the initial stages of RAP.

Multimodal Evaluation of the Fellow Eye of Patients with Retinal Angiomatous Proliferation.

INTRODUCTION: We conducted a multimodal, cross-sectional evaluation. METHODS: Eyes were divided into 4 study groups: controls, early/intermediate age-related macular degeneration (AMD), fellow eyes of retinal angiomatous proliferation (RAP), and RAP eyes. Patients were evaluated with spectral-domain optical coherence tomography (OCT), enhanced depth imaging-OCT, and OCT angiography (OCTA). OCTA images were processed to generate maps of the vessel density and perfusion density of the superficial and deep retinal layers (SRL and DRL) and the choriocapillaris level (CL). The thickness of the outer nuclear layer and choroid was manually assessed. RESULTS: We included 135 eyes of 100 patients (51 controls, 30 AMD, 42 RAP, and 12 fellow eyes). The fellow eyes showed a significantly lower vascular perfusion of the SRL, DRL, and CL (p < 0.02) than the early/intermediate AMD and control eyes did. Similarly, RAP eyes presented a lower vascular perfusion of the DRL and CL (p < 0.05). Besides, structural analyses of the fellow eyes and RAP eyes revealed a significantly higher prevalence of macular pigmentary changes, atrophy of the retinal pigment epithelium, hyperreflective "clumps" above flat drusen, amongst others, than early/intermediate AMD and control eyes (p < 0.05). CONCLUSION: We present the first report on the OCTA analysis of the fellow eye of patients with RAP. The reduced perfusion density and vessel density observed contributes, in association with clearly defined structural changes, to a wider characterization of RAP as a distinctive phenotype.

Development of Age-Related Macular Degeneration (AMD) in the Fellow Eye of Patients with AMD Treated by Treat-and-Extend Intravitreal Therapy with Aflibercept.

PURPOSE: To evaluate the development of neovascular age-related macular degeneration (nAMD) in the fellow eye in patients with unilateral nAMD treated by a treat-and-extend (TAE) regimen with intravitreal aflibercept injections. METHODS: We retrospectively studied 104 patients with treatment-naïve unilateral nAMD. We assessed best-corrected visual acuity (BCVA) and exudative changes in the treated eyes and development of nAMD in the fellow eye for 2 years. RESULTS: The subjects included 46 patients with typical AMD (tAMD), 44 with polypoidal choroidal vasculopathy (PCV), and 14 with retinal angiomatous proliferation (RAP). BCVA was significantly improved after the loading phase in all subtypes. Forty-six patients (44.2%) had no recurrence within 2 years after the loading phase, including 12 (26.1%) with tAMD, 23 (52.2%) with PCV, and 11 (78.6%) with RAP (p < 0.01). Eleven patients (10.6%) developed nAMD in the fellow eye within 2 years, including 4 (8.7%) with tAMD, 0 (0%) with PCV, and 7 (50.0%) with RAP (p < 0.001). CONCLUSIONS: Patients with RAP had significantly more frequent development of nAMD in the fellow eye compared to other subtypes, while they showed significantly less recurrence during the TAE regimen with intravitreal aflibercept injections. Development of nAMD in the fellow eye should be monitored in RAP when the injection interval is extended.

The Role of Hypoxia, Hypoxia-Inducible Factor (HIF), and VEGF in Retinal Angiomatous Proliferation.

In industrialized countries, age-related macular degeneration (AMD) is the leading cause of blindness in elderly people. Hallmarks of the non-neovascular (dry) form of AMD are the formation of drusen and geographic atrophy, whereas the exudative (wet) form of the disease is characterized by invading blood vessels. In retinal angiomatous proliferation (RAP), a special form of wet AMD, intraretinal vessels grow from the deep plexus into the subretinal space. Little is known about the mechanisms leading to intraretinal neovascularization, but age-related changes such as reduction of choroidal blood flow, accumulation of drusen, and thickening of the Bruch's membrane may lead to reduced oxygen availability in photoreceptors. Such a chronic hypoxic situation may induce several cellular response pathways including the stabilization of hypoxia-inducible factors (HIFs) and the production of angiogenic factors, such as vascular endothelial growth factor (VEGF). Here, we discuss the potential contribution of hypoxia and HIFs in RAP disease pathology and in some mouse models for subretinal neovascularization.

OCT angiography demonstrates retinal angiomatous proliferation and chorioretinal anastomosis of type 3 neovascularization.

PURPOSE: To report the OCT angiography findings of type 3 neovascularization. METHODS: Two cases (one each with retinal angiomatous proliferation and chorioretinal anastomosis) are reported, in which the conventional fundus fluorescein angiography and spectral-domain optical coherence tomography findings were inconclusive. RESULTS: OCT angiography demonstrated flow within the abnormal anastomotic network and delineated the extent of the lesion with respect to the retinal layers. CONCLUSION: OCT angiography enables a quick diagnosis of type 3 neovascularization by demonstrating a supranormal flow within the lesion and delineates the lesion within different retinal layers.