ABSTRACT
PURPOSE: To report long-term results from a phase 1/2a clinical trial assessment of a scaffold-based human embryonic stem cell-derived retinal pigmented epithelium (RPE) implant in patients with advanced geographic atrophy (GA). DESIGN: A single-arm, open-label phase 1/2a clinical trial approved by the United States Food and Drug Administration. PARTICIPANTS: Patients were 69-85 years of age at the time of enrollment and were legally blind in the treated eye (best-corrected visual acuity [BCVA], ≤ 20/200) as a result of GA involving the fovea. METHODS: The clinical trial enrolled 16 patients, 15 of whom underwent implantation successfully. The implant was administered to the worse-seeing eye with the use of a custom subretinal insertion device. The companion nonimplanted eye served as the control. The primary endpoint was at 1 year; thereafter, patients were followed up at least yearly. MAIN OUTCOME MEASURES: Safety was the primary endpoint of the study. The occurrence and frequency of adverse events (AEs) were determined by scheduled eye examinations, including measurement of BCVA and intraocular pressure and multimodal imaging. Serum antibody titers were collected to monitor systemic humoral immune responses to the implanted cells. RESULTS: At a median follow-up of 3 years, fundus photography revealed no migration of the implant. No unanticipated, severe, implant-related AEs occurred, and the most common anticipated severe AE (severe retinal hemorrhage) was eliminated in the second cohort (9 patients) through improved intraoperative hemostasis. Nonsevere, transient retinal hemorrhages were noted either during or after surgery in all patients as anticipated for a subretinal surgical procedure. Throughout the median 3-year follow-up, results show that implanted eyes were more likely to improve by > 5 letters of BCVA and were less likely to worsen by > 5 letters compared with nonimplanted eyes. CONCLUSIONS: This report details the long-term follow-up of patients with GA to receive a scaffold-based stem cell-derived bioengineered RPE implant. Results show that the implant, at a median 3-year follow-up, is safe and well tolerated in patients with advanced dry age-related macular degeneration. The safety profile, along with the early indication of efficacy, warrants further clinical evaluation of this novel approach for the treatment of GA. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Subject(s)
Geographic Atrophy , Retinal Pigment Epithelium , Visual Acuity , Humans , Geographic Atrophy/surgery , Geographic Atrophy/physiopathology , Retinal Pigment Epithelium/transplantation , Retinal Pigment Epithelium/pathology , Aged , Visual Acuity/physiology , Female , Aged, 80 and over , Male , Follow-Up Studies , Tomography, Optical Coherence , Human Embryonic Stem Cells/transplantation , Human Embryonic Stem Cells/cytology , Stem Cell Transplantation , Treatment OutcomeABSTRACT
PURPOSE: To investigate the correlation between choroidal vascularity index and the enlargement of geographic atrophy (GA) lesion secondary to age-related macular degeneration during the 2-year follow-up. METHODS: In this longitudinal observational study, 26 eyes (26 patients, mean age 75.7 ± 8.8 years) affected by GA were included. Choroidal vascularity index was calculated in the subfoveal 3000-µm area. The main outcome measure included correlation analysis between baseline choroidal vascularity index and the rate of GA enlargement. RESULTS: During the 2-year follow-up, the mean GA area increased from 6.99 ± 5.28 mm2 to 10.69 ± 6.61 mm2(P < 0.001), accounting for a growth rate of 0.35 ± 0.20 and 0.31 ± 0.17 mm/year after the square root transformation in the first and second year of follow-up, respectively. Stromal choroidal area significantly decreased during the 2-year follow-up (P = 0.002). Interestingly, there was a significant correlation between the baseline choroidal vascularity index and the rate of GA enlargement (r=-0.432, P = 0.027) and between stromal choroidal area and the rate of GA enlargement (r = 0.422, P = 0.032). No other significant relationship was disclosed among choroidal parameters with the rate of GA enlargement. CONCLUSION: Choroidal vascularity index impairment is strictly related to the rate of GA enlargement during the 1-year and 2-year follow-up in patients affected by GA. For this reason, choroidal vascularity index could be considered a predictor of GA progression in the clinical setting, and it could be considered as a new potential biomarker in the efficacy evaluation of new GA interventions.
Subject(s)
Choroid/blood supply , Ciliary Arteries/physiopathology , Geographic Atrophy/diagnostic imaging , Geographic Atrophy/physiopathology , Aged , Aged, 80 and over , Choroid/diagnostic imaging , Ciliary Arteries/diagnostic imaging , Coloring Agents/administration & dosage , Disease Progression , Female , Fluorescein Angiography , Follow-Up Studies , Geographic Atrophy/etiology , Humans , Indocyanine Green/administration & dosage , Macular Degeneration/complications , Macular Degeneration/physiopathology , Male , Middle Aged , Prospective Studies , Regional Blood Flow/physiology , Tomography, Optical Coherence , Visual Acuity/physiologyABSTRACT
OBJECTIVES: To evaluate clinical characteristics of eyes in which investigator-determined new-onset exudative age-related macular degeneration (eAMD) developed during the FILLY trial. DESIGN: Post hoc analysis of the phase 2 study of intravitreal pegcetacoplan in geographic atrophy (GA). SUBJECTS: Patients with GA secondary to age-related macular degeneration (AMD), n = 246. INTERVENTION: Either 15 mg intravitreal pegcetacoplan or sham given monthly or every other month for 12 months followed by a 6-month off-treatment period. MAIN OUTCOME MEASURES: Time of new eAMD onset in the study eye, history of eAMD in the fellow eye, presence of double-layer sign (DLS) on structural OCT in the study eye, changes in retinal anatomic features by structural OCT and fluorescein angiography (FA), and changes in visual acuity. RESULTS: Exudation was reported in 26 study eyes across treatment groups over 18 months. Mean time to eAMD diagnosis was 256 days (range, 31-555 days). Overall, a higher proportion of patients with a baseline history of eAMD in the fellow eye (P = 0.016) and a DLS in the study eye (P = 0.0001) demonstrated eAMD. Among study eyes in which eAMD developed, 18 of 26 (69%) had history of fellow-eye eAMD and 19 of 26 (73.1%) had DLS at baseline, compared with 76 of 217 study eyes (35%; P = 0.0007) and 70 of 215 study eyes (32.5%; P < 0.0001), respectively, in which eAMD did not develop. All 21 patients with structural OCT imaging at the time of eAMD diagnosis demonstrated subretinal fluid, intraretinal cysts, or both consistent with exudation. Among 17 patients who underwent FA at eAMD diagnosis, 10 showed detectable macular neovascularization (MNV), all occult lesions. Development of eAMD did not have an appreciable impact on visual acuity, and all patients responded to anti-vascular endothelial growth factor (VEGF) therapy. CONCLUSIONS: Intravitreal pegcetacoplan slowed the rate of GA growth and was associated with an unexpected dose-dependent increased incidence of eAMD with no temporal clustering of onset. Exudative AMD seemed to be associated with baseline eAMD in the contralateral eye and a DLS, suggestive of nonexudative MNV, in the study eye. The safety profile of pegcetacoplan was acceptable to proceed to phase 3 studies without adjustments to enrollment criteria.
Subject(s)
Complement C3/antagonists & inhibitors , Complement Inactivating Agents/adverse effects , Geographic Atrophy/drug therapy , Peptides, Cyclic/adverse effects , Wet Macular Degeneration/chemically induced , Aged , Aged, 80 and over , Complement Inactivating Agents/administration & dosage , Exudates and Transudates , Female , Fluorescein Angiography , Geographic Atrophy/diagnosis , Geographic Atrophy/physiopathology , Humans , Intravitreal Injections , Male , Middle Aged , Peptides, Cyclic/administration & dosage , Prospective Studies , Single-Blind Method , Subretinal Fluid , Time Factors , Tomography, Optical Coherence , Visual Acuity/physiology , Wet Macular Degeneration/diagnosis , Wet Macular Degeneration/physiopathologyABSTRACT
PURPOSE: The complement pathway may play a key role in the pathogenesis of age-related macular degeneration (AMD). The safety and efficacy of avacincaptad pegol (Zimura, IVERIC bio Inc, New York, NY), a C5 inhibitor, were assessed in participants with geographic atrophy (GA) secondary to AMD (GATHER1 Study). DESIGN: International, prospective, randomized, double-masked, sham-controlled, pivotal phase 2/3 clinical trial. PARTICIPANTS: A total of 286 participants with GA secondary to AMD. MAIN OUTCOME MEASURES: The primary efficacy endpoint was the mean rate of change in GA over 12 months measured by fundus autofluorescence (FAF) at 3 timepoints: baseline, month 6, and month 12. RESULTS: The reduction in the mean rate of GA growth (square root transformation) over 12 months was 27.4% (P = 0.0072) for the avacincaptad pegol 2 mg cohort and 27.8% (P = 0.0051) for the avacincaptad pegol 4 mg cohort compared with their corresponding sham cohorts. The results for both dose groups were statistically significant. Avacincaptad pegol was generally well tolerated after monthly administration over 12 months. There were no avacincaptad pegol-related adverse events (AEs) or inflammation. Further, there were no ocular serious AEs (SAEs) and no cases of endophthalmitis. The most frequent ocular AEs were related to the injection procedure. CONCLUSIONS: Intravitreal administration of avacincaptad pegol 2 mg and 4 mg led to a significant reduction of GA growth in eyes with AMD over a 12-month period. Because C5 inhibition theoretically preserves C3 activity, it may offer additional safety advantages. A second confirmatory pivotal clinical trial is underway to confirm the efficacy and safety of avacincaptad pegol in slowing the GA growth (GATHER2 Study).
Subject(s)
Aptamers, Nucleotide/therapeutic use , Complement C5/antagonists & inhibitors , Complement Inactivating Agents/therapeutic use , Geographic Atrophy/drug therapy , Aged , Aged, 80 and over , Double-Blind Method , Female , Fluorescein Angiography , Follow-Up Studies , Geographic Atrophy/diagnosis , Geographic Atrophy/physiopathology , Humans , Intravitreal Injections , Macular Degeneration/diagnosis , Macular Degeneration/drug therapy , Macular Degeneration/physiopathology , Male , Prospective Studies , Visual Acuity/physiologyABSTRACT
The progressive and sight-threatening disease, age-related macular degeneration (AMD), is a growing public health concern due to ageing demographics, with the highest unmet medical need for the advanced stage of dry AMD, geographic atrophy. The pathogenesis underlying AMD is driven by a complex interplay of genetic and environmental factors. There is ample evidence that inflammation is strongly involved in AMD development. Interleukin-33 (IL-33) has been proposed to be critically involved in retinal degeneration, but a protective role in eye pathophysiology was also demonstrated. The current study investigated the therapeutic potential of IL-33trap, a novel IL-33-neutralizing biologic, in dry AMD/geographic atrophy and, based on controversial data regarding the protective versus detrimental functions of IL-33 in neovascularization, evaluated the risk of progression to wet AMD by IL-33 neutralization. Repeated intravitreal (IVT) injections of IL-33trap in the mouse laser-induced choroidal neovascularization model did not exacerbate neovascularization or leakage, while it significantly inhibited inflammatory cell infiltration in the retinal pigment epithelium and choroid. On the contrary, IVT treatment with IL-33trap significantly induced retinal inflammation and could not prevent retinopathy induction in the mouse sodium iodate (NaIO3) model. Overall, these data suggest a complex and dichotomous role of IL-33 in eye pathology and indicate that IL-33 neutralization is not able to prevent onset and progression of dry AMD pathogenesis.
Subject(s)
Choroidal Neovascularization/drug therapy , Disease Models, Animal , Geographic Atrophy/drug therapy , Interleukin-33/therapeutic use , Animals , Choroidal Neovascularization/diagnosis , Choroidal Neovascularization/physiopathology , Electroretinography , Fluorescein Angiography , Geographic Atrophy/diagnosis , Geographic Atrophy/physiopathology , Immunohistochemistry , Inflammation/prevention & control , Laser Coagulation , Male , Mice , Mice, Inbred C57BL , Tomography, Optical CoherenceABSTRACT
PURPOSE: To evaluate and compare paralesional and perilesional choriocapillaris vascular impairment in eyes with geographic atrophy with and without outer retinal tubulations (ORT). METHODS: Using swept-source optical coherence tomography angiography, 6 × 6 mm scans of eyes with geographic atrophy with and without ORT were acquired. Choriocapillaris en-face flow and structural images were binarized, before flow signal deficit (FD) analysis in the paraatrophy zone (a 500-µm-wide band adjacent to the geographic atrophy) and the periatrophy zone (a 500-µm-wide band adjacent to the latter). RESULTS: Twenty-four eyes of 19 patients with ORT and 18 eyes of 15 patients without ORT were analyzed. With and without ORT, mean percental area of FD (%FD) was greater in para- than in periatrophy zone. The difference of %FD between para- and periatrophy zone (deltaFD) was lower in eyes with ORT (mean 1.8477%, 95% confidence interval 0.8607-2.8346) than without ORT (mean 4.0018%, 95% confidence interval 2.8622-5.1414). CONCLUSION: In eyes with geographic atrophy caused by non-neovascular age-related macular degeneration, smaller reductions in FDs were found between the para- and periatrophy zone in eyes with ORT. In both cohorts, the paraatrophy zone had more FD than the periatrophy zone.
Subject(s)
Choroid/blood supply , Fluorescein Angiography/methods , Geographic Atrophy/physiopathology , Regional Blood Flow/physiology , Retinal Pigment Epithelium/diagnostic imaging , Retinal Vessels/physiopathology , Tomography, Optical Coherence/methods , Aged , Cross-Sectional Studies , Female , Fundus Oculi , Geographic Atrophy/diagnosis , Humans , Male , Retinal Vessels/diagnostic imaging , Retrospective StudiesABSTRACT
PURPOSE: To ascertain the pathogenesis of macular hole (MH) associated with age-related macular degeneration (AMD) and its surgical outcomes. METHODS: Patients with full-thickness MH associated with AMD (higher grades than intermediate) were enrolled. The mechanism of MH formation and closure rate after vitrectomy (surgical outcome) were determined using optical coherence tomography imaging. RESULTS: The mechanism of MH formation (35 eyes) associated with AMD was classified into four types: vitreomacular traction (42.9%), gradual retinal thinning caused by subretinal drusen or pigment epithelial detachment (22.9%), massive subretinal hemorrhage (20.0%), and combined (14.3%). In the 41 eyes that underwent vitrectomy, the logarithm of the minimum angle of resolution best-corrected visual acuity improved from 0.82 (0.10-2.30) preoperative to 0.69 (0.10-2.30) postoperative (P = 0.001). Successful closure of the MH was achieved in 33 eyes (80.5%) after vitrectomy. No significant association was observed between the closure rate of MH after vitrectomy and mechanism of MH formation (P = 0.083). CONCLUSION: The mechanism of MH formation associated with AMD was classified into four types and was not related to its surgical outcome. Considering visual improvement and surgical outcome after vitrectomy in our study, active surgical treatment can be considered for MH associated with AMD.
Subject(s)
Geographic Atrophy/complications , Retinal Perforations/etiology , Retinal Perforations/surgery , Wet Macular Degeneration/complications , Aged , Endotamponade , Female , Fluorocarbons/administration & dosage , Geographic Atrophy/physiopathology , Humans , Male , Middle Aged , Retinal Perforations/diagnostic imaging , Retinal Perforations/physiopathology , Retrospective Studies , Silicone Oils/administration & dosage , Sulfur Hexafluoride/administration & dosage , Tomography, Optical Coherence , Treatment Outcome , Visual Acuity/physiology , Vitrectomy , Wet Macular Degeneration/physiopathologyABSTRACT
PURPOSE: Although there have been many population-based studies of age-related macular degeneration (AMD), only limited information is available in Asia on the epidemiology of geographic atrophy (GA). We aimed to determine the prevalence and patterns of GA through an analysis of multiple studies conducted within the Asian Eye Epidemiology Consortium (AEEC). DESIGN: Cross-sectional meta-analyses. PARTICIPANTS: A total of 97 213 individuals aged 40 years and older. METHODS: Data from 22 population-based studies from countries belonging to the AEEC were included. In all studies, AMD was defined on the basis of standardized grading systems. Geographic atrophy was defined as an area of pallor in the fundus with visibility of the underlying choroidal blood vessels and sharply defined borders. Random-effects meta-analysis was performed to estimate overall and age-, gender-, and region-specific pooled prevalence of GA. MAIN OUTCOME MEASURES: Prevalence of GA per 1000 persons. RESULTS: The mean age was 60.8 ± 10.0 years, and 42 673 (43.9%) were male. Overall, a total of 223 individuals (0.2%) had GA. The pooled overall prevalence of GA was 1.57 per 1000 persons (95% confidence interval [CI], 1.04-2.10), which was 3 times less than that of neovascular AMD of 5.20 per 1000 persons (95% CI, 3.97-6.43). Compared with those aged 50 to 59 years, the prevalence of GA increased from 0.34 per 1000 persons (95% CI, 0.07-0.62) to 2.90 per 1000 persons (95% CI, 1.55-4.25) in those aged ≥70 years. The GA prevalence per 1000 persons was similar between urban (2.22; 95% CI, 1.22-3.23) and rural residents (1.33; 95% CI, 0.70-1.96). Geographic atrophy was more prevalent in South Asia (based on studies from India and Nepal, 3.82 per 1000 persons; 95% CI, 1.72-5.93) compared with East Asia (based on studies from China, Korea, Hong Kong, Taiwan, and Japan, and the Singapore Chinese Eye Study, 0.76 per 1000 persons; 95% CI, 0.31-1.22, P = 0.005). CONCLUSIONS: Geographic atrophy is uncommon in Asian populations compared with those of European ancestry. Even within Asia, geographic differences in GA prevalence were seen. The findings of this meta-analysis suggest that better dissection of risk factors in the Asian population for GA may provide insights into the biological pathways that drive these late-stage manifestations, thus suggesting better targets for prevention.
Subject(s)
Geographic Atrophy/epidemiology , Visual Acuity , Asia/epidemiology , Geographic Atrophy/physiopathology , Humans , PrevalenceABSTRACT
PURPOSE: To investigate differences in the development of macular atrophy (MA) over 24 months between treat-and-extend (T&E) ranibizumab and aflibercept in patients with neovascular age-related macular degeneration (nAMD). DESIGN: A phase 4 randomized, partially masked, multicenter study. PARTICIPANTS: Individuals 50 years of age or older diagnosed with active, treatment-naïve subfoveal choroidal neovascularization secondary to nAMD with baseline best-corrected visual acuity (BCVA) of 23 logarithm of minimum angle of resolution letters or more. METHODS: Patients were randomized 1:1 to receive either intravitreal injections of ranibizumab 0.5 mg or aflibercept 2.0 mg and were treated according to the same reading center-guided T&E regimen after 3 initial monthly injections. MAIN OUTCOME MEASURES: The primary outcome was mean change in square root area of MA from baseline to month 24. Key secondary outcomes included number of injections and mean change in BCVA from baseline to months 12 and 24. RESULTS: Two hundred seventy-eight patients were included in the analysis (ranibizumab 0.5 mg, n = 141; aflibercept 2.0 mg, n = 137). Mean change in square root area of MA from baseline to month 24 was +0.36 mm (95% confidence interval [CI], 0.27-0.45 mm) for ranibizumab and +0.28 mm (95% CI, 0.19-0.37 mm) for aflibercept (treatment difference, +0.08 mm [95% CI, -0.05 to 0.21 mm]; P = 0.24). The proportion of patients with MA increased from 7% (10/141) to 37% (43/117) for ranibizumab and from 6% (8/137) to 32% (35/108) for aflibercept from baseline to month 24. The average number of injections received per year was similar between both groups: 9.6 (95% CI, 9.2-10.0) for ranibizumab and 9.5 (95% CI, 9.1-9.9) for aflibercept. The mean change in BCVA from baseline to month 24 was +6.6 letters (95% CI,4.7-8.5 letters) for the ranibizumab group and +4.6 letters (95% CI, 2.7-6.6 letters) for the aflibercept group ( P = 0.15). Rates of adverse events (AEs) were similar between both groups. CONCLUSIONS: No significant differences in the rate of development or growth of MA over 24 months were observed between ranibizumab and aflibercept in nAMD patients treated using an identical T&E regimen.
Subject(s)
Angiogenesis Inhibitors/therapeutic use , Choroidal Neovascularization/drug therapy , Geographic Atrophy/diagnosis , Ranibizumab/therapeutic use , Receptors, Vascular Endothelial Growth Factor/therapeutic use , Recombinant Fusion Proteins/therapeutic use , Wet Macular Degeneration/drug therapy , Aged , Aged, 80 and over , Choroidal Neovascularization/diagnosis , Choroidal Neovascularization/physiopathology , Double-Blind Method , Female , Fluorescein Angiography , Geographic Atrophy/physiopathology , Humans , Intravitreal Injections , Male , Prospective Studies , Tomography, Optical Coherence , Treatment Outcome , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Visual Acuity/physiology , Wet Macular Degeneration/diagnosis , Wet Macular Degeneration/physiopathologyABSTRACT
PURPOSE: To report the natural history of untreated neovascular age-related macular degeneration (nAMD) regarding subsequent macular atrophy. DESIGN: Prospective cohort within a randomized, controlled trial of oral micronutrient supplements. PARTICIPANTS: Age-Related Eye Disease Study (AREDS) participants (55-80 years) who demonstrated nAMD during follow-up (1992-2005), prior to anti-vascular endothelial growth factor (VEGF) therapy. METHODS: Color fundus photographs were collected at annual study visits and graded centrally for late age-related macular degeneration (AMD). Incident macular atrophy after nAMD was examined by Kaplan-Meier analysis and proportional hazards regression. MAIN OUTCOME MEASURES: Incident macular atrophy after nAMD. RESULTS: Of the 4757 AREDS participants, 708 eyes (627 participants) demonstrated nAMD during follow-up and were eligible. The cumulative risks of incident macular atrophy after untreated nAMD were 9.6% (standard error, 1.2%), 31.4% (standard error, 2.2%), 43.1% (standard error, 2.6%), and 61.5% (standard error, 4.3%) at 2, 5, 7, and 10 years, respectively. This corresponded to a linear risk of 6.5% per year. The cumulative risk of central involvement was 30.4% (standard error, 3.2%), 43.4% (standard error, 3.8%), and 57.0% (standard error, 4.8%) at first appearance of atrophy, 2 years, and 5 years, respectively. Geographic atrophy (GA) in the fellow eye was associated with increased risk of macular atrophy (hazard ratio [HR], 1.70; 95% confidence interval [CI], 1.17-2.49; P = 0.006). However, higher 52-single nucleotide polymorphism AMD genetic risk score was not associated with increased risk of macular atrophy (HR, 1.03; 95% CI, 0.90-1.17; P = 0.67). Similarly, no significant differences were observed according to SNPs at CFH, ARMS2, or C3. CONCLUSIONS: The rate of incident macular atrophy after untreated nAMD is relatively high, increasing linearly over time and affecting half of eyes by 8 years. Hence, factors other than anti-VEGF therapy are involved in atrophy development, including natural progression to GA. Comparison with studies of treated nAMD suggests it may not be necessary to invoke a large effect of anti-VEGF therapy on inciting macular atrophy, although a contribution remains possible. Central involvement is present in one third of eyes at the outset (similar to pure GA) and increases linearly to half at 3 years.
Subject(s)
Choroidal Neovascularization/complications , Geographic Atrophy/epidemiology , Wet Macular Degeneration/complications , Aged , Aged, 80 and over , Antioxidants/administration & dosage , Choroidal Neovascularization/diagnosis , Choroidal Neovascularization/drug therapy , Female , Follow-Up Studies , Geographic Atrophy/physiopathology , Humans , Incidence , Male , Middle Aged , Proportional Hazards Models , Prospective Studies , Risk Assessment , Surveys and Questionnaires , Visual Acuity/physiology , Wet Macular Degeneration/diagnosis , Wet Macular Degeneration/drug therapy , Zinc Compounds/administration & dosageABSTRACT
PURPOSE: To better characterize visual function decline and geographic atrophy (GA) progression secondary to age-related macular degeneration (AMD). DESIGN: Proxima A (NCT02479386)/Proxima B (NCT02399072) were global, prospective, noninterventional, observational clinical trials. PARTICIPANTS: Eligible patients were aged ≥50 years. Patients in Proxima A had bilateral GA without choroidal neovascularization (CNV) in either eye (N = 295). Patients in Proxima B had GA without CNV in the study eye and CNV±GA in the fellow eye (fellow eye CNV cohort, n = 168) or GA without CNV in the study eye, no CNV/GA in the fellow eye (fellow eye intermediate AMD cohort, n = 32). METHODS: Changes in visual function and imaging/anatomic parameters were evaluated over time using a mixed model for repeated measurement accounting for key baseline characteristics. MAIN OUTCOME MEASURES: Prespecified end points included change in GA area from baseline, best-corrected visual acuity (BCVA) score assessed by Early Treatment Diabetic Retinopathy Study (ETDRS), and visual acuity under low-luminance (LLVA). RESULTS: At 24 months, adjusted mean (standard error) change in GA lesion area from baseline was 3.87 (0.15) mm2 in participants with bilateral GA (Proxima A), 3.55 (0.16) mm2 in the fellow eye CNV cohort (Proxima B), and 2.96 (0.25) mm2 in the fellow eye intermediate AMD cohort (Proxima B). Progression of GA was greater in patients with baseline nonsubfoveal (vs. subfoveal) GA lesions and tended to increase as baseline low-luminance deficit increased (all patients). Conversion to GA or CNV in the fellow eye occurred in 30% and 6.7% of participants, respectively, in the Proxima B intermediate AMD cohort at month 12. Adjusted mean (standard error) changes in BCVA and LLVA (ETDRS letters) in the study eye from baseline to 24 months were -13.88 (1.40) and -7.64 (1.20) in Proxima A, -9.49 (1.29) and -7.57 (1.26) in Proxima B fellow eye CNV cohort, and -11.48 (3.39) and -8.37 (3.02) in Proxima B fellow eye intermediate AMD cohort, respectively. CONCLUSIONS: The prospective Proxima A and B studies highlight the severe functional impact of GA and the rapid rate of GA lesion progression over a 2-year period, including in patients with unilateral GA at baseline.
Subject(s)
Choroidal Neovascularization/diagnosis , Geographic Atrophy/diagnosis , Macular Degeneration/diagnosis , Aged , Aged, 80 and over , Choroidal Neovascularization/complications , Choroidal Neovascularization/drug therapy , Choroidal Neovascularization/physiopathology , Disease Progression , Female , Fluorescein Angiography , Follow-Up Studies , Geographic Atrophy/drug therapy , Geographic Atrophy/etiology , Geographic Atrophy/physiopathology , Humans , Immunoglobulin Fab Fragments/therapeutic use , Macular Degeneration/complications , Macular Degeneration/drug therapy , Macular Degeneration/physiopathology , Male , Middle Aged , Prospective Studies , Vision Disorders/physiopathology , Visual Acuity/physiologyABSTRACT
PURPOSE: To correlate choriocapillaris (CC) flow deficits (FD) in eyes with geographic atrophy (GA) at various distances from the border of the GA lesion with yearly enlargement rate (yER) of GA. METHODS: In this retrospective study, spectral domain optical coherence tomography (SD-OCT) and SD optical coherence tomography angiography (OCTA) images were collected from patients with GA, who were imaged at Doheny Eye Centers between 2016 and 2018, using the Cirrus HD-OCT (Carl Zeiss Meditec, Dublin, CA). All enrolled patients had one baseline 6 × 6 mm OCTA scan and two 6 × 6 mm SD-OCT cubes, one at baseline and one at a follow-up visit at least 12 months later. The border of the GA was manually outlined on the en face OCT fundus image and the yER was calculated after square root transformation. A grid composed of 100-µm-wide successive concentric rings was created around the GA lesion on the OCTA CC slab using ImageJ and the FD% was calculated from the binarized image. FD% from each ring was correlated with the yER of GA. RESULTS: Thirty eyes of 22 patients were included in the study. The mean yER was 0.2 ± 0.15 mm. The FD% in the first five rings (from 0 to 500 µm from the border of GA) was significantly correlated with the yER. However, there was no statistically significant correlation between the yER and CC FD% beyond 500 µm from the GA lesion. CONCLUSIONS: Only the choriocapillaris FD% in the 500-µm region immediately surrounding GA lesions appears to predict the rate of enlargement of these lesions.
Subject(s)
Choroid/blood supply , Geographic Atrophy/physiopathology , Aged , Aged, 80 and over , Blood Flow Velocity/physiology , Choroid/diagnostic imaging , Female , Fluorescein Angiography , Geographic Atrophy/diagnostic imaging , Humans , Image Processing, Computer-Assisted , Male , Regional Blood Flow/physiology , Retrospective Studies , Tomography, Optical CoherenceABSTRACT
PURPOSE: To investigate geographic atrophy (GA) progression using quantitative autofluorescence (qAF) in eyes with solitary GA. METHODS: Forty-three eyes of 26 patients (age 79.7 ± 7.2 years; 28 women; 16 pseudophakic) underwent spectral-domain optical coherence tomography and qAF imaging at baseline and after 12 months. The junctional zone (AJZ) and a nonaffected 300-µm-wide control area (AC) were delineated on spectral-domain optical coherence tomography scans and transferred to the qAF image. Linear mixed models were calculated to investigate the association between GA progression and qAF, age, and baseline GA area. Mixed model analyses of variance were used to investigate differences in qAF between areas. RESULTS: Quantitative autofluorescence of the three inferior sections of both the AJZ (P = 0.028; P = 0.014 and P = 0.032) and the AC (P = 0.043; P = 0.02 and P = 0.028) were significantly associated with GA progression after 12 months. However, qAF measurements were not associated with GA progression in the overall model (P > 0.05). Mean qAF was significantly lower in the AJZ and growth area (AG12) than in the AC (both P ≤ 0.001). CONCLUSION: The authors report a statistically significant association between GA growth area and qAF measurements at specific retinal locations and a significant difference in qAF between the GA border and unaffected areas outside the lesion. Quantitative autofluorescence measurements may be limitedly useful for predicting GA progression.
Subject(s)
Geographic Atrophy/diagnosis , Models, Statistical , Retinal Pigment Epithelium/pathology , Aged , Aged, 80 and over , Disease Progression , Female , Geographic Atrophy/physiopathology , Humans , Male , Optical Imaging , Tomography, Optical Coherence , Visual Acuity/physiologyABSTRACT
PURPOSE: To investigate retinal sensitivity in the junctional zone of geographic atrophy (GA) secondary to age-related macular degeneration using patient-tailored perimetry grids for mesopic and dark-adapted two-color fundus-controlled perimetry. METHODS: Twenty-five eyes with GA of 25 patients (prospective, natural-history Directional Spread in Geographic Atrophy study [DSGA; NCT02051998]) and 40 eyes of 40 normal subjects were included. Patient-tailored perimetry grids were generated using annotated fundus autofluorescence data. Customized software positioned test-points along iso-hulls surrounding the GA boundary at distances of 0.43°, 0.86°, 1.29°, 2.15°, and 3.01°. The grids were used for duplicate mesopic and dark-adapted two-color (cyan and red) fundus-controlled perimetry. Age-adjusted reference-data were obtained through regression analysis of normative data followed by spatial interpolation. RESULTS: The mean sensitivity loss for mesopic testing decreased with the distance to GA (-10.3 dB [0.43°], -8.2 dB [0.86°], -7.1 dB [1.29°], -6.8 dB [2.15°], and -6.6 dB [3.01°]; P < 0.01). Dark-adapted cyan sensitivity loss exceeded dark-adapted red sensitivity loss for all iso-hulls (-14.8 vs. -11.7 dB, -13.5 vs. -10.1 dB, -12.8 vs. -9.1 dB, -11.6 vs. -8.2 dB, -10.7 vs. -8.0 dB; P < 0.01). CONCLUSION: Patient-tailored fundus-controlled perimetry grids allowed for testing of retinal function in the junctional zone of GA with high spatial resolution. A distinct decrease in mesopic sensitivity loss between 0.43° (125 µm) and 1.29° (375 µm) was observed that leveled off at more distant test-points. In proximity to the GA boundary, the results indicate that rod exceeded cone dysfunction.
Subject(s)
Dark Adaptation/physiology , Geographic Atrophy/physiopathology , Macular Degeneration/complications , Mesopic Vision/physiology , Retina/physiopathology , Visual Fields/physiology , Aged , Aged, 80 and over , Female , Geographic Atrophy/etiology , Humans , Male , Middle Aged , Prospective Studies , Reproducibility of Results , Tomography, Optical Coherence , Visual Acuity , Visual Field TestsABSTRACT
PURPOSE: We investigated macular and peripapillary choroidal thickness (CT) and flow voids in the choriocapillaris in eyes with nonexudative age-related macular degeneration. METHODS: We retrospectively reviewed the medical records of patients with nonexudative age-related macular degeneration and classified their eyes into three categories: pachydrusen, drusen, and subretinal drusenoid deposit. Mean macular and peripapillary CT and choriocapillaris flow void area were compared among the three groups. RESULTS: The three groups included 29, 33, and 33 patients, respectively. The mean macular and peripapillary CT findings were 260.64 ± 75.85 µm and 134.47 ± 46.28 µm for the pachydrusen group; 163.63 ± 64.08 µm and 93.47 ± 39.07 µm for the drusen group; and 95.33 ± 28.87 µm and 56.06 ± 11.64 µm for the subretinal drusenoid deposit group (all, P < 0.001). Mean macular and peripapillary flow void area varied among the subretinal drusenoid deposit group (57.07 ± 6.16% and 55.38 ± 6.65%), drusen group (58.30 ± 6.98% and 49.11 ± 9.11%) and pachydrusen group (50.09 ± 5.77% and 45.47 ± 8.06%) (all P < 0.001). CONCLUSION: The peripapillary CT and flow voids in the choriocapillaris varied according to the features of drusen in nonexudative age-related macular degeneration eyes. Greater flow voids and thinner CT in eyes with subretinal drusenoid deposits may suggest that these eyes have diffuse choroidal abnormalities both in and outside the macula.
Subject(s)
Choroid/blood supply , Choroid/pathology , Geographic Atrophy/physiopathology , Retinal Drusen/physiopathology , Aged , Aged, 80 and over , Female , Fluorescein Angiography , Geographic Atrophy/diagnosis , Humans , Macula Lutea/blood supply , Male , Middle Aged , Optic Disk/blood supply , Retinal Drusen/diagnosis , Retrospective Studies , Tomography, Optical CoherenceABSTRACT
PURPOSE: The LIGHTSITE I study investigated the efficacy and safety of photobiomodulation (PBM) treatment in subjects with dry age-related macular degeneration. METHODS: Thirty subjects (46 eyes) were treated with the Valeda Light Delivery System, wherein subjects underwent two series of treatments (3× per week for 3-4 weeks) over 1 year. Outcome measures included best-corrected visual acuity, contrast sensitivity, microperimetry, central drusen volume and drusen thickness, and quality of life assessments. RESULTS: Photobiomodulation-treated subjects showed a best-corrected visual acuity mean letter score gain of 4 letters immediately after each treatment series at Month 1 (M1) and Month 7 (M7). Approximately 50% of PBM-treated subjects showed improvement of ≥5 letters versus 13.6% in sham-treated subjects at M1. High responding subjects (≥5-letter improvement) in the PBM-treated group showed a gain of 8 letters after initial treatment (P < 0.01) and exhibited earlier stages of age-related macular degeneration disease. Statistically significant improvements in contrast sensitivity, central drusen volume, central drusen thickness, and quality of life were observed (P < 0.05). No device-related adverse events were reported. CONCLUSION: Photobiomodulation treatment statistically improved clinical and anatomical outcomes with more robust benefits observed in subjects with earlier stages of dry age-related macular degeneration. Repeated PBM treatments are necessary to maintain benefits. These pilot findings support previous reports and suggest the utility of PBM as a safe and effective therapy in subjects with dry age-related macular degeneration.
Subject(s)
Geographic Atrophy/radiotherapy , Low-Level Light Therapy , Aged , Aged, 80 and over , Contrast Sensitivity/physiology , Double-Blind Method , Female , Geographic Atrophy/diagnosis , Geographic Atrophy/physiopathology , Geographic Atrophy/psychology , Humans , Male , Middle Aged , Prospective Studies , Quality of Life/psychology , Retinal Drusen/pathology , Surveys and Questionnaires , Treatment Outcome , Visual Acuity/physiology , Visual Field Tests , Visual Fields/physiologyABSTRACT
PURPOSE: To report on the development and progression of macular atrophy (MA) and its relationship with morphologic and functional measures in study and fellow eyes in the Inhibition of vascular endothelial growth factor (VEGF) in Age-related Choroidal Neovascularisation trial. DESIGN: Reading center analysis of data from a randomized controlled trial. PARTICIPANTS: Participants with previously untreated neovascular age-related macular degeneration (nAMD) in the study eye. METHODS: Color, fluorescein angiography (FA) and OCT images acquired at baseline and during the 2-year follow-up were graded systematically for presence of MA. Regression models were constructed to explore relationships between MA and lesion morphology and vision measures (best-corrected distance and near acuity, reading speed and index, contrast sensitivity). MAIN OUTCOME MEASURES: Primary outcome was development of intralesional MA (≥175 µm greatest linear dimension of choroidal vessels seen on FA and/or color, aided by OCT) lying within the maximum footprint of the neovascular lesion. RESULTS: Study eye data were available for 594 of 610 participants; 57 (9.6%) showed intralesional MA at baseline. Incident intralesional MA occurred in 24.4% by the final visit and extralesional MA in only 1.54%. In fellow eyes, an established nAMD lesion was present at baseline in 248 of whom 42 (16.9%) showed intralesional MA at baseline and 32 (12.9%) developed incident intralesional MA. The odds of incident intralesional MA by final visit were lower in study eyes that had ≥50% classic CNV at baseline (odds ratio [OR], 0.39; 95% confidence interval [CI], 0.19-0.80; P = 0.010), subretinal fluid at final visit (OR, 0.41; 95% CI, 0.25-0.76; P = 0.004), or pigment epithelial detachment at final visit (OR, 0.40; 95% CI, 0.21-0.74; P = 0.004). Secondary analyses of incident or progressed intralesional MA in study eyes supported these findings, with odds increasing if the fellow eye had baseline intralesional MA (OR, 2.43; 95% CI, 1.09-5.44; P = 0.030). No significant associations were observed between development of intralesional MA and any other morphologic or visual function measure. CONCLUSIONS: Macular atrophy frequently develops within an nAMD lesion in eyes receiving anti-VEGF therapy over 2 years. No associations between incident MA and drug or treatment frequency or visual function were detected, providing some reassurance to clinicians; however, the longer-term effects remain unknown.
Subject(s)
Angiogenesis Inhibitors/therapeutic use , Choroidal Neovascularization/drug therapy , Geographic Atrophy/diagnosis , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Wet Macular Degeneration/drug therapy , Aged , Aged, 80 and over , Bevacizumab/therapeutic use , Choroidal Neovascularization/physiopathology , Contrast Sensitivity/physiology , Female , Fluorescein Angiography , Geographic Atrophy/physiopathology , Humans , Intravitreal Injections , Male , Multimodal Imaging , Prospective Studies , Ranibizumab/therapeutic use , Tomography, Optical Coherence , Tonometry, Ocular , Treatment Outcome , Visual Acuity/physiology , Wet Macular Degeneration/physiopathologyABSTRACT
Data from human dry and wet age-related macular degeneration (AMD) eyes support the hypothesis that constant 'tickover' of the alternative complement pathway results in chronic deposition of the complement membrane attack complex (MAC) on the choriocapillaris and the retinal pigment epithelium (RPE). Sub-lytic levels of MAC lead to cell signaling associated with tissue remodeling and the production of cytokines and inflammatory molecules. Lytic levels of MAC lead to cell death. CD59 is a naturally occurring inhibitor of the assembly of MAC. CD59 may thus be therapeutically efficacious against the pathophysiology of dry and wet AMD. The first gene therapy clinical trial for geographic atrophy - the advanced form of dry AMD has recently completed recruitment. This trial is studying the safety and tolerability of expressing CD59 from an adeno-associated virus (AAV) vector injected once into the vitreous. A second clinical trial assessing the efficacy of CD59 in wet AMD patients is also under way. Herein, the evidence for the role of MAC in the pathophysiology of dry as well as wet AMD and the scientific rationale underlying the use of AAV- delivered CD59 for the treatment of dry and wet AMD is discussed.
Subject(s)
CD59 Antigens/therapeutic use , Complement Membrane Attack Complex/physiology , Genetic Therapy , Geographic Atrophy/physiopathology , Wet Macular Degeneration/physiopathology , Animals , CD59 Antigens/genetics , Clinical Trials as Topic , Dependovirus/genetics , Genetic Vectors , Geographic Atrophy/therapy , Humans , Intravitreal Injections , Wet Macular Degeneration/therapyABSTRACT
PURPOSE: This work aimed to describe the morphology of pigment epithelial detachment (PED) using optical coherence tomography angiography and to investigate its potential to detect choroidal neovascularization in various types of PEDs. METHODS: In this retrospective study, 53 patients diagnosed with PED after undergoing both optical coherence tomography angiography (AngioPlex, CIRRUS HD-OCT) and spectral domain optical coherence tomography (Spectralis SD-OCT) were included. RESULTS: Among the 53 eyes, flat vascularized PED (vPED) affected 21 eyes (40%), peaked vPED affected 10 eyes (19%), serous PED affected 12 eyes (23%), drusenoid PED affected 6 eyes (11%), and 4 eyes (7%) had multiple PED subtypes. The main underlying etiologies were pachychoroid spectrum disorder (30.2%), wet age-related macular degeneration (28.3%), central serous chorioretinopathy (18.9%), dry age-related macular degeneration (11.3%), and polypoidal choroidal vasculopathy (11.3%). Optical coherence tomography angiography identified neovascularization in 29 (94%) of the vPED eyes, 2 (17%) of the serous PED eyes, and all 4 (100%) mixed PED eyes. CONCLUSION: Optical coherence tomography angiography successfully identified neovascularization in both vPEDs and PEDs previously considered to be nonneovascular. However, structural OCT and blood flow analysis should be combined to interpret PED-associated neovascularization accurately in the clinic.
Subject(s)
Choroid/blood supply , Choroidal Neovascularization/diagnosis , Geographic Atrophy/diagnosis , Retinal Detachment/diagnosis , Retinal Pigment Epithelium/physiopathology , Wet Macular Degeneration/diagnosis , Adult , Aged , Aged, 80 and over , Blood Flow Velocity , Choroidal Neovascularization/physiopathology , Coloring Agents/administration & dosage , Female , Fluorescein Angiography , Geographic Atrophy/physiopathology , Humans , Indocyanine Green/administration & dosage , Male , Middle Aged , Regional Blood Flow , Retinal Detachment/physiopathology , Retrospective Studies , Tomography, Optical Coherence , Visual Acuity/physiology , Wet Macular Degeneration/physiopathologyABSTRACT
PURPOSE: To analyze the prevalence, incidence, and clinical characteristics of eyes with geographic atrophy (GA) in age-related macular degeneration (AMD), including clinical and genetic factors affecting enlargement. DESIGN: Prospective cohort study within a controlled clinical trial. PARTICIPANTS: Age-Related Eye Disease Study 2 (AREDS2) participants, aged 50-85 years. METHODS: Baseline and annual stereoscopic color fundus photographs were evaluated for GA presence and area. Analyses included GA prevalence and incidence rates, Kaplan-Meier rates, mixed-model regression, and multivariable analysis of the square root of GA, area adjusted for covariates, including clinical/imaging characteristics and genotype. MAIN OUTCOME MEASURES: (1) Presence or development of GA; (2) change in the square root of GA area over time. RESULTS: At baseline, 517 eyes (6.2%) of 411 participants (9.8%) had pre-existing GA (without neovascular AMD), with the following characteristics: 33% central, 67% noncentral; and the following configurations: 36% small, 26% solid/unifocal, 24% multifocal, 9% horseshoe/ring, and 6% indeterminate. Of the remaining 6530 eyes at risk, 1099 eyes (17.3%) of 883 participants developed incident GA without prior neovascular disease during mean follow-up of 4.4 years. The Kaplan-Meier rate of incident GA was 19% of eyes at 5 years. In eyes with incident GA, 4-year risk of subsequent neovascular AMD was 29%. In eyes with incident noncentral GA, 4-year risk of central involvement was 57%. GA enlargement rate (following square root transformation) was similar in eyes with pre-existing GA (0.29 mm/year; 95% confidence interval 0.27-0.30) and incident GA (0.28 mm/year; 0.27-0.30). In the combined group, GA enlargement was significantly faster with noncentrality, multifocality, intermediate baseline size, and bilateral GA (P < 0.0001 for interaction in each case) but not with AREDS2 treatment assignment (P = 0.33) or smoking status (P = 0.05). Enlargement was significantly faster with ARMS2 risk (P < 0.0001), C3 non-risk (P = 0.0002), and APOE non-risk (P = 0.001) genotypes. CONCLUSIONS: Analyses of AREDS2 data on natural history of GA provide representative data on GA evolution and enlargement. GA enlargement, which was influenced by lesion features, was relentless, resulting in rapid central vision loss. The genetic variants associated with faster enlargement were partially distinct from those associated with risk of incident GA. These findings are relevant to further investigations of GA pathogenesis and clinical trial planning.