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To develop deep learning models for annualized geographic atrophy (GA) growth rate prediction using fundus autofluorescence (FAF) images and spectral-domain OCT volumes from baseline visits, which can be used for prognostic covariate adjustment to increase power of clinical trials.This retrospective analysis estimated GA growth rate as the slope of a linear fit on all available measurements of lesion area over a 2-year period. Three multitask deep learning models-FAF-only, OCT-only, and multimodal (FAF and OCT)-were developed to predict concurrent GA area and annualized growth rate.Patients were from prospective and observational lampalizumab clinical trials.The 3 models were trained on the development data set, tested on the holdout set, and further evaluated on the independent test sets. Baseline FAF images and OCT volumes from study eyes of patients with bilateral GA (NCT02247479; NCT02247531; and NCT02479386) were split into development (1279 patients/eyes) and holdout (443 patients/eyes) sets. Baseline FAF images from study eyes of NCT01229215 (106 patients/eyes) and NCT02399072 (169 patients/eyes) were used as independent test sets.Model performance was evaluated using squared Pearson correlation coefficient (rOn the holdout data set, rWe show the feasibility of using baseline FAF images and OCT volumes to predict individual GA area and growth rates using a multitask deep learning approach. The deep learning-based growth rate predictions could be used for covariate adjustment to increase power of clinical trials.

Purpose Macular atrophy (MA) of retinal pigment epithelium (RPE) and photoreceptors leads to vision loss in neovascular age-related macular degeneration (nAMD) despite successful treatment with antiangiogenic agents. To enhance understanding of MA, fortify the cellular basis of fundus autofluorescence (FAF) imaging, and inform management of nAMD, we performed histologic analysis of an eye with multimodal clinical imaging and apparent prior exudation due to nAMD. Design Case study and clinicopathologic correlation. Participant A White woman in whom age-related macular degeneration (AMD) findings of inactive subretinal fibrosis (right eye) were followed for 9 years using FAF and OCT, with no detectable subretinal fluid or other recurrent exudation and no intravitreal injections before her death at age 90 years. Methods The right eye was preserved 6.25 hours after death, postfixed in osmium tannic acid paraphenylenediamine, and prepared for submicrometer epoxy resin sections (n = 115), with 19 matched to clinical OCT B-scans. Main Outcome Measures Light microscopic morphology of a hyperautofluorescent (hyperFAF) area due to prior exudation (“floodplain” hyperFAF), hypoautofluorescent (hypoFAF) spots of MA, and areas of unremarkable FAF. Results Floodplain hyperFAF was visible throughout the 9 years of follow-up, with several hypoFAF atrophic spots expanding within it over time. The hyperFAF pattern corresponded to outer retinal atrophy (ORA) on OCT and photoreceptor loss over dysmorphic yet continuous RPE in histology. The hypoFAF spots inside the floodplain corresponded to complete RPE and outer retinal atrophy (cRORA) on OCT and loss of both photoreceptors and RPE in histology. In contrast, areas of unremarkable FAF showed continuous RPE accompanied by full-length photoreceptors and a thick outer nuclear layer. Conclusions This direct clinicopathologic correlation for FAF imaging is the first for nAMD. Fundus autofluorescence is a projection image that involves optical signal modulation by photoreceptors as well as emission signal sources in RPE. Hyperautofluorescence due to an exudative floodplain signifies loss of photoreceptors over continuous RPE. Hypoautofluorescence in MA signifies loss of both cell layers. For maximal value, fundus autofluorescence imaging should be interpreted with the multilayer perspective provided by OCT. Prevention of exudation in nAMD may preserve photoreceptors.

Objective/PurposeTo investigate intraretinal neovascularization and microvascular anomalies by correlating in vivo multimodal imaging with corresponding ex vivo histology in a single patient.DesignA case study comprising clinical imaging from a community-based practice, and histologic analysis at a university-based research laboratory (clinicopathologic correlation).ParticipantsA white woman in her 90’s treated with numerous intravitreal anti-vascular endothelial growth factor (VEGF) injections for bilateral type 3 macular neovascularization (MNV) secondary to age-related macular degeneration (AMD).Intervention(s)/ MethodsClinical imaging comprised serial infrared reflectance, eye-tracked spectral-domain optical coherence tomography (OCT), OCT angiography, and fluorescein angiography. Eye tracking, applied to the two preserved donor eyes, enabled correlation of clinical imaging signatures with high-resolution histology and transmission electron microscopy.Main Outcome(s) and Measure(s)Histologic/ ultrastructural descriptions and diameters of vessels seen in clinical imaging.ResultsSix vascular lesions were histologically confirmed (type 3 MNV, n=3; deep retinal age-related microvascular anomalies (DRAMA), n=3). Pyramidal (n=2) or tangled (n=1) morphologies of type 3 MNV originated at the deep capillary plexus (DCP) and extended posteriorly to approach without penetrating persistent basal laminar deposit. They did not enter the sub-retinal pigment epithelium (RPE)-basal laminar space or cross Bruch’s membrane. Choroidal contributions were not found. The neovascular complexes included pericytes and non-fenestrated endothelial cells, within a collagenous sheath covered by dysmorphic RPE cells. DRAMA lesions extended posteriorly from the DCP into the Henle fiber and the outer nuclear layers, without evidence of atrophy, exudation, or anti-VEGF responsiveness. Two DRAMA lacked collagenous sheaths. External and internal diameters of type 3 MNV and DRAMA vessels were larger than comparison vessels in the index eyes and in aged normal and intermediate AMD eyes.ConclusionsType 3 MNV vessels reflect specializations of source capillaries and persist during anti-VEGF therapy. The collagenous sheath of type 3 MNV lesions may provide structural stabilization. If so, vascular characteristics may be useful in disease monitoring in addition to fluid and flow signal detection. Further investigation with longitudinal imaging before exudation onset will help determine if DRAMA are part of the type 3 MNV progression sequence.

A panel of imaging experts was assembled to review neovascular age-related macular degeneration optical coherence tomography angiography descriptors published to date, and test agreement on use of these terms, which was found to be low. Optical coherence tomography angiography (OCTA) has been used to identify and characterize macular neovascularization (MNV) secondary to age-related macular degeneration (AMD). 1 , 2 , 3 , 4 Many studies have explored OCTA morphological features of MNV that might serve as biomarkers to assess disease activity and response to treatment. 1 , 2 , 3 , 4 , 5 , 6 The proliferation of studies however has resulted in an OCTA terminology that has been variable and inconsistent. To address inconsistency of nomenclature and allow harmonization, a multidisciplinary panel of retinal imaging experts with a history of relevant research contributions to the field was assembled with the purpose of reviewing published terminology and to recommend a reduced list of key terms pertinent to OCTA. The group was called UNICORN, because of its ultimate goal of generating a UNIfied COmmentary of the committee of inteRnational experts on the nomenclature for Neovascular AMD in OCTA. In this report we describe the first steps, which included a review of OCTA descriptors of neovascular AMD (nAMD) published to date, and an exercise that tested agreement of these terms among retinal imaging experts. Prior to the first UNICORN meeting, a non-systematic review of the literature was performed, using the search terms “optical coherence tomography angiography” or “OCT angiography” or “OCT-A”, AND “neovascular macular degeneration” or “neovascular age-related macular degeneration” or “neovascular AMD” or “nAMD” or “wet age-related macular degeneration” or “wet AMD” or “wet ARMD”. A dictionary of OCTA descriptors relating to the features of MNV in AMD was generated and circulated to the panel.

Introduction: This retrospective analysis assessed geographic atrophy (GA) progression in fellow eyes from the Proxima B trial intermediate age-related macular degeneration (iAMD) subcohort using high-resolution multimodal imaging anchored on optical coherence tomography (OCT). Methods: Thirty-two patients from the Proxima B iAMD subcohort were assessed; all had GA with no macular neovascularization (MNV) in the contralateral eye. Imaging data, including color fundus photography, fluorescein angiography, near-infrared reflectance, fundus autofluorescence (FAF), and spectral-domain OCT, were obtained. Features preceding progression/conversion to advanced AMD (drusen, reticular pseudodrusen [RPD], MNV, incomplete/complete retinal pigment epithelium and outer retinal atrophy [iRORA/cRORA]) were assessed. Results: Of 30 fellow eyes with available follow-up images, 12 converted to GA (FAF), 2 converted to MNV, and 16 were nonconverters during the review period (median: 17.8 months). iRORA/cRORA features (present in all converters at baseline) were identified on OCT in eyes that progressed to GA. Median time interval from iRORA to cRORA and from cRORA to GA was 7 months each. GA development/progression was either drusen- or RPD-associated (n = 6 each). Eyes with baseline RPD showed faster GA progression versus eyes with drusen (1.49 vs. 0.38 mm2/year). Conclusions: RPD presence was associated with rapid GA lesion enlargement and may provide an early indication of faster GA progression.

Purpose To assess visual function outcomes to 48 weeks in patients with bilateral geographic atrophy (GA) secondary to age-related macular degeneration included in 2 interventional clinical trials: relationship to baseline lesion size, outcomes by baseline lesion characteristic subgroups, and correlation of visual function outcomes with GA area. Design The Chroma and Spectri studies ( ClinicalTrials.gov identifiers, NCT02247479 and NCT02247531 , respectively) were identically designed phase 3, double-masked, multicenter, randomized, sham injection-controlled clinical trials that evaluated intravitreal lampalizumab in GA. Participants Eligible patients were 50 years of age or older with well-demarcated bilateral GA (lesion size, 1–7 disc areas) without evidence of or previous treatment for choroidal neovascularization in either eye and best-corrected visual acuity (BCVA) letter score of 49 letters or more (≥1 GA lesion within 250 μm of foveal center if BCVA ≥79 letters). Methods Patients (pooled n = 1881) were randomized 2:1:2:1 to lampalizumab every 4 weeks, sham every 4 weeks, lampalizumab every 6 weeks, or sham every 6 weeks. Sham arms were pooled for analysis. Main Outcome Measures Functional end points included change in BCVA from baseline to week 48, low-luminance visual acuity, mesopic microperimetry (number of absolute scotomatous points, mean macular sensitivity), binocular and monocular maximum reading speed, and 2 validated patient-reported outcome measures: Functional Reading Independence Index and 25-item National Eye Institute Visual Function Questionnaire. Results Enlargement of GA area, approximately 2 mm2/year on average across all treatment groups in each study, was accompanied by overall deterioration in all functional end points. No statistically significant differences were found between lampalizumab or sham arms for changes from baseline in functional assessment scores. Of visual function tests, only microperimetry outcomes were correlated moderately with GA lesion area when assessed cross-sectionally at baseline and week 48. Conclusions Chroma and Spectri provide a unique data set of functional end points in GA that are relevant for future clinical trials. Patients with bilateral GA experienced a consistent decline in visual function over 48 weeks, but measures of visual function were not correlated strongly with GA lesion area. It is not possible to predict visual function outcomes from GA lesion size.

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.

BACKGROUND: To analyse cellular and spatiotemporal factors of neurodegeneration and gliosis in a patient with submacular haemorrhage (SMH) secondary to type 1 macular neovascularization in neovascular age-related macular degeneration (nAMD). METHODS: This is a case study and clinicopathologic correlation of an 84-year-old white man with nAMD treated with antiangiogenic drugs and photodynamic therapy during a 6-year follow-up. Eyes were recovered for histology 8.23 h after death. In vivo multimodal imaging including optical coherence tomography (OCT) and en face modalities was compared with ex vivo OCT and high-resolution histologic images, using a custom image registration procedure. SMH components were defined (intraretinal, subretinal, sub-retinal pigment epithelium (RPE), and dehemoglobinized blood). Neurodegenerative changes in each of these areas were described. One anonymous donor eye with haemorrhagic nAMD was also reviewed as a comparator. RESULTS: By in vivo OCT, progressive resolution of the haemorrhage and gradual transformation of sub-RPE fluid to fibrous hyperreflective tissue, progressive macular atrophy, and variation in external limiting membrane (ELM) visibility were observed. Histology showed intense photoreceptor loss with preservation and self-adhesion of macular Müller glia resulting in ELM condensation. The comparator eye exhibited shed cone inner segments among subretinal erythrocytes. CONCLUSION: This is the most detailed clinicopathologic correlation of nAMD with SMH resolution to date, and the first in the OCT era. Our results reveal profound macular neurodegeneration and gliosis, signified by condensed ELM, soon after haemorrhage begins. Intensified OCT reflectivity of the ELM, an important retinal barrier, has potential as a biomarker for severe photoreceptor loss and gliosis.

PURPOSE OF REVIEW Predicting treatment response and optimizing treatment regimen in patients with neovascular age-related macular degeneration (nAMD) remains challenging. Artificial intelligence-based tools have the potential to increase confidence in clinical development of new therapeutics, facilitate individual prognostic predictions, and ultimately inform treatment decisions in clinical practice. RECENT FINDINGS To date, most advances in applying artificial intelligence to nAMD have focused on facilitating image analysis, particularly for automated segmentation, extraction, and quantification of imaging-based features from optical coherence tomography (OCT) images. No studies in our literature search evaluated whether artificial intelligence could predict the treatment regimen required for an optimal visual response for an individual patient. Challenges identified for developing artificial intelligence-based models for nAMD include the limited number of large datasets with high-quality OCT data, limiting the patient populations included in model development; lack of counterfactual data to inform how individual patients may have fared with an alternative treatment strategy; and absence of OCT data standards, impairing the development of models usable across devices. SUMMARY Artificial intelligence has the potential to enable powerful prognostic tools for a complex nAMD treatment landscape; however, additional work remains before these tools are applicable to informing treatment decisions for nAMD in clinical practice.

IMPORTANCE: By validating optical coherence tomography angiography (OCTA) in the analysis of type 3 macular neovascularization secondary to age-related macular degeneration, the overall value of clinical OCTA for disease observation, diagnosis, and staging is increased. OBJECTIVE: To assess the association of in vivo OCTA of type 3 macular neovascularization secondary to age-related macular degeneration with corresponding ex vivo histology. DESIGN, SETTING, AND PARTICIPANTS: This study included clinical imaging, laboratory microscopy, and eye-tracked clinicopathologic correlation of a single case from a community-based practice evaluated at a university-based research laboratory from 2014 to 2019. EXPOSURES: Infrared reflectance and eye-tracked spectral-domain OCTA clinical imaging was correlated with ex vivo high-resolution histologic images of the preserved donor eye. Eye tracking, applied to the donor eye, enabled identification of histologic features corresponding with clinical OCTA signatures. Projection artifact removal based on 2-dimensional vessel-shape estimation and a Gaussian blur filter demonstrated a robust preservation of neovascular flow signal. MAIN OUTCOMES AND MEASURES: Histology findings associated with clinical OCTA signatures. Three-dimensional view of neovascularization via video. RESULTS: A White woman in her 90s with type 3 neovascularization secondary to age-related macular degeneration was treated with 37 intravitreal injections of ranibizumab and aflibercept in the right eye. The index lesion displayed a drusenoid pigment epithelium detachment, characteristic of type 3 neovascularization. OCTA decorrelation signal in the index lesion corresponded in histology to a collagen-ensheathed vascular complex contacting basal laminar deposit that outlasted the retinal pigment epithelium. The subretinal pigment epithelium-basal laminar space contained calcified material and glial processes. No connection between the choriocapillaris and this space was observed. Video showed a columnar tangle of flow signal in the outer nuclear layer, with inflow and outflow vessels connecting to the superficial artery and vein. CONCLUSIONS AND RELEVANCE: While this study presents only 1 case in which a vascular connection between subretinal pigment epithelium-basal laminar space and choriocapillaris was undetected, these results support the potential value of OCTA for diagnosis. OCTA decorrelation signal of type 3 neovascularization corresponded with intraretinal neovessels on histology. Projection artifact removal based on 2-dimensional vessel-shape estimation and Gaussian blur filter demonstrated their potential value for further use in OCTA decorrelation signal processing.

PURPOSE To report a case of acute zonal occult outer retinopathy in which adaptive optics (AO) facilitated visualization of abnormal photoreceptors previously thought to be in an area of normal retina on conventional optical coherence tomography (OCT). METHODS Case report. RESULTS A 51-year-old woman presents with 11-month history of photopsias and scotoma in the temporal visual field of her left eye. Ocular imaging including fluorescein angiography, fundus autofluorescence and OCT suggested the diagnosis of acute zonal occult outer retinopathy in the left eye. Adaptive optics optical coherence tomography (AO-OCT) revealed photoreceptor abnormalities not previously identified in conventional OCT, in areas apparently normal on multimodal imaging. On enface and cross-sectional AO-OCT, round and evenly spaced hyperreflectivity corresponding to normal cone mosaic (Pattern 1) was adjacent to unevenly and disrupted cone hyperreflectivity (Pattern 2) and areas with hyporeflectivity or no cone reflectivity (Pattern 3). Cross-sectional AO-OCT of Patterns 2 and 3 also revealed attenuation of ellipsoid zone with loss of interdigitation zone. CONCLUSION Adaptive optics OCT documented cone photoreceptors in finer details than conventional OCT and revealed early changes in a patient with acute zonal occult outer retinopathy, in an area of the retina thought to be normal on conventional multimodal imaging. These findings may provide important insight into pathogenesis and progression of the disease.

To correlate in vivo imaging to histology in an eye with macular atrophy owing to age-related macular degeneration (AMD; complete retinal pigment epithelium [RPE] and outer retinal atrophy [cRORA]) to evaluate the utility of new optical coherence tomography (OCT) suggested by previous histology.Case study with clinicopathologic correlation.In vivo eye-tracked cross-sectional OCT scans at 13 and 8 months before death were compared to postmortem histopathology. On OCT, the atrophy border was identified as either the descent of the external limiting membrane (ELM) toward the Bruch membrane (BrM) (representing gliosis) or the presence of choroidal hypertransmission (representing lack of shadowing by RPE). Thicknesses of RPE, basal laminar deposit (BLamD), and BrM were measured at 500 and 100 μm on the nonatrophic and atrophic sides of these borders, on in vivo eye-tracked OCT and histology matched to the same location.In all OCT scans, the ELM descent was visible. The RPE-BLamD band significantly thickened toward it (P.005), over time (P = .015 and P = .043, at 500 and 100 μm, respectively). On OCT, the ELM descent delineated a smaller atrophic area than did hypertransmission. RPE-BLamD thicknesses manually measured on OCT overestimated histologic thicknesses. BrM visibility varied with RPE status.Visible on OCT, the ELM descent is a histopathologic atrophy border supporting new terminology of cRORA, whereas hypertransmission reveals RPE degeneration. RPE-BLamD thickening across the macula, toward the atrophy and over time is confirmed. The presence of gliosis and thick RPE-BLamD suggests that macular atrophy is a late stage in disease progression, encouraging anatomic endpoints at earlier AMD stages than atrophy enlargement.

Geographic atrophy (GA) is an advanced form of age-related macular degeneration (AMD) that leads to progressive and irreversible loss of visual function. Geographic atrophy is defined by the presence of sharply demarcated atrophic lesions of the outer retina, resulting from loss of photoreceptors, retinal pigment epithelium (RPE), and underlying choriocapillaris. These lesions typically appear first in the perifoveal macula, initially sparing the foveal center, and over time often expand and coalesce to include the fovea. Although the kinetics of GA progression are highly variable among individual patients, a growing body of evidence suggests that specific characteristics may be important in predicting disease progression and outcomes. This review synthesizes current understanding of GA progression in AMD and the factors known or postulated to be relevant to GA lesion enlargement, including both affected and fellow eye characteristics. In addition, the roles of genetic, environmental, and demographic factors in GA lesion enlargement are discussed. Overall, GA progression rates reported in the literature for total study populations range from 0.53 to 2.6 mm2/year (median, ∼1.78 mm2/year), assessed primarily by color fundus photography or fundus autofluorescence (FAF) imaging. Several factors that could inform an individual's disease prognosis have been replicated in multiple cohorts: baseline lesion size, lesion location, multifocality, FAF patterns, and fellow eye status. Because best-corrected visual acuity does not correspond directly to GA lesion enlargement due to possible foveal sparing, alternative assessments are being explored to capture the relationship between anatomic progression and visual function decline, including microperimetry, low-luminance visual acuity, reading speed assessments, and patient-reported outcomes. Understanding GA progression and its individual variability is critical in the design of clinical studies, in the interpretation and application of clinical trial results, and for counseling patients on how disease progression may affect their individual prognosis.

PURPOSE: Melanotic cells with large spherical melanosomes, thought to originate from retinal pigment epithelium (RPE), are found in eyes with neovascular age-related macular degeneration (nvAMD). To generate hypotheses about RPE participation in fibrosis, we correlate histology to clinical imaging in an eye with prominent black pigment in fibrotic scar secondary to nvAMD. METHODS: Macular findings in a white woman with untreated inactive subretinal fibrosis due to nvAMD in her right eye were documented over 9 years with color fundus photography (CFP), fundus autofluorescence (FAF) imaging, and optical coherence tomography (OCT). After death (age 90 years), this index eye was prepared for light and electron microscopy to analyze 7 discrete zones of pigmentation in the fibrotic scar. In additional donor eyes with nvAMD, we determined the frequency of black pigment (n = 36 eyes) and immuno-labeled for retinoid, immunologic, and microglial markers (RPE65, CD68, Iba1, TMEM119; n = 3 eyes). RESULTS: During follow-up of the index eye, black pigment appeared and expanded within a hypoautofluorescent fibrotic scar. The blackest areas correlated to melanotic cells (containing large spherical melanosomes), some in multiple layers. Pale areas had sparse pigmented cells. Gray areas correlated to cells with RPE organelles entombed in the scar and multinucleate cells containing sparse large spherical melanosomes. In 94% of nvAMD donor eyes, hyperpigmentation was visible. Certain melanotic cells expressed some RPE65 and mostly CD68. Iba1 and TMEM119 immunoreactivity, found both in retina and scar, did not co-localize with melanotic cells. CONCLUSION: Hyperpigmentation in CFP results from both organelle content and optical superimposition effects. Black fundus pigment in nvAMD is common and corresponds to cells containing numerous large spherical melanosomes and superimposition of cells containing sparse large melanosomes, respectively. Melanotic cells are molecularly distinct from RPE, consistent with a process of transdifferentiation. The subcellular source of spherical melanosomes remains to be determined. Detailed histology of nvAMD eyes will inform future studies using technologies for spatially resolved molecular discovery to generate new therapies for fibrosis. The potential of black pigment as a biomarker for fibrosis can be investigated in clinical multimodal imaging datasets.

La consapevolezza dell’intima connessione tra il principio di trasparenza e la prevenzione dei fenomeni corruttivi è un’acquisizione relativamente recente del nostro legislatore, in ciò condizionato positivamente dal contesto internazionale. Ci si riferisce, in particolare, alla United Nations Conventions Against Corruption (UNCAC), il primo strumento internazionale delle Nazioni Unite per la lotta alla corruzione, approvato nel 2003 e ratificato in Italia con legge di autorizzazione alla ratifica 3 agosto 2009, n. 116 e alla Criminal Law Convention on corruption firmata a Strasburgo nel 1999 e ratificata dall’Italia con legge di autorizzazione alla ratifica 28 giugno 2012, n. 110. Il Group of States against Corruption (Groupe d'États contre la corruption, GRECO), organo di controllo contro la corruzione del Consiglio d'Europa, istituito nel 1999, ha indirizzato all’Italia alcune specifiche Raccomandazioni, che hanno fornito indicazioni sul percorso di riforma da seguire per contrastare il fenomeno corruttivo, percepito, secondo i rapporti e le analisi internazionali, come usuale e diffuso nel settore pubblico, suggerendo sia l’adozione di misure preventive, ritenendo insufficienti quelle esclusivamente repressive, sia la necessità di un coordinamento tra tutte le istituzioni preposte al contrasto dei fenomeni corruttivi. Nell’arco di un quinquennio, quindi, a partire dalla fine del 2012, si è radicato e sviluppato il nuovo sistema di prevenzione e contrasto amministrativo della corruzione. La struttura fondamentale del sistema discende dalla legge n. 190 del 2012 che, sulla base delle deleghe ivi contenute, è stata completata dal d.lgs. n. 33 del 2013, in materia di trasparenza amministrativa, dal d.lgs. n. 39 del 2013, in materia di incompatibilità e inconferibilità degli incarichi nella pubblica amministrazione, e dal regolamento che disciplina il codice di comportamento dei dipendenti pubblici (d.P.R. n. 62 del 2013). Gli sviluppi normativi successivi – il d.l. n. 90 del 2014, che ha disposto l’abolizione dell’Autorità per i contratti pubblici (AVCP), trasferendo le relative funzioni e il personale all’Autorità Nazionale Anticorruzione (A.N.AC.), il d.lgs. n. 97 del 2016 che ha riformato la disciplina in materia di trasparenza amministrativa, introducendo il c.d. FOIA, e il d.lgs. n. 50 del 2016, di approvazione del Codice dei Contratti pubblici che ha dettato disposizioni specifiche anti corruzione in materia – hanno ulteriormente definito i caratteri attuali del “modello” italiano e si sono dimostrati coerentemente orientati a rinforzare il ruolo dell’A.N.AC. e tutto il sistema dell’anticorruzione. Tuttavia, con l’approvazione del d.l. n. 32 del 2019 (il c.d. decreto sbocca-cantieri), convertito con modifiche dalla legge n. 55 del 2019, sembra registrarsi un’inversione di tendenza e un indebolimento del potere regolatorio dell’A.N.AC.: ai fini dell’attuazione del Codice dei contratti pubblici, infatti, è stata prevista l’adozione del Regolamento unico, ex art. 216, comma 27-octies del Codice, destinato a sostituire, almeno in parte, il sistema della c.d. “Soft Law” in materia, con l’eliminazione delle linee guida vincolanti dell’A.N.AC., lasciando uno spazio residuo alle sole linee guida non vincolanti.

To assess visual function outcomes to 48 weeks in patients with bilateral geographic atrophy (GA) secondary to age-related macular degeneration included in 2 interventional clinical trials: relationship to baseline lesion size, outcomes by baseline lesion characteristic subgroups, and correlation of visual function outcomes with GA area.The Chroma and Spectri studies (ClinicalTrials.gov identifiers, NCT02247479 and NCT02247531, respectively) were identically designed phase 3, double-masked, multicenter, randomized, sham injection-controlled clinical trials that evaluated intravitreal lampalizumab in GA.Eligible patients were 50 years of age or older with well-demarcated bilateral GA (lesion size, 1-7 disc areas) without evidence of or previous treatment for choroidal neovascularization in either eye and best-corrected visual acuity (BCVA) letter score of 49 letters or more (≥1 GA lesion within 250 μm of foveal center if BCVA ≥79 letters).Patients (pooled n = 1881) were randomized 2:1:2:1 to lampalizumab every 4 weeks, sham every 4 weeks, lampalizumab every 6 weeks, or sham every 6 weeks. Sham arms were pooled for analysis.Functional end points included change in BCVA from baseline to week 48, low-luminance visual acuity, mesopic microperimetry (number of absolute scotomatous points, mean macular sensitivity), binocular and monocular maximum reading speed, and 2 validated patient-reported outcome measures: Functional Reading Independence Index and 25-item National Eye Institute Visual Function Questionnaire.Enlargement of GA area, approximately 2 mmChroma and Spectri provide a unique data set of functional end points in GA that are relevant for future clinical trials. Patients with bilateral GA experienced a consistent decline in visual function over 48 weeks, but measures of visual function were not correlated strongly with GA lesion area. It is not possible to predict visual function outcomes from GA lesion size.

To better characterize visual function decline and geographic atrophy (GA) progression secondary to age-related macular degeneration (AMD).Proxima A (NCT02479386)/Proxima B (NCT02399072) were global, prospective, noninterventional, observational clinical trials.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).Changes in visual function and imaging/anatomic parameters were evaluated over time using a mixed model for repeated measurement accounting for key baseline characteristics.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).At 24 months, adjusted mean (standard error) change in GA lesion area from baseline was 3.87 (0.15) mmThe 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.

Supplemental Digital Content is Available in the Text. Direct clinicopathologic correlation of an eye with geographic atrophy secondary to age-related macular degeneration provides histologic correlates of features commonly seen by optical coherence tomography, such as end-stages of drusen, subretinal drusenoid deposit, plaques near the Bruch membrane, and hyporeflective wedge., Purpose: In an eye with geographic atrophy (GA) secondary to age-related macular degeneration, we correlated ex vivo histologic features with findings recorded in vivo using optical coherence tomography (OCT), near-infrared reflectance imaging, and fundus autofluorescence. Methods: In the left eye of an 86-year-old white woman, in vivo near-infrared reflectance and eye-tracked OCT B-scans at each of 6 clinic visits and a baseline fundus autofluorescence image were correlated with high-resolution histologic images of the preserved donor eye. Results: Clinical imaging showed a small parafoveal multilobular area of GA, subfoveal soft drusen, refractile drusen, hyperreflective lines near the Bruch membrane, subretinal drusenoid deposit (reticular pseudodrusen), and absence of hyperautofluorescent foci at the GA margin. By histology, soft drusen end-stages included avascular fibrosis with highly reflective cholesterol crystals. These accounted for hyperreflective lines near the Bruch membrane in OCT and plaques in near-infrared reflectance imaging. Subretinal drusenoid deposit was thick, continuous, extracellular, extensive outside the fovea, and associated with distinctive retinal pigment epithelium dysmorphia and photoreceptor degeneration. A hyporeflective wedge corresponded to ordered Henle fibers without cellular infiltration. The external limiting membrane descent, which delimits GA, was best visualized in high-quality OCT B-scans. Retinal pigment epithelium and photoreceptor changes at the external limiting membrane descent were consistent with our recent histologic survey of donor eyes. Conclusion: This case informs on the extent, topography, and lifecycle of extracellular deposits. High-quality OCT scans are required to reveal all tissue features relevant to age-related macular degeneration progression to GA, especially the external limiting membrane descent. Histologically validated signatures of structural OCT B-scans can serve as references for other imaging modalities.

To describe qualitative and quantitative optical coherence tomography (OCT) angiography (OCTA) parameters for choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD) and their applicability as potential clinical trial endpoints.A review of current literature related to the topic of OCTA and AMD.There are a number of promising OCTA parameters that can be used to diagnose the presence of CNV and to monitor the activity and progression of the lesion, pre- and post-treatment morphological characteristics, CNV dimensions, and automated quantitative parameters such as vessel density.The OCTA parameters described in this review have promise for the future development of clinical trial endpoints, but require further validation before they can be widely used.

Nonexudative choroidal neovascularization (CNV) is a new phenomenon that has only recently been described in the literature with the advent of optical coherence tomography angiography (OCTA) imaging. The authors present a 1-year longitudinal follow-up of a nonexudative CNV lesion secondary to age-related macular degeneration. This report describes the appearance of the lesion on two commercially available spectral-domain OCTA devices and one prototype swept-source OCTA device. Management of these cases is still debatable. Watchful waiting with regular follow-up using serial OCTA to monitor disease progression has been valuable in this case., National Institutes of Health (U.S.) (Grant R01-EY011309), United States. Air Force Office of Scientific Research (Grant FA9550-15-1-0473), United States. Air Force Office of Scientific Research (Grant FA9550-12-1-0499)

The body of knowledge of in vivo investigation of the choroid has been markedly enhanced by recent technological advances in optical coherence tomography (OCT). New insights elucidating the morphological features of the choriocapillaris and choroidal vasculature, in both physiological and pathological conditions, indicate that the choroid plays a pivotal role in many posterior segment diseases. In this article, a review of the histological characteristics of the choroid, which must be considered for the proper interpretation of in vivo imaging, is followed by a comprehensive discussion of fundamental principles of the current state-of-the-art in OCT, including cross-sectional OCT, en face OCT, and OCT angiography using both spectral domain OCT and swept source OCT technologies. A detailed review of the tomographic features of the choroid in the normal eye is followed by relevant findings in prevalent chorioretinal diseases, focusing on major causes of vision loss such as typical early and advanced age-related macular degeneration, polypoidal choroidal vasculopathy, central serous chorioretinopathy, pachychoroid spectrum disorders, diabetic choroidopathy, and myopia.

Purpose We explored via multimodal imaging and histology an eye with mixed-types 1 and 2 macular neovascularization (MNV) and complete retinal pigment epithelium (RPE) and outer retinal atrophy (cRORA) in age-related macular degeneration. Methods An 82-year-old white man was followed 7 years by optical coherence tomography and treated with intravitreal anti-vascular endothelial growth factor for 3 years. At the last clinic visit, visual acuity was stable at 20/50. Two months later the patient died, and eyes were preserved at 8.33 hours after death. Submicrometer epoxy resin sections of osmicated tissue were stained with toluidine blue and evaluated by oil immersion microscopy. Results A shallow irregular RPE elevation on optical coherence tomography correlated with type 1 MNV with fibrocellular scar and neocapillaries (close to RPE), at a density similar to underlying native choriocapillaris (0.37 vs. 0.42). Type 2 MNV covered the native RPE and was enveloped at the margins by RPE, without neocapillaries. Native RPE cells transdifferentiated from age-normal to melanotic and entered type 1 MNV and choroid. Some photoreceptors persisted over MNV. The cRORA initiated at a collapsed druse, expanded during follow-up, and exhibited low choriocapillaris density (0.05). Conclusions An eye with maintained vision on 3 years of anti-vascular endothelial growth factor therapy had type 1 MNV sustaining RPE. Type 2 MNV enveloped by RPE was visible in optical coherence tomography and histology. Persistence of photoreceptors and RPE over MNV contrasted with drusen-associated cRORA. Translational relevance Vision during long-term anti-vascular endothelial growth factor treatment persists by MNV partially preserving outer retinal cells and by RPE enveloping type 2 MNV.

Geographic atrophy (GA) is a progressive, advanced form of age-related macular degeneration leading to visual function impairment and irreversible vision loss. Standard clinical tests to evaluate visual function in patients with GA provide poor anatomic-functional correlation, whereas fundus imaging does not assess the visual function deficit. Microperimetry is a psychophysical visual function test that spatially maps retinal sensitivity and allows for identification of correlation of anatomic features with visual function. In this review, we present an overview of mesopic microperimetry for GA, including commercially available microperimetry devices, strategies to capture a mesopic microperimetry test, and strategies to assess and interpret microperimetry data in patients with GA. We demonstrate the importance of microperimetry data for assessing GA progression and for evaluating visual function loss through anatomic-functional correlations. Although valuable, current microperimetry tests require an extensive time commitment from the patient and examiner, and the development of faster, more reproducible and accessible methods is important to enable broader use of microperimetry in both clinical and research settings.

Purpose Geographic atrophy (GA) is an advanced form of age-related macular degeneration. GA often initially spares the center of the fovea, leading to a functional disconnect between reading speed and distance visual acuity. This study was designed to determine the correlation between baseline GA lesion size, change in lesion size, and maximum reading speed (MRS) over 18 months. Methods Post hoc analysis included US patients from the phase 2 Mahalo study of intravitreal lampalizumab with Minnesota low-vision reading (MNREAD) assessments at baseline and 6, 12, and 18 months. Binocular MRS was assessed using MNREAD Acuity Charts and GA lesion size by fundus autofluorescence. Correlations were estimated using Spearman's rank correlation coefficient. Results Seventy-seven patients were included in the analysis. Baseline MRS correlated with baseline GA lesion size (correlation coefficient, -0.47; 95% confidence interval, -0.63 to -0.28; P < 0.0001). In patients with lesions ≥10 mm2 (four disc areas), the proportion reading below a nonfluent level (MRS

Supplemental Digital Content is Available in the Text. High-resolution histology at the border of geographic atrophy (or complete retinal pigment epithelium and outer retinal atrophy) secondary to age-related macular degeneration reveals marked gliosis and near-total photoreceptor depletion, abundant extracellular deposits, and long-standing abnormalities of Bruch membrane and choriocapillaris, indicating severe and potentially irreversible tissue damage at this stage of the disease., Purpose: To systematically characterize histologic features of multiple chorioretinal layers in eyes with geographic atrophy, or complete retinal pigment epithelium (RPE) and outer retinal atrophy, secondary to age-related macular degeneration, including Henle fiber layer and outer nuclear layer; and to compare these changes to those in the underlying RPE-Bruch membrane—choriocapillaris complex and associated extracellular deposits. Methods: Geographic atrophy was delimited by the external limiting membrane (ELM) descent towards Bruch membrane. In 13 eyes, histologic phenotypes and/or thicknesses of Henle fiber layer, outer nuclear layer, underlying supporting tissues, and extracellular deposits at four defined locations on the non-atrophic and atrophic sides of the ELM descent were assessed and compared across other tissue layers, with generalized estimating equations and logit models. Results: On the non-atrophic side of the ELM descent, distinct Henle fiber layer and outer nuclear layer became dyslaminated, cone photoreceptor inner segment myoids shortened, photoreceptor nuclei and mitochondria translocated inward, and RPE was dysmorphic. On the atrophic side of the ELM descent, all measures of photoreceptor health declined to zero. Henle fiber layer/outer nuclear layer thickness halved, and only Müller cells remained, in the absence of photoreceptors. Sub-RPE deposits remained, Bruch membrane thinned, and choriocapillaris density decreased. Conclusion: The ELM descent sharply delimits an area of marked gliosis and near-total photoreceptor depletion clinically defined as Geographic atrophy (or outer retinal atrophy), indicating severe and potentially irreversible tissue damage. Degeneration of supporting tissues across this boundary is gradual, consistent with steady age-related change and suggesting that RPE and Müller cells subsequently respond to a threshold of stress. Novel clinical trial endpoints should be sought at age-related macular degeneration stages before intense gliosis and thick deposits impede therapeutic intervention.

Purpose To describe the retinal microvasculature of the eyes with nonarteritic retinal artery occlusion (RAO) based on optical coherence tomography angiography. Methods Cross-sectional, prospective, observational study performed from September 2014 through February 2015. En face projection of optical coherence tomography angiography images centered at the macula and optic disk of the eyes presenting with RAO were acquired using the RTVue XR Avanti with AngioVue software. Qualitative analysis of the morphology of the superficial and deep retinal capillary plexuses, and radial peripapillary capillaries was performed. Retinal vasculature images using optical coherence tomography angiography were correlated with fluorescein angiography images. Results Seven patients (seven eyes) were enrolled in the study, including three eyes with central RAO and four eyes with branch RAO. Distinct differences in the distribution of zones of decreased vascular perfusion between the superficial and deep retinal capillary plexus corresponding to areas of delayed dye perfusion on fluorescein angiography were demonstrated in 6 of 7 (86.5%) eyes. Conclusion This small series suggests that optical coherence tomography angiography imaging can accurately discern retinal capillary plexuses at different levels in the eyes with RAO and may be sensitive for more precisely characterizing the extent of macular ischemia and monitoring vascular flow changes during the course of the disease.

The choroidal vasculature is the primary source of both oxygen and blood-borne nutrients to the outer retina, including the retinal pigment epithelium (RPE), photoreceptors, and otherwise avascular...