Sebastian M. Waldstein

Influence of the vitreomacular interface on outcomes of ranibizumab therapy in neovascular age-related macular degeneration.

PURPOSE To investigate the influence of the vitreomacular interface (VMI) on the functional and anatomic efficacy of ranibizumab therapy in patients with neovascular age-related macular degeneration (AMD). DESIGN Subanalysis of a prospective, 12-month, multicenter, phase IIIb trial. PARTICIPANTS A total of 353 treatment-naïve patients with subfoveal choroidal neovascularization (CNV) receiving quarterly or monthly ranibizumab therapy. METHODS On monthly optical coherence tomography (OCT) scan sets, the VMI configuration was graded by a certified reading center into one of the following conditions: continuous posterior vitreoretinal attachment (PVA), vitreomacular adhesion (VMA), partial vitreous detachment without vitreomacular contact, or complete posterior vitreous detachment (PVD). Best-corrected visual acuity (BCVA) and central retinal thickness (CRT) measurements were performed at monthly intervals. Analysis included patients with a minimum of 10 OCT examinations, including baseline and month 12 (n = 251). After integration of the VMI configuration over 12 months, patients were divided into one of the following categories: PVD (n = 162), release of vitreomacular contact (RELEASE; n = 48), VMA (n = 37), or PVA (n = 4). General estimation equation analyses were applied to test for noninferiority of quarterly versus monthly treatment. MAIN OUTCOME MEASURES The BCVA and CRT changes at month 12. RESULTS Mean BCVA changes in letters were +4.7 (PVD), +3.2 (RELEASE), and -0.2 (VMA) in the quarterly regimen and +4.9 (PVD), +12.7 (RELEASE), and +7.5 (VMA) in the monthly regimen. No difference in therapeutic efficiency between monthly and quarterly intervention was found in eyes with PVD, and quarterly treatment was noninferior to monthly treatment (P = 0.001). However, monthly treatment was superior to quarterly treatment in the RELEASE (P = 0.008) and VMA (P = 0.043) groups. Mean CRT changes were -98 and -96 μm (PVD), -117 and -136 μm (RELEASE), and -93 and -87 μm (VMA) in the monthly and quarterly regimens, respectively, without statistically significant differences. CONCLUSIONS The configuration of the VMI seems to have an important effect on visual outcomes and need for retreatment. In patients with PVD, a lower treatment frequency may be feasible, whereas patients with RELEASE or VMA may benefit from intensive retreatment. These findings may serve as a basis for individualized treatment decisions in anti-angiogenic therapy of neovascular AMD and perhaps other indications.

A paradigm shift in imaging biomarkers in neovascular age-related macular degeneration.

Neovascular age-related macular degeneration (AMD) has undergone substantial break-throughs in diagnostic as well as therapeutic respect, with optical coherence tomography (OCT) allowing to identify disease morphology in great detail, and intravitreal anti-vascular endothelial growth factor therapy providing unprecedented benefit. However, these two paths have yet not been combined in an optimal way, real-world outcomes are inferior to expectations, and disease management is largely inefficient in the real-world setting. This dilemma can be solved by identification of valid biomarkers relevant for visual function, disease activity and prognosis, which can provide solid guidance for therapeutic management on an individual level as well as on the population base. Qualitative and quantitative morphological features obtained by advanced OCT provide novel insight into exudative and degenerative stages of neovascular AMD. However, conclusions from structure/function correlations evolve differently from previous paradigms. While central retinal thickness was used as biomarker for guiding retreatment management in clinical trials and practice, fluid localization in different compartments offers superior prognostic value: Intraretinal cystoid fluid has a negative impact on visual acuity and is considered as degenerative when persisting through the initial therapeutic interval. Subretinal fluid is associated with superior visual benefit and a lower rate of progression towards geographic atrophy. Detachment of the retinal pigment epithelium was identified as most pathognomonic biomarker, often irresponsive to therapy and responsible for visual decline during a pro-re-nata regimen. Alterations of neurosensory tissue are usually associated with irreversible loss of functional elements and a negative prognosis. Novel OCT technologies offer crucial insight into corresponding changes at the level of the photoreceptor--retinal pigment epithelial--choriocapillary unit, identifying the biological limits of therapeutic interventions. To optimally benefit from high-resolution multi-modal imaging, an integrated analysis of all functional and structural features is required involving reliable automated algorithms and computational data analyses. Using innovative analysis methods, retinal biomarkers can be used to provide efficient personalized therapy for the individual patient, predictive disease- and population-based models for large-scale management and identifying promising targets for the development of novel therapeutic strategies.

Pigment Epithelial Detachment Followed by Retinal Cystoid Degeneration Leads to Vision Loss in Treatment of Neovascular Age-Related Macular Degeneration

PURPOSE Intravitreal antiangiogenic therapy is the major therapeutic breakthrough in neovascular age-related macular degeneration (AMD). Optical coherence tomography (OCT) is the leading diagnostic tool, but solid criteria for optimal therapeutic outcomes are lacking. A comprehensive analysis of structure/function correlations using Food and Drug Administration- and European Medicines Agency-approved substances and fixed and flexible regimens was performed. DESIGN Post hoc analysis of a prospective, randomized multicenter clinical trial including 189 study sites. PARTICIPANTS A total of 1240 patients with active neovascular AMD. METHODS Participants received intravitreal ranibizumab or aflibercept. A fixed regimen was used for 48 weeks followed by a flexible regimen until week 96. At monthly intervals, best-corrected visual acuity (BCVA) was measured and retinal morphology was assessed by standardized OCT, including intraretinal cysts (IRCs), subretinal fluid (SRF), and pigment epithelial detachment (PED), presenting with a width ≥400 μm or a height of ≥200 μm. Results were correlated for each regimen, feature, and time. MAIN OUTCOME MEASURES The BCVA outcomes in relation to retinal pathomorphology based on noninferiority for all treatment arms. RESULTS In neovascular AMD, only IRC at baseline and persistent through week 12 had a negative impact on BCVA. With therapeutic intervention, exudative features such as IRC and SRF resolved rapidly in 74% of eyes, whereas PED responded only slowly with 38%. Independent of the type of regimen, fixed or flexible, retinal morphology correlated tightly with visual function. Intraretinal cysts consistently showed the lowest BCVA gains with either regimen or substance. With the switch from a fixed to a flexible pro re nata (PRN) regimen, progressive visual loss occurred exclusively in the group with primary PED presenting as the hallmark of neovascular activity and was induced by secondary formation of IRC in the neurosensory retina. CONCLUSIONS The efficacy of antiangiogenic therapy in neovascular AMD is strongly determined by morphologic features. The subretinal pigment epithelium lesion underlying PED appears to be the primary indicator for progressive disease activity, whereas secondary cystoid degeneration is the most relevant imaging marker for visual function. Clinically, PED emerged as trigger for consecutive vision loss in PRN treatment.

Predicting Semantic Descriptions from Medical Images with Convolutional Neural Networks

Learning representative computational models from medical imaging data requires large training data sets. Often, voxel-level annotation is unfeasible for sufficient amounts of data. An alternative to manual annotation, is to use the enormous amount of knowledge encoded in imaging data and corresponding reports generated during clinical routine. Weakly supervised learning approaches can link volume-level labels to image content but suffer from the typical label distributions in medical imaging data where only a small part consists of clinically relevant abnormal structures. In this paper we propose to use a semantic representation of clinical reports as a learning target that is predicted from imaging data by a convolutional neural network. We demonstrate how we can learn accurate voxel-level classifiers based on weak volume-level semantic descriptions on a set of 157 optical coherence tomography (OCT) volumes. We specifically show how semantic information increases classification accuracy for intraretinal cystoid fluid (IRC), subretinal fluid (SRF) and normal retinal tissue, and how the learning algorithm links semantic concepts to image content and geometry.

Three-dimensional automated choroidal volume assessment on standard spectral-domain optical coherence tomography and correlation with the level of diabetic macular edema.

PURPOSE To measure choroidal thickness on spectral-domain optical coherence tomography (SD OCT) images using automated algorithms and to correlate choroidal pathology with retinal changes attributable to diabetic macular edema (DME). DESIGN Post hoc analysis of multicenter clinical trial baseline data. METHODS SD OCT raster scans/fluorescein angiograms were obtained from 284 treatment-naïve eyes of 142 patients with clinically significant DME and from 20 controls. Three-dimensional (3D) SD OCT images were evaluated by a certified independent reading center analyzing retinal changes associated with diabetic retinopathy. Choroidal thicknesses were analyzed using a fully automated algorithm. Angiograms were assessed manually. Multiple endpoint correction according to Bonferroni-Holm was applied. Main outcome measures were average retinal/choroidal thickness on fovea-centered or peak of edema (thickest point of edema)-centered Early Treatment Diabetic Retinopathy Study grid, maximum area of leakage, and the correlation between retinal and choroidal thicknesses. RESULTS Total choroidal thickness is significantly reduced in DME (175 ± 23 μm; P = .0016) and nonedematous fellow eyes (177 ± 20 μm; P = .009) of patients compared with healthy control eyes (190 ± 23 μm). Retinal/choroidal thickness values showed no significant correlation (1-mm: P = .27, r(2) = 0.01; 3-mm: P = .96, r(2) < 0.0001; 6-mm: P = .42, r(2) = 0.006). No significant difference was found in the 1- or 3-mm circle of a retinal peak of edema-centered grid. All other measurements of choroidal/retinal thickness (DME vs healthy, DME vs peak of edema-centered, DME vs fellow, healthy vs fellow, peak of edema-centered vs healthy, peak of edema-centered vs fellow eyes) were compared but no statistically significant correlation was found. By tendency a thinner choroid correlates with larger retinal leakage areas. CONCLUSIONS Automated algorithms can be used to reliably assess choroidal thickness in eyes with DME. Choroidal thickness was generally reduced in patients with diabetes if DME is present in 1 eye; however, no correlation was found between choroidal/retinal pathologies, suggesting different pathogenetic pathways.

Unsupervised Anomaly Detection with Generative Adversarial Networks to Guide Marker Discovery

Obtaining models that capture imaging markers relevant for disease progression and treatment monitoring is challenging. Models are typically based on large amounts of data with annotated examples of known markers aiming at automating detection. High annotation effort and the limitation to a vocabulary of known markers limit the power of such approaches. Here, we perform unsupervised learning to identify anomalies in imaging data as candidates for markers. We propose AnoGAN, a deep convolutional generative adversarial network to learn a manifold of normal anatomical variability, accompanying a novel anomaly scoring scheme based on the mapping from image space to a latent space. Applied to new data, the model labels anomalies, and scores image patches indicating their fit into the learned distribution. Results on optical coherence tomography images of the retina demonstrate that the approach correctly identifies anomalous images, such as images containing retinal fluid or hyperreflective foci.

Impact of Vitreomacular Adhesion on Ranibizumab Mono- and Combination Therapy for Neovascular Age-Related Macular Degeneration

PURPOSE To investigate the influence of vitreomacular adhesion on the efficacy of pro re nata (PRN) ranibizumab monotherapy and verteporfin photodynamic therapy (PDT) combination therapy for neovascular age-related macular degeneration. DESIGN Post hoc analysis of prospective randomized 12-month multicenter clinical trial data. METHODS PATIENT POPULATION Total of 255 treatment-naïve patients with subfoveal choroidal neovascularization. OBSERVATION PROCEDURE Assessment of the vitreomacular interface on monthly optical coherence tomography with division of patients into the following categories according to continuous 1-year grading: posterior vitreous detachment (n=154), dynamic release of vitreomacular adhesion (n=32), stable vitreomacular adhesion (n=51). MAIN OUTCOME MEASURES Mean best-corrected visual acuity (BCVA) letter and central retinal thickness changes at month 12 in the vitreomacular interface groups. RESULTS Mean BCVA changes at month 12 were +3.5 (posterior vitreous detachment), +4.3 (release of vitreomacular adhesion), and +6.3 (vitreomacular adhesion) in patients receiving monotherapy (P=.767), and +0.1 (posterior vitreous detachment), +6.6 (release of vitreomacular adhesion), and +9.2 (vitreomacular adhesion) in patients receiving combination therapy (P=.009). Mean central retinal thickness changes were -113 μm (posterior vitreous detachment), -89 μm (release of vitreomacular adhesion), and -122 μm (vitreomacular adhesion) in monotherapy (P=.725) and -121 μm (posterior vitreous detachment), -113 μm (release of vitreomacular adhesion), and -113 μm (vitreomacular adhesion) in combination therapy (P=.924). Mean ranibizumab retreatments during 12 months were 4.9 (posterior vitreous detachment), 6.6 (release of vitreomacular adhesion), and 5.3 (vitreomacular adhesion) in monotherapy (P=.018) and 4.7 (posterior vitreous detachment), 5.2 (release of vitreomacular adhesion), and 5.8 (vitreomacular adhesion) in combination therapy (P=.942). CONCLUSION This study adds evidence that the vitreomacular interface status impacts functional outcomes and retreatment requirements. Patients with posterior vitreous detachment achieve acceptable results with fewer injections in PRN monotherapy, but lose potential vision gain with PDT. Patients with other vitreomacular interface configurations may potentially achieve optimized vision outcomes by combination of antiangiogenic treatment and vaso-occlusive PDT.

Influence of vitreomacular adhesion on the development of exudative age-related macular degeneration: 4-year results of a longitudinal study.

Purpose: To investigate the influence of vitreomacular adhesion (VMA) on development of choroidal neovascularization (CNV) in eyes with age-related macular degeneration. Methods: In a prospective study, patients with Age-Related Eye Disease Study Category IV age-related macular degeneration underwent standardized examinations, including optical coherence tomography and fluorescein angiography every 3 months for 4 years. Vitreomacular adhesion was evaluated using time- and spectral-domain optical coherence tomography. Development of CNV was detected using fluorescein angiography and optical coherence tomography. Incidences of CNV were compared concerning the presence or absence of VMA. Results: Forty-nine patients were available for follow-up according to protocol. Vitreomacular adhesion was present at baseline in 18% (9 of 49) and absent in 82% (40 of 49) of patients. Thirty-seven percent of patients (18 of 49) developed exudative changes during the observation period. In patients with preexisting VMA, de novo development of CNV occurred in 33% (3 of 9). In patients without VMA, 38% developed CNV (15 of 40). Mean interval from baseline to disease progression was 20 ± 19 months in patients with VMA and 22 ± 13 months in patients without VMA. There was no significant difference between the groups regarding rate of CNV development or time to disease progression (P = 0.64). Conclusion: No significant influence of VMA on the development of exudative age-related macular degeneration could be found during a 4-year prospective observation of a high-risk cohort.

Correlation of 3-Dimensionally Quantified Intraretinal and Subretinal Fluid With Visual Acuity in Neovascular Age-Related Macular Degeneration

IMPORTANCE Robust and sensitive imaging biomarkers for visual function are an unmet medical need in the management of neovascular age-related macular degeneration. OBJECTIVE To determine the correlation of 3-dimensionally quantified intraretinal cystoid fluid (IRC) and subretinal fluid (SRF) with best-corrected visual acuity (BCVA) in treatment-naive neovascular age-related macular degeneration and during antiangiogenic therapy. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study between November 2009 and November 2011 at an institutional referral center and reading center of patients with treatment-naive subfoveal choroidal neovascularization receiving intravitreal ranibizumab or aflibercept over 12 months. All individual IRC and SRF lesions were manually delineated on each of the 128 B-scan sections of spectral-domain optical coherence tomographic volume scans at baseline and months 1, 6, and 12. Correlations were computed between the IRC and SRF parameters and the baseline BCVA, final BCVA, and BCVA change. A systematic parameter search was conducted to detect annotation-derived variables with best predictive value. An exponential model for BCVA change balancing for the ceiling effect was constructed. MAIN OUTCOMES AND MEASURES Goodness of fit of correlations between the IRC and SRF parameters and the baseline BCVA, final BCVA, and BCVA change. RESULTS Thirty-eight patients were included (25 female, 13 male; mean [SD] age at enrollment, 78.49 [8.23] years; mean [SD] BCVA score at baseline, 54 [16] Early Treatment Diabetic Retinopathy Study letters [Snellen equivalent approximately 20/160], with a gain to 63 [19] letters [Snellen equivalent approximately 20/100] at month 12). A total of 19,456 scans underwent complete quantification of IRC and SRF. The best correlation with BCVA at baseline was achieved using a coverage-based, foveal area-weighted IRC parameter (R2 = 0.59; P < .001). The same baseline parameter also predicted BCVA at 12 months (R2 = 0.21; P = .003). The BCVA gain correlated with IRC decrease in the exponential model (R2 = 0.40; P < .001) and linear model (R2 = 0.25; P = .002). No robust associations were found between SRF and baseline BCVA (R2 = 0.06; P = .14) or BCVA change (R2 = 0.14; P = .02). CONCLUSIONS AND RELEVANCE In this proof-of-principle study, IRC-derived morphometric variables correlated well with treatment-naive BCVA and BCVA outcomes in antiangiogenic therapy. While IRC reduction was associated with BCVA gains, some IRC-mediated neurosensory damage remained permanent.

Morphology and Visual Acuity in Aflibercept and Ranibizumab Therapy for Neovascular Age-Related Macular Degeneration in the VIEW Trials.

PURPOSE To compare the efficacy of intravitreal aflibercept and ranibizumab on the exudative activity of neovascular age-related macular degeneration (nAMD) using optical coherence tomography (OCT) and to correlate morphologic findings with visual acuity (VA) outcomes. DESIGN Post hoc analysis of the prospective VIEW trials. PARTICIPANTS Data of 1815 patients randomized to 0.5 mg ranibizumab every 4 weeks (Q4wks), 2 mg aflibercept Q4wks, or 2 mg aflibercept every 8 weeks (Q8wks). METHODS Standardized OCT evaluation was performed by masked reading centers for the presence of intraretinal cystoid fluid (IRC), subretinal fluid (SRF), and pigment epithelial detachment (PED). Rates of feature resolution were compared between drugs and regimen. Associations between morphologic features and VA were analyzed using multivariate modeling. MAIN OUTCOME MEASURES Resolution rates of IRC, SRF, and PED, and associations between morphology and VA. RESULTS At baseline, the proportions of eyes with IRC, SRF, and PED were balanced between the aflibercept and ranibizumab groups. At week 12, IRC resolved in 50% of eyes with both agents. Subretinal fluid resolved in 70% of pooled aflibercept-treated eyes and in 59% of ranibizumab-treated eyes, and PED resolved in 29% and 24% of pooled aflibercept-treated eyes and ranibizumab-treated eyes, respectively. At week 52, IRC resolved in 57% (aflibercept Q4wks), 50% (aflibercept Q8wks), and 52% (ranibizumab) of patients; SRF resolved in 75% (both aflibercept Q4wks/Q8wks) and 66% (ranibizumab) of patients; and PED resolved in 40% (aflibercept Q4wks), 34% (aflibercept Q8wks), and 28% (ranibizumab) of patients. During fixed dosing (weeks 12-52) all exudative features showed synchronized fluctuations after treatment-free visits in the Q8wks aflibercept regimen. During pro re nata dosing (weeks 52-96), greater proportions of patients showed recurrent fluid in all treatment arms. Presence of IRC was generally associated with lower VA at baseline, which translated into poorer final VA outcomes. CONCLUSIONS Fluid resolution in all compartments was consistently greater for aflibercept Q4wks than for aflibercept Q8wks and ranibizumab. At week 52, Q8wks aflibercept-treated eyes were, on average, as dry as or drier than with ranibizumab despite the extended treatment interval. Independent of agent or regimen, preexisting morphologic features of the retina at baseline markedly influenced VA outcomes.