Effect of subthreshold nanosecond laser on retinal structure and function in intermediate age-related macular degeneration.

BACKGROUND: Subthreshold nanosecond laser (SNL) treatment has been studied as a potential intervention in intermediate age-related macular degeneration (iAMD). This study investigated the effect of 100 SNL treatment spots on retinal structure and function. METHODS: A prospective single-arm interventional pilot study. SNL treatment was delivered as 100 spots around the retinal vascular arcades of the study eye (worst visual acuity) in a single session in subjects with iAMD. Multimodal retinal imaging and dark-adapted chromatic perimetry were performed at baseline and at 0.5, 3, 6 and 12 months post treatment. Post treatment changes in best corrected visual acuity (BCVA), retinal thickness, relative ellipsoid zone reflectivity (rEZR) and rod-mediated functional parameters were compared to baseline. RESULTS: Twenty-one subjects with iAMD were recruited. SNL treatment was associated with an increase in retinal thickness (p = 0.008) and decrease in rEZR (p < 0.001) at 2 weeks post laser. Recovery of retinal thickness and rEZR was observed at the 3-month post laser visit. A gradual improvement in BCVA was observed after laser treatment. The mean change in BCVA between baseline and 12-month visit was +1.9 ± 3.3 letters for the SNL treated eyes, compared to -0.4 ± 3.0 letters for the fellow eyes (p = 0.027). Rod-mediated function improved at 3 months post laser (p < 0.001) and returned to the baseline levels at 12 months post treatment. CONCLUSIONS: A single treatment with 100 SNL spots causes a short-term change in retinal structure and improvement in retinal function that are apparent at 3 months post treatment.

Conversion from Intermediate Age-Related Macular Degeneration to Geographic Atrophy in a Proxima B Subcohort Using a Multimodal Approach.

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.

Assessment of Exudative Activity of Choroidal Neovascularization in Age-Related Macular Degeneration by OCT Angiography.

PURPOSE: Based on exudative activity, choroidal neovascularization (CNV) in age-related macular degeneration (AMD) can be classified as "active" aCNV, pretherapied "silent" sCNV (i.e., a treatment-free interval >12 weeks), or treatment-naïve "quiescent" qCNV. We evaluated the qualitative and quantitative optical coherence tomography angiography (OCTA) features of these CNV subgroups. METHODS: The presence of small-caliber vessels, peripheral arcades, and a -perilesional OCTA signal attenuation as well as values for vessel length, density, and branching index were evaluated for each CNV network in a 6 × 6 mm OCTA scan pattern. RESULTS: Fifty-one eyes of 51 patients with AMD (age 75.9 ± 7.5 years; 20 males [39.2%]) were included. The qCNV subgroup (n = 8) showed the highest prevalence of qualitative and quantitative values for OCTA activity criteria, reaching significance with regard to small-caliber vessels (p = 0.003), peripheral arcades (p = 0.039), vessel length (p = 0.020), and branching index (p < 0.001) when compared to the aCNV (n = 32) and sCNV (n = 11) subgroups. Qualitative criteria were inversely associated with the number of previous anti-VEGF injections (each p < 0.03), while quantitative metrics also suggested lower values. CONCLUSIONS: These findings suggest that OCTA may be supportive in the phenotypical differentiation of CNV lesions secondary to AMD, while the assessed structural changes appeared to be more indicative of previously administered anti-VEGF therapy than current exudative activity.

Correction to: Visual impairment and blindness in institutionalized elderly in Germany.

The original version of this article inadvertently contained a mistake. Authors incorrectly listed in PDF version while correctly presented in the html version.

Visual impairment and blindness in institutionalized elderly in Germany.

PURPOSE: To determine the prevalence of and identify factors associated with visual impairment and blindness in institutionalized elderly in Germany. METHODS: In this prospective multicenter cross-sectional study, ophthalmic health care need and provision were investigated in institutionalized elderly in 32 nursing homes in Germany. All participants underwent a standardized examination including medical and ocular history, refraction, visual acuity testing, tonometry, biomicroscopy, and dilated funduscopy. A standardized questionnaire was used to identify factors associated with eye healthcare utilization, visual impairment and/or blindness. RESULTS: Visual acuity of 566 (94.3%; 413 women and 153 men) of a total of 600 institutionalized elderly was determined. Mean age of the included patients was 82.9 years (± 9.8). Of all participants, 30 (5.3%; 95% CI 3.4-7.2%) were blind and 106 (18.7%; 95% CI 15.5-21.9%) were moderately or severely visually impaired according to the World Health Organization definition. The 136 blind and moderately or severely visually impaired participants were older (OR, Odds Ratio = 1.1, 95% CI 1.0-1.1; p < 0.001), and more likely to have reduced mobility (OR = 12.6, 95% CI 2.8-57.6; p = 0.001). CONCLUSION: A high proportion of blindness and visual impairment was found amongst nursing home residents. Age and reduced mobility were factors associated with an increased likelihood of blindness and visual impairment. Any surveys of blindness and visual impairment excluding nursing homes may considerably underestimate the prevalence of visual impairment and blindness.

PROGNOSTIC VALUE OF SHAPE-DESCRIPTIVE FACTORS FOR THE PROGRESSION OF GEOGRAPHIC ATROPHY SECONDARY TO AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To systematically compare the prognostic value of multiple shape-descriptive factors in the natural course of the disease. METHODS: A total of 296 eyes of 201 patients (female patients 130; mean age: 72.2 ± 13.08 years) with a median follow-up of 2.38 years from 2 prospective, noninterventional natural history studies (Fundus-Autofluorescence-in-Age-related-Macular-Degeneration [clinicaltrials.gov identifier NCT00393692], Directional-Spread-in-Geographic-Atrophy [NCT02051998]) were included in the analysis. Serial fundus autofluorescence images were annotated using semiautomated image analysis software to determine the lesion area, circularity, perimeter, and caliper diameters. These variables and the fundus autofluorescence phenotype were evaluated for prediction of the future square root progression rates using linear mixed-effects models. RESULTS: For the combined model, leave-one-out cross validation on patient level (Scenario 1: previously unknown patient) resulted in a goodness-to-fit (R value) of 0.244 and leave-one-out cross validation on visit level (Scenario 2: previous observation of the patient) in a R value of 0.391. This indicated that shape-descriptive factors could explain 24.4% of the variance in geographic atrophy progression in previously unknown patients and 39.1% in patients with previous observation. CONCLUSION: These findings confirm the relevance of shape-descriptive factors and previous progression as prognostic variables for geographic atrophy progression. However, a substantial part of the remaining variation in geographic atrophy progression seems to depend on other variables, some of which are visible in optical coherence tomography.

[Dry Age-Related Macular Degeneration - Epidemiology and Classification]. / Trockene altersabhängige Makuladegeneration ­ Epidemiologie und Klassifikation.

Age-related macular degeneration (AMD) is clinically divided into early and late stages. The term "dry" AMD is widely used when there are no "exudative" changes in the ocular fundus. There are numerous studies on the epidemiology of AMD. Most studies differentiate between early and late forms of AMD, but without further differentiation of the "dry" late form. In addition, different studies may employ different classifications of AMD, which inevitably leads to deviations in epidemiological data on AMD. New classification systems take into account microstructural changes that can be detected by high resolution in vivo imaging of the retina. A new consensus classification of AMD-associated atrophy will allow future studies to be conducted according to uniform definitions.

LONGITUDINAL CHANGE OF OUTER NUCLEAR LAYER AFTER RETINAL PIGMENT EPITHELIAL TEAR SECONDARY TO AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To investigate longitudinal changes of outer nuclear layer (ONL) thickness in patients with retinal pigment epithelium tears secondary to neovascular age-related macular degeneration. METHODS: This is an institutional retrospective interventional case series. Twenty-six eyes of 22 patients with retinal pigment epithelium tears identified between April 2009 and March 2015. The patients underwent intravitreal injection of anti-vascular endothelial growth factor agents as needed. Volume scans of optical coherence tomography at first diagnosis of tear (baseline) and after 12 months were analyzed. Outer nuclear layer was segmented, and average ONL thickness inside the tear area, at the border of the tear, and in areas outside the tear was measured. Change of ONL thickness. We also explored several factors for their association with ONL thinning including tear area, number of treatments, and the duration with persistent subretinal fluid. RESULTS: Thinning of ONL was found in all the investigated areas (P < 0.01, respectively). Among the investigated factors, larger tear area was associated with greater ONL thinning outside the tear area (standardized ß = -0.37, P = 0.030), and younger age was associated with greater ONL thinning inside the tear area (standardized ß = 0.37, P = 0.041). CONCLUSION: After an retinal pigment epithelium tear, thinning of ONL occurs in the area devoid of retinal pigment epithelium and also in adjacent areas. Few factors were predictive for the degree of ONL thinning. These results provide new insight in disease progression of this particular neovascular age-related macular degeneration subphenotype.

Longitudinal Analysis of Drusen Volume in Intermediate Age-Related Macular Degeneration Using Two Spectral-Domain Optical Coherence Tomography Scan Patterns.

PURPOSE: To evaluate two different spectral-domain optical coherence tomography (SD-OCT) scan patterns in eyes with intermediate age-related macular degeneration (AMD) for the longitudinal assessment of drusen volume. METHODS: The data of 38 eyes of 38 AMD patients (age 69.97 ± 6.08 years) were included. The longitudinal drusen volume over 4 years was analyzed by annual SD-OCT raster scanning (field size 20 × 15°). Two raster scan patterns (A/B) differed in the distance between neighboring B-scans (240 vs. 30 µm) and in the number of averaged frames (4 vs. 15). RESULTS: The mean drusen volume at baseline was 0.213 ± 0.100 mm3 (pattern A) and 0.219 ± 0.103 mm3 (pattern B) (p = 0.937). Linear mixed-effect models showed no significant difference for the change within 4 years for both pattern A (p = 0.8) and pattern B (p = 0.8). CONCLUSIONS: The results indicate that the performance of interpolation algorithms may be sufficient to balance for less dense raster scanning with regard to quantification of longitudinal drusen volume, which can be used as a surrogate marker for AMD progression in future clinical trials.

DEVELOPMENT OF INTRARETINAL CYSTOID LESIONS IN EYES WITH INTERMEDIATE AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To evaluate the development of intraretinal cystoid lesions (ICLs) in eyes with intermediate age-related macular degeneration. METHODS: Serial multimodal retinal imaging data of 105 eyes from 87 age-related macular degeneration subjects (median age of 75.0 years) with no late age-related macular degeneration at baseline from the prospective longitudinal natural history "molecular diagnostic of age-related macular degeneration-study" were included. The presence of ICLs-defined as lacunar hyporeflective areas within the neurosensory retina-was determined by spectral-domain optical coherence tomography at Month 24. Both baseline and further follow-up data were additionally evaluated. RESULTS: At Month 24, ICLs were identified in 12 of 105 (11.7%) eyes of which 4 had developed signs of choroidal neovascularization since baseline. Intraretinal cystoid lesions in these four eyes with choroidal neovascularization were mostly found at the level of the outer nuclear layer. Intraretinal cystoid lesions in the remaining 8 eyes occurred mainly at the level of the inner nuclear layer, showed smaller horizontal and vertical dimensions, and were not spatially confined to an increase in retinal thickness. CONCLUSION: The results indicate that ICLs may develop also in the absence of active neovascularization. Distinctive morphologic features and localization of ICLs may be indicative of different underlying pathogenetic mechanisms. If no manifest choroidal neovascularization can be established in the presence of ICLs, close monitoring as well as awareness and self-monitoring seem to be advisable.

Relative Ellipsoid Zone Reflectivity in Macular Telangiectasia Type 2.

Purpose: The relative ellipsoid zone reflectivity (rEZR) has been proposed as an innovative biomarker for photoreceptor integrity. This study evaluates the rEZR in macular telangiectasia type 2 (MacTel) eyes of different disease stages. Methods: The mean rEZR (ratio ellipsoid zone [EZ]/external limiting membrane [ELM] reflectivity [arbitrary units {AUs}], grey level range = 0-1) was analyzed for an entire spectral domain optical coherence tomography volume scan (global) and for each subfield of the Early Treatment Diabetic Retinopathy Study (ETDRS) grid (topographic) in patients with MacTel and controls. MacTel disease severity was classified according to Gass and Blodi. Results: Linear mixed-model analysis of 145 eyes of 74 patients and 50 eyes of 25 controls revealed globally lower, yet not statistically significant, rEZR values in MacTel eyes. Topographically, most pronounced decreases were found in stages 3 and 4/5 for the temporal inner (coefficient estimates [CEs] = -25.4 [-38.2; -12.6] and -34.1 [-48.7; -19.6] AU, both: P < 0.001), the inferior inner (-29.9 [-44.6; -15.6] and -35.3 [-52.1; -18.5] AU, both: P < 0.001), the nasal inner (-21.5 [-35.52; -7.4] and -31.6 [-47.6; -15.6] AU, P = 0,003 and P < 0.001), and in the superior inner subfield of stage 4/5 (-25.0 [-42.0; -7.9] AU, P = 0.004). Conclusions: The rEZR showed association with disease severity and the predilection area of MacTel. Given the current understanding of the pathophysiological concept of MacTel, these findings underscore the value of the rEZR as a potential novel biomarker for outer retinal integrity. Longitudinal studies are demanded to better characterize its value as a biomarker for early photoreceptor alterations and disease progression in MacTel.

Characteristics and Spatial Distribution of Structural Features in Age-Related Macular Degeneration: A MACUSTAR Study Report.

PURPOSE: To report the prevalence and topographic distribution of structural characteristics in study participants with age-related macular degeneration (AMD) and controls in the cross-sectional study part of the MACUSTAR study (ClinicalTrials.gov Identifier: NCT03349801). DESIGN: European, multicenter cohort study. SUBJECTS: Overall, 301 eyes of 301 subjects with early (n = 34), intermediate (n = 168), and late AMD (n = 43), as well as eyes without any AMD features (n = 56). METHODS: In study eyes with intermediate AMD (iAMD), the presence of structural AMD biomarkers, including pigmentary abnormalities (PAs), pigment epithelium detachment (PED), refractile deposits, reticular pseudodrusen (RPD), hyperreflective foci (HRF), incomplete/complete retinal pigment epithelium (RPE), and outer retinal atrophy (i/cRORA), and quiescent choroidal neovascularization (qCNV) was systematically determined in the prospectively acquired multimodal retinal imaging cross-sectional data set of MACUSTAR. Retinal layer thicknesses and the RPE drusen complex (RPEDC) volume were determined for the total study cohort in spectral-domain (SD) OCT imaging using a deep-learning-based algorithm. MAIN OUTCOME MEASURES: Prevalence and topographic distribution of structural iAMD features. RESULTS: A total of 301 study eyes of 301 subjects with a mean (± standard deviation) age of 71.2 ± 7.20 years (63.1% women) were included. Besides large drusen, the most prevalent structural feature in iAMD study eyes were PA (57.1%), followed by HRF (51.8%) and RPD (22.0%). Pigment epithelium detachment lesions were observed in 4.8%, vitelliform lesions in 4.2%, refractile deposits in 3.0%, and qCNV in 2.4%. Direct precursor lesions for manifest retinal atrophy were detected in 10.7% (iRORA) and 4.2% (cRORA) in iAMD eyes. Overall, the highest RPEDC volume with a median of 98.92 × 10-4 mm³ was found in iAMD study eyes. Spatial analysis demonstrated a predominant distribution of RPD in the superior and temporal subfields at a foveal eccentricity of 1.5 to 2 mm, whereas HRF and large drusen had a distinct topographic distribution involving the foveal center. CONCLUSIONS: Detailed knowledge of the prevalence and distribution of structural iAMD biomarkers is vital to identify reliable outcome measure for disease progression. Longitudinal analyses are needed to evaluate their prognostic value for conversion to advanced disease stages. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Reticular Pseudodrusen: Interreader Agreement of Evaluation on OCT Imaging in Age-Related Macular Degeneration.

Purpose: To determine the interreader agreement for reticular pseudodrusen (RPD) assessment on combined infrared reflectance (IR) and OCT imaging in the early stages of age-related macular degeneration across a range of different criteria to define their presence. Design: Interreader agreement study. Participants: Twelve readers from 6 reading centers. Methods: All readers evaluated 100 eyes from individuals with bilateral large drusen for the following: (1) the presence of RPD across a range of different criteria and (2) the number of Stage 2 or 3 RPD lesions (from 0 to ≥ 5 lesions) on an entire OCT volume scan and on a selected OCT B-scan. Supportive information was available from the corresponding IR image. Main Outcome Measures: Interreader agreement, as assessed by Gwet's first-order agreement coefficient (AC1). Results: When evaluating an entire OCT volume scan, there was substantial interreader agreement for the presence of any RPD, any or ≥ 5 Stage 2 or 3 lesions, and ≥ 5 definite lesions on en face IR images corresponding to Stage 2 or 3 lesions (AC1 = 0.60-0.72). On selected OCT B-scans, there was also moderate-to-substantial agreement for the presence of any RPD, any or ≥ 5 Stage 2 or 3 lesions (AC1 = 0.58-0.65) and increasing levels of agreement with increasing RPD stage (AC1 = 0.08, 0.56, 0.78, and 0.99 for the presence of any Stage 1, 2, 3, and 4 lesions, respectively). There was substantial agreement regarding the number of Stage 2 or 3 lesions on an entire OCT volume scan (AC1 = 0.68), but only fair agreement for this evaluation on selected B-scans (AC1 = 0.30). Conclusions: There was generally substantial or near-substantial-but not near-perfect-agreement for assessing the presence of RPD on entire OCT volume scans or selected B-scans across a range of differing RPD criteria. These findings underscore how interreader variability would likely contribute to the variability of findings related to the clinical associations of RPD. The low levels of agreement for assessing RPD number on OCT B-scans underscore the likely challenges of quantifying RPD extent with manual grading. Financial Disclosures: Proprietary or commercial disclosure may be found after the references.

Axitinib modulates hypoxia-induced blood-retina barrier permeability and expression of growth factors.

This study investigates the effects of the multikinase inhibitor axitinib on the expression of vascular endothelial growth factor (VEGF) receptors 1/2 (VEGFR-1/2) and platelet-derived growth factor (PDGF) receptor beta (PDGFR-ß), hypoxia-induced increased tissue permeability, occludin, zonula occludens protein 1 (ZO-1), VEGF-A, and PDGF expression of human retinal pigment epithelial (RPE) cells and human umbilical vein endothelial cells (HUVECs). Primary human RPE cells and HUVECs were exposed to hypoxia and axitinib. Viability of cells, tissue permeability, and expression of occludin, ZO-1, VEGF, PDGF, VEGFR-1/2 and PDGFR-ß, and their mRNAs, were investigated by reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, western blotting, and immunohistochemistry. Treatment with axitinib reduced expression of VEGFR-1/2 and PDGFR-ß. Hypoxia decreased cell viability, occludin, and ZO-1 expression and increased tissue permeability, expression, and secretion of VEGF and PDGF. Axitinib significantly reduced hypoxia-induced effects on HUVEC and RPE cells. Our in vitro results suggest that axitinib may have promising properties as a potential treatment for diabetic macular edema.

Inhibitory activity of ranibizumab, sorafenib, and pazopanib on light-induced overexpression of platelet-derived growth factor and vascular endothelial growth factor A and the vascular endothelial growth factor A receptors 1 and 2 and neuropilin 1 and 2.

BACKGROUND: Cumulative light exposure is significantly associated with progression of age-related macular degeneration. Growth factors and growth factor receptor signaling are known to have a substantial impact on the development of age-related macular degeneration. This study explored the effects of ranibizumab, sorafenib, and pazopanib on vascular endothelial growth factor A (VEGF) receptors 1 and 2 and neuropilin 1 and 2 expression in human retinal pigment epithelial cells. In addition, their effects on light-induced overexpression of VEGF and platelet-derived growth factor were investigated. METHODS: Primary human retinal pigment epithelial cells were exposed to white light and then treated with ranibizumab (0.125 mg/mL), sorafenib (1 µg/mL), or pazopanib (1 µg/mL). Viability of cells, expression of VEGF receptors 1 and 2 and neuropilin 1 and 2 and their mRNA, and secretion of VEGF and platelet-derived growth factor were investigated by reverse transcription-polymerase chain reactions, immunohistochemistry, and enzyme-linked immunosorbent assays. RESULTS: Treatment with sorafenib or pazopanib reduced the expression of VEGF receptors 1 and 2 and neuropilin 1, and sorafenib also reduced neuropilin 2. Light exposure decreased cell viability and increased expression and secretion of VEGF and platelet-derived growth factor. Sorafenib and pazopanib significantly reduced light-induced overexpression and secretion of VEGF and platelet-derived growth factor. Ranibizumab reduced secreted VEGF in cell culture supernatants only. CONCLUSION: Our in vitro results suggest that multikinase inhibitors have promising properties as a potential antiangiogenic treatment for age-related macular degeneration.

Natural History of the Relative Ellipsoid Zone Reflectivity in Age-Related Macular Degeneration.

PURPOSE: Relative ellipsoid zone reflectivity (rEZR) has been reported to be reduced in intermediate age-related macular degeneration (iAMD). However, longitudinal changes in rEZR remain unknown. This study investigated the natural history of rEZR in iAMD and its association with risk factors for disease progression, including the presence or extent of drusen volume, reticular pseudodrusen (RPD), and pigmentary abnormalities (PAs). DESIGN: Longitudinal observational study. PARTICIPANTS: Subjects with bilateral large drusen. METHODS: Spectral-domain (SD) OCT images of both eyes from each participant were obtained every 6 months for 3 years. Using an automated rEZR determination approach, the average rEZR of the central 20° macula was determined for each SD-OCT volume scan. Linear mixed models were used to determine the rate of change in rEZR with age (using the cross-sectional data at baseline) and over time (longitudinal data) and the interactions between the rate of rEZR changes with AMD risk factors at baseline. MAIN OUTCOME MEASURES: Relative ellipsoid zone reflectivity and its rate of change with age and over time. RESULTS: A total of 280 eyes from 140 individuals with bilateral large drusen were included in this study. Cross-sectional data showed that rEZR reduced with increasing age (-8.4 arbitrary units [AUs] per decade; 95% confidence interval [CI], -11.5 to -5.2; P < 0.001). Longitudinal data showed that, on average, rEZR declined at a rate of -2.1 AU per year (95% CI, -2.6 to -1.6 AU per year; P < 0.001). Larger RPD area (P = 0.042) at baseline was associated with a faster rate of rEZR decline over time, whereas the presence of PAs and the drusen volume at baseline showed no significant association with rEZR decline over time (P = 0.068 and P = 0.529, respectively). CONCLUSIONS: The rEZR significantly reduces over 3 years in subjects with iAMD, and both the presence and increasing extent of coexistent RPD at baseline are associated with a faster rate of decline. These findings warrant further studies to understand the value of rEZR as a biomarker of AMD progression.

Short-term real-world outcomes following intravitreal brolucizumab for neovascular AMD: SHIFT study.

BACKGROUND: Brolucizumab has recently been approved in Europe as a novel treatment for patients with neovascular age-related macular degeneration (nAMD). We report on early experiences with real-world outcomes of switch to brolucizumab therapy in previously anti-vascular endothelial growth factor (anti-VEGF)-treated patients. METHODS: Patients with recalcitrant nAMD were switched to brolucizumab therapy. Functional and structural parameters 4 weeks after first brolucizumab injection were evaluated including best-corrected visual acuity (BCVA (logMAR)), foveal centre point (FCP (µm)), central subfield retinal thickness (CSRT (µm)) and macular volume (mm³). RESULTS: Sixty-three eyes of 57 patients with nAMD (52.6% females) with a mean (±SD) age of 79.5±6.7 years were included. Mean change of BCVA was 0.03±0.14 logMAR (p=0.115). Significant reductions were recorded for FCP with a mean (±SD) change of -66.81±72.63 µm, -66.76±60.71 µm for CSRT and -0.27±0.24 mm³ for macular volume (all p<0.001). Intraocular inflammation was observed in seven eyes of seven patients, including one case of retinal vasculitis. CONCLUSIONS: The results of the SHIFT study indicate that switch to brolucizumab may represent a treatment option in patients with nAMD poorly responsive to other anti-VEGF agents. Further long-term analyses appear prudent to assess efficacy and safety of brolucizumab in a routine clinical setting.

Relative ellipsoid zone reflectivity and its association with disease severity in age-related macular degeneration: a MACUSTAR study report.

Quantification of the relative ellipsoid zone reflectivity (rEZR) might be a structural surrogate parameter for an early disease progression in the context of age-related macular degeneration (AMD). Within the European multicenter, cross-sectional MACUSTAR study, we have devised an automatic approach to determine the mean rEZR [arbitrary units, AU] at two independent visits in SD-OCT volume scans in study participants. Linear mixed-effects models were applied to analyze the association of AMD stage and AMD associated high-risk features including presence of pigmentary abnormalities, reticular pseudodrusen (RPD), volume of the retinal-pigment-epithelial-drusenoid-complex (RPEDC) with the rEZR. Intra-class correlation coefficients (ICC) were determined for rEZR reliability analysis. Within the overall study cohort (301 participants), we could observe decreased rEZR values (coefficient estimate ± standard error) of - 8.05 ± 2.44 AU (p = 0.0011) in the intermediate and of - 22.35 ± 3.28 AU (p < 0.0001) in the late AMD group. RPD presence was significantly associated with the rEZR in iAMD eyes (- 6.49 ± 3.14 AU; p = 0.0403), while there was a good ICC of 0.846 (95% confidence interval: 0.809; 0.876) in the overall study cohort. This study showed an association of rEZR with increasing disease severity and the presence of iAMD high-risk features. Further studies are necessary to evaluate the rEZR's value as a novel biomarker for AMD and disease progression.

Intersession Repeatability of Structural Biomarkers in Early and Intermediate Age-Related Macular Degeneration: A MACUSTAR Study Report.

Purpose: To analyze the intersession repeatability of structural biomarkers in eyes with early and intermediate age-related macular degeneration (iAMD) within the cross-sectional part of the observational multicenter MACUSTAR study. Methods: Certified site personnel obtained multimodal imaging data at two visits (38 ± 20 [mean ± standard deviation] days apart), including spectral-domain optical coherence tomography (SD-OCT). One junior reader performed systematic and blinded grading at the central reading center, followed by senior reader review. Structural biomarkers included maximum drusen size classification (>63 to ≤125 µm vs. >125 µm), presence of large pigment epithelium detachments (PEDs), reticular pseudodrusen (RPD), vitelliform lesions, and refractile deposits. Intrasession variability was assessed using Cohen's κ statistics. Results: At the first visit, 202 study eyes of 202 participants were graded as manifesting with either early (n = 34) or intermediate (n = 168) AMD. Grading of imaging data between visits revealed perfect agreement for the maximum drusen size classification (κ = 0.817; 95% confidence interval, 0.70-0.94). In iAMD eyes, perfect to substantial agreement was determined for the presence of large PEDs (0.87; 0.69-1.00) and RPD (0.752; 0.63-0.87), while intersession agreement was lower for the presence of vitelliform lesions (0.649; 0.39-0.65) and refractile deposits (0.342; -0.029-0.713), respectively. Conclusions: Multimodal retinal imaging analysis between sessions showed a higher repeatability for structural biomarkers with predefined cutoff values than purely qualitative defined parameters. Translational Relevance: A high repeatability of retinal imaging biomarkers will be important to implement automatic grading approaches and to establish robust and meaningful structural clinical endpoints for future interventional clinical trials in patients with iAMD.

Comparability of automated drusen volume measurements in age-related macular degeneration: a MACUSTAR study report.

Drusen are hallmarks of early and intermediate age-related macular degeneration (AMD) but their quantification remains a challenge. We compared automated drusen volume measurements between different OCT devices. We included 380 eyes from 200 individuals with bilateral intermediate (iAMD, n = 126), early (eAMD, n = 25) or no AMD (n = 49) from the MACUSTAR study. We assessed OCT scans from Cirrus (200 × 200 macular cube, 6 × 6 mm; Zeiss Meditec, CA) and Spectralis (20° × 20°, 25 B-scans; 30° × 25°, 241 B-scans; Heidelberg Engineering, Germany) devices. Sensitivity and specificity for drusen detection and differences between modalities were assessed with intra-class correlation coefficients (ICCs) and mean difference in a 5 mm diameter fovea-centered circle. Specificity was > 90% in the three modalities. In eAMD, we observed highest sensitivity in the denser Spectralis scan (68.1). The two different Spectralis modalities showed a significantly higher agreement in quantifying drusen volume in iAMD (ICC 0.993 [0.991-0.994]) than the dense Spectralis with Cirrus scan (ICC 0.807 [0.757-0.847]). Formulae for drusen volume conversion in iAMD between the two devices are provided. Automated drusen volume measures are not interchangeable between devices and softwares and need to be interpreted with the used imaging devices and software in mind. Accounting for systematic difference between methods increases comparability and conversion formulae are provided. Less dense scans did not affect drusen volume measurements in iAMD but decreased sensitivity for medium drusen in eAMD.Trial registration: ClinicalTrials.gov NCT03349801. Registered on 22 November 2017.