Dilated retinal large vessels and capillaries associated with diabetic macular edema and photoreceptor loss respectively.

PURPOSE: Previously, we measured retinal large vessels and capillaries separately on optical coherence tomography angiography (OCTA). In the present study, we aim to evaluate the role of these parameters in association to diabetic macular edema (DME) and ellipsoid zone disruption (EZD). METHODS: In this cross-sectional study, 54 eyes from 31 patients (10 females, 31 Asians) with severe non-proliferative diabetic retinopathy (25 eyes) or proliferative diabetic retinopathy (PDR, 29 eyes) were enrolled. All eyes underwent 3 × 3 mm OCTA scans centered on the fovea. Perfusion density (PD), vessel length density (VLD), and vessel diameter index (VDI) were calculated for retinal large vessels and superficial capillaries separately. Other OCTA findings included suspended scattering particles in motion (SSPiM), number of microaneurysms (MA) in all retinal layers, and the area of foveal avascular zone (FAZ) of superficial capillary plexus. DME and EZD were evaluated on B-scans. Both univariate and multivariate analysis were performed. RESULTS: Of the 54 study eyes, 31 (57%) had DME and 21 (40%) had EZD. Multivariate regression model showed that PDR (ß = 27.8, 95% confidence interval (CI): 2.7-282.8, p = 0.005), more MA (ß = 2.5, 95% CI: 1.3-4.5, p = 0.003), and increased VDI of larger vessels (ß = 1.9, 95% CI: 1.0-3.5, p = 0.047) were risk factors for DME. As for EZD, presence of SSPiM (ß = 5.5, 95% CI: 1.2-26.1, p = 0.032) and increased VDI of capillaries (ß = 3.9, 95% CI: 1.1-13.8, p = 0.034) were risk factors. CONCLUSIONS: In eyes with diabetic retinopathy, dilation of retinal larger vessels was associated with macular edema, while dilation of retinal capillaries was associated with ellipsoid zone disruption.

Spectral-Domain OCT Analysis of Risk Factors for Macular Atrophy Development in the HARBOR Study for Neovascular Age-Related Macular Degeneration.

PURPOSE: To identify baseline risk factors for macular atrophy (MA) development in HARBOR via a longitudinal assessment of monthly spectral-domain (SD)-OCT scans. Previous analyses of MA in HARBOR examined data from color fundus photography (CFP) and fluorescein angiography (FA). DESIGN: Retrospective, post hoc analysis of SD-OCT images from HARBOR (ClinicalTrials.gov identifier, NCT00891735), a phase 3, multicenter, prospective, randomized, double-blind, active treatment-controlled clinical trial. PARTICIPANTS: Patients (N = 1097) with subfoveal choroidal neovascularization secondary to neovascular age-related macular degeneration (nAMD) treated with intravitreal ranibizumab 0.5 mg monthly (n = 275), 0.5 mg pro re nata (PRN) after 3 loading doses (n = 275), 2.0 mg monthly (n = 274), or 2.0 mg PRN (n = 273). METHODS: Evaluable SD-OCT macular cube scans from patients with 24 months of follow-up (N = 941) were examined monthly from baseline to month 24 by masked reading center-trained graders. Atrophy diagnosis criteria were consistent with those proposed by the Classification of Atrophy Meetings (CAM) group: hypertransmission of light into the choroid, loss of retinal pigment epithelium, and loss of outer retinal layers. Multivariable proportional hazards regression was performed for time to atrophy development. MAIN OUTCOME MEASURES: Risk factors for MA as determined by time to MA development over 24 months of treatment. RESULTS: Baseline risk factors for MA were confirmed from prior analyses that used CFP and FA data: absence of subretinal fluid, presence of intraretinal cysts, presence of Type 3 neovascularization, and presence of atrophy in the fellow eye. This analysis of SD-OCT data identified new baseline risk factors for MA: higher central drusen volume, lower choroidal thickness, presence of nascent atrophy, presence of reticular pseudodrusen, and increased central foveal thickness. Ranibizumab treatment regimen and dose level were not found to be risk factors for MA development. CONCLUSIONS: In this analysis of a major nAMD trial using CAM atrophy criteria, new baseline risk factors for MA development were identified using an SD-OCT dataset. Risk factors for MA development identified by prior analyses were confirmed. Monthly treatment with ranibizumab 0.5 mg was not found to be a risk factor for MA development over 24 months.

Near-Infrared Reflectance Imaging for Quantification of Atrophy Associated with Age-Related Macular Degeneration.

PURPOSE: To compare measurements of area of geographic atrophy (GA) in dry age-related macular degeneration (AMD) obtained by fundus autofluorescence (FAF) to those obtained by near-infrared reflectance (NIR). DESIGN: Interrater reliability analysis. METHODS: Ninety-seven confocal NIR images (Heidelberg HRA + Spectralis) and FAF images from 97 patients/eyes with GA with dry AMD were collected retrospectively from existing anonymized Doheny Image Reading Center datasets. Two masked reading center graders (N.S., J.S.) independently and blindly performed manual segmentation of the GA lesions on each NIR and FAF image using GNU Image Manipulation Program software (version 2.8.22). GA on NIR/FAF images was defined in accordance to recently published Classification of Atrophy Meeting criteria as sharply demarcated hyperreflective regions ≥250 µm in diameter. The difference and point-to-point correspondence between gradings in GA area measurements between NIR and FAF were assessed by mean difference, overlap ratio, and Dice similarity coefficient. RESULTS: Among the 97 eyes with dry AMD, the mean GA area was 7.62 ± 7.77 mm2 from FAF images and 7.65 ± 7.83 mm2 from NIR, with a mean nonsignificant difference of 0.31 ± 0.55 mm2 (2-tailed t test, P = .65). The overlap ratio in the segmented GA lesion between modalities was 0.84 ± 0.28 with a Dice similarity coefficient of 0.87 ± 0.27. Intermodal reliability was high (intraclass correlation coefficient = 0.998, P < .01). Of note, in 5 cases (5.2%), the GA lesion could be identified on the FAF image but not on the NIR image, translating into a sensitivity of 94.8%. CONCLUSIONS: GA lesions in dry AMD can be identified and quantified reliably using NIR images in many cases, though eyes with a thin choroid resulting in isoreflective GA lesions may be challenging. NIR imaging is comfortable for patients and is commonly obtained along with OCT, and therefore NIR-based GA assessment may be a useful surrogate in clinical settings.

Spectral-Domain OCT-Based Prevalence and Progression of Macular Atrophy in the HARBOR Study for Neovascular Age-Related Macular Degeneration.

PURPOSE: Previous studies of macular atrophy (MA) in HARBOR analyzed color fundus photography and fluorescein angiography image data. This study performed a longitudinal assessment of monthly spectral-domain (SD) OCT scans to determine MA prevalence, incidence, and progression in HARBOR. DESIGN: Post hoc analysis of SD OCT images from HARBOR (ClincalTrials.gov identifier, NCT00891735), a phase 3 multicenter, prospective, randomized, double-blind, active treatment-controlled clinical trial. PARTICIPANTS: Patients (n = 1097) with subfoveal choroidal neovascularization secondary to neovascular age-related macular degeneration (nAMD) treated with ranibizumab 0.5 mg monthly (n = 275), 0.5 mg pro re nata (PRN) after 3 loading doses (n = 275), 2.0 mg monthly (n = 274), or 2.0 mg PRN (n = 273). METHODS: Evaluable SD OCT macular cube scans from patients with 24 months of follow-up (N = 941) were examined by masked reading center-trained graders monthly from baseline to month 24. Atrophy diagnosis criteria were consistent with those proposed by the Classification of Atrophy Meetings (CAM) group: hypertransmission of light into the choroid, retinal pigment epithelium loss, and loss of outer retinal layers. Macular atrophy was considered Definite if all 3 criteria were met and Questionable if 2 were met. Study arms were compared for time to MA detection (log-rank test) and enlargement rates (time × arm interaction test). MAIN OUTCOME MEASURES: Prevalence, incidence, and enlargement rates of MA. RESULTS: At baseline, imbalance in MA rates across ranibizumab arms was evident (0.5 mg monthly, 19.1%; 0.5 mg PRN, 16.1%; 2.0 mg monthly, 10.1%; 2.0 mg PRN, 10.5%). At month 24, new MA development rates in eyes without baseline MA were similar between ranibizumab doses (0.5 mg, 25.9%; 2.0 mg, 25.4%) and treatment regimens (monthly, 26.4%; PRN, 25.0%). No significant differences in enlargement rate of new atrophy area (P = 0.479, square-root transformed) or time to detection of new MA (P = 0.997) were evident among study arms. CONCLUSIONS: In this analysis of a major nAMD trial using CAM atrophy criteria, no differences were observed in incidence or progression rates of new MA among study arms, ranibizumab doses, or treatment regimens. Monthly versus PRN treatment did not influence MA incidence or progression.

OCT Risk Factors for Development of Late Age-Related Macular Degeneration in the Fellow Eyes of Patients Enrolled in the HARBOR Study.

PURPOSE: To evaluate the relationship between OCT features and progression to late age related-macular degeneration (AMD) in the fellow eyes of patients enrolled in the Study of Ranibizumab Administered Monthly or on an As-needed Basis in Patients With Subfoveal Neovascular AMD (HARBOR) (ClinicalTrials.gov identifier, NCT00891735). DESIGN: Post hoc analysis of a phase 3 multicenter, prospective, randomized, double-masked, active treatment-controlled clinical trial. PARTICIPANTS: Evaluable patients (n = 501) with macular neovascularization (MNV) secondary to neovascular AMD and early or intermediate AMD in the fellow eye. METHODS: Volume OCT scans from 501 fellow eyes of 501 patients with MNV were reviewed. Baseline OCT features that were assessed included intraretinal hypereflective foci (IHRF), hyporeflective foci (hRF) within drusenoid lesions (DLs), subretinal drusenoid deposits (SDDs), and drusen volume (DV) of 0.03 mm3 or more. OCT images obtained at months 6, 12, 18, and 24 were graded by masked graders for late AMD (defined as MNV, complete retinal pigment epithelium and photoreceptor atrophy [cRORA], or both). Participant demographic characteristics (age, gender, and smoke exposure) and baseline OCT features were correlated with progression to late AMD. MAIN OUTCOME MEASURES: Incidence of late AMD, hazard ratio (HR) for demographics, and OCT risk factors. RESULTS: At month 24, 33.13% of eyes (166/501) demonstrated late AMD: 20.96% (105/501) demonstrated cRORA, whereas 12.18% (61/501) demonstrated MNV. Baseline demographic factors were not associated significantly with development of late AMD, whereas significant associations were identified for all OCT features. Intraretinal hypereflective foci had an HR of 5.21 (95% confidence interval [CI], 3.29-8.26), hRF within DLs had an HR of 2.42 (95% CI, 1.74-3.38), SDD had an HR of 1.95 (95% CI, 1.34-2.82), and DV of 0.03 mm3 or more had an HR of 1.46 (95% CI, 1.03-2.07). The correlation remained significant when considering only the progression to cRORA and MNV alone, except for DV, which was not associated significantly with progression to MNV. CONCLUSIONS: We confirmed that 4 previously reported OCT risk factors were associated with progression to late AMD in the fellow eyes of patients newly diagnosed with MNV. Although outcomes of more than 2 years were not evaluated, these findings may help to identify high-risk AMD patients.

Repeatability and Reproducibility of Quantification of Superficial Peri-papillary Capillaries by four Different Optical Coherence Tomography Angiography Devices.

This study was performed to test the repeatability and reproducibility of measurements of peri-papillary capillaries from four optical coherence tomography angiography (OCTA) devices. 109 healthy eyes were imaged with four OCTA devices (Spectralis, Optovue, Triton and Cirrus). A 3 × 3 mm scan pattern centered on the disc was repeated twice by each device. En face images of superficial capillary plexus were screened and processed for calculation. Vessel length density (VLD) was calculated on four equally divided parts of a ring between two concentric circles manually centered on the disc. General linear model (GLM) was used to test the impact of device and location on VLD. Intraclass correlation coefficient (ICC) of VLD between repeated scans was calculated. Of 218 acquisitions, 36%, 92%, 76% and 88% were eligible for analysis from Spectralis, Optovue, Triton and Cirrus, respectively. ICC was 0.94, 0.90, 0.84 and 0.87 for the four devices. GLM showed measurements significantly varied among devices (P < 0.001) and locations (P < 0.001). Pairwise comparison showed Triton = Spectralis >Optovue >Cirrus, and temporal = nasal >superior = inferior in measuring capillary VLD. This study revealed the repeatability of measuring peri-papillary capillaries was high for all four devices, while the reproducibility among the machines was unfavorable.

Comparison of short-wavelength blue-light autofluorescence and conventional blue-light autofluorescence in geographic atrophy.

BACKGROUND/AIMS: To systematically compare the intermodality and inter-reader agreement for two blue-light confocal fundus autofluorescence (FAF) systems. METHODS: Thirty eyes (21 patients) with a diagnosis of geographic atrophy (GA) were enrolled. Eyes were imaged using two confocal blue-light FAF devices: (1) Spectralis device with a 488 nm excitation wavelength (488-FAF); (2) EIDON device with 450 nm excitation wavelength and the capability for 'colour' FAF imaging including both the individual red and green components of the emission spectrum. Furthermore, a third imaging modality (450-RF image) isolating and highlighting the red emission fluorescence component (REFC) was obtained and graded. Each image was graded by two readers to assess inter-reader variability and a single image for each modality was used to assess the intermodality variability. RESULTS: The 95% coefficient of repeatability (1.35 mm2 for the 488-FAF-based grading, 8.13 mm2 for the 450-FAF-based grading and 1.08 mm2 for the 450-RF-based grading), the coefficient of variation (1.11 for 488-FAF, 2.05 for 450-FAF, 0.92 for 450-RF) and the intraclass correlation coefficient (0.994 for 488-FAF, 0.711 for 450-FAF, 0.997 for 450-RF) indicated that 450-FAF-based and 450-RF-based grading have the lowest and highest inter-reader agreements, respectively. The GA area was larger for 488-FAF images (median (IQR) 2.1 mm2 (0.8-6.4 mm2)) than for 450-FAF images (median (IQR) 1.0 mm2 (0.3-4.3 mm2); p<0.0001). There was no significant difference in lesion area measurement between 488-FAF-based and 450-RF-based grading (median (IQR) 2.6 mm2 (0.8-6.8 mm2); p=1.0). CONCLUSION: The isolation of the REFC from the 450-FAF images allowed for a reproducible quantification of GA. This assessment had good comparability with that obtained with 488-FAF images.

Topographic Correspondence of Macular Atrophy With Choroidal Neovascularization in Ranibizumab-treated Eyes of the TREX-AMD Trial.

PURPOSE: To quantify the extent of topographic correspondence between baseline (BSL) choroidal neovascularization (CNV) and macular atrophy (MA) at follow-up in eyes with neovascular age-related macular degeneration (NVAMD). DESIGN: Post hoc analysis of randomized controlled clinical trial data. METHODS: Sixty treatment-naïve NVAMD patients from the TREX-AMD trial were followed for 18 months. Regions of month 18 macular atrophy (MA) were graded on fundus autofluorescence (FAF) with guidance of spectral-domain optical coherence tomography (SDOCT). CNV lesions were graded manually on fluorescein angiography (FA) with lesion components including classic and occult CNV delineated. FAF and FA images were registered to quantitate area and location of overlap between CNV and MA. Outcome measures included overlap of month 18 MA to BSL CNV subtype and progression of MA from BSL to month 18. RESULTS: Twenty-six eyes had both MA at month 18 and CNV at BSL. A total of 84.6% of eyes showed evidence of MA and CNV overlap. MA appeared by month 18 in regions corresponding to BSL classic CNV in 36.4% of eyes and occult CNV in 40.9%, and in both regions in 22.7%, with more area of MA (AMA) in regions of occult than classic CNV. MA position at BSL corresponded to BSL classic CNV in 76.9% of eyes and occult CNV in 61.5%, and to both regions in 15.4%, with more AMA in regions of occult than classic CNV. Among eyes with MA and CNV at BSL but with no overlap, 50% progressed to involve regions with BS -CNV. Six eyes had no BSL MA but developed MA at month 18 within regions of BSL CNV. CONCLUSIONS: In ranibizumab-treated eyes with NVAMD, more MA lesions develop within the region of baseline CNV (type 1, CNV-based MA) than outside (type 2, CNV-independent MA). Baseline-MA also tends to be located within regions of CNV in the pretreatment phase.

Distinctive Analysis of Macular Superficial Capillaries and Large Vessels Using Optical Coherence Tomographic Angiography in Healthy and Diabetic Eyes.

Purpose: To quantify and evaluate macular superficial capillaries and large vessels separately using an optical coherence tomographic angiography (OCTA)-based automatic segmentation algorithm. Methods: In this cross-sectional study, all eyes were scanned using an OCTA device with 3 × 3 mm cube centered on the fovea. Retinal large vessels (arterioles/venules) were automatically segmented from superficial vasculature en-face images. All images were normalized, binarized, and skeletonized for quantification. Metrics of retinal capillaries were calculated by subtracting the measurements of large vessels from total vasculature. Perfusion density (PD), vessel length density (VLD), and vessel diameter index (VDI) within Early Treatment Diabetic Retinopathy Study (ETDRS) 3-mm ring were calculated for total superficial vasculature, large vessels (PDlarge, VLDlarge, and VDIlarge) and capillaries (PDcap, VLDcap, and VDIcap), respectively. Results: Fifty-nine eyes from 59 healthy participants (mean age, 45 ± 14 years, 36 females) and 118 eyes from 67 patients with diabetes mellitus (mean age, 57 ± 10 years, 28 females) were included. The diabetic cohort included four subgroups (35 eyes without diabetic retinopathy, 30 eyes with mild to moderate nonproliferative diabetic retinopathy [NPDR], 27 eyes with severe NPDR, and 26 eyes with PDR). Linear regression showed that all above metrics were correlated with the disease stage (from healthy state to PDR), and the ß value was -0.76, 0.24, -0.78, 0.80, 0.30, 0.77, -0.81, 0.16, and -0.82 for VD, VDlarge, VDcap, VDI, VDIlarge, VDIcap, VLD, VLDlarge, and VLDcap, respectively. Conclusions: Retinal capillaries and large vessels responded differently in the context of diabetes. VLD of capillary is a potentially reliable metric in diabetic retinopathy staging.

Subfoveal choroidal thickness predicts macular atrophy in age-related macular degeneration: results from the TREX-AMD trial.

BACKGROUND: Our purpose was to evaluate the relationship between subfoveal choroidal thickness (SCT) and development of macular atrophy (MA) in eyes with age-related macular degeneration (AMD). METHODS: This was a prospective, multicenter study. Sixty participants (120 eyes) in the TREX-AMD trial (NCT01648292) with treatment-naïve neovascular AMD (NVAMD) in at least one eye were included. SCT was measured by certified reading center graders at baseline using spectral domain optical coherence tomography (SDOCT). The baseline SCT was correlated with the presence of MA at baseline and development of incident MA by month 18. Generalized estimating equations were used to account for information from both eyes. RESULTS: Baseline SCT in eyes with MA was statistically significantly less than in those without MA in both the dry AMD (DAMD) (P = 0.04) and NVAMD (P = 0.01) groups. Comparison of baseline SCT between MA developers and non-MA developers revealed a statistically significant difference (P = 0.03). Receiver operating characteristic curve (ROC) analysis showed the cut-off threshold of SCT for predicting the development of MA in cases without MA at baseline was 124 µm (AUC = 0.772; Sensitivity = 0.923; Specificity = 0.5). Among eyes without MA at baseline, those with baseline SCT ≤124 µm were 4.3 times more likely to develop MA (Odds ratio: 4.3, 95% confidence interval: 1.6-12, P = 0.005) than those with baseline SCT >124 µm. CONCLUSIONS: Eyes with AMD and MA had less SCT than those without MA. Eyes with less baseline SCT also appear to be at higher risk to develop MA within 18 months.

Neovascular age-related macular degeneration management in the third year: final results from the TREX-AMD randomised trial.

BACKGROUND/AIMS: Prospectively evaluate outcomes in the third year of neovascular age-related macular degeneration (AMD) management using ranibizumab with continued treat and extend (TREX) dosing compared with monthly visits with retreatment upon evidence of exudative disease activity (PRN, pro re nata). METHODS: Subjects with treatment-naïve neovascular AMD were randomised 1:2 to Monthly or TREX and managed through 2 years. In the third year, subjects randomised to Monthly were managed PRN while subjects randomised to TREX were continued on TREX dosing or transitioned to PRN after achieving an interval of 12 weeks between visits. RESULTS: Sixty subjects enrolled and 46 (77%) completed month 36 (M36). Transition from Monthly to PRN was associated with a decline in best corrected visual acuity (BCVA) (+10.5 letters (month 24) to +5.4 (M36, p=0.09)); three (15%) subjects required no dosing during year 3, and 47% (114/243) of possible PRN injections were delivered, yielding a mean of 6.1 injections during year 3. Among the 9 (23%) TREX subjects transitioned to PRN, the need for ongoing anti-vascular endothelial growth factor retreatments was small, with 4 (4%) intravitreal injections being delivered among 106 PRN visits; this subgroup displayed an inferior BCVA trajectory compared with the remainder of subjects. Outcomes among subjects continued on TREX were more favourable, with a mean gain of +5.0 letters at M36. CONCLUSIONS: Upon transition to PRN, subjects randomised to monthly dosing experienced a decline in BCVA. Among subjects initially randomised to TREX who transitioned to PRN after achieving a 12-week interval between visits, the overall need for additional treatment was low. TRIAL REGISTRATION NUMBER: NCT01748292, Results.

Postreceptor Neuronal Loss in Intermediate Age-related Macular Degeneration.

PURPOSE: To investigate the relationship between ganglion cell complex (GCC) thickness and photoreceptor alterations in eyes with intermediate age-related macular degeneration (AMD). DESIGN: Retrospective case-control study. METHODS: We collected data from 68 eyes with intermediate AMD from 68 patients with spectral-domain optical coherence tomography (SDOCT) imaging. A control group of 50 eyes from 50 healthy subjects was included for comparison. Our main outcome measures for comparison between groups were (1) the average and minimum GCC thickness and (2) the "normalized" reflectivity of the ellipsoid zone (EZ) en face image. RESULTS: The average and minimum GCC thicknesses were thinner in AMD patients (69.54 ± 9.30 µm and 63.22 ± 14.11 µm, respectively) than in healthy controls (78.57 ± 6.28 µm and 76.28 ± 6.85 µm, P < .0001 and P < .0001, respectively). Agreement was found to be excellent in the "normalized" EZ reflectivity assessment (intraclass correlation coefficient = 0.986, coefficient of variation = 1.11). The EZ "normalized" reflectivity was 0.67 ± 0.11 in controls and 0.61 ± 0.09 in the AMD group (P = .006). In univariate analysis, EZ "normalized" reflectivity was found to have a significant direct relationship with average (P < .0001) and minimum (P < .0001) GCC thickness in AMD patients, but not in controls (P = .852 and P = .892, respectively). CONCLUSIONS: Eyes with intermediate AMD exhibit GCC thinning, as well as a reduced EZ "normalized" reflectivity, and these parameters are correlated. This study supports the concept of postreceptor retinal neuronal loss as a contributor to retinal thinning in intermediate AMD.

Proposal of a simple optical coherence tomography-based scoring system for progression of age-related macular degeneration.

PURPOSE: To develop a simple, clinically practical, optical coherence tomography (OCT)-based scoring system for early age-related macular degeneration (AMD) to prognosticate risk for progression to late AMD. METHODS: We retrospectively reviewed OCT images (512 × 128 macular cube, Cirrus) from 138 patients diagnosed of early AMD in at least one eye and follow-up of at least 12 months. For patients with early AMD in both eyes, only the right eye was chosen as the study eye for longitudinal assessment. Scans were graded on four SD-OCT criteria associated with disease progression in previous studies: drusen volume within a central 3-mm circle ≥0.03 mm3, intraretinal hyperreflective foci (HRF), hyporeflective foci (hRF) within a drusenoid lesion (DL), and subretinal drusenoid deposits (SDD). Each criterion was assigned one point. For risk assessment of the study eye, the baseline status of the fellow eye was also considered, and thus these four features were also assessed in the fellow eye. The number of risk factors were summed for both eyes, yielding a total score (TS) of 0 to 8 for each patient. A fellow eye with evident choroidal neovascularization (CNV) or atrophy automatically received 4 points. Scores were then grouped into four categories to facilitate comparative analysis: I. (TS of 0, 1, 2), II. (TS of 3, 4), III. (TS of 5, 6) and IV. (TS of 7, 8). Correlation of baseline category assignment with progression to late AMD (defined as the presence of atrophy or CNV on OCT) by the last follow-up visit was evaluated with logistic regression analysis. RESULTS: The rate of progression to late AMD was 39.9% (55/138). Progression rates by category (I to IV) were 0, 14.3, 47.5, and 73.3%, respectively. Logistic regression analysis showed risk of progression to late AMD was 3.0 times (95% CI: 1.2-7.9) higher for an eye assigned to category IV than for an eye in category III and 16.4 (95% CI: 4.7-58.8) times higher than for an eye in category II. CONCLUSIONS: A simple scoring system relevant to prognosis for early AMD, and practical for use in a busy clinic, can be developed using SD-OCT criteria alone.

Variability of Retinal Thickness Measurements in Tilted or Stretched Optical Coherence Tomography Images.

PURPOSE: To investigate the level of inaccuracy of retinal thickness measurements in tilted and axially stretched optical coherence tomography (OCT) images. METHODS: A consecutive series of 50 eyes of 50 patients with age-related macular degeneration were included in this study, and Cirrus HD-OCT images through the foveal center were used for the analysis. The foveal thickness was measured in three ways: (1) parallel to the orientation of the A-scan (Tx), (2) perpendicular to the retinal pigment epithelium (RPE) surface in the instrument-displayed aspect ratio image (Ty), and (3) thickness measured perpendicular to the RPE surface in a native aspect ratio image (Tz). Mathematical modeling was performed to estimate the measurement error. RESULTS: The measurement error was larger in tilted images with a greater angle of tilt. In the simulation, with axial stretching by a factor of 2, Ty/Tz ratio was > 1.05 at a tilt angle between 13° to 18° and 72° to 77°, > 1.10 at a tilt angle between 19° to 31° and 59° to 71°, and > 1.20 at an angle ranging from 32° to 58°. Of note with even more axial stretching, the Ty/Tz ratio is even larger. Tx/Tz ratio was smaller than the Ty/Tz ratio at angles ranging from 0° to 54°. The actual patient data showed good agreement with the simulation.The Ty/Tz ratio was greater than 1.05 (5% error) at angles ranging from 13° to 18° and 72° to 77°, greater than 1.10 (10% error) angles ranging from 19° to 31° and 59° to 71°, and greater than 1.20 (20% error) angles ranging from 32° to 58° in the images axially stretched by a factor of 2 (b/a = 2), which is typical of most OCT instrument displays. CONCLUSIONS: Retinal thickness measurements obtained perpendicular to the RPE surface were overestimated when using tilted and axially stretched OCT images. TRANSLATIONAL RELEVANCE: If accurate measurements are to be obtained, images with a native aspect ratio similar to microscopy must be used.

Randomized Trial of Treat-and-Extend versus Monthly Dosing for Neovascular Age-Related Macular Degeneration: 2-Year Results of the TREX-AMD Study.

PURPOSE: To evaluate a prospective treat-and-extend (TREX) management strategy compared with monthly dosing with intravitreal ranibizumab (Lucentis) in neovascular age-related macular degeneration (AMD). DESIGN: Prospective, randomized, multicenter clinical trial. PARTICIPANTS: Sixty patients with treatment-naïve neovascular AMD randomized 1:2 to monthly or TREX cohorts. METHODS: Patients with Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA) of 20/32 to 20/500 (Snellen equivalent) were randomized to receive intravitreal 0.5 mg ranibizumab monthly or, according to a TREX protocol, no less frequently than every 12 weeks. After interval extension, if recurrent exudative disease was identified, this maximum interval between treatments was rechallenged according to a strict prospective protocol. MAIN OUTCOME MEASURE: Change in ETDRS BCVA from baseline. RESULTS: Sixty patients were enrolled and 50 completed month 24, at which point mean ETDRS BCVA letter gains were similar: 10.5 and 8.7 for the monthly and TREX cohorts, respectively (P = 0.64). At month 24, 4 patients (20%) and 12 patients (30%) in the monthly and TREX cohorts, respectively, gained at least 15 letters (P = 0.41). No monthly cohort patient lost more than 2 letters, whereas 5 TREX cohort patients (13%) lost at least 15 letters. Anatomic improvements were similar between the cohorts. Through month 24, the mean number of injections administered was 25.5 (range, 22-27) and 18.6 (range, 10-25) for the monthly and TREX cohorts, respectively (P < 0.001). Among TREX patients completing month 24, 14 (47%) were at an extension interval of 8 weeks or more, and the mean maximum tolerated extension was 8.5 weeks over the course of 2 years. Of the 26 TREX patients (65%) who demonstrated recurrent exudation upon interval extension, the first maximum extension interval was consistent in most eyes (n = 19 [73%]). CONCLUSIONS: The TREX neovascular AMD management protocol used with ranibizumab in the Treat-and-Extend Protocol in Patients with Wet Age-Related Macular Degeneration (TREX-AMD) study resulted in visual and anatomic gains comparable with those obtained with monthly dosing, and most patients randomized to TREX therapy demonstrated a relatively consistent maximum extension interval.

Perspective of ophthalmology residents in the United States about residency programs and competency in relation to the International Council of Ophthalmology guidelines.

PURPOSE: To evaluate the perspective of ophthalmology residents in the US about their residency programs and compare the competency of residency programs to international competency levels set by the International Council of Ophthalmology (ICO). METHODS: A cross-sectional web-based survey extracted from the ICO published competency standards was sent to program directors of ophthalmology residency programs in the US to forward it to current PGY-3, 4 residents, and residency graduates from 2011 to 2014. RESULTS: Eighty-seven responses were received, comprising 61 residents and 26 graduates. Most respondents were highly satisfied with their programs (93.6%). Clinic-based training was rated satisfactorily. Insufficient exposure to low-vision rehabilitation (38.5%), refraction and contact lenses prescription (38.5%), and vitreo-retinal surgeries (38.5%) was reported. Respondents were satisfied with their overall surgical experiences, with the vast majority (>83%) rating case volume, complexity, and variety as satisfactory or better. A significant group stated they had insufficient exposure to extra-capsular cataract extraction (26.3%), refractive surgery (19.7%), and orbital surgery (64.5%). All graduates surveyed passed their Ophthalmic Knowledge Assessment Program (OKAP) examinations, and 72% felt their residency programs adequately prepared them for the examinations. All respondents reported insufficient training in certain nonclinical areas, such as practice management, staffing, and administration skills. CONCLUSIONS: Ophthalmology residents in the US express high levels of satisfaction with their residency training programs. While most programs adequately address most ICO core objectives, certain curriculum modifications should be considered.

Molecular underpinnings of corneal angiogenesis: advances over the past decade.

The cornea is maintained in an avascular state by maintaining an environment whereby anti-angiogenic factors take the upper hand over factors promoting angiogenesis. Many of the common pathologies affecting the cornea involve the disruption of such equilibrium and the shift towards new vessel formation, leading to corneal opacity and eventually-vision loss. Therefore it is of paramount importance that the molecular underpinnings of corneal neovascularization (CNV) be clearly understood, in order to develop better targeted treatments. This article is a review of the literature on the recent discoveries regarding pro-angiogenic factors of the cornea (such as vascular endothelial growth factors, fibroblast growth factor and matrix metalloproteinases) and anti-angiogenic factors of the cornea (such as endostatins and neostatins). Further, we review the molecular underpinnings of lymphangiogenesis, a process now known to be almost separate from (yet related to) hemangiogenesis.

Contralateral assessment of sub-Bowman keratomileusis (SBK) microkeratome suction duration on laser-assisted in-situ keratomileusis (LASIK) flap characteristics.

PURPOSE: To describe the effect of prolonging the standard suction duration during laser-assisted in-situ keratomileusis (LASIK) and its effect on flap thickness and hinge length using sub-Bowman keratomileusis (SBK) microkeratome. METHODS: Fifty-six eyes (28 patients) were included and divided into 2 groups; Group-A: eyes with flatter corneas (36 eyes, 18 patients) and mean keratometric readings ranging from 40.13 to 43.71 diopters (D). Group-B: eyes with steeper corneas (20 eyes, 10 patients) with mean keratometric readings ranging from 43.85 to 46.72 D. One-Use-Plus SBK microkeratome was used for flap creation. For right eyes, flap was created immediately once suction was built up. In left eyes, the surgeon waited for 10 s after suction was built up before flap creation. Flap hinge length and flap thickness were measured using surgical caliper and ultrasonic pachymetry, respectively. RESULTS: Statistically significant differences were observed in corneal flap hinge size between right eyes versus left eyes, with a mean of 3.98 ± 0.48 vs. 3.78 ± 0.55 mm (p < 0.001). Mean flap thickness in both eyes did not prove to be statistically significantly different with either surgical technique (90.2 ± 1.68 vs. 90.07 ± 1.44 µm, p = 0.8). Sub-group analysis of Group-A vs. Group-B revealed hinge sizes that were significantly larger in steeper corneas (p < 0.01 and p < 0.05, respectively). However, flap thickness in both groups was unaffected by surgical procedure (p = 0.5). CONCLUSIONS: Increasing suction duration increases flap hinge length and stabilizes the flap, especially in steeper corneas.

PROGRESSION OF MACULAR ATROPHY IN PATIENTS WITH NEOVASCULAR AGE-RELATED MACULAR DEGENERATION UNDERGOING ANTIVASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY.

PURPOSE: To define the frequency and quantify the progression of macular atrophy (MA) in patients with neovascular age-related macular degeneration undergoing treatment with antivascular endothelial growth factor therapy for >2 years. METHODS: Fifty-four eyes of 46 patients (86.7 ± 6.8 years, 53.7% women) diagnosed with wet age-related macular degeneration were included in this retrospective study. Eyes that received photodynamic therapy or laser treatment were excluded. All eyes were imaged at baseline and after 2 years with the Cirrus spectral domain optical coherence tomography using a 512 × 128 macular cube scan protocol centered on the fovea. Optical coherence tomography en face fundus images were obtained for each 3-dimensional data set using the U.S. Food and Drug Administration-cleared Advanced RPE Analysis software, which automatically identifies atrophic areas by segmenting regions of increased reflectivity in en face choroidal slab images. Segmentation errors were manually corrected by trained Doheny Image Reading Center graders using a standardized grading protocol. The prevalence rates of atrophy at baseline and at 2-years follow-up and enlargement rates were computed. Baseline demographic factors and types and numbers of antivascular endothelial growth factor injections received over time were correlated with the development and enlargement of atrophy. RESULTS: Macular atrophy was noted at baseline in 32 (59.3%) eyes and progressed in all eyes over the next 2 years. Among the 28 eyes without atrophy at baseline, MA developed by 2 years in 6 eyes (21.4% of eyes without MA at baseline). Of note, 22 eyes (40.7% of overall cohort) never developed atrophy during the course of the study. Among eyes with atrophy at baseline, the annual growth rate of MA was found to be 0.89 ± 0.93 mm. A multiple regression analysis was performed to evaluate the influence of gender, age, smoking status, medication injected, and number of injections on MA. Except for the number of total injections (R = 0.3, P < 0.01), the studied variables could not significantly predict development or progression of MA (F [0.73, 13] = 0.378, P = 0.86, R = 0.05). However, the study was not powered to detect small effects. CONCLUSION: Macular atrophy is a frequent finding in eyes with wet age-related macular degeneration both before and after antivascular endothelial growth factor therapy. The frequency of new optical coherence tomography-defined atrophy (21% at 2 years) after starting therapy was close to the rates reported in CATT, IVAN, and HARBOR. The rate of MA enlargement was positively correlated with the number of injections, but did not appear to be greater than that reported for atrophy in the absence of choroidal neovascularization.

Drusen Volume as a Predictor of Disease Progression in Patients With Late Age-Related Macular Degeneration in the Fellow Eye.

PURPOSE: Increasing drusen volume was proposed to be a predictor of disease progression in age-related macular degeneration (AMD). In patients with late AMD in one eye, the fellow eyes without neovascularization are known to be at higher risk of developing exudative AMD. We evaluated the relationship between drusen volume in these fellow eyes and their progression to late AMD. METHODS: A retrospective analysis included fellow eyes with drusen associated with nonexudative AMD. All eyes with neovascular AMD were treated with intravitreal ranibizumab, aflibercept, and/or bevacizumab and followed for 2 years. All eyes were scanned with the Cirrus HD-OCT using a 512 × 128 scan pattern. Optical coherence tomography (OCT) data at baseline, month 12, and month 24 were collected using the advanced RPE analysis tool to quantify drusen volume within 3- and 5-mm-diameter circles centered on the fovea. Optical coherence tomography scans were also evaluated for the development of geographic atrophy (GA) or macular neovascularization (MNV). RESULTS: Eighty-nine patients who had neovascular AMD in only one eye were studied. Optical coherence tomography drusen volume in the absence of MNV could be measured in 61 participants (68.5%). After 12 months, 4 eyes (4.5%) developed MNV and 15 eyes (16.9%) developed GA. By 24 months of follow-up, an additional 5 eyes (7.1%) developed MNV and an additional 10 eyes (14.3%) developed GA. At month 24, the eyes that developed GA or MNV had baseline drusen volumes that were significantly larger than in eyes that did not develop late AMD. Patients with a drusen volume over 0.03 mm3 had a greater than 4-fold increased risk for developing late AMD compared with those with lower drusen volumes. CONCLUSIONS: Baseline drusen volume appears to be an important predictor for the development of late AMD within 2 years in eyes that have fellow eyes being actively treated for MNV. This suggests that OCT-derived drusen volume measurements may be a useful biomarker to identify eyes at the highest risk for progression to late AMD.