Srinivas R Sadda

Prospective Trial of Treat-and-Extend versus Monthly Dosing for Neovascular Age-Related Macular Degeneration: TREX-AMD 1-Year Results

PURPOSE To assess prospectively a treat-and-extend (TREX) management strategy compared with monthly dosing of intravitreal ranibizumab in treatment-naïve neovascular age-related macular degeneration (AMD) patients. DESIGN Phase IIIb, multicenter, randomized, controlled clinical trial. PARTICIPANTS Sixty patients with treatment-naïve neovascular AMD randomized 1:2 to monthly or TREX management. METHODS Patients with Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA) from 20/32 to 20/500 (Snellen equivalent) were randomized to receive intravitreal 0.5 mg ranibizumab monthly or according to a TREX protocol. The TREX patients were treated monthly for at least 3 doses, until resolution of clinical and spectral-domain optical coherence tomography evidence of exudative disease activity; the interval between visits then was individualized according to a strict prospective protocol. MAIN OUTCOME MEASURES Mean ETDRS BCVA change from baseline. RESULTS At baseline, mean age was 77 years (range, 59-96 years), mean BCVA was 20/60 (Snellen equivalent), and mean central retinal thickness (CRT) was 511 μm. Fifty-seven eyes (95%) completed month 12, at which point mean BCVA improved by 9.2 and 10.5 letters in the monthly and TREX cohorts, respectively (P = 0.60). The mean number of injections administered through month 12 was 13.0 and 10.1 (range, 7-13) in the monthly and TREX cohorts, respectively (P < 0.0001). Among TREX patients, 7 (18%) were maximally extended, 4 (10%) demonstrated fluid at every visit, and at month 12, 18 (45%) had achieved an extension interval of 8 weeks or more; the mean maximum extension interval between injections after the first 3 monthly doses was 8.4 weeks (range, 4-12 weeks). Most TREX patients who demonstrated recurrent exudative disease activity (17/24 [71%]) were unable to extend beyond their initial maximum extension interval. CONCLUSIONS The TREX neovascular AMD management strategy used in this prospective, randomized, controlled trial resulted in visual and anatomic gains comparable with those obtained with monthly dosing.

A Promising Future for Optical Coherence Tomography Angiography.

Fluorescein angiography has been the gold standard imaging modality for the retinal vasculature since its groundbreaking introduction in 1961 by Alvis and Novotny and has revolutionized our ability to diagnose diseases of the retinal vasculature and to identify retinal and choroidal neovascularization.1 Its greatest advantage may lie in its ability to detect dynamic patterns of dye transit and leakage. Various innovations have broadened the use of angiography, including the application of indocyanine green, wide-field image acquisition, confocal scanning laser ophthalmoscopy, and adaptive optics. However, a major limitation of traditional angiography resides in its inability to image the entire retinal capillary system or to directly visualize nascent vessels, leaving the practitioner to deduce the presence of neovascularization on the basis of other indicators such as fluid, leakage, or edema. Optical coherence tomography (OCT) angiography applies high-speed OCT scanning to detect blood flow by analyzing signal decorrelation between scans. Compared with stationary areas of the retina, the movement of erythrocytes within a vessel generates a decorrelated signal. The split-spectrum amplitude decorrelation angiography (SSADA) algorithm improves the signal to noise ratio by splitting the source spectrum into 4 parts and averaging the resultant 4 signals. High-density raster scanning of a 2-dimensional area of the retina generates a volumetric rendering of blood flow from the internal limiting membrane to the choroid and allows for direct visualization of normal and abnormal blood vessels. The currently available Optovue AngioVue System uses spectral-domain technology, an 840-nm laser, and the SSADA algorithm (Figure). The 70-kHz A-scan rate on this device allows a 3 × 3-mm OCT angiography volume to be acquired in 3 seconds. The lateral and axial resolutions are both 15 μm; the axial resolution is significantly less than that for structural OCT (5 μm) owing to signal averaging. Another device under development by Zeiss will feature a swept-source laser centered at 1040 nm with the potential for augmented signal penetration depth. Future devices may use other approaches for OCT angiography, such as phase contrast or intensity variance. Unlike traditional angiography, which uses a fluorescent dye and provides limited 3-dimensional information, OCT angiography requires no exogenous contrast and uses dense volumetric scanning to provide depth-resolved visualization of the retinal and choroidal vasculature. The retinal vasculature of the central macula is predominantly a 3-layered capillary bed. Even though one can identify the superficial retinal capillary plexus using fluorescein angiography, this angiographic technique poorly visualizes the intermediate and deep plexuses that are a critical focus of retinal vascular disease.1,2 Using the SSADA technique, Spaide et al1 were the first to demonstrate distinct superficial and deep capillary networks, the latter of which includes both the deep and intermediate plexuses. The use of OCT angiography could greatly enrich our understanding of the ischemic processes affecting different layers of the retinal vasculature, such as cotton-wool spots (superficial plexus ischemia), paracentral acute middle maculopathy (deep plexus ischemia),2 and macular telangiectasia type 2.3 Optical coherence tomography angiography may also have the potential to dissect the long-debated origin and microvascular anatomy of neovascularization in age-related macular degeneration, including type 1 (sub– retinal pigment epithelium), type 2 (subretinal), and type 3 (intraretinal; retinal angiomatous proliferation) neovascularization. In a seminal study, Jia et al4 generated 3-dimensional reconstructions of choroidal neovascularization and en face OCT renderings to highlight the precise vascular anatomy of choroidal neovascularization. It may be possible to identify distinct morphologies of choroidal neovascularization and then correlate these subtypes with disease course, prognosis, and response to treatment. In addition to providing enhanced anatomic detail, OCT angiography intrinsically generates data on vascular flow. This powerful feature has enormous implications for understanding tissue perfusion in the absence of obvious morphological changes. A flow index of the optic nerve head can be used to ascertain disc perfusion. For example, glaucomatous optic discs and discs damaged by optic neuritis have significantly diminished flow indices compared with normal discs.5,6 Remarkably, OCT angiographic measurements are sensitive

Swept-source OCT angiography imaging of the foveal avascular zone and macular capillary network density in diabetic retinopathy

PURPOSE We compared the area of the foveal avascular zone (FAZ) and macular capillary network density at different retinal layers using swept-source optical coherence tomography angiography (OCT-A) in normal individuals and patients with diabetic retinopathy (DR). METHODS Images (a 3 × 3 mm cube centered on the fovea) were acquired in 40 eyes of 22 normal individuals and 28 eyes of 18 patients with varying levels of DR using a swept-source OCT-A device (central wavelength 1050 nm; A-scan-rate of 100,000 scans per second). En face images of the retinal vasculature were generated from the superficial and deep retinal layers (SRL/DRL). Quantitative analysis of the vessel density (VD) and FAZ area was performed. Vessel density was assessed as the ratio of the retinal area occupied by vessels. RESULTS Among the DR subjects (mean age, 72 years; 61% male), 35.7% of the eyes had mild, 35.7% moderate, and 7.1% severe nonproliferative DR (NPDR), and 21.4% and proliferative DR (PDR). The mean FAZ area in patients with DR and in normal individuals was 0.518 and 0.339 mm2, respectively, for the SRL (P = 0.003), and 0.615 and 0.358 mm2, respectively, for the DRL (P < 0.001). The mean VD (ratio) at the SRL and DRL was statistically significantly lower in patients with DR (SRL, P < 0.001; DRL, P = 0.028). CONCLUSIONS Swept-source OCT-A of the microcirculation in eyes of patients with DR can be used to quantitatively demonstrate alterations in the FAZ and VD in the SRL/DRL of the macula compared to normal eyes. Future longitudinal studies may use these metrics to evaluate changes over time or in response to treatment.

Retinal Imaging in the Twenty-First Century: State of the Art and Future Directions

Assessment of chorioretinal disease is dependent on the ability to visualize pathologic changes occurring in the posterior segment of the eye using optical instruments, termed ophthalmoscopy. Ophthalmoscopy, in turn, has been enhanced greatly by the development of techniques that allow recording of these changes, termed retinal imaging. As well as documenting pathologic features, retinal and fundal imaging facilitates the identification of morphologic features not visible to the clinician on biomicroscopy. As such, advances in retinal imaging have proven fundamental to many paradigm shifts in our understanding and treatment of ocular disease. In the 1950s, with the advent of electronic flashes and 35-mm cameras, the field of modern fundus photography was born. Similarly, in the 1960s and 1970s, the introduction of fluorescein and indocyanine green angiography revolutionized our ability to assess the integrity of the chorioretinal vasculature. More recently, in the 1990s, the introduction of a wholly new form of noninvasive cross-sectional imaging, optical coherence tomography, has greatly facilitated use of emerging pharmacotherapies in diagnosing and monitoring chorioretinal disease. In this translational science review, we provide an overview of current, state-of-the-art retinal imaging technologies, as well as highlight many emerging imaging technologies that we believe are likely to transform the provision of eye care in the 21st century.

Optical Coherence Tomography Angiography Evaluation of the Parafoveal Vasculature and Its Relationship With Ocular Factors

PURPOSE To determine the size and characteristics of the superficial and deep foveal avascular zone (FAZ) in healthy adults by using optical coherence tomography angiography (OCT-A), and to ascertain the effects of demographic and ocular parameters on the FAZ size. METHODS In a prospective cohort study of 117 healthy volunteers, foveal-centered 3 × 3-mm OCT-A scans were manually graded by certified graders to determine the size of the superficial and deep FAZ. Multiple linear regression analyses were performed to evaluate the impact of demographics and ocular factors, including central retinal thickness (CRT), choroidal thickness, axial length (AL), and spherical equivalent (SE) on superficial and deep FAZ areas. RESULTS The mean age of the participants was 22.5 years, with mean AL of 25.4 mm and mean SE of -4.3 diopters. The mean CRT was 262.8 μm (range, 220-316 μm). The mean superficial FAZ area was 0.24 mm2, while the deep FAZ area was 0.38 mm2 (P < 0.001). Females had a larger superficial (P < 0.001) and deep FAZ (P < 0.001). On univariate linear regression, both superficial and deep FAZ areas had significant correlations with CRT, sex, AL, and SE, but not with age. By multiple linear regression analysis, in normal eyes, superficial FAZ area varied significantly with CRT and sex. Among eyes with high myopia, both superficial and deep FAZ varied significantly with CRT, sex, and choroidal thickness. CONCLUSIONS The superficial and deep FAZ areas varied significantly among healthy eyes. Factors such as CRT, sex, SE, AL, and choroidal thickness influence the size of the FAZ.

Measuring the precise area of peripheral retinal non-perfusion using ultra-widefield imaging and its correlation with the ischaemic index

Objective To determine the calculated, anatomically correct, area of retinal non-perfusion and total area of visible retina on ultra-widefield fluorescein angiography (UWF FA) in retinal vein occlusion (RVO) and to compare the corrected measures of non-perfusion with the ischaemic index. Methods Uncorrected UWF FA images from 32 patients with RVO were graded manually for capillary non-perfusion, which was calculated as a percentage of the total visible retina (uncorrected ischaemic index). The annotated images were converted using novel stereographic projection software to calculate precise areas of non-perfusion in mm2, which was compared as a percentage of the total area of visible retina (‘corrected non-perfusion percentage’) with the ischaemic index. Results The precise areas of peripheral non-perfusion ranged from 0 mm2 to 365.4 mm2 (mean 95.1 mm2), while the mean total visible retinal area was 697.0 mm2. The mean corrected non-perfusion percentage was similar to the uncorrected ischaemic index (13.5% vs 14.8%, p=0.239). The corrected non-perfusion percentage correlated with uncorrected ischaemic index (R=0.978, p<0.001), but the difference in non-perfusion percentage between corrected and uncorrected metrics was as high as 14.8%. Conclusions Using stereographic projection software, lesion areas on UWF images can be calculated in anatomically correct physical units (mm2). Eyes with RVO show large areas of peripheral retinal non-perfusion.

Quantitative OCT Angiography of the Retinal Microvasculature and the Choriocapillaris in Myopic Eyes

Purpose To study the retinal capillary microvasculature and the choriocapillaris (CC) in myopic eyes using quantitative optical coherence tomography angiography (OCTA) analysis. Methods Macular OCTA images of 3 × 3 mm were obtained using the RTVue-XR Avanti with AngioVue. Quantitative measurements of the retinal capillary microvascular layers and the CC were analyzed using en face projection images. Vessel density and fractal dimension of the superficial and deep retinal capillary plexus, and area and density of flow reduction in the CC were analyzed, quantified, and compared with an age-matched control group. Results Fifty eyes with myopia and 34 age-matched healthy eyes were included in this study. The vessel density and the vessel branching complexity using fractal dimension of the retinal capillary microvasculature were significantly lower in myopic eyes (P < 0.001 and P = 0.001). The total number of flow voids in the CC was lower (108.93 vs. 138.63, P = 0.001) but the total and average flow void area was significantly higher (total area 3.715 ± 0.257 vs. 3.596 ± 0.194 mm2, P = 0.026; average area 0.044 ± 0.029 vs. 0.028 ± 0.010 mm2, P = 0.002) compared with the healthy control group. Average choroidal thickness was lower in the myopic group versus the normal control cohort (123.538 ± 73.477 vs. 246.97 ± 41.745 μm, P < 0.05) and significantly reduced in eyes with lacquer cracks (LC) compared with myopic eyes without LC formation (P = 0.003). There was no correlation between choroidal thickness and quantitative parameters of the CC in the myopic eyes. Conclusions The density of the retinal capillary microvasculature is reduced and the area of flow deficit in the CC is increased in eyes with greater myopia. The relevance of microvascular alterations in the setting of myopia warrants further study.

Image artefacts in swept-source optical coherence tomography angiography

Purpose To describe optical coherence tomography angiography (OCTA) image artefacts in eyes with and without ocular pathologies. Methods The OCTA images of healthy subjects and patients with age-related macular degeneration, diabetic retinopathy and retinal vascular occlusions were retrospectively reviewed. All OCTA images were obtained using a swept-source OCTA instrument (Triton, Topcon). The frequency of various image artefacts including segmentation, banding, motion, projection, masking, unmasking, doubling of the retinal vessels, blink, stretching, out-of-window and crisscross artefacts was assessed. The impact of the artefact on the grading of the images for the foveal avascular zone in deep and superficial retinal layers, capillary non-perfusion and choroidal neovascularisation (CNV) was evaluated. Results OCTA images of 57 eyes of 48 subjects including 23 eyes (40.3%) with CNV, 13 eyes (22.8%) with dry age-related macular degeneration, 9 eyes (15.7%) with cystoid macular oedema due to diabetic retinopathy or retinal vein occlusion and 12 normal eyes (21.1%) were available for evaluation. At least one type of artefact was present in the images from 51 eyes (89.4%). Banding artefact, segmentation, motion, unmasking, blink, vessel doubling, masking and out-of-window artefacts were found in 51 (89.4%), 35 (61.4%), 28 (49.1%), 9 (15.8%), 5 (8.8%), 1 (1.7%), 1 eye (1.7%) and 1 eye (1.7%), respectively. Projection artefact, stretch artefact or crisscross artefact was not observed. Banding, motion and segmentation artefacts were statistically significantly more frequent in eyes with ocular pathology compared with control eyes (all p<0.001). Eyes with choroidal diseases had significantly higher rate of segmentation error in the choriocapillaris slab compared with eyes with only retinal disease (p=0.02). In nine eyes (17.6%), the artefacts were deemed severe enough by the graders to preclude accurate grading of the image. Conclusions Image artefacts occur frequently in OCTA images. The artefacts are more frequent in eyes with pathology.

Retinal Capillary Network and Foveal Avascular Zone in Eyes with Vein Occlusion and Fellow Eyes Analyzed With Optical Coherence Tomography Angiography.

PURPOSE To evaluate the perifoveolar retinal capillary network at different depths and to quantify the foveal avascular zone (FAZ) in eyes with retinal vein occlusion (RVO) compared with their fellow eyes and healthy controls using spectral-domain optical coherence tomography angiography (SD-OCTA). METHODS We prospectively recruited 23 patients with RVO including 15 eyes with central RVO (CRVO) and 8 eyes with branch RVO (BRVO), their fellow eyes, and 8 age-matched healthy controls (8 eyes) for imaging on prototype OCTA software within RTVue-XR Avanti. The 3 × 3 mm and 6 × 6 mm en face angiograms of superficial and deep retinal capillary plexuses were segmented. Perifoveolar retinal capillary network was analyzed and FAZ was quantified. RESULTS Decrease in vascular perfusion at the deep plexus was observed in all eyes with CRVO (8/8, 100%) and BRVO (6/6, 100%) without cystoid macular edema, and in 8 of 15 (53%) and 2 of 8 (25%) of the fellow eyes, respectively. Vascular tortuosity was observed in 13 of 15 (87%) CRVO and 5 of 8 (63%) BRVO eyes. Collaterals were seen in 10 of 15 (67%) CRVO and 5 of 8 (63%) BRVO eyes. Mean FAZ area was larger in eyes with RVO than their fellow eyes (1.13 ± 0.25 mm2 versus 0.58 ± 0.28 mm2; P = 0.007) and controls (1.13 ± 0.25 mm2 versus 0.30 ± 0.09 mm2; P < 0.0001), and in fellow eyes of RVO patients when compared to controls (0.58 ± 0.28 mm2 versus 0.30 ± 0.09 mm2; P = 0.01). CONCLUSIONS Spectral-domain OCTA reveals abnormalities at different levels of perifoveolar retinal capillary network and is able to quantify the FAZ in RVO. Longitudinal studies may be considered to evaluate the clinical utility of OCTA in RVO and other retinal vascular diseases.

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.