David Sarraf

Tears Of The Retinal Pigment Epithelium: An Old Problem in a New Era

Background/Purpose: Recent attention has focused upon several reports of retinal pigment epithelium (RPE) tears following vascular endothelial growth factor (VEGF)–modulating therapy. The authors review the clinical features, etiologies, imaging characteristics, and pathogenesis of RPE tears and their relationship with intravitreal anti-VEGF treatments. Methods: The authors conducted a comprehensive literature search of RPE tears or rips of any etiology using the PubMed database. They have also included a retrospective analysis of an additional five cases of RPE tears following anti-VEGF therapy, four after bevacizumab and one after ranibizumab. Results: Thirty-three cases of RPE tear after treatment with pegaptanib, bevacizumab, or ranibizumab have been previously reported in the literature. The authors have collected and analyzed the clinical features for 25 of these cases for which this information was available. The authors have also included analysis of an additional five cases. Common features of each of these 30 cases included advanced age of the patient, the presence of fibrovascular pigment epithelial detachment (PED) or PED associated with choroidal neovascularization (CNV), and diagnosis of the tear within 4 to 8 weeks of the first or second injection. Conclusions: RPE tears may develop during the course of anti-VEGF therapy for age-related macular degeneration–related PED. Patients with high-risk lesions, especially large irregular PED associated with CNV, should be counseled and monitored for this complication, which may limit visual prognosis.

Predictors Of Anti-vegf-associated Retinal Pigment Epithelial Tear Using Fa And Oct Analysis

Purpose: To identify fluorescein angiography and optical coherence tomography (OCT) predictors for retinal pigment epithelial (RPE) tear in eyes with pigment epithelium detachment (PED) associated with neovascular age-related macular degeneration treated with intravitreal vascular endothelial growth factor (VEGF) modulating therapy. Design: Retrospective comparative case series. Methods: In a single institutional center, 60 consecutive patients with PED and neovascular age-related macular degeneration treated with VEGF modulating therapy (either pegaptanib, bevacizumab, or ranibizumab) for more than a 27-month period were included in the study. Fluorescein angiography (FA) and OCT imaging was performed before and after anti-VEGF therapy. Formal statistical analysis comparing the tear group to the nontear group was performed to identify high-risk features for RPE tear. Results: RPE tear rate for eyes with vascularized PED receiving anti-VEGF therapy was 17% (10/60). There were highly statistically significant differences in the median PED size on fluorescein angiography (greatest linear diameter) (3.2 mm versus 1.8 mm, respectively; P < 0.001) and in the median maximum PED height on OCT (394 &mgr;m versus 149 &mgr;m, respectively; P = 0.001) between the tear group and nontear group. There was also a significant difference in terms of the presence of subretinal fluid on OCT between the two groups (87.5% versus 39%, respectively; P = 0.019). Conclusion: Large PED basal diameter and vertical height are correlated with an increased risk of developing an RPE tear after anti-VEGF therapy. Patients with large vascularized PED by fluorescein angiography and/or OCT analysis should be alerted of the risk for vision loss due to RPE tear after anti-VEGF therapy.

Acute macular neuroretinopathy: long-term insights revealed by multimodal imaging.

Purpose: To report the structural and functional changes in acute macular neuroretinopathy (AMN) and their long-term evolution. Multimodal retinal imaging was acquired, including Fourier domain optical coherence tomography (OCT), infrared (IR) reflectance, and near IR autofluorescence (NIA). Methods: In this retrospective observational case series, detailed clinical history and multimodal imaging are reported in eight patients with AMN. Manual segmentation of the Fourier domain OCT volume scans was done in one patient with the largest AMN lesion to yield retinal sublayer topographic maps. Results: Two patients were seen within the first 1 to 2 days of symptoms, and both showed outer nuclear and outer plexiform layer hyperreflectivity. Both patients developed enlargement of the lesion over the first week on IR reflectance imaging with a corresponding lateral extension of the outer retinal disruption on Fourier domain OCT. Thinning of the outer nuclear layer persisted in all patients with lesions >100 &mgr;m width, and in one patient this thinning worsened over the course of follow-up, as noted on the sublayer maps. This structural abnormality correlated with long-term functional deficits, persisting up to 14 months after the initial episode. Infrared reflectance highlights the lesion best, and abnormalities on near IR autofluorescence may be present. Conclusion: Acute macular neuroretinopathy acutely affects the outer nuclear and plexiform layers manifesting as OCT hyperreflectivity. The hallmark long-term changes are outer nuclear thinning on Fourier domain OCT and a fading dark lesion on IR reflectance imaging. These changes correspond to focal disruption of the outer segment/retinal pigment epithelium junction on OCT, and not the inner segment/outer segment junction, as previously reported. Optical coherence tomography and near IR autofluorescence abnormalities suggest previously unrecognized melanin and retinal pigment epithelium derangements in this condition.

Paraneoplastic and non-paraneoplastic retinopathy and optic neuropathy: Evaluation and management

Paraneoplastic syndromes involving the visual system are a heterogeneous group of disorders occurring in the setting of systemic malignancy. Timely recognition of one of these entities can facilitate early detection and treatment of an unsuspected, underlying malignancy, sometimes months before it would have otherwise presented, and gives the patient an increased chance at survival. We outline the clinical features, pathogenesis, and treatment strategies for the retinal- and optic nerve-based paraneoplastic syndromes: cancer-associated retinopathy; melanoma-associated retinopathy; paraneoplastic vitelliform maculopathy; bilateral diffuse uveal melanocytic proliferation; paraneoplastic optic neuropathy; and polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome. Distinguishing these disorders from their non-paraneoplastic counterparts (e.g., autoimmune-related retinopathy and optic neuropathy, and acute zonal occult outer retinopathy) and determining appropriate systemic evaluation for the responsible tumor can be challenging. In addition, we discuss the utility and interpretation of autoantibody testing.

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

OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY OF TYPE 3 NEOVASCULARIZATION SECONDARY TO AGE-RELATED MACULAR DEGENERATION.

Purpose: To characterize the vascular structure of Type 3 neovascularization secondary to age-related macular degeneration using optical coherence tomography angiography. Methods: Optical coherence tomography angiography cube scans (3 mm × 3 mm) were acquired in 29 eyes of 24 patients with Type 3 lesions secondary to age-related macular degeneration using the RTVue XR Avanti with AngioVue, Split-spectrum amplitude-decorrelation, and motion correction technology. Automated layer segmentation boundaries were adjusted to best visualize the neovascular complex on en face projection images. Results: A distinct neovascular complex could be identified in 10 (34%) eyes, all of which were active on optical coherence tomography imaging. In all 10 eyes, the neovascular complex appeared as a small tuft of bright, high-flow tiny vessels with curvilinear morphology located in the outer retinal layers with a feeder vessel communicating with the inner retinal circulation (i.e., deep retinal capillary plexus). The mean (SD) size of the neovascular complex measured 0.07 (± 0.07) mm2. Conclusion: With optical coherence tomography angiography, it is possible to identify small intraretinal neovascular complexes communicating with the deep retinal capillary plexus in eyes with Type 3 neovascularization secondary to age-related macular degeneration. Qualitative and quantitative analyses of Type 3 neovascular complexes can be performed using optical coherence tomography angiography.

RPE tears after pegaptanib treatment in age-related macular degeneration.

Purpose: To describe retinal pigment epithelial (RPE) tears in patients with age-related macular degeneration (AMD) status post pegaptanib (Macugen) injection. Methods: Six eyes from six patients who developed RPE tears while undergoing treatment with pegaptanib for AMD-related fibrovascular pigment epithelial detachment (PED) and occult choroidal neovascularization (CNV) were identified retrospectively. Diagnosis of pre-pegaptanib fibrovascular PED and post-pegaptanib RPE tears were made by clinical examination, fluorescein angiography (FA), and optical coherence tomography (OCT) imaging of the macula. Results: Four patients developed an RPE tear within 8 weeks after the first pegaptanib injection, while RPE tears were found in two patients following a second injection. Only one of the patients reported acute vision loss, although three of six eyes had a decrease in objective visual acuity in the affected eye to the count fingers level. All six cases displayed the classic clinical and angiographic appearance of RPE tears. In addition, OCT imaging showed an irregular, hyperreflective RPE layer with a focal defect. Conclusions: RPE tears are known to occur in the setting of PED spontaneously or after laser treatment, but have only recently been described in association with intravitreal pegaptanib. OCT imaging of eyes status post pegaptanib therapy may be helpful in identifying this complication. Patients with AMD, especially those with occult CNV and fibrovascular PED, receiving pegaptanib therapy should be monitored for RPE tears, which may warrant deferral of further injections.

A New Grading System For Retinal Pigment Epithelial Tears

Purpose: The purpose of this study was to assess the prognostic value of a new grading system for retinal pigment epithelium (RPE) tears that developed after antivascular endo-thelial growth factor (VEGF) therapy for exudative age-related macular degeneration. Methods: The authors performed a retrospective review of consecutive eyes that developed an RPE tear after intravitreal injection of an anti-VEGF agent (pegaptanib, bevacizumab, or ranibizumab) within a 4.5-year period (January 2005 to January 2009) at a single center. Fundus photography, fluorescein angiography, and optical coherence topography were studied for each case of RPE tear, and using fluorescein angiography analysis, a measurement of greatest linear diameter (millimeter) was obtained and a grading scale devised. The grade of RPE tear was correlated with visual and anatomical outcomes and response to continued anti-VEGF therapy. Results: Twenty-one eyes from 20 patients were evaluated in this study. Retinal pigment epithelium tears were graded from one to four based on the greatest length in the vector direction of the tear and involvement of the fovea. Nineteen percent (n = 4) of eyes had Grade 1 tears (diameter smaller than 200 μm), 14% (n = 3) had Grade 2 tears (diameter between 200 μm and 1-disk diameter), 19% (n = 4) had Grade 3 tears (diameter greater than 1-disk diameter), and 48% (n = 10) had Grade 4 tears (Grade 3 tears that involved the foveal center). Lower grade tears were more likely to have better visual acuity and better response to continued anti-VEGF therapy and less likely to develop a disciform scar but were at risk of progressing to a higher grade tear over time. Conclusion: The grading of RPE tears according to greatest linear diameter may have prognostic value in predicting visual acuity and anatomical outcome with or without continued anti-VEGF therapy. Lower grade tears have better visual acuity and response to anti-VEGF therapy. Grade 4 tears have a very poor prognosis with or without anti-VEGF therapy.

Retinal Capillary Density and Foveal Avascular Zone Area Are Age-Dependent: Quantitative Analysis Using Optical Coherence Tomography Angiography.

Purpose The purpose of this study was to quantify retinal capillary density and the foveal avascular zone (FAZ) area in normal subjects according to age, using optical coherence tomography angiography (OCTA). Methods All eyes in this cross-sectional study underwent OCTA using RTVue XR Avanti with AngioVue. OCTA scans were analyzed and processed, and vessel density and FAZ dimensions were calculated. Results A total of 113 normal eyes from 70 subjects were included (30 males, 40 females; mean 48 ± 20 years of age). The mean vessel density and FAZ dimensions were significantly smaller in the superficial retinal capillary plexus (SCP) than in the deep retinal capillary plexus (DCP), using quantitative OCTA analysis (all P< 0.0001). With 3 × 3-mm scans, the mean vessel density was 13.431 ± 1.758 mm-1 in the SCP, 18.812 ± 1.796 mm-1 in the DCP, and 5.913 ± 1.308 mm-1 and 10.447 ± 1.262 mm-1 with 6 × 6-mm scans in the SCP and DCP, respectively. Mean FAZ areas were 0.289 ± 0.108 mm2 at the SCP and 0.614 ± 0.200 mm2 at the DCP. Age was a predictor of SCP and DCP vessel density and FAZ area in the SCP. Vessel density decreased 0.0393 mm-1 (0.26%) per year in the SCP and 0.0574 mm-1 (0.27%) per year in the DCP. FAZ areas increased 0.0014 mm2 (0.63%) and 0.0011 mm2 (0.20%) per year in the SCP and DCP, respectively. Conclusions SCP and DCP vessel density decreased with increasing age, while FAZ area increased with age. Normal age-matched measurements provide important standardized values that may facilitate management of retinal vascular disorders.

The use of ultra wide field fluorescein angiography in evaluation and management of uveitis.

Purpose: Uveitis can occur in all segments of the eye and has multiple etiologies, (many of which remain poorly understood). Appropriate diagnosis and subsequent management can depend on elucidation of the clinical signs. Many diagnostic features are often best identified with Fluorescein angiography. However these signs are often peripheral and visualization can be difficult with traditional angiography. Optos ultra wide field scanning laser ophthalmoscope (Optos Panoramic 200MA; Optos PLC, Dunfermline, Scotland, United Kingdom) performs ultra wide angle fluorescein angiography and its benefit in uveitis was reviewed. Design: The Jules Stein Eye Institute retina division imaging database was reviewed and five common cases were selected. Methods: The relative benefits of wide field angiography were evaluated in each of these cases. Results: Ultra wide field angiography was found to have advantages compared to traditional angiography. It allowed clear identification of peripheral signs and accurate documentation of disease progression. Conclusion: In this division ultra wide field angiography has become the investigation of choice (over traditional angiography) in cases of intermediate and posterior uveitis.