A Quantitative Approach to Predict Differential Effects of Anti-VEGF Treatment on Diffuse and Focal Leakage in Patients with Diabetic Macular Edema: A Pilot Study.


We use semiautomated segmentation of fluorescein angiography (FA) to determine whether anti-vascular endothelial growth factor (VEGF) treatment for diabetic macular edema (DME) differentially affects microaneurysm (MA)-associated leakage, termed focal leakage, versus non-MA-associated leakage, termed diffuse leakage.We performed a retrospective study of 29 subjects treated with at least three consecutive injections of anti-VEGF agents for DME (mean 4.6 injections; range, 3-10) who underwent Heidelberg FA before and after anti-VEGF therapy. Inclusion criteria were macula center involving DME and at least 3 consecutive anti-VEGF injections. Exclusion criteria were macular edema due to cause besides DME, anti-VEGF within 3 months of initial FA, concurrent treatment for DME besides anti-VEGF, and macular photocoagulation within 1 year. At each time point, total leakage was semiautomatically segmented using a modified version of our previously published software. Microaneurysms were identified by an expert grader and leakage within a 117 μm radius of each MA was classified as focal leakage. Remaining leakage was classified as diffuse leakage. The absolute and percent changes in total, diffuse, and focal leakage were calculated for each subject.Mean pretreatment total leakage was 8.2 mm2 and decreased by a mean of 40.1% (P < 0.0001; 95% confidence interval [CI], [-28.6, -52.5]) following treatment. Diffuse leakage decreased by a mean of 45.5% (P < 0.0001; 95% CI, [-31.3, -59.6]) while focal leakage decreased by 17.9% (P = 0.02; 95% CI, [-1.0, -34.8]). The difference in treatment response between focal and diffuse leakage was statistically significant (P = 0.01).Anti-VEGF treatment for DME results in decreased diffuse leakage but had relatively little effect on focal leakage as assessed by FA. This suggests that diffuse leakage may be a marker of VEGF-mediated pathobiology. Patients with predominantly focal leakage may be less responsive to anti-VEGF therapy.Fluorescein angiography can define focal and diffuse subtypes of diabetic macular edema and these may respond differently to anti-VEGF treatment.





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Publication Info

Allingham, Michael J, Dibyendu Mukherjee, Erin B Lally, Hossein Rabbani, Priyatham S Mettu, Scott W Cousins and Sina Farsiu (2017). A Quantitative Approach to Predict Differential Effects of Anti-VEGF Treatment on Diffuse and Focal Leakage in Patients with Diabetic Macular Edema: A Pilot Study. Translational vision science & technology, 6(2). p. 7. 10.1167/tvst.6.2.7 Retrieved from https://hdl.handle.net/10161/17288.

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Michael John Allingham

Assistant Professor of Ophthalmology

Michael Allingham, MD PhD is a retina fellowship-trained clinician scientist with expertise in the diagnosis and treatment of medical conditions affecting the retina. Trained in the interpretation of retinal vascular imaging techniques, including video fluorescein angiography (FA) and indocyanine green (ICG) angiography, he specializes in the use of these imaging studies to guide injection and laser-based treatment of disease. His research focuses on using a mouse model of retinal edema to elucidate the role of Müller cell dysfunction in diseases such as diabetic macular edema and retinal vein occlusion. He also studies the use of computer aided image analysis in predicting response to specific treatment modalities in patients with diabetic macular edema. Dr. Allingham’s ultimate goal is to develop new therapies for macular edema and to better utilize ocular image analysis techniques to guide individualized treatment of his patients.

Dr. Allingham attended Duke University where he earned a B.S. in Chemistry with Distinction. He next pursued his M.D./Ph.D. at the nearby University of North Carolina. He earned his Ph.D. in Cell and Developmental Biology in the lab of Keith Burridge, Ph.D., an internationally recognized expert in cell adhesion. As a graduate student, Dr. Allingham studied the role of leukocyte-endothelial adhesive interactions in the endothelial regulation of leukocyte diapedesis. Upon completing his M.D./Ph.D., he returned to Duke for his internship, residency in ophthalmology and fellowship in medical retina before accepting a faculty position in the Duke Eye Center Department of Ophthalmology.


Priyatham S Mettu

Assistant Professor of Ophthalmology

Dr. Mettu, MD is a fellowship-trained ophthalmologist, specializing in the diagnosis, treatment, and research of macular diseases. His clinical practice focuses on the medical treatment of diabetic retinopathy, age-related macular degeneration, and retinal vascular diseases. He has an active clinical and laboratory research program at the Duke Center for Macular Diseases as part of the National Institutes of Health-sponsored K12 program. Dr. Mettu is actively involved in clinical trials of new therapies for macular diseases. He is developing novel imaging technologies that will facilitate customized treatment plans for patients with diabetic macular edema and age-related macular degeneration. Dr. Mettu is a recipient of the prestigious Heed Foundation Fellowship and the Isbey Award for excellence in clinical care, ethics, and research.


Scott William Cousins

Robert Machemer, M.D. Distinguished Professor of Ophthalmology

Scott W. Cousins, M.D. is currently the Robert Machemer, M.D. Professor of Ophthalmology and Immunology, Vice Chair for Research, and Director of the Duke Center for Macular Diseases at Duke Eye Center. As Vice Chair, he oversees all basic science research as well as the Ophthalmology Site-Based Research Group, which administrates clinical research for Duke Eye Center. Dr. Cousins is also Medical Director of Hospital-Based Imaging and Procedures for Duke Eye Center.

Dr. Cousins is a retina-trained ophthalmologist who specializes in the diagnosis and treatment of macular diseases, especially age-related macular degeneration (AMD), diabetic retinopathy, and retinal vascular diseases. Dr. Cousins is active in both clinical and laboratory research. In his clinical practice, Dr. Cousins is involved in many trials and innovative therapies for the treatment of macular diseases, especially AMD and diabetic retinopathy. He has served as site PI for numerous phase1-3 clinical trials in AMD, diabetic retinopathy, and other retinal disorders. He has served as a consultant or member of data safety monitoring committees (DSMC) for numerous pharmaceutical and biotechnology startup companies.

In his scientific laboratory, Dr. Cousins pursues both NIH-funded and industry-funded research in various areas of dry and wet AMD. In particular, he is studying the role of circulating bone marrow-derived progenitors (stem cells) in contributing to wet AMD. His laboratory is attempting to develop treatments for dry macular degeneration and improving vision in eyes with wet macular degeneration. His program is also developing blood tests and new imaging technologies for the identification of patients who are at high risk for progressing into complications.

Dr. Cousins has published over 100 peer-reviewed manuscripts, book chapters, and other publications addressing topics of research or clinical care of retinal disease, especially AMD. In 2006, Dr. Cousins was awarded the prestigious Alcon Research Foundation Clinician Scientist Award. In 2008, the National Institutes of Health invited Dr. Cousins to join the National Advisory Eye Council. Dr. Cousins is also a member of the American Academy of Ophthalmology, the American Society of Retina Specialists, the Retina Society, the Association for Research in Vision and Ophthalmology, the American Association of Immunologists, and the American Medical Association.

In 2010, Dr. Cousins was named one of the “Top 34 Ophthalmologists in the United States” by Becker’s ASC Review, a leading source of business and legal news for ambulatory surgery centers. They cited his leadership of the Duke Center for Macular Diseases and his ongoing research in macular degeneration as reasons for the honor.


Sina Farsiu

Anderson-Rupp Professor of Biolmedical Engineering

I am the director of the Vision and Image Processing (VIP) Laboratory. Along with my colleagues, we investigate how to improve early diagnostic methods and find new imaging biomarkers of ocular and neurological diseases in adults (e.g. age-related macular degeneration, diabetic retinopathy, Glaucoma, Alzheimer) and children (e.g. retinopathy or prematurity). We also develop automatic artificial intelligence machine learning and deep learning algorithms to detect/segment/quantify anatomical/pathological structures seen on medical images.

On another front, we study efficient signal processing based methods to overcome the theoretical and practical limitations that constrain the achievable resolution of any imaging device. Our approach, which is based on adaptive extraction and robust fusion of relevant information from the expensive and sophisticated as well as simple and cheap sensors, has found wide applications in improving the quality of imaging systems such as ophthalmic SD-OCT, digital X-ray mammography, electronic and optical microscopes, and commercial digital camcorders. We are also interested in pursuing statistical signal processing based projects, including super-resolution, demosaicing, deblurring, denoising, motion estimation, compressive sensing/adaptive sampling, and sensor fusion.

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