Clinical Strategies in the Management of Diabetic Retinopathy

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1 Clinical Strategies in the Management of Diabetic Retinopathy

3 Francesco Bandello Marco Attilio Zarbin Rosangela Lattanzio Ilaria Zucchiatti Editors Clinical Strategies in the Management of Diabetic Retinopathy A step-by-step Guide for Ophthalmologists

4 Editors Francesco Bandello Department of Ophthalmology University Vita-Salute Scientific Institute San Raffaele Milano Italy Marco Attilio Zarbin Department of Ophthalmology Rutgers University Newark, NJ USA Rosangela Lattanzio Department of Ophthalmology University Vita-Salute Scientific Institute San Raffaele Milan Italy Ilaria Zucchiatti Department of Ophthalmology University Vita-Salute Scientific Institute San Raffaele Milan Italy ISBN ISBN (ebook) DOI / Springer Heidelberg New York Dordrecht London Library of Congress Control Number: Springer-Verlag Berlin Heidelberg 2014 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. Exempted from this legal reservation are brief excerpts in connection with reviews or scholarly analysis or material supplied specifically for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work. Duplication of this publication or parts thereof is permitted only under the provisions of the Copyright Law of the Publisher's location, in its current version, and permission for use must always be obtained from Springer. Permissions for use may be obtained through RightsLink at the Copyright Clearance Center. Violations are liable to prosecution under the respective Copyright Law. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. While the advice and information in this book are believed to be true and accurate at the date of publication, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper Springer is part of Springer Science+Business Media (

5 This book is dedicated to Professor Rosario Brancato who was a Master and a Pioneer in the fi eld of Diabetic Retinopathy diagnosis and treatment.

7 Foreword A new era in the management of diabetic retinopathy has started, offering for the first time recovery of visual acuity compared to previous treatments, such as laser photocoagulation which aimed at disease stabilization. However, in this new environment of recently approved treatments and new promising therapeutic strategies, clinicians are faced with difficult decisions to choose the appropriate practice in each individual case. The purpose of this practical guide is to assist ophthalmologists in making decisions in the management of diabetic retinopathy. This richly illustrated manual is based on the best evidence available and provides the practical and complete recommendations to guide clinicians in the management of diabetic retinopathy, including diagnosis, decision-making, and treatment. This book is designed to address all the different and complex stages of diabetic retinopathy starting from the early stages up to the more advanced and sightthreatening levels of the disease. The publication provides also new insights in the management and surgical approach of diabetic retinopathy, providing the more updated techniques to fight this serious eye disease. The chapters of this manual are enriched by practical tables and easy-to-read summaries that explain the progression of the disease and help the clinician to choose the best therapeutic approach. Moreover, the manual is enriched by algorithms that describe the suggested treatment approach, helping ophthalmologists in the difficult task of making treatment decisions. The text is supplemented by almost one hundred illustrations, which contain in some of the cases a further follow-up. Several clinical cases are presented through multipart figures that represent the evolution from baseline to final follow-up of the clinical features of the eyes that have been treated with the more recently introduced drugs and surgeries. The case reports run in parallel with the text, showing practical examples of the effects of the treatment described in the text. Clinical strategies in the management of diabetic retinopathy examine all stages of diabetic retinopathy to provide the latest developments in diagnosis and treatment of this severe disease. I believe that this contribution is timely and will be appreciated by anyone that is faced on a day-to-day basis with the management of diabetic patients with retinal disease. Coimbra, Portugal José Cunha-Vaz vii

9 Preface Diabetic retinopathy remains the leading cause of visual impairment among the working-age population. There is evidence that visual loss could be reduced substantially by strict glycometabolic and effective blood pressure control. Nevertheless, diabetic macular edema and proliferative diabetic retinopathy currently remain the more dramatic and sight-threatening complications, which need a prompt and effective treatment. For nearly a half century, focal laser photocoagulation was the only scientifically proven effective treatment to prevent visual loss due to diabetic macular edema. Recently, new intravitreal agents, such as anti-vascular endothelium growth factor agents and steroids, have been introduced in the management of the disease. The main advantage of the intravitreal injections compared to focal laser photocoagulation is the chance not only to prevent visual decline but also to promote visual recovery. In addition, combination therapy involving intravitreal injection and laser photocoagulation recently has been considered a promising strategy to improve the results further. In some cases of diabetic macular edema and advanced proliferative diabetic retinopathy, surgical intervention with pars plana vitrectomy and membrane peeling remains the mainstay of treatment. Considerable evidence now shows that prompt treatment is necessary to prevent the visual impairment from non-proliferative as well as from proliferative diabetic retinopathy. However, the introduction of several treatment strategies has created the need for new worldwide guidelines to manage all the stages of diabetic retinopathy. This book derives from two different schools, the European and the American groups, which are geographically distant from each other, but share the same approach and methodology in the management of this complex disease, diabetic retinopathy, resulting from evidence-based medicine and from randomized clinical trials. This clinical manual covers all the stages of diabetic retinopathy, including clinical manifestations, imaging, and treatment, from the early signs to the more advanced levels of severity. This guide is designed to present to the reader multiple practical and useful suggestions for the management of each stage of diabetic retinopathy, using algorithms, tables, and summaries. ix

10 x Preface Images of sample cases help the reader to deepen his or her understanding of the effects of the different therapies, including benefits and side effects. Novel perspectives in the imaging and treatment are described clearly in order to show where current research in the field is focused. Milan, Italy Newark, NJ, USA Milan, Italy Milan, Italy Francesco Bandello, MD, FEBO Marco Attilio Zarbin, MD, PhD Rosangela Lattanzio, MD Ilaria Zucchiatti, MD

11 Contents 1 Epidemiology, Risk Factors, and Pathophysiology of Diabetic Retinopathy... 1 Neelakshi Bhagat and Marco Attilo Zarbin 2 Non-proliferative Diabetic Retinopathy Francesco Bandello, Rosangela Lattanzio, Ilaria Zucchiatti, and Giuseppe Petruzzi 3 Diabetic Macular Edema Francesco Bandello, Ilaria Zucchiatti, Rosangela Lattanzio, and Chiara Preziosa 4 Proliferative Diabetic Retinopathy Francesco Bandello, Rosangela Lattanzio, Ilaria Zucchiatti, and Gisella Maestranzi 5 Advanced Proliferative Diabetic Retinopathy Neelakshi Bhagat and Marco Attilo Zarbin xi

13 Contributors Francesco Bandello, MD, FEBO Department of Ophthalmology, University Vita-Salute, Scientific Institute San Raffaele, Milan, Italy Neelakshi Bhagat, MD, MPH, FACS Institute of Ophthalmology and Visual Science, New Jersey Medical School, Rutgers University, Newark, NJ, USA José Cunha-Vaz, MD, PhD AIBILI Association for Innovation and Biomedical Research on Light and Image, Faculty of Medicine of University of Coimbra, Coimbra, Portugal Rosangela Lattanzio, MD Department of Ophthalmology, University Vita-Salute, Scientific Institute San Raffaele, Milan, Italy Gisella Maestranzi, MD Department of Ophthalmology, University Vita-Salute, Scientific Institute San Raffaele, Milan, Italy Giuseppe Petruzzi, MD Department of Ophthalmology, University Vita-Salute, Scientific Institute San Raffaele, Milan, Italy Chiara Preziosa, MD Department of Ophthalmology, University Vita-Salute, Scientific Institute San Raffaele, Milan, Italy Marco Attilio Zarbin, MD, PhD Department of Ophthalmology, University Hospital, Newark, NJ, USA Institute of Ophthalmology and Visual Science, New Jersey Medical School, Rutgers University, Newark, NJ, USA Ilaria Zucchiatti, MD Department of Ophthalmology, University Vita-Salute, Scientific Institute San Raffaele, Milan, Italy xiii

15 Acronyms AAO ACCORD ACE ADA AGEs AMPK AOA AOSLO ARB BCVA BOLT BRB CARDS CME CRT CSME CT CTGF CVD DA VINCI DCCT DEGAS DEX DIRECT DiVFuSS DM DME DR DRCR.net DRS DRVS EDI American Academy of Ophthalmology Action to Control Cardiovascular Risk in Diabetes Angiotensin-Converting Enzyme American Diabetes Association Advanced Glycation End Products 5 Adenosine Monophosphate-activated Protein Kinase American Optometric Association Adaptive Optics Scanning Laser Ophthalmoscope Angiotensin Receptor Blocker Best-Corrected Visual Acuity Bevacizumab or Laser Therapy Study Blood-Retinal Barrier Collaborative Atorvastatin Diabetes Study Cystoid Macular Edema Central Retinal Thickness Clinically Significant Macular Edema Choroidal Thickness Connective Tissue Growth Factor Cardiovascular Disease Phase 2 Primary Results of VEGF Trap-eye in Patients with Diabetic Macular Edema Study Diabetes Control and Complications Trial Dose-ranging Evaluation of Intravitreal sirna PF for Diabetic Macular Edema Study Dexamethasone Diabetic Retinopathy Candesartan Trial Diabetes Visual Function Supplement Study Diabetes Mellitus Diabetic Macular Edema Diabetic Retinopathy Diabetic Retinopathy Clinical Research Network Diabetic Retinopathy Study Diabetic Retinopathy Vitrectomy Study Enhanced Depth Imaging xv

16 xvi Acronyms EDIC Epidemiology of Diabetes Intervention and Complications Study ELM External Limiting Membrane ERG Electroretinogram ERM Epiretinal Membrane ETDRS Early Treatment Diabetic Retinopathy Study EU European Union EUCLID EURODIAB Controlled Trial of Lisinopril in Insulin-Dependent Diabetes Mellitus FA Fluorescein Angiography FAME Fluocinolone Acetonide in Patients with Diabetic Macular Edema Study FDA Food and Drug Administration FIELD Fenofibrate Intervention and Event Lowering in Diabetes Study GCC Ganglionar Cell Complex GIP Glucose-dependent Insulinotropic Peptide GLP-1 Glucagon-Like Peptide-1 HbA1c Glycated/glycosylated Hemoglobin HDL High-Density Lipoprotein HDL-C High-Density Lipoprotein Cholesterol IBEME Intravitreal Triamcinolone versus Bevacizumab for Treatment of Refractory Diabetic Macular Edema Study IBEPE Intravitreal Bevacizumab for Persistent New Vessels in Diabetic Retinopathy Study ICAM-1 Intercellular Adhesion Molecule-1 IL-6 Interleukine-6 ILM Internal Limiting Membrane IOP Intraocular Pressure IRMA Intraretinal Microvascular Abnormality IS/OS Internal Segment/Outer Segment IVA Intravitreal Aflibercept IVB Intravitreal Bevacizumab IVFA Intravitreal Fluocinolone Acetonide IVP Intravitreal Pegaptanib IVR Intravitreal Ranibizumab IVTA Intravitreal Triamcinolone Acetonide LDL Low-Density Lipoprotein LDL-C Low-Density Lipoprotein Cholesterol MATISSE Dose Escalation Study, and Evaluation of PF With/Without Ranibizumab in Diabetic Macular Edema metdrs Modified Early Treatment Diabetic Retinopathy Study mferg Multifocal Electroretinogram MLP Macular Laser Photocoagulation MMG Mild Macular Grid MMP-9 Matrix Metallopeptidase 9 MMPs Metalloproteinases MPC Macular Photocoagulation MVL Moderate Visual Loss

17 Acronyms xvii NPDR Non-Proliferative Diabetic Retinopathy NSAID Non-Steroidal Anti-Inflammatory Drug NV/NVs New Vessels NVD Neovascularization of the Disc NVE Neovascularization Elsewhere NVI Neovascularization of the Iris NVG Neovascular Glaucoma OCT Optical Coherence Tomography OLE Open-Label Extension ONL Outer Nuclear Layer OPL Outer Plexiform Layer PASCAL Pattern Scan Laser PDR Proliferative Diabetic Retinopathy PEDF Pigment Epithelium-Derived Factor P-VEP Pattern Visual Evoked Potentials PGF Placental Growth Factor PKC Protein Kinase C PKC-DRS Protein Kinase C Beta Inhibitor Diabetic Retinopathy Study PKC-DRS2 Protein Kinase C Diabetic Retinopathy Study 2 PKC-β β-isoform of PKC POC1 Proof-of-Concept 1 POC2 Proof-of-Concept 2 PPAR Peroxisome Proliferator-Activated Receptor PPV Pars Plana Vitrectomy PRN Pro Re Nata PRP Panretinal Photocoagulation PVD Posterior Vitreous Detachment RAGEs Receptors for Advanced Glycation End Products RAS Renin-Angiotensin System RASS Renin-Angiotensin System Study RBX Ruboxistaurin RCT Randomized Clinical Trial RD Retinal Detachment READ-1 Ranibizumab for Edema of the Macula in Diabetes Study 1 READ-2 Ranibizumab for Edema of the Macula in Diabetes Study 2 RESOLVE Safety and Efficacy of Ranibizumab in Diabetic Macular Edema with Center Involvement Study RESTORE Ranibizumab Monotherapy or Combined with Laser versus Laser Monotherapy for Diabetic Macular Edema Study RIDE Ranibizumab Injection in Subjects with Clinically Significant Macular Edema (ME) with Center Involvement Secondary to Diabetes Mellitus Study RISE Ranibizumab Injection in Subjects with Clinically Significant Macular Edema (ME) with Center Involvement Secondary to Diabetes Mellitus Study RNFL Retinal Nerve Fiber Layer

18 xviii Acronyms ROCK RPE SD-OCT SDRT sirna SLO SMVL srage SRD SVL T1DM T2DM TGF-ß2 TNF TNF-α TRD UKPDS US VAS VCAM-1 VEGF VH VLDL VMA VMT VTDR WESDR RhoA/Rho kinase Retinal Pigment Epithelium Spectral-Domain Optical Coherence Tomography Sponge-like Diffuse Retinal Thickening Small-interfering RNA Scanning Laser Ophthalmoscopy Severe and Moderate Visual Loss Soluble Receptor for Advanced Glycation End Product Serous Retinal Detachment Severe Visual Loss Type 1 Diabetes Mellitus Type 2 Diabetes Mellitus Transforming Growth Factor-ß2 Tumor Necrosis Factor Tumor Necrosis Factor α Traction Retinal Detachment United Kingdom Prospective Diabetes Study Ultrasonography Visual Analog Scale Vascular Cell Adhesion Molecule-1 Vascular Endothelium Growth Factor Vitreous Hemorrhage Very Low-Density Lipoprotein Vitreo-Macular Adhesion Vitreo-Macular Traction Vision-Threatening Diabetic Retinopathy Wisconsin Epidemiologic Study of Diabetic Retinopathy

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