Diabetic Macular Edema

Foreword
Preface
Contents
About the Editors
1: Diabetic Macular Edema: An Introduction
	1.1	 Diabetic Macular Edema: Introduction
	References
2: Pathophysiology of Diabetic Macular Edema
	2.1	 Introduction
	2.2	 Pathophysiology of Diabetic Macular Edema
		2.2.1	 Alteration of Blood–Retinal Barrier
		2.2.2	 Outer Blood–Retinal Barrier
		2.2.3	 Inner Blood–Retinal Barrier
	2.3	 Mechanisms of Disease
		2.3.1	 Oxidative Stress
		2.3.2	 Mitochondrial Alterations
		2.3.3	 Vascular Dysfunction
	2.4	 Inflammation
		2.4.1	 Molecules Involved and Therapeutic Potential
		2.4.2	 Growth Factors
		2.4.3	 Cytokines and Chemokines
	2.5	 Pharmacotherapies in Diabetic Macular Edema
	2.6	 Strategies for the Future: Current Clinical Trials in DME
	2.7	 Conclusion
	References
3: Optical Coherence Tomography Biomarkers in Diabetic Macular Edema
	3.1	 Introduction
	3.2	 OCT Biomarkers in Diabetic Macular Edema
	3.3	 Retinal Biomarkers
		3.3.1	 Retinal Thickness
		3.3.2	 Disorganization of Retinal Inner Layers
		3.3.3	 Hyperreflective Retinal Foci and Hard Exudates
		3.3.4	 Intraretinal Cystoid Spaces
		3.3.5	 Pearl Necklace Sign
		3.3.6	 Bridging Retinal Processes
		3.3.7	 Subfoveal Neurosensory Detachment
		3.3.8	 Vitreomacular Interface
		3.3.9	 Integrity of External Limiting Membrane and Ellipsoid Zone
		3.3.10	 Photoreceptor Outer Segment
		3.3.11	 Outer Retinal Layer Thickness [41]
		3.3.12	 Retinal Pigment Epithelium Thickness
		3.3.13	 Foveal Eversion
		3.3.14	 Parallelism
	3.4	 Choroidal Biomarkers
		3.4.1	 Subfoveal Choroidal Thickness
		3.4.2	 Choroidal Vascularity Index
		3.4.3	 Hyperreflective Choroidal Foci
	3.5	 OCT Angiography Biomarkers in Diabetic Macular Edema
		3.5.1	 Foveal Avascular Zone
			3.5.1.1	 Vessel Density in Superficial Capillary Plexus [53]
			3.5.1.2	 Loss of Deep Capillary Plexus
			3.5.1.3	 Middle Capillary Plexus
	3.6	 Summary
	References
4: Optical Coherence Tomography Angiography in Diabetic Macular Edema
	4.1	 Introduction
	4.2	 Diabetic Macular Edema Biomarkers in OCT
		4.2.1	 Bridging Retinal Processes
		4.2.2	 Choroidal Vascular Index
		4.2.3	 Disorganization of Retinal Inner Layers
		4.2.4	 Hyperreflective Retinal Foci and Hard Exudates
		4.2.5	 Hyperreflective Choroidal Foci
		4.2.6	 Intraretinal Cystoid Spaces
		4.2.7	 Integrity of External Limiting Membrane and Ellipsoid Zone
		4.2.8	 Retinal Thickness
		4.2.9	 Photoreceptor Outer Segment
		4.2.10	 Subfoveal Choroidal Thickness
		4.2.11	 Subfoveal Neurosensory Detachment
		4.2.12	 Taut Posterior Hyaloid Membrane
	4.3	 DME Biomarkers in OCT Angiography
		4.3.1	 Foveal Avascular Zone
		4.3.2	 Intercapillary Spacing
		4.3.3	 Microaneurysms, Intraretinal Microvascular Abnormalities, Neovascularization, Nonperfusion Areas
		4.3.4	 Retinal Vascular Density
		4.3.5	 Suspended Scattering Particles in Motion
	References
5: Targeted Screening of Macular Edema by Spectral Domain Optical Coherence Tomography for Progression of Diabetic Retinopathy: Translational Aspects
	5.1	 Introduction
	5.2	 Spectral Domain Optical Coherence Tomography-Based Evaluation of Diabetic Macular Edema
	5.3	 Vascular Endothelial Growth Factor and Diabetic Macular Edema
	References
6: Anti-Vascular Endothelial Growth Factor Agents for Diabetic Macular Edema
	6.1	 Treatment of Diabetic Macular Edema Before Anti-VEGF
	6.2	 History of VEGF Blockade Development [2]
	6.3	 Anti-VEGF Agents for DME: The Present Day
		6.3.1	 Avastin (Bevacizumab)
		6.3.2	 Lucentis (Ranibizumab)
		6.3.3	 Eylea (Aflibercept)
	6.4	 Adverse Effects of Anti-VEGF Agents
	6.5	 Treatment Regimens
		6.5.1	 When to Treat?
		6.5.2	 PRN Regimen
		6.5.3	 Treat and Extend Regimen
	6.6	 Cost-Effectiveness
	6.7	 Anti-VEGF Agents: Head-to-Head
	6.8	 Future of Anti-VEGF
		6.8.1	 Conbercept
		6.8.2	 Beovu (Brolucizumab)
		6.8.3	 Faricimab
	6.9	 Novel Therapies in Production [21]
		6.9.1	 Abicipar Pegol
		6.9.2	 Port Delivery System
		6.9.3	 Thermosensitive Hydrogels
		6.9.4	 Microparticles
		6.9.5	 Gene Therapy
	6.10	 Conclusion
	References
7: Agents Targeting Angiopoietin/Tie Pathway in Diabetic Macular Edema
	7.1	 Roles of Angiopoietin/Tie Pathway in Retinal Diseases and Diabetic Macular Edema
	7.2	 Razuprotafib (AKB-9778)
		7.2.1	 Razuprotafib Mechanism of Action
		7.2.2	 Phase 1 DME Study
		7.2.3	 Phase 2 TIME-2 Study
	7.3	 Nesvacumab + Aflibercept Coformulation (REGN910-3)
		7.3.1	 Nesvacumab Mechanism of Action
		7.3.2	 Phase 1 Trial
		7.3.3	 Phase 2 RUBY Study
	7.4	 Faricimab (RG7716)
		7.4.1	 Faricimab Mechanism of Action
		7.4.2	 Phase 2 BOULEVARD Study
		7.4.3	 Phase 3 RHINE and YOSEMITE Studies
		7.4.4	 RHONE-X Study
	7.5	 Other Potential Agents Targeting Angiopoietin/Tie Pathway for DME
		7.5.1	 AXT107
		7.5.2	 BI 836880
	7.6	 Summary
	References
8: DRCR.net Trials for Diabetic Macular Edema
	8.1	 Introduction
	8.2	 Protocol A: A Pilot Study of Laser Photocoagulation for Diabetic Macular Edema
	8.3	 Protocol B: A Randomized Trial Comparing Intravitreal Triamcinolone Acetonide and Laser Photocoagulation for Diabetic Macular Edema
	8.4	 Protocol H: A Phase 2 Evaluation of Anti-VEGF Therapy for Diabetic Macular Edema: Bevacizumab (Avastin)
	8.5	 Protocol I: Intravitreal Ranibizumab or Triamcinolone Acetonide in Combination with Laser Photocoagulation for Diabetic Macular Edema
	8.6	 Protocol T: A Comparative Effectiveness Study of Intravitreal Aflibercept, Bevacizumab, and Ranibizumab for Diabetic Macular Edema
	8.7	 Protocol TX: A Comparative Effectiveness Study of Intravitreal Aflibercept, Bevacizumab, and Ranibizumab for Diabetic Macular Edema: Follow-Up Extension Study
	8.8	 Protocol U: Short-Term Evaluation of Combination Corticosteroid + Anti-VEGF Treatment for Persistent Central-Involved Diabetic Macular Edema Following Anti-VEGF Therapy
	References
9: Effect of Anti-VEGF Therapy on Inner and Outer Retinal Layers on Spectral-Domain Optical Coherence Tomography in Diabetic Macular Edema
	9.1	 Introduction
	9.2	 Pathogenesis of Diabetic Macular Oedema: Role of Vascular Endothelial Growth Factor
	9.3	 Pathomorphology of Different Layers of Retina in Diabetic Macular Edema
	9.4	 SD-OCT-Based Changes in Inner Retinal Layers in Diabetic Macular Edema
	9.5	 SD-OCT-Based Changes in Outer Retinal Layers in Diabetic Macular Edema
	9.6	 Role of Anti-VEGF Therapy in DME
	9.7	 Changes in Inner and Outer Layers of Retina Post Anti-VEGF Therapy Based on SD-OCT
	9.8	 Conclusion
	References
10: Diabetic Macular Ischemia and Anti-VEGF Therapy
	10.1	 Introduction
	10.2	 DMI
		10.2.1	 Pathogenesis
		10.2.2	 Diagnosis: FA
		10.2.3	 Diagnosis: OCTA
		10.2.4	 Visual Prognosis
	10.3	 DMI and Anti-VEGF
		10.3.1	 Influence of DMI on Anti-VEGF Therapy in Eyes with DME
		10.3.2	 Influence of Anti-VEGF on DMI
	References
11: Dexamethasone Implant in Diabetic Macular Edema
	11.1	 Introduction
	11.2	 Role of Inflammation in DME
	11.3	 Cataract Surgery and DME
	11.4	 Steroids as Therapeutic Option in DME
	11.5	 Dexamethasone Implant: Introduction
	11.6	 Role of Dexamethasone Implant in Current Clinical Practice: An Evidence-Based Approach
	11.7	 Dexamethasone Implant and Imaging Biomarkers of DME
		11.7.1	 Subretinal Fluid (SRF)/Subfoveal Serous Retinal Detachment (SSRD)
		11.7.2	 Hyperreflective Foci (HRF)
		11.7.3	 Hard Exudates
		11.7.4	 Disorganization of Retinal Inner Layers (DRIL)
	11.8	 Contraindications of DEX Implant
	11.9	 Summary
	References
12: Laser Photocoagulation for Diabetic Macular Edema
	12.1	 Introduction
	12.2	 Pathophysiology of DME
	12.3	 Clinical Diagnosis of DME
	12.4	 Definitions of DME
	12.5	 Laser Therapy for Diabetic Retinopathy
		12.5.1	 Types of Laser
		12.5.2	 Properties of Laser [19]
		12.5.3	 Laser Absorption Characteristics of Tissues
		12.5.4	 Laser Treatment of Macular Edema
		12.5.5	 Mechanism of Action
		12.5.6	 Complications
		12.5.7	 Newer Forms of Laser Therapy
			12.5.7.1	 Selective Laser Therapy
			12.5.7.2	 Subthreshold Diode Micropulse Laser
			12.5.7.3	 Pattern Laser for DME
			12.5.7.4	 Image Guided Laser Therapy: Navigated Laser
		12.5.8	 Perspective of Intravitreal Pharmacotherapy
		12.5.9	 Current Indications for Laser Therapy in DME
	References
13: Surgical Management for Diabetic Macular Edema
	13.1	 The Role of the Vitreous in the Genesis of Diabetic Macular Edema
		13.1.1	 The Role of Epiretinal Membrane in Diabetic Macular Edema
	13.2	 History of Vitrectomy for the Treatment of Diabetic Macular Edema
		13.2.1	 Limits of Early Studies
	13.3	 Present Knowledge and Adequate Surgical Indications
		13.3.1	 Vitreomacular Interface Alterations
		13.3.2	 Diffuse DME Without a Clinically Evident Tractional Component
		13.3.3	 Unresponsive Cases
		13.3.4	 Special Situations
	13.4	 Surgical Technique
		13.4.1	 The Role of ILM Peeling
			13.4.1.1	 Present Knowledge on ILM Peeling
		13.4.2	 Combined Treatments
		13.4.3	 Postoperative Complications
	13.5	 Postoperative Outcomes
		13.5.1	 Factors Affecting Postoperative Prognosis
	13.6	 Clinical Cases
		13.6.1	 Clinical Case 1
		13.6.2	 Clinical Case 2
		13.6.3	 Clinical Case 3
		13.6.4	 Clinical Case 4
		13.6.5	 Clinical Case 5
	References
14: Management of DME: One Minute Preceptor
	14.1	 Introduction
	14.2	 Clinical Cases
	References
15: Artificial Intelligence in the Management of Diabetic Macular Edema
	15.1	 Introduction
	15.2	 Diabetic Retinopathy Screening
	15.3	 Assessing Impact of Diabetes on Retinal Vasculature
	15.4	 Detecting Diabetic Macular Edema
	15.5	 Treatment of Diabetic Macular Edema
	15.6	 Limitations of Artificial Intelligence for Diabetic Retinopathy
	15.7	 Conclusion
	References
16: Endpoints of Anti-Vascular Endothelial Growth Factor Clinical Trials for Diabetic Macular Edema
	16.1	 Overview of Diabetic Macular Edema
	16.2	 Outcomes of a Clinical Trial
	16.3	 Endpoints of Anti-VEGF Trial for DME
	16.4	 Limitations of Endpoints in the Pre-(High-Definition) OCT Era
	16.5	 Newer Biomarkers for DME
		16.5.1	 Structural Biomarkers
		16.5.2	 Functional Biomarkers
	References
17: Nutrient Supplementation in Diabetic Macular Edema
	17.1	 Introduction
	17.2	 Macronutrients
		17.2.1	 Carbohydrates
		17.2.2	 Fats
		17.2.3	 Proteins and Co-Factors
			17.2.3.1	 Amino-Levulinic Acid
			17.2.3.2	 Coenzyme Q10
			17.2.3.3	 Lipoic Acid (LA, Alpha Lipoic Acid, Thioctic Acid)
			17.2.3.4	 N-Acetyl Cysteine
			17.2.3.5	 Trimethylglycine
			17.2.3.6	 Arginine
			17.2.3.7	 Homocysteine
	17.3	 Micronutrients
		17.3.1	 Vitamins
			17.3.1.1	 Vitamin A
			17.3.1.2	 Vitamin B
			17.3.1.3	 Vitamin B9, B12 and Homocysteine
			17.3.1.4	 Vitamin C and E
			17.3.1.5	 Vitamin D
		17.3.2	 Minerals
			17.3.2.1	 Zinc
			17.3.2.2	 Calcium
			17.3.2.3	 Magnesium
	17.4	 Naturaceuticals
	17.5	 Diet
	17.6	 Conclusion
	References
18: Quality of Life in Diabetic Macular Edema
	18.1	 Introduction
	18.2	 Scales for Assessment of QoL
		18.2.1	 EQ-5D
		18.2.2	 NEI VFQ-25
		18.2.3	 RetDQoL
	18.3	 Impact of QOL After Treatment
		18.3.1	 Laser Therapy
		18.3.2	 Anti-VEGF Therapy
	18.4	 Conclusion
	References
19: Diabetic Macular Edema in Young Adults
	19.1	 Introduction
	19.2	 Diabetic Macular Edema
		19.2.1	 Epidemiology
		19.2.2	 Risk Factors
			19.2.2.1	 Glycemic Control
			19.2.2.2	 Hypertension
			19.2.2.3	 Diabetic Nephropathy
			19.2.2.4	 Lipid Profile
		19.2.3	 Other Risk Factors
	19.3	 Diagnosis
		19.3.1	 Central Subfoveal Thickness
		19.3.2	 Morphological Phenotypes
		19.3.3	 Hyperreflective Foci
		19.3.4	 Angiographic Manifestations in DME
			19.3.4.1	 OCT Angiography
	19.4	 Treatment
		19.4.1	 Laser Therapy
		19.4.2	 Steroids
		19.4.3	 Anti-VEGF Therapy
		19.4.4	 Surgery
	19.5	 Systemic Diabetic Disease and Management
		19.5.1	 The Role of Metabolic Control
	19.6	 Conclusion
	References
20: Diabetic Retinopathy and Diabetic Macular Edema: Fighting the Emerging Global Burden
	20.1	 Introduction
	20.2	 Understanding the Disease Burden
	20.3	 Strategies for Disease Prevention
	20.4	 Role of National Screening Programmes for DR and DME
	20.5	 Role of Public Health Policy for Diabetic Retinopathy
	20.6	 Newer Advances and Future Prospects
		20.6.1	 Diagnosis and Screening
		20.6.2	 Predictive Medicine
		20.6.3	 Pharmacotherapy
		20.6.4	 Genetics and Epigenetics
	20.7	 Conclusion
	References