Pathophysiology of PDR

Diabetic retinopathy (DR) is a manifestation of end-organ ocular damage from systemic diabetes and chronically elevated blood glucose levels.1 While early stages of DR are typically classified as nonproliferative with varying stages of severity, proliferative diabetic retinopathy (PDR) develops as the disease progresses, often with significant visual consequences.1,2

Chronic hyperglycemia from diabetes leads to tissue damage from various mechanisms, including microvascular damage, increased vascular permeability, inflammation, oxidative stress, and capillary occlusion.2 As capillary occlusion progresses, retinal hypoxia and ischemia worsen, triggering the upregulation of neovascular factors, including vascular endothelial growth factor (VEGF).2 VEGF perpetuates the damaging effects of diabetes by elevating local inflammatory factors, increasing vascular permeability, and promoting local inflammatory infiltrates.2

Increasing levels of VEGF from continued ischemia stimulates neovascularization to bypass occluded retinal vasculature. These new blood vessels originate from existing capillaries, mainly between perfused and non-perfused retina.2 However, neovascularization can also occur in the optic disc, iris, or filtration angle.1 Vessels from neovascularization are fragile, permeable, and bleed very easily, leading to complications like vitreous or preretinal hemorrhages, retinal detachments, and neovascular glaucoma.1

Neovascularization blood vessels can cross the retinal internal limiting membrane (ILM) into the vitreous cavity, using the posterior vitreous face as a scaffold.6 Not only do these vessels bleed easily, but they are often accompanied by fibrous proliferation.6 This fibrotic scar tissue sticks to the vitreous and ILM.6 The fibrous tissue can contract, pulling on the retina and leading to retinal vessel rupture and vitreous hemorrhage with or without tractional retinal detachment.6

Over time, chronic inflammation and vascular damage also lead to a breakdown in the blood-retina barrier and increased retinal vascular permeability.2,8 This ultimately results in fluid leaking into the tissues of the retina, especially under the macula, termed diabetic macular edema (DME).2

DME can be seen at any stage of DR and sometimes progresses independently of the other DR findings.3 The pathogenesis of DME is not well understood, but it likely involves all of the pathways previously mentioned, including angiogenesis, inflammation, and oxidative stress.8 Protein deposits from this edema lead to waxy, yellow findings referred to as hard exudates.2 DME is classified based on whether the edema involves the 1 mm center subfield zone.3

PDR is the most severe form of diabetic retinopathy, and vision loss can be exacerbated by CI-DME.1 Severe complications, such as vitreous or preretinal hemorrhages, retinal detachments, fibrosis, and neovascular glaucoma are consequences of PDR that can lead to significant visual impairment.1


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Scientific Council

Neil M. Bressler, MD

James P. Gills Professor of Ophthalmology
Professor of Ophthalmology, Johns Hopkins University School of Medicine
Wilmer Eye Institute, Johns Hopkins Medicine
Baltimore, MD

A. Paul Chous, MA, OD, FAAO

Specializing in Diabetes Eye Care & Education, Chous Eye Care Associates
Adjunct Professor of Optometry, Western University of Health Sciences
AOA Representative, National Diabetes Education Program
Tacoma, WA

Steven Ferrucci, OD, FAAO

Chief of Optometry, Sepulveda VA Medical Center
Professor, Southern California College of Optometry at Marshall B. Ketchum University
Sepulveda, CA

Julia A. Haller, MD

Wills Eye Hospital
Philadelphia, PA

Allen C. Ho, MD, FACS

Director, Retina Research
Wills Eye Hospital
Professor and Chair of the Department of Ophthalmology
Thomas Jefferson University Hospitals
Philadelphia, PA

Charles C. Wykoff, MD, PhD

Director of Research, Retina Consultants of Houston
Associate Professor of Clinical Ophthalmology
Blanton Eye Institute & Houston Methodist Hospital
Houston, TX


Clinician Scientific & Educational Resources

The RELIEF Clinical Toolkit is an online tool that aims to provide clinicians with up-to-date information on the presentation, prognosis, pathophysiology, and treatment strategies for diabetic retinopathy (DR) in patients with diabetes who have or are at risk for developing DR. Click on one of the options below to learn more about DR.

This activity for Diabetic Retinopathy education is provided by Med Learning Group.
This activity is supported by an independent medical education grant from Regeneron Pharmaceuticals, Inc.

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