Background

Diabetic retinopathy (DR) Is a progressive complication of diabetes in which retinal vascular damage and abnormalities can lead to vision impairment and blindness.

Types of Diabetic Retinopathy

There are 3 types of DR:

  • Nonproliferative DR characterized by retinal vascular abnormalities
    • Mild cases only involve microaneurysms
    • Moderate and severe cases involve additional vascular abnormalities
  • Proliferative DR characterized by retinal neovascularization in addition to vascular abnormalities
  • Diabetic macular edema characterized by thickening of the retina near the macula

Risk Factors

Risk factors for DR include:


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  • Cataract surgery
  • Diabetes duration ( ≥ 20 years reported to be associated with DR in 50%-90% of patients)
  • Hyperglycemia
  • Hypertension
  • Nephropathy
  • Pregnancy/puberty associated with DR progression

Etiology and Pathogenesis

  • Hyperglycemia and associated altered metabolic pathways can lead to:
    • Neurodegeneration and thinning retinal ganglion cell and nerve fiber layers 
    • Vascular damage, which results in:
      • Retinal capillary nonperfusion
      • Increased vascular leaking/retinal hemorrhages
    • Impaired neurovascular function that impairs ability of retina to regulate local blood flow
  • As DR progresses, retinal vessels close resulting in reduced perfusion and retinal ischemia
  • Proliferative DR involves neovascularization and consequent complications:
    • New vessels forming on disc, retina, and iris, which are more likely to bleed
    • Fibrous proliferation can lead to epiretinal membrane formation, vitreoretinal traction, retinal tears, retinal detachment, and neovascular glaucoma
    • Vision loss can occur due to capillary nonperfusion or edema in the macula, vitreous hemorrhage, and distortion or traction retinal detachment

Taking a History 

  • Patients may be asymptomatic
  • If present, symptoms of retinopathy may include:
    • Blurred vision
    • Narrowed field of vision
    • Seeing dark spots/difficulty seeing in dim light
    • Feeling of pressure or pain in eye
  • Ask about:
    • How long patient has had diabetes and how well HbA1c is controlled  
    • History of ocular disease, procedures, or damage
    • Current/past history of:
      • Hyperlipidemia
      • Hypertension
      • Neuropathy
      • Obesity
      • Renal disease

Physical Examination

  • Evaluation based on careful and thorough eye examination with fundoscopic retinal exam
  • Also assess:
    • Intraocular pressure
    • Pupils for optic nerve dysfunction
    • Visual acuity

Differential Diagnosis

  • For nonproliferative diabetic retinopathy
    • Central or branch retinal vein occlusion
    • Hypertensive retinopathy
    • Ocular ischemic syndrome
    • Radiation retinopathy
  • For proliferative diabetic retinopathy
    • Embolization from IV drug use (talc retinopathy)
    • Hypercoagulable states (antiphospholipid syndrome)
    • Inflammatory conditions such as systemic lupus erythematosus
    • Neovascular complications of central retinal artery/vein occlusion
    • Ocular ischemic syndrome complications
    • Radiation retinopathy
    • Sarcoidosis
    • Sickle cell retinopathy

Diagnosis

  • Diabetic retinopathy is a potential complication in any patient with diabetes; regular screening is needed to ensure early treatment and reduce risk of progression and vision loss
  • Suspect DR in any patient with diabetes who has recent vision impairments, especially if long-duration diabetes, chronic hyperglycemia, nephropathy, hypertension, or dyslipidemia
  • Clinical features on funduscopic exam vary by disease severity; microaneurysms are generally the first clinically detectable sign of early stage disease
  • Diagnosis and classification based on findings from retinal exam (with dilated pupil)

Retinal Exam

  • Retinal exam can include:
    • Direct/indirect fundoscopy
    • Fundus photography
    • Slit lamp biomicroscopy
    • Undilated gonioscopy
  • Nonproliferative DR characterized by retinal vascular abnormalities
    • Cotton wool spots
    • Hard exudates (lipids)
    • Intraretinal hemorrhages
    • Intraretinal microvascular abnormalities (irmas) – tortuous intraretinal vascular segments usually about 1/4 the width of a major vein at disc margin
    • Microaneurysms
    • Retinal edema
    • Venous dilation/beading/loops
  • Proliferative DR characterized by retinal neovascularization in addition to vascular abnormalities
    • Neovascularization first occurs at inner surface of retina
    • New vessels more likely to cause vitreous hemorrhage and undergo fibrosis/contraction
  • Testing beyond retinal exam not necessary for diagnosis, but additional ocular testing may better characterize retina, such as:
    • Fluorescein angiography (FA)
    • Fundus photography (red-free and color)
    • Optical coherence tomography (OCT)
    • Optical coherence tomography angiography (OCTA)
    • Ultrasound

Classification by Retinal Exam Findings

Nonproliferative Diabetic Retinopathy (NPDR)

  • Mild – microaneurysms without other retinal findings
  • Moderate – microaneurysms plus additional signs of vascular abnormalities but not meeting criteria for severe
  • Severe
    • United States definition
      • Microaneurysms plus any of
        • Severe intraretinal hemorrhages/microaneurysms in each quadrant
        • Venous beading in ≥ 2 quadrants
        • Moderate intraretinal microvascular abnormalities in ≥ 1 quadrants
      • Not meeting additional criteria for proliferative diabetic retinopathy
    • International definition
      • Microaneurysms plus any of
        • > 20 intraretinal hemorrhages in each quadrant
        • Definite venous beading in ≥ 2 quadrants
        • Prominent intraretinal microvascular abnormalities in ≥ 1 quadrants
      • Not meeting additional criteria for proliferative diabetic retinopathy

Proliferative Diabetic Retinopathy (PDR)

  • Characteristics of severe NPDR plus neovascularization and/or vitreous/preretinal hemorrhage
  • High-risk PDR – any 3 of following 4
    • Neovascularization present
    • Neovascularization at or near the optic disc
    • Moderate/worse neovascularization, defined as
      • New vessels within 1 disc diameter of optic nerve head (>1/4 disc area in size)
      • New vessels >1 disc diameter of optic nerve head (≥1/2 disc area in size)
    • Vitreous/preretinal hemorrhage

Diabetic Macular Edema (DME)

  • Clinically significant macular edema – any of:
    • Retinal thickening within 500 micrometers of macula center
    • Hard exudates within 500 micrometers of macular center with adjacent retinal thickening  
    • ≥1 zones of retinal thickening of 1 disc area or larger (with any portion within 1 disc diameter of macula center)
  • Center-involved DME – retinal thickening in the macula involving central subfield zone that is 1 mm in diameter

Management

  • To slow progression of DR, encourage patients with diabetes to be as compliant as possible with:
    • Glycemic control
    • Blood pressure management
    • Serum lipid control
  • Regular screening crucial for early identification of disease
    • Regular ophthalmologic exams
    • Screening with high-quality retinal photographs
    • Referral to ophthalmologist for close follow-up/possible treatment as needed
  • Management strategies depends on severity of DR, status of diabetic macular edema, and patient characteristics
    • For all patients with DR, conduct a dilated and comprehensive eye exam at least annually and more frequently with greater severity and/or if retinopathy is progressing
    • For mild-to-moderate nonproliferative DR
      • Retina-focused management may not be needed if without any DME
    • For high-risk proliferative DR or select patients with severe nonproliferative DR
      • Panretinal photocoagulation laser therapy is indicated
    • For proliferative DR and DME with central involvement
      • Intravitreal antivascular endothelial growth factor (anti-VEGF) therapy is indicated  
    • For patients with DME, consider
      • Focal and/or grid laser therapy
      • Intravitreal corticosteroids as second-line option (but may increase risk of elevated intraocular pressure and cataract-related adverse events)
  • Vitrectomy surgery
    • Usually only considered if persistent disease activity despite laser photocoagulation surgery and/or antivascular endothelial growth factor therapy
    • Indications may include:
      • Nonclearing vitreous hemorrhage
      • Tractional retinal detachment threatening the macula
      • Combined rhegmatogenous and tractional retinal detachment
      • Dense premacular subhyaloid hemorrhage
  • Aspirin does not increase the risk of retinal hemorrhage or worsen diabetic retinopathy; diabetes is not a contraindication to aspirin use for other medical indications

Complications and Prognosis

  • Impaired vision and possibly blindness — diabetic retinopathy is most common cause of new onset blindness in adults
  • Without treatment, DR progresses from mild to more severe, including progression from nonproliferative DR to proliferative DR and increased risk of blindness
  • Reported risk of progression to PDR within 1 year
    • 5% with mild NPDR
    • 20% with moderate NPDR
    • 50% with severe NPDR

Kendra Church, MS, PA-C, is a physician assistant at Dana-Faber Cancer Institute/Brigham & Women’s Hospital and is also an Associate Deputy Editor for DynaMed, an evidence-based point-of-care database.

Sources

1. Wong TY, Cheung CMG, Larsen M, Sharma S, Simó  R. Diabetic retinopathy. Nat Rev Dis Primers. 2016;2:16012. doi:10.1038/nrdp.2016.12

2. Flaxel CJ, Adelman RA, Bailey ST, et al. Diabetic retinopathy preferred practice®. Ophthalmology. 2020;127(1):P66-P145. doi:10.1016/j.ophtha.2019.09.025

3. American Diabetes Association Professional Practice Committee. Retinopathy, neuropathy, and foot care: standards of medical care in diabetes-2022Diabetes Care. 2022;45(Suppl 1):S185-S194. doi:10.2337/dc22-S012

4. Wong TY, Sun J, Kawasaki R, et. al. Guidelines on diabetic eye care: the international council of ophthalmology recommendations for screening, follow-up, referral, and treatment based on resource settings. Ophthalmology.  2018;125(10):1608-1622. doi:10.1016/j.ophtha.2018.04.007