NONPROLIFERATIVE DIABETIC RETINOPATHY
Sasha Hubschman, MD and Jayanth Sridhar, MD
- Hyperglycemia results in endothelial damage in retinal capillaries, leading to vascular remodeling, leakage, and occlusion.
- Twenty-three percent of people with type 1 diabetes mellitus develop diabetic retinopathy (DR) after 5 years, 80% after 15 years. Up to 21% of patients with type 2 diabetes mellitus already have retinopathy at time of initial diagnosis of diabetes.
- Intense glycemic control is associated with reduced progression to severe nonproliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR).
Figure 2-1. NPDR with intraretinal hemorrhages (short arrow) and exudates (long arrow).
Signs and Symptoms
Blurred vision, usually due to presence of macular edema (see the Diabetic Macular Edema section) or, less commonly, from macular ischemia
Exam Findings
- Mild NPDR (5% risk of progression to PDR in 1 year): > 1 microaneurysm, criteria not met for other levels of DR
- Moderate NPDR (15% risk of progression to PDR in 1 year): hemorrhage/microaneurysm (Figure 2-1) or soft exudates (cotton wool spots [CWS]), venous beading that do not meet criteria for severe NPDR
- Severe NPDR (52% risk of progression to PDR in 1 year): 4:2:1 rule; hemorrhage/microaneurysm in all 4 quadrants or venous beading in ≥ 2 quadrants or intraretinal microvascular abnormalities (IRMA) in at least 1 quadrant
- Diabetic macular edema (DME): may arise at any stage
- Severe NPDR (52% risk of progression to PDR in 1 year): 4:2:1 rule; hemorrhage/microaneurysm in all 4 quadrants or venous beading in ≥ 2 quadrants or intraretinal microvascular abnormalities (IRMA) in at least 1 quadrant
Testing
- Systemic: fasting blood glucose, hemoglobin A1C every 3 months; check blood pressure; blood test for hyperlipidemia if extensive exudate is present
- Optical coherence tomography (OCT): evaluate for presence and severity of DME
- Fluorescein angiography (FA): identify areas of ischemia, leakage from microaneurysms, and neovascularization (Figure 2-2)
- Optical coherence tomography angiography (OCTA): dye-less alternative to FA to assess severity of retinopathy (microaneurysms, capillary non-perfusion, etc; Figure 2-3)
Differential Diagnosis
Branch or central retinal vein occlusion (CRVO), ocular ischemic syndrome, hypertensive retinopathy, radiation retinopathy
Management
- Tight glycemic, blood pressure, and lipid control regardless of stage
- Regular follow-up is crucial to assess for progression of disease
- In type 1 diabetics: Initial exam 5 years after onset, then annually if retinopathy present. Frequency of follow-up based on previous retinal exam and A1C level. Optimal screening intervals range from months in patients with severe NPDR to every year for those without retinopathy.
- In type 2 diabetics: Initial exam upon diagnosis and then annually. More frequent screening may be necessary based on stage of NPDR.
- In type 1 diabetics: Initial exam 5 years after onset, then annually if retinopathy present. Frequency of follow-up based on previous retinal exam and A1C level. Optimal screening intervals range from months in patients with severe NPDR to every year for those without retinopathy.
Figure 2-2. FA can demonstrate microaneurysms (arrows) in NPDR.
- Pregnancy poses higher risk of developing worsening retinopathy and patient should be examined during first trimester and followed closely until 1 year post-partum. Vitreous surgery, intravitreal corticosteroids, and laser therapy are safe during pregnancy. No randomized controlled trials to prove safety of anti-VEGF during pregnancy and is therefore generally avoided.
Figure 2-3. OCTA of the superficial plexus (6 × 6 mm) reveals areas of non-perfusion (long arrows) as well as microaneurysmal changes (short arrow).
- Mild and moderate NPDR: generally not treated unless DME is present
- Severe or very severe NPDR and patients with higher risk of progressing to PDR: May consider anti-VEGF therapy to reduce retinopathy severity and rate of progression even in absence of DME. Panretinal photocoagulation may also be considered, particularly if there is heightened concern for non-compliance with recommended follow-up.
Figure 2-4. PDR with NVD (arrow) and elsewhere (arrowheads).
PROLIFERATIVE DIABETIC RETINOPATHY
Michael J. Venincasa, MD and Jayanth Sridhar, MD
- PDR is the leading cause of vision loss in working-age Americans.
- Prevalence ↑ with duration of diabetes mellitus. Other risk factors include hypertension, smoking, nephropathy, dyslipidemia, and pregnancy.
- Pathophysiology: diabetic microvascular changes → retinal ischemia → increased angiogenic growth factors → secondary neovascularization (Figure 2-4) → complications (eg, vitreous hemorrhage [VH], tractional retinal detachment [TRD])
Signs and Symptoms
Many are initially asymptomatic; blurred vision, floaters, shadows, pain if intraocular pressure (IOP) is elevated
Exam Findings
- Stages of PDR
- Early: neovascularization is present, but does not meet high-risk criteria
- High-risk: (1) neovascularization of the optic disc (NVD) ≥ 1/3 to 1/2 disc area, or (2) NVD and vitreous or preretinal hemorrhage, or (3) neovascularization elsewhere (NVE) ≥ 1/2 disc area and VH or preretinal hemorrhage
- Severe: posterior fundus obscured by VH or preretinal hemorrhage or macula center detached
- Early: neovascularization is present, but does not meet high-risk criteria
- Macular edema can be present at any stage of PDR and should be addressed concomitantly (see the Diabetic Macular Edema section)
Testing
- FA: although PDR can be diagnosed on exam, FA (particularly wide-field FA) is helpful to identify retinal ischemia and capillary non-perfusion, leakage from neovascularization, and can often show more than is readily apparent on clinical examination
- OCT: can assist with assessment of macular edema and monitoring for progression to macular involvement in cases with TRD (Figure 2-5)
- Other testing: HbA1C, lipid profile, blood pressure
Differential Diagnosis
Radiation retinopathy, branch retinal vein occlusion (BRVO)/CRVO, macular telangiectasia, retinal vasculitis, sarcoidosis, ocular ischemic syndrome, sickle cell retinopathy
Figure 2-5. PDR complicated by (A) TRD confirmed with subretinal fluid (*) visible in the macula on (B) OCT.
Management
- Good glycemic and blood pressure control can reduce risk of PDR progression
- Panretinal Photocoagulation (PRP): mainstay of treatment for decades that reduces retinal response to hypoxia, induces regression of neovascularization, and based on the Diabetic Retinopathy Study, reduces vision loss by 50%1
- Intravitreal anti-VEGF therapy
- A Phase 3 clinical trial2 found this noninferior to PRP for PDR in terms of visual acuity. Secondary outcomes including visual field loss and rates of vitrectomy favored anti-VEGF therapy slightly over PRP.
- First-line treatment for DME, so this is increasingly favored as initial therapy in patients with both DME and PDR
- If utilized as monotherapy, patient compliance to the follow-up and treatment schedule is critical as the treatment effect is not durable like PRP.
- A Phase 3 clinical trial2 found this noninferior to PRP for PDR in terms of visual acuity. Secondary outcomes including visual field loss and rates of vitrectomy favored anti-VEGF therapy slightly over PRP.
- Pars plana vitrectomy (PPV) surgery is indicated for dense or non-clearing VH and macula-involving TRD.
- Glaucoma filtering surgery may be indicated if there is angle closure due to neovascularization.
Jordan D. Deaner, MD and Carl D. Regillo, MD
- Common manifestation of DR that reduces central vision and is the leading cause of vision loss in developed world
- Etiology: Chronic hyperglycemia leads to breakdown in the blood-retinal barrier (maintained by pericytes and endothelial cell tight junctions) and increased vasopermeability (mediated by VEGF).
Signs and Symptoms
Decreased vision, metamorphopsia
Exam Findings
- Slit lamp biomicroscopy: thickening (edema) of macula with or without cystoid changes centrally, microaneurysms, and lipid exudation
- Clinically significant macular edema (CSME) as defined by Early Treatment Diabetic Retinopathy Study (ETDRS; Figure 2-6)3
- Retinal thickening within 500 μm of center of the fovea
- Hard exudate with adjacent retinal thickening at or within 500 μm of center of the macula
- Retinal thickening 1 disc area or larger, any part of which is within 1 disc diameter of center of macula
- Retinal thickening within 500 μm of center of the fovea
Testing
- OCT: shows retinal thickening typically with cystic change and subretinal fluid when severe (Figure 2-7)
- Allows quantification of degree and location (central vs non-central) of edema
- Reveals associated vitreoretinal interface abnormalities, such as epiretinal membrane (ERM) or vitreomacular traction (VMT)
- Useful for monitoring response to therapy
- Allows quantification of degree and location (central vs non-central) of edema
Figure 2-6. Color fundus photograph demonstrating CSME, hard exudates (black *), and retinal hemorrhages (white *) in severe NPDR.
Figure 2-7. OCT shows mild cystic macular edema (white *) and hard exudates (black *) in the central macula of a patient with DME and moderate NPDR.
Figure 2-8. Intravenous FA demonstrating numerous microaneurysms and late macular leakage (*) in a patient with severe NPDR and DME.
- FA: reveals leakage from incompetent capillaries or microaneurysms along with other features of DR (Figure 2-8)
- OCTA: noninvasive alternative to FA shows status of macular perfusion and can rule out other pathology such as choroidal neovascularization (Figure 2-9)
- Miscellaneous: blood glucose, hemoglobin A1c (HbA1c), lipid panel, blood pressure
Differential Diagnosis
Post-operative cystoid macular edema (Irvine-Gass syndrome), cystoid macular edema from medications (epinephrine, E2-prostaglandins, nicotinic acid), retinal vein occlusion (RVO), choroidal neovascularization, hypertensive retinopathy, ocular ischemic syndrome, radiation retinopathy, retinal arterial macroaneurysm; uveitis
Figure 2-9. OCT angiography showing enlargement of the foveal avascular zone and focal loss of the deep vascular plexus (*) in a patient with DME.
Management
- Asymptomatic patients with mild and/or non–center-involving macular edema may initially be observed.
- Intravitreal anti-VEGF agents are first-line therapy for center-involving (CI) DME.
- Ranibizumab and aflibercept are approved by the Food and Drug Administration (FDA) for treating DME.
- Bevacizumab is used off-label.
- Results of DRCR Network Protocol T4 show that aflibercept, bevacizumab, and ranibizumab all improved vision and decreased macular thickness.
- Worse presenting visual acuity (< 20/40): Aflibercept group had greater degree of vision improvement at 1 year compared to other agents. At 2 years, no significant difference between ranibizumab and aflibercept.
- Both on-label drugs had either better visual outcomes or better reduction in DME at 2 years compared with bevacizumab in eyes with more severe DME at presentation (Table 2-1)
- Results of DRCR Network Protocol T4 show that aflibercept, bevacizumab, and ranibizumab all improved vision and decreased macular thickness.
- Ranibizumab and aflibercept are approved by the Food and Drug Administration (FDA) for treating DME.
- Corticosteroids (intravitreal triamcinolone, dexamethasone implant, fluocinolone implant) are generally considered to be second-line therapy for CI DME
- Longer-lasting than anti-VEGF agents: up to 3 to 4 months for intravitreal triamcinolone and dexamethasone implant; 2 to 3 years for fluocinolone implant
- Often used when there is inadequate response to anti-VEGF agents or as an alternative to ongoing, frequent anti-VEGF injections
- Side effects: IOP elevation and cataract progression
- Longer-lasting than anti-VEGF agents: up to 3 to 4 months for intravitreal triamcinolone and dexamethasone implant; 2 to 3 years for fluocinolone implant
- Focal macular laser photocoagulation: proven in ETDRS3 to decrease risk of vision loss in eyes with CSME, but inferior to anti-VEGF or corticosteroids (DRCR Network Protocol I5) as far as improving vision in eyes with CI DME
- May be considered for non-CI DME that has not completely responded to intravitreal pharmacotherapy
- PPV and membrane peeling may be considered if vitreomacular interface abnormalities are contributing to macular edema, particularly if response to medical treatment is suboptimal.
Ashley Khalili, MD and David Y. Rhee, MD
- Represent focal areas of nerve fiber layer ischemia and thrombosis of the precapillary arteriole, resulting in swelling of ganglion cell axons due to interrupted axoplasmic flow (Figure 2-10)
- Histopathology: hallmark finding of cytoid bodies within the CWS, which are eosinophilic segments of ganglion cell axons that are dilated due to interrupted axoplasmic flow and accumulation of intracellular material
Figure 2-10. A patient with inferior BRVO occlusion with a sectoral area of CWS on color fundus photography.
Signs and Symptoms
Often asymptomatic unless there is foveal involvement, occasionally scotoma or vague description of blurred vision, systemic symptoms of an underlying etiology may be present
Exam Findings
Focal white or yellow-white, slightly elevated and fluffy lesions in the superficial retina, usually smaller than 1/3 disc areas in diameter and most commonly in the posterior pole; usually disappear within 4 to 12 weeks, but may last longer in diabetes.
Figure 2-11. CWS. OCT of the CWS with localized retinal nerve fiber layer thickening.
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