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Jun.09.2021

Diabetic Retinopathy

Synopsis

Key Points

  • Diabetic retinopathy is a vision-threatening complication of diabetes that occurs within 20 years of diagnosis in the majority of patients r1
  • Patients may present with sudden, painless vision loss; floaters; and blurry or hazy vision
  • Optimal diagnosis is made through suggestive history, dilated fundus examination, and digital retinal photography
  • Fluorescein angiography is useful to rule out other conditions with similar features, determine the extent of retinopathy, and guide therapy
  • Primary treatment is aimed at delaying progression or onset of retinopathy by optimizing management of diabetes and comorbidities such as hypertension or hyperlipidemia r2
    • Photocoagulation and intravitreal vascular endothelial growth factor inhibitors are reserved for some higher-risk or severe cases, especially when macular edema is present and clinically significant
    • Vitrectomy is used only when other therapies fail or when vitreous hemorrhage or traction on macula warrant r3
  • Complications include macular edema, vitreous hemorrhage, and retinal detachment r4r5r6

Urgent Action

  • Rapidly assess (by comprehensive eye examination with ophthalmoscopy) any patient with painless, sudden vision loss or blurry vision, which may indicate retinal/vitreous hemorrhage, retinal tear, or traction retinal detachment
  • Urgent laser photocoagulation or cryopexy is indicated for treatment of proliferative diabetic retinopathy to prevent development of complications such as vitreous hemorrhage

Pitfalls

  • Underlying nonocular cancers (eg, lymphoma, multiple myeloma) or viral infection (eg, HCV, cytomegalovirus) may also masquerade with findings similar to those of diabetic retinopathy and should be ruled out
  • Diabetic retinopathy may coexist with ocular ischemic syndrome, so if there is unilateral or marked asymmetry of retinopathy in a patient with diabetes, evaluate for possible carotid artery occlusive disease r7

Terminology

Clinical Clarification

  • Diabetic retinopathy is a microvascular complication of type 1 or type 2 diabetes mellitus, characterized by damage to the retinal blood vessels and resulting in progressive loss of vision caused by the following: r4
    • Microaneurysms
    • Blot hemorrhages
    • Exudative, ischemic, and proliferative changes
    • Macular edema

Classification

  • Diabetic retinopathy progresses from mild nonproliferative stage to more advanced vision-threatening proliferative retinopathy, which can be complicated by neovascular glaucoma or retinal detachment r8r9
    • Diabetic macular edema can occur at any stage of diabetic retinopathy r8
  • Nonproliferative retinopathy r10
    • Mild
      • Presence of more than 1 microaneurysm
    • Moderate
      • Presence of more than 1 microaneurysm, hemorrhages, and hard protein exudates
    • Severe
      • Presence of any of the following:
        • Diffuse intraretinal hemorrhages (20 or more according to international definition)r9 and microaneurysms in all 4 quadrants
        • Venous beading in more than 2 quadrants
        • Intraretinal microvascular abnormalities in more than 1 quadrant
  • Proliferative retinopathy r11
    • Characterized by neovascularization of the disk, retina, or iris
    • Associated with vitreous hemorrhages, gliosis, traction retinal detachment, and macular edema
      • Early proliferative retinopathy
        • Neovascularization of the optic disk in less than one-third of disk area
        • Neovascularization of the optic disk without preretinal or vitreous hemorrhage
        • Neovascularization elsewhere in less than one-half of disk area and/or without preretinal or vitreous hemorrhage
      • High-risk proliferative retinopathy
        • Neovascularization of the optic disk in one-quarter to one-third of disk area
        • Neovascularization of the optic disk and preretinal or vitreous hemorrhage
        • Neovascularization in the retina outside of the disk in at least one-half of disk area and preretinal or vitreous hemorrhage
      • Severe proliferative retinopathy
        • Preretinal or vitreous hemorrhage that obscures posterior fundus or central macular detachment
  • Diabetic macular edema
    • Clinically significant macular edema consists of retinal thickening with or without hard exudates involving the center of macula or close to it; this term has largely been replaced by the following terms: r9r12
      • Non-central involved diabetic macular edema (mild) r13
        • Retinal thickening in macula that is 1 mm or greater in diameter around the fovea and does not involve the central subfield zone
      • Central-involved diabetic macular edema (severe) r13
        • Retinal thickening in macula that is 1 mm or greater in diameter and involves the central subfield zone

Diagnosis

Clinical Presentation

History

  • Most patients are asymptomatic until advanced stages of disease; presentation includes history of c1
    • Preexisting type 1 diabetes c2
      • Over 90% of patients with type 1 diabetes will develop diabetic retinopathy by 20 years postdiagnosis r1
    • Preexisting type 2 diabetes
      • Over 60% of patients with type 2 diabetes will develop diabetic retinopathy by 20 years postdiagnosis r11
  • Symptoms, when present, can include:
    • New onset of floaters, shadows, or black debris in the vision due to vitreous hemorrhage r1c3c4c5
    • Impaired contrast sensitivity c6
    • Decreased visual acuity not amenable to correction with refraction c7
    • Sudden loss of vision (caused by vitreous hemorrhage or retinal detachment) c8
    • Dark curtain in vision due to detached retina r3c9

Physical examination

  • Changes observed on stereoscopic funduscopy r14
    • Mild nonproliferative retinopathy
      • Microaneurysms: earliest clinical sign and appear as small red dots c10
      • Dot/blot hemorrhages: small, round, ruptured microaneurysms in the deeper layers of the retina (confined to the internal limiting membrane) c11c12
    • Moderate nonproliferative retinopathy
      • Microaneurysms c13
      • Dot/blot hemorrhages c14c15
      • Hard exudates: precipitated protein/lipids with a yellow, whitish, and waxy particulate matter appearance that have leaked out of the retinal capillaries with increased permeability c16
      • Macular edema: breakdown of the blood-retina barrier in the macular region, resulting in protein and fluid deposition that causes swelling and thickening of the macula c17
      • Venous beading c18
      • Cotton wool spots: infarctions in the retinal nerve fiber layer c19
    • Severe nonproliferative retinopathy
      • Marked capillary loss c20
      • Increased venous beading (retinal ischemia) c21c22
      • Multiple intraretinal hemorrhages in all 4 quadrants of the fundus c23
      • Venous beading in more than 2 quadrants c24
      • Intraretinal microvascular abnormality: shunt vessels appearing as abnormal dilation or branching of existing capillaries in more than 1 quadrant c25
    • Early proliferative retinopathy c26
      • Neovascularization in the disk area and elsewhere c27
      • Preretinal hemorrhage: rupture of new blood vessels between the retinal layers and the vitreous c28
      • Vitreous hemorrhage: rupture of new blood vessels and leakage of blood into the vitreous humor c29
      • Multiple intraretinal hemorrhages in all 4 quadrants of fundus c30
      • Venous beading in more than 2 quadrants c31
    • High-risk proliferative retinopathy
      • Neovascularization of disk area (one-quarter to one-half of the disk area) c32
      • Vitreous or preretinal hemorrhage c33c34
    • Severe proliferative retinopathy
      • Posterior fundus obscured by preretinal or vitreous hemorrhage c35
      • Central macular detachment c36
    • Clinically significant macular edema
      • The Early Treatment Diabetic Retinopathy Study definition of clinically significant macular edema included: r15r16
        • Thickening of retina at or within 500 µm of the center of the macula c37
        • More than 1 disk area of retinal thickening, any part of which is within 1 disk diameter of the center of the macula
        • Hard exudates at or within 500 µm of the center of the macula with adjacent retinal thickening c38
      • Posterior fundus obscured by preretinal or vitreous hemorrhage c39
      • Central macular detachment c40
      • Macular cysts on ocular coherence tomography c41
      • Subretinal fluid on ocular coherence tomography c42

Causes and Risk Factors

Causes

  • Chronic hyperglycemia results in vascular leakage, angiogenesis, neuronal damage, and inflammatory insults r4c43
    • Primary contributor is chronic capillary nonperfusion and retinal ischemia r17c44
    • Injuries to the retinal neurovascular unit include: r18
      • Microaneurysms, hemorrhages, and angiogenesis c45c46c47
      • Retinal detachment c48
      • Macular edema c49
    • Specific vascular events include: r19
      • Altered microvascular permeability c50
      • Focal hypoxic events c51
      • Abnormal production of growth factors (especially VEGF [vascular endothelial growth factor]) and cytokines c52

Risk factors and/or associations

Age
  • Age of type 1 diabetes onset influences risk for retinopathy r20
    • Patients with onset of diabetes between the ages of 5 and 14 years are at highest risk c53c54
    • Patients with onset of diabetes between the ages of 15 to 40 years are at lowest risk c55c56
  • Younger age of type 2 diabetes onset (younger than 45 years at diagnosis) is associated with a higher prevalence and severity of retinopathy r21r22c57c58c59c60
Sex
  • May vary by ethnicity, but overall, equally prevalent in men and women in the United States r23c61c62
Genetics
  • Diabetic retinopathy is a polygenic disorder c63
  • Heritability is high: estimated at about 27% for any diabetic retinopathy and about 52% for proliferative diabetic retinopathy r24
  • Associated with several genes, including AKR1B1 (aldose reductase), eNOS (endothelial NOS), ICAM-1 (intercellular adhesion molecule-1), VEGF (vascular endothelial growth factor), ITGA2 (α2β1 integrin), PON (paraoxonase), TNF-β (tumor necrosis factor-β), and APOEe4 (ε4 allele of the apolipoprotein E gene) r19
Ethnicity/race
  • More prevalent in African American (38.8%) and Mexican American (34%) populations than in White populations (26.4%) r25c64c65c66c67
Other risk factors/associations r26
  • Duration of diabetes r27c68
    • Prevalence of retinopathy increases progressively with increased duration of diabetes
    • Incidence of retinopathy in patients with type 1 diabetes approaches more than 90% at 20 years postdiagnosis
    • Incidence of retinopathy in patients with type 2 diabetes is between 50% and 80% at 20 years postdiagnosis
  • Hyperglycemia: increases incidence and progression of diabetic retinopathy r10r21c69
  • Hypertension: association exists between elevated blood pressure and presence of retinopathy; however, whether blood pressure causally influences development is unclear r28c70
  • Hyperlipidemia: weak association exists between serum lipid levels (largely LDL) and presence of diabetic retinopathy r27c71
  • Pregnancy: increases risk for progression of retinopathy r27c72
  • Nephropathy: closely associated with diabetic retinopathy, possibly owing to undesirable effects on lipids and platelets r28c73
  • Establishment of good glycemic control after a period of uncontrolled diabetes (paradoxical early worsening): increases risk for progression of retinopathy

Diagnostic Procedures

Primary diagnostic tools

  • Comprehensive eye examination and evaluation includes visual acuity testing, evaluation of intraocular pressure, pupillary assessment, dilated slit lamp examination employing biomicroscopy with a handheld lens (90- or 78-diopter) and indirect ophthalmoscopy c74
  • Dilated funduscopic examination is the primary method for detecting diabetic retinopathy r2r17c75
    • Used to examine any changes in the fundus that are suggestive of retinopathy such as retinal microaneurysms, changes in the retinal vasculature, and/or hemorrhage
    • Posterior pole and midperipheral retina are best visualized using slit lamp biomicroscopy with a handheld lens (90- or 78-diopter); peripheral retina may be examined using slit lamp biomicroscopy or indirect ophthalmoscopy r9
  • Retinal (fundus) photography is an alternative method for detecting vision-threatening diabetic retinopathy r2r29c76
    • High-resolution method of examining retina and its vasculature
    • May include 30° to wide-field, ultrawide-field, monophotography, stereophotography, and dilated or undilated photography r8
    • Most cases of clinically significant diabetic retinopathy can be detected in this manner and it is particularly useful where there is limited access to ophthalmologists r2r17
    • Can also be used to document severity of diabetes, presence of neovascularization, and need for additional treatment r9
    • Considered a highly accurate, time- and cost-effective method of fundus assessment; however, it is not a substitute for comprehensive eye examination as described above r17
  • Ancillary testing may include the following:
    • Optic coherence tomography r9c77
      • Not used for screening but may be used to evaluate unexplained visual acuity loss in patients with diabetic retinopathy. It is the standard tool for guiding management of patients diagnosed with diabetic retinopathy
    • Fluorescein angiography c78
      • Not routinely necessary at time of diagnosis or for evaluating patients with no or minimal nonproliferative diabetic retinopathy
      • Used to examine circulation of blood within blood vessels of the retina and aid in diagnosis of macular edema and proliferative diabetic retinopathy r9
    • Optic coherence tomography angiography r9c79
      • Emerging noninvasive technology that is useful for detecting areas of intraretinal microvascular anomalies and neovascularization r17r30r31
      • Preclinical microvascular changes and macular nonperfusion, which may correlate to severity of diabetic retinopathy, can be detected r9
    • B-scan ultrasonography r9c80
      • Useful to assess retina and detect retinal detachment in cases of vitreous hemorrhage or other media opacity
  • Evaluation should also include assessment or review of blood pressure and laboratory parameters such as hemoglobin A1C, lipid levels, and renal function tests r8c81c82c83

Imaging

  • Optic coherence tomography r32c84
    • Noninvasive technology that provides high-resolution mapping of the vitreoretinal interface, neurosensory retina, and subretinal space r9r33
    • Used to quantify retinal thickness, and detect macular edema, vitreomacular traction, and other forms of macular disease r9
    • Often used to guide therapeutic decisions when changes are made to existing treatments (eg, repeat anti-VEGF [vascular endothelial growth factor] injections versus initiate laser treatment) r9

Procedures

IV fluorescein angiography r34r35c85
General explanation
  • Fluorescent dye (fluorescein), delivered by IV injection, highlights the retinal vasculature; image is captured by a retinal camera
  • Used to detect areas of retinal ischemia and leaking microaneurysms before laser photocoagulation treatment of eyes with clinically significant macular edema
  • Useful to differentiate diabetic macular swelling from other macular disease or for a patient with unexplained vision loss r9
Indication
  • To exclude conditions such as retinal/arterial vein occlusions, tumors, macular degeneration, or hereditary retinal diseases
  • To determine if laser therapy is indicated
Contraindications
  • Known allergy to dyes, iodine, or shellfish
  • Previous history of anaphylaxis to fluorescein
  • Severe renal impairment
  • First trimester of pregnancy is a relative contraindication as fluorescein is a pregnancy risk category C compound r36r37r38
Complications
  • Anaphylaxis (rare) r39
Interpretation of results
  • Hyperfluorescence: indicates vessel leakage caused by microaneurysms, retinal edema, or neovascularization
  • Hypofluorescence: indicates vessel blockage or areas blocked by presence of exudates and/or blood

Other diagnostic tools

  • Ocular telehealth programs c86
    • Nonmydriatic camera used for retinal imaging and remote evaluation of images at a telemedicine reading center are being used as a screening strategy for diabetic retinopathy in some geographic areas where qualified ophthalmologists are not available; systems utilizing artificial intelligence are also available r29r40
    • Screening results using nonmydriatic camera images assessed through telemedicine generally agree with findings from dilated fundus photography r41
    • Retinal photography may serve as a screening tool for retinopathy but is not a substitute for in-person comprehensive eye examination, which is recommended for first evaluation and for follow-up when abnormalities are detected r2

Differential Diagnosis

Most common

  • Central retinal vein occlusion r7c87d1
    • Occlusion of the retinal vasculature resulting in visual loss similar to that of diabetic retinopathy
    • Differentiate using stereoscopic fundus examination
      • Retinal veins are dilated and tortuous in central vein occlusion, whereas they are dilated and beaded in diabetic retinopathy
      • Microaneurysms and hard exudates are uncommon in central retinal vein occlusion, whereas they are common in diabetic retinopathy
      • Optic disk is swollen in central retinal vein occlusion
    • Differentiate using IV fluorescein angiography
      • Prolonged arteriovenous transit time is observed in central retinal vein occlusion, whereas arteriovenous transit time is within reference range in diabetic retinopathy
  • Ocular ischemic syndrome r7c88
    • Ocular hypoperfusion caused by stenosis or occlusion
    • Both diabetic retinopathy and ocular ischemic syndrome present with visual loss, but pain occurs in up to 40% of patients with ocular ischemic syndrome r42r43
    • Differentiate using stereoscopic fundus examination
      • Retinal veins are dilated but nontortuous in optic ischemic syndrome, whereas they are dilated and beaded in diabetic retinopathy
      • Microaneurysms are observed in the midperiphery in optic ischemic syndrome, whereas they are located in the posterior pole in diabetic retinopathy
      • Hard exudates are not observed in optic ischemic syndrome, whereas they are common in diabetic retinopathy
    • Differentiate using IV fluorescein angiograph
      • Macular edema is rarely observed in optic ischemic syndrome, whereas it is common in diabetic retinopathy
      • Delayed and patchy choroidal filling is observed in optic ischemic syndrome, whereas choroidal filling is usually normal in diabetic retinopathy
  • Valsalva retinopathy r44c89
    • Preretinal hemorrhages caused by a sudden increase in intrathoracic pressure
    • Subconjunctival hemorrhages may be present
    • Typically unilateral but may be bilateral
    • Differentiate using optic coherence tomography
      • Hemorrhage located in subhyaloid or sub–internal limiting membrane space
  • Sickle cell retinopathy r45c90d2
    • Ischemia of the retina associated with existing sickle cell disease
    • Consequent vitreous hemorrhage and retinal detachment can lead to irreversible vision loss, similar to diabetic retinopathy
    • In sickle cell disease, retinopathy is often associated with anterior uveitis
    • Differentiate using optic coherence tomography
      • Macular ischemia with retinal thinning is consistent with sickle cell retinopathy
  • Radiation retinopathy c91
    • Complication of radiation that may present with macular edema and vitreous hemorrhage, similar to diabetic retinopathy
    • Unlike diabetic retinopathy, characterized by a loss of vascular endothelial cells while sparing the pericytes
    • Differentiate by a recent history of radiation therapy

Treatment

Goals

  • Prevent onset of retinopathy by optimizing metabolic and blood pressure control (primary prevention) r2
  • Delay progression of retinopathy r2
  • Preserve and improve vision r46

Disposition

Recommendations for specialist referral

  • Refer to an ophthalmologist for initial screening and diagnosis of diabetic retinopathy, and when there is any nonproliferative diabetic retinopathy, proliferative retinopathy, or macular edema r9
  • Consult ophthalmologist urgently for sudden loss of vision, which may be caused by vitreous/retinal hemorrhage or retinal detachment r47
  • Refer patients with low-vision (those with visual acuities less than 20/40, scotomas, field loss, or contrast loss) to vision rehabilitation services r9

Treatment Options

Treatment strategies include medical, intravitreal, laser, and surgical approaches r28

  • Choice of treatment is individualized depending on type of retinopathy and patient and physician preferences r9
    • Treatment may be deferred until visual acuity is affected in patients with central-involved diabetic macular edema and no vision loss r48
    • Intravitreal anti-VEGF (vascular endothelial growth factor) agents are the recommended treatment for central-involved diabetic macular edema with vision loss
    • Focal laser photocoagulation surgery is the preferred treatment for non-central-involved diabetic macular edema
    • Pan-retinal laser photocoagulation surgery is the preferred treatment for proliferative diabetic retinopathy
  • Medical therapy
    • For all patients, optimize glycemic control, treat dyslipidemia, and lower blood pressure to reduce the risk of retinopathy or slow its progression; however, these measures do not ameliorate vision impairment r4r12
      • Pharmacologic therapy for diabetes
        • Intensive diabetes management with the goal of achieving near-normoglycemia can prevent or delay onset and progression of diabetic retinopathy r49r50
          • General hemoglobin A1C target to strive for is 7% or less (American Diabetes Association) or 6.5% to 7.5% (International Diabetes Federation) r13r51
        • Note: a period of very strict glycemic control with rapid improvement in hyperglycemia can temporarily worsen retinopathy in patients with more severe retinopathy and/or very poor glycemic control r52
      • Antihypertensive drugs
        • Measures to control blood pressure have a greater effect on preventing incident diabetic retinopathy, rather than slowing progression r53
        • However, ACE inhibitors and angiotensin receptor blockers are effective in reducing progression of preexisting diabetic retinopathy r54
        • Aggressive attempts to achieve tight targets (systolic blood pressure less than 120 mm Hg) do not provide greater benefits r50
      • Lipid-lowering therapies
        • Addition of fenofibrate to lipid-lowering therapy may slow progression of retinopathy, particularly with very mild nonproliferative diabetic retinopathy at baseline r13r55
  • Intravitreal agents
    • First line for patients with macular edema if edema involves the center of the macula (central-involved macular edema)
    • VEGF (vascular endothelial growth factor) inhibitors
      • For most patients with central-involved macular edema, vascular endothelial growth factor inhibitors are first line agents and are preferred over focal laser photocoagulation r9
      • Can consider vascular endothelial growth factor inhibitors for management of proliferative diabetic retinopathyr56 as an adjunct or alternative to panretinal photocoagulation, especially if both proliferative diabetic retinopathy and central-involved macular edema are present r2r31
        • Vascular endothelial growth factor inhibitors may be more effective than panretinal photocoagulation alone in the short term; however, they are associated with higher cost and risk of loss of follow-up resulting in delayed treatment and significant progression of disease r57
        • In patients with vitreous hemorrhage secondary to proliferative diabetic retinopathy, there was no significant difference in visual acuity following initial treatment with intravitreous aflibercept compared to vitrectomy with panretinal photocoagulation r58
      • Comparison of agents
        • All 3 available vascular endothelial growth factor inhibitors—aflibercept, bevacizumab, and ranibizumab—are effective in reducing diabetic retinopathy, but aflibercept may be more effective in patients with proliferative retinopathy at baseline
        • For central-involved macular edema and acuity of 20/50 or worse, aflibercept is most effective at improving vision r59r60
          • Aflibercept confers advantage over ranibizumab and bevacizumab for improving vision in the presence of diabetic macular edema assessed at 1 year; longer term effects are still unknown r59
        • For central-involved macular edema and acuity of 20/40 or better, each agent effectively improves visual acuity to a similar extent r60
    • Intravitreal corticosteroids r61
      • Approved for central-involved macular edema, but typically used as second line treatment (after vascular endothelial growth factor inhibitors) for those whose condition responds insufficiently to a series of anti-vascular endothelial growth factor injections
      • Intravitreal corticosteroids are appropriate for pseudophakic eyes or in patients being considered for cataract surgery in the near future
      • Risks include cataract progression, elevation of intraocular pressure, and endophthalmitis
  • Laser photocoagulation therapy r3
    • Focal photocoagulation is used for patients with clinically significant macular edema
      • Preferred treatment for non-central-involved diabetic macular edema and mild visual impairment r9r13
    • Panretinal photocoagulation is the cornerstone treatment for high-risk and severe proliferative diabetic retinopathy r19
      • Can be considered for some cases of early proliferative diabetic retinopathy or severe nonproliferative diabetic retinopathy
  • Surgical treatment
    • Vitrectomy is indicated for severe diabetic retinopathy, under the following circumstances: r3
      • Unresponsive to photocoagulation
      • Unresponsive to intravitreal vascular endothelial growth factor inhibitors
      • Associated with vitreous hemorrhage
      • Vitreomacular traction
      • Tractional retinal detachments threatening the macula and combined tractional-rhegmatogenous retinal detachments r17

Drug therapy c92

  • Antihypertensives c93
    • ACE inhibitors c94
      • Reduce risk of progression of mild to moderate nonproliferative diabetic retinopathy (by 65%) in patients with type 1 diabetes r62
      • Enalapril c95
        • Enalapril Maleate Oral tablet; Adults: 10 mg PO once daily (range, 5 to 20 mg/day PO in 1 or 2 divided doses). Initial doses used in trials vary. Usually begin with a low dose and titrate to response and tolerance.
    • Angiotensin receptor blockers c96
      • Losartan c97
        • Reduces risk of progression of mild to moderate nonproliferative diabetic retinopathy (by 65%) in patients with type 1 diabetes r62
        • Losartan Potassium Oral tablet; Adults: 50 mg PO once daily, initially. The dose should be increased to 100 mg PO once daily based on blood pressure response.
      • Candesartan c98
        • Reduces incidence of diabetic retinopathy in patients with type 1 diabetes r63
        • May enable regression of existing nonproliferative diabetic retinopathy in patients with type 2 diabetes r64
        • Candesartan Cilexetil Oral tablet; Adults: Initially, 16 mg PO once daily, unless the patient is volume-depleted. The dosage range is 8 to 32 mg/day PO, given in 1 to 2 divided doses.
  • VEGF (vascular endothelial growth factor) inhibitors c99
    • Aflibercept r65c100
      • Indicated for treatment of central-involved macular edema related to diabetic retinopathy or for proliferative diabetic retinopathy
      • Shown to improve visual acuity by gain in reading ability of more than 15 letters in 31.1% to 41.6% of patients with macular edema caused by diabetic retinopathy when compared with macular laser photocoagulation (7.8%-9.1%)
      • Aflibercept Solution for injection; Adults: 2 mg via intravitreal injection every 4 weeks (monthly) for 5 months, then 2 mg via intravitreal injection every 8 weeks. Although monthly dosing may continue, additional efficacy was not demonstrated in most patients dosed every 4 weeks vs. every 8 weeks in chronic use. However, some patients may continue to require every 4 week (monthly) dosing after the first 5 months. Recommended as first-line therapy for central-involved diabetic macular edema by the ADA.
    • Ranibizumab r66c101
      • Indicated for the treatment of central-involved macular edema related to diabetic retinopathy or in the treatment of high-risk proliferative diabetic retinopathy
      • Shown to improve visual acuity and reduce macular edema, but requires frequent injections
      • Ranibizumab provides superior visual outcomes compared with focal laser for the treatment of diabetic macular edema r67r68
      • Ranibizumab Solution for injection; Adults: 0.3 mg by intravitreal injection to affected eye once a month (about every 28 days). ADA recommends as first-line therapy for central-involved diabetic macular edema; may consider for proliferative diabetic retinopathy, especially if high-risk characteristics are present.
    • Bevacizumab r66r69c102
      • Off-label use for treatment of central-involved macular edema related to diabetic retinopathy r12
      • Actions/effect of ranibizumab and bevacizumab are comparable
      • Bevacizumab (Hamster) Solution for injection; Adults: Recommended by the ADA as a potential therapy for proliferative diabetic retinopathy, especially if high-risk characteristics are present. Limited data suggest 1.25 mg (0.05 mL) by intravitreal injection alone or in combination with panretinal photocoagulation may be effective in slowing progression.
  • Corticosteroids c103
    • Intravitreal triamcinolone acetonide r70c104
      • Off-label use for treatment of diabetic retinopathy
      • Improvement in visual acuity shown to be inferior to treatment with focal or panretinal photocoagulation
      • Associated with higher risk of increased intraocular pressure, need for glaucoma medications, and need for glaucoma surgery
      • Triamcinolone Acetonide Suspension for injection; Adults: Use not established; not FDA-approved. Data from several clinical studies suggest 4 mg intravitreally into the affected eye(s) may result in improved visual acuity, reduced retinal thickness, and decreased macular edema. Steroid intravitreal injections are considered second-line treatment options by the ADA.
    • Implantable fluocinolone acetonide r71c105
      • Indicated for patients who have been previously treated with a course of intravitreal corticosteroids without experiencing clinically significant rise in intraocular pressure
      • Shown to improve visual acuity by gain in reading ability of more than 15 letters in 31.9% to 33% of patients treated with implantable fluocinolone acetonide compared with 21.4% of patients treated with sham procedure
      • Fluocinolone Acetonide Implant; Adults: Inject 1 implant (0.19 mg fluocinolone acetate) intravitreally. The implant releases fluocinolone acetonide at an initial rate of 0.25 mcg/day, and lasts 36 months. Considered a second-line alternative treatment option by the ADA.
    • Implantable dexamethasone (corticosteroid) r72c106
      • Indicated for the treatment of macular edema related to diabetic retinopathy in adult patients with pseudophakia
      • Shown to improve visual acuity by gain in reading ability of more than 15 letters in 18.4% to 22.2% of patients treated with implantable dexamethasone compared with 12% of patients treated with sham procedure
      • Dexamethasone Implant; Adults: Inject the implant (containing 0.7 mg dexamethasone in a solid polymer delivery system) intravitreally. Monitor the patient for elevated intraocular pressure and endophthalmitis. Considered second-line alternative treatment options by the ADA.

Nondrug and supportive care

Encourage lifestyle measures that optimize glycemic control, blood pressure, and cholesterol in optimal range to delay progression or prevent onset of retinopathy r3c107c108c109

Physical activity c110

  • Vigorous aerobic or resistance exercise may be contraindicated if proliferative diabetic retinopathy or severe nonproliferative diabetic retinopathy is present because there is risk of triggering vitreous hemorrhage or retinal detachment r73
Procedures
Laser retinal photocoagulation r70c111
General explanation
  • Panretinal: hundreds of small laser burns are used to cauterize the peripheral retina to reduce ischemia
  • Focal: cauterization of specific microaneurysms near the macula to reduce plasma leakage and intraretinal swelling
Indication
  • Proliferative diabetic retinopathy
  • Patients with clinically significant macular edema r3
  • Severe nonproliferative retinopathy, particularly in patients with type 2 diabetes
Complications
  • Panretinal r74
    • Corneal abrasions
    • Visual field loss
    • Reduced color vision
    • Reduced contrast sensitivity
  • Focal r9
    • Laser scars
    • Paracentral scotomas
    • Choroidal neovascularization
Interpretation of results
  • Laser photocoagulation reduces the chance of visual loss and increases the likelihood of attaining partial to complete resolution of diabetic macular edema, compared with no intervention r75
Vitrectomy r27r76c112
General explanation
  • Partial or complete surgical removal of vitreous humor (typically blood from a vitreous or retinal hemorrhage)
    • Allows for examination and further treatment of the posterior ocular pole
Indication
  • Removal of vitreous hemorrhage
  • Repair of traction retinal detachment
Complications
  • Neovascular glaucoma r77
  • Cataracts r78
  • Vitreous hemorrhage r78
  • Epiretinal membrane r78

Special populations

  • Pregnant patients r79
    • Retinopathy is known to worsen during pregnancy, which may or may not regress postpartum
    • Counsel women with preexisting type 1 or type 2 diabetes who are planning to become pregnant or who are pregnant about risk of development or progression of diabetic retinopathy r29
    • Eye examinations ideally occur before pregnancy or in the first trimester in patients with preexisting type 1 or type 2 diabetes
    • Consider laser photocoagulation earlier in management of pregnant patients with proliferative diabetic retinopathy
  • Treatment options according to severity of diabetic retinopathyME, macular edema; VEGF, vascular endothelial growth factor.Data from American Academy of Ophthalmology Retina/Vitreous Preferred Practice Pattern Panel: Preferred Practice Pattern: Diabetic Retinopathy 2019. AAO website. Published 2019. Accessed May 17, 2021. https://www.aao.org/preferred-practice-pattern/diabetic-retinopathy-ppp
    Severity of retinopathyMacular edemaPanretinal laser photocoagulationFocal laser photocoagulationIntravitreal anti-VEGF
    Nonproliferative diabetic retinopathy
    No or minimal nonproliferative diabetic retinopathyNoNoNoNo
    Mild nonproliferative diabetic retinopathyNoNoNoNo
    Non center-involved MENoSometimesNo
    Center-involved MENoRarelyUsually
    Moderate nonproliferative diabetic retinopathyNoNoNoNo
    Non center-involved MENoSometimesRarely
    Center-involved MENoRarelyUsually
    Severe nonproliferative diabetic retinopathyNoSometimesNoSometimes
    Non center-involved MESometimesSometimesSometimes
    Center-involved MESometimesRarelyUsually
    Proliferative diabetic retinopathy
    Early proliferative diabetic retinopathyNoSometimesNoSometimes
    Non center-involved MESometimesSometimesSometimes
    Center-involved MESometimesSometimesUsually
    High-risk proliferative diabetic retinopathyNoRecommendedNoSometimes
    Non center-involved MERecommendedSometimesSometimes
    Center-involved MERecommendedSometimesUsually
  • Monitoring

    • General monitoring r29
      • Follow-up intervals depend on severity of retinopathy and presence of macular edema
      • If there is no evidence of retinopathy for 1 or more annual eye examinations and glycemia is well controlled, refer patient to ophthalmologist or optometrist for dilated and comprehensive eye examinations every 1 to 2 years r80c113c114c115
      • If any level of diabetic retinopathy is present, refer to ophthalmologist or optometrist for subsequent dilated retinal examinations at least annually
      • If retinopathy is progressing or sight-threatening, examinations are required more frequently
      • Follow-up intervals for established retinopathyData from American Academy of Ophthalmology Preferred Practice Patterns Retina/Vitreous Panel et al: Diabetic retinopathy PPP 2019. AAO website. Published 2019. Accessed May 17, 2021. https://www.aao.org/preferred-practice-pattern/diabetic-retinopathy-ppp
        Severity of retinopathyPresence of macular edemaTime interval to follow-up (months)
        Nonproliferative diabetic retinopathy
        Mild nonproliferative diabetic retinopathyNo12
        Non center-involved ME3-6
        Center-involved ME1
        Moderate nonproliferative diabetic retinopathyNo12
        Non center-involved ME3-6
        Center-involved ME1
        Severe nonproliferative diabetic retinopathyNo3-4
        Non center-involved ME2-4
        Center-involved ME1
        Proliferative diabetic retinopathy
        Early proliferative diabetic retinopathyNo3-4
        Non center-involved ME2-4
        Center-involved ME1
        High-risk proliferative diabetic retinopathyNo2-4
        Non center-involved ME2-4
        Center-involved ME1
    • Monitoring after intravitreal injections
      • After anti-vascular endothelial growth factor or corticosteroid injections, monitor patient monthly for elevation in intraocular pressure and endophthalmitis r9
    • Monitoring after laser photocoagulation
      • Ophthalmology follow-up occurs 3 to 4 months after laser surgery to monitor for choroidal neovascularization r9
    • Monitoring during pregnancy
      • Monitor pregnant patients every trimester and for 1 year postpartum as indicated by degree of retinopathy r29

    Complications and Prognosis

    Complications

    • Clinically significant macular edema associated with diabetic retinopathy r4c116
      • Can occur at any stage of the retinopathy (nonproliferative or proliferative)
      • Leading cause of blindness in patients with diabetes
    • Vitreous hemorrhage r6c117
    • Retinal detachment r5c118
    • Glaucoma r81c119

    Prognosis

    • Visual improvement and maintenance correlates with optimal management of underlying diabetes and/or coexisting hypertension/hyperlipidemia r27
      • Appropriate treatment can prevent severe vision loss in 90% of cases r3
    • Associated with increased risk of morbidity and mortality owing to increased incidence of cardiovascular events (eg, myocardial infarction, stroke) compared with patients without retinopathy r82

    Screening and Prevention

    Screening

    At-risk populations

    • Patients with type 1 diabetes
      • Begin screening (by an ophthalmologist) within 3 to 5 years after onset of diabetes r2
    • Patients with type 2 diabetes
      • Refer for comprehensive ophthalmic examination at the time of diagnosis r2
    • Pregnant women with preexisting type 1 or type 2 diabetes
      • Refer to ophthalmologist each trimester and follow closely until 1 year postpartum as indicated by degree of retinopathy r2
    • Schedule for retinopathy screening
      • After initial examination, if retinopathy is identified, refer for an annual dilated and comprehensive eye examination
      • After initial examination, in the absence of any findings of retinopathy, refer for a dilated and comprehensive eye examination every 2 years
      • Individualized schedules for retinopathy screening (based on the current state of retinopathy and hemoglobin A1C level) may reduce the frequency of eye examinations without delaying the diagnosis of clinically significant disease; however, this approach has not been fully adopted by professional society guidelines r83

    Screening tests

    • Comprehensive evaluation by an ophthalmologist includes visual acuity testing, evaluation of intraocular pressure, pupillary assessment, dilated slit lamp examination employing biomicroscopy with a handheld lens (90- or 78-diopter) and direct or indirect ophthalmoscopy r8r9c120c121
    • Other additional testing may include optic coherence tomography and fluorescein angiography r11c122c123
    • In areas where qualified eye care professionals are not readily available, retinal photography with remote reading by expert ophthalmologists or interpretation by artificial intelligence systems can be a substitute screening strategy for diabetic retinopathy r29r84
      • This type of telemedicine screening needs to be followed with timely referral for a comprehensive eye examination if abnormalities are identified
      • Artificial intelligence systems should not be used for screening patients with known retinopathy, prior treatment for retinopathy, or visual impairment r29
      • Retinal and fundus photography (digital or color film) are not substitutes for a comprehensive eye examination, which should be performed at least initially r2

    Prevention

    • Intensive diabetes management with the goal of achieving near-normoglycemia reduces the risk of developing retinopathy and slows its progression in type 1r49 and type 2r50 diabetes c124
      • Reduces ocular surgery rates in patients with type 1 diabetes r85
    • Lowering blood pressure (systolic less than 140 mm Hg) slows progression of retinopathy in type 2 diabetes r53c125
      • Aggressive lowering of systolic blood pressure to less than 120 mm Hg does not provide further benefit in terms of retinopathy r50
    • Treatment of dyslipidemia with fenofibrate slows progression of retinopathy by up to 40% among those with nonproliferative retinopathy r55c126
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