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Jun.20.2019

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
    • Photocoagulation and intravitreal VEGF 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
  • Complications include macular edema, vitreous hemorrhage, and retinal detachment

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 r2

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: r3
    • Microaneurysms
    • Blot hemorrhages
    • Exudative, ischemic, and proliferative changes
    • Macular edema

Classification

  • Nonproliferative retinopathy r4
    • 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 hemorrhage and microaneurysms in all 4 quadrants
        • Venous beading in more than 2 quadrants
        • Intraretinal microvascular abnormalities in more than 1 quadrant
  • Proliferative retinopathy r5
    • 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

Diagnosis

Clinical Presentation

History

  • Most patients are asymptomatic until advanced stages of disease; presentation includes history of c1c2
    • Preexisting type 1 diabetes
      • 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 r5
  • 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) c8c9
    • Dark curtain in vision due to detached retina r6c10

Physical examination

  • Changes observed on stereoscopic funduscopy r7
    • Mild nonproliferative retinopathy
      • Microaneurysms: earliest clinical sign and appear as small red dots c11
      • Dot/blot hemorrhages: small, round, ruptured microaneurysms in the deeper layers of the retina (confined to the internal limiting membrane) c12c13
    • Moderate nonproliferative retinopathy
      • Microaneurysms c14
      • Dot/blot hemorrhages c15c16
      • 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 c17
      • 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 c18
      • Venous beading c19
      • Cotton wool spots: infarctions in the retinal nerve fiber layer c20
    • Severe nonproliferative retinopathy
      • Marked capillary loss c21
      • Increased venous beading (retinal ischemia) c22c23
      • Multiple intraretinal hemorrhages in all 4 quadrants of the fundus c24
      • Venous beading in more than 2 quadrants c25
      • Intraretinal microvascular abnormality: shunt vessels appearing as abnormal dilation or branching of existing capillaries in more than 1 quadrant c26
    • Early proliferative retinopathy c27
      • Neovascularization in the disk area and elsewhere c28
      • Preretinal hemorrhage: rupture of new blood vessels between the retinal layers and the vitreous c29
      • Vitreous hemorrhage: rupture of new blood vessels and leakage of blood into the vitreous humor c30
      • Multiple intraretinal hemorrhages in all 4 quadrants of fundus c31
      • Venous beading in more than 2 quadrants c32
    • High-risk proliferative retinopathy
      • Neovascularization of disk area (one-quarter to one-half of the disk area) c33
      • Vitreous or preretinal hemorrhage c34c35
    • Severe proliferative retinopathy
      • Posterior fundus obscured by preretinal or vitreous hemorrhage c36c37
      • Central macular detachment c38
    • Clinically significant macular edema
      • The Early Treatment Diabetic Retinopathy Study definition of clinically significant macular edema included: r8r9
        • Thickening of retina at or within 500 µm of the center of the macula c39
        • 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 c40
      • Posterior fundus obscured by preretinal or vitreous hemorrhage c41c42
      • Central macular detachment c43
      • Macular cysts on ocular coherence tomography c44
      • Subretinal fluid on ocular coherence tomography c45

Causes and Risk Factors

Causes

  • Chronic hyperglycemia results in vascular leakage, angiogenesis, neuronal damage, and inflammatory insults r3c46
    • Primary contributor is chronic capillary nonperfusion and retinal ischemia r10
    • Injuries to the retinal neurovascular unit include: r11
      • Microaneurysms, hemorrhages, and angiogenesis
      • Retinal detachment
      • Macular edema
    • Specific vascular events include: r12
      • Altered microvascular permeability
      • Focal hypoxic events
      • Abnormal production of growth factors (especially VEGF [vascular endothelial growth factor]) and cytokines

Risk factors and/or associations

Age
  • Age of type 1 diabetes onset influences risk for retinopathy r13
    • Patients with onset of diabetes between the ages of 5 and 14 years are at highest risk c47c48
    • Patients with onset of diabetes between the ages of 15 to 40 years are at lowest risk c49c50
  • Younger age of type 2 diabetes onset (younger than 45 years at diagnosis) is associated with a higher prevalence and severity of retinopathy r14c51c52c53c54
Sex
  • May vary by ethnicity, but overall equally prevalent in men and women in the United States r15c55c56
Genetics
  • Diabetic retinopathy is a polygenic disorder c57c58
  • Heritability is high: estimated at about 27% for any diabetic retinopathy and about 52% for proliferative diabetic retinopathy r16
  • 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) r12
Ethnicity/race
  • More prevalent in African American (38.8%) and Mexican American (34%) populations than in white populations (26.4%) r17c59c60c61c62
Other risk factors/associations r18
  • Duration of diabetes r19c63
    • 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 r4c64
  • Hypertension: association exists between elevated blood pressure and presence of retinopathy; however, whether blood pressure causally influences development is unclear r20c65
  • Hyperlipidemia: weak association exists between serum lipid levels (largely LDL) and presence of diabetic retinopathy r19c66
  • Pregnancy: increases risk for progression of retinopathy r19c67
  • Nephropathy: closely associated with diabetic retinopathy, possibly owing to undesirable effects on lipids and platelets r20c68
  • 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

  • Dilated funduscopic examination (direct ophthalmoscopy) is gold standard for detecting diabetic retinopathy r10r21c69
    • 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
  • 7-field stereoscopic color fundus photography r5
    • Alternative method for detecting vision-threatening diabetic retinopathy, but it requires expensive equipment, trained retinal photographers, and expert readers
    • Can be used diagnostically, but especially indicated for monitoring response to treatment in patients with nonproliferative diabetic retinopathy, proliferative retinopathy, or macular edema
  • Fluorescein angiography
    • Ancillary test used by retinal specialists to detect areas of retinal ischemia and leaking microaneurysms before laser photocoagulation treatment of eyes with clinically significant macular edema
    • Not routinely necessary at time of diagnosis or for evaluating patients with no or minimal nonproliferative diabetic retinopathy
    • Useful to differentiate diabetic macular swelling from other macular disease or for a patient with unexplained vision loss r22
  • Optical coherence tomography r22
    • Rapid and noninvasive examination of retinal blood flow
    • Not used for screening but may be used to evaluate unexplained visual acuity loss in patients with diabetic retinopathy. Standard tool for guiding management of patients diagnosed with diabetic retinopathy
    • Necessary to diagnose macular edema, in combination with an eye examination and, occasionally, fluorescein angiography
    • Optical coherence tomography angiography is an emerging technology that is useful for detecting areas of intraretinal microvascular anomalies and neovascularization r10

Imaging

  • Digital stereoscopic fundus/retinal photography is the recommended imaging test of choice r10c70c71
    • Considered a highly accurate, time- and cost-effective method of fundus assessment
    • High-resolution method of examining the retina and its vasculature
    • Images can be shared for consultation and opinion from other specialists
    • Fundus photography and ophthalmoscopy are considered complementary and adjunctive to one another
  • Optical coherence tomography r23c72
    • Noninvasive technology that provides high-resolution mapping of the vitreoretinal interface, neurosensory retina, and subretinal space r24
    • Assesses retinal thickness and determines layer in which a hemorrhage resides; can also determine presence of macular edema and aid in monitoring
    • Allows an objective assessment of the amount and location of retinal thickening
    • Often used to guide therapeutic decisions when changes are made to existing treatments (eg, repeat anti-VEGF injections versus initiate laser treatment) r22

Procedures

IV fluorescein angiography r25r26c73
General explanation
  • Fluorescent dye (fluorescein), delivered by IV injection, highlights the retinal vasculature; image is captured by a retinal camera
  • Used to examine circulation of blood within blood vessels of the retina
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 r27r28r29
Complications
  • Anaphylaxis (rare) r30
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 c74
    • 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 r31
    • Screening results using nonmydriatic camera images assessed through telemedicine generally agree with findings from dilated fundus photography r32
    • 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 r21

Differential Diagnosis

Most common

  • Central retinal vein occlusion r2c75d1
    • 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 r2c76
    • 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 r33r34
    • 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 r35c77
    • Preretinal hemorrhages caused by a sudden increase in intrathoracic pressure
    • Subconjunctival hemorrhages may be present
    • Typically unilateral but may be bilateral
    • Differentiate using optical coherence tomography
      • Hemorrhage located in subhyaloid or sub–internal limiting membrane space
  • Sickle cell retinopathy r36c78d2
    • 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 optical coherence tomography
      • Macular ischemia with retinal thinning is consistent with sickle cell retinopathy
  • Radiation retinopathy c79
    • 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) r21
  • Delay progression of retinopathy r21
  • Preserve and improve vision r37

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 r22
  • Consult ophthalmologist urgently for sudden loss of vision, which may be caused by vitreous/retinal hemorrhage or retinal detachment r38
  • Refer patients with low-vision (those with visual acuities less than 20/40, scotomas, field loss, or contrast loss) to vision rehabilitation services r22

Treatment Options

Treatment strategies includes medical, ophthalmic, intravitreal, and surgical approaches r20

  • Medical
    • For all patients, optimize glycemic control, treat dyslipidemia, and lower blood pressure to reduce the risk of incident retinopathy or slow its progression; however, these measures do not ameliorate vision impairment r3
      • Pharmacologic therapy for diabetes
        • Intensive diabetes management with the goal of achieving near-normoglycemia can prevent or delay onset and progression of diabetic retinopathy r39r40
          • General hemoglobin A1C target to strive for is 7% or less (according to American Diabetes Association) r41
        • Note: a period of very strict glycemic control can temporarily worsen retinopathy in patients with more severe retinopathy and/or very poor glycemic control
      • Antihypertensive drugs
        • Measures to control blood pressure have a greater effect on preventing incident diabetic retinopathy, rather than slowing progression r42
        • However, ACE inhibitors and angiotensin receptor blockers are effective in reducing progression of preexisting diabetic retinopathy r43
        • Aggressive attempts to achieve tight targets (systolic blood pressure less than 120 mm Hg) do not provide greater benefits r40
      • Lipid-lowering therapies
        • Addition of fenofibrate to lipid-lowering therapy may slow progression of retinopathy, particularly with very mild nonproliferative diabetic retinopathy at baseline r44
  • Intravitreal
    • 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, VEGF inhibitors are first line agents and are preferred over focal laser photocoagulation r22
      • Can consider VEGF inhibitors for management of proliferative diabetic retinopathyr45 as an adjunct or alternative to panretinal photocoagulation, especially if both proliferative diabetic retinopathy and central-involved macular edema are present r21
      • Comparison of agents
        • All 3 available VEGF 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 r46r47
          • 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 r46
        • For central-involved macular edema and acuity of 20/40 or better, each agent effectively improves visual acuity to a similar extent r47
    • Intravitreal corticosteroids r48
      • Approved for central-involved macular edema, but typically used as second line treatment (after VEGF inhibitors) for those whose condition responds insufficiently to a series of anti-VEGF 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
  • Ophthalmic
    • Laser photocoagulation therapy r6
      • Panretinal photocoagulation is the cornerstone treatment of high-risk and severe proliferative diabetic retinopathy r12
        • Can be considered for some cases of early proliferative diabetic retinopathy or severe nonproliferative diabetic retinopathy
      • Focal photocoagulation is used for patients with clinically significant macular edema
    • Retinal cryotherapy may be indicated in extreme cases where laser therapy cannot be performed, although it has largely been replaced by photocoagulation r49
  • Surgical
    • Vitrectomy is indicated for severe diabetic retinopathy, under the following circumstances: r6
      • Unresponsive to photocoagulation
      • Unresponsive to intravitreal VEGF inhibitors
      • Associated with vitreous hemorrhage
      • Vitreomacular traction
      • Tractional retinal detachments threatening the macula and combined tractional-rhegmatogenous retinal detachments r10

Drug therapy c80

  • Antihypertensives c81
    • ACE inhibitors c82
      • Reduce risk of progression of mild to moderate nonproliferative diabetic retinopathy (by 65%) in patients with type 1 diabetes r50
      • Enalapril c83
        • Enalapril Maleate Oral tablet; Adults: 10 mg PO once daily (range, 5 mg/day up 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. Guidelines recommend the use of an angiotensin converting enzyme (ACE) inhibitor to slow the progression of renal disease in hypertensive patients and in diabetic patients regardless of the presence of hypertension.
    • Angiotensin receptor blockers c84
      • Losartan c85
        • Reduces risk of progression of mild to moderate nonproliferative diabetic retinopathy (by 65%) in patients with type 1 diabetes r50
        • Losartan Potassium Oral tablet; Adults: Initially, 50 mg PO once daily; titrate to 100 mg PO once daily based on blood pressure response.
      • Candesartan c86
        • Reduces incidence of diabetic retinopathy in patients with type 1 diabetes r51
        • May enable regression of existing nonproliferative diabetic retinopathy in patients with type 2 diabetes r52
        • 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 inhibitors c87c88
    • Aflibercept r53c89c90
      • 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 r54c91c92
      • 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 r55r56
      • 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 r54r57c93c94
      • Off-label use for treatment of central-involved macular edema related to diabetic retinopathy
      • 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 c95c96
    • Intravitreal triamcinolone acetonide r58c97c98
      • 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 r59c99c100
      • 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) r60c101c102
      • 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 r6c103c104c105

Physical activity c106

  • 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 r61
Procedures
Laser retinal photocoagulation r58c107c108c109
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 r6
  • Severe nonproliferative retinopathy, particularly in patients with type 2 diabetes
Complications
  • Panretinal r62
    • Corneal abrasions
    • Visual field loss
    • Reduced color vision
    • Reduced contrast sensitivity
  • Focal r22
    • 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 r63
Vitrectomy r19r64c110c111
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 r65
  • Cataracts r66
  • Vitreous hemorrhage r66
  • Epiretinal membrane r66
Retinal cryotherapy r49c112c113
General explanation
  • Use of subfreezing temperatures to ablate the retinal vessels and promote adhesion between the choroid and retina
Indication
  • Used in conjunction with scleral buckling to repair retinal detachment associated with diabetic retinopathy
  • To reduce neovascular growth associated with proliferative diabetic retinopathy

Comorbidities c114

Special populations

  • Pregnant patients r67
    • 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 r68
    • 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 retinopathyCSME, clinically significant macular edema; ME, non–clinically significant macular edema; VEGF, vascular endothelial growth factor.Data from American Academy of Ophthalmology Retina/Vitreous Preferred Practice Pattern Panel: Preferred Practice Pattern: Diabetic Retinopathy. AAO website. Published December 2017. Accessed April 16, 2019. https://www.aao.org/preferred-practice-pattern/diabetic-retinopathy-ppp-updated-2017
    Severity of retinopathyMacular edemaPanretinal laser photocoagulationFocal laser photocoagulationIntravitreal anti-VEGF
    Nonproliferative diabetic retinopathy
    No or minimal nonproliferative diabetic retinopathyNoNoNoNo
    Mild nonproliferative diabetic retinopathyNoNoNoNo
    MENoNoNo
    CSMENoPossiblePossible
    Moderate nonproliferative diabetic retinopathyNoNoNoNo
    MENoNoNo
    CSMENoPossiblePossible
    Severe nonproliferative diabetic retinopathyNoPossibleNoNo
    MEPossibleNoNo
    CSMEPossiblePossiblePossible
    Proliferative diabetic retinopathy
    Early proliferative diabetic retinopathyNoPossibleNoNo
    MEPossibleNoNo
    CSMEPossiblePossiblePossible
    High-risk proliferative diabetic retinopathyNoYesNoAlternative
    MEYesPossibleYes
    CSMEYesPossibleYes
  • Monitoring

    • General monitoring
      • 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 r68
      • If any level of diabetic retinopathy is present, refer to ophthalmologist or optometrist for subsequent dilated retinal examinations at least annually r68
      • If retinopathy is progressing or sight-threatening, examinations are required more frequently r68
      • Follow-up intervals for established retinopathyData from American Academy of Ophthalmology Preferred Practice Patterns Retina/Vitreous Panel et al: Diabetic retinopathy PPP - updated 2017. American Academy of Ophthalmology website. Published February 2016, updated 2017. Accessed April 16, 2019. https://www.aao.org/preferred-practice-pattern/diabetic-retinopathy-ppp-updated-2017
        Severity of retinopathyPresence of macular edemaTime interval to follow-up (months)
        Nonproliferative diabetic retinopathy
        Mild nonproliferative diabetic retinopathyNo12
        Macular edema4-6
        CSME1
        Moderate nonproliferative diabetic retinopathyNo12
        Macular edema3-6
        CSME1
        Severe nonproliferative diabetic retinopathyNo4
        Macular edema2-4
        CSME1
        Proliferative diabetic retinopathy
        Early proliferative diabetic retinopathyNo4
        Macular edema2-4
        Clinically significant macular edema1
        High-risk proliferative diabetic retinopathyNo4
        Macular edema4
        Clinically significant macular edema1
    • Monitoring after intravitreal injections
      • After anti-VEGF or corticosteroid injections, monitor patient monthly for elevation in intraocular pressure and endophthalmitis r22
    • Monitoring after laser photocoagulation
      • Ophthalmology follow-up occurs 3 to 4 months after laser surgery to monitor for choroidal neovascularization r22
    • Monitoring during pregnancy
      • Monitor pregnant patients every trimester and for 1 year postpartum as indicated by degree of retinopathy r68

    Complications and Prognosis

    Complications

    • Clinically significant macular edema associated with diabetic retinopathy r3c115
      • Can occur at any stage of the retinopathy (nonproliferative or proliferative)
      • Leading cause of blindness in patients with diabetes
    • Vitreous hemorrhage r69c116
    • Retinal detachment r70c117
    • Glaucoma r71c118

    Prognosis

    • Visual improvement and maintenance correlates with optimal management of underlying diabetes and/or coexisting hypertension/hyperlipidemia r19
      • Appropriate treatment can prevent severe vision loss in 90% of cases r6
    • Associated with increased risk of morbidity and mortality owing to increased incidence of cardiovascular events (eg, myocardial infarction, stroke) compared with patients without retinopathy r72

    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 r21
    • Patients with type 2 diabetes
      • Refer for comprehensive ophthalmic examination at the time of diagnosis r21
    • 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 r21
    • 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 r73

    Screening tests

    • Comprehensive evaluation by an ophthalmologist includes dilated slit lamp examination employing biomicroscopy with a handheld lens (90- or 78-diopter) and indirect ophthalmoscopy r5c119c120
    • Other additional testing may include optical coherence tomography and fluorescein angiography r5c121c122
    • Retinal and fundus photography (digital or color film) are not substitutes for a comprehensive eye examination, which should be performed at least initially r21
    • In areas where qualified eye care professionals are not readily available, retinal photography with remote reading by expert ophthalmologists can be a substitute screening strategy for diabetic retinopathy r68
      • This type of telemedicine screening needs to be followed with timely referral for a comprehensive eye examination if abnormalities are identified

    Prevention

    • Intensive diabetes management with the goal of achieving near-normoglycemia reduces the risk of developing retinopathy and slows its progression in type 1r39 and type 2r40 diabetes c123
      • Reduces ocular surgery rates in patients with type 1 diabetes r74
    • Lowering blood pressure (systolic less than 140 mm Hg) slows progression of retinopathy in type 2 diabetes r42c124
      • Aggressive lowering of systolic blood pressure to less than 120 mm Hg does not provide further benefit in terms of retinopathy r40
    • Treatment of dyslipidemia with fenofibrate slows progression of retinopathy by up to 40% among those with nonproliferative retinopathy r44c125
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