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Retinopathy, Diabetic
Richard W. Allinson, MD
image BASICS
DESCRIPTION
  • Noninflammatory retinal disorder characterized by retinal capillary closure and microaneurysms. Retinal ischemia leads to release of a vasoproliferative factor, stimulating neovascularization on retina, optic nerve, or iris.
  • Most patients with diabetes mellitus (DM) will develop diabetic retinopathy (DR). It is the leading cause of new cases of legal blindness among residents in the United States between the ages of 20 and 64 years.
  • DR can be divided into three stages.
    • Nonproliferative (background)
    • Severe nonproliferative (preproliferative)
    • Proliferative
  • System(s) affected: nervous
Geriatric Considerations
Prevalence will increase, as population generally ages and patients with diabetes live longer.
Pregnancy Considerations
  • Pregnancy can exacerbate condition.
  • Pregnant diabetic women should be examined in 1st trimester, then every 3 months until delivery.
EPIDEMIOLOGY
Incidence
  • Peak incidence of type 1, juvenile-onset DM is between the ages of 12 and 15 years.
  • Peak incidence of type 2, adult-onset DM is between the ages of 50 and 70 years.
  • Incidence of DR is directly related to the duration of diabetes.
  • <10 years of age, it is unusual to see DR, regardless of DM duration
Prevalence
  • 6.6% of the U.S. population between ages of 20 and 74 years has DM.
  • ˜25% of the diabetic population has some form of DR.
  • Predominant age
    • Risk increases after puberty.
    • 2/3 of juvenile-onset diabetics who have had DM for at least 35 years will develop proliferative DR and will develop macular edema. Proportions are reversed for adult-onset diabetes.
  • Predominant sex: male = female (type 1, juvenile-onset DM); female > male (type 2)
ETIOLOGY AND PATHOPHYSIOLOGY
  • Related to development of diabetic microaneurysms and microvascular abnormalities
  • Reduction in perifoveal capillary blood flow velocity, perifoveal capillary occlusion, and increased retinal thickness at the central fovea in diabetic patients are associated with visual impairment in patients with diabetic macular edema.
RISK FACTORS
  • Duration of DM (usually >10 years)
  • Poor glycemic control
  • Pregnancy
  • Renal disease
  • Systemic hypertension (HTN)
  • Smoking
  • Elevated lipid levels associated with increased risk of retinal lipid deposits (hard exudates)
  • Myopic eyes (eyes with longer axial length) have a lower risk of DR.
GENERAL PREVENTION
  • Monitor and control of blood glucose.
  • Schedule yearly ophthalmologic eye exams.
COMMONLY ASSOCIATED CONDITIONS
  • Glaucoma
  • Cataracts
  • Retinal detachment
  • Vitreous hemorrhage
  • Disc edema (diabetic papillopathy); may occur in type 1/type 2 DM
image DIAGNOSIS
PHYSICAL EXAM
  • Eye exam: measurement of visual acuity and documentation of the status of the iris, lens, vitreous, and fundus
  • Nonproliferative (background) DR
    • Microaneurysms
    • Intraretinal hemorrhage
    • Macular edema causing decrease in central vision
    • Lipid deposits
  • Severe nonproliferative (preproliferative) DR
    • Nerve fiber layer infarctions (“cotton wool spots”)
    • Venous beading
    • Venous dilatation
    • Intraretinal microvascular abnormalities
    • Extensive retinal hemorrhage
  • Proliferative DR
    • New blood vessel proliferation (neovascularization) on the retinal surface, optic nerve, and iris
    • Visual loss caused by vitreous hemorrhage, traction retinal detachment
GENERAL MEASURES
  • The Diabetes Control and Complications Trial (DCCT) recommended that for most patients with insulin-dependent DM, blood glucose levels should be as close to the nondiabetic range as is safe to reduce the risk and rate of progression of DR.
    • In the DCCT, insulin-dependent DM patients were randomly assigned into either conventional or intensive insulin treatment. Conventional treatment consisted of one to two daily insulin injections, with daily self-monitoring of urine/blood glucose. Intensive treatment consisted of insulin administered ≥3 times daily by injection/an external pump, with self-monitored blood glucose levels measured at least 4 times per day.
    • The DCCT demonstrated that intensive insulin therapy reduced the risk of macular edema and retinal neovascularization. The benefit of intensive insulin therapy and the reduced risk of DR-associated microvascular complications persist for at least 10 years.
  • In the DCCT, intensive insulin therapy was more effective in reducing the risk of progression of DR in the less advanced stages. However, advanced DR also benefited from the intensive insulin therapy. The Early Treatment Diabetic Retinopathy Study demonstrated that aspirin therapy did not prevent the development of proliferative DR or reduce the risk of visual loss associated with DR.
  • Microvascular complications, including proliferative DR, are increased when blood sugar levels are ≥200 mg/dL.
  • Poor glycemic control is associated with an increased risk both for development and progression of DR, regardless of the type of DM; that hyperglycemia itself is causative is not established, especially for type 2 DM.
  • Cataracts are more common among those with DM. Try to delay cataract surgery in DM patients with retinopathy until the symptoms are severe. Cataract surgery can cause retinopathy to worsen and increase the risk for development of diabetic macular edema.
  • HTN has a detrimental effect on DR and must be controlled.
DIFFERENTIAL DIAGNOSIS
Other causes of retinopathy (e.g., radiation, retinal venous obstruction, HTN)
DIAGNOSTIC TESTS & INTERPRETATION
Diagnostic Procedures/Other
  • Fluorescein angiography demonstrates retinal nonperfusion, retinal leakage, and proliferative DR.
  • Optical coherence tomography (OCT) can be used to help detect diabetic macular edema by measuring retinal thickness.
Test Interpretation
  • Increased capillary permeability
  • Microaneurysms
  • Hemorrhages in retina
  • Exudates in retina
  • Capillary nonperfusion
image TREATMENT
MEDICATION
  • Treatment with the angiotensin-receptor blocker candesartan has been shown to result in regression of DR in some patients (1)[B].
  • Nutritional antioxidant intake of vitamins C and E and of &bgr;-carotene has no protective effect on DR.
  • Atorvastatin may reduce the severity of lipid deposits with clinically significant diabetic macular edema in type 2 DM and dyslipidemia.
SURGERY/OTHER PROCEDURES
  • Laser photocoagulation treatment: recommended for patients with proliferative DR and for those with clinically significant macular edema; destroys leaking blood vessels and areas of neovascularization
  • The Diabetic Retinopathy Study demonstrated that panretinal photocoagulation reduced overall rate of severe visual loss from 15.9% in untreated eyes to 6.4% in treated eyes. In certain subgroups, the incidence of severe visual loss in untreated eyes was as high as 36.9% within 2 years.
  • The Early Treatment Diabetic Retinopathy Study demonstrated that eyes with significant diabetic
    P.915

    macular edema benefited from focal laser treatment. Clinically significant diabetic macular edema (CSDME) is defined as the following:
    • Thickening of the retina within 500 &mgr;m of the center of the macula
    • Hard exudates within 500 &mgr;m of the center of the macula associated with thickening of the adjacent retina
    • Zone of retinal thickening ≥1 disc area within 1 disc diameter of the center of the macula
  • Patients with CSDME and high-risk proliferative disease can have simultaneous focal and panretinal photocoagulation without adversely affecting the visual outcome.
  • Vitrectomy may benefit some with diffuse macular edema. This may apply especially to eyes with vitreomacular traction found on OCT and with persistent CSDME.
  • Intravitreal triamcinolone may be used for DM-related macular edema that fails laser treatment. No long-term benefit of intravitreal triamcinolone relative to focal/grid photocoagulation in patients with CSDME. This is an off-label use (2)[C].
  • Ranibizumab, an antibody fragment that binds vascular endothelial growth factor (VEGF), can be used to treat CSDME when injected intravitreally. Ranibizumab 0.3 mg given monthly to treat CSDME resulted in improved vision and reduced central foveal thickness (3)[A]. It is indicated for diabetic macular edema (DME) and for DR in patients with DME.
    • Anti-VEGF therapy is the preferred method of treatment for visual impairment resulting from (DME). Anti-VEGF treatment results in superior clinical outcomes compared to laser photocoagulation for DME (4)[A].
    • The 5-year results suggest focal/grid laser treatment at the initiation of intravitreal ranibizumab injection (IRI) is no better than deferring laser treatment for ≥24 weeks in eyes with DME involving the central macula with vision impairment (5)[A].
    • Intravitreal ranibizumab treatment for diabetic macular edema may also improve DR severity and reduce the risk of DR progression (6)[A].
    • Monthly (IRI) can slow, but not completely prevent, retinal capillary closure in patients with DME (7)[B].
  • Bevacizumab, a full-length antibody that binds VEGF, can be used to treat CSDME when injected intravitreally. This is an off-label use.
    • Intravitreal bevacizumab and ranibizumab have comparable efficacy in treating DME (8)[C].
  • Aflibercept, a soluble decoy receptor for VEGF. Aflibercept 2 mg (0.05 mL) injected intravitreally every 4 weeks for the first 5 injections followed by 2 mg (0.05 mL) intravitreally once every 8 weeks. It is indicated for patients with DME and for DR in patients with DME.
    • Intravitreal aflibercept injection (IAI) has demonstrated significant superiority in functional and anatomic endpoints over macular laser photocoagulation (9)[A].
    • At worse levels of initial visual acuity (20/50 or worse) in patients with DME, IAI was more effective in improving vision than ranibizumab or bevacizumab (10)[A]. When the initial vision loss was mild (20/32 to 20/40) in patients with DME, there was no significant difference between aflibercept, ranibizumab, or bevacizumab (10)[A].
  • Preoperative bevacizumab can be used as an adjuvant to vitrectomy for complications of proliferative DR. This is an off-label use:
    • At ˜10 days after intravitreal injection of bevacizumab, the vascular component of proliferation is markedly reduced, and the contractile components are not yet very significant. Patients with dense fibrovascular proliferation need to be monitored closely for evidence of traction retinal detachment (11)[C].
  • Intraocular steroid implants for DME. A dexamethasone implant and a fluocinolone acetonide implant. Complications of these implants include cataract and glaucoma.
  • Vitrectomy: recommended for patients with severe proliferative DR, traction retinal detachment involving the macula, and nonclearing vitreous hemorrhage
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
Scheduled ophthalmologic eye exams
  • Yearly follow-up if no retinopathy
  • Every 6 months with background DR
  • At least every 3 to 4 months with preproliferative DR
  • Every 2 to 3 months with active proliferative DR
DIET
Follow prescribed diet for patients with diabetes.
PATIENT EDUCATION
  • Patient education should include regular ophthalmic exams.
  • Stress importance of strict blood glucose control through diet, exercise, drugs/insulin, and monitoring of blood glucose.
PROGNOSIS
If the condition is diagnosed and treated early in development, outlook is good. If treatment is delayed, blindness may result.
REFERENCES
1. Sjølie AK, Klein R, Porta M, et al. Effect of candesartan on progression and regression of retinopathy in type 2 diabetes (DIRECT-Protect 2): a randomised placebo-controlled trial. Lancet. 2008;372(9647):1385-1393.
2. Beck RW, Edwards AR, Aiello LP, et al. Three-year follow-up of a randomized trial comparing focal/grid photocoagulation and intravitreal triamcinolone for diabetic macular edema. Arch Ophthalmol. 2009;127(3):245-251.
3. Brown DM, Nguyen QD, Marcus DM, et al. Long-term outcomes of ranibizumab therapy for diabetic macular edema: the 36-month results from two phase III trials: RISE and RIDE. Ophthalmology. 2013;120(10):2013-2022.
4. Mitchell P, Wong TY. Management paradigms for diabetic macular edema. Am J Ophthalmol. 2014;157(3):505.e8-513.e8.
5. Elman MJ, Ayala A, Bressler NM, et al. Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: 5-year randomized trial results. Ophthalmology. 2015;122(2):375-381.
6. Ip MS, Domalpally A, Sun JK, et al. Long-term effects of therapy with ranibizumab on diabetic retinopathy severity and baseline risk factors for worsening retinopathy. Ophthalmology. 2015;122(2):367-374.
7. Campochiaro PA, Wykoff CC, Shapiro H, et al. Neutralization of vascular endothelial growth factor slows progression of retinal nonperfusion in patients with diabetic macular edema. Ophthalmology. 2014;121(9):1783-1789.
8. Nepomuceno AB, Takaki E, Paes de Almeida FP, et al. A prospective randomized trial of intravitreal bevacizumab versus ranibizumab for the management of diabetic macular edema. Am J Ophthalmol. 2013;156(3):502.e2-510.e2.
9. Korobelnik JF, Do DV, Schmidt-Erfurth U, et al. Intravitreal aflibercept for diabetic macular edema. Ophthalmology. 2014;121(11):2247-2254.
10. Wells JA, Glassman AR, Ayala AR, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015;372(13):1193-1203.
11. El-Sabagh HA, Abdelghaffar W, Labib AM, et al. Preoperative intravitreal bevacizumab use as an adjuvant to diabetic vitrectomy: histopathologic findings and clinical implications. Ophthalmology. 2011;118(4):636-641.
12. Bressler SB, Almukhtar T, Bhorade A, et al. Repeated intravitreous ranibizumab injections for diabetic macular edema and the risk of sustained elevation of intraocular pressure or the need for ocular hypotensive treatment. JAMA Ophthalmol. 2015;133(5):589-597.
See Also
&NA;
Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2
Codes
&NA;
ICD10
  • E11.319 Type 2 diabetes mellitus with unspecified diabetic retinopathy without macular edema
  • E10.319 Type 1 diabetes mellitus with unspecified diabetic retinopathy without macular edema
  • E10.329 Type 1 diab w mild nonprlf diabetic rtnop w/o macular edema
Clinical Pearls
&NA;
  • Options for the treatment of diffuse macular edema include focal laser treatment, intravitreal triamcinolone, intravitreal ranibizumab, intravitreal bevacizumab, intravitreal aflibercept, intraocular steroid implants, and vitrectomy.
  • High BP should be controlled to reduce the risk of diabetic eye complications.
  • Blood glucose levels should be well controlled to help reduce the risk and rate of DR progression.
  • Schedule yearly ophthalmologic eye exams.