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A. Introduction navigator

  1. Leading cause of blindness in the USA in ages 20-60
  2. Presence of retinopathy in diabetics related to duration of disease [3]
    1. After ~4 years, about 20% of Type I DM patients have retinopathy
    2. After ~4 years, about 25% of Type II DM patients have retinopathy
  3. However, retinopathy develops in nearly all Type I DM patients
    1. Type I >15 years: ~98% have some retinopathy
    2. Type II >15 years: ~60-80% have some retinopathy
  4. Classification of stages
    1. Non-Proliferative (NPDR): Mild (Stage I) and Moderate/Severe (Stage II)
    2. Proliferative (PDR): presence of neovascularization

B. Pathogenesis [4] navigator

  1. Hyperglycemia
    1. Leads to many biochemical changes related to glycating biomolecules
    2. Degree and duration of hyperglycemia directly correlated with visual problems [5]
    3. Non-enzymatic glycation products appear to stimulate process
    4. These products lead to increased intracellular signalling
    5. Protein kinase C activity is increased substantially
    6. Biochemical pathway hyperglycemia to retinopathy has not been clarified [1]
  2. Early Effects on Retinal Capillaries
    1. Capillary pericytes are selectively affected first
    2. These cells appear to regulate vessel diameter and control blood flow
    3. Loss of capillary pericytes appears to lead to microaneurysms early in process
    4. These microaneurysms have no clinical importance except as marker for retinopathy
    5. Thus, the total number of microaneurysms correlates with progression of retinopathy
    6. Microaneurysms are a marker for proliferative retinopathy: new vessel formation
    7. Vascular occlusion occurs which further stimulates new blood vessel proliferation
    8. New vessels extend into vitreous and can cause vitreous hemorrhage (blindness)
    9. New vessels can also cause tractional retinal detachments
    10. Progression of new vessels can obstruct aqueous humor outflow causing neovascular glaucoma
  3. Macular Edema
    1. Capillary permeability is increased through breakdown in blood-retinal barrier
    2. This leads to leakage of plasma from small vessels in macula (central part of retina)
    3. Macular edema causes swelling of central retina which can be observed
    4. Resorption of plasma leads to deposition of lipid and lipoproteins
    5. Excess lipid deposits which form "hard exudates" which obscure central vision
    6. Macular edema occurs in ~20% of DM1 and DM2 over 10 years
    7. Over 10 years with DM2 macular edema occurs in ~25% on insulin; without insulin ~13%
    8. Insulin may stimulate growth hormone and/or insulin-like growth factor
  4. Angiogenesis and Neovascularization
    1. Ischemia due to abnormal capillaries, reduced blood flow, and clot formation occurs
    2. Growth factors, particularly for blood vessels, are released in retina
    3. Production of vasoactive compounds is abnormally elevated
    4. Vascular endothelial growth factor (VEGF) is a major angiogenic protein released
    5. Erythropoietin (EPO) is also likely a major retinal angiogenic factor [15]
    6. Median levels of VEGF and EPO are 100X and 10X elevated, respectively, in DM retinopathy [15]
    7. Fibroblast growth factor (FGF) and other vasoactive hormones are released
    8. Pigment epithelium derived factor (PEDF), anti-angiogenic, levels are reduced
    9. Endothelial proliferation and neovascularization occurs
    10. Fibrous tissue accompanies new blood vessel formation
  5. Systemic Hypertension (HTN)
    1. Major contributing risk factor for diabetic retinopathy
    2. Patients with DM are at increased risk for HTN
    3. HTN increases risk for neovascularization
    4. Angiotensin II blockade is effective in treating HTN and reducing diabetic complications
    5. Suggests that HTN and/or angiotensin II play a role in retinopathy progression

C. Mild Non-Proliferative Retinopathy (NPDR)navigator

  1. Microaneurysms
    1. Temporal and/or macular region - fluffy white patches
    2. Resolution complete or small white dots left over for several months
    3. First sign of diabetic retinal disease
  2. Intraretinal Hemorrhage
    1. Dot, Blot, or Flame hemorrhage in nerve fiber layer
    2. May resorb without trace or with lipid deposition
    3. May significantly affect vision, often acutely, if located in foveal region
  3. Hard Exudates
    1. Yellow, discrete deposits with sharp borders
    2. Lipid deposition accompanies increased vascular permeability
    3. The fluid is resorbed, leaving residual lipid deposits
    4. The amount of lipid correlates with serum lipid levels
    5. May enlarge or become more dense; or may resorb without a trace
    6. If very dense, may lead to fibrous scarring
  4. Macular Edema
    1. Serous fluid collection in outer and/or inner plexiform layers
    2. May be visualized with fluorescein angiogram (to find sites of leakage
    3. May form cystic cavities, particularly in fovea
    4. Due to focal capillary leak, possibly microaneurysms
    5. Leads to thickened retina, swelling of macula
    6. Often have progressive central vision deterioration

D. Moderate - Severe NPDRnavigator

  1. Focal and diffuse areas of capillary closure
  2. Severe NPDR is defined by the "4:2:1" Rule
    1. Four (4) quadrants of hemorrhages (microaneurysms greater than a standard photograph)
    2. Two (2) quadrants of venous bleeding
    3. One (1) quadrant of intraretinal microvascular abnormalities
    4. Severe NPDR needs to be recognized: 50% progress to proliferative retinopathy in 1 year
  3. Venous Beading
    1. Irregular constriction and dilatation of vein lumen
    2. Reminiscent of "Sausage String"
  4. Nerve Fiber Infarctions may also be seen
    1. Seen as Soft Exudates or "Cotton-Wool Spots"
    2. Focal infarctions in nerve fiber layer with axon swelling due to capillary closure
  5. Intraretinal Microvascular Abnormalitites (IRMA)
    1. Shunt vessels formed
    2. These are capillaries which frequently leak
    3. May look like neovascularization but are found within the plane of the retina

E. Proliferative Diabetic Retinopathy (PDR) [4] navigator

  1. Defined as new vessels growing on the surface of the retina or optic disk
  2. Blood vessels
    1. At this stage, vessels erupt through surface of retina
    2. Tend to initiate on posterior surface of vitreous
    3. The new vessels are associated with retinal ischemia
    4. May proliferate into vitreous space
    5. May be accompanied by fibrous ingrowth
  3. Development of new vessels
    1. Neovascularization of Disk (NVD)
    2. Neovascularization Elsewhere (NVE; peripheral)
    3. Neovascularization of Iris (NVI): potential for development of glaucoma
  4. Hemorrhage
    1. New vessels tend to be very weak
    2. May bleed into or behind vitreous
    3. This can lead to decrease or complete loss of vision
  5. Vitreoretinal Traction
    1. New vessels may regress, leaving fibrovascular tissue attached to vitreous and retina
    2. Vitreous anchor strains may cause variety of problems including:
    3. Vitreous hemorrhage
    4. Traction retinal detachment
    5. Rhegmatogenous detachment of retina (if break occurs)
  6. Etiology [13]
    1. Release of vascular endothelial growth factor (VEGF) due to retinal hypoxia
    2. VEGF stimulates growth of new vessels
    3. Growth of new vessels is rapid once it begins
  7. High Risk Factors for Development of Severe Visual Loss (Vision < 5/200)
    1. Neovascular disease in more than 1/3 of disc area
    2. Any neovascular disease with viteous hemorrhage
  8. VEGF Inhibitors [13]
    1. Approved for macular degeneration and may be effective in diabetic retinopathy with neovascularization
    2. Pegaptanib (anti-VEGF aptamer, Macugen®) - approved for macular degeneration
    3. Ranibizumab (monoclonal anti-VEGF Ab fragment) - in Phase III studies

F. Prevention of Diabetic Retinopathy [1,2,4,5] navigator

  1. Prevention has been clearly proved to be best at saving sight in diabetics
    1. Frequent screening
    2. Control blood glucose and blood pressure (BP) [2]
    3. Retinal laser photocoagulation
    4. Vitrectomy for nonclearing vitreous hemorrhage or tractional retinal detachment
  2. Ophthalmology Examination
    1. All diabetics should have careful ocular examinations with frequent followups
    2. Mydriatic retinal photography is most effective test for detection [6]
  3. Glucose control
    1. Diabetes Control and Complications Trial (DCCT) in Type 1 DM showed that intensive insulin therapy reduces risk of ocular progression 65-80% [7]
    2. The DCCT was carried out over 6.5 years
    3. Over time, intensive insulin therapy may have less impact on glycemic control compared with standard therapy, but still reduces progression of retinopathy in Type 1 DM [8]
    4. Similar studies on Type 2 DM patients showed reduction in diabetic retinopathy with improved glycemic control using intensive therapy
    5. Improved glycemic control also reduces risk of other micovascular complication of DM
  4. HTN Control
    1. Angiotensin II converting enzyme inhibitors (ACE-I) or angiotensin II receptor blockers (ARB) are first line therapy
    2. ACE-I and ARB are very effective in treating HTN and reducing diabetic nephropathy
    3. Lisinopril reduced progression of retinopathy by 50% over two years in Type I DM [9]
    4. Aggressive HTN treatment with ACE-I or ARB first line strongly recommended
  5. Intensive therapy with various ACE-I + Vitamin E + Vitamin C in Type II DM with microalbuminuria reduced progression of retinopathy >50% over three years [10]
  6. Fenofibrate (TriCor®) 200mg/day (lipid lowering) given to type 2 DM patients reduced diabetic retinopathy and need for retinal laser treatment ~35% [16]
  7. Experimental Therapies
    1. Aldose reductase inhibitors - blocks conversion of glucose to sorbitol
    2. No clinical benefit on retinopathy to date with aldose reductase inhibitors
    3. Anti-angiogenic compounds in clinical development
    4. inhibitors of protein glycosylation
    5. Inhibitors of secretion and action of growth hormone

G. Management [2,3,4]navigator

  1. Patients without retinopathy can be screened every 3 years [3]
  2. Mild NPDR
    1. Examine annually unless macular edema present
    2. Yearly or more frequent screening if higher grade of retinopathy
  3. Moderate NPDR
    1. Examine semiannually unless macular edema present
    2. Every 2-4 month checkups to watch for proliferation
    3. Therapy as above
  4. Severe NPDR - examine every 3-4 months to check for proliferative disease
  5. Macular Edema [2,11]
    1. Early Treatment Diabetic Retinopathy Study (ETDRS) is key
    2. Assessed treatment of clinically significant macular edema (CSME) with laser therapy
    3. Found focal laser therapy reduced 3 year risk of moderate visual loss by 50%
    4. CSME includes retinal thickening, hard exudates in fovea region, and others
    5. Followup evaluation is done 2-4 months after laser therapy
    6. Hard exudates and foveal edema may respond to danaparoid [12]
  6. PDR [2]
    1. Laser panretinal photocoagulation indicated when high risk characteristics present
    2. Serves to decrease retinal metabolic demands and therefore ischemia
    3. Laser works by ablating peripheral retina not used in central vision
    4. Therefore, main side effect is constricted visual field
    5. Reduces risk of severe visual loss over 2 years by 50-60%
  7. Indications for Vitrectomy [14]
    1. Nonclearing (severe) vitreous hemorrhages
    2. Traction retinal detachment involving macula
    3. Combined traction and rhegmatogenous retinal detachment
    4. Iris neovascularization (some subsets)

References navigator

  1. Frank RN. 2004. NEJM. 350(1):48 abstract
  2. Mohamed Q, Gillies MC, Wong TY. 2007. JAMA. 298(8):902 abstract
  3. Younis N, Broadbent DM, Vora JP, Harding SP. 2003. Lancet. 361(9353):195 abstract
  4. Ferris FL III, Davis MD, Aiello LM. 1999. NEJM. 341(9):667 abstract
  5. Reichard P, Nilsson B-Y, Rosenqvist U. 1993. NEJM. 329:304 abstract
  6. Hutchinson A, McIntosh A, Peters J, et al. 2000. Diabet Med. 17:495 abstract
  7. DCCT Research Group. 1993. NEJM. 329:977 abstract
  8. DCCT Research Group. 2000. NEJM. 342(6):381 abstract
  9. Chaturvedi N, Sjolie AK, Stephenson JM, et al. 1998. Lancet. 351:28 abstract
  10. Gaede P, Vedel P, Parving HH, Pedersen O. 1999. Lancet. 353(9153):617 abstract
  11. Early Treatment Diabetic Retinopathy Study Report #2. 1986. Ophthalmology. 94:761
  12. van der Pijl JW, van der Woude FJ, Swart W, et al. 1997. Lancet. 350(9093):1743 abstract
  13. van Wijngaarden P, Coster DJ, Williams KA. 2005. JAMA. 293(12):1509 abstract
  14. Smiddy W, Feuer W, Irvine WD, et al. 1995. Ophthalmology. 102:1688 abstract
  15. Watanabe D, Suzuma K, Matsui S, et al. 2005. NEJM. 353(8):782 abstract
  16. Keech AC, Mitchell P, Summanen PA, et al. 2007. Lancet. 370(9600):1687 abstract