Diabetic Retinopathy

Diabetic Retinopathy

1. DIABETIC RETINOPATHY

2. References Ryan Retina (6 th edition) Yanoff Ophthalmology (5 th edition) Kanski’s clinical Ophthalmology (9 th edition) Parson’s (23 rd edition)

3. Introduction Diabetes mellitus is the most common disorder of energy metabolism causing microvascular complications including nephropathy, neuropathy, and also affects eye Ophthalmic complications include; Retinopathy Iridopathy Unstable refraction Recurrent styes reduced corneal sensation accelerated age related cataract NVG motor nerve palsy Papillopathy (rare)

4. Introduction Diabetic Retinopathy is a leading cause of blindness among individuals between 25 and 74 years of age in the industrialized world It is composed of a characteristic group of lesions in retina of individuals having had Diabetes mellitus for several years. “ DR is predominantly a microangiopathy in which small blood vessels are particularly vulnerable to damage from high glucose levels ”.

5. Introduction Changes in early stages include vascular occlusion and dilations. As the disease advances it progresses into: Proliferative Retinopathy with the growth of new blood vessels. Macular edema which can significantly decrease visual acuity.

6. Epidemiology It is more common in type 1 Diabetes than in type 2 Diabetes . The crude prevalence of Diabetic retinopathy (DR) in diabetics is 40% . The crude prevalence of sight threatening disease is 10% . Type 1 are at high risk ,showing incidence of 90% in 30 years

7. Wisconsin Epidemiologic Study on Diabetic Retinopathy (WESDR) Population based study (1980 – 1982 ). Provided estimates of the prevalence and severity of DR. WESDR found prevalence: Type-I DM Type-II DM Retinopathy 71% 47% Proliferative Retinopathy 23% 6% Macular edema 11% 8%

8. Diabetes Control & Complications Trial DCCT showed that type 1 diabetics who closely monitored their blood glucose via tight control (4 measurements per day) had: 76% reduction in the rate of development of any retinopathy & 54% reduction in progression of established retinopathy As compared with the conventional treatment group (1 measurement per day).

9. Diabetes Control & Complications Trial The DCCT has shown that for every 1% decrease in the hemoglobin A1C (HbA1C) level, the incidence of diabetic retinopathy decreases 28%. DCCT was halted early after 6.5 years when the benefit of tight control was deemed unlikely to be reversed with time.

10. EDIC study EDIC – Epidemiology of Diabetics Interventions and Complications Study The EDIC study showed continued benefit for the former tight control group over the former conventional treatment group, despite normalization of glucose control even after 7 years of follow-up.

11. United Kingdom Prospective Diabetes Study The UKPDS results establish that retinopathy, nephropathy, and possibly neuropathy are benefited* by lowering blood glucose levels in type 2 diabetes with intensive therapy , which achieved a median HbA 1c  of 7.0% compared with conventional therapy with a median HbA 1c  of 7.9% . United Kingdom Prospective Diabetes Study (UKPDS) revealed a 21% reduction in the 1-year rate of progression of retinopathy

12. Risk factors Duration of diabetes - DR remains the number one cause of new blindness in most industrialized countries because of delays in seeking treatment. Duration of retinopathy is most closely associated with the incidence of DR and remains the best predictor of diabetic retinopathy. Duration of Type-I DM Incidence First 5 years Very low risk of DR 5 to 10 years 27% > 10 years 71 to 90% 20 to 30 years 95% (of which 30-50% - PDR)

13. Risk Factors Type-II Diabetes mellitus : 14 Duration of Type-II DM Prevalence (Yanko et al) At presentation 5% 11 to 13 years 23% > 16 years 60%

14. Risk Factors Poor control of diabetes Type 1 DM patients obtain greater benefit from good control than Type 2 Raised HbA1c is associated with increaced risk of proliferative disease. 3. Hypertension, Hyperlipidaemia , Smoking, Cataract surgery and Obesity 4. Nephropathy: if severe is associated with worsening of DR. 15

15. Risk Factors 5. Pregnancy Pregnant women without retinopathy – 10% risk of developing NPDR Pregnancy is sometimes associated with rapid progression of DR Risk of progression is related to severity of DR in 1 st trimester. About 4% of pregnant women with NPDR progress to PDR Predisposing factors: - greater pre-pregnancy severity of retinopathy - poor pre- pregnancy control of diabetes - rapid control exerted during early pregnancy - Pre- eclampsia 16

16. Pathogenesis 17 1 2 3 4

17. Anatomical L esions Loss of pericytes Capillary basement membrane thickening Microaneurysms Capillary acellularity Break down of blood retinal barrier 18

18. Loss of Pericytes Pericytes are contractile cells that play important role in microvascular autoregulation. They are spaced regularly along the capillary wall – appear as “bumps on a log”. Loss of pericytes: Earliest & most specific signs of DR observable histologically. Leads to alterations of vascular intercellular contacts & blood retina barrier. 19

19. Normal arrangement of Pericytes and Endothelial cells P – Pericytes E – Endothelial cells 20 Pericyte loss P – Pericytes E – Endothelial cells G – Pericyte ghosts

20. Loss of P ericytes The mechanism by which hyperglycemia leads to pericyte degeneration remains largely unknown. Two hypotheses: Aldose reductase pathway PDGF-β PDGF-β Endothelial cells express PGDF-β and pericytes (invitro) express PGDF-β receptors. In case of PGDF-β deficiency in developing capillaries, pericytes fail to develop during angiogenesis. 21

21. Loss of Pericytes Aldose reductase pathway: Aldose reductase is found in high concentration in retinal pericytes . It converts sugars into their alcohols. Glucose  Sorbitol & Galactose  Galactitol . Their accumulation leads to osmotic forces causing water to diffuse into the cell  cell damage.

22. Capillary Basement Membrane Thickening Well documented lesion of diabetic retinopathy & visible on electron microscopy. Exact biochemical mechanism – unknown. Studies suggest role of: Aldose reductase and sorbitol pathway Glycation of basement membrane collagen by enzymatic and non-enzymatic mechanisms. 23

23. Microaneurysms Earliest clinically visible of Diabetic retinopathy. Ophthalmoscopically – tiny, intraretinal red dots located in inner retina. 24

24. Microaneurysms Light microscopy grape like or spindle shaped dilatations of retinal capillaries . Fluorescein angiography punctate hyperfluorescent dots with variable amount of fluorescein leakage . 25

25. Microaneurysms Microaneurysms (MA’s) – can be either: Hypercellular Acellular Occurs due to: Pericytes – contain myofibrils with contractile properties and counteracts transmural pressure in capillaries. Loss of pericyte tone  focal dilatation of vessel wall  Microaneurysm. 26

26. Microaneurysms Pericytes – antiproliferative effect on endothelium. Pericyte death/loss thus leads to formation of Hypercellular MA’s. Hypercellular MA’s  Acellular MA’s by endothelial & pericyte apoptosis. 27 Cellular Microaneurysm MA with Endothelial cell proliferation due to pericyte loss

27. Capillary A cellularity Complete loss of capillary cellular elements – seen as a more advanced microvascular lesion. Mechanism of capillary acellularity – unknown. Acellular capillaries: non-functional appear as non-perfusion regions on Fluorescein angiography. 28

28. Break Down Of Blood Retinal Barrier It is the important pathophysiologic feature of diabetic retinopathy that leads to the development of macular edema, the leading cause of vision loss in diabetic patients . Mechanisms: VEGF Kallikrein kinin system 29

29. Break Down Of Blood Retinal Barrier VEGF One mechanism by which the function of this barrier becomes altered involves opening of the tight junctions ( Zonula occludens ) between vascular endothelial cell processes. Vascular endothelial growth factor (VEGF) has been found to be an important mediator leading to the breakdown of the inner blood-retina barrier. The mechanism by which VEGF leads to the breakdown of the inner blood-retina barrier appears to involve alteration of endothelial cell tight junctions. 30

30. Break Down Of Blood Retinal Barrier Kallikrein-kinin system Another important factor promoting retinal vascular permeability involves the kallikrein-kinin system . Components of the kallikrein kinin system, including plasma kallikrein, factor XII, and kininogen. The mechanism by which the kallikrein kinin system promotes vascular permeability probably involves Bradykinin . Bradykinin, via nitric oxide, induces vasorelaxation of retinal arterioles . 31

31. Biochemical Mechanisms Aldose reductase theory Advanced Glycation End-product (AGE) theory Photoreceptor mechanism theory Reactive oxygen intermediates (ROI) theory Protein Kinase C (PKC) theory Insulin receptors & glucose transporters 32

32. 1. Aldose Reductase Theory Elevation of intracellular glucose levels ↓ Activation of Aldose reductase pathway ↓ Glucose reduced to  SORBITOL ↓ Sorbitol is oxidized by Sorbitol dehydrogenase to  Fructose ↓ Decline in NADPH, increase in NADH/NAD + ratio ↓

33. 1. Aldose Reductase Theory ↓ Alters the cellular redox balance ↓ Oxidative stress & cellular damage ↓ Pericyte loss, development of MA’s and capillary acellularity SORBINIL RETINOPATHY TRIAL Sorbinil – Aldose reductase inhibitor However, it was found not to be effective in humans. Dose limiting side effects may have precluded it from achieving therapeutic levels. 34

34. 2. Advanced Glycation End-product (AGE) theory AGE’s – Protein, lipids & nucleic acids that undergo irreversible modification by reducing sugars or sugar derived products. Maillard reaction Series of chemical reactions leading to the formation of AGE’s. Responsible for browning of tissue while aging Initial step – Early glycation : involves reversible non-enzymatic binding of sugar to amino acid groups of protein, lipids & nucleic acids. 35

35. Continued… Rearrange to form On further reactions Early glycation ↓ Schiff bases ↓ Amadori products Glycosylated Hb (HbA1C) & Fluctosamine ↓ AGE’s 36

36. Direct cell damage By impairing function of a variety of proteins like collagen or intracellular proteins RAGE mediated cell damage R eceptor for A dvanced G lycated E nd products 37 AGE’s

37. 3. Photoreceptor mechanism theory HYPERGLYCEMIA ↓ Increased cellular NADH/NAD + redox ratio ↓ Oxidative stress ↓ PSEUDOHYPOXIA DARK ADAPTATION ↓ Rods expend more energy (4 times higher than light cond.) and consume high level of O2 (low PO2 of inner Retina) ↓ ANOXIA OF INNER RETINA 38 INCREASED VEGF PRODUCTION +

38. PAN-RETINAL PHOTOCOAGULATION ↓ Destroys some of the P hotoreceptors ↓ Reduces the Oxygen consumption in outer retina ↓ Allows more Oxygen to flow from Choroid to inner retina 39 Supporting Photoreceptor mechanism theory….

39. 4. Reactive Oxygen Intermediates (ROI) theory One of the oldest theory. There is some evidence of increased oxidative stress in Diabetic patients. Usual metabolic pathway of glucose  Glycolysis & Tricarboxylic Acid cycle (Occurs in mitochondria) Chronic hyperglycemia  metabolic complications  Oxidative stress. 40

40. 4. Reactive Oxygen Intermediates (ROI) theory Chronic H yperglycemia ↓ increased Glycolysis & TCA cycle ↓ increased formation of reducing equivalents ↓ Oxidative phosphorylation (Product) (By-product) ATP Free radicals Eg : Superoxide anion ↓ OXIDATIVE STRESS 41

41. 4. Reactive Oxygen Intermediates (ROI) theory Increased Oxidative stress leads to ; Damage mitochondrial DNA and cellular proteins Decreased Nitric oxide levels Promotes leucocyte adhesion to endothelium Decreases barrier function of endothelial cells Activates Protein Kinase-C by increasing the formation of Diacyl glycerol (DAG)

42. 5. Protein Kinase-C (PKC) theory Protein Kinase-C: Ubiquitous enzyme Promote development of many of the complications of Diabetes Pathologic activation of Protein Kinase-C cause vascular damage mediated through: Increased vascular permeability Disruption of Nitric oxide regulation Increased leucocyte adhesion to vessel walls Changes in blood flow Overexpression of VEGF  changes in retinal vascularity. 43

43. Increased glucose levels ↓ Activation of Glycolytic pathway ↓ ↑ed levels of Gluteraldehyde-3-Phosphate ↓ Diacyl Glycerol (DAG) ↓ AGE Activates Protein Kinase-C ROI VEGF Endothelin 44 denovo synthesis of

44. RUBOXISTAURIN Protein Kinase-C inhibitor Blocked many vascular abnormalities in Endothelial & contractile cells from retinal arteries & renal glomeruli (in animal models). PKCDRS - 2 (Protein Kinase-C Diabetic Retinopathy Study – 2) 6 years study period. Conclusion : 5 years Ruboxistaurin group showed less sustained moderate vision loss compared to those in original placebo group (on 2 years Ruboxistaurin ) . 45

45. 6. Insulin receptors & glucose transporters Insulin receptors (IR) have been reported on the pericytes and endothelial cells of retinal micro-vessels. Blood -Retinal Barrier stabilizes Insulin access to retina. The retinal IRs, when stimulated with Insulin, possesses Tyrosine kinase activity towards an exogenous substrate. IR in RPE cells  possible role in unidirectional insulin transport from choroidal circulation to photoreceptors. 46

46. 6. Insulin receptors & glucose transporters GLUT’s (1,2,3,4 & 5) – facilitated cell membrane glucose transporters GLUT 1 - Unique portal of entry of Glucose into endothelial cells of inner BRB. Changes in Retinal endothelial GLUT 1 expression  major impact in providing substrate to the various pathogenic processes  DR 47

47. Genetic Factors There is good evidence that diabetic retinopathy has a genetic predisposition. Nearly all individuals with type 1 diabetes, and most with type 2 disease will demonstrate some of the lesions of early retinopathy with sufficient disease duration, but only 50% or less will develop proliferative disease. HLA association – increased risk of PDR in subjects with the HLA DR4 & DR3 phenotype. DCCT research group examined familial clustering - associations were found when the correlation of retinopathy severity among family members was investigated. 48

48. Genetic Factors VEGF - of th e best-known and most well studied genes is the vascular endothelial growth factor gene. Epigenetics – involves alterations in gene expression via DNA methylation, histone modification and microRNA. BCOR methylation differences and may be use as a biomarker to predict PDR. MiR-29b upregulation – has been determined to be protective against retinal ganglion cell apoptosis in early stages of diabetes. 49

49. Genetic Factors PDR and endstage renal disease (ESRD) are two of the most common and severe microvascular complications of diabetes. Erythrop oietin (EPO) – potent angiogenic factor observed in the diabetic human and mouse eye. EPO gene significantly associated with PDR and ESRD. 50

50. Other Ocular F actors Glaucoma (Becker 1967)  associated with decreased prevalence & severity of DR in affected eyes. Myopia (Rand et al)  Myopia > 2D is associated with decreased prevalence & severity of DR. Retinochoroidal scarring from trauma, inflammatory disease etc ,  has markedly reduced prevalence & severity of DR. 51

51. Pathogenesis Of DR Loss of Pericytes ↓ Dilatations of the vessels seen as Microaneurysms ↓ Breakdown of the Blood–Retinal barrier ↓ Leakage of the vascular contents ↓ Oedema , hard exudates, haemorrhages capillary non-perfusion & Ischaemia of the retina ↓ Intraretinal microvascular abnormalities (IRMA) 52

52. Pathogenesis Of DR Extensive closure of the capillaries leads to ischemia of the Retina . Re-establishment of blood supply by opening up shunt vessels occurs by: Intraretinal microvascular abnormalities (IRMA) or Elaborating Vasoproliferative substances (VEGF) This lead to Neovascularization . Neovascular tissue is more friable, bleeds easily and incites a fibroblastic response. 53

53. Classifications & Scaling Of Diabetic Retinopathy Stage 1: Background DR Stage 2: Pre-proliferative DR Stage 3: Proliferative DR Diabetic maculopathy 54

54. MILD NPDR MODERATE NPDR SEVERE NPDR EARLY PDR HIGH-RISK PDR Early Treatment of Diabetic Retinopathy Scale (ETDRS) 55

55. Modified Airlie House classification – ETDRS seven standard 30 photographic fields 56

56. Continued… MILD NPDR At least one microaneurysm, and Criteria not met for more severe Retinopathy MODERATE NPDR Hemorrhages/ Microaneurysms > standard photograph 2A And/Or Cotton wool spots, venous beading or IRMA definitely present And criteria not met for more severe retinopathy Stages of ETDRS 57

57. Continued… SEVERE NPDR Cotton wool spots, venous beading and IRMA definitely present in at least two of photographic fields 4 to 7; Or two of the three preceding features present in at least two fields 4 to 7 and hemorrhages/microaneurysms present in fields 4 to 7 > standard photograph 2A in at least one of them; Or IRMA present in each of fields 4 to 7 and > standard photograph 8A in at least two of them; And criteria not met for more severe retinopathy 58

58. EARLY PDR New vessels; And criteria not met for high risk PDR HIGH-RISK PDR New vessels on or within one disc diameter of the optic disc (neovascularization of the disc) NVD > standard photograph 10A (approximately 1/4 - 1/3 disc area) with or without vitreous or preretinal hemorrhage; Or vitreous and/or preretinal hemorrhage accompanied by new vessels, either NVD < standard photograph 10A or new vessels elsewhere (NVE) > 1/4 disc area 59

59. International clinical Diabetic Retinopathy Disease severity scale 60 Proposed disease severity level Findings (dilated Ophthalmoscopy) No apparent retinopathy No abnormalities Mild NPDR Microaneurysms only Moderate NPDR More than just microaneurysms but less than severe NPDR Severe NPDR Any of the following: 20 intraretinal hemorrhages in each of 4 quadrants. Definite venous beading in 2 quadrants. Prominent IRMA in 1+ quadrant And no signs of proliferative retinopathy PDR One or more of the following: Neovascularisation Vitreous/preretinal hemorrhage

60. International DME Disease severity scale 61 Proposed disease severity level Findings (dilated Ophthalmoscopy) DME absent No retinal thickening or hard exudates (HE) in the posterior pole. DME present Some retinal thickening or HE in the posterior pole. Categorization of DME Mild DME Some retinal thickening or HE in the posterior pole but distant from centre of macula (ETDRS DME but not CSME) Moderate DME Retinal thickening or HE in the posterior pole approaching the centre of the macula but not involving the centre (ETDRS CSME) Severe DME Retinal thickening or HE in the posterior pole involving the centre of macula (ETDRS CSME)

61. Mild DME 62 Some retinal thickening or HE in the posterior pole but distant from centre of macula. H ard exudates are located far from the center of the fovea

62. Moderate DME 63 Retinal thickening or HE in the posterior pole approaching the centre of the macula but not involving the centre. Even though there is no thickening involving the center of the fovea, the hard exudates are threatening the center of the fovea.

63. Severe DME 64 Retinal thickening or HE in the posterior pole involving the centre of macula. The centre of the fovea is involved with hard exudate and thickening

64. ETDRS classification of DME It is based on “ proportion of Microaneurysmal Fluorescein leakage ”. 65 Type of DME Microaneurysmal leakage (%) Focal > 67% Intermediate 33% to 67% Diffuse < 33%

65. Grade OCT features I Diffuse retinal thickening II Cystoid macular edema III Posterior hyaloid traction IV Subretinal fluid / Serous Retinal detachment V Tractional Retinal Detachment OCT classification of DME 66

66. Clinical Features Initial stages – asymptomatic More advanced stages: Blurred vision Floaters Distortion (Metamorphopsia) Progressive visual acuity loss 67

67. Clinical features 68

68. Signs of NPDR 69

69. Microaneurysms Localized saccular outpouchings, formed either by: focal dilatation of the capillary wall where pericytes are absent (or) fusion of two arms of a capillary loop Best visualized by – Trypsin digested retinal mounts MA’s are the earliest sign and hallmark of DR. MA’s measure – 25 to 100 µm in diameter MA’s may leak plasma constituents into the retina as a result of breakdown in the blood–retinal barrier (or) may thrombose. 70

70. Microaneurysms Seen ophthalmoscopically as small red dots in: Middle retinal layers (IPL) typically in the macula frequently adjacent to the areas of capillary non-perfusion. 71

71. Microaneurysms Fluorescein Angiography Differentiates between dot haemorrhages and non-thrombosed MA’s. Early frames – tiny hyperfluorescent dots Late frames – diffuse hyperfluorescence due to leakage 72

72. Black circle – hyperfluorescent in FA  Microaneurysm White circle – hypofluorescent in FA  Hemorrhage 73

73. Hemorrhages Occur from capillary leakage or rupture of microaneurysm in the middle retinal layers (Dot-blot hmge ). Can be: Flame shaped/splinter hemorrhages Dot-blot hemorrhages Deep dark round hemorrhages 74

74. Flame shaped/Splinter hemorrhages: Arise from – larger superficial precapillary arterioles. Located in – Nerve fibre layer. Characteristic flame shape – due to architecture of the retinal nerve fibre layer. 75

75. Dot-blot hemorrhages: Arise from – venous end of the capillaries. Located in – compact middle layers. i.e , Inner nuclear layer / Outer plexiform layer. Appear similar to Microaneurysms (but dot-blot hmge is hypofluorescent in FA). 76

76. Deep dark round hemorrhages: Represent hemorrhagic retinal infarcts. L ocated within the middle retinal layers. E xtent of involvement is a significant marker of the likelihood of progression to PDR. 77

77. Hard exudates Occur due to chronic localized edema. Composed of leaked lipoproteins and lipid filled macrophages mainly within Outer plexiform layer . Yellowish-white waxy-looking patches with distinct margins. Located at the junction of normal & edematous retina. Arranged in clumps or in circinate pattern & commonly seen in the macular area. 78

78. 79 Hard exudates Circinate pattern When leakage ceases, exudates absorb spontaneously over a period of months, either into healthy surrounding capillaries or by phagocytosis.

79. Soft exudates/Cotton wool spots These are nerve fiber infarcts. Occur as a result of ischemia, not exudation . Local ischemia ↓ Obstruction of Axoplasmic flow ↓ Swelling of nerve fibers ↓ Characteristic white fluffy appearance 80

80. Cotton wool spots 81

81. Venous abnormalities Venous beading – important sign of sluggish retinal circulation. Venous loops – adjacent to large areas of capillary nonperfusion 82 Venous loop Venous beading

82. Intra Retinal Microvascular Abnormalities IRMA are dilated capillaries Function as collateral channels Capillary hypoperfusion often surrounds IRMA Difficult to differentiate from surface retinal neovascularization. FA – Fluorescein does not leak from IRMAs, but leaks profusely from neovascularization 83

83. Diabetic macular edema & maculopathy M ost common cause of visual impairment in diabetic patients. Diabetic maculopathy: Foveal edema Exudates (or) Ischaemia Diffuse retinal edema – caused by extensive capillary leakage Localized edema – focal leakage from MA’s & dilated capillary segments. 84

84. Cystoid macular edema – central accumulation of fluid: Fovea assumes cystoid appearance Readily detectable in OCT FA – Central flower petal pattern MACULOPATHY Focal maculopathy Diffuse maculopathy Ischemic maculopathy 85 Cystoid macular edema - FA

85. 1. Focal maculopathy D efined as edema caused by focal leakage of microaneurysms. Well-circumscribed retinal thickening Associated with complete or incomplete rings of exudates - Circinate. FA – late, focal hyperfluorescence due to leakage, usually with good macular perfusion. ( Microaneurysmal leakage > 67%) 86

86. 2. Diffuse maculopathy G eneralized breakdown of the inner blood/retinal barrier i.e , Microaneurysms, retinal capillaries and even arterioles contribute to the leakage. Diffuse retinal thickening associated with cystoid changes. L ocalization of the fovea impossible – due to edema obscuring landmarks FA shows mid & late phase diffuse hyperfluorescence and also demonstrates CME if present. ( Microaneurysmal leakage < 33%) 87

87. 3. Ischemic maculopathy Macula may look relatively normal despite reduced visual acuity. FA – capillary non-perfusion at the fovea (an enlarged FAZ). 88 Enlarged FAZ Capillary non-perfusion

88. Clinically significant Macular edema Retinal thickening within 500 μm of the centre of the macula. Exudates within 500 μm of the centre of the macula, if associated with retinal thickening. Retinal thickening one disc area (1500 μm ) or larger, any part of which is within one disc diameter of the centre of the macula. 89

89. Clinically significant Macular edema 90 1 2 3

90. About two-thirds of Type-I diabetics are likely to develop proliferative diabetic retinopathy over three decades. Approximately 50% of patients with very severe NPDR progress to PDR within 1 year. Proliferative vessels usually arise from Retinal veins . Path of new vessel growth - along the route of least resistance 91 Proliferative Diabetic Retinopathy

91. Fibrotic tissue can be either Vascular or Avascular . Fibrovascular type : found in association with vessels that extend into the vitreous cavity (or) abnormal new vessels on the surface of the retina or disc. Avascular type : Results from organization or thickening of the posterior hyaloid face. Vitreous traction is transmitted to the retina along these proliferations and may lead to traction retinal detachment. 92 Components of proliferative tissue

92. Occurrence of Neovascularisation over the changes of very severe NPDR is the hallmark of PDR. Risk factors for progression to PDR, observed in ETDRS include presence of: IRMAs Multiple increasing intraretinal haemorrhages Venous beading and loops, and Wide spread capillary non-perfusion (CNP) areas. 93

93. Neovascularisation in PDR : Proliferation of new vessels from the capillaries, in the form of: Neovascularization at the optic disc (NVD) or Neovascularisation elsewhere (NVE) in the fundus NVE usually occurs along the course of the major temporal retinal vessels. 94

94. Neovascularisation on Disc Proliferative vessels on or within 1 disc diameter of the optic nerve are referred to as NVD. NVD and NVE leak fluorescein into the vitreous. 95 NVD

95. Neovascularisation elsewhere Proliferative vessels further than 1 disc diameter away are referred to as NVE. NVE nearly always grows toward and into zones of retinal ischemia (until posterior vitreous detachment occurs) ↓ then vessels are lifted into vitreous cavity ↓ Regression of vascular tissue (end stage) 96 NVE

96. CONTRACTION OF CONNECTIVE TISSUE COMPONENTS ↓ Sub-hyaloid bands Thickening of posterior hyaloid face Formation of retinal breaks, Retinoschisis & Retinal detachment PVD Posterior vitreous detachment in diabetics is characterized by a slow, overall shrinkage of the entire formed vitreous. Contracting vitreous has a role in  Vitreous hemorrhage, Retinal breaks and Retinal detachment. 97

97. Advanced eye disease Rubeosis Iridis ( Neovascularisation on Iris) 98 Vitreous Hemorrhage Retinal Detachment

98. Vitreous Hemorrhage Sudden vitreous contractions tear the fragile new vessels, causing vitreous hemorrhage. M ajority of diabetic vitreous hemorrhages occur during sleep. Possibly because of an increase in blood pressure secondary to early morning hypoglycemia or to rapid eye movement sleep. Very few Vitreous hemorrhages occur during exercise. 99

99. Fate of Vitreous Hemorrhage Erythrocytes behind posterior vitreous face ↓ Quickly settle to the bottom of the eye ↓ Absorbed When Erythrocytes break into vitreous body ↓ Adhere to the gel ↓ Clearing may take months to years

100. Sub-internal Limiting Membrane Hemorrhages Large superficial round, oval or boat shaped hemorrhages. S eparate the internal limiting membrane from the rest of the retina. Blood remain between the layers for weeks and months before breaking into vitreous. 101

101. Pre-retinal (or) Sub-hyaloid hemorrhages Occur between the internal limiting membrane & the cortical vitreous. Tight hemorrhages are dangerous because they may progress rapidly to traction retinal detachment. 102

102. Retinal Detachment 103 Diabetic Retinal detachments (2 types) Rhegmatogenous (Retinal break) Borders extend to Ora serrata Dull or greyish borders. Undulates d/t retinal mobility Shifting of SRF occurs (+) Non- rhegmatogenous (Traction) Confined to posterior fundus Taut and shiny surface Concave towards pupil No shifting of SRF occurs (-)

103. Neovascular Glaucoma Neovascular glaucoma (NVG) occurs when new vessels proliferate onto the iris surface and over the anterior chamber angle structures (TM). Most common pathological processes involved in the development of Neovascular glaucoma (NVG): 104 Pathological process % of NVG cases CRVO 36% Diabetic Retinopathy 32% Carotid artery occlusive disease 13%

104. Neovascularisation of Iris / Rubeosis iridis Grading Of NVI: 105

105. Neovascular Glaucoma SEQUENCE OF EVENTS Retinal capillary non-perfusion ↓ Secretion of Vasoproliferative substances ↓ Neovascularisation / fibrovascular membranes over angle ↓ End stage Glaucoma Early diagnosis is key as profound vision loss occurs once IOP increases.

106. Stages of Neovascular Glaucoma 107 Stage I: Rubeosis Iridis Normal IOP NVI with or without NVA Vascular tufts at pupillary margin Stage II: Open angle glaucoma Elevated IOP Increased NVI & NVA No synechial angle closure Stage III: Closed angle glaucoma Elevated IOP Reduced visual acuity Synechial angle closure

107. THANK YOU 108