proliferative diabetic retinopathy

1. DIABETIC RETINOPATHY

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

3. Introduction
• Diabetes mellitus is the most common disorder of energy metabolism
causing microvascular complications including nephropathy, neuropathy,
and also affects eye
• Retinopathy
• Iridopathy
• Unstable refraction
• Ophthalmic complications include;
• 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
blood
the growth of new
vessels.
- Macular edema which can
visual
decrease
significantly
acuity.

7. 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

8. 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%

9. 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
measurement per day).
group (1

10. 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.

11. 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.

12. 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 HbA1c of
7.0% compared with conventional therapy with a median HbA1c of
7.9%.
• United Kingdom Prospective Diabetes Study (UKPDS) revealed a 21%
reduction in the 1-year rate of progression of retinopathy

13. Risk factors
1. 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)

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

15. 15
Risk Factors
2. 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.

16. 16
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 1st 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

17. Pathogenesis
Anatomical lesions
Biochemical mechanisms
Genetic factors
Other ocular factors
1
17
2
3
4

18. 18
Anatomical Lesions
1. Loss of pericytes
2. Capillary basement membrane thickening
3. Microaneurysms
4. Capillary acellularity
5. Break down of blood retinal barrier

19. 19
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.

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

21. Loss of Pericytes
• The mechanism by which hyperglycemia leads to pericyte degeneration
remains largely unknown.
• Two hypotheses:
1. Aldose reductase pathway
2. 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

22. 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.

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

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

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

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

27. 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.
Cellular Microaneurysm
MA with Endothelial cell proliferation
due to pericyte loss
27

28. 28
Capillary Acellularity
• 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.

29. 29
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:
1. VEGF
2. Kallikrein kinin system

30. 30
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.

31. 31
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.

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

33. 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
↓

34. 1. Aldose Reductase Theory
34
↓
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.

35. 35
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.

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

37. Direct cell damage
By impairing function of a variety of
proteins like collagen or intracellular
proteins
RAGE mediated cell damage
Receptor for Advanced Glycated End
products
AGE’s
37

38. 3. Photoreceptor mechanism theory
HYPERGLYCEMIA
↓
Increased cellular NADH/NAD+
ratio
↓
Oxidative stress
↓
PSEUDOHYPOXIA
redox
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
INCREASED VEGF PRODUCTION
38
+

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

40. 40
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.

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

42. 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)

43. 43
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:
a) Increased vascular permeability
b) Disruption of Nitric oxide regulation
c) Increased leucocyte adhesion to vessel walls
d) Changes in blood flow
e) Overexpression of VEGF  changes in retinal vascularity.

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

45. 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

46. 46
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.

47. 47
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

48. 48
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.

49. 49
Genetic Factors
• VEGF - of the 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.

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

51. 51
Other Ocular Factors
• 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.

52. 52
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)

53. 53
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:
1. Intraretinal microvascular abnormalities (IRMA) or
2. Elaborating Vasoproliferative substances (VEGF)
• This lead to Neovascularization. Neovascular tissue is more friable,
bleeds easily and incites a fibroblastic response.

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

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

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

57. 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
Continued… 57
Stages of ETDRS

58. 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
Continued… 58

59. 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

60. 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

61. 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)

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

63. Moderate DME
• 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

64. 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

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

66. 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

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

68. Clinical features
68

69. Signs of NPDR
69

70. 70
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.

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

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

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

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

75. 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

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

77. Deep dark round hemorrhages:
• Represent hemorrhagic
infarcts.
retinal
• Located within the middle retinal
layers.
• Extent of involvement is a significant
marker of the likelihood of progression
to PDR.
77

78. 78
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.

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

80. 80
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

81. Cotton wool spots
81

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

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

84. 84
Diabetic macular edema & maculopathy
• Most 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.

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

86. 86
1. Focal maculopathy
• Defined 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%)

87. 87
2. Diffuse maculopathy
• Generalized 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.
• Localization 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%)

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

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

90. Clinically significant Macular edema
1
90
2
3

91. • 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
Proliferative Diabetic Retinopathy
91

92. • Fibrotic tissue can be either Vascular or Avascular.
A. 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.
B. 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.
Components of proliferative tissue
92

93. 93
• 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:
1. IRMAs
2. Multiple increasing intraretinal haemorrhages
3. Venous beading and loops, and
4. Wide spread capillary non-perfusion (CNP) areas.

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

95. 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.
NVD
95

96. 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)
NVE
96

97. 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

98. 98

99. 99
Vitreous Hemorrhage
• Sudden vitreous contractions tear the fragile
causing vitreous hemorrhage.
new vessels,
• Majority 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.

100. 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

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

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

103. Retinal Detachment
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

104. 104
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):
Pathological process % of NVG cases
CRVO 36%
Diabetic Retinopathy 32%
Carotid artery occlusive disease 13%

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

106. 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.

107. 107
Stages of Neovascular Glaucoma
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

108. 108
THANK YOU