1. Dr. K. Vasantha M.S., F.R.C.S
Director ,
Regional Institute of Ophthalmology Chennai Rtd
2. Earliest response to hyperglycemia is dilatation of blood
vessels and blood flow changes
1.Micro vasculopathy: apoptosis of pericytes, endothelial
cells and thickening of basement membrane which leads
on to impairment of blood retinal barrier, occlusion and
ischemia
2. Inflammation: increased level of chemokines,
cytokines like TNF alpha, interleukins are corellated with
severity of retinopathy
3. Inflammation causes leucostasis
3. due to hyperglycemic stress microglia are activated.
These release cytokines and VEGF. Then Muller cells and
astrocytes amplify the inflammatory response
4. Neuro degeneration: degeneration of neurons, up
regulation of apoptosis, mitochondrial dysfunction and
oxidative stress cause neuronal apoptosis, loss of
ganglion cells. This happens even before retinopathy is
evident
4. Structural changes
◦ pericytes loss
◦ Loss of endothelial cells
◦ Endothelial cell dysfunction
◦ Basement membrane thickening
Rheological changes
◦ Decreased deformability of RBCs
◦ Increased platelet aggregation
5. Retina is a highly metabolic tissue dependent on perfect
supply of blood and oxygen
Chronic hyperglycemia with advanced glycation end
products alters the biochemicals resulting in altered
hemodynamics of the retinal vessels resulting in hypoxia
Compensatory measures like up regulation of vascular
endothelial factor result in increased vascular
permeability, micro aneurysms, vascular occlusion and
capillary closure
6. Increasing evidence suggest inflammation plays an
important role in DR
Intercellular adhesion molecule 1 (ICAM-1) is an
immunoglobulin involved in immune activation and
inflammation
CD18 is its counter receptor
Both cause leukocyte migration in to inflamed areas
which adhere to the vascular endothelium leading on to
apoptosis and increased vascular permeability and
nonperfusion
7. Chronic polyol pathway hyperactivity will cause osmotic
and oxidative stress leading on to
Release of reactive oxygen species ROS -> pro
inflammatory stress and apoptosis
Increased protein kinase C activation
Enhanced glycation via fructose and its metabolites ->
advanced glycation end products -> leukocyte adhesion
and complement activation
8. Due to stress caused by reactive oxygen species and
nitrogen species
Increased apoptosis of ganglion cells
Increased glial cell and microglial activity
Loss of insulin mediated trophic support
Injury due to accumulation of excess hexosamines, TNF
alpha and glutamate
Muller cells undergo reactive gliosis
But antioxidants have not proved to be effective
clinically
9. This is present in vascular pericytes, endothelium,
ganglion cells and Muller’s cells. Polymorphism of AR
gene have been linked to diabetic retinopathy and other
complications in diabetics
But use of Sorbinil an aldose reductase inhibitor did not
show much effect
10. Microaneurysms
Dot and blot hemorrhages
Cotton wool spots
Macular edema
New vessels
Fibro vascular proliferation causing traction
Detachment – both traction and rhegmatogenous
Vitreous hemorrhage
11. Usually the first sign seen and hall mark of non
proliferative diabetic retinopathy (NPDR)
15 – 60 microns in size seen as deep red dots in the
posterior pole
If it is less than 26 microns will be seen only in FFA
These are saccular out pouching of the capillary wall due
to loss of the pericytes, weak wall and increased intra
luminal pressure. Endothelial cell proliferation may also
play a role
Found both on the arterial and venular side, more on the
venous side
12. These can be mistaken for dot hemorrhages.
With FFA microaneurysms appear hyper fluorescent,
whereas the hemorrhages block fluorescence
They appear and disappear over time. They get occluded
by excess basement membrane material. Usually takes
about 120 days to disappear.
13. Retinal vessels are more affected as the number of
pericytes are more in the retinal vessels and vessels in
the brain compared to other vessels in the body
If the number increases it is significant as it denotes
progression of the retinopathy
No visual symptoms
14. Vascular endothelial growth factor (VEGF)is normally
present in the retina. It increases when there is hypoxia
The receptors for VEGF are located in the endothelial
cells and promotes endothelial cell proliferation,
migration, apoptosis and vascular tube formation
Causes retinal edema by causing changes in the tight
junctions of the endothelial cells leading on to leakage of
plasma
It may also contribute to the inflammatory component by
up regulating intercellular adhesion molecule 1 (ICAM 1)
15. Located in the inner nuclear layer
May be mistaken for microaneurysms
Venous abnormalities: venous dilatation, beading
Venous caliber changes denote severe hypoxia, so areas
of nonperfusion will be seen next to these changes
After PRP the veins will become less dilated and more
regular in shape
16.
17.
18. Edema may wax and wane
But chronic edema in the macular region will cause
disruption of the delicate architecture and cause severe
visual loss
Hard exudates will accompany the edema. The exudates
will be situated at the border of the edematous and non
edematous retina. This is due to lipoprotein leakage
which is again due to loss of tight junction
19. Protein kinase C-beta may also increase the vascular
permeability. This also causes increase in basement
membrane thickness and prolonged retinal circulation
time
Can occur anywhere, but if it occurs in the macular area
there is gross loss of vision
20. Hard exudates within
500 microns of the
center of macula with
retinal edema
Edema one DD or
larger part of which is
within one DD from the
center of macula
24. Initially there is patchy areas of capillary closure
Then they increase and become confluent
Finally the terminal arterioles also will close
The microaneurysms are seen close to these occluded
capillaries
The dilated capillaries near this closure will be seen as
IRMA
Later new vessels will develop
25. Capillary drop outs occur first in the mid peripheral
retina
Capillary closure is due to death/apoptosis of cells and
occlusion by WBCs or platelets
26.
27. Micro aneurysms both superficial and deep are clearly
seen. These are seen as solid round, round with dark
center or fusiform in shape
Retinal non perfusion areas and IRMA are clearly made
out. IRMA is seen as looping of vessels near capillary
non perfusion areas which is greater in caliber
28. Foveal avascular zone: microvascular changes are seen
before clinical changes. FAZ is larger in diabetic
retinopathy
Reduced para foveal and perifoveal vascular density
In diabetic macular edema micro aneurysms are more in
the deep plexus. Flow void is seen in cystoid spaces
29. Found in the outer plexiform layer
In the posterior pole
Hard exudates are removed by macrophages in about 6
months
30. Dilated cellular capillary arises from an arteriole and
connects to a venule without entering in to a capillary
bed.
These capillaries are “anuclear” which are just conduits
for the blood to flow
This is just a dilated preexisting vessel or a new vessel.
But it will be always below the internal limiting
membrane
31. IRMA is secondary to hypoxia
Often found adjacent to a cotton wool spot
Multiple IRMAs denote severe NPDR and new vessels are
likely to develop within a short time
May rarely leak and may develop in to a new vessel
38. Occurs as a result of vitreous traction on the new
vessels
Contraction of the fibro vascular proliferation may cause
avulsion of a retinal vessel – usually a vein
May be associated with Valsalva’s maneuver
Can occur with insulin reactions
39. The pool of blood will outline the inferior extent of the
vitreous detachment forming a fluid level or boat shape
in pre retinal hemorrhage.
Sometimes there may be a thin line of blood mostly in
front of the equator in the inferior retina
In the upper quadrant the blood tends to become
deposited in thin meridional streaks on the detached
posterior surface of the vitreous
Blood in fluid vitreous will remain red, clears fast
In formed vitreous it will turn white require months to
clear
40.
41.
42.
43. Dragging of the macula often nasally and upwards
Vision may remain good initially if macula is not involved
Fibro vascular tissue may obscure the macula and affect
vision
Later macular edema will develop and vision will come
down
Diplopia and metamorphopsia will develop
Traction will lead on to detachment or retinoschisis
Rhegmatogenous detachment also can occur
44. When new vessels develop other signs may not be there
Cotton wool spots disappear in 6 to 12 months
Hemorrhages and IRMA tend to disappear once capillary
closure occurs
The number of small vascular branches comes down
Some will appear as white strands
Macular detachment, edema and ischemia and optic
nerve disease will affect vision
45. Nonproliferative retinopathy
Mild NPDR : at least one microaneurysm
Have a 5% risk of PDR within 1 year and 15% risk to high
risk PDR within 5 years
47. Moderate nonproliferative retinopathy
Hemorrhages or microaneurysms mild to moderate in
less than 4 quadrants
Cotton wool spots
Venous beading
Intraretinal micro vascular abnormalities- definite
PDR within 1 yr- 12 to 27% and high risk PDR in 5 yrs
33%
48. Any one of the following
Severe intraretinal hemorrhages/microaneurysms in four
quadrants
Venous beading in two or more quadrants
Moderately severe IRMA in one quadrant
49. Any two of the following
Severe intraretinal hemorrhages in four quadrants
Venous beading in two quadrants
Moderately severe IRMA in one quadrant
50. Early PDR: NVE or NVD less than standard photo 10A
High risk PDR
NVD on or within 1DD of the optic disc
NVD and NVE: severity of the NVD equal to or greater
than Photograph 10A or greater than ¼ to 1/3 disc area
NVE equal to or greater than ½ DD
Preretinal or vitreous hemorrhage
51.
52. Eyes with NVD > or equal to ¼ to 1/3 DD. (Location of
new vessels on or within 1 disc diameter of the optic disc
is risky)
Mild NVD but associated with vitreous or preretinal
hemorrhage
NVE (neovascularization elsewhere) > or equal to ½ disc
area if associated with vitreous or preretinal hemorrhage
Tractional retinal detachment
Neovascularization of the iris angle or both
53. Wisconsin epidemiology study
Prevalence of macular edema is about 20% in type 1,
25% in type 2 on insulin and 14% in type 2 on oral drugs
after 15 years
Increased serum cholesterol – more hard exudates
If bilateral moderate NPDR is present the risk
progression to PDR increased 40 fold after 4 years
compared to those with only microaneurysms in only
one eye
54. It was seen that in both Type 1 and 2 those who were on
insulin had more progression of retinopathy
Elevated HbA1c – more severe retinopathy
Elevated diastolic pressure and male sex were
associated with more severe retinopathy in younger
onset group and elevated systolic in older onset group
55. Done in 1971
To find out whether photocoagulation would prevent the
development of severe visual loss
One eye was given xenon arc or argon laser
photocoagulation. Other eye served as control
After 2 yrs photocoagulation was found to reduce the
risk of severe visual loss by >50% in eyes with high risk
retinopathy
Clear treatment benefit was seen after 4 yrs follow up
56. In eyes with less than high risk retinopathy or severe
NPDR the same clear benefit was not seen
DRS did not recommend prompt laser for this group of
eyes
Side effects of PRP like decrease in visual acuity (? Due
to macular edema) and constriction of the fields were
noted
This was seen more in xenon than argon
57. In severe NPDR or PDR with vision 20/100 or better 50%
reduction in visual loss was seen in eyes which received
photocoagulation either scatter or focal than eyes which
did not receive laser
Diabetic retinopathy study says that neovascularization
near the disc with or without vitreous hemorrhage and
neovascularization with vitreous hemorrhage are high
risk
Did not assess the timing of photocoagulation
58. To study whether intense insulin treatment with pump or
3 to 4 times daily is better than twice daily – 4 to 9 yrs in
Type 1 diabetes
Development and progression reduced but not
eliminated
If retinopathy was already present it progressed initially
For every 10% reduction in HbA1c 35 to 40% reduction in
progression was seen
59. To achieve this HbA1c must be below 7% and if possible
below 6%
Severity was associated with increase in triglycerides
and inversely associated with HDL
60. Follow up of DCCT
In both conventional and intensive worsening was low
with good control
In intensive treatment group even when the HbA1c
reached around 8 progression was low suggestive of
metabolic memory (cells remember tight control for
prolonged periods)
So early intervention and tight control is important
61. United kingdom prospective diabetes study done in type
2 diabetes also demonstrated that tight control
decreases but not eliminate retinopathy
Group a – intensive control with sulphonyl ureas or
insulin
Group b – diet control with drugs only when there was
symptoms of hyperglycemia or fasting glucose >15m
mol/ L.
Good control reduced the risk of any diabetes related
micro vascular end point
62. Theoretically hypertension will stretch the endothelial
cells resulting in increased release of VEGF
UKPDS found that intensive control of BP reduced the
risk of proliferative retinopathy
63. 10.3% of patients with no retinopathy, 21.1% with only
microaneurysms and 18.8% of mild NPDR progressed
But 54.8% of moderate to severe NPDR worsened.
Additional risks associated are hypertension and poor
control prior to conception
Hence glucose levels must be under strict control and
severe NPDR must be treated with PRP before pregnancy
1st trimester another check up
Less than severe NPDR every 3 months
More severe every 1 -3 months
65. A. eyes with very severe NPDR or mild to moderate PDR
had a 60 fold increased risk of developing high risk PDR
after one year follow up compared with eyes with mild
NPDR
B. after 5 yrs there was still 5 fold increased risk
66. In this study people with diabetic retinopathy in both
eyes with less than high risk PDR with or without
macular edema was studied
One eye was treated and treatment was deferred in the
other eye which acted as control
Showed a small drop in vision initially in the treated
eyes, but after 5 years rate of reduction was low in both
early treatment groups and deferred groups
67. For eyes with mild to moderate NPDR rates of visual loss
were even lower. But the side effects of
photocoagulation has to be considered
But in severe, very severe NPDR and PDR less than high
risk, risk benefit ratio is more favourable, esp. in type 2
diabetes
Scatter laser must be considered as an eye reaches high
risk stage and should not be delayed if the eye reaches
high risk proliferative stage
68. ETDRS showed that macular edema will worsen if scatter
PRP is done before treating the macular edema
In eyes with mild to moderate NPDR with macular edema
if grid/focal photocoagulation was done initial reduction
in vision was seen. But eyes which had undergone laser
had 50% lesser risk of moderate visual loss
If a large plaque of hard exudate was seen close to the
center immediate treatment has to be given
69. Found aspirin did not affect the progression of diabetic
retinopathy. It did not increase the risk either
Did not increase the risk of vitreous hemorrhage in
proliferative diabetic retinopathy
So if co existing cardio vascular problems are there
aspirin can be given
70. Dipyradamole Aspirin Microangiopathy of Diabetes Study
(DAMAD)and Ticlopidine Microangiopathy of Diabetes
Study found that antiplatelet drugs did not have any
effect
71. Sorbinil Retinopathy Trial: Using aldose reductase
inhibitors which will reduce accumulation of sorbitol did
not have any effect on retinopathy
Protein kinase C inhibitors like oral Ruboxystaurin a
modulator of diabetes induced retinal hemodynamic
abnormalities was found to reduce the rate of moderated
visual loss
72. A. severity of new vessels, fibrous proliferation and
vitreo retinal adhesions was greater in Type1 than Type 2
diabetes
But Type 2 diabetes had more prevalence of PDR
Before this study vitrectomy was deferred for at least 1
year
When patients with vitreous hemorrhage for 5 months
were studied – for Type 1 cases early vitrectomy had an
advantage
73. In Type 2 little difference between early and conventional
In very severe PDR with visual acuity > or equal to 10/200
with extensive new vessels and fibro vascular
proliferations, with attached macula early vitrectomy was
found to be useful
74. Albuminuria, proteinuria or renal failure are risk factors
in some but not all
In some studies anemia was found to be a risk
Diabetic neuropathy and cardio vascular autonomic
neuropathy are associated with increased risk of
progression of retinopathy
75. While both retinopathy and nephropathy are
microvascular problems, after a long duration many
diabetics develop retinopathy but less no of them
develop nephropathy.
There is a possible genetic differences
But when there is retinopathy renal structural
abnormalities may co exist, suggesting retinopathy may
be a marker for subclinical renal disease
76. Depends on the severity of retinopathy and the presence
of macular edema which can be present at any stage
There is a gross reduction in visual loss when Laser was
done in patients with severe NPDR or PDR
For mild to moderate NPDR treatment can be deferred
In full scatter photocoagulation 1200 to 1600 burns were
given for severe and very severe NPDR and early PDR
77. Macular edema is treated 6 to 8 weeks earlier than PRP, if
PRP is also planned, or along with PRP
Follow up every 4 months
Retreatment for persistent or recurrent lesions like CSME
new neovascularization, rarely feeder vessels to NVD
May be additional scatter , local laser to NVE or focal
laser to edema will be needed
(See the next presentation on macular edema)
78. Previously xenon arc photocoagulation was used
Now Argon green (514 nm) is used commonly
Argon blue is given up as it was causing retinal toxicity
to the treating surgeon
Dye yellow is well absorbed by blood and can be used to
for direct treatment of new vessels
Krypton red can penetrate nuclear cataract and vitreous
hemorrhage, but is more painful
79. Solid state diode laser (780 to 850 nm) instruments are
smaller in size and so portable.
They require less power
As the wave length is longer it can penetrate media
opacities
But they require more power to create retinal burns and
hence create more patient discomfort
80. Through slit lamp, indirect ophthalmoscope or endolaser
probe
Indirect ophthalmoscope laser is available with argon,
krypton or diode laser. Used when the patient is under
GA and in recumbent position
Endolaser is used after vitrectomy
81. When Rodenstock panfundoscopic lens and Volk
qudraspheric lens are used the image is inverted and
magnified.
Relatively more power is needed due to the
magnification effect
Periphery can be reached only with Goldmann lens, but
the area viewed is small
82. Spot size chosen – 500 micro meter for Goldmann and
200 for Rodenstock to achieve a 500 micron burn
Duration 0.1 to 0.2 second. In the presence of media
opacity longer duration will be needed
When rubeosis is present larger burns are needed
A gray white burn has to be achieved
For heavily pigmented aphakic and pseudophakic eyes
lower settings are kept first
83. DRS protocol said 800 to 1600 burns of 500 microns are
needed. With Rodenstock – 600 to 1000
Burns should be 1 to 1.5 burn width apart
Confluent burns for NVE
More area is treated inferiorly than superiorly so that
lower field is more preserved
84. On the temporal side burns must e 2.5 DD temporal to
the center of macula
Only peripheral retina is coagulated, beyond the arcades
and on nasal side about starting 2 DD nasal to the disc
Care must be taken while treating the horizontal region
to avoid the long ciliary nerves
85. Can be given in a single sitting
But transient choroid and exudative detachments are
less if given with multiple sittings
Lower quadrants are treated first as in case bleeding
occurs while treating upper quadrant, further treatment
will be delayed
Regression of neovascularization occurs in 30 to 55% of
patients
86. By destroying the peripheral retina the area of retina
which is hypoxic is converted to anoxic and hence
amount of VEGF is reduced.
The available blood supply is used by the more
important central area.
But of course the peripheral field will be reduced
PRP increases the diffusion of oxygen from choroidal
circulation thereby supplementing the retinal blood
supply
87. Can be given as pattern scanning laser
Micro pulse laser
Sub threshold laser so that collateral damage can be
minimized
Navigational laser system (NAVILAS) for accurate laser
spots
Targetted photocoagulation also is done now
88. Semi-automated pattern generation technique that allows the
rapid delivery of 532 nanometer single shot laser pulses in a
predetermined sequence
56 spots in approximately 0.6 seconds.
• Advantages are multiple burns placement, short duration burns
and more rapid and efficient delivery of burns
• Less pain and increased comfort for the patient
89. Side effects
Pain more when peripheral retina is treated
Anxiety, shock , seizure
Constriction of field and nyctalopia
Serous or choroidal detachment
90. Foveal burn, traction
Macular edema
Rarely acute angle closure glaucoma
Corneal or lens burns
Internal ophthalmoplegia – these are less with multiple
sessions
91. Vitreous hemorrhage – if it is not clearing or when PRP is
needed
Traction Rd
Macular distortion or traction
Retinal detachment – traction or combined
Rubeosis with vitreous hemorrhage when PRP is
essential
ERM or opacity in the posterior vitreous face
No response to PRP
93. Rubeosis usually associated with retinal detachment
Anterior hyaloidal fibrovascular proliferation is seen
more in juvenile diabetics
Endophthalmitis
94. VEGF level is increased because of hypoxia,
hyperglycemia, activation of protein kinase C, increased
production of free radicals and activation of oncogenes
and cytokines
It has 5 gluco protein growth factors, ABCDE and
placental growth factor
Vascular endothelial factor – A is the major cause for
ocular pathology. Mediator of retinal permeability and
angiogenesis by acting on VEGFR 1 and 2
95. VEGF is needed for endothelial and neuronal cell
survival. But in the presence of hyperglycemia and
oxidative stress it causes apoptosis
VEGF- increases the vascular permeability by causing
dysfunction of tight junctions and activating vascular-
vacuolar organelles.
VEGF up regulates formation of plasminogen which
further contributes to increased vascular permeability.
96. Blockage of VEGF can be achieved by inhibiting Protein
Kinase C (PKC) like pegaptanib or antibodies like
Ranibizumab or Bevacizumab which act against VEGF
Pegaptanib neutralizes only one isoform. Hence it is
given up
Anti VEGF agents restore the occluding proteins in tight
junctions
97. Protocol S study done by Diabetic Retinopathy Clinical
Research Network (DRCR net) found that Ranibizumab
was better than PRP
Peripheral field loss, need for vitrectomy and macular
edema were more in PRP group
However PRP was cost effective and durable
98. Used in cancer therapy
Recombinant humanized monoclonal immunoglobulin
G1 antibody targeting all forms of VEGF-A and both 1
and 2 endothelial receptors
Produced fro Chinese hamster ovary cells
Acts even when given systemically. But this can cause
intestinal perforation, neutropenia and hemorrhages
which can be fatal
99. Fragmented humanized recombinant monoclonal
antibody produced from Escheridia Coli cells
Binds with VEGF isoforms and also prevents binding
with the receptors
Its molecular weight and half life are shorter than
Bevacizumab
As it is fragmented and has less molecular weight it can
penetrate the retinal layers better and is 5-20 times more
potent
100. It is a VEGF trap
A fusiform protein
It binds with VEGF – A,B and placenta growth factor
101. Though the results are promising with regard to
regression of new vessels it is limited to short duration
Injections given every month is found to be better than
PRP
Can be used for regression of new vessels after PRP
When there is media opacity precluding PRP
Rubeosis with media opacity
As preoperative measure before vitrectomy, as this is
found to reduce intra and post operative vitreous
hemorrhage
102. Intra cameral for iris new vessels
Ranibizumab before PRP is found to reduce exacerbation
of macular edema
Intra vitreal anti VEGF before and with PRP shows
beneficial effects in the treatment of high risk PDR
Because of its short duration benefits and high cost anti
VEGF injections cannot replace PRP which has durability
103. This study found that
Ranibizumab given monthly is better than PRP
The loss of peripheral vision and night vision with PRP is
not there
If associated with macular edema Ranibizumab is better
PRP can be added after some injections. Here the
number of burns needed will be less
104. Infection
Retinal tear- Retinal detachment
Artery occlusion
Trauma to lens- cataract
Uveitis and
Sub conjunctival hemorrhage.
105. Receptors of advance glycation end products are
reduced by thiazolidinediones (Rosiglitazone) or calcium
channel blockers like nifedipine. So these drugs can
reduce the pro inflammatory effects of AGEs
Ruboxystaurin an inhibitor of protein kinase C reduced
the progression of retinopathy and macular edema
106. Statins also may lead on to a reduction in receptors for
AGE activated angiogenesis by suppressing VEGF
Simvastatin inhibits TGF beta2 and in rabbits it
prevented progression of PVR
Atorvostatin suppressed RPE cells migration and
contractility on cultured RPE
Patients on statins had better vision after vitrectomy and
revitrectomies were less in these patients
107. In low doses it may increase angiogenesis. High doses
decrease it
Patients on Simvastatin had lower levels of VEGF and
inflammatory mediator angioprotein and promatrix
metalloproteinase
Statins may increase the incidence of ERM by delaying
healing
108. There is no sign of decrease in the incidence of
retinopathy , but
Decrease in lipids allows macrophage clearance of
exudates
Decrease in ICAM-1 and TNF alpha decreases
inflammation and blood retinal barrier break down
Inhibits reactive oxygen species and thereby decreases
VEGF formation and BRB breakdown
109. Reduces apoptosis of cells
Increased Nitric oxide synthase improves endothelial
structure and function
Improves blood flow
Increases vascular resistance, so decrease in
microaneurysms
Decreases leakage from new vessels
110. Cannabinoids can reduce oxidative stress by
antagonizing N-methyl D-aspartate receptors and thereby
suppressing inflammation
It blocks neuronal damage
Cyclo-oxygenase 2 (COX-2) inhibitors like aspirin and
Celecoxib were not found to useful
IGF-1 , urokinase, MP and integrin inhibitors are also
being tried
111. Sincere thanks to Dr Rajamohan who has added additional
points and clinical pictures