complication in diabetes

1. Dr. K. Vasantha M.S.,F.R.C.S.
Director RIO 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
 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

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 ore 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
 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

17.  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

18.  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

19.  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

20. 1. Sponge-like retinal thickening
2. Cystoid Macular edema
3. Sub-foveal serous retinal detachment
4. Foveal tractional retinal detachment
5. Taut posterior hyaloid membrane

23.  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

24.  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.  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

27.  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

28.  Found in the outer plexiform layer
 In the posterior pole
 Hard exudates are removed by macrophages in about 6
months

29.  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

30.  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

31. To delineate foveal
avascular zone
To differentiate IRMA
from new vessels

36. Preretinal or vitreous hemorrhage
Tractional retinal detachment
Tractional retinoschisis
Rubeosis iridis

37.  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

38.  The pool of blood will outline the inferior extent of the
vitreous detachment forming a fluid level or boat shape.
 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

42.  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

43.  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

44. 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

45. Few microaneurysms FFA showing microaneurysms

46. 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%

47. 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

48. Any two of the following
 Severe intraretinal hemorrhages in four quadrants
 Venous beading in two quadrants
 Moderately severe IRMA in one quadrant

49.  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.  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

52.  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

53.  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

54.  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

55.  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

56.  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

57.  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

58.  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

59.  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

60.  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

61.  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

62.  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

63. ETDRS
Questions:
Is photocoagulation effective for macular edema?
Does aspirin have any effect on the course of DR
When should PRP be initiated so as to be most effective

64.  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

65.  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

66.  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

67.  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

68.  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

69.  Dipyradamole Aspirin Microangiopathy of Diabetes Study
(DAMAD)and Ticlopidine Microangiopathy of Diabetes
Study found that antiplatelet drugs did not have any
effect

70.  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

71.  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

72.  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

73.  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

74.  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

75.  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

76.  Macular edema has to be treated 6 to 8 weeks earlier
than PRP, if PRP is also planned
 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)

77.  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

78.  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

79.  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

80.  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

81.  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

82.  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

83.  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

84.  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

85.  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

86.  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

87.  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

88. Side effects
 Pain more when peripheral retina is treated
 Anxiety, shock , seizure
 Constriction of field and nyctalopia
 Serous or choroidal detachment

89.  Foveal burn, traction
 Macular edema
 Rarely acute angle closure glaucoma
 Corneal or lens burns
 Internal ophthalmoplegia – these are less with multiple
sessions

90.  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

91.  Epithelial defects in the cornea
 Cataract formation
 Postoperative hemorrhage
 Retinal detachment
 Ghost cell glaucoma
 Glial tissue proliferation

92.  Rubeosis usually associated with retinal detachment
 Anterior hyaloidal fibrovascular proliferation is seen
more in juvenile diabetics
 Endophthalmitis

93.  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

94.  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.

95.  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

96.  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

97.  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

98.  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

99.  It is a VEGF trap
 A fusiform protein
 It binds with VEGF – A,B and placenta growth factor

100.  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

101.  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

102. 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

103.  Infection
 Retinal tear- Retinal detachment
 Artery occlusion
 Trauma to lens- cataract
 Uveitis and
 Sub conjunctival hemorrhage.

104.  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

105.  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

106.  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

107.  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

108.  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

109.  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