Recent advances included

1. Diabetic Retinopathy:
Management
Priyanka Bharti
09.03.2016

2. Introduction
• Diabetes mellitus is a major risk factor of potential
blindness in both developing and developed
countries
• Diabetic retinopathy (DR) accounts for 1% of global
blindness
• DR occurs in nearly all type 1 and 75% of type 2
diabetes after 15 years duration of diabetes

3. Clinical signs

4. Clinical signs

5. Abbreviated Early Treatment Diabetic Retinopathy Study
classification of diabetic retinopathy
( The modified Airlie House classification)
Non-proliferative diabetic retinopathy (NPDR)
Very mild Microaneurysms only
Mild Any or all of:
• Microaneurysms, retinal haemorrhages, exudates, cotton wool spots
(up to the level of moderate NPDR)
• No IRMA or significant beading
Moderate • Severe retinal haemorrhages in 1–3 quadrants
(> ETDRS standard photograph 2A) or mild IRMA
• Significant venous beading in no > 1 quadrant
• Cotton wool spots commonly presentStandard photograph No. 2A –
Moderate degree of hemorrhage and microaneurysms

6. Non-proliferative diabetic retinopathy (NPDR)
Severe The 4-2-1 rule; one or more of:
• Severe haemorrhages in all 4 quadrants
• Significant venous beading in 2 or more quadrants
• Moderate IRMA in 1 or more quadrants
Very severe Two or more of the criteria for severe
ETDRS Research Group. Early Treatment Diabetic Retinopathy Study design and baseline patient characteristics:
ETDRS report number 7. Ophthalmology 1991;98:742.

7. Proliferative diabetic retinopathy (PDR)
Mild- moderate New vessels on the disc (NVD) or new vessels elsewhere (NVE),
but extent insufficient to meet the high-risk criteria
High-risk • New vessels on the disc (NVD) > ETDRS standard photograph
10A (about 1/3 disc area)
• Any NVD with vitreous or preretinal haemorrhage
• NVE >1/2 disc area with vitreous or preretinal haemorrhage
Advanced
diabetic eye
disease
Complication of DR- Treatment has been inadequate or
unsuccessful
• Preretinal hemorrhage
• TRD
• Tractinal Retinoschisis
• Rubeosis iridis
Standard photograph No. 10A -
NVD covering one quarter to one third of the disc area

8. NVD ~ 1/3 disc in area
NVD + Haemorrhage
NVE > 1/2 disc area
+ haemorrhage
High-Risk PDR

9. Clinically significant macular oedema (CSMO)

10. Diagnosis and ancillary testing

11. Diagnosis
• DR is essentially a clinical diagnosis
• Fundus evaluation under mydriatic (FEUM)
– Direct ophthalmoscope
– Indirect ophthalmoscope
– Slit lamp biomicroscopy
• Imaging techniques
– Fundus photography
– Fundus fluorescein angiography (FFA)
– Optical coherence tomography (OCT)
– Ultrasonography B scan

12. RECOMMENDED EYE EXAMINATION SCHEDULE
Diabetes type Recommended time for
first examination
Routine minimum follow
up
Type 1 5 years after onset or
during puberty
Yearly
Type 2 At time of diagnosis Yearly
Type 1 or 2 and pregnancy • Before conception
•Early first trimester
• Each trimester or as
frequent as indicated
No retinopathy to mild or
moderate NPDR:
every 3-12 months
Severe NPDR or worse:
every 1-3 months

13. Ancillary testing
• HbA1c:
– The Diabetes Control and Complication Trial (DCCT) and
Epidemiology of Diabetes Interventions and Complications
(EDIC), highlighted effect of good glycemic control on
progression of retinopathy

14. • Serum lipids:
– Recent studies have identified importance of cholesterol
lowering medications in hypercholesterolaemic type 2
diabetics in reducing risk of clinically significant macular
edema (CSME) and diabetic retinopathy progression
• Urea and electrolytes:
– Diabetic nephropathy is an important consequence of
microvascular disease

15. Fundus fluorescein angiography (FFA)
• Widely used test
– Assess severity of diabetic retinopathy
– Used to classify and treat DME into focal and diffuse type
– Aids in diagnosis of CME
– Documentation of angiographic risk factors for progression
of NPDR to PDR
– Know extent of capillary nonperfusion
– Aids in differentiating IRMAs from new vessels

16. FFA: Severe retinal ischemia with rubeosis

17. FFA: Neovascularisation elsewhere (NVE)

18. FFA: Cystoid macular oedema (CMO)

19. FFA: Focal diabetic maculopathy

20. FFA: Diffuse diabetic maculopathy

21. Optical coherence tomography (OCT)
• Non- invasive, non- contact imaging technique
• Fascilitates high resolution cross sectional images
• Uses:
– Quantitative measurement of retinal thickness
– Demonstrates macular edema
– Details the architecture of macula and surrounding
structures

24. OCT: vitreomacular traction

25. Management of diabetic retinopathy

26. Management of diabetic retinopathy
• Multidisciplinary approach
• Role of ophthalmologist, physician and dietician
• Underlying diabetes and risk factors managed
concurrently with ocular complications of diabetes

27. Medical management
• Blood glucose control
– Tight glycemic control reduces incidence and progression of
diabetic retinopathy
– Supported by Diabetes Control and Complications Trial
(DCCT), United Kingdom Prospective Diabetes Study (UKPDS)
and Wisconsin Epidemiologic Study of Diabetic Retinopathy
(WESDR)
Hba1c Prevalence of retinopathy
<7% 12 %
> 10% 40.7 %
Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR)

28. Diabetes Control and Complications
Trial (DCCT)
• Primary prevention and secondary intervention study:
– Intensive control of blood glucose- slow development and progression
of DR
• Enrollment:
1. 726 patients with type1 diabetes mellitus (1-5 years duration) and no
diabetic retinopathy
2. 715 patients with type1 diabetes mellitus ( 1- 15 years duration) and
mild to moderate diabetic retinopathy
• Results :
– Primary prevention: reduced risk of developing DR by 76%
– Secondary intervention: slowed progression by 54%
– For every 1% decrease of HbA1c level, the incidence of DR deceased 28%
– For every 10% decrease in HbA1C - 35% to 40% decrease risk of worsening DR
The effect of intensive treatment of diabetes on the development and progression of long-term complications in
IDDM. DCCT Research Group. N Engl J Med. 1993;329(14):977-986.

29. • Enrolled 3867 patients with newly diagnosed type 2 diabetes
• Intensive blood glucose control with either sulphonylureas or
insulin resulted in
– 17% risk reduction for progression of DR
– 29% risk reduction in the need for laser photocoagulation
– 23% risk reduction for development of vitreous hemorrhage
– 16% risk reduction in legal blindness
United Kingdom Prospective
Diabetes Study (UKPDS)

30. • Blood pressure control
– The current British Hypertension Society guidelines define
hypertension as systolic blood pressure ≥ 140mmHg and/ or
diastolic blood pressure ≥ to 90mmHg
– Targets in diabetic patients should be systolic level <130 mm Hg
and diastolic <80 mm Hg
– In type1 diabetics treatment with ACE inhibitors resulted in a 50%
reduction in progression of retinopathy and progression to
proliferative diabetic retinopathy by 80%
EURODIAB Controlled Trial of Lisinopril in Insulin Dependent Diabetes Mellitus
(EUCLID)
– Type 2 diabetics in UKPDS study showed, tight BP control
prevented progression of retinopathy

31. • Lipid control
– Dyslipidaemia increases risk of diabetic retinopathy
particularly diabetic macular oedema
– Fenofibrate Intervention and Event Lowering in Diabetes
(FIELD) study
• Type 2 diabetic patients treated with fenofibrate were less likely
than controls to need laser treatment (5.2% vs 3.6%, p<0.001)
• Cigarette smoking
– Increases risk of diabetic retinopathy, nephropathy and
neuropathy

32. Laser photocoagulation
• Light Amplification Stimulated Emission Radiation
(LASER)
• Beetham et al. 1969
– First to use laser in treatment of diabetic retinopathy-
Ruby laser photocoagulation
• Zweng et al. 1971
– Use of Argon laser photocoagulation

33. A photon of the “right” energy can be
absorbed and jump an electron into a
higher energy level
Spontaneous emission
An excited electron falls back to its lower
energy level, releasing a photon in a random
direction
According to quantum theory, an electron can exist at one energy level
BASICS OF LASERS

34. BASICS OF LASERS
Stimulated emission
A photon strikes an excited electron
Electron falls to its lower energy level
releasing a photon that is going in same
direction and is in exact phase with original
photon

35. Basic principles of photocoagulation
Light energy absorbed by target tissue and converted into
thermal energy
Denaturation of tissue proteins and coagulative necrosis
Tissue temperature rises above 650C

36. • Commonly used
– Lasers spanning visible light
spectrum of 400- 780 nm
•Light is absorbed principally by ocular
tissues containing melanin, xanthophyll or
hemoglobin
Melanin- excellent absorber of green, yellow, red, and infrared wavelengths
Xanthophyll- absorbs blue, minimal absorption of yellow or red wavelengths
Hemoglobin- absorbs blue, green and yellow with minimal absorption of red
wavelengths

37. Photocoagulation: mechanism
• Exact mechanism not yet clear
• Combined effects of multiple elements including:
– Facilitation of transports of oxygen and nutrients into
retina from choroid
– Transport of metabolic waste out of the retina
– Reduction of retinal metabolic load
– Reduced sequestration of proangiogenic cytokines in
photoreceptors, resulting in net reduction of VEGF
expression

38. Photocoagulation: techniques
• Clinically significant macular edema (CSME)
– Focal treatment
– Grid treatment
• Proliferative diabetic retinopathy (PDR)
– Panretinal photocoagulation (PRP)

39. CSME: treatment
• All eyes with CSME should be considered for laser
photocoagulation irrespective of the level of visual acuity
– Reduces risk of visual loss by 50%
• Management depends on
• Evidence of central macular thickening or
• Vitreomacular traction
• Pre-treatment FA, useful to delineate area and extent of
leakage and to detect ischemic maculopathy

40. Focal diabetic maculopathy Diffuse diabetic maculopathy
CSMEIschemic maculopathy

41. Focal photocoagulation
• Focal maculopathy
• Burns are applied to microaneurysm and microvascular lesions
located 500 – 3000 µm from center of macula
• Laser used- Argon
• Spot size 50 – 100 µm
• Exposure time 0.1 sec
• Gentle whitening
or darkening of lesions

42. Focal photocoagulation

43. Grid pattern photocoagulation
• Burns applied to all areas of diffuse retinal thickening more
than 500 µm from centre of macula and 500 µm from the
temporal margin of optic disc
• Laser used- Argon
• Spot size 100 µm
• Exposure time 0.1 sec
• Light intensity burns

44. Grid pattern photocoagulation

45. Is the centre
involved?
Visual Acuity Phakic/
Pseudophakic
OCT- central
retinal
thickness
Treatment options
No Either Focal/Grid laser
Yes Normal or
>78 letters
Either Focal/Grid
laser/Observation if
lesions too close to
fovea
Yes 78-24 letters
or
symptomatic
Phakic ≥ 250 microns Intravitreal anti- VEGF
with or
without laser. If
unresponsive
consider flucinolone
implant.
Royal College of Ophthalmologists. Diabetic Retinopathy Guidelines, December 2012
Management of diabetic maculopathy

46. Is the
centre
involved?
Visual
Acuity
Phakic/
Pseudophakic
OCT- central
retinal thickness
Treatment options
Yes 78-24
letters
Pseudophakic ≥ 250 microns Intravitreal anti- VEGF or
intravitreal triamcinolone
with or without laser
If unresponsive consider
flucinolone implant
Yes <24
letters
Pseudophakic ≥ 250 microns Observation especially if long
standing or unrepsonsive to
laser. Consider macula
ischaemia. Otherwise consider
anti-VEGF or intravitreal steroid
Yes Either Vitreomacular
traction
Consider vitrectomy with or
without adjunctive intravitreal
anti-VEGF or steroid treatment
Royal College of Ophthalmologists. Diabetic Retinopathy Guidelines, December 2012
Management of diabetic maculopathy

47. Early Treatment Diabetic Retinopathy
Study (ETDRS) 1980- 1985
• Study questions:
1. Is photocoagulation effective for treating DME?
2. Is photocoagulation effective for treating diabetic retinopathy?
3. Is aspirin effective for preventing progression of diabetic
retinopathy?
• Eligibility: Mild to very severe NPDR and/or early PDR, with or without
macular edema, with visual acuity 20/200 or better in each eye
• Randomization: 3711 participants: 1 eye randomly assigned to
photocoagulation (scatter and/ or focal) and 1 eye assigned to no
photocoagulation; patients randomly assigned to 650 mg/day aspirin or
placebo

48. • Aspirin use results:
1. did not alter progression of diabetic retinopathy
2. did not increase risk of vitreous haemorrhage
3. did not affect visual acuity
4. reduced risk of cardiovascular morbidity and mortality
• Early scatter photocoagulation results:
1. small reduction in risk of severe visual loss (<5/200 for atleast 4
months)
2. not indicated for eyes with mild to moderate diabetic retinopathy
3. may be most effective in patients with type2 diabetes
• Macular edema results:
Focal photocoagulation for DME
1. decreased risk of moderate vision loss
2. increased chance of moderate vision gain
3. reduced retinal thickening

49. DRCR.net compared modified ETDRS style laser
photocoagulation (mETDRS) to mild macular grid (MMG) laser
photocoagulation for DME
• mETDRS
– Used both focal and grid
laser treatment
– All leaking microaneurysms
in areas of 500–3000 um
from the center of macula,
but not within 500 um of
the disc are treated
– Mild gray-white burn
• Mild macular grid (MMG)
technique
– Total burns: 200- 300
– Burns applied to entire
area, including
unthickened retina
– No burns within 500 um
from disc
– Barely visible (light gray)
intensity

50. • Results:
– At 12 months, mETDRS more effective in reducing OCT
measured retinal thickening, compared to MMG
– No significant difference in visual outcome
• Conclusion:
– mETDRS technique , gold standard of laser therapy in
treating DME

51. Panretinal photocoagulation ( PRP)
• Scatter ablation of retina extending from retinal vascular
arcades at posterior pole to periphery
• Prevent onset or induce regression of new vessels
• Mostly employed for severe NPDR and PDR
• Lasers used: Argon, Diode, Krypton red
• Avoided in areas of prominent
fibrovascular membranes
vitreoretinal traction and tractional RD

52. Panretinal photocoagulation ( PRP): technique
• Involves 1500- 2000 burns
• Size: 200-500 m for Goldmann lens
100-300 m for Panfundoscopic lens
• One burn width apart
• Duration: 0.05- 0.1 second
• Power: 200-600mW
• Moderate intensity burn
• One or more sessions required

53. Panretinal photocoagulation ( PRP): technique
PRP technique- step 2PRP technique- step 1
PRP technique- step 4PRP technique- step 3

54. PRP: ETDRS recommendations for PDR

55. Follow up treatment after initial PRP

57. Diabetic Retinopathy Study (DRS)
1972- 1975
• Prospective, randomised clinical trial
• Study question: Is photocoagulation (argon or xenon arc) effective for
treating diabetic retinopathy?
• Eligibility: PDR or bilateral severe NPDR, with visual acuity 20/100 or
better in each eye
• Randomization: 1742 participants. One eye randomly assigned to
photocoagulation (argon or xenon arc) and 1 eye assigned to no
photocoagulation
• Outcome variable: Visual acuity less than 5/200 for atleast 4 months
• Results: Photocoagulation reduces risk of severe vision loss by 50% or
greater compared with no treatment. Treated eyes with high risk PDR
achieved the greatest benefit

58. PRP: complications
• Foveal burn
• Optic disc damage
• Macular edema
• Choroidal haemorrhage
• Choroidal neovascularisation
• Choroidal detachment
• Vitreous haemorrhage
• Pain during treatment
• Increased intraocular pressure
• Corneal abrasion
• Loss of visual field
• Loss of dark adaptation
• Lens opacities
• Increase in traction detachments

59. Laser treatments: recent
developments
• Pattern scanning laser (PASCAL)
– Rapid application of multiple laser spots with short pulse
duration of 10-30ms (upto 56 shots)
– Laser used: Nd:YAG
– Advantages:
• Shorter treatment duration
• Increased safety
• Uniform and precise spot placement
• Reduced pain and visual field defect
– Ideal laser method to place accurate “subthresold” focal-
grid laser in DME

61. • Subthreshold diode micropulse (SDM) laser
– Utilises diode laser (810nm) with micropulse technique to
achieve subthresold burns
– Micropulse mode divides single energy delivery of laser burn
with cycles of 100 µs on time and 50 µs off time until full
duration of laser spot (100-300ms) is delivered
– Safety of SDM in transfoveal therapy have been reported
– Advantages:
• Burns are applied to RPE without significantly affecting outer
retina and choriocapillaris*
– Disadvantage:
• Difficult to achieve uniform laser treatment because of inability to
visualise subthreshold laser marks
Laser treatments: recent developments

63. • Navigated laser (NAVILAS)
– Fundus imaging and laser treatment device
– Combined with simultaneous FA, allows to preplan areas of
treatment
– More uniform burns with less pain and shorter treatment
duration compared to conventional lasers
– Can achieve upto 92% hit rate
of microaneurysm compared to
72% for conventional lasers
Laser treatments: recent developments

64. Vitrectomy in diabetic retinopathy

65. Vitrectomy: indications
• Dense, nonclearing (>3months) vitreous haemorrhage
• Tractional retinal detachment involving or threatening macula
• Combined tractional or rhegmatogenous retinal detachment
• Diffuse DME associated with posterior hyaloidal traction
• Significant recurrent vitreous haemorrhage despite maximal PRP
• Fibrovascular proliferation
• Red blood cell induced glaucoma and ghost cell glaucoma
• Media opacities preventing photocoagulation
• Dense premacular subhyaloid haemorrhage

66. Diabetic Retinopathy Vitrectomy
Study (DRVS)
• Evaluated benefit of early (1-6 months) versus late (at 1 year)
vitrectomy for eyes with PDR with severe vitreous haemorrhage and
visual loss (≤ 5/200)
• Results:
– In type1 patients with severe vitreous haemorrhage - significant
benefit of early vitrectomy
– In type2 - no advantage of early vitrectomy
– In eyes with very severe PDR - showed advantage of early
vitrectomy compared with conventional management

67. • Removal of various local growth factors such as VEGF,
angiotensin and inflammatory cytokines (IL-6) helps to retard
progression of DME
Massive peripapillary fibrovascular
proliferation with vitreous hemorrhage
Following pars plana vitrectomy

68. Timing of vitrectomy in PDR
• Urgent
– Neovascularisation of iris with recent vitreous haemorrhage
– Extensive premacular haemorrhage
• Early surgical intervention
– No previous laser treatment
– More extensive fibrovascular proliferation
– Fellow eye with rapidly progressive visual loss/ blind
• Surgical intervention deferred if
– Presence of complete PVD
– Extensive prior PRP
– Comorbidities contraindicating surgical procedure
• Frquent monitoring with ultrasonography

69. Diabetic Retinopathy Clinical Research
Network (DRCR.net) 2010
• Evaluated vitrectomy for DME associated with vitreomacular
traction
• At 6 months
– Median OCT central macular thickness decreased by 160 m
• Central macular thickness <250 m in 43%
• 50% reduction in thickness observed in 68%
• Visual acuity improved by >/=10 letters in 38% and deteriorated
by >/=10 letters in 22%

70. Advances in diabetic vitrectomy
• Viscodissection
– Injecting viscoelastics in between sheet of fibrovascular
membranes and retina
– Useful in thin, atrophic retinas
• Vitrectomy with internal limiting membrane (ILM)
peeling
– A study evaluating efficacy of pars plana vitrectomy (PPV) with
and without inner limiting membrane (ILM) peeling for
persistent diffuse CSME showed structural improvement but
with limited visual improvement
Pars Plana Vitrectomy With and Without Peeling of the Inner Limiting Membrane for Diabetic Macular Edema,
Retina 2006 Jan 26

71. • Tamponading agents in diabetic vitrectomy
– Silicone oil
• Enables rapid visual recovery, fundus examination during
postoperative follow up
• Reduces vascular proliferation and post operative bleeding
• Helps in long term tamponade of multiple retinal breaks
• Regression of anterior segment neovascularisation, possibly via
blocking diffusion of vasculoendothelial growth factor (VEGF)
Advances in diabetic vitrectomy

72. Intravitreal Triamcinolone acetonide
(ITA)
• Favourable results in treatment of
diffuse DME
• Anti- inflammatory effects including decreased inflammatory
cell activation and adhesion and growth signaling factors
• Direct effect on maturation of endothelial cell junctions and
improved barrier properties

73. • Major limitation
– Short duration of action necessitating repeated injections
(3 months)
• Complications
– Intraocular pressure elevation (common, about 25%)
– Cataract (moderate frequency)
– Endophthalmitis
– Needle damage- retinal tears, lens damage, vitreous
hemorrhage
– Injection site pain and bleeding

74. • DRCR net (2008) compared preservative free IVTA and focal/
grid laser for DME
– Randomized 840 eyes to focal/ grid photocoagulation, 1mg
IVTA, or 4 mg IVTA
– Retreatment was given for persistent or new edema at 4
months interval
– Conclusion: focal/ grid laser is better than IVTA in treatment of
DME in long term
– Complications like cataract and glaucoma were more with 4mg
IVTA
– Combination therapy may produce greater benefit

75. • IVTA + Laser versus Ranibizumab (DRCRnet,2008)
– In pseudophakic eyes- IVTA + laser may be as effective as
ranibizumab at improving vision and reducing retinal
thickening
– Phakic eyes- no corresponding visual benefit above laser
- increased rate of cataract by two years
• Laser photocoagulation (panretinal and macular) with IVTA
versus laser photocoagulation alone
– Improved best corrected visual acuity
– Decreased central macular thickness and
– Total macular volume
(Lam et al., 2007; Maia et al., 2009)

76. • Flucinolone acetonide implant (Illuvein)
– Sustained release of drug
– 0.2 g/day
– Used in chronic DME
– Treatment benefit for upto 3 years

77. Anti- vascular endothelial growth
factor (anti- VEGF)
• VEGF is produced by pigment epithelial cells, pericytes and
endothelial cells of retina in response to hypoxia
• VEGF aids inflammation by inducing intracellular adhesion
molecule-1 (ICAM-1) expression and leukocyte adhesion

78. • Specific inhibition of VEGF activity is able to prevent retinal
neovascularization and associated blood flow abnormalities
• Currently four anti- VEGF agents in use
– Pegatanib (Macugen)
– Ranibizumab (Lucentis)
– Bevacizumab (Avastin)
– VEGF- trap (Aflibercept)

79. • Pegaptanib
– Pegylated RNA aptamer directed against VEGF-A 165 isoform
– Dose: 0.3mg/ 0.05ml
– Intravitreal pegaptanib in patients with DME with 36 weeks of
follow-up demonstrated
• Better visual acuity outcomes
• Reduced central retinal thickness and
• Reduced need for additional photocoagulation therapy
– Short- term, marked and rapid regression of diabetic retinal
neovascularisation
Cunningham et al. 2005, Gonzalez et al. 2009

80. • Ranibizumab
– Recombinant humanized monoclonal antibody fragment
– Binds all isoforms of VEGF- A
– Dose: 0.5 mg /0.05ml
– Laser-Ranibizumab-Triamcinolone Study (DRCRnet 2010)
• Intravitreal injection of 0.5 mg ranibizumab, initially given monthly
for 3 months, with prompt or deferred (≥24 weeks) macular laser
had significantly superior visual and OCT outcomes to IVTA + laser
or laser alone in eyes with DME involving fovea

81. • RESTORE study, 2011
– Ranibizumab monotherapy and ranibizumab combined with
laser therapy over conventional laser therapy in DME
– Conclusion: equal superiority of ranibizumab monotherapy and
ranibizumab combined with laser therapy over standard laser
therapy

82. • Bevacizumab (Avastin):
– Recombinant humanized antibody
– Binds all VEGF-A isoforms
– Dose: 1.25 mg/0.05ml or 2.5 mg/o.1ml
– Used in treatment of DME, PDR and iris neovascularisation
– Effects lasts for 4 weeks, need repeated injections
• BOLT study, 2010
– Compared role of IV Bevacizumab Or Laser Therapy (BOLT) in
DME
– IVB- patients are 5.1 times more likely to gain 10 or greater
ETDRS letters over 12 months

83. • Adjunctive treatment to PRP
• Marked regression of retinal and iris neovascularization
• Rapid resolution of vitreous hemorrhage
• Adjunctive to planned PPV
– Fascilitate surgery
– Prevent rebleeding
– Accelerate postoperative vitreous clear-up

84. • VEGF trap-eye (Aflibercept)
– 115 kDa recombinant fusion protein
– Binds to all VEGF A isomers
– Additionally binds to VEGF B and placental growth factor
– Active for 10-12 weeks after intravitreal injection
– DRCRnet (2015) compared intravitreal Aflibercept, bevacizumab
and ranibizumab for treatment of DME involving fovea
• All three drugs improved visual acuity
• No apparent differences between drugs with mild loss of initial
visual acuity
• With worse initial visual acuity, Aflibercept was more effective

85. Pharmacologic vitreolysis
• Enzymatic induction of PVD and vitreous liquifaction to
increase oxygen tension
• A phase III clinical trial showed, 55 IU of highly purified ovine
hyaluronidase (vitrase) helps to clear vitreous hemorrhage
1 month after intravitreal application*
• Intravitreal use of microplasmin induced PVD and vitreous
liquefaction with increased intravitreal oxygen tension
*Kuppermann et al.,2005

86. • Autologous plasmin found to be safe and effective adjunct to
vitrectomy for DME and PDR
– Plasmin assisted vitrectomy allows more complete and less
traumatic posterior vitreous removal with smooth retinal
surface

87. Fibrates
• Lipid lowering agent
• The Fenofibrate Intervention and Event Lowering in Diabetes
(FIELD) Study, 2010
– long-term lipid-lowering therapy with fenofibrate reduced the
progression of diabetic retinopathy and need for laser treatment
• ACCORD Study Group, 2010
– Fenofibrate for intensive dyslipidemia therapy reduced the rate of
progression of diabetic retinopathy

88. Protein kinase C inhibitors
• Protein kinase C (PKC) beta
– Important role in regulating endothelial cell permeability
– Important signaling component for VEGF
• Roboxistaurin (RBX)- PKC β- selective inhibitor
– Dose: 32mg P/o per day
– Reduced visual loss, progression of DME and need for laser
treatment
– Improved visual acuity in NPDR
• Protein Kinase C β inhibitor Diabetic Macular Edema
Study (PKC-DMES), 2007
– RBX treatment showed beneficial effect on DME progression
relative to placebo

89. Aldose Reductase Inhibitors (ARI)
• Aldose reductase plays an important role in polyol pathway,
which generates sorbitol during hyperglycemia
• Sorbitol accumulation, in turn, disrupts the osmotic balance,
destroying retinal cells like pericytes
• ARI such as sorbinil, ponalrestat and tolrestat, have shown
decrease in capillary cell death, microaneurysm count and
fluorescein leakage
• However, clinical trials of ARI had little therapeutic success

90. Summary
• Diabetic retinopathy (DR) is a common, potentially blinding
and visually disabling complication of diabetes
• Laser therapy remains mainstay of treatment

92. • Prevention offers most hope to diabetics
• Onset and progression of DR are delayed significantly with
tight glycemic control
• Screening of asymptomatic diabetic patients is crucial

93. Bibliography
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2. American Academy of Ophthalmology, Retina and Vitreous, 2013-2014, Section
12, Chapter 5; 89-112
3. Yanoff M & Duker JS. Ophthalmology. 4th Edition. Elsevier,2014. Part 6, Chapter
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4. Jack J Kanski, Brad Bowling, Clinical Ophthalmology, A Systemic Approach. 7th
Edition, 2011, Chapter 13
5. Ahmed M. Abu El-Asrar, Hani S. Al-Mezaine. Advances in the treatment of
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6. Samuel H. Yun, Ron A. Adelman Recent Developments in Laser Treatment of
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94. THANK YOU