Management of Diabetic Maculopathy

2. Diabetic maculopathy is the leading cause of visual disability in diabetics
Incidence of Diabetic Retinopathy (DR) : 2.3/100 person/year for the overall diabetic
population &
4.5 for patients on insulin therapy
Prevalence in India : 17.6% to 28.2%.
Prevalence of Diabetes in Chandigarh : 18.6 % Diabetologia 2011;54:3022–7
The number of people with DM : current 67 million to 79.4 million
The number of patients with DR would increase to 22.4 million in another two decades
Economic and social burden of DM and DR
Needs for an effective screening strategy, accurate case detection, and treatment effective for
both DM and DR.
Indian J Ophthalmol 2016;64:14-25.

3. ETDRS Report 12 ,Ophthalmology. 2003;110(9): 1677-1682.
Non proliferative
DR (NPDR)
• Mild
• Moderate
• Severe
• Very severe
Proliferative DR
(PDR)
• Without HRC
• With HRC
Diabetic Macular
Edema(DME)

4. NON PROLIFERATIVE DR [NPDR]
Ophthalmology. 2003;110(9): 1677-1682.
• MICROANEURYSMS onlyMILD
• MICROANEURYSMS
• Other signs :
DOT & BLOT HAEMORRHAGES,
HARD EXUDATES, COTTON WOOL SPOTS
MODERATE
• INTRARETINAL HAEMORRHAGES (>20 in each quadrant)
• VENOUS BEADING (in 2 quadrants)
• INTRARETINAL MICROVASCULAR ABNORMALITIES(IRMA) (in 1
quadrant)
SEVERE

5. PROLIFERATIVE [PDR]
Ophthalmology. 2003;110(9): 1677-1682.
High risk characteristics (HRC)
NVD ˃1/4 – 1/3
disc area
NVD with
preretinal bleed /
vitreous hge
NVE > ½ disc
area with
preretinal bleed /
vitreous hge
NVD –
neovascularisation
at disc or within 1
DD from disc
NVE -
neovascularisation
elsewhere

6. Ophthalmology. 2003;110(9): 1677-1682.
NO DME
No retinal thickening or hard
exudates in the macula
Retinal thickening in the
macula that does not
involve the central subfield
zone that is 1 mm in
diameter
Retinal thickening in the
macula that does
involve the central subfield
zone that is 1 mm in
diameter
NON CENTER
INVOLVING
DME
CENTER
INVOLVING
DME

7. Macular Edema is an inflammatory process
Macular Edema
Vascular
permeability
Blood flow
VEGF
Inflammatory mediators
IL-1,IL-6,IL-8, TNF α, MCP-1
Loss of retinal capillary endothelial cell tight junctions
Chronic Hyperglycemia,

8. diagnosed stereoscopically : retinal thickening in the macula using fundus contact lens
biomicroscopy
Definition : by ETRDS ‘’retinal thickening or presence of hard exudates within 1 disk diameter of
the center of the macula’’.
To characterize the severity of macular edema and for treatment guidelines,
the term clinically significant macular edema (CSME) is used.
24% of eyes with CSME and 33% of eyes with center-involving CSME will have a moderate
visual loss (15 or more letters on the ETDRS chart) within 3 years if untreated
Arch Ophthalmol. 1985;103(12):1796--1806

9. Arch Ophthalmol. 1985;103(12):1796--1806
retinal thickening at or within 500
mm of the center of the macula
hard exudates at or within 500 mm
of the center of the macula,
if associated with thickening of
the adjacent retina
a zone or zones of retinal thickening
1 disk area in size,
at least part of which is within 1
disk diameter of the macular
center.

10. depending on the leakage pattern seen on the fluorescein angiogram (FA).
Surv Ophthalmol 2009:54:1—32.
FOCAL CSME
•discrete points of retinal hyperfluorescence
•focal leakage of microaneurysms
•cause retinal thickening
•leaking microaneurysms are surrounded by
circinate rings of hard exudates.
DIFFUSE DME
•areas of diffuse leakage
•intraretinal leakage from a dilated retinal
capillary bed and/or intraretinal microvascular
abnormalities (IRMA), and/or (in severe cases)
from arterioles and venules
There may be associated cystoid macular
edema (CME).

11. Surv Ophthalmol 2009:54:1—32.

12. Surv Ophthalmol 2009:54:1—32.

13. V : Taut posterior hyaloid membrane (TPHM), leads to recalcitrant DME
IV : Tractional macular edema: FVT present
III : Serous RD: hyporeflective space under NSR
II : CME - Edematous retina has cystic spaces , separated by hyper reflective membrane like
structure. 1st involves ONL & OPL then entire retina.
I : Sponge like retina due to diffuse leakage, macular edema bw OPL & ONL
Surv Ophthalmol 2009 : 54:1—32..

14. Surv Ophthalmol 2009 : 54:1—32..
I : Sponge like retina due to diffuse leakage, macular edema
bw OPL & ONL
II : CME - Edematous retina has cystic spaces , separated by
hyper reflective membrane like structure. 1st involves ONL &
OPL then entire retina.
III : Serous RD: hyporeflective space under NSR
IV : Tractional macular edema: FVT present
V : Taut posterior hyaloid membrane (TPHM), leads to
recalcitrant DME

15. Diagnosis is mainly clinical
DILATED FUNDUS EXAMINATION ON SLIT LAMP BIOMICROSCOPY : +78D OR +90D
INDIRECT OPHTHALMOSCOPY : +20D
DIRECT OPHTHALMOSCOPY
SEVEN FIELD FUNDUS STEREOPHOTOGRAPHY
OCT
FA

17.  Non-proliferative diabetic retinopathy(NPDR)
• Mild
• Moderate (with or without diabetic macular edema )
• Severe
 Proliferative diabetic retinopathy(PDR)
• HRC +/-
 Advanced diabetic eye disease

18. Haemoglobin
Blood glucose levels :
fasting
post prandial
mean blood glucose
HbA1c
Urine : routine & microscopy
24 hours urniary protein
Lipid profile
Serum Cholesterol : Total, HDL, LDL, VLDL
Serum Triglyceride
SERFT

20. Helps to identify type of CSME
Helps to see presence of TPHM / traction
Defines planes which guide the surgical intervention in DR
For long term follow up of patients
Indian J Ophthalmol 2016;64:14-25.

21.  OCT : categorizes DME into
Indian J Ophthalmol 2016;64:14-25.
• good metabolic control,
pharmacotherapy & laser treatment in
the presence of cystic spaces &
massive retinal thickening
Non tractional
DME
• needs PPV
Tractional
DME

22. Indian J Ophthalmol 2016;64:14-25.
Before retreatment in CSME as baseline investigation
If diffuse DME is present, use it to identify sources of perimacular leakage & non-
perfusion, to guide focal & grid laser
Assess signs of likely macular ischemia
Assess amount of ischemia in severe NPDR & subtle NVE
Patients with PDR, or after PRP therapy for PDR to assess response

24. Excellent glycemic control with lifestyle modifications
Normalize blood pressure
Improve renal and cardiac status
Control dyslipidemia
Treat anemia
Anti VEGF drugs
Intravitreal steroids/ Intravitreal implants
PST
Focal/grid laser
PPV for taut hyaloid
Indian J Ophthalmol 2016;64:14-25.

25. Control of blood glucose, blood pressure, blood lipids are at central in management of DME
Indian J Ophthalmol 2016;64:14-25.
TRIAL Study Intervention Major Outcome
DCCT
 Intensive Insulin Therapy
in Type 1 DM
 Reduced incidence of DR by 76 %,
 Reduced risk of DR progression by 54%
EUCLID
 RAS inhibition &
progression of DR
 RAS inhibition with Lisinopril (ACE Inhibitor,
anti-hypertensive) reduced risk of PDR by 50 %
UKPDS
 Blood sugar & blood
pressure control
 Reduced risk of incident DR,
 Reduced need of laser by one third
ACCORD-
Eye
 Lipid control with
Simvastatin + Fenofibrate
 Reduced risk of diabetic retinopathy progression
by 40 %
FIELD
 Lipid-triglyceride control in
Type 2 DM
 Fenofibrate reduced DR progression, reduced
edema; reduced need of laser

26. GOALS OF TREATMENT :
PRIMARY GOAL OF THERAPY – IMPROVEMENT OR RESTORATION OF VA
SECONDARY GOAL - STABILIZATION OF VISION & PREVENTION OF FURTHER
VISION LOSS
TREATMENT RECOMMENDATIONS – BASED ON INVOLVEMENT OF CENTRE OF
MACULA

27.  Till recently, laser has been a gold standard for DME.
ETDRS demonstrated safety & efficacy and showed
approx 50% decrease in moderate visual loss in CSME
HOW LASER WORKS ?
Directly blocks the microaneurysms in focal laser.
Stimulates the RPE cells and activates RPE pump for
fluid absorption.
Acts as anti VEGF
Indian J Ophthalmol 2016;64:14-25.
Step 1
Identify
treatable
lesions on FFA.
Step 2
Focal/ grid
laser
Step 3
Re-treatment at 3
months if required

28. Indian J Ophthalmol 2016;64:14-25.
Focal leaks greater than
500u-3000u from
center of macula
causing retinal
thickness/ or hard
exudates.
Areas of diffuse leakage
from extensive no. of
microaneurysms &
capillary leak
Avascular zones other
than FAZ in this area

29. Indian J Ophthalmol 2016;64:14-25.
Focal leak from microaneurysms Diffuse capillary leak
Focal laser to microaneurysms Grid laser photocoagulation

30. Laser protocol : Focal laser (in centre sparing Focal CSME)
Counselling of patient.
Metabolic control.
OCT < 400 µ.
Laser individual micro aneurysms.
Laser inside the circinate ring.
Not to laser HE.
Follow-up monthly, may take 3 months to resolve.
100 µ 100 m sec 70-80 mw.
Indian J Ophthalmol 2016;64:14-25.

31. Indian J Ophthalmol 2016;64:14-25.
Vn
6/12
3 mths
Vn
6/9
FT 283µm
FT 163µm

32. Laser protocol : Grid laser
Metabolic control.
OCT < 400 µ, if not Anti VEGF/20 mg PST TA, wait 3-4 weeks followed by laser.
Rule out traction by OCT as well.
Leave central 500 µ & laser 3000 µ all around fovea.
100 µ, 100 m sec, One laser burn apart 70 mw onwards.
Indian J Ophthalmol 2016;64:14-25.

33. Indian J Ophthalmol 2016;64:14-25.
Vn 6/36
8 wks
Vn 6/36
FT 367µm
FT 168µm

34. Currently, 2 VEGF-bindings drugs are approved for treatment of DME—
RANIBIZUMAB (LUCENTIS®; NOVARTIS) and
AFLIBERCEPT (EYELEA®; BAYER)
•PEGAPTANIB SODIUM (MACUGEN®; PFIZER) has been earlier used
oBEVACIZUMAB (AVASTIN®; ROCHE) has been tried.
Pan VEGF blocakde : Avastin , Lucentis
Selective VEGF blocakde : Macugen
Indian J Ophthalmol 2016;64:14-25.

35. Results of several randomized trials using ranibizumab are available.
Comparison with sham injection (RESOLVE, RISE, and RIDE),
Comparison with laser treatment (READ-2 and RESTORE),
Comparison with prompt and deferred laser (DRCR.net) Protocol I
intravitreal ranibizumab monotherapy is superior to laser monotherapy or intravitreal
triamcinolone
 additional laser (prompt or deferred) combined with intravitreal ranibizumab does not
necessarily increase vision in DME
Indian J Ophthalmol 2016;64:14-25.

36. RESOLVE study (FU 12 mth)
 Loss of >10 letters was seen in 4.9% of study group vs 24.5% in sham treatment
Safety and efficacy of ranibizumab in diabetic macular edema (RESOLVE Study): a 12-month, randomized, controlled,
double-masked, multicenter phase II study. Diabetes Care 2010; 33: 2399–2405

37. RISE and RIDE trials (FU 36 mth)
Significant improvements in macular edema were noted on OCT, & retinopathy was less likely
to worsen & more likely to improve in ranibizumab-treated patients.
Ranibizumab-treated patients underwent significantly fewer macular laser procedures
FDA approved Ranibizumab for DME, based on the results of these studies in Aug 2012
Ranibizumab for diabetic macular edema:results from 2 phaseIII randomized trials: RISE and RIDE Trials. Ophthalmology.
2012;119:789-801.
Long term efficacy and safety of ranibizumab in diabetic macular edema (DME): 36-month results from RISE and RIDE, two
phase III clinical trials. Presented at: 45th Annual Scientific Meeting of the Retina Society; October 5, 2012; Washington, D.C

38. RESTORE EXTENSION study (FU 12 mth)
The gains in BCVA that were observed during the first 12 months were maintained at month 24
The average number of injections in the ranibizumab monotherapy arm was 3.9, compared
with 3.5 in the combined ranibizumab/laser therapy arm.

39. DRCR network Protocol ‘’I;; (FU 36 mth)
Randomized Trial Evaluating Ranibizumab Plus Prompt or Deferred Laser or Triamcinolone Plus
Prompt Laser for Diabetic Macular Edema
Intravitreal ranibizumab with prompt or deferred laser is more effective at 3 years compared
with prompt laser alone or triamcinolone + prompt laser for DME
Ophthalmology 2010;117:1064--1077

41. DRCR network Protocol ‘’H’’ (FU 36 mth)
Phase 2 randomized trial of intravitreal Bevacizumab for DME
Ophthalmology 2007:114:1860-7
 Focal laser vs bevacizumab 1.25mg vs 2.5 mg vs combination
 Intravit bevacizumab- 1 line greater improvement relative to laser at 12 weeks
 Initial greater reduction in CRT compared to laser, but no significant differences in CRT
beyond 3 weeks
Ophthalmology 2010;117:1064--1077

42. FDA-approved anti-VEGF therapy for exudative age-related macular edema
 Recombinant fusion protein, comprising the key VEGF-binding domains of human VEGF
receptors 1 and 2, possesses a:
• Higher binding affinity for VEGF receptors than does ranibizumab or bevacizumab
• Binding capacity for placental growth factors 1 and 2, which contribute to excessive
vascular permeability and retinal neovascularization
Indian J Ophthalmol 2016;64:14-25.

43. DA VINCI Trial
Compared Aflibercept with laser in DME
Significant reductions in CRT were seen in the aflibercept groups compared with the laser
group.
The DA VINCI study: phase2 primary results of VEGF Trap-Eye in patients with diabetic macular edema. Ophthalmology.
2011;118:1819-26.

44. Evidence from clinical trials
 Results of both RESTORE & REVEAL trials showed that ranibizumab used alone & with laser
therapy produce comparable results.
 Addition of laser therapy did not significantly decrease treatment burden when compared
with ranibizumab monotherapy.
 BOLT study provides evidence supporting long-term use of intravitreous bevacizumab for
persistent center-involving CSME.
Aflibercept therapy has resulted in promising results when compared with laser monotherapy
for treating patients with DME.
Future randomized trials are needed to evaluate the safety and long-term efficacy of the
approved 2-mg dose of the drug in treating DME.
The best VEGF-inhibitor administration protocol—needs to be ascertained
Economic impact needs to be looked into.

45. Advantage : Higher local and sustained drug delivery to the eye with greater posterior segment
penetration
Indian J Ophthalmol 2016;64:14-25.

46. Slow-release intravitreal dexamethasone (0.7mg) implant, Ozurdex, shows efficacy for
treatment of DME
FDA approved for Vascular occlusions and uveitic CME
Substantial improvements in BCVA values & significant reductions of CMT observed in DME.
Preliminary results of an intravitreal dexamethasone implant (Ozurdex®) in patients with persistent diabetic macular edema.
Clinical Ophthalmology 2013:7 1423–1428
Significant improvement is seen from day 3 of the implant.
Peak efficacy - month 1 through to month 3, slowly decreases from month 4 to 6 (reduced
release of drug, or worsening of the chronic diabetes)
Intravitreal dexamethasone implant in patients with persistent diabetic macular edema. Ophthalmologica. 2012;228:117–122.
Indian J Ophthalmol 2016;64:14-25.

47. Retisert® (Bausch & Lomb)
Iluvien device (Alimera Sciences) is low dose intravitreal insert for sustained release of
fluocinolone acetonide lasting up to 36 months.
Alimera announced positive results from phase 3 FAME trials in DME
Chronic DME - especially responds well to this treatment
FAME Study Group. Sustained delivery fluocinolone acetonide vitreous inserts provide benefit for at least 3years in patients with
diabetic macular edema. Ophthalmology. 2012;119:2125-32.
Indian J Ophthalmol 2016;64:14-25.

48. Intravitreal steroids
Major challenge with steroid implants - high rates of intraocular complications (cataracts &
glaucoma)
Anti-VEGF drugs- favorable safety profiles, have become the standard of care when combined
with laser photocoagulation in DME patients.
Intravitreal steroid injections - of value as second-line therapy in pseudophakic patients & in
whom laser & anti-VEGF agents have failed.
Recent phase 3 studies with the sustained release steroid implants suggest that steady, long-
term therapy may produce results superior to traditional pulse therapy.
Because of their favourable pharmacokinetic characteristics, implants are of particular value in
eyes that have previously undergone vitrectomies.

49. SUMMARY
CSME
FOCAL
INVOLVING
CENTRE
METABOLIC
CONTROL &
ANTI-VEGF
CENTRE
SPARING
METABOLIC
CONTROL
FOLLOWED BY
LASER
DIFFUSE
METABOLIC
CONTROL &
ANTI- VEGF
METABOLIC
CONTROL &
DEPOT I/VIT
STEROIDS

50. Anti-VEGF treatment decision tree
(DRCR.net study)
Indian J Ophthalmol 2016;64:14-25.

51. Why use a treat and extend (T&E) regimen in
DME?
Overall, a potential to offer individualized treatment to DME patients
Patient-specific symptom-free interval can be determined with a T&E
regimen
Treat and extend regimen attempts to minimize the clinic visits,
number of injections and ancillary testing

52. CSME WITH TRACTION
Only surgery PPV with PHM removal.
No Role of Laser Rx.

53. 52 M, NIDDM, CSME with TPHM : pt. underwent PPV
Vn
3/60
FT-389µm, TPH on OCT

54. Post PPV, resolution of CSME
6 wks, Vn 6/12

55. RECALCITRANT DME
Definition
Good metabolic control
No dyslipidemia
Renal functions normal
HbA1c normal
BP under control
No tractional element on OCT
Repeatedly lasered
 If Residual CSME still persists, it is labelled as Recalcitrant DME

56. Retreatment by laser after FFA (???)
Anti VEGF
Intra vitreal implant – OZURDEX
PPV – remove posterior hyaloid , along with ILM peeling ( better oxygenation of retinal tissue)
Am J Ophthalmol. 2001 Sep; 132(3):369-77.
Retina. 2008 Mar; 28(3):410-9.

57. Pascal Synthesis Pattern Scanning Laser (Topcon) - first pattern scanning laser designed for
retinal indications.
Used for grid , PRP
More precise guidance of laser delivery , delivered in a pattern
Allows targeted treatment of diseased areas
Minimize collateral damage to surrounding tissue.
Conventional laser therapy may cause “atrophic creep”, or scarring that diminishes vision,
Pascal reduces risk for that complication
Treatment session simpler and more consistent
Other pattern lasers include the Visulas 532s (Carl Zeiss Meditec).

58. PRP using PASCAL laser

59. Navigated laser photocoagulator (NAVILAS) - new prototype of retinal eye-tracking laser
delivery system with integrated digital fundus imaging
Increases effectiveness & efficiency of focal laser therapy for DME by aligning pre-planned
treatment maps with real-time fundus images.
Uses a diode-pumped solid-state laser (532 nm) for both single-spot & pattern retinal .
Eye-tracking mechanisms compensate for eye’s excursions during treatment & utilize
registration of retinal vessel positions & multiple retinal landmarks to limit possibility of
inadvertent placement of laser burns
The Open Ophthalmology Journal. 2013;7

61. UPCOMING RESEARCH
Targeted scatter laser photocoagulation to areas of capillary non-perfusion anterior to the
equator is under evaluation as a potential treatment for DME.
 Development of ultra-wide field imaging with fluorescein angiography allows identification of
& selective treatment to areas of ischemic retina. Treatment in this fashion may allow for better
visual outcomes or less frequent administration of intravitreal agents.

62. CONCLUSION
Etiology of diabetic retinopathy is multifactorial; so treatment too needs to be multimodal &
combined.
Comprehensive control of metabolic status before management, has led to improved
outcomes.
Focal laser preferred treatment for focal DME (centre sparing)
Anti-VEGF + laser preferred than laser alone in diffuse DME