1. Diabetic macular edema (DME) is the most common cause of visual impairment in patients with diabetes and can be focal or diffuse. 2. Clinically significant macular edema is defined by retinal thickening within 500 μm of the macula or hard exudates associated with thickening. 3. Optical coherence tomography and fluorescein angiography are used to diagnose and characterize DME by detecting retinal thickening and leakage patterns.

1. Diabetic macular edema
(DME)

2. Introduction
• Diabetic macular edema (DME) is the most
common cause of visual impairment in
patients with diabetes mellitus

3. CSME
• Macular edema is clinically
significant if one of the following
conditions is present:
1. retinal thickening at or within 500 mm
of the center of the macula and/or
2. hard exudates at or within 500 mm of
the center of the macula if associated
with thickening of the adjacent retina;
and/or
3. 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

4. Focal vs diffuse diabetic macular edema
Depending on the leakage pattern seen on the fluorescein angiogram(FFA)
• The FA is used to identify areas of increased vasopermeability , for
example, leaking microaneurysms or capillary beds, and to evaluate
retinal ischemia.
• Leakage noted on FA is not synonymous with edema or thickening since
extracellular edema requires that the rate of fluid ingress into the retina
(i.e., as indicated by leakage on the FA) exceeds the rate of fluid
clearance from the retina (e.g., via the RPE pump)

5. Focal macular edema
• Well - defined Discrete points of retinal hyperfluorescence are
present on the FA due to focal leakage of microaneurysms
surrounded by circinate rings of hard exudates.
• Responsive to focal laser photocoagulation.

6. Diffuse macular edema
• Areas of diffuse leakage are noted on
the FA due to intraretinal leakage
from a dilated retinal capillary bed
and/or intraretinal microvascular
abnormalities (IRMA), and/or (in
severe cases) from arteriole and
venules
• There may be associated cystoid
macular edema (CME)
• Refractory to laser photocoagulation

7. Epidemiology
• Others
Elevated diastolic blood pressure and abnormal lipid level

8. Pathogenesis
A. BLOOD-RETINAL BARRIER
B. ROLE OF VASOACTIVE FACTORS
C. VITREORETINAL INTERFACE
D. OTHERS

9. • The BRB consists of two major components : the outer barrier and the inner
barrier.
• The movement of water across the BRB is controlled by two mechanisms: passive
(bi-directional) and active (from retina towards choriocapillaris across the RPE
pump).
• The disruption of the BRB leads to abnormal inflow of fluid into the neurosensory
retina that can exceed
the outflow and cause
residual accumulation of
fluid in the intraretinal
layers of the macula.

10. Inner blood retinal barrier: The inner BRB comprises capillary endothelial cells with
intercellular tight junctions within a closely differentiated network of neurons and
glial cells.
1. Glial cells: Astrocytes guide the migration of retinal vessels during fetal life and, in
combination with Mueller cells, induce the formation of barrier properties and
tight junction proteins.
2. Pericytes are microvascular mural cells that provide vascular stability, Loss of
pericytes in early diabetic retinopathy may be related to the retinal capillary
endothelial death that leads to capillary dilation, microaneurysms, retinal
ischemia, production of VEGF, increased vascular permeability, and angiogenesis.
3. Retinal Vascular Endothelial Cells: Endothelial cell death is a hallmark of diabetic
retinopathy. It has been shown that endothelial cell death precedes the
formation of acellular capillaries, which progresses over time. The resultant
acellular capillaries lead to irreversible retinal ischemia.

11. 4. Advanced Glycation End-Products (AGEs): AGEs can cause structural
alterations of the posterior hyaloid that strengthens the
vitreomacular adhesion between the posterior hyaloid and ILM.
• Tight junctional protein: prevent lipids and proteins from diffusing
across the BRB and to create a selective barrier to water and
solutes

12. (B)
1. VEGF : VEGF is produced by RPE cells, ganglion cells, Muller cells, pericytes, endothelial cells, glial cells,
neurons and smooth muscle cells of the diabetic retina. VEGF produce conformational changes in the tight
junctions of retinal vascular endothelial cells
2. PKC:
3. Histamine
4. Angitensin II: directly stimulates the secretion of VEGF in vascular smooth muscles and cardiac endothelial
cells
5. MMPs: implicated in the pathogenesis of partial PVD, proliferative diabetic retinopathy (PDR), and
proliferative vitreo-retinopathy.
6. PDGFs: critical for pericyte viability
7. b-FGF: stimulate endothelial cell production as well as promote formation of capillary like tubes. proliferation
of astrocytes and hyalocytes in the hyaloid promoting tight and taut hyaloid that can exacerbate DME.

13. (C)
• The posterior cortical vitreous and the ILM have the strongest attachment at the
fovea and vitreous base, where the ILM is thinnest. The ILM is penetrated by
densely packe collagen filaments of the posterior vitreous cortex
1. PVD: The risk of developing diffuse macular edema may be 3.4-fold lower in the
group of eyes with complete PVD or complete vitreoretinal separation compared
to the eyes with incomplete PVD.
2. Posterior cortical vitreous: Sustained hyperglycemia can lead to liquefaction and
destabilization of the vitreous. Such destabilization of the central vitreous with
persistent attachment of the vitreous cortex to the retina can also induce
traction on the macula

14. 3. Thickened and Taut Posterior Hyaloid: The thickened hyaloid is due to the
infiltration of the membrane with glial and inflammatory cells. The development
or maintenance of macular edema occurs mechanically by causing tangential
traction on the macula and physiologically through the production of cytokines.
4. Macular Traction in Proliferative Diabetic Retinopathy: The FA will show an area of
diffuse leakage at the site of traction.
5. Role of ILM: The ILM lies in close apposition to th footplates of Muller cells where
the AGE receptors are located. AGEs are found abundantly in posterior cortical
vitreous and ILM. Vitrectomy and ILM peeling has been shown to improve visual
acuity and decrease macular thickening in patients

15. 6. Role of vitreous gel: Vitrectomy may increase oxygenation by
improved fluid currents after removal of the vitreous gel. The major
crosslink in vitreous collagen is over two-fold greater in diabetics
than controls. Removal of vitreous and associated AGEs may
improve ischemia, reduce VEGF production, and decrease
vasopermeability.

16. (D)
• Increased plasma viscosity, decreased erythrocyte deformability,
and increased erythrocyte and platelet aggregation.
• These rheologic changes may lead to reduced blood flow and
subsequent ischemia, which will lead to release of cytokines, such
as VEGF and affect the BRB.

18. Diagnosis:
1. Slit lamp bimicroscopy: Best
done with 78 or 90 D bio
microscopy
Macular oedema-
• Thickening of the macula
• Blurring of the underlying
choroidal pattern
• Loss of foveolar light reflex
when fovea is involved
• Cystoid spaces in severe cases

19. 2. FFA:
Ischemic maculopathy is
diagnosed when capillary
non-perfusion is seen on
the FA.

20. 3. OCT : Kang and coworkers described four patterns of OCT findings associated with
CSME (as defined by the ETDRS):
• foveal thickening with homogenous optical reflectivity throughout the entire
thickness of retina (type 1);
• foveal thickening with decreased optical reflectivity in the outer layers of the
retina (type 2);
• foveal thickening with subretinal fluid accumulation with or without retinal
traction (types 3A and 3B, respectively).

21. • 58% of patients with type 1 pattern OCT had focal
leakage on FA, and 92% of patients who had diffuse
cystoid leakage on the FA had either a type 2 or type
3A OCT pattern.

22. OCT is better than clinical examination in detecting
edema for retinal thickness between 150 and 325
mm; some studies report that clinicians cannot
reliably detect retinal edema unless the retinal
thickness is greater than 300 mm.

23. Treatment
A. MEDICAL TREATMENT
B. LASER PHOTOCOAGULATION FOR DME
C. VITREOUS SURGERY FOR DME
C. OTHER THERAPIES
 Subthreshold Micropulse Diode Laser Photocoagulation (SMDLP)
 Peribulbar Steroid Injection
 Intravitreal Steroid Injection
 Anti-VEGF Therapy

24. Medical therapy
• Metabolic control of diabetes ( blood sugar and HbA1c)
• Hypertension control
• Nephropathy
• Hyperlipidemia control
DCCT Intensive control reduced the risk of developing retinopathy by 76% and
has lowered progression of retinopathy by 54%; intensive control also
reduced the risk of clinical neuropathy by 60% and albuminuria by 54%.
UKPDS showed that control of hypertension was also beneficial in reducing
progression of retinopathy and loss of vision

25. Laser photocoagulation
 It creates an increase in tissue temperature of 10C, with
heat spreading to adjacent RPE cells, photoreceptors, and
choriocapillaries.
• Cell death and scarring (involving gliosis and RPE
hyperplasia) occurs subsequently.
• Oxygen that normally diffuses from the choriocapillaries
into the outer retina can now diffuse through the laser scar
to the inner retina, thus relieving inner retinal hypoxia.

26.  Reduction of the retinal capillary area in the zone of laser
photocoagulation and if the total area of the abnormal leaking
vessels was reduced, the amount of leakage would be reduced,
which would result in the resolution of the macular edema.
 The authors hypothesized that the improved retinal oxygenation
caused by the laser treatment leads to autoregulatory
vasoconstriction, which may improve DME

27. Focal burns to microaneurysms inferior to the center of the macula (spot size: 50--100
μ m, duration: 0.05--0.1 sec, preferred end point: whitening or darkening of
microaneurysm).
Grid pattern of burns above and temporal to the center of the macula (spot size: 50—
200 μ m, duration: 0.05--0.1 sec, preferred end point: mild RPE whitening.
Grid treatment is not placed within 500 μm of the center of the macula or within 500
μm form the disc margin. It can extend up to 2 disk diameters from the center of the
macula).

28. The Early Treatment Diabetic
Retinopathy Study (ETDRS) Results
• Direct treatment to leaking microaneurysms and grid treatment of
diffuse macular edema or nonperfused thickened retina have been
suggested for MILD AND MODERATE NPDR
• Combination scatter laser photocoagulation and focal laser
photocoagulation has been suggested for DME in selected cases of
severe NPDR and in eyes with PDR
• The ETDRS investigators suggested that the reduced rate of moderate
visual loss is due mostly to the effects of early focal photocoagulation,
which should be considered for all eyes with CSME.

29. • With time, RPE atrophy associated with the laser
scars occaisonally progresses under the fovea
causing decreased vision.
• Also, subretinal fibrosis can develop and cause visual
loss (Thus, grid treatment has limited efficacy for
diffuse DME)

30. Surgical treatment
• Vitrectomy to remove the posterior hyaloid and ILM
may be beneficial in two ways:
1) by removing AGE ligand-induced mechanical traction
between the posterior cortical vitreous and the ILM of
macula; and
2) removal of AGEs may also inhibit the activation of the
RAGE axis and its proinflammatory effects.

31. • Yang reported that PPV with posterior hyaloid removal could be beneficial
in eyes with DME with massive hard exudates that have responded poorly
to conventional laser photocoagulation.
369 Macular edema and hard exudates significantly decreased in 13 eyes
(100%). Visual acuity improved in 11 (85%) of 13 eyes.
• The Diabetic Retinopathy Clinical Research Network has conducted a
prospective one year study at 35 sites involving 87 subjects to evaluate the
anatomic and functional outcomes of vitrectomy in eyes with diabetic
macular edema in the presence of vitreomacular traction. Preliminary
results at 6 months follow-up demonstrated significant anatomic
improvement in mean central macular thickening; mean improvement in
visual acuity from baseline, however, was not significant

32. The Reported Complications Encountered With PPV For DME Include
 Cataract (10--7.5%),
 Choroidal Detachment (8%),
 Epiretinal Membrane (8--10.3%),
 Fibrinoid Syndrome (8%),
 Glaucoma (1.7--8%),
 Development Of Hard Exudates (3%),
 Macular Ischemia (10%),
 Neovascular Glaucoma (3.4--8%),
 Retinal Detachment (10%),
 Retinal Tear (10--20.7%),
 Tractional Rhegmatogenous Retinal Detachment (1.7%),
 Vitreous Hemorrhage (12.1--16%)

33. Subthreshold Micropulse Diode Laser
Photocoagulation (SMDLP)
• Produces multiple short exposure burns
centered at the apical portion of the RPE,
with minimal diffusion of heat into the
surrounding structures .
• The mechanism of action is based on the
delivery of laser pulses that are shorter in
duration than the thermal relaxation time
of the RPE cells (a pulse duration of 0.1
msec corresponds to a thermal diffusion
distance of 10 mm [diameter of RPE cell]
in ocular tissue).

34. Peribulbar steroids
• In a phase II study sponsored by the NEI, no
benefit in reducing the retinal thickness was
noted by adding peribulbar steroids to the
focal laser treatment for eyes with mild DME
and good visual acuity

35. Intravitreal Steroid Injection
• Intravitreal injection of triamcinolone acetonide is a method for DME unresponsive
to laser photocoagulation.
• The therapeutic effect of the steroid is typically seen within 1 week, but in many
patients re-injections are needed every three to six months as the effect
diminishes.
• The Diabetic Retinopathy Clinical Research Network reported the mean visual
acuity at 2 years after starting the treatment was better in the laser group
compared to the steroid-injected groups, although visual acuity seemed to
improve more rapidly in the 4-mg triamcinolone group than in the laser group. In
this study , 840 study eyes with CSME were randomized among 3 groups--
focal/grid laser, 1 mg intravitreal triamcinolone, and 4 mg triamcinolone groups.

36. Anti-VEGF Therapy
• VEGF inhibition has been achieved via PKC inhibitors
as well as high affinity binding of either aptamers
(e.g., protein kinase C inhibitor, pegaptanib) or
antibodies (e.g., ranimizumab, bevacizumab)
targeted against VEGF-A.

37. PKC inhibitors
• LY333531, a selective protein kinase C inhibitor, also
called ruboxistaurin (RBX), has been shown to
attenuate the increase in leukocyte entrapment in the
retinal microcirculation during the period of early
diabetes.
• RBX was evaluated in an 18-month randomized,
placebo-controlled, double-masked trial in patients
with DME. RBX was statistically significantly associated
with reduction of retinal vascular leakage in eyes when
marked permeability was present at baseline as
evaluated by vitreous fluorophotometry

38. VEGF aptamers
• VEGFinhibitor, Macugen (pegaptanib; OSI
Pharmaceuticals, LongIsland, NY), an aptamer
that binds the VEGF-165 isoform, has
demonstrated a beneficial effect of this
intravitreal drug on visual acuity and retinal
thickness in the treatment of DME

39. VEGF antibodies
• Ranibizumab and bevamizumab are
antibodies targeted against VEGF-A, are being
used off-label as intravitreal injections for the
treatment of DME.

40. Others
• ACE inhibitors to reduce the progression of
diabetic retinopathy (lisinopril)
• Aminoguanidine is a semi-carbazide derivative
that possesses advanced glycation inhibitory
activity and antioxidant activity

42. • Thank you