Pathophysiology of diabetic retinopathy

1. PATHOPHYSIOLOGY OF
DIABETIC RETINOPATHY

2. Diabetic retinopathy
• Prevalence increases with
– duration of diabetes
– Poor control of diabetis
– Pregnancy
– Hypertension
– nephropathy

3. PATHOGENESIS
• Aldose reductase
• Enzyme that converts sugar to alcohol (ie: glucose to
sorbitol)
• Sarbitol cannot diffuse out of the cell easily – increase
intracellular concentration.
• Osmotic forces draw water into the cell causing
electrolyte imbalance.
• The resultant damage to lens epithelial cells, which have
a high concentration of aldose reductase, is responsible
for the cataracts seen in children with galactosemia and
in animals with experimental diabetes mellitus.

4. • Because aldose reductase is also found in high
concentration in retinal pericytes and Schwann
cells, some investigators suggest that diabetic
retinopathy and neuropathy may be caused by
aldose reductase-mediated damage.

5. VASOPROLIFERATIVE FACTORS
• Hypoxic retina produces a “vasoproliferative factor” that
diffuses to nearby blood vessels inducing
neovascularization.
• Vascular endothelial growth factor (VEGF) has been
implicated in diabetic retinopathy.
• VEGF is found in the vitreous of patients with diabetic
retinopathy and decreases after PRP.
• Experimental intravitreal injections of VEGF produce
retinal ischemia and microangiopathy in primates.
• The use of anti-VEGF compounds in patients with
diabetic retinopathy.

6. PLATELET AND BLOOD VISCOSITY
• Platelet abnormalities in diabetics may contribute to
retinopathy.
• It has been shown that the platelets in diabetic patients
are “stickier” than platelets of patients without diabetes.
• Once some platelets adhere to the basement membrane
or to damaged cell walls, they secrete prostaglandins
which cause other platelets to adhere to them
(aggregation).
• Arachidonic acid -> prostaglandin (thromboxane A2)
• Thromboxe A2 – potent vasoconstrictor and platelet
aggregating agent.

7. • It has been postulated that abnormal platelet adhesion
and aggregation causes focal capillary occlusion and
focal areas of ischemia in the retina, which in turn
contribute to the development of diabetic retinopathy.

8. PATHOGENESIS OF DR
• Progressive dysfunction of the retinal
vasculature secondary to chronic
hyperglycemia
• Leads to vascular leakage, focal ischemia,
retinal hypoxia and neovascularisation
• Thickening of BM and loss of pericytes,
impairing oxygen and nutrient flow
• Final metabolic pathway unknown

9. STAGES OF DR
• Non-proliferative DR
– Mild
– Moderate
– Severe
• Proliferative DR
– Mild - moderate
– High risk
• Macula edema
– Early macula edema
– CSME

10. MILD NPDR
– Microaneurysm are the first ophthalmoscopically
detectable change in diabetic retinopathy.
– Histologically, thickening of the capillary basement
membrane and pericytes dropout.
– Pericytes are mesothelial cells that surround and
support the retinal capillary endothelial cells. Normally
there is one pericyte per endothelial cell.
– the pericytes dies off and are decreased in number.
– Their absence weakens the capillaries and permits thin-
walled dilatations, called microaneurysms, to develop.

11. MICROANEURYSM
– Focal dilatation of the retinal capillaries due to loss of
pericytes
– 10-100 μm in size.
– Appear as a red dot on the superficial retinal layer.
– Fibrin and RBC can accumulate within aneurysms.
– Despite the multiple layers of basement membrane,
microaneurysms are permeable to water and large
molecules, allowing the transudation of fluid and lipid
into the retina.

13. MODERATE NPDR
• Microaneurysms
• Retinal hemorrhages DH /BH
• Hard exudates
• Cotton wool spot
• Venous beading
• IRMA

14. RETINAL HEMORRHAGE
• When the wall of a capillary or microaneurysm is thin, it
may rupture, giving rise to an intraretinal hemorrhage.
• If the hemorrhage is deep
( ie; in the inner nuclear layer or the outer plexiform layer )
• Dot or blot hemorrhage
• Superficial hemorrhage (ie; nerve fiber layer)
• Flame or splinter- shape

15. RETINAL HEMORRHAGE

16. RETINAL HEMORRHAGE
SPLINTER
HEMORRHAGE
DOT /BLOT
HEMORRHAGE

17. Hard exudates
• Yellow deposit of lipid
and protein within the
sensory retinal layer.
• Due to leaking from the
microaneurysm.
• Outer plexiform and inner
nuclear layer.
• Accumulation may cause
a circinate pattern
– it accumulates in a ring
around a group of leaking
microaneurysms.

18. COTTON WOOL SPOT
• Nerve fiber layer infarcts.
• Also known as soft exudates.
• Result from occlusion of the pre-capillary arterioles that
supply the nerve fiber layers.
• Local ischemia causes effective obstruction of
axoplasmic flow in the nerve fiber layer.
• Subsequent swelling of the nerve fibers gives a
characteristic white fluffy appearance to the cotton wool
spot.
• Flourescein angiography shows no capillary perfusion in
the area corresponding to the cotton wool spot.

19. COTTON WOOL SPOT

20. VENOUS BEADING
• Saccular bulges of the wall of retinal veins .
• Indicates sluggish retinal circulation and are nearly
always adjacent to extensive areas of capillary
nonperfusion.
• May represent an area of endothelial proliferation that
fail to develop into new vessels.
• Capillaries next to areas of nonperfusion that dilate and
function as collaterals are referred to as IRMA.

21. IRMA
• Remodelled capillary bed without any
proliferative changes
• Collateral vessels seen on FFA, no leakage
• Usually found in borders of non-perfused retina

22. • IRMA are frequently difficult to differentiate from
surface retinal neovascularization.
• Fluorescein, however, does not leak from IRMA
but leaks profusely from neovascularization.

23. VENOUS BEADING IRMA

24. SEVERE NPDR
• All of the above plus 4:2:1 rule from
ETDRS
– DH / BH in all 4 quadrants.
– Venous beading in 2 quadrants or more.
– IRMA in 1 quadrant or more.

25. PDR
• Mild / moderate PDR
– mild NVD / NVE
• High risk PDR
– NVD about 1/3 Disc
area
– Any NVD plus VH
– NVE > ½ DD with VH

26. What happens in PDR
• New blood vessels arise from the
endothelial cells of post-capillary venules
• Evolve in 3 stages
– Fine NV formation with minimal fibrous tissue
extend beyond ILM
– NV increase in size and fibrous component
– NV regress, leaving fibrovascular proliferation
along post hyaloid

27. • In new vessel formation, the endothelial
cells have to
– become activated
– be released from its surroundings
– migrate
– proliferate

28. Endothelial cell activation
• Ischaemic retina release local growth factors
that activate endothelial cells in healthy
capillaries at the edge of the ischaemic area
• VEGF is released by the retinal pigment
epithelial cells in response to hypoxia
• Also produced by RPE in response to
hyperglycaemia through activation of the protein
kinase C pathway
• Other sources include the platelets and white
blood cells that occlude the capillaries

29. • Breakdown of BM causes migration of
endothelial cells
• Laminin, a major component of the
basement membrane, causes angiogenesis
when degraded
• Breakdown of collagen, found in BM, also
has to occur for angiogenesis

30. Migration and proliferation
• Endothelial cells then migrate from the post-capillary
venules into the surrounding tissue
• As they migrate, more cells and tubes are formed
• Pairs of tubes join together thus forming loops
• The top of the loop then forms further tubes that go
through the same process producing further loops
• Controlled by urokinase-type plasminogen activator
(UPA) and TGF beta
• In response to VEGF
– UPA stimulates cells to migrate
– TGF beta matures the proliferated cells into capillary tubes

31. • New vessels grow from
the walls of post-capillary
venules
• Always form loops, and
loop back to the
originating vessel
• The diameter is often
bigger than the vessel
they originated from
• Grow between the inner
surface of the retina and
the vitreous

32. • May grow into the
posterior hyaloid face
• Results in an
inflammatory response
and scar formation
• Contraction results in
– NV being pulled forward
and appearing to stand up
– NV tearing , leading to
hemorrhage
– combination of both

33. • New vessels always grow on a platform of glial cells
• If the new vessel component predominates then vitreous
haemorrhage occurs
• Sometimes the glial cells predominate.
• Glial cells associated with new vessels growing along the
major vascular arcades are particularly at risk
• The reaction between the glial cells and the vitreous
results in scar formation
• These scars contract, causing retinal folds and
eventually TRD

34. MACULAR EDEMA
• Intercellular fluid from leaking
microaneurysms or diffuse capillary
incompetence
• The fluid initially located between the outer
plexiform layer and inner nuclear layer.
• Later, it may also involve the inner plexiform
and nerve fiber layers,until the entire full
thickness of the retina becomes edematous.

35. CLINICALLY SIGNIFICANT MACULAR EDEMA
• Retinal thickening within 500micrometer of the centre of
the macula.
• Exudate within 500 micrometer of the centre of macula.
• Retinal thickening one disc area (1500 micrometer) or
larger,any part of which is within one disc diameter of the
centre of the macula.

36. CSME

37. Diabetic maculopathy

38. Advanced Diabetic Eye Disease
• Serious vision- threatening complication of DR that occur
in patients in whom treatment has been inadequate or
unsuccessful.
• Clinical feature :
• Hemorrhages – may be preretinal (retrohyaloid),intragel
or both.
• Tractional retinal detachment – cause by progressive
contraction of fibrovascular membranes over areas of
vitroretinal attachment.
• Rubeosis iridis – iris neovascularization (NVI)
• May lead to glaucoma
• NVI particularly common in eyes with severe retinal
ischemia.

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