diabetic retinopathy pathophysiology

PATHOPHYSIOLOGY OF DIABETIC RETINOPATHY

Diabetic retinopathy

• Prevalence increases with– duration of diabetes – Poor control of diabetis– Pregnancy– Hypertension– nephropathy

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.

• 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.

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.

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.

• 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.

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

STAGES OF DR

• Non-proliferative DR– Mild– Moderate– Severe

• Proliferative DR– Mild - moderate– High risk

• Macula edema– Early macula edema– CSME

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.

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.

MODERATE NPDR

• Microaneurysms• Retinal hemorrhages DH /BH• Hard exudates • Cotton wool spot• Venous beading• IRMA

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

RETINAL HEMORRHAGE

RETINAL HEMORRHAGE

SPLINTER HEMORRHAGE

DOT /BLOT HEMORRHAGE

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.

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.

COTTON WOOL SPOT

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.

IRMA

• Remodelled capillary bed without any proliferative changes

• Collateral vessels seen on FFA, no leakage• Usually found in borders of non-perfused retina

• IRMA are frequently difficult to differentiate from surface retinal neovascularization.

• Fluorescein, however, does not leak from IRMA but leaks profusely from neovascularization.

VENOUS BEADING IRMA

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.

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

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

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

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

• 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

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

• 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

• 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

• 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

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.

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.

CSME

Diabetic maculopathy

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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