Diabetic Retinopathy
The word diabetes mellitus comes from Greek words “Diabetes” means “siphon”
and mellitus which means “honey tested urine”
The duration of diabetes is the most important determinant of retinopathy after
the onset of puberty
Characteristic pathological Changes-
1. Pericyte Loss:
Abnormal pericytic deposition of material due to sorbitol or advanced glycation
end products (AGEs) through the aldose reductase polyol pathway.
Pericyte have supportive & possibly regulatory effects on the capillary endothelial cells.BM constituents are secreted by the pericytes and in turn BM may affect the functional & proliferative capabilities of the pericytes Ultra structure of Capillaries: (from inner to outer) 2. BM Changes:
Retinal Capillary Endothelium is covered by a BM, which is approx.0.5µ
normally.In DR, there is an increase in thickness of these Layers.This thickening
may be as much as 5 folds, which results in impairment of diffusion & transfer of
nutrients & metabolites.
3. Microaneurysms:
Microaneurysm is a microvascular abnormalities which is charcteristic but not
pathognomic of DR.
Mechanism Of formation of Microaneurysms:Pericyte loss --local weakeningAlteration of the capillary BMUnrestricted proliferation of the vascular endothelial cellsMay blunted vasoproliferative response to local ischemiaNatural History of Micro aneurysms:Generally Microaneurysm gradually enlarges than regress due to thickening of the vessel wall followed by occlusion of the vascular lumen. They may bleed causing small retinal blot hemorrhages or leak lipoproteins, fibrinogen & other plasma proteins into the retina which accumulates in the outer & inner plexiform layers.
Causes:a. Haemorrheological Abnormalities:- Increased Fibrinogen Conc.
- Increased platelets adhesions- Increased RBC aggregation- Increased blood viscosity- Leucocyte-Capillary endotheila cell interactionb. Increased Capillary BM thickening which decreases the luminal diameter of the capillariesc. Endothelial swelling related to hyperglycemia & increased sorbitol production.
4. Capillary Occlusions:
When a focal area loses its perfusion,the overlying retina suffers acute ischaemic
changes,These occlusions ophthalmoscopically appears as cotton-wool spots(CWS),
caused by accumulation of axoplasmic debris in the nervefibre layer of ischaemic
retina.Microvascular dilatation is often found near areas of capillary obliteration & is
called intraretinal microvascular abnormalities.(IRMA)
5. Neovascularisation:
Vasoproliferative factors, released by the retina itself, retinal vessels, and/or the RPE,
which are thought to induce neovascularisation.Vascular endothelial growth factor,
VEGF which inhibits the growth of retinal endothelial cells are implicated to induce
Clinical Feature:
Non proliferative Diabetic Retinopathy/Background Diabetic Retinopathy:
1. Microaneurysm:
- first ophthalmoscopically detectable signs of DR.
- appears as small red dots with smooth borders & sharp edge in middle retinal layers,
when they are fresh: later on maturation (process of occlusion & hyalinisation) they
become yellowish
- on FFA they are filled up in the early phase & remain hyperfluorescent without any
change in size. but haemorrhages appear as black spots due to blocked fluorescence.
2. Intraretinal Haemorrhages:
When the wall of a capillary or microaneurysm is weakened enough, it may rupture,
giving rise to an intraretinal hemorrhage. If the hemorrhage is deep, i.e. in the inner
nuclear layer or outer plexiform layer, it is usually round or oval ('dot or blot').If the
hemorrhage is superficial, in the nerve fiber layer, it takes on a flame or splinter shape
indistinguishable from a hemorrhage seen in hypertensive retinopathy
of Retinal Layer
particular shape
extracellular space leads the blood to follow the configuration of the axons Deep Haemorrhage
12 to 100µm ; those greater than 30µm is visible ophthalmoscopically. They
are not to be larger than 125µm
Haemorrhages: red spots larger than 125µm (Early treatment DR Study)
3 .Hard Exudates:
HEs are seen as a yellowish , well circumscribed accumulation, deep to the retinal vessels
in the outer plexiform nerve fibre layer.
HE are formed by the deposition of lipid & lipoproteins and are sign of abnormal
vascular permeability
Although HE can be found anyhwere in the retina, they have a particular predilection to
congregate in the macula.Pt mayhave moderate to severe loss of visual loss if the fovea
is involved.
HE may resolve , particularly after laser photocoagulation, but scar tissue may form if the
exudates were very thick.
HE occurs in two types of retinal distribution:-
Circinate pattern: a complete or partial circle separated from the leaking
vessels by a clear zone.
Macular star: lipid accumulate in the fine layer of Henle surrounding the
4. Macular Edema:
ME is a result of abnormal permeablity of the retinal vascular endothelial cells of
capillaries, microaneurysm & IRMA.
The extravasated lipoproteins accumulate in the extracellular space, causing retinal
Diagnosis of ME is made on the clinical finding of retinal thickening on slitlamp
examination biomicroscopy using either a handheld or contact lens and not by FFA.
ME is described in two distinct forms:IschemicNon Ischemic Focal ME = result of leakage from discrete microaneurysms or clusters of aneurysmsDifuse ME= result of leakage from segments of diseased capillary, microaneurysms or arterioles located within a generally dilated capillary bed 5. Cotton - Wool Spots / Soft Exudates / Cytoid Bodies / Nerve Infarcts:
Lie in the nerve fibre layers of retina
Represents ophthalmoscopic appearance of a microinfarct, their presence implies ischaemic microvascular disease.
Appear initially as white fluffy patches, most commonly in the posterior pole (retinal nerve fibre layer is the thickest), become smaller & more circumscribed with time, absorbing completely after 6-8 weeks (more in DR) All neurons in our body transport intracellular organelles bidirectionally
between nucleus and the synapse, a process known as axoplasmic transport.
CWS results from the accumulation of organelles as a result of interrupted
axoplasmic transport. These interruption may be of two types:
Orthograde Transport: Transport between retinal ganglion cells & its
synapse in the LGB
Retrograde Transport: Transport between retinal ganglion cell synapse
synapse in the LGB& retinal ganglion cells
Orthograde Transport is more common. Electron microscopy shows that the
axonal stumps at the edges of a microinfarcts are packed with mitochondria
which produce the white appearance.

6. Venous loops, venous beading:
Indicative of extensive ischaemia of the retina and manifests as saccular bulges in the
wall of the vein. Frequently adjacent to areas of nonperfusion.
 Reflects increasing retinal ischemia  Most significant predictor of progression to PDR 7.Intraretinal microvascular abnormalities (IRMA)
Remodeled capillary beds without proliferative changes
Collateral vessels that do not leak on fluorescein angiography
Usually can be found on the borders of the nonperfused retina
Very mild NPDR:
only a few microaneurysm.
Mild NPDR: a few microaneurysn + Retinal Haemorrhages + Hard exudates in 1-3
Moderate NPDR: above finding in 2-3 quadrants
Severe NPDR: above finding in all 4 quadrants + any of the below:

Venous Beading in more than 2 quadrants Very severe NPDR: atleast 2-3 signs of severe NPDR
Proliferative Diabetic Retinopathy:
Roughly 50% of patients with very severe nonproliferative diabetic retropathy progress to
PDR within 1 year.
Characterised by-
Neovascularisation -New vessels from retina & OD and proliferate along the retinal
surface or into the vitreous with or without a fibrous component.
Proliferative vessels usually arise from retinal veins and often begin as a collection of
fine naked vessels. When they arise at or within 1 disc diameter of the optic disc they are
referred to as neovascularization of the disc(NVD) .
When they arise further than one disc diameter away, they are called neovascularization
elsewhere (NVE) .
The main contributory factor for neovascularisation appears to be retinal hypoxia which
is clinically manifested by capillary closure & loss of the retinal capillary bed.
The most important factor in retinal neovascularisation is Vascular Endothelial Growth
Factor (VEGF) which targets mainly vascular endothelial cells but can also act on RPE
Vessels of Neovascularisation:
All new vessels appearing in eye lack barrier properties and leak fluroscein
rapidly & intensively during FFA.
New vessels are sight threatening because they are fragile and tend to bleed to
obscure the media
They are associated with fibrosis & membrane formation which lead to traction
retinal detachment
Deposition of HE does not occur with NVD or NVE,but it is a common feature
of choroidal neovascularisation
Course of Neovascularisation:
Once the stimulus for growth of new vessels is present, the path of subsequent growth
taken by neovascularization is along the route of least resistance. For example, the
absence of a true internal limiting membrane on the disc could explain the prevalence of
new vessels at that location. Also, neovascularization seems to grow more easily on a
preformed connective tissue framework. Thus, a shallowly detached posterior vitreous
face is a frequent site of growth of new vessels.
The new vessels, initially naked, undergoes through a stage of further proliferation with
connective tissue formation. As PDR progresses, the fibrous component becomes more
prominent, with the fibrotic tissue being either vascular or avascular.
• The fibrovascular variety usually is found in association with vessels that extend into the vitreous cavity or with abnormal new vessels on the surface of the retina or disc. • The avascular variety usually results from organization or thickening of the posterior hyaloid face. Vitreous traction is transmitted to the retina along these proliferations and may lead to traction retinal detachment.
Severity of new vessels increases on a four step scale:
 None NVENVDNeovascularisation of the AC angle with neovascular glaucoma (NVG)  Begin as fine loops or networks of vessels lying on the surface of the disc or  Seen as fine network of vessels appearing like cartwheels or lace, usually arising from the retinal veins,venuals or capillaries and bridging between the arterial and venous circulations.
 NVE usually originates from perfused retina just posterior to an area of capillary nonperfusion.They usually arise from large vein but rarely from smaller venules & capillaries too.
 94% of NVE is located within 6 disc diameters of the optic nerve head NVE nearly always grows toward and into zones of retinal ischemia until posterior vitreous detachment occurs. Then, the vessels are lifted into the vitreous cavity.Actually neovascular vessels do not 'grow' forward into the vitreous cavity; they are pulled into it by the contracting vitreous to which they are adherent.
Finally, the end stage is characterized by regression of the vascular systems. No further damage may take place, but there may be contraction of the connective tissue components, development of subhyatoid bands, thickening of the posterior vitreous face, and the appearance of retinoschisis, retinal detachment, and formation of retinal breaks.
Sudden vitreous contractions tear the fragile new vessels, causing vitreous hemorrhage. However, the majority of diabetic vitreous hemorrhages occur during sleep, possibly because of an increase in blood pressure secondary to early morning hypoglycemia or to rapid eye movement sleep. Since so few hemorrhages occur during exercise, it is not necessary to restrict the activity of patients who have proliferative retinopathy. When a hemorrhage occurs, if the erythrocytes are all behind the posterior vitreous face, they usually quickly settle to the bottom of the eye and are absorbed. However, when erythrocytes break into the vitreous body, they adhere to the gel and clearing may take months or years.
Other Ocular Complications of DM:
Corneal sensitivity is decreased in proportion to both the duration of the disease and the
severity of the retinopathy
Diabetics are more likely to have corneal abrasions than are those without the disease,
because adhesion between the basement membrane of the corneal epithelium and the
corneal stroma is not as firm as that found in normal corneas. Hyperglycemia and the
aldose reductase pathway probably play a ajor role in epithelial abnormalities, because
aldose reductase inhibitors accelerate healing of corneal abrasions.
Neovascularization of the iris usually is seen only in diabetics who have proliferative
diabetic retinopathy (PDR). Panretinal photocoagulation (PRP) not only has protective
value against NVI, it also is an effective treatment against established NVI.
The risk of cataract is 2-4 times greater in diabetics than in nondiabetics and may be 15-
25 times greater in diabetics under 40 years old.
Complications of Cataract surgery:
1. The most dreaded anterior complication is neovascularization of the iris. It was hoped
that modern surgery, which leaves an intact posterior capsule, would protect the eye from
neovascularization of the iris by reducing the diffusion of vasoproliferative factors into
the anterior chamber, but several studies indicate that it does not. Furthermore, a yttrium-
aluminum-garnet (Nd:YAG) laser capsulotomy does not increase the risk.
2. Pupillary block,
3. Posterior synechiae,
4. Pigmented precipitates on the implant, and
5. Severe iritis.
1. Chronic cystoid macular edema is about 14 times more common in diabetics than in
2. Proliferative retinopathy,
3. Vitreous hemorrhage, and
4. Traction retinal detachment.
Optic Neuropathy
Many diabetic patients without retinopathyhave subclinical optic neuropathy. In addition,
they often have anterior ischemic optic neuropathy identical to that seen in nondiabetics.
Finally, diabetics are susceptible to diabetic papillopathy which is characterized by acute
disc edema without the pale swelling of anterior ischemic optic neuropathy. It is bilateral
in one half of cases and may not show an afferent pupillary defect.
Cranial Neuropathy:
Extraocular muscle palsies may occur in diabetics secondary to neuropathy involving the
third, fourth, or sixth cranial nerves.
mechanism:localized demyelinization of the nerve secondary to focal ischemia.
Pain may or may not be experienced, and not infrequently an extraocular muscle palsy
may be the initial clue to a latent diabetic condition. Recovery of extraocular muscle
function in diabetic cranial nerve neuropathy generally takes place in 1-3 months.
When the third nerve is involved, pupillary function is usually normal. Pupillary sparing in diabetic third nerve palsy is an important diagnostic feature, distinguishing it from other causes of oculomotor involvement such as intracranial tumor or aneurysm.
Risk Factors in DR:
Retinopathy Risk Factors (DRS)
PRESENCE of new vessels
LOCATION of new vessels on or within one disc diameter of the optic disc (NVD)
SEVERITY of new vessels
For NVD, greater than or equal to 1/ to 1/ disc area in extent If both NVD & NVE count severity of NVD HAEMORRHAGE: vitreous or pre retinal
4 quadrants of severe microaneurysms &/or intraretinal haemorrhages
2 quadrants of venous beading
1 quadrant of atleast moderately severly IRMA
Clinically Significant Diabetic Macular Edema,ETDRS Thickening of retina at or within 500 µm of the centre of the macula Hard Exudates at or within 500µm of the centre of the macula if associated with thickening of the adjacent retina and not residual HE remaining after the disappearance of retinal thickening A zone/ zones of retinal thickening of 1 disc area or more, any part of which is within 1 disc diameter of the centre of macula.
First Examination:
Patients with Juvenile onset diabetes: 5 years after diagnosis (Retinopathy rarely
found in these group)
Patients with Adult onset diabetes: at the time of diagnosis
Follow up:
Patients with minimal to no DR: annually
Patients with mild to moderate DR without macular edema : 6-12 months
Patients with severe nonproliferative DR: 3-4 months
Patients with early proliferative disease & treatment is deferred: 2-3 months
Although aspirin inhibits platelet secretion and aggregation, it does not influence the
progression of retinopathy, affect visual acuity, or influence the incidence of vitreous
hemorrhages, for either better or worse.
Ticlopidine (ticlid)
Ticlopidine inhibits adenosine diphosphate-induced platelet aggregation; as with aspirin,
the effect is permanent for the life of a labeled platelet. It has also been shown to decrease
the risk of stroke in patients who have transient ischemic attack
Antihypertensive Agents:
The patients with better BP control had a 37% risk reduction in microvascular changes.
Lisinopril, an ACEI has been shown to decrease the progression of NPDR & PDR in
normotensive diabetics as well.
Antiangiogenesis Agents:
Inhibition of protein kinase C , an enzyme critical in casecade that activates VEGF
expression is thought to play a major role in the progression of DR
An oral inhibitor of protein kinase C has been shown to suppress the retinal
Pentoxifylline (oxpentifylline)
Pentoxifylline increases retinal capillary blood flow velocity, probably by improving
erythrocyte and leukocyte flexibility; it also decreases blood viscosity. To date, however,
a clinical benefit has not been shown.
DRS proved that both xenon arc and argon laser PRP significantly decrease the likelihood that an eye with high risk characteristics (HRC) progresses to severe visual loss. Eyes with high risk characteristics are defined as those with  Neovascularization of the disc greater than half the disc area, Any neovascularization of the disc and vitreous hemorrhage, or Neovascularization elsewhere greater than half the disc area and vitreous or Mechanism: exact mechanism remains unknown
PRP decreases the production of vasoproliferative factors by eliminating some of the
hypoxic retina or by stimulating the release of antiangiogenic factors from the retinal
pigment epithelium.
Chronic hypoxia stimulates neovascularization by causing vessel dilatation which
results in endothelial cell proliferation.
By thinning the retina, PRP increases oxygenation of the remaining retina as it enables
an increased diffusion of oxygen from the choroid and so decreases vasodilatation.
Finally, others suggest that PRP leads to an increase in vasoinhibitors by stimulating the
retinal pigment epithelium to produce inhibitors of vasoproliferation.
Laser used: Argon green or Krypton red or appropiate corresponding wavelengths with the dye laser / diode laser delivery systemGreen wavelengths are generally better tolerated, since longer red wavelenghts are absorbred deeper in the retina & can potentially cause more painRed wavelengths are generally reserved for eye with media opacities -- dense cataract or vitreous haemorrhages Recommended Therapy:Goal of PRP : is to arrest or to cause regression of the neovascularization.
No. of burns: 1500-2,000 burnsSpot Size (Diameter):500µm in diameter delivered through the Goldmann lens or the same number of 200µm burns delivered through the Rodenstock panfunduscope.
Power:200-600mWDuration: 0.1s ( to achieve burns intense enough to whiten the overlying retina)If krypton red is used the duration should be incresed to 0.2 seconds duration to avoid inadvherent Bruch’s Membrane with the short concentrated shots of energy.
Positioning: Laser spots are placed about one burn width apart and upto 1 DD from the OD scattered outside the post. pole.
NVD is never treated with PRP Duration of therapy: PRP is given in divided session at 10day - 3 wk interval .Traetment at any sitting of more than 1000 burns www.eophtha.com

Source: http://www.eophtha.com/eophtha/pdf%20files/pdfGallery/Diabetic%20Retinopathy.pdf


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