Diabetic Retinopathy

• Retinopathy is the most important ocular complication of diabetes.

• Diabetic Retinopathy is more common in type 1 DM than type 2 DM.

• Proliferative Diabetic Retinopathy (PDR) affects 5-10% of diabetic

population.

• Type 1 Diabetes are at particular risks, with an incidence of upto 90%

after 30 years.
Etiology
• Type 1 diabetes mellitus (T1DM) is characterized by the destruction of beta cells in
the pancreas by an autoimmune mechanism, whereas type 2 diabetes mellitus
(T2DM) is a relationship between lifestyle and genetics.

• There is a stronger genetic association between T2DM compared to T1DM.

Multiple genetic factors have been named in the development of T2DM including
TCF7L2 , NOTCH2, KCNQ1, JAZF1, and MODY

• Over 90% of people with a new diagnosis of T1DM have measurable antibodies
against specific pancreatic β-cell proteins (insulin, islet antigen 2, zinc transporter
8, etc.)
Risk factors
1. Duration of diabetes

• Most important

• Patient diagnosed before age 30 years

 50% DR after 10 years

 90% DR after 30 years

• Poor metabolic control, Increased HbA1c associated with increased risk.

2. Pregnancy

• Associated with rapid progression of DR

• Predicating factors : poor pre-pregnancy control of DM, too rapid control during
the early stages of pregnancy, preeclampsia and fluid imbalance.

3. Hypertension

• Very common in patients with DM type 2

• Should strictly control (<140/80 mmHg)

4. Nephropathy

• Associated with worsening of DR

• Renal transplantation may be associated with improvement of DR and better

response to photocoagulation

5. Obesity, increased BMI, high waist-to-hip ratio

6. Hyperlipidemia

7. Anemia
Pathophysiology
Pathological pathways
Pathogenesis

Microangiopathy occurs and it

leads to:

• Microvascular occlusion

• Microvascular leakage
 Characterised by
• Loss of pericytes

• Thickening of capillary basement membrane

(sorbitol pathway)

• Loss of vascular smooth muscle cells (capillary

acellularity)

• Endothelial proliferation

• Abnormalities of RBCs (leading to defective oxygen

transport) and WBCs

• Increased platelet stickiness and adhesion

Breakdown of blood retinal barrier
Retinal barrier is composed of 2 parts-

• Inner BRB - tight junctions of retinal capillaries,

endothelial cells

• Outer BRB - tight junctional complexes (zonula

occludes and zonula adherens) located between
adjacent RE cells

• Breakdown of this BRB leads to leakage of

lipoproteins responsible for formation of exudates.
Symptoms
• Blurred vision

• Floaters and flashes

• Distorted vision

• Dark areas in the vision

• Poor night vision

• Impaired color vision

• Partial or total loss of vision

Signs of diabetic retinopathy
• Microaneurysm

• Retinal hemorrhage

• Hard exudates

• Cotton wool spot

• Venous beading

• Intraretinal microvascular abnormalities(IRMA)

• Retinal blood vessels

• Macular oedema
Microaneurysm
• Localized saccular outpouchings of capillary wall ->
red dots

• Focal dilatation of capillary wall where pericytes are

absent

• Fusion of 2 arms of capillary loop

• Usually seen in relation to areas of capillary non-

perfusion at the posterior pole in temporal to fovea

• It is the earliest sign of DR

Early frames show tiny hyperfluorescent dots, typically more numerous than
visible clinically. Late frames show diffuse hyperfluorescence due to leakage.

scattered hyperfluorescent microaneurysms leak constituents

into retina
 Retinal hemorrhage
• Capillary or microaneurysm is weakened, hemorrhages rupture

• Deep hemorrhage - inner nuclear layer or outer plexiform layer, represent hemorrhagic infarcts, Usually round or oval

• Dot hemorrhages - bright red dots (same size as large microaneurysms)

• Blot hemorrhages - larger lesions

• Flame-shape or splinter hemorrhages - More superficial - in nerve fiber layer, Absorbed slowly after several weeks

• Retinal hemorrhage spreads along the line of least resistance. Therefore a superficial bleed will track parallel to the
nerve fiber layer resulting in a longitudinal spread becoming flame shaped.

• Deeper in the retina,since the layers are vertically oriented it results in circumscribed, round hemorrhages (dot and
blot).
 Hard exudate
• Exudates are caused by chronic localized
retinal oedema.

• composed of lipoprotein and lipid-filled

macrophages located mainly within the outer
plexiform layer

• May form a circinate pattern

• Hyperlipidemia may correlate with the

development of hard exudates
• When leakage ceases, exudates absorb
spontaneously over a period of months,
either into healthy surrounding capillaries or
by phagocytosis.

• Chronic leakage leads to enlargement and

the deposition of crystalline cholesterol

• FA will commonly show hypofluorescence

only with large dense exudates.
 Cotton wool spot
• Small fluffy whitish superficial lesions that obscure underlying
blood vessels

• Result from occlusion of retinal pre-capillary arterioles supplying

the nerve fiber layer with concomitant swelling of local nerve
fiber axons

• Composed of accumulations of neuronal debris within the nerve

fibre layer.

• Also called “soft exudates” or “nerve fiber layer infarctions”

• Fluorescein angiography shows no capillary perfusion in the area

of the soft exudate, focal hypofluorescence due to local
ischaemia and blockage of background choroidal fluorescence.
Venous anamolies
• Venous anomalies seen in ischaemia
consist of generalized dilatation and
tortuosity, looping, beading (focal
narrowing and dilatation) and sausage-
like segmentation
Intraretinal microvascular
abnormalities (IRMA)
• Intraretinal microvascular abnormalities (IRMA)
are arteriolar – venular shunts that run from
retinal arterioles to venules

• often seen adjacent to areas of marked capillary

hypoperfusion

• FA shows focal hyperfluorescence associated

with adjacent areas of capillary closure
(‘dropout’) but without leakage.
 IRMA New vessels
• Location: intraretinal (not at disc) • Location: grow on top of the
• Appearance: Outline may be retina (often at disc)
angulated with sharp corners. Do
• Appearance: Outline may be fan-
not cross over major retinal blood
like with dilated tips. Can cross
vessel
over major retinal blood vessel
• Fluorescein angiography: Don’t
• Fluorescein angiography: Leak
leak
• OCT: Breach the ILM
• OCT: Don’t breach the ILM
Diabetic macular edema
• extensive capillary leakage and localized oedema by focal leakage from
microaneurysms and dilated capillary segments.

• The fluid is initially located between the outer plexiform and inner nuclear layers.

• Later it may also involve the inner plexiform and nerve fibre layers, until
eventually the entire thickness of the retina becomes oedematous

• With central accumulation of fluid, the fovea assumes a cystoid appearance –

cystoid macular oedema (CMO)
1. Focal maculopathy:

• well-circumscribed retinal thickening associated

with complete or incomplete rings of exudates

• FA shows late,focal hyperfluorescence due to

leakage, usually with good macular perfusion.

2. Diffuse maculopathy:

• diffuse retinal thickening, which may be associated

with cystoid changes.

• There are typically also scattered microaneurysms

and small haemorrhages
3. Ischaemic maculopathy

• Signs are variable and the macula may look relatively

normal despite reduced visual acuity.

• In other cases, PPDR may be present.

• FA shows capillary non-perfusion at the fovea (an enlarged

FAZ) and frequently other areas of capillary non-perfusion
at the posterior pole and periphery.
Clinically Significant Macular
Edema(CSME)
Classification
Non proliferative diabetic retinopathy
• Mild: few microaneurysms

• Moderate: increased number of microaneurysms and dot-blot hemorrhages. Cotton

wool spots and hard exudates may be present.

• Severe: "4-2-1 rule" -- 4 quadrants of diffuse retinal hemorrhages and

microaneurysms, 2 or more quadrants of venous beading, or 1 or more quadrant of
IRMA

• very severe: >= 2 of the criteria for severe

Proliferative Diabetic Retinopathy Advanced Diabetic eye disease:
• Preretinal and/ intragel hemorrhage
1. mild - moderate
• Tractional retinal detachment
• Any NVD <1/3 of disc area
• Tractional retinoschisis
• Any NVE <1/2 of disc area
• Rubeosis iridis
2. High Risk
• NVD > 1/4 to 1/3 disc area

• Any NVD associated with vitreous or

preretinal hemorrhage
• Any NVE >1/2 of disc area associated with
vitreous or preretinal hemorrhage
Nonproliferative diabetic retinopathy
Very Mild:

• Indicated by the presence of atleast 1

micro aneurysm.

Mild:

• Microaneurysms, retinal
haemorrhage, exudates, cotton wool
spots.
Moderate:

• Includes the presence of hemorrhages (1-

3 quadrants), micro -aneurysms, hard
exudates and Cotton wool spot.
Severe:

The (4-2-1) rule; one or more of:

• Hemorrhages and microaneurysms in 4

quadrants.

• Venous beading in at least 2 quadrants.

• Intraretinal microvascular abnormalities

in at least 1 quadrant
 Proliferative diabetic retinopathy
• over one-quarter of the retina must be non-perfused before PDR develops.

• most commonly seen at the posterior pole.

• Fibrous tissue, initially fine, gradually develops as vessels increase in size.

 New vessels at the disc (NVD): neovascularization on or within one disc diameter of the optic nerve
head
 NVE: neovascularization further away from the disc. It may be associated with fibrosis if long-standing.

 New vessels on the iris (NVI), also known as rubeosis iridis, may progress to neovascular glaucoma.

 FA highlights neovascularization during the early phases of the angiogram and shows irregular
expanding hyperfluorescence during the later stages due to intense leakage
 Advanced Eye disease
• serious vision-threatening complication of DR that occurs in patients in whom treatment has been
inadequate or unsuccessful.

• Clinical features:

 Haemorrhage may be preretinal (retrohyaloid), intragel or both.

 Intragel haemorrhages usually take longer to clear than preretinal because the former is usually more
substantial.

 In some eyes, altered blood becomes compacted on the posterior vitreous face to form an ‘ochre
membrane’.

• Ultrasonography is used in eyes with dense vitreous haemorrhage to detect the possibility of
associated retinal detachment.
• Tractional retinal detachment is caused by progressive contraction of fibrovascular membranes over
areas of vitreoretinal attachment.

• Posterior vitreous detachment in eyes with PDR is often incomplete due to the strong adhesions
between cortical vitreous and areas of fibrovascular proliferation.

• Haemorrhage often occurs at these sites due to stress exerted on NV

• Rubeosis iridis (iris neovascularization – NVI) may occur in eyes with PDR and if severe may lead to
neovascular glaucoma.

• NVI is particularly common in eyes with severe retinal ischaemia or persistent retinal detachment
following unsuccessful pars plana vitrectomy
Diagnostic testing
1. Optical Coherence Tomography(OCT):

• Non contact

• Non invasive

• Micro resolution

• Cross-sectional study of retina

• Correlates very well with the retinal histology

Qualitative analysis:

• Description by location

• Description of form and structure

• Identification of anomalous structures

• Observation of the reflective qualities of the retina

Quantitative analysis:

• Retinal thickness and volume

• Nerve fiber layer thickness.

 Retinal anatomy compared to OCT
• The vitreous - black space on the top of the image

• Fovea - normal depression

• Umbo- central hyper reflective dot within foveola

• The nerve fiber layer (NFL) and the retinal pigment
epithelium (RPE) highly reflective than the other
layers of the retina (red - yellow)
• Retinal nerve fiber layer - thicker on nasal side of
macula

• Areas of minimal signals ( blue - black)

• Outer nuclear layer- thickest portion

2. Fundus Fluorescein Angiography:

• To guide treatment of CSME

• To identify Ischemic maculopathy Intraretinal microvascular

abnormalities vs Neovascularization

• It can be used for evaluation in hazy media

• It is not a screening modality

• It is not a routine investigation

3. Ultrasonography (B- scan) :

• When opaque media preclude retinal

examination.

• Useful in ruling out-

Retinal detachment

Traction threatening macular detachment

Retinal Detachment

Vitreous hemorrhage.
4. Fundus Photography:

• For documentation purpose

Management

• Medical treatment.

Observation & Laser therapy .

• Anti VEGF Agents

• Vitrectomy.
General
• Patient education

• Diabetic control

• Systemic hypertension and hyperlipidaemia should be controlled

• Fenofibrate 200 mg daily

• Smoking should be discontinued

• anaemia and renal failure should be addressed as necessary

Medical treatment
• Glucose control - maintaining the HbA1C level in the 6-7% range.

• Maintaining a healthy lifestyle with regular exercise can help reduce

the complication of diabetes and DR.

• Blood pressure control,

• Lipid-lowering therapy.
Supported by Diabetes Control and Complications Trial (DCCT), United Kingdom
Prospective Diabetes Study (UKPDS) and Wisconsin Epidemiologic Study of Diabetic
Retinopathy (WESDR)
Laser therapy
Panretinal photocoagulation (PRP)

• High-risk PDR (3/4)

• Vitreous or preretinal hemorrhage

• New vessels on optic disc or within 1,500 microns from optic disc rim

• Large new vessels

• Iris or angle neovascularization

• CSME
Procedure
• fully dilated pupil & topical anaesthesia.

• Initial settings on the Argon laser would be 500 um spot size, a 0.1 second exposure and 250-270 mw power.
1 burn apart.

• 1600-3000 burns are placed in 1 or more sittings.

• Burns are placed 2 to 3 disc diameters away from the center of the macula and 1 disc diameter away from
the disc extending upto the equator & beyond

• Should not be applied over major retinal veins, preretinal hemorrhages, darkly pigmented chorioretinal
scars, or within 1 DD of center of macula.

• Favor quadrants with active new vessels or areas with intraretinal microvascular abnormalities.
Lenses for PRP
Pattern scanning laser (PASCAL)
• Rapid application of multiple laser spots with
short pulse duration of 10-30ms (upto 56 shots)

• Laser used: Nd:YAG

• Advantages:

 Shorter treatment duration

 Increased safety

 Uniform and precise spot placement

 Reduced pain and visual field defect

 Ideal laser method to place accurate
"subthresold" focal- grid laser in DME
Complications of PRP
• Foveal burn • Pain during treatment

• Optic disc damage • Increased intraocular pressure

• Macular edema • Corneal abrasion

• Choroidal haemorrhage • Loss of visual field

• Choroidalneovascularisation • Loss of dark adaptation

• Choroidal detachment • Lens opacities

• Vitreous haemorrhage • Increase in traction detachments

Indicators of regression
• Indicators of regression include blunting of vessel tips, shrinking and disappearance
of NV, often leaving ‘ghost’ vessels or fibrosis, regression of IRMA, decreased venous
changes, absorption of retinal haemorrhages, disc pallor.

• Contraction of regressing vessels or associated induction of vitreous separation can

precipitate vitreous haemorrhage. Significant fibrous proliferation can lead to
tractional retinal detachment.

• Patients should remain under observation, as recurrence can occur with a

requirement for additional PRP.
Lasers in DME
Limitations :

• Patient must have clear lens and vitreous

• If cataract present, treat before laser PRP

• If vitreous hemorrhage, vitrectomy + laser photocoagulation

ETDRS guidelines for follow-up treatment after initial PRP based on six factors

1. Change in new vessels since the last treatment/last visit

2. Appearance of the new vessels (calibre, degree of network formation, extent

of accompanying fibrous tissue)

3. Frequency and extent of vitreous haemorrhage

4. Status of vitreous detachment

5. Extent of photocoagulation scars

6. Extent of tractional retinal detachment and fibrous proliferation.

Factors favouring additional photocoagulation

• Lack of regression within 6-8 weeks of the initial treatment.

• Active new vessels (tight networks, little fibrous tissue, rapid growth in size).

• Recurring vitreous hemorrhage, whether the source is visible or not.

• Extensive intraretinal lesions (venous beading,intra retinal microvascular

anomalies (IRMA), blot hemorrhages, retinal edema).

• Skip areas
 Intravitreal Anti VEGF Agents
• Indication: Treatment of rubeosis iridis, Treatment of PDR prior to cataract surgery

• Bevacizumab, Ranibizumab, Aflibercept

• Protocol S concludes that intravitreal ranibizumab treatment is as effective as PRP in patients at high
risk of PDR for up to 5 years.

• The macular oedema rate is reduced and the visual field is slightly better maintained with anti-VEGF
treatment.

• Irrespective of the therapeutic option, approximately half will experience a vitreous haemorrhage over
that period.

• Anti-VEGF treatment should be avoided and PRP provided if follow-up is likely to be poor or if cost is an
issue.
Pars plana vitrectomy (PPV)
• Indications:

- Severe persistent vitreous hemorrhage

- Progressive tractional RD (threatening or involving macula)

- Combined tractional and rhegmatogenous RD

- Premacular subhyaloid hemorrhage

- Recurrent vitreous hemorrhage after laser PRP

Vitrectomy:

• Removes blood

• Removes Traction

• Allows PRP
Basic setup

• Vitrectomy machine

• Surgical microscope and wide-angle viewing system

• Infusion cannula: to maintain intraocular pressure set by the

vitrectomy machine

• Endoillumination light source: for visualization of the posterior

segment including vitreous and retina

• Vitrectomy cutter (or vitrector): for vitreous removal, aspiration,

and peeling and cutting membranes among other functions
Dyes

• Triamcinolone acetonide

• Trypan blue

• Brilliant blue

• Indocyanine green
 Steps
• Trocars are inserted in the pars plana using a beveled incision technique.

• Core vitrectomy is performed to remove the central vitreous gel.

• Posterior vitreous detachment is induced if a natural one has not already occurred.

• Peripheral vitrectomy is performed and traction is released over the detached retina, at the retinal
tears, and any areas of lattice degeneration.

• Retina is flattened by draining subretinal fluid from a pre-existing break or a newly created drainage
retinotomy while performing a fluid-air exchange, typically using a soft tip cannula.

• Once the retina is flattened, endolaser is then performed around the retinal breaks.

• Intraocular tamponade is inserted.

• SF6 (lasting 2-3 weeks) and C3F8 (lasting 6-8 weeks) gas are most commonly used although there are
indications for silicone oil if longer tamponade is needed
Complications
• Injury to the cornea; epithelial defects due to surgical procedures

• Cataract formation due to direct lens injury or use of expansive gases

• Post operative hemorrhages

• Retinal detachment (from unrecognised retinal hole or traction )

• Iris and angle neovascularisation ( due to rheg RD or retinal ischemia)

• Endophthalmitis ( rare)
Management of Diabetic Retinopathy in
Special Circumstances
1. Pregnancy

• Informed on the need for assessment of DR before and during pregnancy.

• Retinal assessment : First antenatal clinic appointment and again at 28 weeks

if the first assessment is normal.

• If any DR is present, additional retinal assessment should be performed at 16-

20 weeks.

• Should not be considered a contraindication to vaginal birth.

2. Cataract

• mild cataract - carefully assess DR status. Patients without vision loss

with clear fundusview may not require cataract surgery.

• advanced cataract with poor fundus view - consider early cataract

surgery followed by assessment and treatment as necessary.

• If ME is present, consider anti-VEGF before surgery, at the time of

surgery, or after surgery if ME is discovered when the media is
cleared.
Screening of DR
• Patients with Type 1 diabetes should have an ophthalmologic examination
within 5 years after onset.

• Patients with Type 2 DM should have an ophthalmologic examination at the

time of the diabetes diagnosis.

• If there is no DR then one annual examination required.

• If any level of DR, progression and sight threatening, then examination will
be required more frequently
• Women with pre existing type 1 or type 2 DM who are planning
pregnancy or pregnant should be counseled on risk of development
&/or progression of DR.

• Eye examinations should be started from 1st trimester and monitored

every trimester and for 1 year of postpartum period.
Fundus diagram
STUDIES IN DIABETIC RETINOPATHY
i. Studies which measured the efficacy of photocoagulation:

a. DRS—proved the use of photocoagulation in the treatment

b. ETDRS—gave data regarding when to do photocoagulation

ii. Study which measured the efficacy of vitrectomy:

DRVS—proved the advantage of early vitrectomy in VH complicating PDR

iii. Studies which measured the efficacy of metabolic control:

a. DCCT—showed the advantage of intensive insulin therapy in the treatment of DM

b. UKPDS—United Kingdom prospective diabetes study

Diabetic Retinopathy Study (DRS)
• Objective: If photocoagulation reduced the risk of severe visual loss in proliferative diabetic
retinopathy.

• methodology:

1. Randomization

2. One eye of each patient was assigned randomly to PHC (argon or xenon) and other eye for follow up.
Eye on treatment was randomly assigned to argon or xenon arc.

• Inference:

i. Photocoagulation reduced risk of severe visual loss by 50% or more

ii. Modest risks of decrease in visual acuity and constriction of visualfields (more for xenon)

iii. Treatment benefit outweighs risks for eyes with high risk PDR.
Early Treatment Diabetic
Retinopathy Study (ETDRS)
• Objective:

i. Is photocoagulation effective in treating diabetic macular edema?

ii. Is photocoagulation effective for treating diabetic retinopathy?

iii. Is aspirin effective for preventing progression of diabetic

retinopathy?
• Result:

i. Aspirin use results:

a. Aspirin use did not alter progression of diabetic retinopathy but reduced risk of cardiovascular
morbidity and mortality.

ii. Early scatter photocoagulation results:

a. Early scatter photocoagulation resulted in a small reduction in therisk of severe visual loss.

b. Early scatter photocoagulation is not indicated for eyes with mildto moderate diabetic retinopathy

c. Early scatter photocoagulation may be most effective in patients with type 2 diabetes.

iii. Macular edema results:

a. Focal photocoagulation for DME decreased risk of moderate visual loss, reduced retinal thickening
and increased the chance of moderate visual gain.
Diabetic Retinopathy Vitrectomy
Study(DRVS)
• Objective: To evaluate the natural course and effect of surgical intervention on severe PDR
and its complications.

• Result:

1. Early vitrectomy is advantageous for severe vitreous hemorrhage causingsignificant

decrease in vision especially in type I diabetics.

2. Greater urgency for early surgery in uncontrolled fibrovascular proliferation or when

proliferation has been treated partially by scatter photocoagulation.

3. Eyes with traction detachment not involving the fovea and producing visual loss do not
need surgery until there is detachment of fovea, provided proliferation process is not severe.
Diabetes control and Complication
trial (DCCT)
a. Primary prevention study: Will intensive control of blood glucose
slow development and subsequent progression of diabetic retinopathy?

b. Secondary prevention study: Will intensive control of blood glucose

slow progression of diabetic retinopathy?
• Result:

i. Intensive control reduced the risk of developing retinopathy and also

slowed the progression of retinopathy.

ii. Intensive control also reduced the risk of clinical neuropathy and

albuminuria.
United Kingdom Prospective Diabetes
study (UKPDS)
• Objective:

Will intensive control of blood glucose and intensive control of blood pressure
reduce the risk of microvascular complications of DR?

• Result:

Intensive control of diabetes and blood pressure slowed the progression of

diabetic retinopathy and reduced the risk of other microvascular complications
of DR.
THANK YOU