DR WANI'S TALK ON DIABETIC RETINOPATHY PART I FOR KLE RESIDENTS.pptx

Diabetic Retinopathy Part I
Dr. Vivek B Wani MS FRCSEd
Consultant Vitreosurgeon
KLES Dr. Prabhakar Kore Hospital and MRC
Belagavi

Diabetic retinopathy Part I
I) Epidemiology and the burden of Diabetic Retinopathy(DR)
II) Risk factors for DR
III) Pathogenesis
IV) Clinical features &
V) Classification of DR
PART II
Investigations
DME and treatment
Diabetic papillopathy
Treatment and recent advances
Prognosis
4/12/2020 DR.Wani's lecture on DR for KLE residents 2

Diabetic Retinopathy
• It is the most common retinal vascular
disease and is potentially vision threatening
• DR is the most common cause of visual
impairment in persons aged 20-64 years

Why should we know how many
diabetics are there?
• Because DR develops in diabetic patients!
• Nearly 8.5% of adults above 18 years were
suffering from DM in the world as in 2014
https://www.who.int/news-room/fact-sheets/detail/diabetes
• 463 million people aged 20-79 are living with
DM as in 2019
https://www.idf.org/aboutdiabetes/what -is diabetes/facts-figures.html

Indian scenario
• An estimated 65 million diabetics
are present in India
• ICMR conducted a survey in 15 states
and reported that 7.3% of
population aged >20 years had DM
RM Anjana et al. Lancet diabetes endocrinology. 2017 online

How many diabetic patients have DR?-
global scenario
• DR was seen in 34% of diabetic
patients according to a large meta-
analysis- one in 3 will have DR
• 10% of these patients will have sight
threatening DR
Yau et al Diabetes Care. 2012 Mar; 35(3):556-64.

Prevalence of Diabetic Retinopathy in
Indian population
• In India 18.1% of DM patients aged >50
years had some DR-meta-analysis
Jotheeshwaran et al Indian J Endocr Metob 2016;20:51-8
• Visual impairment due to DR was seen
in 4% of 1414 individuals with DM in one
study
PK Rani et al Middle East Afr J Ophthalmol .2012;19(1):129-34

II) What are the risk factors for DR?
Non modifiable factors
• Age- increasing age is a risk
factor
• Sex –M<F
• Duration of DM*
• Cataract surgery-worsens
• Primary Open angle Glaucoma
POAG –association
• Pregnancy- uncontrolled DM
at start of pregnancy, DR at
the start of pregnancy are risk
factors for progression of DR
• Genetic factors
Modifiable factors
• Control of DM
• Hypertension
• Hyperlipidaemia-hard Ex
• Obesity
• CKD
• Presence of other diabetic
complications peripheral
neuropathy, foot ulcer and
amputation

Duration of DM –important risk factor
Duration of DM increases so does
DR
Applies to both type I and II DM

DR in Type I DM and duration of DM
Duration
of DM
ANY DR PDR DME
<5 YEARS 2% 0 0
>15 YEARS 97% 67% 23%
Klein et al Diabetes in America, 2nd ed. Bethesda, Maryland: National Institute of Health.
1995;293-338
Klein R et al Arch Ophthalmol. 1984;102:520-52

Type II DM duration of DM
• Clinical diagnosis of type II DM is
usually delayed by 5-10 years
Harris MI et al Diabetes Care. 1992;15(7):815-819
• 5% of Type II DM will have DR at
the time of diagnosis of DM

DR Insulin takers Non insulin
takers
DM>15 years
Any DR 87% 57%
10 years incidence
of PDR
24% 10%
10years incidence
CSME
18% 9%
Klein R et al Arch Ophthalmol. 1984;102:527-532
Klein R et al Arch Ophthalmol. 1994;112:1217-1228, Klein R et al Ophthalmol. 1995;102:7-16)
Duration of Type II DM And
Incidence of DR

Two important take away points for
management from these stats are
• Type I DM –Do first exam for DR at
about 3 years after diagnosis of DM
• Type II DM- Do first exam for DR at
the time of detection of DM

Control of DM or hyperglycemia-Type I DM
• Diabetes Control and Complications
Trial (DCCT) showed that strict control
of Type I DM
Reduce the incidence of new DR by
76% over a period of three years
Reduce the progression of DR by 54%
DCCT research group N Engl J Med 1993;329:977-86

Control of DM -Type II DM
UKPDS study (United Kingdom
Prospective Diabetes Study)
• If we reduce the HbA1C by 1%
the risk of DR was reduced by
37%
Stratton IM, Adler AI, Neil HA, et al BMJ 2000 Aug 12;321(7258):405-12)

DCCT Type I DM AND BP
• If baseline and/or follow up blood
pressures were high then it was
significant factor for predicting
development of DR, loss of vision or
development of macular edema
• Klein R et al Ophthalmol. 1989;96:1501-1510.
• Klein R et al Arch Ophthalmol. 1995;113:601-606.
• Janka et al. Diabetes. 1989;38:460-464.

Type II- UKPDS and blood pressure
• In patients with hypertension and DM
• If the mean blood pressure 144/82 mm Hg over 9 years
vs mean BP of 154/97
 Progression of DR reduced by 34%
 Reduced VA deterioration by 47%
 Reduced need of laser by 35%
• BP lowering had better effect than lowering the BS!
UKPDS group BMJ. 1998;317:703-713.

III) Pathogenesis of DR
• It is not fully understood
• Many pathways are implicated in the
pathogenesis of DR

Cheung et al Lancet. 2010;367:124-136
Leucocyte
Adhesion
Platelet
Aggregation
RBC roulex
Formation
PDGF

Falcao et al The Open Circulation & Vascular Journal 2010;3:30-42

Mechanisms regulating VEGF
• Simo R et al.Diabetes care. 2014;37:893-899

Blood retinal barrier
Blood retina barrier damaged
Capillary leakage Macular edema
PROTEIN KINASE C ACTIVITY
Phosphorylation of occludin in tight junctions
Increased VEGF production
VEGF

IV) Clinical Features of DR
A)Presentation
Symptoms-
 Asymptomatic-detected during DR screening
 Diminished vision is the most common
 Gradual- indicates macular edema, thick and opacified posterior
hyaloid , slowly developing TRD
 Sudden- Vitreous hemorrhage, diabetic papillopathy
 Floaters – due to small vitreous hemorrhage
 Distorted vision-metamorphopsia –traction on macula
 Pain and redness- sudden onset indicates development of
neovascular glaucoma

B) Signs of DR
i) Anterior segment
Normal
Pseudophakia – past cataract surgery is a risk
factor for worsening of DR
IRIS –look for NVI
Angle- look for NVA
IOP-POAG is a risk factor for DR, NVG,
hemolytic glaucoma

ii) Retinal signs in DR
• Microaneurysms
• Retinal hemorrhages-dot and blot and flame shaped hgs
• Cotton wool spots(CWS)
• Hard exudates
• Retinal thickening
• Venous changes –venous dilatation, beading, looping, doubling,
• Arterial-closure
• Neovascularization
• Subhyaloid hg , Vitr hg
• TRD
• Papillopathy
• Macuopathy

a) Microaneurysms
They are the first sign of DR
How do they form?
• There is one pericyte per each
endothelial cell in capillaries
• Pericytes give structural support
to the capillary
• Loss of pericytes of capillaries
due to DM
• Capillary wall weakness
• Weakened wall bulges out or
dilates in a saccular manner to
form microaneurysm

Microaneurysm
• MA are found in Inner capillary plexus in inner nuclear
layer
• Typically measuring 10–125 µm in diameter
• Red dots either singly or in groups
• Mostly posterior pole but later outside arcades too
• Found in the center of hard exudate rings, area of
retinal edema and near area of capillary non-perfusion
• They undergo cycle of appearance, fibrosis and
disappear in 3-4 mo

FFA
• They appear as hyper fluorescent spots on FFA
if they are patent
• Leak dye later and become fuzzy
• Hyper cellular MA and fibrosed MA do not fill
up

Microaneurysms

Significance of MA
• They leak plasma and later RBCs
retinal edema
macular edema
hard exudates
Retinal hgs
• Number of MA indicates severity of the DR
• A high microaneurysm turn over rate on color
fundus photographs taken sequentially is a good
biomarker for progression of DR

MA -DD
• DR
• Venous occlusions –CRVO, BRVO
• HT retinopathy
• Radiation retinopathy
• Leukemias, anemia
• Coat’s disease
• Eales disease

b) Retinal Hemorrhages
• Flame shaped hgs-superficial hgs
• Dot and blot hgs –deep hgs

Flame shaped -superficial haemorrhages
• Arise from the larger superficial pre-capillary
arterioles
• Present in the nerve fiber layer(NFL)
• Flame-shaped because of the architecture of the
retinal nerve fibers
• Excessive number should alert us to measure BP
• Also associated with HT and other hematological
disorders –anemia, leukemias, Eales, collagen
vascular disorders, vasculitis of any cause

Dot - blot hemorrhages
• Arise from the venous end of capillaries
• Located in the middle layers of the retina
• Red dot hgs may look like MA but usually
larger than 125mu
• Differentiate except by FFA
• Large dark blot Hemorrhage represents
hemorrhagic retinal infarcts

Dot and blot hemorrhages Hgs

Significance
• Their number indicates severity of the DR

c) Hard Exudates
Waxy, yellow lesions with relatively distinct margins
• Arranged in clumps and/or rings at the posterior pole
• Typically surround area of retinal edema with leaking
micro-aneurysms in the center –circinate retinopathy
• They form at the border between edematous and
normal retina
• They are located in the outer plexiform layer but may
break in to superficial layers if accumulate
• They are composed of lipoproteins and lipid ingested
macrophages

Hard exudates

Hard exudates
Significance
• They are part of the CSME and risk of visual
loss+
• Extensive hard exudates can go to settle under
neurosensory retina & damage
photoreceptors and cause irreversible of
vision
• Take many months to disappear -3-6 months
• Cholesterol profile should be paid attention to

d) Retinal Edema
• Retinal edema is retinal thickening seen with
stereoscopic fundus examination by slit lamp
biomicroscopy with 90D lens
• This is usually in the posterior pole seen as
elevation the choroidal pattern will be less
visible through the edematous retina
• If it involves fovea the foveal reflex would be
lost
• Best detected with OCT

Retinal Edema
• FFA reveals leaking microaneurysm and
dilated capillaries as cause of retinal edema

e) Cotton wool spots or soft exudates
 White or grayish white lesion
 Feathery borders as they are in superficial nerve fiber
layer
 Commonly seen along the arcades and near the disc
 May obscure the underlying blood vessels
 Stoppage of axoplasmic flow in the nerve fiber layer
due to ischemia
 Disruption of axoplasmic flow in axons results in the
swollen ends known as cytoid bodies (globular
structures in the NFL) on histopathology
Common in HT patients
But can occur in Non HT diabetic patients

CWS
• FFA –block fluorescence over the area of CWS
• OCT will show hyper-reflectivity in NFL

Cotton wool spots or soft exudates
• Small, whitish, fluffy superficial lesions which
obscure underlying blood vessels

CWS
Significance
• Indicate worsening DR but are of less
significance than Hgs, VB and IRMAs
DD of only CWS
• Hypertensive retinopathy, Blood diseases-
anemia, leukemia, collagen vascular disorders,
Purschers retinopathy, HIV, Takayasus disease,
acute pancreatitis and many others

f) Intra Retinal Microvascular abnormality
(IRMA)
• Fine, reddish, irregular blood vessels that run
from arterioles to venules-shunt vessels
• They bypass the capillary bed
• Intraretinal
• Signify progressive retinal ischemia
• They don’t cross major vessels, they have
Intraretinal location and do not leak on FFA
VS NVE

Standard 8a photograph
Patients with severe NPDR have
moderate IRMA of at least this
severity in at least one quadrant.

IRMA
Significance
• May be present in Moderate NPDR but
severity less than the standard photograph

g) Venous changes in DR
• Venous dilatation
• Venous beading
• Venous looping
• Venous doubling

Venous dilatation
• Indicates loss of autoregulation with increased
blood flow initially
• Can be present from the beginning
• Not a specific sign

Venous beading
• Major vessels have beaded appearance
• It may be seen in moderate NPDR but severity
will be less or present in only one quadrant
• They are very important signs of worsening DR

Venous beading

Standard

Venous looping

h) Arterial changes
• Arteriolar closure

• Till now the signs we saw are all part of Non
proliferative DR(NPDR)
• There are no new vessels or fibrosis in NPDR
• Once new vessels appear on the retina then it
is Proliferative Diabetic Retinopathy PDR

i) Neovascularization-PDR
• New vessels are the hallmark of Proliferative
Diabetic retinopathy(PDR)
• When DR progresses there is progressive
vascular occlusion ---hypoxia and up-
regulation of VEGF
• VEGF causes endothelial proliferation and
their migration leading to neovascularization
• VEGF levels in vitreous of patients with PDR
are higher than those eyes without PDR

New vessels indicate
• Worsening condition
• Possibility of severe visual loss
• Immediate treatment
• Points to the probability of other
health issues of DM like IHD , CKD,
stroke, neuropathy etc

Neovascularization
•Retina
•Iris and angle

New vessels
1) Neovascularization on the disc -NVD
Grow on the disc or within ONE disc diameter
of the disc

2) Neovascularization elsewhere –NVE
On the surface of the retina outside of ONE
disc diameter of the disc

New vessels
• They are seen as bright red or fibrovascular
membranes on the retinal surface
• Sometimes they may be seen protruding in to
the vitreous

New vessels growing between ILM and
post hyaloid
New vessels grow from retinal vessels on the retinal surface
They pierce the inner limiting membrane of the retina (ILM)
Once they pierce ILM they grow on the post hyaloid surface

What do the new vessels do?
• They are fragile and may break
Vitreous hg
Subhyaloid Hg
When the bleeding breaks the posterior hyaloid
face and enters the vitreous gel –Vitr hg
When the blood collects between retina (ILM)
and post hyaloid face then it is subhyaloid hg

What do the new vessels do?
• They leak proteins in to the vitreous n cause changes in
it
• Posterior hyaloid face starts slowly to detach from the
retina
• The new vessels attached to the PH FACE are pulled
now and may bleed
• New vessels may regress slowly replaced by fibrous
tissue and are adherent to the PH face
• Posterior hyaloid may pull up the FVM attached to it
along with retina –tractional retinal detachment
• Fibrosis may cause thickening of the posterior hyaloid

New vessels growing between ILM and
post hyaloid

TRD

Iris and NVA
• Indicate severe ischemia in the retina and
need urgent attention and treatment

Signs of DR
• Microaneurysms
• Retinal hemorrhages-dot and blot and flame shaped hgs
• CWS
• Hard exudates
• Retinal thickening
• Venous changes –venous dilatation, beading, looping, doubling,
• Arterial-closure
• Neovascularization
• Subhyaloid hg , Vitr hg
• TRD
• Iris and angle neovascularization
• Maculopathy
• Papillopathy

V) Classification of DR
DR
Non
proliferative
Proliferative

Classification system for DR
• International Clinical Disease
Severity Scale for DR
Wilkinson et al Ophthalmology 2003; 110: 1677-1682

V) A. Classification of DR
NPDR
Mild
Very Severe
Moderate
Severe

Normal -NO DR
• There are no diabetic retinopathy changes
• Need annual follow ups
• 5-10% develop some DR in one year
• No need to do any investigations for the eye
• Control BS and BP

Mild NPDR
• Microaneurysms only- at least one MA +
• No other lesions
• Need annual follow up if there are no MA
within 1 DD of foveal center
• If there are MA within 1 DD of fovea
follow up 6 months

Mild NPDR

Moderate NPDR
• There are MAs, Hgs, IRMAs, Hex, VB, CWS
either all of them may be present or some of
them are present
• But their number and severity do not meet
the criteria to diagnose it as SEVERE NPDR

Standard photograph 2A, the standard for hemorrhages/microaneurysms. Eyes with severe NPDR have this
degree of severity of hemorrhages and microaneurysms in all four midperipheral quadrants.
In moderate NPDR this severity is present but
Only up to 3 quadrants

Standard photograph 6A, less severe of two standards for venous beading. Two main branches of the superior
temporal vein show beading that is definite, but not severe.
In moderate NPDR less severe VB may be
present or severe VB in only one quadrant

Severe VB can be present in one quadrant only- in Mod NPDR

IRMA-can be present in MOD NPDR but severity is less
than the standard photograph

Moderate NPDR
• Risk of progression to PDR is about 26% in one
year risk of HRC PDR is about 8%
• Follow up every 4 months if there is no
maculopathy
• If maculopathy present more often
• CSME present every 2-4 months or treat

Severe NPDR
• 4-2-1 Rule
• Any one of the below conditions to be present
• H/MA =/>standard photo 2A in all 4 quadrants
• VB (venous beading-6A or worse)in 2 or more
quadrants
• IRMA ≥ standard photo 8A in at least 1
quadrant
• No new vessels, vitr or subhyaloid hg present

Severe NPDR Hgs in all 4 quadrants

VB in two quadrants

IRMA in at least in one quadrant ≥ than standard photo

IRMA in at least one quadrant

Severe NPDR
• Nearly 50% will develop PDR in a year
• High risk PDR in 15% in one year
• Follow ups are needed every 3-4 months if
maculopathy is not present
• If maculopathy is present –treat or every 2-3
months
• Selected cases do PRPC
• BUT THE TREATMENT PARADIGM HAS CHANGED
RECENTLY

VERY severe NPDR
• For severe NPDR 4 or 2 or 1 should
be present (of the rule 4-2-1)
• For very severe NPDR more than
one condition of the 4-2-1 rule is
present (hgs+MA and VB or VB
&IRMA)

V B) Proliferative Diabetic
Retinopathy(PDR)
Presence of
• NVD
• NVE
• Vitreous or subhyaloid( pre-retinal hg)
• Fibrous tissue proliferation
• NVI/NVA in absence of CRVO or other causes
• TRD
• Combined TRD and RH RD

PDR
i)Early PDR
ii) High Risk PDR
iii) Advanced PDR

Early PDR
• New vessels on the retina or disc but criteria
not met for HRC PDR

HRC PDR
• NVD >/=1/4 DD
• NVD <1/4 DD but associated with vitreous
hemorrhage
• NVE >1/2DD with vitreous hemorrhage

Standard photograph 10A defines the lower border of moderate NVD. NVD covers approximately
one-third the area of the standard disc. This extent of NVD alone would constitute HR PDR

NVD

Advanced PDR
• Vitreous hemorrhage
• Sub-hyaloid hemorrhage
• Tractional RD
• Combined Tractional and rhegmatogenous RD

Tractional RD
• Has a concave configuration
• May or may not involve macula
• May remain stable or progress
• May cause tractional changes in retina and
macula

TRD LE

Combined TRD and Rh RD
• When traction by membrane causes a hole or
break in the retina then the TRD gets
converted in to combine TRD and Rh RD

Combined TRD and Rh RD

Next talk we will cover
Investigations
DME and treatment
Diabetic papillopathy
Treatment of DR and PDR
Prognosis

D. Early PDR
E. High risk PDR
New vessels present (criteria
not met E)
Any one or more of the
following criteria :
1. NVD with VH
2. NVD > ¼ - 1/3 DD without
VH
3. NVE > ½ with VH
Stages of Proliferative Diabetic Retinopathy - PDR
26% 4%
(<5/200) within 2 yrs
Without treatment With
treatment
26% 9%
30% 7%
Risk of severe visual loss

NVI
• New vessels may be present on the iris
without presence of new vessels on the retina
• NVI indicates risk of NVG and early treatment
of PRPC is needed in these cases
• Pay attention to carotids too –doppler of
carotids is needed

Treatment of PDR
• STANDARD TREATMENT
• PRPC
• Started as early as possible
• From the arcades to equator around 2500
laser spots are placed
• Treatment is carried out in 3-4 sessions
• Titrate the laser treatment according to
severity of the PDR

Treatment of PDR
• Laser used is usually argon laser green or
Double frequency YAG laser (532 nm)
• Duration of laser burn is around 0.07-0.1
microns
• Size is usually 200-500 microns
• Power is usually started at 150mw and
increased in 20mw increments to attain a
reasonably white burn

Treatment of PDR

Diabetic macular edema
• Clinically macular edema is any retinal
thickening or presence of hard exudates
within 1 DD of the center of the fovea
• Retinal thickening is recognized by
stereoscopic examination of the macula by slit
lamp biomicroscopy with contact lens/non
contact lens

Hard exudates within
a radius of one disc diameter
of the centre of the fovea

CSME
• This entity was defined by EDTRS Study which
studied the effect of laser on macular edema
of specific type –CSME

Clinically significant macular edema (CSME)
Hard exudates within 500 m
of centre of fovea with
adjacent edema
Retinal edema one disc area within one disc
diameter (1500 m) of centre of fovea
Retinal edema
within 500 m of
centre of fovea

CSME
• Diabetic macular edema tends to be a chronic
disease. Although spontaneous recovery is not
uncommon, 24% of eyes with CSME and 33% of eyes
with center-involving CSME will have a moderate
visual loss (15 or more letters on the ETDRS chart)
within 3 years IF untreated
• The incidence of macular edema increases
significantly with increasing severity of diabetes in
both younger onset and older onset diabetic patients

Diffuse versus Focal CSME
• Clinically significant macular edema is further
classified into focal or diffuse, depending on
the leakage pattern seen on the fluorescein
angiogram

Diffuse or Focal
• Leakage on the angiogram does not
necessarily indicate retinal edema since
extracellular edema requires that the rate of
fluid ingress into the retina (i.e., as indicated
by leakage on the FA) exceed the rate of fluid
clearance from the retina (e.g., via RPE pump)

Focal CSME
• In focal CSME discrete points of retinal
hyperfluorescence are present on the FA due to focal
leakage of microaneurysms
• The discrete leaking microaneurysms are thought to
cause retinal thickening. Commonly, these leaking
microaneurysms are surrounded by circinate rings of
hard exudates
• The exudates are lipoprotein deposits in the outer
retinal layers

Diabetic maculopathy
• Diabetic macular edema
• CSME
• Ischemic maculopathy
• Intraretinal or preretinal hemorrhage in the
macula
• Tractional maculopathy –macular hole
formation
• Combination of the above

Retinal signs

DR WANI'S TALK ON DIABETIC RETINOPATHY PART I FOR KLE RESIDENTS.pptx

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