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Review Article
Diabetic Retinopathy: An Overview
Ajay Sharma, Trishna Taye, SB Rasel
Abstract: Diabetic Retinopathy (DR) is the most common micro vascular complication of diabetes mellitus and a major
cause of legal blindness.Both ocular & systemic factors are responsible for the pathogenesis of DR. The morbidity from
DR has a great impact on the society.Early diagnosis and prompt treatment reduces the complication and economic
burden .The major treatments for this condition have largely remained unchanged for long years: laser photocoagulation
for proliferative diabetic retinopathy and macular edema, under guidelines of the Early Treatment Diabetic Retinopathy
Study (ETDRS) . However, new therapeutic strategies have appeared, which raise the prospect that the years ahead will
see very significant additions to the options for treatment of diabetic retinopathy. Both corticosteroids and anti-VEGF
treatments are serving as additional options in the clinical management of Diabetic Retinopathy. The emergence of anti-
VEGF treatments strongly highlights the advent of rational drug therapy based on the identification of causative
mechanisms and molecular targets. Though Diabetic Retinopathy is irreversible, early diagnosis & prompt treatment
reduces the risk of visual loss, complications and economic burden on the society.
Key Words : Diabetic Retinopathy, Laser Photocoagulation, Macular oedema, Anti-VEGF
Introduction
Diabetes mellitus (DM) is a multi-factorial metabolic
disorder characterized by altered insulin production or
activity, clinically manifested as elevated blood glucose.
DM can be divided into type 1 or insulin dependent DM
(IDDM) and type 2 or non insulin dependent DM
(NIDDM).10% to 15% have IDDM and are generally
diagnosed before 40yrs of age, but the majority have
NIDDM and are generally diagnosed after 40yrs. DM
causes numerous long term systemic complications that
have considerable associated morbidity.
Diabetic retinopathy (DR) is a highly specific vascular
complication of both type 1 and type 2 DM. The
development and progression of Diabetic Retinopathy is
multi factorial and depends on the duration of DM among
other factors. The exact mechanism by which diabetes
causes retinopathy remains unclear, but several theories
have been postulated to explain the typical course and
history of the disease1, 2. The morbidity and suffering caused
by visual loss, the economic impact from diabetic
retinopathy is tremendous.
Epidemiology
According to the World Health Organization (WHO) the
total numbers of people with diabetes were 171 million in
2000, and are projected to rise up to 366 million in 2030.
80% of people with diabetes live in low and middle income
countries. India has 31.7 million diabetic subjects at
present1 .Projected figures for 2025 are 54 million. In the
Andhra Pradesh Eye Disease Study (APEDS) of self-
reported diabetics, the prevalence of DR was 22.4%2.In
the Chennai Urban Rural Epidemiology Study (CURES)
prevalence of DR was 17.6%.3 After 20 yrs of DM nearly
all patients with IDDM and more than 60% with NIDDM
have some degree of retinopathy. These figures clearly
indicate the magnitude of problem .
Risk factors for DR: The following are the risk factors
which can aggravate DR.
� Duration of Diabetes: Duration of diabetes is a major
risk factor associated with development of DR. After 5
yrs, 25% of type -1 DM patients have some form of
Diabetic Retinopathy, after 10 yrs, 60% and after 15 yrs
80% have DR4,5.
Severity of diabetes: Severity of hyperglycemia is a key
alterable risk factor associated with the development of
DR. Once retinopathy is present, duration of diabetes
appears to be a less important factor than hyperglycemia
for progression from earlier to later stages of retinopathy.6
� Hypertension : Studies, such as The Wisconsin
Epidemiological study of Diabetic Retinopathy (WESDR)
and UK Prospective Diabetes study (UKPDS), suggest that
1Ajay Sharma MS, FIVRS, 2Trishna Taye MS FIVRS,2SB Rasel FCPS, FIVRS1Head of Dept. 2Fellow, Vitreo-Retina departmnent,
Sankar foundation, Visakhapatnam, AP, India
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hypertension increases the risk and progression of DR and
Diabetic Macular Oedema (DME). Intensive management
of HTN has been demonstrated to slow retinopathy
progression.7,8
� Nephropathy: The presence of gross proteinuria at
baseline has been reported to be associated with 95%
increased risk of developing DME among type I patients
in the WESDR. The prevalence of PDR was much higher
in patients with persistent micro albuminuria.9
� Serum lipid: ETDRS has reported a positive correlation
between serum lipids and risk of retinal hard exudates in
type 2 DM. Recently, Gupta et al. have reported reduction
in edema, severity of hard exudates and sub-foveal lipid
migration in patients with type 2 diabetes and
dyslipidaemia, using a lipid-lowering drug, atorvastatin,
as an adjunct to macular photocoagulation10 .
� Pregnancy; Pregnant women with type 1 Diabetes, have
twice the risk of developing PDR than non-pregnant
women. Ideally, young mothers should be examined for
retinopathy before the onset of pregnancy11 .
� Other risk factors include anemia, smoking, cataract
surgery, obesity, cardiovascular disorder etc.
PATHOPHYSIOLOGY:
DR is predominantly a micro-angiopathy in which small
blood vessels are particularly vulnerable to damage from
hyperglycemia. Direct hyperglycemic effects on retinal
cells are also likely to play a role.
Various studies have shown that chronic hyperglycemia,
hypertension and hyperlipidemia contribute to the
pathogenesis of DR. Hyperglycemia damages retinal
vasculature in several ways and progression of DR is
generally related to the severity and duration of
hyperglycemia. The exact mechanism by which raised
glucose levels lead to vascular disruption seen in
retinopathy is poorly defined. However, various
biochemical pathways have been suggested to demonstrate
correlation between hyperglycemia and micro-vascular
complications of retinopathy. Among these pathways,
increased activity of protein kinase C (PKC) and glycation
of key proteins that lead to formation of advanced glycation
end products (AGEs) are more important than polyol
accumulation, oxidative stress, growth factor etc.
Six basic patho-physiologic processes are recognized in
the development of lesions of DR.
1. Loss of pericyte functions of retinal capillaries.
2. Out pouching of capillary walls to form micro aneurysms
3. Closure of capillaries and arterioles
4. Breakdown of blood/retinal barrier
5. Proliferation of new vessels and fibrous tissue.
6. Contraction of vitreous and fibrous proliferation with
subsequent vitreous hemorrhage and retinal detachment
due to traction.
DIAGNOSIS
The initial examination for a patient with diabetes includes
all features of the comprehensive adult medical eye
examination with particular attention to those aspects
relevant to DR.
HISTORY: An initial history should consist of the
following elements:
�Complaints (ocular and systemic) �Duration of diabetis4,6,
Past glycaemic control (hemoglobin A1c)6 and medication.
�Medical history; eg.:Obesity, renaldisease4, hypertention4,
serum lipids, pregnancy, past treatment.
EXAMINATION:
The initial examination should include the following
elements:
� Visual acuity � Slit lamp biomicroscopy
� Intraocular pressure � Dilated fundoscopy including
stereoscopic examination of the posterior pole
� For evidence of macular oedema
EXAMINATION SCHEDULE: Depends upon type of
DM
1. Type 1 DM: Many studies of patients with type 1 DM
reported a direct relationship between the prevalence and
severity of DM and duration of diabetes.12 The
development of vision threatening retinopathy is rare in
children before puberty. Among the patients with type 1
DM, substantial retinopathy may develop as early as 6-7
years after onset of disease4.Ophthalmic examination
should be performed beginning 3-5 years after diagnosis
of type 1 DM4 .
2. Type 2 DM: The time of onset of type 2 DM is often
difficult to determine and may precede the diagnosis by
number of years. 3% of patients whose diabetes is first
diagnosed at age 30 or later will have CSME or high risk
characteristics at the time of initial diagnosis of
diabetes4.About 30% of patients have some manifestations
of DR at the time of diagnosis. Ophthalmic examination
should be performed once at the time of diagnosis of type
2 DM.
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3. DIABETES ASSOCIATED WITH PREGNANCY:
DR can worsen during pregnancy due to metabolic
changes. Patients with DM who become pregnant should
be encouraged to have their eyes examined prior to
conception, and during early pregnancy, should be
counseled on the risk of development and progression of
DR, and should be counselled to make every attempt to
lower their blood glucose level to as near normal as
possible for their own heath and the health of the fetus.
Woman who developed gestational DM do not require eye
examination during pregnancy, because such individual
are not at increased risk for DR during pregnancy.
Table 1- Follow up schedule:
Diabetic type Recommended time of first
ExaminationRecommended follow up*
Type 1 3-5 yrs after diagnosis Yearly
Type 2 At the diagnosis Yearly
Prior to pregnancy type 1/2 Prior to conception & early in No retinopathy to mild or
the first trimester moderate NPDR;Every 3-12
months. severe NPDR or worse
;every 1-3 months
*Abnormal findings may dictate more frequent follow
up examination
CLINICAL FEATURES:
Symptoms:
In the initial stages of diabetic retinopathy, patients are
generally asymptomatic; in more advanced stages, patients
may experience symptoms of floaters, blurred vision and
progressive or sudden visual loss.
SIGNS:
Micro aneurysm: The earliest clinical sign of DR is a
micro-aneurysm. They are located in the inner nuclear layer
of the retina and appear as red dots.
Intra retinal hemorrhage: Dot blot hemorrhages are
located in the middle layers of the retina. Flame shaped
hemorrhages are located in the nerve fiber layers and
follow their course.
Hard Exudates: They are yellow waxy appearance mainly
located at the posterior pole
Cotton-wool spots: They result from nerve fiber layer
infarctions from occlusion of pre-capillary arterioles. They
are frequently bordered by micro-aneurysms and vascular
hyper permeability.
Retinal oedema: It is characterized by retinal thickening
which obscures the underlying RPE.
Intra retinal micro vascular abnormalities (IRMA): They
are either new vessel growth within the retina or, more
likely, pre-existing vessels that become shunts through
areas of non perfusion.
Venous caliber abnormality: They are indicators of severe
retinal ischemia. They can be venous dilatation, beading,
loop formation.
Neovascularization: May be on the disc (NVD), or
elsewhere on the retina(NVE).
Pre-retinal hemorrhages and vitreous hemorrhage:
Appear as pockets of blood within the potential space
between the retina and the posterior hyaloid phase. As
blood pools within this space, the hemorrhages may appear
boat shaped. Vitreous hemorrhage may appear as diffuse
haze or clump in the Vitreous gel.
Fibrovascular tissue proliferation and Traction retinal
detachments
DIABETIC MACULOPATHY: Maculopathy is a
disease of macula and can accompany any stage of DR
including background retinopathy. Maculopathy is a
serious condition and may affect central vision. It is
characterized by macular edema and ischemic
Maculopathy. Macular edema is due to extravasations of
plasma proteins due to damage of blood-retinal barrier.
Ischemic Maculopathy arises due to extensive micro
vascular occlusion and may cause severe loss of central
vision.
Diabetic Maculopathy is of the following types:
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Table 2- Classification of Diabetic Retinopathy (From ETDRS)
Severity Lesion Present
Non Proliferative
No Diabetic Retinopathy No retinal lesion
Microaneurysms only No lesions other than microaneurysms
Mild NPDR Microaneurysms plus retinal hemorrhages,hard exudates
Moderate NPDR Mild NPDR plus cotton-wool spots and/or IRMA
Severe NPDR Presence of one of the following features:microaneurysms plus venous
beading and /or H/MA standard photograph 2A in four quadrants,or
marked venous beading in two or more quadrants or moderate IRMA
(standard photograph 8A) in one or more quadrants)
Very severe NPDR Two or more of the above features described in severe NPDR
Proliferative
PDR without HRC New vessels and/or fibrous proliferations;or preretinal and /or vitreous
hemorrhage
PDR with HRC NVD standard photograph 10A ;or less extensive NVD, if vitreous or
preretinal hemorrhage is present;or NVE half disc area.if vitreous or
preretinal hemorrhage is present
Advanced PDR Extensive vitreous hemorrhage precluding grading ,retinal detachment
involving macula,or phthisis bulbi or enucleation secondary to a
complication of diabetic retinopathy.
1. Clinically Significant Macular Oedema (CSME).
2. Ischemic , with or without associated CSME
3. Cystoid macular edema
4. Non-CSME
CLINICALLY SIGNIFICANT DIABETIC
MACULAR OEDEMA (CSME):(figure 1)
The following are the criteria for CSME
1. Thickening of the retina located at or within
500microns from the center of the macula or
2. Hard exudates with thickening of the adjacent retina
located at or within 500microns from the center of
the macula or
3. A zone of retinal thickening, 1 disc area or larger in
size located at or within one disc area from the
center of the macula.
INVESTIGATIONS
Diabetic retinopathy is essentially a clinical diagnosis.
Investigations are required to aid the diagnosis, plan and
execute the treatment and document for review and
research purposes.
Fundus fluorescein angiography
ETDRS has documented the angiographic risk factors for
progression of NPDR to PDR.13FFA is used to classify
and treat DME into focal and diffuse variety and it also
aids in the diagnosis of CME.
Fig 1: Severe NPDR: Retinal hemorrhages ( red arrow)
seen extensively in all four quadrants. Dilated veins
indicating ischemia( Blue arrow). Also note hard
exudates( yellow arrow).
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Optical coherence tomography(OCT)
OCT generates cross-sectional image which provides us
with quantitative measurement of thickness in the
posterior pole area with reasonable accuracy, thus aiding
in establishing the diagnosis of CSME.14 Some important
features of Diabetic retinopathy are depicted in figures
2 to 4.
Management of DR:
The management of DR can be broadly classified into
1. Control of risk factors 2. Specific treatment
CONTROL OF RISK FACTORS :
Although specific treatment modalities for retinopathy
threatening vision have improved over years of clinical
and research experience, importance of preventive
measures (Good glycemic and blood pressure (BP)
control, smoking cessation, regular eye screening) cannot
be underestimated
Specific treatment: According to ETDRS
Normal or minimal NPDR : The patient with no DR or
minimal NPDR (e.g. with rare microaneurysm) should
be re examined annualy4, because within one year only
5% to 10% of them will develop DR. Existing retinopathy
will worsen by a similar percentage15,16,17. Laser, colour
fundus or angiography are not indicated .
Mild to moderate NPDR without macular edema
(figure5):Patients with mild to moderate NPDR should
have a repeat examination within 6-12 months; because
lesion progression is common15. Laser, surgery and FFA
are not indicated for this group of patients. Color fundus
photo may occasionally be helpful as a baseline for future
comparison and documentation.
Fig.2: CME: OCT showing Cystoid macular edema with
elevation of retinal sensory layers (white arrow) and
cystic spaces (yellow arrow)
Fig.3:OCT showing epiretinal membrane (white arrows)
Fig.4: OCT showing macular edema with pigment
epithelial detachment (white arrow).
Fig.5: PDR with CSME: Hard exudates ( yellow arrow)
with retinal thickening seen within 500 microns from the
foveal center, indicating CSME. Fibro-Vascular
proliferation( Red arrow) can be seen along the superior
temporal arcade.
40
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For patients of mild NPDR, the 4 years incidence of earlier
CSME or macular edema that is not clinically significant
is 12%.For moderate NPDR, this risk increased to 23%
for the patients of type1 and type 2 DM18 . Patients with
macular edema with no CSME should be rechecked within
3-4 months, because they are at risk of developing
CSME19..
Mild to Moderate NPDR with CSME: FFA should be
done prior to laser surgery to identify treatable lesions and
for identifying pathologic enlargement of FAZ (Foveal
Avascular zone) .The treatment of CSME has traditionally
been laser. The ETDRS results showed that the risk of
moderate visual loss is reduced by more than 50% for the
patients who undergo appropriate laser surgery,when
compared to untreated.
More recently data from the diabetic retinopathy clinical
research network (DRCR.net) and other studies have
demonstrated that intravitreal anti VEGF agents and
corticosteroids are effective treatments for CSME19,20 . The
visual acuity gain and reduction in macular thickness
following the administration of the combination of
intravitreal Ranibizumab, with prompt or deferred laser
were greater than the laser alone at 2 years of follow up.
When treatment for macular edema is deferred, as may be
desirable when the centre of macula is not involved or
immediately threatened, the patients should be observed
closely ( at least every 3-4 months) for progression.
SEVERE NPDR AND NON HIGH RISK PDR (figure
6): ETDRS data showed that severe NPDR and non high
risk PDR have a similar clinical course and subsequent
recommendation for treatment are similar .In eyes with
severe NPDR, the risk of progression to proliferative
disease is high. Half of severe NPDR will develop PDR
within 1 year, and 15% will be developing high risk
PDR18.The ETDRS compared early PRP with deferral of
PRP, defined as careful follow up (at 4 month interval)
and prompt PRP if progression to high risk PDR occurred.
When retinopathy is more severe, PRP should be
considered and should not be delayed if the eye has reached
the high risk proliferative stage18. If laser surgery is
indicated, full PRP is a proven surgical technique, and
partial PRP is not recommended 21.
HIGH RISK PDR (figure 7): The risk of severe visual
loss in patient of high risk PDR can be reduced
substantially by means of PRP as described in the ETDRS
and DRS .Most patients of high risk PDR should receive
PRP expeditiously22,23,24 .
HIGH RISK PDR NOT AMENABLE TO
PHOTOCOAGULATION (figure 8) : Victrectomy is
frequently indicated in patients with tractional macular
detachment specially of recent onset, combined tractional
and rhegmatogenous retinal detachment,vitreous
hemorrhage with rubeosis iridis and vitreous hemorrhage
precluding PRP.
Fig.6: PDR: Dilated and tortuous veins indicating
ischemia.(Blue arrows) Multiple new vessels seen
temporal to the fovea(Orange arrow)
Fig.7: High risk PDR: Massive NVD causing bleed and
preretinal hemorrhage seen in the peri papillary
area(Orange arrow). .Hard exudates( Yellow arrow) seen
in the superior macular area.
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Surgical management of DR
The indications for surgery are as follows
1. Persistent Vitreous hemorrhage (V.H)
2. Tractional Retinal detachment (R.D) involving macula
3. Combined tractional and Rhegmatogenous R.D
4. Dense persistent premacula, subhyaloid hemorrhage
5. Rubeosis iridis with V.H
Management of CSME:
The treatment technique is divided into two main
categories:
1. Focal laser: direct treatment of fluorescein leaks
2. Grid laser: treatment of diffuse areas of leakage or
non-perfused retinal thickening.
Pharmacotherapy
Pharmacological agents aim at preventing or reducing
the release of growth factors in response to retinal
ischemia from alterations in the structure and cellular
composition of the microvasculature.
Pharmacological agents:
a. Anti VEGF : 1. Pegaptanib sodium
2. Bevacizumab 3. Ranibizumab
b. Corticosteroids: Triamcinolone acetonide
Indications for Anti VEGF:1. Severe PDR25 . 2.Diabetic
macular edema26 . 3. Prior to PRP and in severe PDR27,28.
4. Rubeosis iridis and neovascular glaucoma29 .
42
Fig.8: PDR with TRD: Extensive fibro vascular
proliferation along major vessel (Blue arrow) and
tractional retinal detachment seen.
Recent advances
�Fenofibrate: Fenofibrate is a peroxisome proliferactor–
activated receptor (PPAR)-á agonist indicated for the
treatment of hypertriglyceridemia and mixed dyslipidemia.
Fenofibrate (200 mg once daily) reduced the need of laser
treatment for macular edema by 31% and for proliferative
retinopathy by 30%.
�Aflibercept: Aflibercept is currently being used in
clinical trials for both exudative Age related Macular
Degeneration and DME. Aflibercept has a higher binding
affinity than other anti-VEGF agents, which translates
into greater activity at lower biological levels and,
consequently, a longer duration of action.
�Sustained drug delivery system:
1) Triamcinolone acetonide (TA) implant (I-vation ).
2) Dexamethasone intravitreal implant (Ozurdex) 0.7 mg
for diabetic macular edema (DME) in pseudophakic
patients or phakic patients scheduled for cataract surgery.
3) Ocriplasmin (Jetrea; ThromboGenics, Belgium) has
been approved by the FDA for the treatment of
vitreomacular adhesion and has some efficacy in inducing
a PVD30.
Conclusion:
Diabetic Retinopathy may be present without any
symptoms. Visual loss due to Diabetic Retinopathy is
usually irreversible. Moreover the awareness of Diabetic
Retinopathy is low among the general public.
Patient access, careful medical and ophthalmological
follow-up, and timely laser photocoagulation are
fundamental to the successful elimination of blindness in
people with diabetes mellitus.
Method of Literature Search
This review was written based on Medline searches with
key words and References as appropriate and using articles
cited in the references of journal articles.
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