Current
Perspectives of Diabetic Retinopathy
A
Photo-Essay for Health Professionals-
John
G. O'Shea MD, Robert
B. Harvey FRCSE
Epidemiology
l
l
lDiabetes
is one of the most serious challenges to health care world-wide. According
to recent projections it will affect 239 million people by 2010- doubling in
prevalence since 1994.
Diabetes
will affect 28 million in western Europe, 18.9 million in North America
138.2 million in Asia, 1.3
million in Australasia.
l
lDiabetes
mellitus is the most common cause of blindness amongst individuals of
working-age ( 20-65 years). The prevalence of blindness due to DR in Western
Communities is estimated as between 1.6-1.9/ 100,000
About
8% of UK BD8 registrations are due to diabetes.
(
The World Health Organisation (1992) definition of
blindness is vision less than 3/60 in the better eye with best
available spectacle correction. )
lAbout
2% of type 2 diabetics have CSME at diagnosis and 10.2% have other signs of
DR already present when their diabetes is discovered.
l
Mitchell
and co- workers found that 15.8 % of undiagnosed diabetics in an elderly
Australian population had signs of DR, according
to the recent Blue Mountains Eye Study. Indeed it may often take from 9-12
years for type 2 diabetes to be diagnosed
A
Classification of Diabetic Retinopathy
l
A
useful clinical classification according to the types of lesions detected on
lfundoscopy
is as follows:
l
lNon-proliferative
diabetic retinopathy (NPDR)
l
lMild
non-proliferative diabetic retinopathy
lMicroaneurysms
lDot
and blot haemorrhages
lHard
( intra-retinal ) exudates
l
lModerate-to-severe
non-proliferative diabetic retinopathy
l
lThe
above lesions, usually with exacerbation,
plus:
lCotton-wool
spots
lVenous
beading and loops
lIntraretinal
microvascular abnormalities ( IRMA )
l
lProliferative
diabetic retinopathy
l
lNeovascularization
of the retina, optic disc or iris
lFibrous
tissue adherent to vitreous face of retina
lRetinal
detachment
lVitreous
haemorrhage
lPre
retinal haemorrhage
l
lMaculopathy
lClinically
significant macular oedema (CSME
)
lIschaemic
Maculopathy
l
Pathogenesis
of Diabetic Microangiopathy and Characteristic Fundus Lesions
lHyperglycaemia
causes-
lBM
thickening
lnon
enzymaitc glycosylation
lincreased
free radical activity
lincreased
flux through the polyol pathway
losmotic
damage
lHaemostatic abnormalities of the microcirculation-
lIt has also been postulated that platelet abnormalities in
diabetics may contribute to diabetic retinopathy. There are three
steps in platelet coagulation: initial adhesion, secretion, and
further aggregation. It has been shown that the platelets in
diabetic patients are "stickier" than platelets of
non-diabetics They secrete prostaglandins that cause other platelets
to adhere to them (aggregation) and blockage of the vessel and
endothelial damage.
Microaneurysms
lRetinal
microaneurysms are focal dilatations of retinal capillaries, 10 to 100
microns in diameter, and appear as red dots. They are usually seen at the
posterior pole, especially temporal to the fovea. They may apparently
disappear whilst new lesions appear at the edge of areas of widening
capillary non-perfusion. Microaneurysms are the first ophthalmoscopically
detectable change in diabetic retinopathy.
lBeginning as dilatations in areas in
the capillary wall where pericytes are absent, microaneurysms
are initially thin-walled. Later, endothelial cells proliferate and lay down
layers of basement membrane material around themselves.
lFibrin
and erythrocytes may accumulate within the aneurysm. Despite multiple layers
of basement membrane, they are permeable to water and large molecules,
allowing the accumulation of water and lipid in the retina. Since
fluorescein passes easily through them, many more microaneurysms are usually
seen on fluorescein angiography than are apparent on ophthalmoscopy
Perifoveal microaneuryisms and haemorrhages
Retinal Haemorrhages
lWhen
the wall of a capillary or microaneurysm is sufficiently weakened, it
may rupture, giving rise to an intraretinal haemorrhage. If the
hemorrhage is deep (i.e., in the inner nuclear layer or outer plexiform
layer), it usually is round or oval ("dot or blot")
lDot
haemorrhages appear as bright red dots and are the same size as large
microaneurysms. Blot
haemorrhages are larger lesions they are located within the mid retina
and often within or surrounding areas of ischaemia. (1,4,)
lIf
the hemorrhage is more
superficial and in the nerve fiber layer, it takes a flame or splinter
shape, which is indistinguishable from a hemorrhage seen in hypertensive
retinopathy. They often absorb slowly after several weeks. Their
presence strongly suggests the co-existence of systemic hypertension.
lDiabetics
with normal blood pressure may have multiple splinter haemorrhages.
Nevertheless, when an ophthalmologist sees numerous splinter
haemorrhages in a diabetic patient, the patient's blood pressure must be
checked because a frequent complication of diabetes is systemic
hypertension.
l
Cotton
wool spots result from occlusion of retinal pre-capillary arterioles
supplying the nerve fibre layer with concomitant swelling of local nerve
fibre axons. Also called "soft exudates" or "nerve fibre
layer infarctions" they are white, fluffy lesions in the nerve fibre
layer. Fluorescein angiography shows no capillary perfusion in the area of
the soft exudate. They are very common in DR, especially if the patient is
also hypertensive
Hard exudates ( Intra-retinal lipid exudates )
lHard
exudates ( Intra-retinal lipid exudates ) are yellow deposits of lipid
and protein within the sensory retina. Accumulations of
lipids leak from surrounding capillaries and microaneuryisms,
they may form a circinate pattern. Hyperlipidaemia may correlate with
the development of hard exudates.
lAccumulations
of
lipids leak from surrounding capillaries and microaneuryisms, they
may form a circinate pattern.
Late
non proliferative changes
Intra-retinal
microvascular abnormalities ( IRMA) are abnormal, dilated retinal
capillaries or may represent intraretinal neovacularization which has not
breached the internal limiting membrane of the retina.
l They
indicate severe non-proliferative diabetic retinopathy that may rapidly
progress to proliferative retinopathy. Venous beading has an
appearance resembling sausage-shaped
dilatation of the retinal veins. It is another sign of severe non
proliferative diabetic retinopathy.
Diabetic
Maculopathies
Characteristics
of Clinically Significant Macular (O)Edema ( CSME )
lMacular
oedema is thus an important manifestation of DR because it is now the
leading cause of legal blindness in diabetics. The intercellular fluid comes
from leaking microaneurysms or from diffuse capillary leakage .It should be
stressed however that current regimes now lay emphasis on the treatment of
retinal thickening by grid laser than direct treatment of microaneuyrisns
and other discreet lesions.
lThe
leading cause of visual loss
amongst diabetics. Diagnosed by
stereoscopic assessment of retinal thickening, usually by slit lamp
biomicroscopy.
lDefined
as the presence of one or more of the following, ( Modified Airlie -House
Criteria )
lRetinal
oedema within 500 microns of
the centre fovea.
lHard
exudates within 500 microns of fovea if associated with adjacent retinal
thickening
lRetinal
oedema that is one disc diameter or larger,
any part of which is within one disc diameter of the centre of the
fovea.
lLaser
grid photocoagulation reduces the risk of visual loss by 50% at
2 years
l
l
Ischaemic Maculopathy
Maculopathy
in type 1 diabetics is often due to drop out of the perifoveal capillaries
with non perfusion and the consequent development of an ischaemic
maculopathy.
lEnlargement
of the foveal avascular zone (FAZ) is frequently seen on fluorescein
angiography. Ischaemic
maculopathy is not uncommon in type 2 diabetics, maculopathy in this group
may show both changes due to ischaemia but also retinal thickening.
l
Proliferative
diabetic retinopathy
Retinal
ischaemia due to widespread capillary non perfusion results in the
production of vasoproliferative substances and to the development of
neovascularization. Neovascularization can involve the retina, optic disc or
the iris( rubeosis iridis).
lRubeosis
iridis is a sign of severe proliferative disease, it may cause intractable
glaucoma.
lBleeding
from fragile new vessels involving the retina or optic disc can result in
vitreous or retinal haemorrhage. Retinal damage can result from persistent
vitreous haemorrhage.
lPre-retinal
haemorrhages are often associated with retinal
neovascularization, they
may dramatically reduce vision within a few minutes.
Above-
Proliferative retinopathy and Iris Neovascularisation (NVI)
Contraction
of associated fibrous tissue formed
by
proliferative disease tissue can result in deformation of the retina
and tractional retinal detachment
l
There are two characteristic types of diabetic retinal
detachments: those caused by traction alone (non-rhegmatogenous) and those
caused by traction and retinal break formation (rhegmatogenous)
lCharacteristics
of nonrhegmatogenous detachment in PDR include the following: (1) the
detached retina is usually confined to the posterior fundus and infrequently
extends more than two thirds of the distance to the equator; (2) it has a
taut and shiny surface; (3) it is concave toward the pupil; and (4) there is
no shifting of subretinal fluid.
Screening
and Monitoring the Progress of Diabetic Retinopathy
Cost effective community screening for DR
lThe
current consensus of opinion from Europe and the United States is that
screening for DR by suitably trained and experienced practitioners is
cost effective and results in reduced morbidity due to blindness.
lAn
inter -disciplinary approach is commonly used, optometrists for example, are
becoming increasingly involved in the care of diabetics.
lThe
characteristics of a good screening programme being that the target patients
in the community are found and seen at the prescribed intervals, and that
the practitioners who conduct the screening have adequate training, that is
they must be familiar with both the manifestations of diabetic eye disease
and, if possible, with slit lamp biomicroscopy or with methods of
photoscreening.
lPatient
education and growing community awareness concerning diabetes is likely to
bring newly diagnosed and undiagnosed diabetics into the screening system.
l
Ophthalmoscopic methods of diabetic screening
Screening
should include the following:
The
history of any visual symptoms or changes in vision
l2.
Measurement of visual acuity (unaided,
with spectacles / pinhole as necessary)
l3.
Iris examination by slit lamp biomicroscopy
prior to pupil mydriasis.
l4.
Pupil mydriasis. ( tropicamide 0.5 % ) -the risk of precipitating angle
closure glaucoma is actually very small.
Patients should be
accompanied by a relative and instructed not to drive home.
l5.
Examination of the crystalline lens by slit lamp biomicroscopy.
l6.
Fundus examination by slit lamp biomicroscopy using diagnostic contact lens
or slit lamp indirect ophthalmoscopy.
lThe direct ophthalmoscope enables
adequate examination of only the posterior pole
whilst the indirect ophthalmoscope provides insufficient magnification. Slit
lamp examination ( using either indirect ophthalmoscopy with a convex
aspheric lens or diagnostic contact lens)
yields much more information by providing
stereoscopic assessment of retinal thickening and proliferative
retinopathy, particularly important when assessing possible retinal
traction. It is therefore imperative to facilitate cost-effective screening
more that more practitioners are trained in slit lamp biomicroscopy of the
fundus with emphasis on detection and monitoring of diabetic eye disease.
The use of ophthalmoscopy however has the
disadvantage that there is no hard record, which makes quality assurance
more difficult.
Audit
of test positives or of adverse events is not sufficient for quality
assurance purposes, and patients would need to be recalled to assess test
negatives, for which attendance rates may be very low.
The personnel performing the examination require considerable
training and accreditation.
l
Photoscreening
lAn
alternative to slit lamp biomicroscopy
is the photoscreening of diabetic patients with a fundus
camera. Photoscreening is
very popular in some parts of the United Kingdom and the USA - the
physician or ophthalmologist subsequently examining the photographs
for evidence of DR - this
approach also obviates the need to be proficient with a slit lamp
and also provides a permanent record of the contemporary status of
DR. The camera can also be bought to remote rural areas and
the pictures later examined.
lPhotoscreening
will not always detect subtle signs of DR , such as retinal
thickening, but a success rate of 80-92% in detecting DR is claimed
by researchers. There are numerous photographic techniques used
ranging from a single photograph to a
9 photograph collage. Three
photographs spread across the posterior pole are now widely regarded
as being most cost efficient.
lSensitivities
for the detection of sight-threatening retinopathy are lower with
instant polaroid photographs.
lDigital
images have the advantage that they are easier to acquire, store and
transfer than 35mm film, and that images can be reviewed with the
patient at the time of screening. patients also find the lower
intensity flash more comfortable
EFFECTIVENESS
OF DIFFERENT SCREENING METHODS
Direct ophthalmoscopy
Studies from the UK have shown sensitivity levels for the detection
of sight-threatening diabetic retinopathy of 41-67% for general
practitioners, 48-82% for optometrists, 65% for an ophthalmologist, and
27-67% for diabetologists and hospital physicians using direct
ophthalmoscopy.
There are few studies specifically assessing the use of dilated
slit-lamp indirect ophthalmoscopy, but it does appear that the required
standards may be achieved by trained individuals. Sensitivities for the
detection of referable retinopathy by optometrists have been found to be
77-100%, with specificities of 94-100%.
The use of mydriasis results in improved sensitivity for the
detection of sight-threatening retinopathy and fewer ungradeable images.
Sensitivities for the detection of sight-threatening diabetic
retinopathy of 87-100% have been found for a variety of trained personnel
reading mydriatic 45° retinal photographs, with specificities of 83-96%.
lThe
results were similar between different personnel performing the grading,
including trained non-medical graders. it appears that there is good
agreement in the grading of retinopathy between 35mm colour film and digital
images despite the lower resolution of the latter.
lIn
the United Kingdom the National Screening Committee has recently
considered the issues surrounding screening for diabetic retinopathy and
after wide consultation has provided recommendations on screening and the
practicalities of a national programme. Details of these can be seen on the
website:
www.diabetic-
retinopathy-screening.nhs.uk
l
Principal recommendations
of the National Screening Committee (UK) -
Annual screening for all diabetic patients
aged over 12 years, or post-puberty.
lThe
screening programme should be accessible to all patients with diabetes. The
exact details of a programme for a particular area will be determined by
local factors.
lThe
proposed national programme would be rolled out over a period of 3-4 years,
as both funding and trained staff become available.
lDigital imaging is the preferred modality.
lQuality assurance should be included in any programme.
lDirect
ophthalmoscopy should not be used as a primary method for systematic
screening as it does not meet the required quality criteria.
lIndirect
slit-lamp ophthalmoscopy may meet the sensitivity and specificity
requirements but requires considerable skills and training, and it is hard
to perform adequate quality assurance.
Therapeutics
MEDICAL-
General
aspects of the ocular care of diabetics
lFactors
that can worsen diabetic retinopathy- and indeed the general prognosis of
diabetes, include poor diabetic control, systemic
hypertension,hyperlipidaemia, cigarette smoking, diabetic nephropathy,
anaemia, pregnancy and cataract surgery
Glycaemic
control
lIt
is now proven that good diabetic control may slow the development and
progression of diabetic retinopathy in both type 1 and type 2 diabetes.
lFor
example, the United Kingdom Prospective Diabetes Study 1998 (UKPDS)
followed 5,102 newly diagnosed type 2 diabetics prospectively since
1977. Those diabetics who were intensively treated and achieved tight
control with either insulin or suphonylurea had diabetic endpoints 12% lower
than less well controlled
diabetics.
l
Overall there was a 25% reduction in microvascular end points in the group
exhibiting good glycaemic control
Systemic
hypertension and DR in type 2 diabetes
lRecent
literature indicates that there is a striking correlation between the
presence of systemic hypertension and progression of
diabetic retinopathy. Recent studies have delineated the role of
treating associated hypertension and the slowing of the progress of DR. It
is important to note that many type 2 diabetics will need a combination of
anti-hypertensive agents to lower their blood pressure.
Cotton
wool spots and flame shaped heamorrhages on fundoscopy often indicate
concomitant hypertension.
lThe
hypertension in diabetes study was launched within
the original UKPDS study in 1987.
lThe
study compared diabetics whose blood pressure was tightly controlled ( BP
< 150/85)with ACE inhibitors and beta blockers with a cohort whose
blood pressure was less tightly controlled. (BP <180/ 95 ) Median
follow up was 8.4 years.
lThe
reduction of macrovascular events was significant with a 32% reduction in
diabetes related deaths. There was a 44% reduction in stroke and a 34%
reduction in overall macrovascular disease.
lUKPDS
is a unique study in that it
also looked at microvascular end points in type 2 diabetics. Overall the
tight control group had a 37% reduction in microvascular disease, this was
a more striking reduction than tight glycaemic control.
lThis
effect was manifested as a reduction
of the risk of having
to undergo laser photocoagulation by 34%.
Systemic
hypertension and DR in type 2 diabetes
lThe
risk of reduction of visual acuity was lowered by 47%.
lAtenolol
and Captopril were equally effective in reducing the risk of
progression of retinopathy in type 2 diabetics.
lThe
Hypertension Optimal Treatment ( HOT ) study indicates that the lowest
incidents of cardiac events occurs when blood pressure is lowered to
82.6 mmHg diastolic and 136 mmHg systolic.
Angiotensin
Converting Enzyme (ACE)
inhibitors in Type 1 diabetes
lThe
EUCLID study is currently investigating the prophylactic treatment of
type 1 diabetics with the Angiotensin Converting Enzyme (ACE)
Inhibitor Lisinopril and
the progression of nephropathy and other microvascular disease
including DR . Preliminary reports are of a specific benefit are
encouraging, with a claimed 50% reduction in progression of DR in type
1 diabetics.
lThe
study did not look at maculopathy- so that implications are unclear
for type 2 diabetics, although no specific advantage of ACE inhibitors
(Captopril) over Atenolol was seen in UKPDS.
Hyperlipidaemia
and diabetic maculopathy
There
is evidence in the literature that diabetics who have exudative
maculopathy with extensive lipid exudes benefit from active treatment of
hyperlipidaemia
Diabetic
nephropathy
lDiabetic
nephropathy accelerates the progression of retinopathy, especially macular
oedema, inter alia via increased levels of fibrinogen and lipoprotein
and associated hypertension.
lThe
visual prognosis is often better
if the nephropathy is treated by renal transplantation rather than by
dialysis
l Any
anaemia resulting from renal disease must be aggressively treated.
lDiabetic
retinopathy is a common prelude to the development of
renal disease.
Tightening
Glycaemic control
lTightening
of glycaemic control may initially produce worsening of retinopathy. The
postulated mechanism includes lowering of retinal blood low or
overproduction of IGF-1 by the liver.
lIt
is therefore recommended that monitoring of retinopathy is increased if
major changes to glycaemic control are made particularly in previously
poorly controlled diabetics. Ideally
glycated haemoglobin ( HbA1c) should be maintained below 7%.
Pregnancy
Pregnancy
may accelerate the progression of diabetic retinopathy. Frequency of
monitoring NPDR should therefore be increased.Women who begin a pregnancy
with no retinopathy, the risk of developing diabetic retinopathy is about
10%.
lThose
with DR at the onset of pregnancy may show progression, with increased
haemorrhages, soft exudates, and macular edema. There is no doubt that
women who maintain good metabolic control during pregnancy have fewer
spontaneous abortions and fewer children with birth defects.
lThose
with untreated PDR at the onset frequently do poorly unless they are
treated with panretinal photocoagulation. Finally, patients with
previously treated PDR often do not worsen during the pregnancy.
lWomen
who begin pregnancy with poorly controlled diabetes and who are suddenly
brought under strict control frequently have severe deterioration of their
retinopathy and do not always recover after delivery
Cataract
surgery
l
Cataract
surgery may lead to progression of pre-existing macular oedema and
proliferative diabetic retinopathy. However, cataracts may impede fundoscopy
and therefore interfere with the treatment of diabetic retinopathy. If
possible, diabetic retinopathy should be treated prior to cataract surgery
SURGICAL-Panretinal laser photocoagulation for proliferative DR
lThe
mainstay of treatment of diabetic retinopathy is retinal laser
photocoagulation, an ablative treatment. Laser therapy is highly
effective; the rate of severe visual loss at 2 years due to proliferative
disease can be reduced by 60%.
lLaser
photocoagulation causes a retinal burn which is visible on fundoscopy.
Retinal and optic disc neovascularization can regress with the use
of retinal laser photocoagulation.
l
lRubeosis
iridis requires urgent panretinal photocoagulation to prevent ocular pain
and blindness from glaucoma.
l
The
technique of laser photocoagulation delivery involves the application of
eyedrops
l(
for pupil dilatation and corneal anaesthesia ) and the application of an
optical contact lens. Mild proliferative retinopathy is usually
treated with at least 600 burns placed between the retinal equator and the
retinal vascular arcades. A complete panretinal photocoagulation treatment
requires at least 1500 burns.
Although laser therapy can be highly effective in preventing
blindness, it is associated with numerous complications.
lRetinal
vein occlusion can follow inadvertent photocoagulation of a retinal vein.
Rarely, there may be loss of central acuity from inadvertent
photocoagulation of the fovea.
lVitreous haemorrhage can follow
photocoagulation of retinal or choroidal
vessels.
lThere
may be visual field restriction, decreased contrast sensitivity,
impaired night vision or impaired colour vision.
lVisual
field constriction may impair fitness to drive although ophthalmologists
increasingly strive to avoid this most undesirable problem, for example by
avoiding confluent laser burns.
lA
recent study indicates that 88% of diabetics who have undergone
laser photocoagulation would pass the Esterman binocular field test
which is the legal criterion for fitness to drive in the United Kingdom,
even if both eyes were treated. 42% of uniocular fields failed to make the
criterion of a 120 degree horizontal field. Patients who have already lost
the sight in one eye therefore have a
significant chance of failing
to meet legal parameters for
fitness to drive in the United Kingdom.
lHeadache can sometimes follow laser
therapy. The headache is
usually
lrelieved
with rest and simple analgesia. Glaucoma must be excluded if the
headache is severe or persistent.
Macular laser grid therapy for CSME
lThe
indications for laser therapy now include CSME which is treated with a
macular laser grid or treatment of focal lesions such as microaneuryisms.
Early referral and detection of disease is important as treatment of
maculopathy is far more
successful if undertaken at an early stage of the disease process.
lThere
is a reduction in the rate of loss of vision by 50% at 2 years with
macular grid therapy.
lVitrectomy,
plays a vital role in the management of severe complications of
diabetic retinopathy.
lThe
major indications are nonclearing vitreous hemorrhage, traction
retinal detachment, and combined traction/rhegmatogenous retinal
detachment. Less common indications are macular edema with a thickened
and taut posterior hyaloid, macular heterotopia, and tight preretinal
macular hemorrhage.
lThe
early detection of diabetic retinopathy leads to a marked reduction of
morbidity due to visual loss.
lMajor
international studies all indicate
therapy is best instituted before serious complications develop, screening
of our diabetic population and of our elderly population to detect
undiagnosed DR should therefore be undertaken.
lKey
lesions of diabetic retinopathy have been described and screening protocols
summarised.
lLaser
photocoagulation, the principal form of therapy,
is also described as are means of modifying lifestyle to decrease the
morbidity of diabetic retinopathy.
l
Contact
Us
Author
: John G. O'Shea MD
Illustrations:
Robert Harvey FRCSEd (from
Practical Ophthalmology, 2002
Palmtrees Publishing)
Webmaster:
David Kinshuck FRCS
E-mail Address :
rob_harvey@msn.com
Birmingham
and Midland Eye Centre, Dudley Rd, Birmingham
B18 7QH, U.K.
