Retinopathy, Diabetic, Background

Background
Diabetes mellitus (DM) is a major medical problem throughout the world. Diabetes causes an array of
long-term systemic complications, which have considerable impact on both the patient and the society
because it typically affects individuals in their most productive years.
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"phthalmic complications of
diabetes include corneal abnormalities, glaucoma, iris neovasculari#ation, cataracts, and neuropathies.
$owever, the most common and potentially most blinding of these complications is diabetic retinopathy.
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Pathophysiology
'he e(act mechanism by which diabetes causes retinopathy remains unclear, but several theories have
been postulated to e(plain the typical course and history of the disease.
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Growth hormone
+rowth hormone appears to play a causative role in the development and progression of diabetic
retinopathy. ,t was noted that diabetic retinopathy was reversed in women who had postpartum
hemorrhagic necrosis of the pituitary gland (-heehan syndrome). 'his led to the controversial practice of
pituitary ablation to treat or prevent diabetic retinopathy in the .*/s. 'his techni0ue has been
abandoned because of numerous systemic complications and the discovery of the effectiveness of laser
treatment.
Platelets and blood viscosity
'he variety of hematologic abnormalities seen in diabetes, such as increased erythrocyte aggregation,
decreased 123 deformability, increased platelet aggregation, and adhesion, predispose to sluggish
circulation, endothelial damage, and focal capillary occlusion. 'his leads to retinal ischemia, which, in
turn, contributes to the development of diabetic retinopathy.
Aldose reductase and vasoproliferative factors
4undamentally, diabetes mellitus (DM) causes abnormal glucose metabolism as a result of decreased
levels or activity of insulin. ,ncreased levels of blood glucose are thought to have a structural and
physiologic effect on retinal capillaries causing them to be both functionally and anatomically incompetent.
5 persistent increase in blood glucose levels shunts e(cess glucose into the aldose reductase pathway in
certain tissues, which converts sugars into alcohol (eg, glucose into sorbitol, galactose to dulcitol).
,ntramural pericytes of retinal capillaries seem to be affected by this increased level of sorbitol, eventually
leading to the loss of its primary function (ie, autoregulation of retinal capillaries).
6oss of function of pericytes results in wea7ness and eventual saccular outpouching of capillary walls.
'hese microaneurysms are the earliest detectable signs of DM retinopathy.
Fundus photograph of early background diabetic retinopathy showing multiple
microaneurysms.
1uptured microaneurysms (M5) result in retinal hemorrhages either superficially (flame-shaped
hemorrhages) or in deeper layers of the retina (blot and dot hemorrhages).
Retinal findings in background diabetic retinopathy, including blot hemorrhages
(arrowhead), microaneurysms (short arrow), and hard exudates (long arrow).
,ncreased permeability of these vessels results in lea7age of fluid and proteinaceous material, which
clinically appears as retinal thic7ening and e(udates. ,f the swelling and e(udation would happen to
involve the macula, a diminution in central vision may be e(perienced. Macular edema is the most
common cause of vision loss in patients with nonproliferative diabetic retinopathy (89D1). $owever, it is
not e(clusively seen only in patients with 89D1, but it also may complicate cases of proliferative diabetic
retinopathy (9D1).
5nother theory to e(plain the development of macular edema deals with the increased levels of
diacylglycerol (D5+) from the shunting of e(cess glucose. 'his is thought to activate protein 7inase 3
(9:3), which, in turn, affects retinal blood dynamics, especially permeability and flow, leading to fluid
lea7age and retinal thic7ening.
5s the disease progresses, eventual closure of the retinal capillaries occurs, leading to hypo(ia. ,nfarction
of the nerve fiber layer leads to the formation of cotton-wool spots (3;-) with associated stasis in
a(oplasmic flow.
More e(tensive retinal hypo(ia triggers compensatory mechanisms within the eye to provide enough
o(ygen to tissues. <enous caliber abnormalities, such as venous beading, loops, and dilation, signify
increasing hypo(ia and almost always are seen bordering the areas of capillary nonperfusion. ,ntraretinal
microvascular abnormalities (,1M5) represent either new vessel growth or remodeling of pree(isting
vessels through endothelial cell proliferation within the retinal tissues to act as shunts through areas of
nonperfusion.
4urther increases in retinal ischemia trigger the production of vasoproliferative factors that stimulate new
vessel formation. 'he e(tracellular matri( is bro7en down first by proteases, and new vessels arising
mainly from the retinal venules penetrate the internal limiting membrane and form capillary networ7s
between the inner surface of the retina and the posterior hyaloid face.
8eovasculari#ation most commonly is observed at the borders of perfused and nonperfused retina and
most commonly occur along the vascular arcades and at the optic nerve head. 'he new vessels brea7
through and grow along the surface of the retina and into the scaffold of the posterior hyaloid face. 2y
themselves, these vessels rarely cause visual compromise. $owever, they are fragile and highly
permeable. 'hese delicate vessels are disrupted easily by vitreous traction, which leads to hemorrhage
into the vitreous cavity or the preretinal space.
'hese new blood vessels initially are associated with a small amount of fibroglial tissue formation.
$owever, as the density of the neovascular frond increases, so does the degree of fibrous tissue
formation. ,n later stages, the vessels may regress leaving only networ7s of avascular fibrous tissue
adherent to both the retina and the posterior hyaloid face. 5s the vitreous contracts, it may e(ert tractional
forces on the retina via these fibroglial connections. 'raction may cause retinal edema, retinal
heterotropia, and both tractional retinal detachments and retinal tear formation with subse0uent
detachment.
Frequency
United States
5ppro(imately = million 5mericans have diabetes, with */> of them not even aware that they have it. "f
those that 7now, only one half receives appropriate eye care. 'hus, it is not surprising that diabetic
retinopathy is the leading cause of new blindness in persons aged %*-?) years in the @nited -tates,
responsible for more than A/// cases of new blindness each year.
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'his means that diabetes is
responsible for %> of blindnessB the rate is even higher among certain ethnic groups.
nternational
'he incidence of diabetes appears to be increasing throughout the world, at least in part due to the
increasing incidence of obesity and sedentary lifestyle. Dietary changes involving diets with higher fat and
carbohydrate inta7e as well as the increasing si#e of portions of food and drin7s over the past several
decades may also be responsible.
Mortality/Morbidity
'he treatment of diabetic retinopathy entails tremendous costs, but it has been estimated that this
represents only one eighth of the costs of social security payments for vision loss. 'his cost does not
compare to the cost in terms of loss of productivity and 0uality of life.
Race
5n increased ris7 of diabetic retinopathy appears to e(ist in patients with 8ative 5merican, $ispanic, and
5frican 5merican heritage.
Sex
-e( does not appear to have any affect on the development of diabetes or diabetic retinopathy.
Age
;ith increasing duration of diabetes, or with increasing age since the onset of diabetes, there is a higher
ris7 of developing diabetic retinopathy and the complications of diabetic retinopathy, including diabetic
macular edema or proliferative diabetic retinopathy.
Clinical
History
,n the initial stages, patients are generally asymptomaticB however, in the more advanced stages of the
disease, patients may e(perience symptoms, including blurred vision, distortion, or visual acuity loss.
Physical
Microaneurysms
o Carliest clinical sign of diabetic retinopathy
o -econdary to capillary wall outpouching due to pericyte loss
o 5ppear as small red dots in the superficial retinal layers
o 4ibrin and 123 accumulation in the microaneurysm lumen
o 1upture produces blotDflame hemorrhages
o May appear yellowish in time as endothelial cells proliferate and produce basement
membrane
Dot and blot hemorrhages
o "ccur as microaneurysms rupture in the deeper layers of the retina such as the inner
nuclear and outer ple(iform layers
o 5ppear similar to microaneurysms if they are smallB may need fluorescein angiography to
distinguish between the two
4lame-shaped hemorrhages - -plinter hemorrhages that occur in the more superficial nerve fiber
layer
1etinal edema and hard e(udates - 3aused by the brea7down of the blood-retina barrier, allowing
lea7age of serum proteins, lipids, and protein from the vessels
3otton-wool spots
o 8erve fiber layer infarction from occlusion of precapillary arterioles
o 4luorescein angiography - 8o capillary perfusion
o 4re0uently bordered by microaneurysms and vascular hyperpermeability
<enous loops, venous beading
o 4re0uently adjacent to areas of nonperfusion
o 1eflects increasing retinal ischemia
o Most significant predictor of progression to 9D1
,ntraretinal microvascular abnormalities
o 1emodeled capillary beds without proliferative changes
o 3ollateral vessels that do not lea7 on fluorescein angiography
o @sually can be found on the borders of the nonperfused retina
Macular edema
o 'his condition is the leading cause of visual impairment in patients with diabetes. 5
reported ?*,/// new cases of macular edema are diagnosed annually.
o 9ossibly due to functional damage and necrosis of retinal capillaries
o 3linically significant macular edema (3-MC) is defined as any of the followingE
1etinal thic7ening located *// Fm or less from the center of the foveal avascular
#one (45G)
$ard e(udates with retinal thic7ening *// Fm or less from the center of the 45G
1etinal thic7ening disc area or larger in si#e located within disc diameter of
the 45G
Mild nonproliferative diabetic retinopathy - 9resence of at least microaneurysm
Moderate nonproliferative diabetic retinopathy
o 9resence of hemorrhages, microaneurysms, and hard e(udates
o -oft e(udates, venous beading, and ,1M5 less than that of severe 89D1
-evere nonproliferative diabetic retinopathy ()-%-)
o $emorrhages and microaneurysms in ) 0uadrants
o <enous beading in at least % 0uadrants
o ,1M5 in at least 0uadrant
Mild 89D1 reflects structural changes in the retina caused by the physiological and anatomical
effects of diabetes. "n the other hand, the more advanced stages of 89D1 reflect the increasing
retinal ischemia setting up the stage for proliferative changes.
Causes
Risk factors
Duration of the diabetes
o ,n patients with type , diabetes, no clinically significant retinopathy can be seen in the first
* years after the initial diagnosis of diabetes is made. 5fter /-* years, %*-*/> of
patients show some signs of retinopathy. 'his prevalence increases to ?*-.*> after *
years and approaches //> after &/ years of diabetes.
o ,n patients with type ,, diabetes, the incidence of diabetic retinopathy increases with the
duration of the disease. "f patients with type ,, diabetes, %&> have 89D1 after -&
years, )> have 89D1 after )-= years, and =/> have 89D1 after = years.
+lucose control
o 'he Diabetic 3ontrol and 3omplications 'rial (D33') has demonstrated that intensive
glucose control reduced the incidence and the progression of diabetic retinopathy in
patients with insulin-dependent diabetes mellitus (,DDM).
o 5lthough no similar trials for patients with nonHinsulinHdependent diabetes mellitus
(8,DDM) have been completed, the 5merican Diabetes 5ssociation (5D5) has
suggested that glycosylated hemoglobin levels of less than ?> (reflecting long-term
glucose levels) should be the goal in all patients to prevent or slow down the onset of
diabetes-related complications.
1enal disease, as evidenced by proteinuria and elevated 2@8Dcreatinine levels, is an e(cellent
predictor of the presence of retinopathy. 'his probably is due to the fact that both conditions are
caused by DM-related microangiopathies such that the presence and severity of one reflects that
of the other. Cvidence suggests that aggressive treatment of the nephropathy may have a
beneficial effect on the progression of diabetic retinopathy and neovascular glaucoma.
-ystemic hypertension, in the setting of diabetic nephropathy, correlates well with the presence of
retinopathy. ,ndependently, hypertension also may complicate diabetes in that it may result in
hypertensive retinal vascular changes superimposed on the pree(isting diabetic retinopathy,
further compromising retinal blood flow.
9roper management of hyperlipidemia (elevated serum lipids) may result in less retinal vessel
lea7age and hard e(udate formation. 'he reason behind this is unclear.
9regnant women without any diabetic retinopathy run a /> ris7 of developing 89D1 during their
pregnancy. "f those with pree(isting 89D1, )> progress to the proliferative type.
Dierential Diagnoses
2ranch 1etinal <ein "cclusion
3entral 1etinal <ein "cclusion
"cular ,schemic -yndrome
1etinopathy, $emoglobinopathies
-ic7le 3ell Disease
"ther Proble#s to Be Considered
1etinopathy, radiation
$orkup
%aboratory Studies
4asting glucose and hemoglobin 5c ($b5c) are important laboratory tests that are performed
to help diagnose diabetes. 'he $b5c level is also important in the long-term follow-up care of
patients with diabetes and diabetic retinopathy. 3ontrolling diabetes and maintaining the $b5c
level in the =-?> range are the goals in the optimal management of diabetes and diabetic
retinopathy. ,f the levels are maintained, then the progression of diabetic retinopathy is reduced
substantially, according to the D33'.
&#aging Studies
4luorescein angiography is an invaluable adjunct in the diagnosis and management of diabetic
retinopathy.
o Microaneurysms would appear as pinpoint hyperfluorescence that does not enlarge but
rather fades in the later phases of the test.
o 2lot and dot hemorrhages can be distinguished from microaneurysms because they
appear as hypofluorescent rather than hyperfluorescent.
o 5reas of nonperfusion appear as homogenous dar7 patches bordered by occluded blood
vessels.
o ,1M5 is evidenced by collateral vessels that do not lea7, usually found in the borders of
the nonperfused retina.
"ther 'ests
"ther tests may include optical coherence tomography ("3'), which uses light to generate a
cross-sectional image of the retina. 'his is used to determine the thic7ness of the retina and the
presence of swelling within the retina as well as vitreomacular traction. 'his test is particularly
used for the diagnosis and management of diabetic macular edema or clinically significant
macular edema.
'reat#ent
Medical Care
+lucose controlE 'he D33' has found that intensive glucose control in patients with ,DDM has
decreased the incidence and progression of diabetic retinopathy.
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5lthough no similar clinical
trials for patients with 8,DDM e(ist, it may be logical to assume that the same principles also
apply. ,n fact, the 5D5 has suggested that all diabetics (8,DDM and ,DDM) should strive to
maintain glycosylated hemoglobin levels of less than ?> to prevent or at the very least to
minimi#e the long-term complications of DM, including DM retinopathy.
'he Carly 'reatment for Diabetic 1etinopathy -tudy (C'D1-) found that =*/ mg of aspirin daily
did not offer any benefit in preventing the progression of DM retinopathy. 5dditionally, aspirin was
not observed to influence the incidence of vitreous hemorrhage in patients who re0uired it for
cardiovascular disease (3<D) or other conditions.
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Surgical Care
'he advent of laser photocoagulation in the .=/s and early .?/s provided a noninvasive treatment
modality that has a relatively low complication rate and a significant degree of success. 'his involves
directing a high-focused beam of light energy to create a coagulative response in the target tissue. ,n
89D1, laser treatment is indicated in the treatment of 3-MC. 'he strategy for treating macular edema
depends on the type and e(tent of vessel lea7age.
,f the edema is due to lea7age of specific microaneurysms, the lea7ing vessels are treated
directly with focal laser photocoagulation.
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,n cases where the foci of lea7age are nonspecific, a grid pattern of laser burns is applied.
Medium intensity burns (//-%// Fm) are placed burn si#e apart covering the affected area.
"ther off-label potential treatments of diabetic macular edema (DMC) include intravitreal
triamcinolone acetonide (:enalog) and bevaci#umab (5vastin). 2oth of these medications can
result in a substantial reduction or resolution of macular edema.
Diet
5 good healthy diet with well-balanced meals is important for all individuals and is particularly important
for individuals with diabetes. 5 well-balanced diet can help to achieve better weight control and also better
control of the diabetes. 'o that end, it can also help to reduce the complications of diabetes.
Acti(ity
Maintaining a good healthy lifestyle with regular e(ercise is important for all individuals, especially for
those individuals with diabetes. C(ercise can help with maintaining weight and with peripheral glucose
absorption. 'his can help with improved diabetes control, and this, in turn, can help to reduce the
complication of diabetes and diabetic retinopathy.
Medication
-everal medications are currently being used in an off-label manner in the treatment of diabetic
retinopathy. 5t present, these medications are administered into the eye by intravitreal injection.
,ntravitreal triamcinolone is being used in the treatment of diabetic macular edema. 5 recent Diabetic
1etinopathy 3linical 1esearch 8etwor7 (D131.net) clinical trial demonstrated that, although some
reduction in macular edema occurred after intravitreal triamcinolone, this effect was not as robust as that
achieved with focal laser treatment at the primary endpoint of % years.
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,n addition, intravitreal
triamcinolone can have some side effects, including steroid response with intraocular pressure increase
and cataracts.
"ther medications that are being used in clinical practice and in clinical trials include intravitreal
bevaci#umab (5vastin) and ranibi#umab (6ucentis). 'hese medications are <C+4 antibodies and
antibody fragments, respectively. 'hey can help to reduce diabetic macular edema and also
neovasculari#ation of the disc or retina. 3ombinations of some of these medications above with focal
laser treatment are being investigated in the D131.net clinical trials.
Follo)*up
Further "utpatient Care
'he fre0uency of follow-up care is dictated primarily on the baseline stage of the retinopathy and
its rate of progression to proliferative diabetic retinopathy (9D1).
o "nly *> of patients with mild 89D1 would progress to 9D1 in year and, thus, could be
monitored every =-% months.
o 5s many as %?> of patients with moderated 89D1 would progress to 9D1 in yearB
therefore, they should be seen every )-A months.
o More than */> of patients with severe 89D1 (preproliferative stage) would progress to
9D1 in a yearB thus, follow-up care as fre0uent as %-) months is mandated to ensure
prompt recognition and treatment.
o 5ny stage associated with clinically significant macular edema (3-MC) should be treated
and observed closely (every %-& mo) to monitor the status of the macula.
Deterrence/Pre(ention
'he Diabetes 3ontrol and 3omplications 'rial (D33') and @nited :ingdom 9rospective Diabetes
-tudy (@:-9D-) were large randomi#ed clinical trials that demonstrated the importance of tight
glucose control with respect to reducing the incidence and progression of diabetes complications
including diabetic retinopathy for both type and type % diabetes.
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Co#plications
'he complications of focal and grid laser therapy include the followingE
o Decreased central vision
o 9aracentral scotomas
o 3horoidal neovasculari#ation
o Cpiretinal membrane formation
o 4urther increase in macular edema
Prognosis
'he Carly 'reatment for Diabetic 1etinopathy -tudy (C'D1-) has found that laser surgery for
macular edema reduces the incidence of moderate visual loss (doubling of visual angle or roughly
a %-line visual loss) from &/> to *> over a &-year period.
4avorable prognostic factors
o 3ircinate e(udates of recent onset
o ;ell-defined lea7age
o +ood perifoveal perfusion
@nfavorable prognostic factors
o Diffuse edemaDmultiple lea7s
o 6ipid deposition in the fovea
o Macular ischemia
o 3ystoid macular edema
o 9reoperative vision of less than %/D%//
o $ypertension
Patient +ducation
"ne of the most important aspects in the management of diabetic retinopathy is patient
education. ,nform patients that they play an integral role in their own eye care. Cmphasi#e the
following factsE
o C(cellent glucose control is beneficial in any stage of diabetic retinopathy. ,t delays the
onset and slows down the progression of the diabetic complications in the eye.
o "ther systemic problems, such as hypertension, renal disease, and hyperlipidemia, may
contribute to the progression of the retinopathy and should be addressed promptly.
o -mo7ing, although not directly proven to affect the course of the retinopathy, may play a
role in further compromising o(ygen delivery to the retina. 'herefore, all efforts should be
made in the reduction, if not outright cessation, of smo7ing.
o <isual symptoms (eg, changes in vision, redness, pain) could be manifestations of
disease progression and should be reported immediately.
o DM in general and diabetic retinopathy in particular are progressive conditions such that
regular follow-up care with a physician is crucial to detect any changes that may benefit
from treatment.
4or e(cellent patient education resources, see eMedicineIs Diabetes 3enter. 5lso, visit
eMedicineIs patient education article Diabetic Cye Disease.
Miscellaneous
Medicolegal Pitalls
4ailure to emphasi#e to the patient that focal or grid laser treatment of clinically significant
macular edema (3-MC) is not aimed at improving vision but rather at reducing the ris7 of
moderate visual loss.
Special Concerns
5ll individuals with diabetes should be aware of the importance of regular dilated retinal
e(aminations. Carly diagnosis and treatment of diabetic retinopathy can help prevent blindness in
more than ./> of cases. $owever, in spite of treatment, sometimes, individuals can still lose
vision. 'he patient, ophthalmologist or retina specialist, and internist or endocrinologist must wor7
together as a team to optimi#e the diabetes control and help to reduce the ris7 of blindness.