Diabetic Retinopathy, Introduction

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.1 Ophthalmic complications of diabetes include
corneal abnormalities, glaucoma, iris neovascularization, cataracts, and neuropathies. However, the most
common and potentially most blinding of these complications is diabetic retinopathy.2,3

Pathophysiology

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 disease.4,5

Growth hormone

Growth hormone appears to play a causative role in the development and progression of diabetic retinopathy.
It was noted that diabetic retinopathy was reversed in women who had postpartum hemorrhagic necrosis of
the pituitary gland (Sheehan syndrome). This led to the controversial practice of pituitary ablation to treat or
prevent diabetic retinopathy in the 1950s. This technique has been abandoned because of numerous systemic
complications and the discovery of the effectiveness of laser treatment.

Platelets and blood viscosity

The variety of hematologic abnormalities seen in diabetes, such as increased erythrocyte aggregation,
decreased RBC deformability, increased platelet aggregation, and adhesion, predispose to sluggish
circulation, endothelial damage, and focal capillary occlusion. This leads to retinal ischemia, which, in turn,
contributes to the development of diabetic retinopathy.

Aldose reductase and vasoproliferative factors

Fundamentally, diabetes mellitus (DM) causes abnormal glucose metabolism as a result of decreased levels or
activity of insulin. Increased 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.

A persistent increase in blood glucose levels shunts excess glucose into the aldose reductase pathway in
certain tissues, which converts sugars into alcohol (eg, glucose into sorbitol, galactose to dulcitol). Intramural
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).

Loss of function of pericytes results in weakness and eventual saccular outpouching of capillary walls. These
microaneurysms are the earliest detectable signs of DM retinopathy.
Ruptured microaneurysms (MA) result in retinal hemorrhages either superficially (flame-shaped
hemorrhages) or in deeper layers of the retina (blot and dot hemorrhages).

Increased permeability of these vessels results in leakage of fluid and proteinaceous material, which clinically
appears as retinal thickening and exudates. If the swelling and exudation would happen to involve the macula,
a diminution in central vision may be experienced. Macular edema is the most common cause of vision loss in
patients with nonproliferative diabetic retinopathy (NPDR). However, it is not exclusively seen only in
patients with NPDR, but it also may complicate cases of proliferative diabetic retinopathy (PDR).
Another theory to explain the development of macular edema deals with the increased levels of diacylglycerol
(DAG) from the shunting of excess glucose. This is thought to activate protein kinase C (PKC), which, in
turn, affects retinal blood dynamics, especially permeability and flow, leading to fluid leakage and retinal
thickening.

As the disease progresses, eventual closure of the retinal capillaries occurs, leading to hypoxia. Infarction of
the nerve fiber layer leads to the formation of cotton-wool spots (CWS) with associated stasis in axoplasmic
flow.

More extensive retinal hypoxia triggers compensatory mechanisms within the eye to provide enough oxygen
to tissues. Venous caliber abnormalities, such as venous beading, loops, and dilation, signify increasing
hypoxia and almost always are seen bordering the areas of capillary nonperfusion. Intraretinal microvascular
abnormalities (IRMA) represent either new vessel growth or remodeling of preexisting vessels through
endothelial cell proliferation within the retinal tissues to act as shunts through areas of nonperfusion.

Further increases in retinal ischemia trigger the production of vasoproliferative factors that stimulate new
vessel formation. The extracellular matrix is broken down first by proteases, and new vessels arising mainly
from the retinal venules penetrate the internal limiting membrane and form capillary networks between the
inner surface of the retina and the posterior hyaloid face.

Neovascularization 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. The new vessels break through and
grow along the surface of the retina and into the scaffold of the posterior hyaloid face. By themselves, these
vessels rarely cause visual compromise. However, they are fragile and highly permeable. These delicate
vessels are disrupted easily by vitreous traction, which leads to hemorrhage into the vitreous cavity or the
preretinal space.

These new blood vessels initially are associated with a small amount of fibroglial tissue formation. However,
as the density of the neovascular frond increases, so does the degree of fibrous tissue formation. In later
stages, the vessels may regress leaving only networks of avascular fibrous tissue adherent to both the retina
and the posterior hyaloid face. As the vitreous contracts, it may exert tractional forces on the retina via these
fibroglial connections. Traction may cause retinal edema, retinal heterotropia, and both tractional retinal
detachments and retinal tear formation with subsequent detachment.

Frequency

United States

Approximately 16 million Americans have diabetes, with 50% of them not even aware that they have it. Of
those that know, only one half receives appropriate eye care. Thus, it is not surprising that diabetic
retinopathy is the leading cause of new blindness in persons aged 25-74 years in the United States,
responsible for more than 8000 cases of new blindness each year.6 This means that diabetes is responsible for
12% of blindness; the rate is even higher among certain ethnic groups.

International

The 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
intake as well as the increasing size of portions of food and drinks over the past several decades may also be
responsible.

Mortality/Morbidity
The 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. This cost does not compare to the cost
in terms of loss of productivity and quality of life.

Race

An increased risk of diabetic retinopathy appears to exist in patients with Native American, Hispanic, and
African American heritage.

Sex

Sex does not appear to have any affect on the development of diabetes or diabetic retinopathy.

Age

With increasing duration of diabetes, or with increasing age since the onset of diabetes, there is a higher risk
of developing diabetic retinopathy and the complications of diabetic retinopathy, including diabetic macular
edema or proliferative diabetic retinopathy.

Clinical
History

In the initial stages, patients are generally asymptomatic; however, in the more advanced stages of the
disease, patients may experience symptoms, including blurred vision, distortion, or visual acuity loss.

Physical

• Microaneurysms
o Earliest clinical sign of diabetic retinopathy
o Secondary to capillary wall outpouching due to pericyte loss
o Appear as small red dots in the superficial retinal layers
o Fibrin and RBC accumulation in the microaneurysm lumen
o Rupture produces blot/flame hemorrhages
o May appear yellowish in time as endothelial cells proliferate and produce basement membrane
• Dot and blot hemorrhages
o Occur as microaneurysms rupture in the deeper layers of the retina such as the inner nuclear
and outer plexiform layers
o Appear similar to microaneurysms if they are small; may need fluorescein angiography to
distinguish between the two
• Flame-shaped hemorrhages - Splinter hemorrhages that occur in the more superficial nerve fiber layer
• Retinal edema and hard exudates - Caused by the breakdown of the blood-retina barrier, allowing
leakage of serum proteins, lipids, and protein from the vessels
• Cotton-wool spots
o Nerve fiber layer infarction from occlusion of precapillary arterioles
o Fluorescein angiography - No capillary perfusion
o Frequently bordered by microaneurysms and vascular hyperpermeability
• Venous loops, venous beading
o Frequently adjacent to areas of nonperfusion
o Reflects increasing retinal ischemia
o Most significant predictor of progression to PDR
 • Intraretinal microvascular abnormalities
o Remodeled capillary beds without proliferative changes
o Collateral vessels that do not leak on fluorescein angiography
o Usually can be found on the borders of the nonperfused retina
• Macular edema
o This condition is the leading cause of visual impairment in patients with diabetes. A reported
75,000 new cases of macular edema are diagnosed annually.
o Possibly due to functional damage and necrosis of retinal capillaries
o Clinically significant macular edema (CSME) is defined as any of the following:
 Retinal thickening located 500 µm or less from the center of the foveal avascular zone
(FAZ)
 Hard exudates with retinal thickening 500 µm or less from the center of the FAZ
 Retinal thickening 1 disc area or larger in size located within 1 disc diameter of the
FAZ
• Mild nonproliferative diabetic retinopathy - Presence of at least 1 microaneurysm
• Moderate nonproliferative diabetic retinopathy
o Presence of hemorrhages, microaneurysms, and hard exudates
o Soft exudates, venous beading, and IRMA less than that of severe NPDR
• Severe nonproliferative diabetic retinopathy (4-2-1)
o Hemorrhages and microaneurysms in 4 quadrants
o Venous beading in at least 2 quadrants
o IRMA in at least 1 quadrant
• Mild NPDR reflects structural changes in the retina caused by the physiological and anatomical
effects of diabetes. On the other hand, the more advanced stages of NPDR reflect the increasing
retinal ischemia setting up the stage for proliferative changes.

Causes

Risk factors

• Duration of the diabetes

o In patients with type I diabetes, no clinically significant retinopathy can be seen in the first 5
years after the initial diagnosis of diabetes is made. After 10-15 years, 25-50% of patients
show some signs of retinopathy. This prevalence increases to 75-95% after 15 years and
approaches 100% after 30 years of diabetes.
o In patients with type II diabetes, the incidence of diabetic retinopathy increases with the
duration of the disease. Of patients with type II diabetes, 23% have NPDR after 11-13 years,
41% have NPDR after 14-16 years, and 60% have NPDR after 16 years.
• Glucose control
o The Diabetic Control and Complications Trial (DCCT) has demonstrated that intensive
glucose control reduced the incidence and the progression of diabetic retinopathy in patients
with insulin-dependent diabetes mellitus (IDDM).
o Although no similar trials for patients with non–insulin–dependent diabetes mellitus (NIDDM)
have been completed, the American Diabetes Association (ADA) has suggested that
glycosylated hemoglobin levels of less than 7% (reflecting long-term glucose levels) should be
the goal in all patients to prevent or slow down the onset of diabetes-related complications.
• Renal disease, as evidenced by proteinuria and elevated BUN/creatinine levels, is an excellent
predictor of the presence of retinopathy. This 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. Evidence suggests that aggressive treatment of the nephropathy may have a beneficial effect on
the progression of diabetic retinopathy and neovascular glaucoma.
 • Systemic hypertension, in the setting of diabetic nephropathy, correlates well with the presence of
retinopathy. Independently, hypertension also may complicate diabetes in that it may result in
hypertensive retinal vascular changes superimposed on the preexisting diabetic retinopathy, further
compromising retinal blood flow.
• Proper management of hyperlipidemia (elevated serum lipids) may result in less retinal vessel leakage
and hard exudate formation. The reason behind this is unclear.
• Pregnant women without any diabetic retinopathy run a 10% risk of developing NPDR during their
pregnancy. Of those with preexisting NPDR, 4% progress to the proliferative type.

Other Problems to Be Considered

Retinopathy, radiation

Workup
Laboratory Studies

• Fasting glucose and hemoglobin A1c (HbA1c) are important laboratory tests that are performed to
help diagnose diabetes. The HbA1c level is also important in the long-term follow-up care of patients
with diabetes and diabetic retinopathy. Controlling diabetes and maintaining the HbA1c level in the 6-
7% range are the goals in the optimal management of diabetes and diabetic retinopathy. If the levels
are maintained, then the progression of diabetic retinopathy is reduced substantially, according to the
DCCT.

Imaging Studies

• Fluorescein 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 Blot and dot hemorrhages can be distinguished from microaneurysms because they appear as
hypofluorescent rather than hyperfluorescent.
o Areas of nonperfusion appear as homogenous dark patches bordered by occluded blood
vessels.
o IRMA is evidenced by collateral vessels that do not leak, usually found in the borders of the
nonperfused retina.

Other Tests

• Other tests may include optical coherence tomography (OCT), which uses light to generate a cross-
sectional image of the retina. This is used to determine the thickness of the retina and the presence of
swelling within the retina as well as vitreomacular traction. This test is particularly used for the
diagnosis and management of diabetic macular edema or clinically significant macular edema.

Treatment
Medical Care

• Glucose control: The DCCT has found that intensive glucose control in patients with IDDM has
decreased the incidence and progression of diabetic retinopathy.7,8,9 Although no similar clinical trials
 for patients with NIDDM exist, it may be logical to assume that the same principles also apply. In fact,
the ADA has suggested that all diabetics (NIDDM and IDDM) should strive to maintain glycosylated
hemoglobin levels of less than 7% to prevent or at the very least to minimize the long-term
complications of DM, including DM retinopathy.
• The Early Treatment for Diabetic Retinopathy Study (ETDRS) found that 650 mg of aspirin daily did
not offer any benefit in preventing the progression of DM retinopathy. Additionally, aspirin was not
observed to influence the incidence of vitreous hemorrhage in patients who required it for
cardiovascular disease (CVD) or other conditions.10,11

Surgical Care

The advent of laser photocoagulation in the 1960s and early 1970s provided a noninvasive treatment modality
that has a relatively low complication rate and a significant degree of success. This involves directing a high-
focused beam of light energy to create a coagulative response in the target tissue. In NPDR, laser treatment is
indicated in the treatment of CSME. The strategy for treating macular edema depends on the type and extent
of vessel leakage.

• If the edema is due to leakage of specific microaneurysms, the leaking vessels are treated directly with
focal laser photocoagulation.12
• In cases where the foci of leakage are nonspecific, a grid pattern of laser burns is applied. Medium
intensity burns (100-200 µm) are placed 1 burn size apart covering the affected area.
• Other off-label potential treatments of diabetic macular edema (DME) include intravitreal
triamcinolone acetonide (Kenalog) and bevacizumab (Avastin). Both of these medications can result
in a substantial reduction or resolution of macular edema.

Diet

A good healthy diet with well-balanced meals is important for all individuals and is particularly important for
individuals with diabetes. A well-balanced diet can help to achieve better weight control and also better
control of the diabetes. To that end, it can also help to reduce the complications of diabetes.

Activity

Maintaining a good healthy lifestyle with regular exercise is important for all individuals, especially for those
individuals with diabetes. Exercise can help with maintaining weight and with peripheral glucose
absorption. This can help with improved diabetes control, and this, in turn, can help to reduce the
complication of diabetes and diabetic retinopathy.

Medication
Several medications are currently being used in an off-label manner in the treatment of diabetic
retinopathy. At present, these medications are administered into the eye by intravitreal injection. Intravitreal
triamcinolone is being used in the treatment of diabetic macular edema. A recent Diabetic Retinopathy
Clinical Research Network (DRCR.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 2 years.12 In addition, intravitreal triamcinolone can have some side
effects, including steroid response with intraocular pressure increase and cataracts.

Other medications that are being used in clinical practice and in clinical trials include intravitreal
bevacizumab (Avastin) and ranibizumab (Lucentis). These medications are VEGF antibodies and antibody
fragments, respectively. They can help to reduce diabetic macular edema and also neovascularization of the
disc or retina. Combinations of some of these medications above with focal laser treatment are being
investigated in the DRCR.net clinical trials.

Further Outpatient Care

• The frequency of follow-up care is dictated primarily on the baseline stage of the retinopathy and its
rate of progression to proliferative diabetic retinopathy (PDR).
o Only 5% of patients with mild NPDR would progress to PDR in 1 year and, thus, could be
monitored every 6-12 months.
o As many as 27% of patients with moderated NPDR would progress to PDR in 1 year;
therefore, they should be seen every 4-8 months.
o More than 50% of patients with severe NPDR (preproliferative stage) would progress to PDR
in a year; thus, follow-up care as frequent as 2-4 months is mandated to ensure prompt
recognition and treatment.
o Any stage associated with clinically significant macular edema (CSME) should be treated and
observed closely (every 2-3 mo) to monitor the status of the macula.

Deterrence/Prevention

• The Diabetes Control and Complications Trial (DCCT) and United Kingdom Prospective Diabetes
Study (UK-PDS) were large randomized 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 1 and type 2 diabetes.13

Complications

• The complications of focal and grid laser therapy include the following:
o Decreased central vision
o Paracentral scotomas
o Choroidal neovascularization
o Epiretinal membrane formation
o Further increase in macular edema

Prognosis

• The Early Treatment for Diabetic Retinopathy Study (ETDRS) has found that laser surgery for
macular edema reduces the incidence of moderate visual loss (doubling of visual angle or roughly a 2-
line visual loss) from 30% to 15% over a 3-year period.
• Favorable prognostic factors
o Circinate exudates of recent onset
o Well-defined leakage
o Good perifoveal perfusion
• Unfavorable prognostic factors
o Diffuse edema/multiple leaks
o Lipid deposition in the fovea
o Macular ischemia
o Cystoid macular edema
o Preoperative vision of less than 20/200
o Hypertension

Patient Education
 • One of the most important aspects in the management of diabetic retinopathy is patient education.
Inform patients that they play an integral role in their own eye care. Emphasize the following facts:
o Excellent glucose control is beneficial in any stage of diabetic retinopathy. It delays the onset
and slows down the progression of the diabetic complications in the eye.
o Other systemic problems, such as hypertension, renal disease, and hyperlipidemia, may
contribute to the progression of the retinopathy and should be addressed promptly.
o Smoking, although not directly proven to affect the course of the retinopathy, may play a role
in further compromising oxygen delivery to the retina. Therefore, all efforts should be made in
the reduction, if not outright cessation, of smoking.
o Visual 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.
• For excellent patient education resources, see eMedicine's Diabetes Center. Also, visit eMedicine's
patient education article Diabetic Eye Disease.

Miscellaneous
Medicolegal Pitfalls

• Failure to emphasize to the patient that focal or grid laser treatment of clinically significant macular
edema (CSME) is not aimed at improving vision but rather at reducing the risk of moderate visual
loss.

Special Concerns

• All individuals with diabetes should be aware of the importance of regular dilated retinal
examinations. Early diagnosis and treatment of diabetic retinopathy can help prevent blindness in
more than 90% of cases. However, in spite of treatment, sometimes, individuals can still lose
vision. The patient, ophthalmologist or retina specialist, and internist or endocrinologist must work
together as a team to optimize the diabetes control and help to reduce the risk of blindness.