Retinopathy, Diabetic, Background

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Retinopathy, Diabetic, Background

Last Updated: September 7, 2006

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Synonyms and related keywords: background diabetic retinopathy, BDR, nonproliferative diabetic retinopathy, NPDR, diabetes mellitus, DM, diabetes mellitus retinopathy, DM retinopathy, blindness, vision loss, visual acuity loss, visual loss, diabetic macular edema, DME

AUTHOR INFORMATION Section 1 of 10

Author InformationIntroductionClinicalDifferentialsWorkupTreatmentFollow-upMiscellaneousPicturesBibliography

Author: Abdhish R Bhavsar, MD, Adjunct Assistant Professor, Department of Ophthalmology, University of Minnesota; Director of Clinical Research, Retina Center, PA; Past Chair, Consulting Staff, Department of Ophthalmology, Phillips Eye Institute

Coauthor(s): Sherman O Valero, MD, Consulting Staff, Department of Ophthalmology, Makati Medical Center, Philippines; John H Drouilhet, MD, FACS, Clinical Associate Professor, Department of Surgery, Section of Ophthalmology, University of Hawaii, John A Burns School of Medicine

Abdhish R Bhavsar, MD, is a member of the following medical societies: Alpha Omega Alpha,

of Ophthalmology, American Medical Association, American Society of Retina Specialists, Association for Research in Vision and Ophthalmology, Minnesota Medical Association, and Phi Beta Kappa

Editor(s): Vytautas A Pakainis, MD, Chief of Ophthalmology, Dorn Veterans Administration Medical Center, Professor of Ophthalmology, Ophthalmology, University of South Carolina School of Medicine;

PharmD, Assistant Professor of Ophthalmology, Jules Stein Eye Institute, University of California at Los Angeles; Chief, Section of Ophthalmology Surgical Services, Veterans Affairs Healthcare Center of West Los Angeles;

Steve Charles, MD, Director of Charles Retina Institute; Clinical Professor, Department of Ophthalmology, University of Tennessee College of Medicine; Lance L Brown, OD, MD, Ophthalmologist, Regional Eye Center, Affiliated With Freeman Hospital and St John's Hospital, Joplin, Missouri; and Hampton Roy, Sr, MD

Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences

INTRODUCTION Section 2 of 10

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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. 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.

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.

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, 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,

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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:

In the US: 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. This means that diabetes is responsible for 12% of blindness; the rate is even higher among certain ethnic groups.

Internationally: 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.

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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

Earliest clinical sign of diabetic retinopathy

Secondary to capillary wall outpouching due to pericyte loss Appear as small red dots in the superficial retinal layers Fibrin and RBC accumulation in the microaneurysm lumen Rupture produces blot/flame hemorrhages

May appear yellowish in time as endothelial cells proliferate and produce basement membrane Dot and blot hemorrhages

Occur as microaneurysms rupture in the deeper layers of the retina such as the inner nuclear and outer

plexiform layers

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

Nerve fiber layer infarction from occlusion of precapillary arterioles Fluorescein angiography - No capillary perfusion

Frequently bordered by microaneurysms and vascular hyperpermeability Venous loops, venous beading

Frequently adjacent to areas of nonperfusion

CLINICAL Section 3 of 10

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Reflects increasing retinal ischemia

Most significant predictor of progression to PDR Intraretinal microvascular abnormalities

Remodeled capillary beds without proliferative changes Collateral vessels that do not leak on fluorescein angiography Usually can be found on the borders of the nonperfused retina Macular edema

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.

Possibly due to functional damage and necrosis of retinal capillaries

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

Presence of hemorrhages, microaneurysms, and hard exudates

Soft exudates, venous beading, and IRMA less than that of severe NPDR Severe nonproliferative diabetic retinopathy (4-2-1)

Hemorrhages and microaneurysms in 4 quadrants Venous beading in at least 2 quadrants

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.

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Duration of the diabetes

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.

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

The Diabetic Complications Control Trial (DCCT) has demonstrated that intensive glucose control

reduced the incidence and the progression of diabetic retinopathy in patients with insulin diabetes mellitus (IDDM).

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

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.

Branch Retinal Vein Occlusion Central Retinal Vein Occlusion Ocular Ischemic Syndrome

Retinopathy, Hemoglobinopathies Sickle Cell Disease

DIFFERENTIALS Section 4 of 10

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Other Problems to be Considered:

Retinopathy, radiation

Lab Studies:

Fasting glucose and hemoglobin A1c (HbA1c) are important laboratory tests that are perf

HbA1c level is also important in the long-term follow-up care of patients with diabetes and and maintaining the HbA1c level in the 6-7% range are the goals in the optimal managem

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. Microaneurysms would appear as pinpoint hyperfluorescence that does not enlarge

test.

Blot and dot hemorrhages can be distinguished from microaneurysms because they

hyperfluorescent.

Areas of nonperfusion appear as homogenous dark patches bordered by occluded blood vessels.

IRMA is evidenced by collateral vessels that do not leak, usually found in the borders of the nonperfused retina. WORKUP

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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. Although no similar clinical trials for patients with NID

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

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.

Surgical Care: The advent of laser photocoagulation in the 1960s and early 1970s provided a relatively low complication rate and a significant degree of success. This involves directing a high a coagulative response in the target tissue. In NPDR, laser treatment is indicated in the treatme 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 treate

In cases where the foci of leakage are nonspecific, a grid pattern of laser burns is applied. Medium intensity burns (100

placed 1 burn size apart covering the affected area.

TREATMENT

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Other off-label potential treatments of diabetic macular edema (DME) include intravitreal

bevacizumab (Avastin). Both of these medications can result in a substantial reduction or resolution of macular edema.

Further Outpatient Care:

The frequency of follow-up care is dictated primarily on the baseline stage of the retinopa

Only 5% of patients with mild NPDR would progress to PDR in 1 year and, thus, could be monitored every 6 As many as 27% of patients with moderated NPDR would progress to PDR in 1 yea

months.

More than 50% of patients with severe NPDR (preproliferative stage) would progress to PDR in a year; thus, follow

frequent as 2-4 months is mandated to ensure prompt recognition and treatment.

Any stage associated with CSME should be treated and observed closely (every 2-Complications:

The complications of focal and grid laser therapy include the following: Decreased central vision

Paracentral scotomas

Choroidal neovascularization Epiretinal membrane formation Further increase in macular edema Prognosis:

The ETDRS has found that laser surgery for macular edema reduces the incidence of mo

or roughly a 2-line visual loss) from 30% to 15% over a 3-year period.

Favorable prognostic factors

Circinate exudates of recent onset Well-defined leakage

Good perifoveal perfusion FOLLOW-UP

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Unfavorable prognostic factors Diffuse edema/multiple leaks Lipid deposition in the fovea Macular ischemia

Cystoid macular edema

Preoperative vision of less than 20/200 Hypertension

Patient Education:

One of the most important aspects in the management of diabetic retinopathy is patient e

integral role in their own eye care. Emphasize the following facts:

Excellent glucose control is beneficial in any stage of diabetic retinopathy. It delays

of the diabetic complications in the eye.

Other systemic problems, such as hypertension, renal disease, and hyperlipidemia,

retinopathy and should be addressed promptly.

Smoking, although not directly proven to affect the course of the retinopathy, may p

delivery to the retina. Therefore, all efforts should be made in the reduction, if not outright cessation, of smoking.

Visual symptoms (eg, changes in vision, redness, pain) could be manifestations of disease progression and should be

reported immediately.

DM in general and diabetic retinopathy in particular are progressive conditions such that regular follow

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.

Medical/Legal Pitfalls:

Failure to emphasize to the patient that focal or grid laser treatment of CSME is not aimed

the risk of moderate visual loss.

MISCELLANEOUS

PICTURES

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Caption: Picture 1. Fundus photograph of early background diabetic retinopathy showing multiple microaneurysms.

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Caption: Picture 2. Retinal findings in background diabetic retinopathy, including blot hemorrhages (arrowhead), microaneurysms (short arrow), and hard exudates (long arrow).

Caption: Picture 3. Fluorescein angiogram demonstrating an area of capillary nonperfusion (arrow).

Caption: Picture 4. Fluorescein angiogram demonstrating foveal dye leakage caused by macular edema.

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Aiello LM, Cavallerano JD, Aiello LP, Bursell SE: Diabetic retinopathy. In: Guyer DR, Yannuzzi LA, Chang S, et al, eds. Retina

Vitreous Macula. Vol 2. 1999: 316-44.

Akduman L, Olk RJ: The early treatment for diabetic retinopathy study. In: Kertes C, ed. Clinical Trials in Ophthalmology

Summary and Practice Guide. 1998: 15-36.

Benson WE, Tasman W, Duane TD: Diabetes mellitus and the eye. Duane's Clinical Ophthalmology. Vol 3. 1994. Bhavsar AR: Diabetic retinopathy: the latest in current management. Retina 2006; 26 (6 Suppl): S71

Federman JL, Gouras P, Schubert H, et al: Systemic diseases. In: Podos SM, Yanoff M, eds. Retina and Vitreous

Ophthalmology. Vol 9. 1994: 7-24.

Frank RN: Etiologic mechanisms in diabetic retinopathy. In: Ryan SJ, ed. Retina. Vol 2. 1994: 1243 Klein R: The Diabetes Control and Complications Trial. In: Kertes C, ed. Clinical Trials in Ophthalmology

Guide. 1998: 49-70.

Retinopathy, Diabetic, Background excerpt Picture Type: Photo

Caption: Picture 5. Fundus photograph of clinically significant macular edema demonstrating retinal exudates within the fovea.

BIBLIOGRAPHY

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