Chapter 117 – Diabetic Retinopathy
BRETT J. ROSENBLATT
WILLIAM E. BENSON
• Progressive dysfunction of the retinal vasculature caused by chronic hyperglycemia.
• Retinal hemorrhages.
• Retinal lipid exudates.
• Cotton-wool spots.
• Capillary nonperfusion.
• Macular edema.
• Vitreous hemorrhage.
• Retinal detachment.
• Neovascular glaucoma.
• Premature cataract.
• Cranial nerve palsies.
Successful management of diabetic retinopathy via a combination of glucose control, laser therapy, and vitrectomy represents one of the most striking achievements of modern ophthalmology. If fundus examinations are initiated prior to the development of significant retinopathy and repeated periodically, and if the recommendations of the Early Treatment Diabetic Retinopathy Study (ETDRS) are followed with respect to the management of subsequent diabetic macular edema or neovascularization, the risk of severe visual loss is less than 5%. Despite this, diabetic retinopathy remains the number one cause of new blindness in most industrialized countries. The vast majority of diabetic individuals who lose vision do so, not because of an inability to treat their disease, but rather due to a delay in seeking medical attention. The key to sight preservation for diabetic patients is routine examinations to detect the earliest signs of retinopathy.
The best predictor of diabetic retinopathy is the duration of the disease. Patients who have had type 1 for 5 years or less rarely show any evidence of diabetic retinopathy. However, 27% of those who have had diabetes for 5–10 years and 71–90% of those who have had diabetes for longer than 10 years have diabetic retinopathy.  After 20–30 years, the incidence rises to 95%, and about 30–50% of these patients have proliferative diabetic retinopathy (PDR).
Yanko et al. described the prevalence of retinopathy in patients with type 2 diabetes. They found that the prevalence of retinopathy 11–13 years after the onset of type 2 diabetes was 23%; after 16 or more years, it was 60%; and 11 or more years after the onset, 3% of the patients had PDR. Klein et al.  found that 10 years after the diagnosis of type 2 diabetes, 67% of patients had retinopathy and 10% had PDR.
The most important determinant of retinopathy is the duration of diabetes after the onset of puberty. For example, the risk of retinopathy is roughly the same for two 25-year-old patients, of whom one developed diabetes at the age of 6 and the other at the age of 12 years.
The Diabetes Control and Complications Trial showed emphatically that patients with type 1 diabetes who closely monitored their blood glucose (four measurements per day = tight control) do far better than patients treated with conventional therapy (one measurement per day). The former had a 76% reduction in the rate of development of any retinopathy (primary prevention cohort) and a 54% reduction in progression of established retinopathy (secondary intervention cohort) as compared with the conventional treatment group. For advanced retinopathy, however, even the most rigorous control of blood glucose may not prevent progression. The value of intensive treatment has been demonstrated for type 2 diabetes, as well. The United Kingdom Prospective Diabetes Study (UKPDS) revealed a 21% reduction in the 1-year rate of progression of retinopathy. 
Renal disease, as evidenced by proteinuria, elevated blood urea nitrogen levels, and elevated blood creatinine levels, is an excellent predictor of the presence of retinopathy. Even patients with microalbuminuria are at high risk of developing retinopathy. Similarly, 35% of patients with symptomatic retinopathy have proteinuria, elevated blood urea nitrogen values, or elevated creatinine levels. Systemic hypertension appears to be an independent risk factor for diabetic retinopathy.
In women who begin a pregnancy without retinopathy, the risk of developing nonproliferative diabetic retinopathy (NPDR) is about 10%. Those with NPDR at the onset of pregnancy and those who have or who develop systemic hypertension tend to show progression, with increased hemorrhages, cotton-wool spots, and macular edema. Fortunately, there is usually some regression after delivery. About 4% of pregnant women with NPDR progress to PDR. Those with untreated PDR at the onset of pregnancy frequently do poorly unless they are treated with panretinal photocoagulation (PRP). However, previously treated PDR usually does not worsen during pregnancy. There is no doubt that women who maintain good metabolic control during pregnancy have fewer spontaneous abortions and fewer children with birth defects. Therefore, obstetricians strive for strict control. Women who begin pregnancy with poorly controlled diabetes who are suddenly brought under strict control frequently have severe deterioration of their retinopathy and do not always recover after delivery.
The final metabolic pathway that causes diabetic retinopathy is unknown. There are several theories.
Aldose reductase converts sugars into their alcohols. For example, glucose is converted to sorbitol and galactose is converted to galactitol. Because sorbitol and galactitol cannot easily diffuse out of cells, their intracellular concentration increases. Osmotic forces then cause water to diffuse into the cell, resulting in electrolyte imbalance. The resultant damage to lens epithelial cells, which have a high concentration of aldose reductase, is responsible for the cataract seen in children and in experimental animals with galactosemia and in animals with experimental diabetes mellitus. Because aldose reductase is also found in high concentration in retinal pericytes and Schwann cells, some investigators suggest that diabetic retinopathy and neuropathy may be caused by aldose reductase–mediated damage. Despite all of these theoretical benefits, clinical trials have thus far failed to show a reduction in the incidence of diabetic retinopathy or of neuropathy by aldose reductase inhibitors, possibly because an effective aldose reductase inhibitor with few systemic side effects has yet to be developed.
Currently intense interest exists in vasoproliferative factors released by the retina itself, retinal vessels, and the retinal pigment epithelium, which are felt to induce neovascularization. Vascular endothelial growth factor (VEGF), which inhibits the growth of the retinal endothelial cells in vitro, has been implicated in diabetic retinopathy. Considerable evidence suggests that VEGF has a direct role in the retinal vascular abnormalities that are found in diabetes. Animal models demonstrate that VEGF expression correlates with the development and regression of neovascularization. The concentration of VEGF is higher in the vitreous of eyes with PDR as compared with eyes with NPDR. Furthermore, inhibitors of VEGF have been successful in suppressing hypoxia-induced neovascularization in animal models. Although the release of growth factors may explain the neovascular response to ischemia, growth factors themselves may or may not represent a direct link between hyperglycemia and retinal vasculopathy.
Platelets and Blood Viscosity
Diabetes is associated with abnormalities of platelet function. It has been postulated that platelet abnormalities or alterations in blood viscosity in diabetics may contribute to diabetic retinopathy by causing focal capillary occlusion and focal areas of ischemia in the retina which, in turn, contribute to the development of diabetic retinopathy.
The earliest stage of diabetic retinopathy is nonproliferative (NPDR). In some patients, there is progression to proliferative retinopathy (PDR).
Early Nonproliferative Diabetic Retinopathy
Microaneurysms are the first ophthalmoscopically detectable change in diabetic retinopathy ( Fig. 117-1,A ), seen as small red dots in the middle retinal layers. When the wall of a capillary or microaneurysm is weakened enough, it may rupture, giving rise to an intraretinal hemorrhage. 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”) (see Fig. 117-1, A ). It is very difficult to distinguish a small dot hemorrhage from a microaneurysm by ophthalmoscopy. Fluorescein angiography helps to distinguish patent microaneurysms because they leak dye ( Fig. 117-1, B ). However, angiography cannot distinguish a hemorrhage from a microaneurysm filled with clotted blood. If the
Figure 117-1 Nonproliferative diabetic retinopathy with microaneurysms. A, Small dot hemorrhages, microaneurysms, hard (lipid) exudates, circinate retinopathy, an intraretinal microvascular abnormality, and macular edema. B, Fluorescein angiography of the eye shown in A. Microaneurysms are seen as multiple dots of hyperfluorescence, but the dot hemorrhages do not fluoresce. The foveal avascular zone is minimally enlarged.
Figure 117-2 Nonproliferative retinopathy with some blot hemorrhages, splinter hemorrhages, and cotton-wool spots.
hemorrhage is superficial, in the nerve fiber layer, it takes a flame or splinter shape indistinguishable from a hemorrhage seen in hypertensive retinopathy ( Figs. 117-2 and 117-3 ). Diabetics who have normal blood pressure may have multiple splinter hemorrhages. Nevertheless, the presence of numerous splinter hemorrhages in a diabetic patient should prompt a blood pressure
Figure 117-3 Nonproliferative retinopathy. A, With soft exudates. B, Fluorescein angiography shows capillary nonperfusion in the area of the superior cotton-wool spot and a larger area just inferonasal to the foveal avascular zone.
check, because a frequent complication of diabetes is systemic hypertension.
Macular edema, or retinal thickening (see Fig. 117-1, A ), is an important manifestation of NPDR and represents the leading cause of legal blindness in diabetics. The intercellular fluid comes from leaking microaneurysms or from diffuse capillary incompetence. Clinically, macular edema is best detected by biomicroscopy with a 60-diopter or contact macular lens. The edema causes scattering of light by the multiple interfaces it creates in the retina by separated retinal cells. This decreases the retina’s translucency such that the normal retinal pigment epithelial and choroidal background pattern is blurred (see Fig. 117-1, A ). Finally, the pockets of fluid in the outer plexiform layer, if large enough, can be seen as cystoid macular edema. Usually cystoid macular edema is seen in eyes that have other signs of severe NPDR such as numerous hemorrhages or exudates. In rare cases, cystoid macular edema due to generalized diffuse leakage from the entire capillary network can be seen in eyes that have very few other signs of diabetic retinopathy.
If the leakage of fluid is severe enough, lipid may accumulate in the retina (see Fig. 117-1, A ); again, the outer plexiform layer is first to be affected. In some cases, lipid is scattered through the macula. In others, it accumulates in a ring around a group of leaking microaneurysms, or around microaneurysms surrounding an area of capillary nonperfusion. This pattern is called circinate retinopathy (see Fig. 117-1, A ).
Advanced Nonproliferative Diabetic Retinopathy
In advanced NPDR, signs of increasing inner retinal hypoxia appear, including multiple retinal hemorrhages, cotton-wool spots
Figure 117-4 Severe nonproliferative retinopathy. A, With cotton-wool spots, intraretinal microvascular abnormalities, and venous beading. B, Fluorescein angiography shows severe capillary nonperfusion.
(see Fig. 117-3 ), venous beading and loops ( Fig. 117-4 ), intraretinal microvascular abnormalities (IRMA) (see Figs. 117-1, A and 117-4 ), and large areas of capillary nonperfusion depicted on fluorescein angiography.
Cotton-wool spots, also called soft exudates or nerve fiber infarcts, result from ischemia, not exudation. Local ischemia causes effective obstruction of axoplasmic flow in the normally transparent nerve fiber layer; the subsequent swelling of the nerve fibers gives cotton-wool spots their characteristic white fluffy appearance. Fluorescein angiography shows no capillary perfusion in the area corresponding to a cotton-wool spot. Microaneurysms frequently surround the hypoxic area (see Fig. 117-3 ).
Venous beading (see Fig. 117-4 ) is an important sign of sluggish retinal circulation. Venous loops nearly always are adjacent to large areas of capillary nonperfusion. IRMAs are dilated capillaries, which seem to function as collateral channels. They frequently are difficult to differentiate from surface retinal neovascularization. Fluorescein dye, however, does not leak from IRMAs but leaks profusely from neovascularization. Capillary hypoperfusion often surrounds IRMA (see Fig. 117-4 ).
The ETDRS found that IRMA, multiple retinal hemorrhages, venous beading and loops, widespread capillary nonperfusion, and widespread leakage on fluorescein angiography were all significant risk factors for the development of proliferative retinopathy. Interestingly, cotton-wool spots were not.
Proliferative Diabetic Retinopathy
Although the macular edema, exudates, and capillary occlusions seen in NPDR often cause legal blindness, affected patients usually maintain at least ambulatory vision. PDR, on the other hand,
Figure 117-5 Approximately one half the disc area shows neovascularization of the disc and initial, incomplete panretinal photocoagulation.
may result in severe vitreous hemorrhage or retinal detachment, with hand-movements vision or worse. Approximately 50% of patients with very severe NPDR progress to proliferative retinopathy within 1 year. Proliferative vessels usually arise from retinal veins and often begin as a collection of multiple fine vessels. When they arise on or within one disc diameter of the optic nerve head they are referred to as NVD (neovascularization of the disc) ( Figs. 117-5 and 117-6 ). When they arise further than one disc diameter away, they are called NVE (neovascularization elsewhere) (see Fig. 117-6, B ). Unlike normal retinal vessels, NVD and NVE both leak fluorescein into the vitreous.
Once the stimulus for growth of new vessels is present, the path of subsequent growth taken by neovascularization is along the route of least resistance. For example, the absence of a true internal limiting membrane on the disc could explain the prevalence of new vessels at that location. Also, neovascularization seems to grow more easily on a preformed connective tissue framework. Thus, a shallowly detached posterior vitreous face is a frequent site of growth of new vessels.
The new vessels usually progress through a stage of further proliferation, with associated connective tissue formation. As PDR progresses, the fibrous component becomes more prominent, with the fibrotic tissue being either vascular or avascular. The fibrovascular variety usually is found in association with vessels that extend into the vitreous cavity or with abnormal new vessels on the surface of the retina or disc. The avascular variety usually results from organization or thickening of the posterior hyaloid face. Vitreous traction is transmitted to the retina along these proliferations and may lead to traction retinal detachment.
NVE nearly always grows toward and into zones of retinal ischemia until posterior vitreous detachment occurs (see Fig. 117-6 ). Then, the vessels are lifted into the vitreous cavity. The end stage is characterized by regression of the vascular systems. No further damage may take place, but there may be contraction of the connective tissue components, development of subhyaloid bands, thickening of the posterior vitreous face, and the appearance of retinoschisis, retinal detachment, or formation of retinal breaks.
Posterior vitreous detachment in diabetics is characterized by a slow, overall shrinkage of the entire formed vitreous rather than by the formation of cavities caused by vitreous destruction. Davis et al.  have stressed the role of the contracting vitreous in the production of vitreous hemorrhage, retinal breaks, and retinal detachment. Neovascular vessels do not “grow” forward into the vitreous cavity; they are pulled into it by the contracting vitreous to which they adhere. Confirmation of the importance of the vitreous in the development and progression of proliferative retinopathy comes from the long-term follow-up of eyes that have undergone successful vitrectomy. The existent neovascularization
Figure 117-6 Neovascularization. A, Neovascularization of the disc with some fibrous proliferation. B, Neovascularization elsewhere.
shrinks, leaks less fluorescein, and new areas of neovascularization rarely arise.
It has long been assumed that sudden vitreous contractions tear the fragile new vessels, causing vitreous hemorrhage. However, the majority of diabetic vitreous hemorrhages occur during sleep, possibly because of an increase in blood pressure secondary to early morning hypoglycemia or to rapid eye movement sleep. Because so few hemorrhages occur during exercise, it is not necessary to restrict the activity of patients with proliferative retinopathy. When a hemorrhage occurs, if the erythrocytes are all behind the posterior vitreous face, they usually quickly settle to the bottom of the eye and are absorbed. However, when erythrocytes break into the vitreous body, they adhere to the gel and clearing may take months or years.
A large superficial hemorrhage may separate the internal limiting membrane from the rest of the retina. Such hemorrhages usually are round or oval but also may be boat shaped. The blood may remain confined between the internal limiting membrane and the rest of the retina for weeks or months before breaking into the vitreous. Sub-internal limiting membrane hemorrhages were formerly thought to occur between the internal limiting membrane and the cortical vitreous and were called subhyaloid or preretinal hemorrhages. It is now felt that true subhyaloid hemorrhages probably are quite rare. Tight sub-internal limiting membrane hemorrhages are dangerous, because they may progress rapidly to traction retinal detachment.
As the vitreous contracts, it may pull on the optic disc, causing traction striae involving the macular area, or actually drag the macula itself, both of which contribute to decreased visual acuity.
Two types of diabetic retinal detachments occur, those which are caused by traction alone (nonrhegmatogenous) and those caused by retinal break formation (rhegmatogenous). Characteristics of nonrhegmatogenous (traction) detachment in PDR include the following:
• The detached retina usually is confined to the posterior fundus and infrequently extends more than two thirds of the distance to the equator.
• The detached retina has a taut and shiny surface.
• The detached retina is concave toward the pupil.
• No shifting of subretinal fluid occurs.
Occasionally, a spontaneous decrease in the extent of a traction detachment may occur, but this is the exception rather than the rule. Traction on the retina also may cause focal areas of retinoschisis, which may be difficult to distinguish from full-thickness retinal detachment; in retinoschisis the elevated layer is thinner and more translucent.
When a detachment is rhegmatogenous, the borders of the elevated retina usually extend to the ora serrata. The retinal surface is dull and grayish and undulates because of retinal mobility due to shifting of subretinal fluid. Retinal breaks are usually in the posterior pole near areas of fibrovascular change. The breaks are oval in shape and appear to be partly the result of tangential traction from the proliferative tissue, as well as being due to vitreous traction. Determination of the location of retinal holes may be complicated by many factors, particularly poor dilatation of the pupil, lens opacity, increased vitreous turbidity, vitreous hemorrhage, intraretinal hemorrhage, and obscuration of the breaks by overlying proliferative tissue.
OTHER OCULAR COMPLICATIONS OF DIABETES MELLITUS
Corneal sensitivity is decreased in proportion to both the duration of the disease and the severity of the retinopathy. Corneal abrasions are more common in people with diabetes, presumably because adhesion between the basement membrane of the corneal epithelium and the corneal stroma is not as firm as that found in normal corneas. Hyperglycemia and the aldose reductase pathway probably play a major role in epithelial abnormalities, because aldose reductase inhibitors may accelerate healing of corneal abrasions. Following vitrectomy, recurrent corneal erosion, striate keratopathy, and corneal edema are more common in diabetics than in nondiabetics.
The relationship between diabetes and primary open-angle glaucoma is unclear. Some population-based studies have found an association but others have not.
Neovascularization of the iris (NVI) usually is seen only in diabetics who have PDR. Panretinal photocoagulation not only has protective value against NVI, it also is an effective treatment against established NVI. If the media are clear, PRP should be performed prior to any other treatment for NVI, even in advanced cases, because regression and permanent pressure control in patients who have extensive angle closure and intraocular pressures as high as 60?mm Hg have been documented. If the media are too cloudy for PRP, trans-scleral laser or peripheral retinal cryoablation are alternative means of treatment (see below).
The risk of cataract is 2–4 times greater in diabetics than in non-diabetics and may be 15–25 times greater in diabetics under 40 years old.
Patients with diabetes mellitus who have no retinopathy have excellent results from cataract surgery, with 90–95% having a final visual acuity of 20/40 or better, but chronic cystoid macular edema is about 14 times more common in diabetics than in nondiabetics. The best-known predictor of postoperative success is the preoperative severity of retinopathy. The most dreaded anterior complication is NVI. It was hoped that modern surgery, which leaves an intact posterior capsule, would protect the eye from NVI by reducing the diffusion of vasoproliferative factors into the anterior chamber, but several studies have shown that it does not. Furthermore, an Nd:YAG laser capsulotomy does not increase the risk. Other anterior segment complications which are more common in diabetics than in non-diabetics are pupillary block, posterior synechiae, pigmented precipitates on the implant, and severe iritis.
Posterior complications of cataract surgery include macular edema, proliferative retinopathy, vitreous hemorrhage, and traction retinal detachment. Studies from the early 1990s suggested that patients with NPDR were likely to develop or have worsening of macular edema. Recent reports suggest that modern, uncomplicated cataract surgery may not accelerate progression of diabetic retinopathy in type 2 diabetics with NPDR. Caution should be observed when considering cataract surgery in patients who have diabetic retinopathy; however, up to 70% of these patients can attain a final visual acuity of 20/40 or better.
Cataract surgery in patients with active PDR often results in still poorer postoperative visual outcome because of the high risk of both anterior and posterior segment complications. In one series, no patient with active PDR or preproliferative diabetic retinopathy achieved better than 20/80. Most experts recommend aggressive preoperative PRP. 
As demonstrated by increased latency and decreased amplitude of the visual evoked potential, many diabetic patients without retinopathy have subclinical optic neuropathy. They have an increased risk for anterior ischemic optic neuropathy. In addition, diabetics are susceptible to diabetic papillopathy, which is characterized by acute disc edema without the pale swelling of anterior ischemic optic neuropathy. It is bilateral in one half of cases and may not show an afferent pupillary defect.  Macular edema is a common concurrent finding and is the most common cause of failure of visual recovery in these patients. Visual fields may be normal or show an enlarged blind spot or other nerve fiber defects. The prognosis is excellent, because most patients recover to 20/50 or better.
Extraocular muscle palsies may occur in diabetics secondary to neuropathy involving the third, fourth, or sixth cranial nerves. The mechanism is believed to be a localized demyelinization of the nerve secondary to focal ischemia. Pain may or may not be experienced, and not infrequently extraocular muscle palsy may be the initial clue to a latent diabetic condition. Recovery of extraocular muscle function in diabetic cranial nerve palsies generally takes place within 1–3 months. When the third cranial nerve is involved, pupillary function is usually normal. This pupillary sparing in the diabetic third cranial nerve palsy is an important diagnostic feature, helping to distinguish it from an intracranial tumor or aneurysm.
DIAGNOSIS AND ANCILLARY TESTING
In nearly all instances, diabetic retinopathy is diagnosed easily via ophthalmoscopic examination. The hallmark lesions are microaneurysms, which usually develop in the posterior pole. Without microaneurysms, the diagnosis of diabetic retinopathy is in doubt. Fasting blood sugar testing, a glucose tolerance test, and hemoglobin A1c determinations all can be used to confirm the presence of systemic hyperglycemia.
Although further diagnostic testing rarely is indicated, intravenous fluorescein angiography is a widely administered ancillary test. Fluorescein angiography is most helpful to assess the severity of diabetic retinopathy, to determine sites of leakage in macular edema, to judge the extent of capillary nonperfusion, and to confirm neovascularization. It is a useful preoperative test to evaluate the extent of retinopathy in patients who are to undergo cataract surgery and have media opacity. Optical coherence tomography is a noninvasive imaging technique that accurately measures retinal thickness. Diabetic patients often show psychophysical abnormalities. One of the early symptoms of diabetic retinopathy is poor night vision (dark adaptation) and poor recovery from bright lights (photostress). Diabetics, even those without retinopathy, are more likely to have abnormal color vision than are nondiabetics matched for age. Blue-yellow discrimination is affected earlier and more severely than is red-green discrimination. As retinopathy advances, color vision deteriorates.
One of the earliest electrophysiological abnormalities seen in diabetic patients without ophthalmoscopically visible retinopathy is diminution of the amplitude of the oscillatory potentials of the electroretinogram at a time when both the A and B waves are normal. This abnormality probably reflects ischemia in the inner nuclear layer of the retina. Diminished oscillatory potentials are a good predictor of progression of retinopathy. As the severity of diabetic retinopathy increases, the amplitude of the B wave decreases.
The differential diagnosis is listed in Box 117-1 .
The earliest histopathological abnormalities in diabetic retinopathy are thickening of the capillary basement membrane and pericyte dropout. Microaneurysms begin as a dilatation in
Differential Diagnosis of Diabetic Retinopathy
Retinal venous obstruction (central retinal vein occlusion [CRVO], branch retinal vein occlusion [BRVO])
The ocular ischemic syndrome
Idiopathic juxtafoveal retinal telangiectasia
Sickle cell retinopathy
Figure 117-7 Microaneurysms, pericyte dropout, and acellular capillaries are seen.
the capillary wall in areas where pericytes are absent; microaneurysms initially are thin walled. Later, endothelial cells proliferate and lay down layers of basement membrane material around themselves. Fibrin may accumulate within the aneurysm, and the lumen of the microaneurysm actually may be occluded ( Fig. 117-7 ). In early cases, microaneurysms are present mostly on the venous side of the capillaries, but later they are seen on the arterial side as well. Despite the multiple layers of basement membrane, they are permeable to water and large molecules, allowing the accumulation of water and lipid in the retina. Because fluorescein passes easily through them, many more microaneurysms are seen on fluorescein angiography than are apparent on ophthalmoscopy (see Figs. 117-1 and 117-3 ).
The ETDRS reported that aspirin 650?mg daily does not influence the progression of retinopathy, affect visual acuity, or influence the incidence of vitreous hemorrhages. However, there was a significant decrease in cardiovascular morbidity in the aspirin-treated group compared with the placebo cohort. Ticlopidine (Ticlid), like aspirin, inhibits adenosine diphosphate–induced platelet aggregation. It has been shown to decrease the risk of stroke in patients with transient ischemic attacks, but there is no clear evidence showing an impact on diabetic retinopathy.
The Hypertension in Diabetes Study, part of the United Kingdom Prospective Diabetes Study, evaluated the effect blood pressure control on the progression of diabetic retinopathy. Patients were treated with angiotensin-converting enzyme inhibitors (ACEIs) or ß-blockers to achieve “tight” control of blood pressure (<150/85?mm Hg) or “less tight” control (<180/105?mm Hg). The group with better blood pressure control had a 37% risk reduction in microvascular changes. There was no differrence in effect between the two agents used. Lisinopril, an ACEI, has been shown to decrease the progression of NPDR and PDR in normotensive diabetics, as well. The patients in this study with the better glycemic control benefited more from lisinopril.
Novel approaches to the prevention and treatment of diabetic retinopathy are based on the hypothesis that local growth factors stimulate retinal vascular alterations. Inhibition of protein kinase C, a compound critical in the cascade that activates VEGF expression, is being pursued actively. An oral inhibitor of protein kinase C has been shown to suppress retinal neovascularization in animal models.  Currently a multicenter, randomized, placebo-controlled study is under way to evaluate this compound in diabetic patients.
The Diabetic Retinopathy Study proved that both xenon arc and argon laser PRP significantly decrease the likelihood that an eye with high-risk characteristics (HRC) will progress to severe visual loss. Eyes with HRC are defined as those with NVD greater than one fourth to one third the disc area, those with any NVD and vitreous hemorrhage, or those with NVE greater than one half the disc area and vitreous or preretinal hemorrhage.
The exact mechanism by which PRP works remains unknown. Some investigators feel that PRP decreases the production of vasoproliferative factors by eliminating some of the hypoxic retina or by stimulating the release of antiangiogenic factors from the retinal pigment epithelium. An alternative hypothesis suggests that by thinning the retina, PRP increases oxygenation of the remaining retina by allowing increased diffusion of oxygen from the choroid. Yet another hypothesis is that PRP leads to an increase in vasoinhibitors by directly stimulating
the retinal pigment epithelium to produce inhibitors of vasoproliferation.
The goal of PRP is to arrest or to cause regression of the neovascularization. The recommended therapy is 1200–2000 burns 500?µm in diameter delivered through the Goldmann lens, or the same number of 200?µm burns delivered through the Rodenstock panfundoscope lens or Volk Superquad lens. The burns should be intense enough to whiten the overlying retina, which usually requires a power of 200–600?mW and duration of 0.1 second (see Fig. 117-5 ). Most ophthalmologists use the argon blue-green or green laser, but a large clinical trial has shown that krypton red is equally effective.
The number of burns necessary to achieve these goals has not been established. Some retinal specialists feel that there is no upper limit to the total number of burns and that treatment should be continued until regression occurs. The only prospective, controlled study found that eyes which received supplementary PRP treatment had no improved outcome over those which received standard PRP only.  About two thirds of eyes with HRC that receive PRP have regression of their HRC by 3 months after treatment.
The ETDRS found that PRP significantly retards the development of HRC in eyes with very severe NPDR and macular edema. After 7 years of follow-up, 25% of eyes that received PRP developed HRC as compared with 75% of eyes in which PRP was deferred until HRC developed. Nevertheless, the ETDRS concluded that treatment of severe NPDR and PDR short of HRC was not indicated for three reasons. First, after 7 years of follow-up 25% of eyes assigned to deferral of PRP had not developed HRC. Second, when patients are closely monitored and PRP is given as soon as HRC develops, severe visual loss can be prevented. After 7 years of follow-up, 4.0% of eyes that did not receive PRP until HRC developed had a visual acuity of 5/200 or less, as compared with 2.5% of eyes assigned to immediate PRP. The difference was neither clinically nor statistically significant. Third, PRP has significant complications. It often causes decreased visual acuity by increasing macular edema or by causing macular pucker. Fortunately, the edema frequently regresses spontaneously over 6 months, but the visual field usually is moderately, but permanently, decreased. Color vision and dark adaptation, which often are already impaired, also are worsened by PRP.
PERIPHERAL RETINAL CRYOTHERAPY.
Peripheral retinal cryotherapy is used to treat HRC in eyes with media too hazy for PRP. Reported benefits include resorption of vitreous hemorrhages and regression of NVD, NVE, and NVI. The main complication is the development or acceleration of traction retinal detachment in 25–38% of eyes.  Therefore, this treatment should be avoided in patients with known traction retinal detachment, and all patients must be monitored carefully.
TREATMENT OF MACULAR EDEMA.
Patz was the first to show that argon laser photocoagulation decreases or stabilizes macular edema. Later, the ETDRS confirmed his results. The ETDRS defined clinically significant macular edema as:
• Retinal thickening involving the center of the macula
• Hard exudates within 500?µm of the center of the macula (if associated with retinal thickening)
• An area of macular edema greater than one disc area but within one disc diameter of the center of the macula
The treatment strategy is to photocoagulate all leaking microaneurysms further than 500?µm from the center of the macula (see Fig. 117-8 )
Figure 117-8 Macular edema. A, In an eye previously treated with panretinal photocoagulation. B, Midphase of fluorescein angiography showing microaneurysms, large areas of capillary nonperfusion, and slight enlargement of the foveal avascular zone. C, Late phase of fluorescein angiography showing diffuse capillary leakage. D, Grid pattern of focal macular photocoagulation in same eye.
and to place a grid of 100–200?µm burns in areas of diffuse capillary leakage and in areas of capillary nonperfusion ( Fig. 117-8 ). After 3 years of follow-up, 15% of eyes with clinically significant macular edema had doubling of the visual angle as opposed to 32% of untreated control eyes. The ETDRS also showed that PRP should not be given to eyes with clinically significant macular edema unless HRC are present. Patients with macular edema who have the best prognosis for improved vision have circinate retinopathy of recent duration or focal, well-defined leaking areas and good capillary perfusion surrounding the avascular zone of the retina. Patients with an especially poor prognosis have dense lipid exudate in the center of the foveola ( Fig. 117-9 ). Other poor prognostic signs include diffuse edema with multiple leaking areas, extensive central capillary nonperfusion, increased blood pressure, and cystoid macular edema. Nevertheless, the ETDRS found that even eyes with these adverse findings still benefited from treatment when compared with control eyes. Small, uncontrolled studies have shown encouraging results with intravitreal injection of triamcinolone acetonide, a corticosteroid, in patients who have refractory diabetic edema.  Long-term efficacy and potential side effects have yet to be clarified.
In summary, the Diabetic Retinopathy Study and the ETDRS conclusively proved that timely laser photocoagulation of diabetic retinopathy can reduce severe visual loss by 95%. Such treatment makes sense, not only from the humanitarian point of view, but also from a cost-effectiveness view. It has been estimated that ETDRS-style therapy saves $250–500 million per year in the United States by enabling patients to avoid disability and welfare. Nevertheless, fully one half of Americans with diabetes do not receive annual eye examinations that include dilatation.
VITRECTOMY IN DIABETIC PATIENTS.
Vitrectomy, introduced by Robert Machemer, plays a vital role in the management of severe complications of diabetic retinopathy. The major indications are nonclearing vitreous hemorrhage, macular-involving or macular-threatening traction retinal detachment, and combined traction–rhegmatogenous retinal detachment. Less common indications are macular edema with a thickened and taut posterior hyaloid, macular heterotopia, epiretinal membrane, severe preretinal macular hemorrhage, and neovascular glaucoma with cloudy media.
To evaluate whether early vitrectomy (in the absence of vitreous hemorrhage) might improve the visual prognosis by eliminating the possibility of later traction macular detachment, the Diabetic Retinopathy Vitrectomy Study (DRVS) randomized 370 eyes with florid neovascularization and visual acuity of 20/400 or better to either early vitrectomy or to observation. After 4 years of follow-up, approximately 50% of both groups had 20/60 or better, and approximately 20% of each group had light perception or worse. Thus, the results indicate that such patients probably do not benefit from early vitrectomy. They should be observed closely so that vitrectomy, when indicated, can be undertaken promptly.
If a patient has a vitreous hemorrhage severe enough to cause a visual acuity of 5/200 or less, the chances of visual recovery within 1 year are only about 17%. The DRVS randomized patients who had a visual acuity of 5/200 or less for more than 6
Figure 117-9 Hard exudate plaque in the center of the macula.
months into two groups, those who received an immediate vitrectomy and those whose vitrectomy was deferred for a further 6 months. The goals of surgery were to release all anterior–posterior vitreous traction and to perform a complete PRP to reduce the incidence of recurrent hemorrhage. Of those who had a deferred vitrectomy, 15% had a final visual acuity of 20/40 or better, as opposed to 25% of those who had an immediate vitrectomy. In patients with type 1 diabetes, 12% of those who had a deferred vitrectomy had a final visual acuity of 20/40 or better, as opposed to 36% of those who had an immediate vitrectomy. The reason for this discrepancy is thought to be excessive growth of fibrovascular proliferation during the waiting period. For this reason, the DRVS concluded that strong consideration should be given to immediate vitrectomy, especially in type 1 diabetics (in type 2 diabetics, the final visual results were similar). Nevertheless, many clinicians feel that in most cases vitrectomy should be deferred for about 6 months or longer if the retina is attached, to give a chance for spontaneous clearing to occur. Some patients will not need the surgery but, more importantly, 25% of the patients in the DRVS who received an immediate vitrectomy had a final visual acuity of no light perception. Exceptions to this general rule are patients who have bilateral visual loss because of vitreous hemorrhage, with chronically recurring hemorrhage, and known traction retinal detachment close to the macula. If surgery is deferred, ultrasonography and electroretinography should be performed at regular intervals to make sure that traction retinal detachment is not developing behind the hemorrhage.
The results of vitrectomy for nonclearing vitreous hemorrhage using this plan are excellent.
In patients who have recurrent vitreous hemorrhage after vitrectomy, a simple outpatient air–liquid exchange may restore vision without the need for a repeat vitrectomy.
Traction retinal detachments are usually a much greater challenge. In general, unless the macula becomes involved, observation is the best therapy for these patients because, in most cases, the detachment does not progress into the macula. These patients should be counseled to consult their ophthalmologists without delay should macular vision suddenly be lost, because vitrectomy at that point becomes an urgent procedure. The surgical objectives are to clear the media, to release all anterior–posterior traction, to release tangential traction via delamination or segmentation (cutting the fibrotic bridges between areas of tractional detachment), and to perform endophotocoagulation to prevent NVI. The prognosis is best in patients who have small areas of traction. An alternative technique is to remove the vitreous and preretinal membranes by the “en bloc” technique. The prognosis is poorest in eyes with table-top detachments, significant preoperative vitreous hemorrhage, no prior PRP, and advanced fibrovascular proliferation. If a lensectomy is required or if iatrogenic breaks are created, the results also are poorer. Approximately 60–70% of patients have improved visual acuity and a final visual acuity of 20/800 or better, but 20–35% have decreased vision after vitrectomy. Cases with severe peripheral fibrovascular proliferation also may require a scleral buckling procedure. Repeated operations are required in about 10% of patients, most commonly for rhegmatogenous retinal detachment and recurrent vitreous hemorrhage.
In traction–rhegmatogenous retinal detachments, the objectives are to find all of the retinal breaks and to release all vitreous traction. After air–fluid exchange to flatten the retina, endolaser photocoagulation is used to treat retinal breaks. Approximately one half of such detachments can be cured. In severe cases, silicone oil is required to maintain reattachment of the retina.
The most common cause of failure following an otherwise successful vitrectomy is NVI resulting in neovascular glaucoma. The risk is higher if there is preoperative NVI (33% versus 17%), if there is persistent retinal detachment after surgery, if the lens is removed during surgery, and if there is florid NVD and retina. In
eyes without these factors, the incidence of neovascular glaucoma is only about 2%. The pathogenesis of this complication is unknown. Some investigators feel that removal of the vitreous allows vasoproliferative factors produced in hypoxic retina to diffuse forward to the iris. Others feel that following vitrectomy increased oxygen diffusion occurs posteriorly out of the anterior chamber, thereby lowering its oxygen tension too far. Fortunately, if an eye does not develop iris neovascularization during the first 4–6 months after vitrectomy, it rarely does so later.
Another vision-threatening complication is neovascularization that originates from the anterior retina and extends along the anterior hyaloid to the posterior lens surface (anterior hyaloidal fibrovascular proliferation). This is more common in young, phakic diabetics who have extensive capillary nonperfusion.
The prognosis for diabetic retinopathy used to be dismal. Today, using timely laser photocoagulation as advocated by the Diabetic Retinopathy Study and the ETDRS, severe visual loss can be reduced by 95%. Nevertheless, many diabetics still become legally blind, because they are not examined regularly by an ophthalmologist. Prevention offers the most hope to diabetics. If blood glucose levels are controlled aggressively, both the onset of retinopathy and the pace of its progression are delayed significantly.
Although all agree that screening of asymptomatic diabetic patients is critical, the most cost-effective timing remains controversial. It generally is agreed that type 2 diabetics should be examined at the onset of their disease, then yearly thereafter. Type 1 diabetics do not have to be examined until 5 years into their disease course, but no sooner than puberty, then yearly thereafter. If retinopathy is detected, the frequency of examinations should be increased appropriately.
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