EARLY NONPROLIFERATIVE DIABETIC RETINOPATHY

Although microaneurysms are the first ophthalmoscopically detectable change in diabetic retinopathy, the earliest abnormalities seen histopathologically are thickening of the capillary basement membrane^1,2 and pericyte dropout.^3,4 Pericytes are mesothelial cells that surround and support the retinal capillary endothelial cells. Normally there is one pericyte per endothelial cell. In people with diabetes, however, the pericytes die off and are decreased in number (Fig. 1). Their absence weakens the capillaries and permits thin-walled dilatations, called microaneurysms, to develop. Later, endothelial cells proliferate and lay down layers of basement membrane material. Fibrin may accumulate within the microaneurysm along with erythrocytes, and the lumen of the microaneurysm may become occluded (Fig. 2). Initially, most microaneurysms are on the venous side of the capillaries, but later they are seen on the arterial side as well. Clinically, they appear as small red dots (Fig. 3). Despite the multiple layers of basement membrane, microaneurysms are permeable to water and large molecules, allowing the transudation of fluid and lipid into the retina.

It is often difficult to distinguish a small dot hemorrhage from a microaneurysm by ophthalmoscopy alone. On fluorescein angiography patent microaneurysms will fill with dye quickly and then leak,⁵ unlike a small dot hemorrhage that will block fluorescence (see Fig. 3). However, angiography cannot distinguish a hemorrhage from a microaneurysm filled with clotted blood. Because fluorescein passes easily though them, we usually see many more microaneurysms on fluorescein angiography than are apparent on examination.⁶

When the wall of a capillary or microaneurysm is thin, 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 has a round or oval shape (“dot or blot”) (see Fig. 3). Superficial (nerve fiber layer) hemorrhages, on the other hand, become flame- or splinter-shaped indistinguishable from that seen in hypertensive retinopathy. Although people with diabetes with normal blood pressure may have multiple splinter hemorrhages, they should nevertheless have their blood pressure checked because a frequent complication of diabetes is systemic hypertension.

Macular edema (retinal thickening) is an important manifestation of NPDR because it is the leading cause of legal blindness in patients with diabetes. The intercellular fluid comes from both leaking microaneurysms and diffuse capillary leakage. It separates retinal cells, causing multiple intraretinal interfaces which scatter light, decreasing the retina's normal translucency and blurring the normal retinal pigment epithelial and choroidal background pattern (Figs. 3, 4, and 5). Clinically, macular edema is detected by biomicroscopy with a contact lens or by a 60- or 80-diopter hand-held lens. Optical coherence tomography (OCT) is a new diagnostic tool that accurately defines retinal thickness and cross-sectional anatomy (see Fig. 5). In severe cases of edema, the pockets of fluid in the outer plexiform layer are large enough to be seen. This is called cystoid macular edema (CME) (Fig. 6). Usually CME is seen in eyes with other signs of severe NPDR such as numerous hemorrhages or hard exudates, but in rare cases, generalized diffuse leakage from the entire capillary network can result in CME with few other signs of diabetic retinopathy.⁷

If the leakage of fluid is severe enough, lipid may accumulate in the retina (see Figs. 4 and 5). 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 areas of capillary nonperfusion (see Figs. 4 and 5). This pattern is called circinate retinopathy.

In addition to the retinal vascular abnormalities, the choriocapillaris may be involved in NPDR. Initially there is a thickening of the basement membrane.⁸ Later, a periodic acid-Schiff (PAS)–positive material accumulates, which impinges on and may occlude the lumen of the choroidal capillaries in the posterior pole.⁴

ADVANCED NONPROLIFERATIVE DIABETIC RETINOPATHY

In advanced NPDR, signs of increasing retinal hypoxia appear, including multiple retinal hemorrhages, cotton-wool spots (Fig. 7), venous beading and loops (Figs. 7 and 8), intraretinal microvascular abnormalities (IRMA) (see Figs. 7 and 8), and large areas of capillary nonperfusion.

Cotton-wool spots, also referred to as soft exudates, are actually nerve fiber layer infarctions. They are white, fluffy-appearing lesions in the nerve fiber layer that result from occlusion of precapillary arterioles. Fluorescein angiography confirms the lack of capillary perfusion. Microaneurysms frequently surround older cotton-wool spots as well as larger areas of capillary nonperfusion.

Venous beading (see Fig. 7) and venous loops (see Fig. 8) indicates sluggish retinal circulation and are nearly always adjacent to extensive areas of capillary nonperfusion. Focal vitreous traction is thought to contribute to their formation.⁹ Capillaries next to areas of nonperfusion that dilate and function as collaterals are referred to as IRMA. They are frequently difficult to differentiate from surface retinal neovascularization. Fluorescein, however, does not leak from IRMA but leaks profusely from neovascularization (see Fig. 7).

The Early Treatment Diabetic Retinopathy Study (ETDRS)¹⁰ found that IRMA, multiple retinal hemorrhages, venous beading and loops, widespread capillary nonperfusion, and widespread leakage on fluorescein angiography are all significant risk factors for the development of proliferative retinopathy. Interestingly, cotton-wool spots, in the absence of the other findings, are not. Approximately 50% of patients with severe NPDR progress to proliferative retinopathy with high-risk characteristics (discussed later) within 1 year.¹¹

PROLIFERATIVE DIABETIC RETINOPATHY

Proliferative vessels usually arise from veins and often begin as a collection of fine vessels. When they arise on or within 1 disc diameter of the optic disc they are referred to as neovascularization of the disc (NVD) (Fig. 9). When they arise further than 1 disc diameter away, they are called neovascularization elsewhere (NVE) (Fig. 10). NVE nearly always grows toward and into zones of retinal capillary nonperfusion, but capillary nonperfusion is nearly always more widespread in eyes with NVD than it is in NVE.¹² Interestingly, it is seen more often in patients younger than 40 compared to older patients with diabetes.¹³

Once the stimulus for growth of new vessels is present the vessels grow along the path of least resistance. The absence of the internal limiting membrane over the optic disc could explain the proclivity of new vessel growth at that location. Neovascularization grows readily along connective tissue scaffolding such as the posterior hyaloidal face (Fig. 11).

The new vessels, initially naked, usually progress through a stage of further proliferation with associated connective tissue formation. As PDR progresses, the fibrous component becomes more prominent. Fibrotic tissue can be vascular or avascular. The fibrovascular variety is usually found in association with vessels extending 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.

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.¹⁴ Davis¹⁵ has 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 are adherent (see Fig. 11). Vitrectomized eyes rarely develop new areas of neovascularization and existent neovascularization tends to regress. If severe enough, posterior vitreous detachment may result in retinoschisis, retinal detachment, and retinal break formation. In eyes fortunate enough not to develop these complications, the neovascularization may burn out, leading to atrophy of the new vessels.

An additional complication of contracting vitreous is traction involving the optic nerve that causes stria of the macula or even macular heterotopia (Fig. 13)²⁰; both may cause decreased visual acuity.

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, often results in severe vitreous hemorrhage or retinal detachment with hand-movements vision or worse. It has long been assumed that sudden vitreous contractions tear the fragile new vessels, causing vitreous hemorrhage. However, 62% to 83% of diabetic vitreous hemorrhages occur during sleep,^16,17 possibly because of an increase in blood pressure secondary to early morning hypoglycemia or to rapid eye movement (REM) sleep. Because so few hemorrhages occur during exercise, we do not restrict the activity of patients with proliferative retinopathy. The location of the hemorrhage is important in predicting whether it will clear on its own. If blood is behind the posterior vitreous face it is likely to settle to the bottom of the eye and be absorbed. However, when hemorrhage breaks into formed vitreous it is less likely to clear spontaneously.

A large superficial hemorrhage may separate the internal limiting membrane from the rest of the retina. Such hemorrhages usually are round or oval but may also be boat-shaped (Fig. 12). The blood may remain confined between the internal limiting membrane and the underlying retina for weeks or months before breaking into the vitreous. Subinternal limiting membrane hemorrhages were formerly thought to lie between the internal limiting membrane and the cortical vitreous and were called subhyaloid or preretinal hemorrhages. It is now felt that true subhyaloid hemorrhages are probably quite rare. Tight subinternal limiting membrane hemorrhages are dangerous beause they may progress to traction retinal detachment.^18,19

Two types of diabetic retinal detachments occur, those that are caused by traction alone (nonrhegmatogenous) (Fig. 14), and those caused by retinal break formation (rhegmatogenous) (Figs. 15 and 16). Characteristics of nonrhegmatogenous (traction) detachment in PDR include the following: (1) the detached retina is usually confined to the posterior fundus and infrequently extends more than two-thirds of the distancd to the equator, (2) it has a taut and shiny surface, (3) it is concave toward the pupil, and (4) there is no shifting of subretinal fluid.

Vitreous traction may also cause focal areas of retinoschisis that may be difficult to distinguish from full-thickness traction retinal detachment. In retinoschisis the elevated layer is thinner and more translucent (Fig. 17).

In combined traction/rhegmatogenous detachment, 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 caused by shifting subretinal fluid. The causative retinal breaks are usually found in the posterior pole near areas of fibrovascular proliferation. They are oval in shape and appear to be partly the result of tangential traction from the proliferative tissue as well as vitreous traction. Determining the location of retinal holes may be complicated by many factors, particularly poor dilation of the pupil, lens opacity, increased vitreous turbidity, vitreous hemorrhage, intraretinal hemorrhage, and obscuration of the breaks by overlying proliferative tissue. Often they are only located during vitrectomy surgery.

DURATION OF DIABETES

The best predictor of diabetic retinopathy is the duration of the disease.^21–28 Patients who have had type 1 or insulin-dependent diabetes mellitus (IDDM) for 5 years or less rarely show any evidence of diabetic retinopathy.^27,29 However, 27% of those who have had diabetes for 5 to 10 years and 71% to 90% of those who have had diabetes for longer than 10 years have diabetic retinopathy.³⁰ After 20 to 30 years, the incidence rises to 95% and approximately one-third to one-half of these patients have PDR.²⁹

Determining the role of duratioo of diabetes as a predictor of retinopathy in type 2 or noninsulin dependent diabetes mellitus (NIDDM) is more difficult because of the uncertainty of the onset in many patients. In some, the diagnosis of diabetes is made only after retinopathy is discovered. With these limitations, the best studies are from Wisconsin and Israel. Yanko and co-workers³⁰ found that the prevalence of nonproliferative retinopathy 11 to 13 years after the onset of type 2 diabetes was 23%. After 16 or more years, it was 60%. Eleven or more years after the onset, 3% of the patients had proliferative retinopathy. Klein found that 10 years after the diagnosis of type 2 diabetes, 67% of patients had retinopathy and 10% had PDR. The risk was lowest in patients who did not require insulin.³¹

AGE OF THE PATIENT

Although the duration of diabetes is the most important determinant of retinopathy, the years that a patient has diabetes before the onset of puberty do not count against him or her. In other words, the risk of retinopathy is roughly the same in two 25 year-old patients, one of whom developed type 1 at the age of 6 and the other of whom developed it at age 12 or 13.^21,25,28

SYSTEMIC FACTORS

Control of Blood Glucose

The decades-old controversy regarding whether or not intensive metabolic control prevents the development or progression of retinopathy was finally laid to rest by the Diabetes Control and Complications Trial (DCCT) ^31,32 and the United Kingdom Prospective Diabetes Study (UKPDS).³³ In the DCCT, patients who closely monitored their blood glucose and who were treated with insulin at least three times per day by injection or by insulin pump were compared to patients treated with conventional therapy. The intensive-treatment group had a 76% reduction in the rate of development of any retinopathy and an 80% reduction in progression of established retinopathy. Ophthalmologists must be aware that after institution of strict control, there is often an initial worsening of preproliferative retinopathy.^36–38 Fortunately, after 2 years of control, the strict-control groups had the same or less retinopathy than groups treated conventionally.39 The UKPDS was a randomized, controlled clinical trial involving newly diagnosed type 2 diabetics. Patients were randomly assigned to intensive glycemic control with sulfonylurea agents or insulin or to conventional control with diet. After 12 years of follow-up, progression of diabetic retinopathy in the intensive-control group was reduced by 21%.³⁴

The benefits of rigorous control of blood glucose do not extend to all eyes with advanced retinopathy. Even patients who are made normoglycemic by pancreatic transplantation continue to show progression.⁴⁰

Renal Disease

Most patients with renal disease, as evidenced by proteinuria, elevated blood urea nitrogen (BUN), and elevated blood creatinine, also have retinopathy.^28,41–43 Even patients with microalbuminuria are at high risk of having retinopathy.^44–48 On the other hand, only 35% of patients with symptomatic retinopathy have proteinuria, elevated BUN or elevated creatinine.⁴⁹

Systemic Hypertension

The literature indicates that elevated systolic blood pressure is a moderate risk factor for diabetic retinopathy.^28,42,43,50 Other studies have found, however, that when patients with nephropathy are excluded, blood pressure is not a strong risk factor.^51–53

The Hypertension in Diabetes Study (HDS), part of the UKPDS, evaluated the effect blood pressure control on the progression of diabetic retinopathy. Patients who were kept under strict control of blood pressure (< 150/85 mm Hg) had a 34% risk reduction in microvascular changes compared to the conventional blood pressure control group (< 180/105).⁵⁴ For every 10-mm Hg reduction in systolic blood pressure there was an associated 13% reduction of microvascular end points. Lisinopril, an angiotensin-converting enzyme inhibitor, has been shown in another study to decrease by 50% the progression of NPDR in normotensive type 1 diabetics; suggesting a benefit for some antihypertensives independent of there blood pressure lowering effect.⁵⁵

Pregnancy

Women with diabetes who begin a pregnancy with no retinopathy have a 10% to 26% risk of developing some NPDR.^56–58 Those who have NPDR at the onset of pregnancy and those who have low hemoglobin or systemic hypertension tend to show accelerated progression, with increased hemorrhages, cotton-wool spots and macular edema.^58–60 Fortunately, there is usually some regression of NPDR after delivery.^61–63

Women who begin pregnancy with NPDR have a 22% to 40% incidence of progression to PDR.^58,61,64 Those with untreated PDR at the onset frequently do poorly unless they are treated with aggressive panretinal photocoagulation (PRP),^65,66 but those with previously treated PDR usually do well.

There is no doubt that women who maintain good metabolic control during pregnancy have fewer spontaneous abortions and fewer children with birth defects.⁶⁷ Therefore, obstetricians strive for strict control. However, 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.^56,59,62,68 It is probably best to gradually bring the blood glucose under control.

Race

Retinopathy is more likely to be present in blacks than in whites.⁶⁹ Moreover, blacks have a higher rate of severe macular edema and of blindness possibly because of a higher incidence of systemic hypertension.⁷⁰ Contrary to these findings, the study by Arfkin and co-workers⁷¹ 'suggested that blacks had a slightly slower rate of progression than whites.

Cigarette Smoking

Cigarette smoking, because it increases blood carbon monoxide, platelet aggregation, and causes vasoconstriction, might be expected to accelerate diabetic retinopathy but a large study recently found no effect.⁷²

Serum Lipids

Elevated serum cholesterol is a strong predictor for the rate of visual loss. Patients with both elevated cholesterol and low-density lipoprotein (LDL) cholesterol are much more likely to have vision loss associated with hard exudates in the macula.⁷³

ALDOSE REDUCTASE

Aldose reductase is an enzyme that converts sugars, when present in high concentration, into alcohols. For example, glucose is converted to sorbitol (and later to fructose by polyol dehydrogenase) and galactose is converted to dulcitol. Because sorbitol, dulcitol, and fructose cannot easily diffuse out of cells, their intracellular concentration increases. Osmotic forces draw water into the cells resulting in electrolyte imbalance. The resultant damage to lens epithelial cells, which have a high concentration of aldose reductase, is responsible for the cataracts seen in children 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.^74,75 Strong support for this theory is that aldose reductase inhibitors inhibit cataract formation,⁷⁶ permeability to small molecules,⁷⁷ capillary basement membrane thickening,^78,79 and pericyte loss.⁸⁰ Furthermore, they improve nerve conduction velocity,^81,82 decrease pain from peripheral neuropathy,⁸³ decrease proteinuria,⁸⁴ and decrease vascular permeability.^77,85

However, clinical trials have thus far failed to show a reduction in the incidence of diabetic retinopathy or of neuropathy by aldose reductase inhibitors,^87,88 possibly because an effective aldose reductase inhibitor with few systemic side effects has yet to be developed.⁸⁹

VASOPROLIFERATIVE FACTORS

In 1954, Michaelson⁹⁰ first proposed that hypoxic retina produces a “vasoproliferative factor” that diffuses to nearby blood vessels inducing neovascularization. There is some clinical evidence for such a substance. First, neoplasms produce a diffusible substance, tumor angiogenic factor, which causes blood vessels from adjacent normal tissues to grow toward and into the tumor, thereby providing the tumor with oxygen and other nutrients. Second, in many conditions (e.g., branch retinal vein occlusion, sickle cell disease, Eales' disease, and retinopathy of prematurity), ischemic areas of retina are adjacent to or near to areas of neovascularization that tends to grow into the hypoxic area.^91–93 Third, the development of neovascularization of the optic disc and iris, both of which can be reversed by PRP, argues for a diffusible factor. Finally, several laboratory studies have found substances that induce neovascularization. Experimental evidence suggests that a diffusible factor exists.⁹⁴ Vascular endothelial growth factor (VEGF), which inhibits the growth of retinal endothelial cells in vitro, has been implicated in diabetic retinopathy. VEGF is found in the vitreous of patients with diabetic retinopathy and decreases after PRP.^95–97 Furthermore, experimental intravitreal injections of VEGF produce retinal ischemia and microangiopathy in primates.⁹⁸ Studies are underway evaluating the use of anti-VEGF compounds in patients with diabetic retinopathy.

GROWTH HORMONE

After Poulson⁹⁹ noted reversal of florid diabetic retinopathy in a woman who had postpartum hemorrhagic necrosis of the pituitary gland (Simmonds' syndrome), growth hormone was suspected to play a causative or at least an important supportive role in the development and progression of diabetic vascular complications. In the 1950's and 1960's surgical pituitary ablation was considered by some to be an effective treatment for diabetic retinopathy, but was hotly debated. The success of PRP ended the argument. More recently, growth hormone deficiency was found to be somewhat protective against retinopathy.¹⁰⁰

PLATELETS AND BLOOD VISCOSITY

Several lines of evidence strongly suggest that platelet abnormalities in diabetics may contribute to retinopathy.¹⁰¹ There are three steps in platelet coagulation: initial adhesion, secretion, and further aggregation. Adhesion refers to the propensity of platelets, aided by von Willebrand factor (factor VIII) to stick to basement membrane, damaged endothelial cells, and collagen.¹⁰² It has been shown that the platelets in diabetic patients are “stickier” than platelets of patients without diabetes.¹⁰³

Once some platelets adhere to the basement membrane or to damaged cell walls, they secrete prostaglandins which cause other platelets to adhere to them (aggregation) (Fig. 18). This is initiated shortly after adhesion when phospholipase releases arachadonic acid frol an arachadonic acid–phospholipid ester in the platelet's cell membrane. Arachadonic acid is then convdrted through several prostaglandin intermediaries to another prostaglandin, thromboxane A₂, which is one of the most potent vasoconstricting and platelet aggregating agents known. As a byproduct of these events, adenosine diphosphate (ADP), another platelet aggregating agent, is released. Diabetic platelets are especially sensitive to thromboxane and to other aggregating agents such as epinephrine.^103,104 It has been postulated that abnormal platelet adhesion and aggregation causes focal capillary occlusion and focal areas of ischemia in the retina, which in turn contribute to the development of diabetic retinopathy.¹⁰¹ However, it should be mentioned that PDR has been reported in patients with severe platelet dysfunction.¹⁰⁵

OTHER HEMATOLOGIC ABNORMALITIES

Other hematologic abnormalities seen in diabetics are increased blood viscosity,¹⁰⁶ increased erythrocyte aggregation,¹⁰⁷ and decreased erythrocyte deformacility,¹⁰⁸ all of which may contribute to sluggish circulation and endothelial damage.

PSYCHOPHYSICAL ABNORMALITIES

One of the early symptoms of diabetic retinopathy is poor night vision (dark adaptation) and poor recovery from bright lights (photostress).^113–116 Also, patients with diabetes, even those without retinopathy, are more likely to have abnormal color vision than are those without diabetes matched for age.^117–120 Blue–yellow discrimination is affected earlier and more severely than is red–green discrimination. As retinopathy advances, color vision deteriorates. Contrast sensitivity may be abnormal in patients without diabetic retinopathy at a time that Snellen visual acuity is normal.^121–123 Ocular hypertension worsens both color vision and contrast sensitivity.¹²⁴

ELECTROPHYSIOLOGIC ABNORMALITIES

One of the earliest electrophysiologic aboormalities seen in patients with diabetes without ophthalmoscopically visible retinopathy is diminution of the amplitude of the oscillatory potentials (OP's) of the electroretinogram at a time when both the a- and b-waves are normal.^125–129 This abnormality probably reflects ischemia in the inner nuclear layer of the retina. Diminished OP's are a good predictor of progression of retinopathy.¹³⁰ As the severity of diabetic retinopathy increases, the amplitude of the b-wave decreases.

REDUCTION OF SYSTEMIC RISK FACTORS

Medical Therapy

ASPIRIN.

Aspirin blocks the conversion of arachadonic acid to prostaglandins, thereby inhibiting platelet secretion and aggregation (see Fig. 18). Because of its success in decreasing the incidence of transient ischemic attacks (TIAs), clinicians theorized that it might retard the progression of diabetic retinopathy. The Early Treatment Diabetic Retinopathy Study found that 650 mg of aspirin daily did not influence the progression of retinopathy, did not affect visual acuity, and did not influence the incidence of vitreous hemorrhages.¹⁰⁹ On the other hand, another group found that 990 mg of aspirin daily alone or combined with 225 mg of dipyridamole (Persantine) significantly slowed the annual appearance of new microaneurysms, but the study was not carried out long enough to demonstrate any clinical significance.¹¹⁰

TICLOPIDINE.

Ticlopidine (Ticlid) inhibits ADP-induced platelet aggregation. Similar to aspirin, the effect is permanent for the life of a labeled platelet. It has been shown to decrease the risk of stroke in patients with TIAs. One short-term study showed statistically significant reduction in the development of diabetic retinopathy.¹¹¹

PENTOXIFYLLINE.

Pentoxifylline (Trental) increases retinal capillary blood flow velocity probably by improving erythrocyte and leukocyte flexibility. It decreases blood viscosity. To date, however, a clinical benefit has not been shown for diabetic retinopathy.¹¹²

Panretinal Photocoagulation

When well-focused, intense light is absorbed by pigmented cells (such as erythrocytes or pigment epithelial cells), it is converted to heat, coagulating the cells and surrounding tissues. The first photocoagulator, the xenon arc, produced an intense light that was successful in obliterating neovascularization that was either on the surface of the retina or only slightly elevated (Fig. 19). Clinicians thought that eyes treated with xenon arc photocoagulation had good regression of retinopathy and fewer vitreous hemorrhages than would have been expected had they not been treated. However, xenon arc photocoagulation had severe limitations. First, the heat generated was often insufficient to obliterate highly elevated neovascularization. Second, neovascularization arising from the optic nerve could not be directly treated because the intense light beam damaged the optic nerve. Finally, in many cases, all of the neovascularization was initially obliterated, but new areas of neovascularization later developed. For these reasons, the long-term results of photocoagulation were considered by many observers to be no better than no treatment at all.

To prevent new areas of neovascularization, several ophthalmologists began to photocoagulate not only neovascularization but all intraretinal hemorrhages as well (“shoot the red”), on the grounds that they represented areas of hypoxia that could later develop into proliferative retinopathy. They soon noted that the cases that had the most intraretinal hemorrhages and therefore received the most initial photocoagulation frequently had the best long-term results, with permanent regression of neovascularization (Fig. 20). In such cases, the optic disc often became pale, indicating optic atrophy.

At about the same time, Aiello and co-workers,^132,133 and others^134–137 noted that patients with unilateral high myopia, extensive chorioretinal scarring, glaucoma, and optic nerve atrophy frequently had markedly asymmetrical retinopathy. The prior retinal or optic nerve damage seemed to protect that eye from diabetic retinopathy (Fig. 21). These investigators initiated the concept of PRP (Fig. 22). They theorized that photocoagulation burns scattered throughout the retina would decrease the retina's need for oxygen and thereby prevent neovascularization from developing or might even cause regression of existent neovascularization. Early studies showing the benefits of PRP were criticized on statistical and other grounds and were not widely accepted.^138,139

It remained for a national collaborative study initiated by Davis and sponsored by the National Institutes of Health (The Diabetic Retinopathy Study (DRS)) to prove that both xenon-arc and argon-laser PRP significantly decrease the likelihood that an eye with high-risk characteristics will progress to severe visual loss.^140–142 High-risk characteristics are defined as eyes with (1) NVD greater than one-fourth to one-third disc area, (2) any NVD and vitreous hemorrhage, or (3) NVE greater than one-half disc area and vitreous or preretinal hemorrhage (see Fig. 20). The main findings of the DRS are summarized in Table 1.

TABLE 1. Results of the DRS at Three Years

After PRP, retinal circulation is definitely improved. There is a better regulatory response to hypoxia and decreased blood flow.^143,144 The exact mechanism by which PRP works remains unknown. Some investigators believe that PRP decreases production of vasoproliferative factors first by eliminating some of the hypoxic retina or by stimulating the release of anthangiogenic factors from the retinal pigment epithelium.¹⁴⁵ An alternative hypothesis is that vessel dilatation caused by chronic hypoxia is the direct stimulus for endothelial cell proliferation and neovascularization and that PRP works by thinning the retina. Vasodilatation is reduced by increased diffusion of oxygen from the choroid.^146–149 Another possibility is that PRP decreases choroidal circulation in the midperiphery, which in turn shunts blood flow centrally, (“reverse choroidal steal”) decreasing the stimulus for NVD.¹⁵⁰ Finally, others suggest that PRP leads to an increase in vasoinhibitors either by stimulating the retinal pigment epithelium to produce inhibitors of vasoproliferation^145,151 or by causing a breakdown of the blood–retinal barrier so that serum vasoinhibitors can diffuse into the vitreous.¹⁵²

The goal of PRP is to arrest or to cause regression of the proliferating new vessels. The currently recommended therapy is 1600 to 2000 burns, 500 μm in diameter delivered through a wide-field or three-mirrored lens.¹⁵³ The burns should be intense enough to whiten the overlying retina. This usually requires a power of 200 to 600 mW and duration of 0.1 seconds. The usual PRP decreases the electroretinogram by 40% to 70%^154,155 and destroys approximately 14% of the total retinal area.¹⁵⁵ Most ophthalmologists use the argon blue–green or green laser, but a large clinical trial has shown that krypton red is equally effective.¹⁵⁶

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.^157–160 However, it remains to be proven that the eye benefits from thousands of burns. In fact, the only prospective, controlled study found that eyes that received supplementary treatment had no difference in reduction in risk factors or better visual acuity than did eyes that received only a standard PRP.¹⁶¹

Once the DRS had proved that PRP was effective in preventing severe visual loss in patients with high-risk characteristics, the question arose as to whether treatment of mild PDR or severe NPDR would lower still further the risk of blindness from diabetic retinopathy. The ETDRS found that PRP significantly retards the development of high-risk characteristics in eyes with severe NPDR and macular edema.¹¹ After 7 years of follow-up, 25% of eyes that received PRP developed high-risk characteristics compared to 75% of eyes in which PRP was deferred until high-risk characteristics developed. Nevertheless, the ETDRS concluded that treatment of PPDR and of PDR short of high-risk characteristics was not indicated. First, after 7 years of follow-up, 25% of eyes assigned to deferral of PRP never developed high-risk characteristics. Second, when patients are closely monitored and PRP is given as soon as high-risk characteristics develop severe visual loss can be prevented. After 7 years of follow-up, 4.0% of eyes that did not receive PRP until high-risk characteristics developed had a visual acuity of 5/200 or less compared to 2.5% of eyes assigned to immediate PRP. The difference was neither clinically nor statistically significant. So, if all eyes with severe NPDR received PRP, many would be treated unnecessarily. Third, PRP has significant complications. PRP often causes decreased visual acuity by increasing macular edema^162–164 or by causing macular pucker. Fortunately, the edema frequently regresses spontaneously over 6 months. The visual field is usually moderately decreased.¹¹³ Color vision and dark adaptation, which are often already impaired, are also worsened by PRP.^114–116 Finally, PDR is associated with an increased risk of myocardial infarction and increased mortality.¹⁶⁵ Many patients will die before they develop complications of the PDR.

Peripheral Retinal Cryotherapy

Peripheral retinal cryotherapy (PRC) is used to treat eyes with high-risk characteristics and with media too hazy for PRP. Reported benefits include resorption of vitreous hemorrhages and regression of NVD, NVE, and NVI.^166–172 The main complication is the development or acceleration of traction retinal detachment in 25% to 38% of eyes.^170,173 Therefore, this treatment should be avoided in patients with known traction retinal detachment and all patients must be carefully monitored. An alternative treatment in eyes with hazy media is transscleral diode laser photocoagulation.

Treatment of Macular Edema

Patz and co-workers¹⁷⁴ were the first to show that focal argon laser photocoagulation decreases or stabilizes macular edema. Later, the ETDRS confirmed their results. The ETDRS defined clinically significant macular edema (CSME) as (1) retinal thickening involving the center of the macula, (2) hard exudates within 400 μm of the center of the macula (if they are associated with retinal thickening), or (3) an area of macular edema greater than one disc area which is within one disc diameter of the center of the macula. The treatment strategy was to treat all leaking microaneurysms farther than 500 μm from the center of the macula (Fig. 23) and to place a grid of 100 to 200 μ burns in areas of diffuse capillary leakage and in areas of capillary nonperfusion. After 3 years of follow-up, 15% of eyes with eyes with CSME had doubling of the visual angle as opposed to 32% of nontreated control eyes.¹⁷⁵ Recent subgroup analysis showed that treatment could be deferred in eyes in which the center of the fovea is not thickened as long as hard exudates are not threatening the center. However, such eyes must be closely observed.¹⁷⁵

The ETDRS also showed that PRP is not part of the treatment strategy of CSME. Eyes that received PRP along with their focal treatment were much more likely to have an immediate decrease in visual acuity than were eyes that received focal treatment alone.¹¹ An alternative treatment to the ETDRS strategy is a grid treatment (Fig. 24).¹⁷⁶

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 fovea (Fig. 25). Other poor prognostic signs include diffuse edema with multiple leaking areas, capillary closure around the fovea (Fig. 26), increased blood pressure, and cystoid macular edema.^174,177 Nevertheless, the ETDRS found that even eyes with these adverse findings benefited from treatment compared to control eyes.¹⁷⁵ The use of intravitreal steroids is also receiving attention for its potential role in the treatment of persistent diabetic edema. Small uncontrolled series have demonstrated dramatic reduction of macula thickness with associated improvement in visual function.^178,179 Although encouraging, intravitreal corticosteroids are associated with frequent elevated intraocular pressure and occasionally endophthalmitis.^180,181

Vitrectomy techniques are also increasingly being considered for diabetic edema management. Early reports found up to 90% of eyes undergoing vitrectomy for the treatment of edema associated with a taut or thickened posterior hyaloid had visual improvement.^182,183 Recent larger series confirm the efficacy of vitrectomy for eyes with abnormal hyaloid–macula interface.^184,185 The success in this subgroup of patients is predicted by the hypothesis that tangential traction exerted by attached vitreous contributes to macular edema.¹⁸⁶

More modest results have been reported with vitrectomy for the treatment of eyes with attached hyaloid that were not taut or thickened. Published series report approximately one-half of the eyes improve by only a line of acuity.¹⁸⁷ Interestingly macular edema resolved in most of these eyes. Otani and colleagues¹⁸⁸ reviewed seven patients with symmetric diabetic edema without an abnormally taut hyaloid who had one eye randomized to vitrectomy. They used OCT to demonstrate an average decrease in macular thickness of 353 μm postoperatively compared to a 60 μm average decrease in thickness in the fellow eyes.

In summary, DRS and the ETDRS conclusively proved that timely laser photocoagulation of diabetic retinopathy can reduce severe visual loss by 95%.¹⁸⁹ Such treatment makes sense not only from the humanitarian point of view but is extremely cost-effective as well, saving approximately $250 to $500 million per year by keeping patients off disability and welfare.^190–192 Nevertheless, only half of Americans with diabetes, especially the poor and minority population, fail to receive an annual dilated eye examination.^193–194 The American Diabetes Association recommends that patients with type 1 diabetes should be screened annually beginning 5 years after the onset of the disease and patients with type 2 should be screened immediately and then annually thereafter.¹⁹⁵ Alternatives methods of screening when ophthalmologists are not available include the use of primary care physicians or digital photography with remote image interpretation. Although primary care physicians commonly fail to detect significant retinopathy with direct ophthalmoscopy, training significantly improves their ability.^86,196

Vitrectomy in Patients with Diabetes

Regarding this topic, the reader should also consult Chapter 56, Volume 6 for details.²⁰² Vitrectomy, introduced by Robert Machemer, plays a vital role in the management of severe complications of diabetic retinopathy. The major indications are non-clearing vitreous hemorrhage, traction retinal detachment, and combined traction/rhegmatogenous retinal detachment. Less common indications are macular edema with a thickened and taut posterior hyaloid,^203,204 macular heterotopia, and tight preretinal macular hemorrhage,^18,19

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 10/200 or better to either early vitrectomy or to observation.²⁰⁵ 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 promptly be undertaken.

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 approximately 17%.²⁰⁶ The DRVS randomized patients who had a visual acuity of 5/200 or less for more than 6 months into two groups: those who received an immediate vitrectomy and those for whom vitrectomy was deferred for an additional 6 months.²⁰⁷ Fifteen percent of those who had a deferred vitrectomy 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 was 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.) In most cases, vitrectomy should be deferred for approximately 6 months or longer if the retina is attached to give the patient a chance for spontaneous clearing. Some patients will never need the surgery, but more importantly, 25% of the patients in the DRVS who received an immediate vitrectomy had a final visual acuity of NLP. Patients with bilateral visual loss because of vitreous hemorrhage, with chronically recurring hemorrhage, with no history of PRP, and with known traction retinal detachment close to the macula are offered surgery sooner. If surgery is deferred, ultrasonography should be performed at regular intervals to make sure that traction retinal detachment is not developing behind the hemorrhage. The goals of surgery are to release all anterior–posterior vitreous traction and to perform a complete PRP to reduce the incidence of recurrent hemorrhage. Furthermore, the results of vitrectomy for nonclearing vitreous hemorrhage are excellent (Table 2).

TABLE 2. Overal Visual Results

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.²⁰⁹

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 will not progress into the macula.²¹⁰ These patients should be counseled to consult their ophthalmologist without delay should macular vision be suddenly lost, because vitrectomy at that point becomes a relative emergency.²⁰² The surgical objectives are to clear the media, to release all anterior–posterior traction, to release tangential traction by cutting bridges between areas of traction detachment or by delamination, and to perform endophotocoagulation to prevent neovascularization of the iris. The prognosis is best in patients with small areas of traction. An alternative technique is to remove the vitreous and preretinal membranes by the “en bloc” technique.^211,212 The prognosis is poorest in eyes with extensive fibrous adhesion to the retina (table-top) detachments, significant preoperative vitreous hemorrhage, no prior PRP, and advanced fibrovascular proliferation. If a lensectomy is required and if iatrogenic breaks are created, the results are also poorer. ^{202–208,210} Approximately 60% to 70% of patients have increased visual acuity and a final visual acuity of 20/800 or better, but 20% to 35% have decreased vision after surgery. Cases with severe peripheral fibrovascular proliferation may also require a scleral buckling procedure.²¹⁹ Reoperations are required in approximately 10% of patients, most commonly the repair of rhegmatogenous retinal detachment or for clearing of recurrent vitreous hemorrhage.²²⁰

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.^221,222 In severe cases, silicone oil is required to reattach the retina.^223–225

Neovascularization of the iris (NVI) that progresses to neovascular glaucoma is a common cause of failure following otherwise successful vitrectomy. The risk is higher if there is preoperative neovascularization of the iris (17% versus 33%) if there is persistent retinal detachment after surgery, if the lens is removed during surgery, and if there is florid NVD and NVE. In eyes without these factors, the incidence of neovascular glaucoma is only about 2%.²²⁶ 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 the main problem is that oxygen diffuses posteriorly from the anterior chamber lowering its oxygen tension too far. Fortunately, if an eye does not develop rubeosis iridis in the first 4 to 6 months after vitrectomy, it rarely will do so later.

Another vision-threatening complication is neovascularization originating from the anterior retina and extending along the anterior hyaloid to the posterior lens surface (anterior hyaloidal fibrovascular proliferation).²²⁷

CORNEA

Several investigations have found decreased corneal sensitivity in patients with diabetes.^228–231 The severity of the hypesthesia has been correlated with both the duration of the disease²³⁰ and the severity of the retinopathy.^228,231

The adhesion between the basement membrane of the corneal epithelium and the corneal stroma is not as firm as that found in normal corneas, probably because of a decreased number of hemidesmosomes between the stroma and the epithelium. When the epithelium is scraped from a normal cornea, the bottom half of the cells forming the basal layer are broken and remain attached to the basement membrane, which remains attached to the stroma. In diabetics, the entire epithelium is removed intact. Hyperglycemia and the aldose reductase pathway probably play a major role in epithelial abnormalities because aldose reductase inhibitors accelerate healing of corndal abrasions.^232–234 After vitrectomy, recurrent corneal erosion, striate keratopathy, and corneal edema are more common in patients with diabetess than in tjose without diabetes. Although it has been shown that the endothelial cell density is normal in diabetics,²³⁵ it is not yet known whether or not endothelial cellular dysfunction contributes to these complications.

GLAUCOMA

Becker²³⁶ found that in patients with diabetes there is a higher incidence of open-angle glaucoma and marked elevation of intraocular pressure after prolonged administration of topical corticosteroids than there is in patients without diabetes. Moreover, patients with diabetes are more susceptible to visual field loss than those who do not have diabetes.

NVI is rarely associated with NPDR alone. It is usually seen only in eyes with PDR. By the end of the follow-up period of the DRS, Tasman and co-workers²³⁷ found NVI in 3.8% of the patients who had not received PRP as opposed to 2.0% in those who had. Thus, PRP appears to have some protective value against NVI. PRP is also an effective treatment against established NVI.^238–240 Regression of the iris vessels and stabilization of any areas of angle closure and of intraocular pressure have been reported in 80% of cases treated. If the media are clear, PRP should be performed prior to any other treatment of NVI, even in advanced cases. Jacobson and associates²³⁸ reported successful results as long as the intraocular pressure was less than 40 mm Hg and there was less than 270 degrees of angle closure. We have seen regression and permanent pressure control in patients with pressures as high as 60 mm Hg. If the media are too cloudy for PRP, peripheral retinal cryoablation and transscleral diode laser photocoagulation are alternative means of treatment (see above).

If the angle is completely sealed and there is reasonable visual potential, a Molteno or other tube shunt offers the best chance for preserving vision.²⁴¹ Cyclocryodestructive procedures often result in phthisis.

LENS

Because the lens in patients with diabetes has multiple biochemical abnormalities,²⁴² the risk of cataract is 2 to 4 times greater in than in patients without diabetes^243–247and may be 15 to 25 times greater in patients with diabetes under 40 years of age.²⁴⁸ Furthermore, the occurrence of cataract is a predictor of increased mortality.²⁴²

Patients with diabetes mellitus who have no retinopathy have excellent results from cataract surgery, with 90% to 95% having a final visual acuity of 20/40 or better, but, chronic cystoid macular edema is approximately 14 times more common in patients with diabetes than in those without.^249–251 In patients with mild to moderate NPDR without macular edema, approximately 70% to 80% attain 20/40; outcomes are significantly worse in eyes with more severe retinopathy.^252–254 Risk factors for progression and worse vision include an older age,²⁵⁵ poor glycemic control,²⁵² poor renal function, and most significant preoperative macular edema. In many eyes the edema is self-limited and behaves clinically like postcataract CME; focal laser should be delayed when differentiation between diabetic edema cannot be made. The majority of eyes with CME will improve in 6 months.²⁵⁶

The most dreaded anterior complication is NVI. It was hoped that modern surgery that leaves an intact posterior capsule would protect the eye from neovascularization of the iris, by reducing the diffusion of vasoproliferative factors into the anterior chamber but several studies have shown that it does not. Eyes of patients with diabetes more frequently develop significant posterior capsular opacification²⁵⁷; fortunately capsulotomy does not seem to increase the risk of anterior segment neovascularization.²⁴⁷ Other anterior segment complications that are more common in patients with diabetes than in those without are pupillary block, posterior synechiae, pigmented precipitates on the implant, and severe iritis.²⁵⁰

Posterior complications include macular edema and ischemia,^255,256,258 proliferative retinopathy,^249,259 vitreous hemorrhage, and traction retinal detachment.^251,258,260 In patients with active NPDR and no preoperative macular edema, as many as 50% to 75% will develop it and 30% will develop PDR. Approximately 8% will develop NVH. If macular edema is present prior to the surgery, it nearly always worsens. Only approximately 50% will have a final visual acuity of 20/40 or better. The risk of the development of or progression of macular edema is nearly doubled in patients who are older than 63 years of age.²⁶⁷ Clearly, caution must be observed when considering cataract surgery in patients who have diabetic retinopathy.

Cataract surgery in patients with active PDR often results in still poorer postoperative visual outcome because of the high risk of both anterior²⁶² and posterior segment complications. In one series, no patient with active PDR or PPDR achieved better than 20/80. Anteriorly, fibrinous uveitis is seen in more than 50% of patients with active PDR. Most experts recommend aggressive preoperative PRP.^258,268

OPTIC NEUROPATHY

As demonstrated by increased latency and decreased amplitude of the visual evoked potential, many patients with diabetes without retinopathy have subclinical optic neuropathy.^269,270 In addition, patients with diabetes can develop two types of acute optic neuropathy. The first, anterior ischemic optic neuropathy (AION) is identical to that seen in patients without diabetes. The patients report a sudden decrease in visual acuity or a sudden visual field loss.^271–273 The main ocular finding is a “pale swelling” of the optic nerve head with, considering the degree of disc edema, very few hemorrhages (Fig. 27). On fluorescein angiography segmental nonfilling or slow filling is seen (Fig. 27). An afferent pupillary defect (Marcus Gunn) is nearly always present. Visual fields commonly show altitudinal or nerve fiber bundle defects. The disc progresses to optic atrophy (Fig. 27), and improvement in visual function is rare.

The other type of acute optic neuropathy, commonly called diabetic papillopathy, is characterized by acute disc edema without the pale swelling of AION. It is bilateral in one-half of cases. The vision usually recovers to better than 20/50 with or without an afferent pupillary defect.²⁷⁴ Macular edema is a common finding and is the most common cause of failure of visual recovery.²⁷⁴ Visual fields may be normal, show an increased blind spot, or have disc-related defects. The prognosis is excellent as nearly all patients recover to 20/30 or better.^275–277

CRANIAL NEUROPATHY

Extraocular muscle palsies may occur in patients with diabetes secondary to neuropathy involving the third, fourth, or sixth cranial nerves. The mechanism is believed to be a localized demyelination of the nerve secondary to focal ischemia. Pain may or may not be experienced, and not infrequently an extraocular muscle palsy may be the initial clue to a latent diabetic condition. Recovery of extraocular muscle function in diabetic cranial nerve neuropathy generally takes place in 1 to 3 months.²⁷⁸

When the third nerve is involved, pupillary function is usually normal. This pupillary sparing in the diabetic third-nerve palsy is an important diagnostic feature, distinguishing it from other causes of oculomotor involvement such as intracranial tumor or aneurysm.

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