Diabetes Mellitus

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Diabetes Mellitus

Natural History

I. Diabetes mellitus (DM) is a heterogeneous group of disorders characterized by elevated blood glucose and other metabolic abnormalities.

The HbA1c (glycated hemoglobin) level is important in making the diagnosis of diabetes and is used as a measure of the quality of diabetic care. It is also predictive of mortality and associated with significant variations in single nucleotide polymorphisms (SNPs) based on racial and ethnic differences in populations. New susceptibility loci for diabetes type 2 are also being discovered. The presence of prediabetes varies considerably on a racial basis.

A. The disorder may result from decreased circulating insulin or from ineffective insulin action in target cells.

B. DM, which affects approximately 5% of the U.S. population and 29% of the population 65 years or older, is classified as either type 1 (previously called insulin-dependent) or type 2 (previously called noninsulin-dependent) DM.

Traditionally, type 2 diabetes has been a disease of adults. As the prevalence of obesity among adolescents has risen, there has been an emergence of type 2 diabetes in that segment of the population.

C. Type 1 diabetes, which is an autoimmune disorder probably related to infections, early childhood diet, and insulin resistance, represents a worldwide epidemic.

D. Worldwide, there are approximately 93 million people with diabetic retinopathy, 17 million with proliferative diabetic retinopathy, 21 million with diabetic macular edema, and 28 million with vision-threatening diabetic retinopathy. Longer diabetes duration and poorer glycemic and blood pressure control are strongly associated with diabetic retinopathy (DR).

In 2010, worldwide there were twice as many deaths attributed to diabetes as in 1990. By 2025, 380 million people worldwide are expected to have diabetes.

E. Intensive lifestyle interventions can prevent the onset of diabetes in high-risk individuals. Control of blood sugar levels, blood pressure, and blood lipids can prevent or delay the onset of diabetes-related complications. Type 2 DM accounts for approximately 90% of diabetic patients. Target cell resistance occurs in both types, but it is a central feature in type 2. Genetic defects in the cellular insulin receptor may account for the insulin resistance.

II. DR is a leading cause of blindness in the United States.

A. More than three-fourths of the blind are women.

B. There is a significantly higher prevalence of DR in individuals of black or Latino descent compared to whites or Chinese.

C. The most important factor in the occurrence of DR is how long the patient has been diabetic.

1. Although approximately 60% of patients develop retinopathy after 15 years of diabetes, and almost 100% after 30 years, the risk of legal blindness in a given diabetic person is only 7–9% even after 20–30 years of DM.

a. When the onset of type 1 DM is before 30 years of age and no DR is present at onset, approximately 59% of patients have developed DR four years later, and almost 100% 20 years later. In this group, the incidence of proliferative DR (PDR) stabilizes after 13 or 14 years of diabetes at between 14% and 17%.

b. When the onset of type 1 DM is after 30 years of age and no DR is present at onset, approximately 47% of patients have developed DR four years later. Among patients older than 30 years of age who develop type 2 DM, 34% develop DR four years later. In this group of patients with type 1 DM, 7% who were free of PDR at onset of DM developed PDR four years later; 2% of the patients with type 2 DM developed PDR four years later.

c. The prevalence of diabetic retinopathy and vision-threatening diabetic retinopathy is particularly high among non-Latino black individuals.

2. Overall, there has been a decline in the cumulative incidence of severe DR in patients with type 1 diabetes. Similarly, the rate of nonproliferative DR is declining in the United States.

3. Over a 25-year follow-up period, the mortality in diabetic blind individuals is 61% compared to 41% for those who are not blind. Moreover, there is significant racial difference in the quality-adjusted life-years for individuals with diabetes and visual impairment, with whites having a higher quality-adjusted life expectancy compared to black individuals.

Factors associated with mortality are glycemic regulation, dyslipidemia, and creatinine level.

4. Baseline factors associated with progression to blindness include the presence of maculopathy and glycemic control (HbA1 level).

5. Ocular symptoms occur in approximately 20–40% of diabetic patients at the clinical onset of the disease, but these symptoms are mainly caused by refractive changes rather than by DR.

6. The low frequency of retinopathy in secondary diabetes (e.g., chronic pancreatitis, pancreatectomy, hemochromatosis, Cushing’s syndrome, and acromegaly) may be due to the decreased survival among patients with secondary diabetes.

A positive correlation exists between the presence of DR and nephropathy (Kimmelstiel–Wilson disease).

7. It appears that the risk for developing DR in type 1 DM is reduced if glycemic control is achieved from the time of diagnosis; conversely, if DR is already present, early intensive insulin treatment can initially worsen the DR in approximately 10% of those individuals. The worsening may be related to increased vascular endothelial growth factor (VEGF) production. Control of accompanying hypertension can facilitate the regression of diabetic retinopathy.

8. Among diabetic individuals, plasma lipid levels are associated with the presence of hard retinal exudates. Carotid artery intima–media wall thickness is associated with retinopathy; however, other manifestations of atherosclerosis and most of its risk factors are not associated with the severity of DR.

9. Diabetic retinopathy is independently associated with coronary artery calcification suggesting that common pathophysiologic processes may underlie both micro- and macrovascular disease.

III. In juvenile DM, PDR is uncommon in patients younger than 20 years of age and almost unheard of in patients younger than 16 years of age.

A. Background DR (BDR; especially microaneurysms), however, can be demonstrated on fluorescein angiography in juvenile diabetic patients as young as three years of age, and it is present in most patients older than 10 years of age.

The autoimmune process leading to type 1 diabetes involves a T-cell response with the pancreatic β cell as the target. Enteroviruses, especially coxsackievirus B4 virus, have been suggested as potential inducers or aggravating factors of type 1 diabetes in genetically predisposed individuals. Others question the virus’s causative role. It also must be noted that viruses not only may contribute to the pathogenesis of type 1 diabetes by accelerating the progression of the disease but also may provide protection from autoimmunity. In addition, viruses can infect pancreatic β cells, with results ranging from functional damage to cell death.

IV. Most diabetic patients never acquire PDR, and in those who do, it develops only after at least 15 years of DM.
Rarely, a patient presents with BDR, or even with PDR, before any systemic evidence of DM (e.g., hyperglycemia) is discovered.

V. Other associations

A. Primary open- and closed-angle glaucoma occurs more often in diabetic patients than in nondiabetic individuals.

The presence of type 2 diabetes and longer duration of type 2 diabetes are associated with an increased risk of open-angle glaucoma in individuals of Latino descent.

B. DR is approximately 6% more frequent in diabetic patients who have a diagonal earlobe crease than in those individuals who do not have a diagonal earlobe crease. A positive association also exists between a diagonal earlobe crease and coronary artery disease in diabetic patients.

C. A positive association exists between DR and the presence of elevated blood pressure (especially increased diastolic blood pressure), glycosylated hemoglobin, and smoking.

Poor control in DM adversely impacts nerve fiber layer thickness as measured by the scanning laser polarimeter. This finding does not appear to be acute because it is not reversed by short-term blood glucose regulation.

D. Other risk factors for the development of DR include hypertension and abdominal obesity.

VI. Diabetic peripheral neuropathy affects approximately 50% of diabetic patients.

Retinal Vasculature in Normal Subjects and Diabetic Patients

Figure 15.1 shows examples of retinal vasculature in normal subjects and diabetic patients (see also section Neural Retina, later in this chapter).

Fig. 15.1 Retinal vasculature (normal and diabetic). A, Periodic acid–Schiff- and hematoxylin-stained trypsin digest of normal neural retina shows the optic nerve (o) and major blood vessels. The arterioles (a), darker and slightly smaller than the venules (v) (ratio of vein to artery, 5 : 4), are surrounded by a narrow, characteristic, capillary-free zone. The foveal avascular zone (faz) is clearly seen. B, Diagram of healthy retinal capillary shows normal 1 : 1 ratio of pericyte to endothelial cell nuclei. The ratio is decreased in the diabetic patient because of a loss of pericyte nuclei, perhaps by apoptosis. C, Trypsin digest of normal neural retina shows retinal capillary with its normal 1 : 1 ratio of pericyte (p) to endothelial (e) cell nuclei. D, Trypsin digest of diabetic neural retina shows capillary with a decreased pericyte-to-endothelial cell nuclei ratio. Endothelial cell nuclei are present but appear pyknotic. Pericyte nuclei are absent from their basement membrane shells (sr).

Conjunctiva and Cornea

I. Conjunctiva

A. Conjunctival microaneurysms may be found in diabetic individuals, but they are of questionable diagnostic significance because they also occur in nondiabetic subjects.

B. Transmural lipid imbibition may occur in conjunctival capillaries in diabetic lipemia retinalis (Fig. 15.2). Histologically, lipid-laden cells, either endothelial cells or subintimal macrophages, are present projecting into and encroaching on conjunctival capillary lumens.

Fig. 15.2 Lipemia retinalis. Right eye (A and C) and left eye (B and D) of same patient taken one month apart. Lipemia retinalis is more marked in C and D than in A and B. Transmural lipid imbibition may also occur in conjunctival capillaries in diabetic lipemia retinalis.

C. The conjunctiva may show decreased vascularity in the capillary bed, increased capillary resistance, and decreased area occupied by the microvessels.

Microvascular abnormalities have even been detected in the conjunctiva of pediatric diabetic patients. The severity of these findings correlates with hemoglobin A1c levels but not with the duration of the disease. Such conjunctival microvascular changes correlate significantly with disease severity in type 2 diabetes but not with disease duration since diagnosis.

D. The prevalence and grade of pinguecula are more significant in diabetics than in nondiabetic individuals.

E. Conjunctival vasculopathy in type 2 diabetes may precede retinal changes, thereby possibly providing a window of opportunity for earlier intervention in these individuals.

F. Inflammatory markers such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) are upregulated in the conjunctiva of type 2 diabetic individuals with or without retinopathy. ICAM-1, VEGF, and p53 are strongly expressed in the conjunctival of patients with PDR compared to nondiabetic controls, and they are expressed to some degree even in diabetic individuals lacking PDR.

The presence of upregulation for these mediators in the conjunctiva, often before the presence of clinical retinopathy, suggests a possible role for these mediators in the pathogenesis of diabetic microangiopathy.

II. Cornea

A. Epithelium

1. Corneal epithelium and its basement membrane may be abnormal in diabetes; epithelial erosions are common; corneal sensation may be reduced; and the stroma may be thickened. Tear production is more frequently reduced in diabetic patients than in nondiabetics.

Decreased penetration of “anchoring” fibrils from the corneal epithelial basement membrane into the corneal stroma may be responsible for the loose adhesion between the corneal epithelium and the stroma. The corneal epithelium in diabetic patients is much easier to wipe off, often in a single sheet (e.g., during vitrectomy procedures), than is the epithelium of nondiabetic patients. Approximately 50% of diabetic patients undergoing vitrectomy surgery have corneal complications following the procedure, with 44.6% having an epithelial disturbance and 23.8% exhibiting corneal edema. These complications are significantly correlated with the degree of surgical invasion during the procedure.

2. Diabetic ocular surface disease following cataract surgery is ameliorated with oral aldose reductase inhibitor treatment by improving ocular surface sensitivity.

Keratoepitheliopathy, conjunctival squamous metaplasia, and abnormal corneal sensitivity, tear breakup time, Schirmer test, and tear secretion level are all related to the status of metabolic control, diabetic neuropathy, and stage of DR. The prevalence of keratoepithelialiopathy is 22.8% in diabetic individuals, but 8.5% in nondiabetics, and it is associated with tear film abnormalities, particularly nonuniformity of the tear lipid layer, in diabetic patients.

B. Endothelium

1. Specular microscopic studies show corneal endothelial structural abnormalities reflected in an increased coefficient of variation of cell area, a decreased percentage of hexagonal cells, an increased corneal autofluorescence, polymegathism and pleomorphism, and an increased intraocular pressure. The changes in corneal endothelium resemble those that occur with aging.

2. In the Ocular Hypertension Treatment Trial, increased central corneal thickness was associated with younger age, female gender, and diabetes.

3. Contact lens studies in patients who have type 2 DM have demonstrated that the diabetic corneal endothelium shows significantly lower function than the nondiabetic corneal endothelium, even though the morphometry of corneal endothelial cells and central corneal thickness in diabetic patients who wear soft contact lenses are not appreciably different from the values found in contact lens-wearing control individuals.

4. Corneal endothelial cell density is reduced in subjects with type 2 diabetes. Endothelial cell density is inversely correlated with HbA1c levels, which are correlated with mean endothelial cell area. These corneas also are thicker than those of healthy control subjects.

Corneal endothelial cells of diabetic individuals are more susceptible to damage during cataract surgery than are those of nondiabetics. Such patients may exhibit a delay in recovering from postoperative corneal edema. Diabetes is also a significant risk factor for unsuccessful initial corneal transplant grafts because of endothelial failure.

C. Corneal nerves

1. The evaluation of corneal nerve morphology with confocal microscopy and histopathology demonstrates significant changes in the diabetic corneal nerve paralleling other forms of diabetic polyneuropathy.

2. The abnormalities are more pronounced in patients with PDR. Sub-basal nerve abnormalities correlate with reduced corneal epithelial basal cell density.

a. Corneal nerve tortuosity may relate to the severity of the neuropathy in diabetic patients.

b. Corneal confocal microscopy demonstrates that corneal nerve fiber density and branch density are reduced in diabetic patients compared to control individuals, and these measures tend to be worse in individuals with more severe neuropathy.

c. Corneal nerve morphology as evaluated by confocal microscopy improves with improvement in risk factors for diabetic neuropathy.

d. Morphologic changes in corneal nerve fibers can be detected earlier in diabetes than abnormalities in corneal sensation testing and vibration assessment.

e. Corneal Langerhans’ cell density is increased in diabetic patients, particularly in the earlier phases of corneal nerve damage, suggesting a possible immune-mediated mechanism for corneal nerve damage.

Lens

I. “Snowflake” cataract of juvenile diabetic patient

A. The cataract consists of subcapsular opacities with vacuoles and chalky-white flake deposits.

B. The whole lens may become a milky-white cataract (occasionally the process is reversible), and even may be bilateral.

C. The histopathology has not been defined.

II. Adult-onset diabetic cataract (Fig. 15.3)

A. The cataract (cortical and nuclear) is indistinguishable clinically and histopathologically from the “usual” age-related cataracts. Diabetic patients, however, are at an increased risk for cataracts compared with nondiabetic subjects. Nevertheless, diabetes is not universally accepted as a risk factor for nuclear cataracts.

1. Diabetes is a strong risk factor for the development of posterior subcapsular cataract.

Decreased antioxidant protection may contribute to diabetic cataracts. Other factors that may contribute to diabetic cataracts are zinc deficiency, socioeconomic issues in various cultures, and abnormalities related to the advanced glycation process. Improved diabetic control and smoking prevention may reduce the risk of developing cataracts in diabetes.

2. Apoptosis plays an important role in the development of cataracts in DR compared to senile cataract.

3. Nuclear fiber compaction analysis demonstrates no difference in compaction between diabetic and nondiabetic cataracts, although diabetes does appear to accelerate the formation of cataracts that are similar to age-related nuclear cataracts.

Decreased proliferation of lens epithelial cells and increased expression of ICAM-1 may play a role in the progression of cataract in type 2 diabetes. Similarly, the density of lens epithelial cells is decreased in type 2 diabetes and correlates with the level of erythrocyte aldose reductase and the level of HbA1c or diabetic retinopathy. Thus, the polyol pathway mediated by aldose reductase may be associated with the reduction in lens epithelial cells in diabetes.

B. Patients with diabetes may have transient lens opacities and induced myopia during hyperglycemia.

Aldose reductase probably plays an important role in initiating the formation of lens opacities in diabetic patients, as it does in galactosemia. Calpains may be responsible for the unregulated proteolysis of lens crystallins, thereby contributing to diabetic cataract development.

C. Cataract surgery and progression of DR

1. Compared to individuals without diabetes, cataract surgery takes place approximately 20 years earlier in type 1 diabetic patients. Moreover, age and maculopathy at baseline are both predictive of cataract surgery.

2. The visual prognosis for patients who have pre-existing DR, both nonproliferative and proliferative, and who undergo cataract extraction and posterior chamber lens implantation is less favorable than that for patients who have no retinopathy.

3. The poorer prognosis results from increased frequency of cystoid macular edema (CME) and progression of DR, both background and proliferative, after cataract extraction, which may result, in part, from changes in concentrations of angiogenic, antiangiogenic, and anti-inflammatory factors after cataract surgery.

4. Posterior capsule opacification is greater in diabetic individuals following cataract surgery than in nondiabetic control patients; however, among diabetic individuals, neither the stage of DR nor the systemic status of the diabetes correlates with the degree of posterior capsule opacification.

5. There are significant internal structural changes in the type 1 diabetic lens compared to that of type 2 diabetics or normal controls. Specifically, there is an increase in thickness of the lens nucleus and different cortical layers in type 1 diabetes.

6. Higher postoperative levels of cytokine activities and accompanying lens epithelial cell morphologic changes may indicate increased proliferative activity and contribute to strong anterior lens capsule contraction.

Fig. 15.3 Cataract. Histologic section shows marked cortical and nuclear cataractous changes in diabetic patient. The changes are nonspecific and, therefore, indistinguishable from those in nondiabetic patients.

Iris

I. Vacuolation of iris pigment epithelium (Fig. 15.4)

A. Vacuolation of the iris pigment epithelium is present in 40% of enucleated diabetic eyes. The vacuoles contain glycogen.

Rupture of the vacuoles when the intraocular pressure is suddenly reduced, as in entering the anterior chamber during cataract surgery, results in release of pigment into the posterior chamber. The pigment is visible clinically as a cloud moving through the pupil into the anterior chamber. Lacy vacuolation and “damage” to the overlying dilator muscle may be the cause of delayed dilatation of the iris after instillation of mydriatics.

B. Pinpoint “holes” may be seen clinically with the slit lamp when transpupillary retroillumination is used. The holes may be seen in at least 25% of known diabetic patients who have blue irises.

In autopsy eyes from diabetic patients, vacuolation of the iris pigment epithelium may be related to increased blood glucose levels before death. The vacuolation is also seen histologically in neonates and in patients who have systemic mucopolysaccharidoses (the vacuoles contain acid mucopolysaccharides), Menkes’ syndrome, and multiple myeloma.

Fig. 15.4 Lacy vacuolation of iris pigment epithelium. A, Transpupillary retroillumination shows myriad pinholes of transillumination of the iris just to the right of pupil (light coming from left). Fine points of light tend to follow pattern of circumferential ridges of posterior pigment epithelial layer. Transmission caused by swelling of epithelial cells and displacement of pigment, not by loss of pigment from cells. B, Vacuolation involves both layers of iris pigment epithelium and ceases abruptly at the iris root. Vacuoles appear empty in sections stained with hematoxylin and eosin. C, Vacuoles stain positively with periodic acid–Schiff stain. Circumferential ridges (cut here meridionally) are greatly accentuated. D, Glycogen particles (very dark, tiny dots) present throughout pigment epithelial vacuoles, along with large melanin granules. Plasma membranes separate adjacent cells. (A, Modified from Fine BS, Berkow JW, Helfgott JA: Diabetic lacy vacuolation of iris pigment epithelium. Am J Ophthalmol 69:197. © Elsevier 1970. B and C, modified from Yanoff M: Ocular pathology of diabetes mellitus. Am J Ophthalmol 67:21. © Elsevier 1969.)

II. Neovascularization of iris (rubeosis iridis; Fig. 15.5; see also Figs. 9.13 and 9.14)

A. Rubeosis iridis is the clinical descriptive term for iris neovascularization.

1. It is present in fewer than 5% of diabetic patients without PDR, but it is present in approximately 50% of patients who have PDR.

2. The new iris vessels arise from venules.

Ischemic retina resulting in proliferative DR increases the intraocular level of VEGF, resulting in the proliferation of new, abnormal blood vessels on the iris surface. Access of VEGF to the anterior chamber inducing the development of iris neovascularization is facilitated by lensectomy and vitrectomy, both of which remove these barriers leading to the development of iris neovascularization in approximately 50% of cases.

B. Neovascularization of the iris may arise from the anterior chamber angle, the pupillary border, midway between, or all three.

Infrequently, the anterior iris stroma, between the pupil and the collarette, may show a very fine neovascularization that can remain stationary for years without the development of angle neovascularization.

C. Early, anterior chamber angle neovascularization causes a secondary, open-angle glaucoma that progresses rapidly to a closed-angle glaucoma, caused by peripheral anterior synechiae.

As the fibrovascular tissue on the anterior iris surface contracts, ectropion uveae may develop. The term ectropion uveae refers to traction by a contracting membrane resulting in drawing the pigment epithelium from the region of the posterior pupillary border onto the anterior iris surface. This result can be caused by other membranes on the iris surface, such as an endothelial membrane, and is not specific for a neovascular membrane. The new blood vessels often give a reddish hue to the iris surface. This finding is commonly called rubeosis irides. These newly formed blood vessels tend to bleed easily, hence the misused and poor term hemorrhagic glaucoma; neovascular glaucoma is the preferred term so as not to confuse the entity with glaucoma secondary to traumatic hemorrhage. Even without the development of iris neovascularization, an increased incidence of both primary open- and closed-angle glaucoma exists in diabetes.

Fig. 15.5 Neovascularization of iris. A, Clinical appearance of rubeosis iridis. Histologic section (B) and scanning electron microscopy (C) of another case show peripheral anterior synechia, secondary angle closure, and tissue anterior to the anterior border layer of the iris; the last, which constitutes iris neovascularization, is shown with increased magnification in D and E. (C and E, Courtesy of Drs. RC Eagle, Jr and JW Sassani.)

Ciliary Body and Choroid

I. Basement membrane of ciliary pigment epithelium (external basement membrane of ciliary epithelium; Fig. 15.6)

A. The multilaminar basement membrane of the pigment epithelium is diffusely thickened in the region of the pars plicata.

B. The diffuse thickening of the external basement membrane of ciliary pigment epithelium in diabetic patients is different from the “spotty” or “patchy” thickening that may be seen in nondiabetic subjects.

Fig. 15.6 Ciliary body. A, Periodic acid–Schiff stain shows diffuse thickening of the pigmented ciliary epithelial basement membrane of the pars plicata. B, Increased magnification shows the thickened basement membrane characteristic of diabetes. Note marked decrease in number of core capillaries. C, Multilaminar external basement membrane (m-bm) of ciliary epithelium in region of pars plicata thickened markedly. Distal edge demarcated by plane of attenuated nonpigmented uveal cells (ce). Numerous small granules (arrows), presumably calcific, present in distal parts of basement membrane (pep, bases of pigment epithelial cells; c, collagen). D, Normally thick homogeneous external basement membrane (bm) of ciliary epithelium in region of pars plana not altered; sample from same patient as in C (c, collagen; el, elastic lamina). E, Capillary in pars plicata shows diffuse and asymmetric homogeneous thickening of basement membrane (arrows).

II. The multilaminar basement membrane of ciliary nonpigmented epithelium (internal basement membrane of ciliary epithelium) is not affected.

III. Fibrovascular core of ciliary processes (see Fig. 15.6)

A. Fibrosis results in obliteration of capillaries in the “core” of the ciliary processes.

B. The capillary basement membrane is often significantly thickened.

IV. Choriocapillaris, Bruch’s membrane, and retinal pigment epithelium (Figs. 15.7 and 15.8)

A. Periodic acid–Schiff-positive material thickens and may partially obliterate the lumen of the choriocapillaris in the macula.

B. The cuticular portion of Bruch’s membrane (basement membrane of the retinal pigment epithelium; basal laminar-like deposits) may become thickened, and the lumen of the choriocapillaris may become narrowed by endothelial cell proliferation and basement membrane elaboration.

The incidence of choriocapillaris degeneration is approximately fourfold greater in diabetic patients than in nondiabetic individuals.

C. Drusen are common.

D. Scanning electron microscopy of choroidal vascular casts shows increased tortuosity, dilatation and narrowing, hypercellularity, vascular loop and microaneurysm formation, “dropout” of choriocapillaris, and formation of sinus-like structures between choroidal lobules.

Fig. 15.7 Choroidopathy. A, Histologic section of the foveomacular region shows diffuse thickening of choroidal vessels, especially involving the choriocapillaris, which are partially occluded by periodic acid–Schiff-positive material. B, Electron micrograph shows choroidal arteriole apposed to characteristic basement membrane material of outer layer of Bruch’s membrane. Note red blood cell (r) in small lumen of vessel. Endothelial cells swollen and junctional attachments (arrows) present. Smooth muscle cells in arteriole wall also present.

Fig. 15.8 Choroidopathy. A, Histologic section of foveal region shows choroidal artery partially occluded by eosinophilic material. Choriocapillaris occluded in this area. B, Periodic acid–Schiff (PAS) stain of same region shows PAS-positive material in walls of arterioles and choriocapillaris. C, Inner choroid, foveomacula. Segment of choriocapillaris (ch) is small. Thickening of the basement membrane is most apparent along the outer capillary wall. Masses of disordered banded (trilaminar) basement membrane form the intercapillary columns. Masses of multilaminar (m), homogeneous (h), and disordered banded (db) basement membrane lie along the inner wall of a deeper choroidal vessel. A moderately thickened basement membrane lies along the vessel outer wall (bm, normally thin basement membrane of pigment epithelium). D, Region of choriocapillaris (ch), foveomacula. Thin basement membrane (arrows) of pigment epithelium (pep) is unaltered. Focal hyperproduction of choriocapillaris homogeneous basement membrane has occurred along the inner capillary wall (“drusen” of choriocapillaris). Segments of ordered banded basement membrane are present in the choriocapillaris drusen. Adjacent, to the left, are myriad fragments of disordered banded (trilaminar) basement membrane. The outer capillary basement membrane (bm) is also focally thickened. (A and B, Modified from Yanoff M: Ocular pathology of diabetes mellitus. Am J Ophthalmol 67:21. © Elsevier 1969.)

V. Arteries and arterioles of choroid (see Figs. 15.7 and 15.8)

Arteriosclerosis occurs at a younger age in diabetic patients than in the general population.

A. The incidence increases sharply beyond the 15th year of the disease.

B. The change is reflected in atherosclerosis and arteriolosclerosis of the choroidal vessels.

Neural Retina

I. The cause(s) of DR (Table 15.1; see also discussion of PDR later in this section)

A. Although DR is usually discussed relative to the characteristic and clinically apparent vascular changes, recent evidence suggests that DR involves alterations in all of the retinal cellular elements, including vascular endothelial cells and pericytes; glial cells, including macroglia (Müller cells and astrocytes) and microglia; and neurons, including photoreceptors, bipolar cells, amacrine cells, and ganglion cells (Table 15.2). Each of these elements makes unique contributions to visual function and participates in multiple homeostatic relationships to the other cellular elements.

Retinal neuronal damage, as diagnosed by spectral-domain optical coherence tomography, may precede clinical evidence of diabetic neuropathy.

B. Damage to multiple retinal neuronal elements through apoptosis, and accompanying glial cell reactivity and microglial activation, suggest that DR might be classified as a neurodegenerative disorder and not simply as a vasculopathy.

Support for the concept of a neurodegenerative proces in diabetes is found in the fact that neurovisual tests are abnormal in type 1 diabetic individuals prior to the onset of clinically apparent retinopathy. Viewed from this perspective, it is doubtful that the entity that we call “diabetic retinopathy” is the manifestation of a single pathophysiologic disturbance or of the malfunction of one cell type. Rather, as can be seen in Table 15.2, multiple pathophysiologic mechanisms come into play in DR, including structural alterations, cell death, inflammation, cellular proliferation, and atrophy. These apparent alterations must require the participation of numerous biologically active mediators. For example, in DR, advanced glycation end products (AGEPs) and/or lipoxidation end products form on the amino groups of proteins, lipids, and DNA and may impact the retina by modifying the structure and function of proteins and/or cause intramolecular and intermolecular cross-link formation. AGEPs not only alter structure and function of molecules but also increase oxidative stress. AGEPs with polyol pathway activation may mediate the direct impairment of retinal endothelial cell barrier function caused by high glucose levels.

C. Apoptosis probably contributes to retinal ganglion cell death in DR, and glial cells may modify the expression of such apoptosis.

D. Inflammation appears to play a significant role in the pathogenesis of diabetic retinopathy.

1. VCAM-1, ICAM-1, and proinflammatory cytokines [interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and C-reactive protein (CRP)] are inflammatory mediators that are upregulated in diabetes with the development and progression of diabetic microvascular complications.

2. Mueller cells exhibit a proinflammatory response in diabetes that may be regulated, in part, by the receptor for advanced glycation and end products (RAGE) and its ligands.

Upregulation of anti-inflammatory mediators and their receptors, such as the retinal pigment epithelial receptor GPR109A and its ligand β-HB, appears to be an attempt by ocular tissue to suppress this inflammatory response. Activated microglia and microglial vasculitis has been implicated in the pathogenesis of diabetic vasculopathy, neuropathy, and retinopathy. Declining retinal microvascular blood flow correlates with the progression of insulin resistance in diabetes.

TABLE 15.1

Proposed Pathogenic Mechanisms for Diabetic Retinopathy

Proposed Mechanism*	Putative Mode of Action	Proposed Therapy
Aldose reductase	Increases production of sorbitol (sugar alcohol produced by reduction of glucose) and may cause osmotic or other cellular damage	Aldose reductase inhibitors (clinical trials in retinopathy and neuropathy thus far have been unsuccessful)
Inflammation	Increases adherence of leukocytes to capillary endothelium, which may decrease flow and increase hypoxia; may also increase breakdown of blood–retinal barrier and enhance macular edema	Aspirin (ineffective in the Early Treatment Diabetic Retinopathy Study but did not increase vitreous hemorrhage; therefore not contraindicated in patients with diabetes who require it for other reasons); corticosteroids (intravitreal injection or slow-release implants for macular edema now being tested)
Protein kinase C	Protein kinase C upregulates VEGF and is also active in “downstream” actions of VEGF following binding of the cytokine to its cellular receptor. Protein kinase C activity is increased by diacylglycerol, which is accelerated by hyperglycemia.	Clinical trials of a protein kinase Cβ isoform inhibitor in retinopathy have thus far been unsuccessful.
Reactive oxygen species	Oxidative damage to enzymes and to other key cellular components	Antioxidants (limited evaluation in clinical trials)
Nonenzymatic glycation of proteins; advanced glycation end products	Inactivation of critical enzymes; alteration of key structural proteins	Aminoguanidine (clinical trial for nephropathy halted by sponsor)
Inducible form of nitric oxide synthase	Enhances free radical production; may upregulate VEGF	Aminoguanidine
Altered expression of critical gene or genes	May be caused by hyperglycemia in several poorly understood ways; may cause long-lived alteration of one or more critical cellular pathways	None at present
Apoptotic death of retinal capillary pericytes, endothelial cells	Reduces blood flow to retina, which reduces function and increases hypoxia	None at present
VEGF	Increased by retinal hypoxia and possibly other mechanisms; induces breakdown of blood–retinal barrier, leading to macular edema; induces proliferation of retinal capillary cells and neovascularization	Reduction of VEGF by extensive (panretinal) laser photocoagulation; several experimental medical therapies being tested (specific VEGF inhibitors are used to treat neovascularization and macular edema)
PEDF	Protein normally released in retina inhibits neovascularization; reduction in diabetes may eliminate this infection.	PEDF gene in nonreplicating adenovirus introduced into eye to induce PEDF formation in retina (phase I clinical trial ongoing)
Growth hormone and IGF-1	Permissive role allows pathologic actions of VEGF; reduction in growth hormone or IGF-1 prevents neovascularization.	Hypophysectomy (now abandoned); pegvisomant (growth hormone receptor blocker; brief clinical trial failed); octreotide (somatostatin analogue, clinical trial now in progress)

^* For all the proposed mechanisms, hyperglycemia accelerates the progression to diabetic retinopathy.

VEGF, vascular endothelial growth factor; PEDF, pigment epithelium-derived factor; IGF-1, insulin-like growth factor-1.

(Modified from Frank RN: Diabetic retinopathy. N Engl J Med 350:48, 2004.)

TABLE 15.2

Diabetic Alterations in Retinal Cellular Elements

Cell Type	Changes
Vascular	Altered tight junctions
Vascular	Endothelial cell and pericyte death
Glial	Altered contacts with vessels
	Release inflammatory mediators
	Impaired glutamate metabolism
Microglial	Increased numbers
Microglial	Release inflammatory mediators
Neuronal	Death of ganglion cells, inner nuclear layer
Neuronal	Axonal atrophy

(Modified from Gardner TW, Antonetti DA, Barber AJ et al.: Diabetic retinopathy: More than meets the eye. Surv Ophthalmol 47(Suppl 2):S253. © Elsevier, 2002.)

II. The diagnosis of DR—the best way to diagnose DR is by means of a thorough fundus examination through a dilated pupil.

Ancillary studies, such as spectral-domain optical coherence tomography (OCT), can be very helpful in demonstrating the scope of retinal involvement. For example, retinal thickness has been found to be abnormal diffusely (but not uniformly) in the retina and not just in the areas exhibiting clinically apparent retinopathy. Microaneurysms, acellular capillaries, and pericyte ghosts are more numerous in the temporal retina than in the nasal retina; however, retinal capillary basement membrane thickness does not exhibit such regional variation.

III. Specific constellation of vascular findings—clinical BDR

A. Loss of capillary pericytes (see Fig. 15.1)

Capillary pericytes probably contribute to the mechanical stability of the capillary wall.

1. In the normal retinal capillary, the pericyte-to-endothelial cell ratio is 1 : 1.

2. In the diabetic retinal capillary, the pericyte-to-endothelial cell ratio is less than 1 : 1 because of a selective loss of pericytes.

3. Pericyte death is accompanied by morphologic nuclear changes and lack of inflammation characteristic of apoptosis (see Chapter 1). Activation of nuclear factor-κB, induced by high glucose in diabetes, may regulate a proapoptotic program in retinal pericytes.

4. Multiple anatomic and anatomic/functional abnormalities contribute to retinal vascular changes and loss of the blood–retinal barrier in diabetes and include changes in tight junctions, pericyte loss, endothelial cell loss, retinal vessel leukostasis, upregulation of vesicular transport, increased permeability of the surface membranes of retinal vascular endothelium and retinal pigment epithelial cells, activation of advanced glycation end product receptors, downregulation of glial cell-derived neurotropic factors, retinal vessel dilation, and vitreoretinal traction.

B. Capillary microaneurysms (Figs. 15.9 and 15.10)

1. Many more retinal capillary microaneurysms (RCMs) are detected microscopically and by fluorescein angiography than are seen clinically with the ophthalmoscope.

OCT provides a noninvasive tool for the detection of early diabetic retinal changes. Mean macular thickness, as measured by OCT, correlates with visual acuity in DR. Retinal thickness is increased in diabetic individuals without clinically apparent retinopathy compared to nondiabetic control subjects. In individuals with type 2 diabetes and mild nonproliferative DR, areas of increased retinal thickness are associated with retinal vascular leakage at those sites. Similarly, perimetry can provide more useful information than visual acuity testing relative to functional loss in diabetes.

2. An increase in the number of RCMs can be directly correlated with the loss of pericytes.

3. RCMs are formed in response to a hypoxic environment in which abortive attempts at neovascularization or regressed changes or both have been made in a previously proliferating vessel.

a. RCMs, which are randomly distributed across the arteriolar and venular sides of the capillary network, start as thin outpouchings (saccular) from the wall of a capillary.

b. The retinal capillary endothelial cells proliferate and lay down increased amounts of basement membrane (Figs. 15.10 and 15.11).

c. Ultimately, all of the endothelial cells may disappear; ghost retinal capillaries result.

d. The lumen of the RCM may remain patent or may become occluded by the accumulated basement membrane material.

Fig. 15.9 Background diabetic retinopathy. A, Background diabetic retinopathy consists of retinal capillary microaneurysms (RCMs), hemorrhages, edema, and exudates (here in a circinate pattern). B, The RCMs are seen more easily with fluorescein. The areas of circinate retinopathy show leakage (see also Figs. 15.12 and 15.13). C, Trypsin digest preparation shows that an RCM consists of a proliferation of endothelial cells (n, nonviable capillaries; m, microaneurysm). D, A histologic section shows a large blood-filled space lined by endothelium (m, microaneurysm). The caliber is approximately that of a venule. Venules, however, do not occur in this location (in the inner nuclear layer) but, rather, are mainly found in the nerve fiber layer. By a process of elimination, the “vessel” is therefore identified as a cross-section of an RCM. (A and B, Courtesy of Dr. GE Lang.)

Fig. 15.10 Retinal capillary microaneurysm (RCM). A, RCMs randomly distributed between arterioles and venules. “Young” RCMs appear as saccular capillary outpouchings that contain a few proliferated endothelial cells. “Older” RCMs appear as larger sacs that contain numerous endothelial cells and increased periodic acid–Schiff (PAS) positivity (increased basement membrane deposition). “Oldest” RCMs appear as solid black balls with their lumina obliterated by PAS-positive material. B, Foveomacular area shows “broken” foveal capillary ring and scattered microaneurysms.

Fig. 15.11 Diabetic retinal vessels. A, Diabetic retinal capillary in nerve fiber layer of macula. Lumen (l) is exceedingly narrow and contains small amount of fibrinous, proteinaceous material. Endothelial cell junctional attachments (adherentes) are present (arrows). Basement membrane of capillary wall is thickened. B, Small retinal vessel from foveomacular ganglion cell layer of diabetic patient. Lower endothelial cell (E1) hypertrophic, whereas upper endothelial cell (E2) necrotic (liquefaction). Vessel lumen (l) greatly narrowed. Adherentes of cell junctions present (arrows). Secondarily (age-related) vacuolated basement membrane of vessel wall probably normal thickness for age.

C. Thickening of retinal capillary basement membrane (see Figs. 15.1, 15.10, and 15.11)

D. Arteriolovenular connections (“shunts”: actually, collaterals; Fig. 15.12)

1. Arteriolovenular connections (collaterals) are secondary phenomena (i.e., secondary to the surrounding environmental hypoxic stimulus).

2. The arteriolovenular connections have a decreased rate of blood flow, unlike true shunts.

Fig. 15.12 Background and preproliferative diabetic retinopathy. A, Cotton-wool spot of recent onset is present just inferior to the superior arcade. Note also retinal “hard” exudates, capillary microaneurysms, and hemorrhages. B, Trypsin digest preparation shows sausage-shaped dilated venules. C, Arteriolovenular collateral vessel (av) is present (a, arteriole; v, venule). D, Intraretinal microvascular abnormalities are present in the form of dilated capillaries, capillary buds and loops, and areas of capillary closure.

E. Other findings

1. Often, an irregular, large foveal avascular zone is present (its irregularity and greater size with BDR are even more pronounced with PDR).

2. Diabetic patients show an abnormal macular capillary blood flow velocity, and decreased entoptically perceived leukocytes, compared to age-matched nondiabetic subjects. Conversely, choroidal blood flow is significantly decreased in the foveal region, particularly in diabetic macular edema (DME).

Pulsatile ocular blood flow is unaffected in early DR, increases significantly in eyes with moderate to severe nonproliferative DR, and decreases following laser treatment of PDR.

3. Partitions of the larger retinal venules by a double layer of endothelial cells anchored to a thin basement membrane are associated with the formation of venous loops and reduplications that are caused by gradual venous occlusion.

4. In general, wider venular caliber and narrower retinal arteriolar caliber are associated with diabetes. Patients with retinal arteriolar narrowing are significantly more likely to have nephropathy and macrovascular disease.

IV. Exudative retinopathy (Figs. 15.13 and 15.14)

A. “Hard” or “waxy” exudates (Fig. 15.13; see also Figs. 15.9 and 15.12)

1. Hard or waxy discrete exudates are collections of serum and glial–neuronal breakdown products located predominantly in the outer plexiform (Henle) layer.

One of the earliest changes in the neural retina in diabetic patients, often before BDR is evident clinically, is a breakdown of the blood–neural retinal barrier in the retinal capillaries. Fluorescein angiography and vitreous fluorophotometry can show “leakage” of fluorescein from retinal capillaries in diabetic patients who do not show signs of DR when examined by conventional clinical methods. In patients who have BDR, elevated serum lipids are associated with an increased risk of retinal hard exudates.

2. The discrete exudates are removed by macrophages in 4–6 months; it may take one year or more if the exudates are confluent.

3. When they are distributed around the fovea, hard exudates may form a macular “star.”

Although macular edema is common in diabetic patients, macular star formation is uncommon, unlike in grades III and IV hypertensive retinopathy, in which a macular star is quite common.

B. Macular edema

1. Clinically significant macular edema (CSME) is the greatest single cause of vision impairment in diabetic patients and affects approximately 75,000 new patients in the United States annually.

a. The overall incidence of CSME is approximately 3–8% in the diabetic population after four years’ follow-up from the baseline examination; 32% after 20 years of younger age-onset, insulin-dependent diabetes; 18% after 20 years of non-insulin-dependent, older age-onset diabetes; and 32% after the same period of older age-onset, insulin-dependent diabetes.

b. The greater incidence is associated with younger age or more severe DR at the baseline examination, increased levels of glycosylated hemoglobin, increased duration of the diabetes, and an absence of posterior vitreous detachment.

c. Systemic factors that can contribute to CSME in diabetes include poor metabolic control of the diabetes, elevated blood pressure, intravascular fluid overload, anemia, and hyperlipidemia. Fluid overload is relative, and it may reflect decreased serum oncotic pressure, such as from decreased serum albumin.

2. Figure 15.15 summarizes factors implicated in the pathogenesis of diabetic macular edema. Morphologic evidence suggests that macular edema may be caused by functional damage to the retinal vascular endothelium (e.g., hypertrophy or liquefaction necrosis of endothelial cells of the retinal capillaries or venules; see Fig. 15.11); pericyte degeneration probably also plays a role.

a. Fluid leaks out of the retinal vessels, enters Müller cells, and causes intracellular swelling.

b. Mild to moderate amounts of intracellular fluid collections in Müller cells may result in macular edema (Figs. 15.15 and Fig. 15.16), a reversible process.

c. Excessive swelling (ballooning) and rupture or death of Müller cells produces pockets of fluid and cell debris (i.e., cystoid macular edema), a process that may be irreversible.

d. Adjacent neurons undergo similar changes secondarily.

Laser retinal photocoagulation has been the standard of care for diabetic macular edema and reduces the risk of moderate visual loss by approximately 50%. Nevertheless, new strategies in the treatment of DME are being evaluated, particularly the use of antibodies against VEGF, a potent endothelial-specific mitogen. These drugs are delivered by intravitreal injection and are growing in acceptance. Intravitreal steroid injections have also been employed.

3. The presence of a cilioretinal artery may worsen DME.

C. Microcystoid degeneration of the neural retinal macula (see Figs. 15.16 and Fig. 15.17)

1. Exudates or edema fluid or both may cause pressure atrophy of the neural retina or enlargement of the intercellular spaces and result in microcystoid degeneration, especially in the macular area.

2. Microcystoid neural retinal degeneration may progress to macular retinoschisis (cyst) and even partial (inner layer of schisis) or complete macular hole formation.

D. “Soft” exudates or “cotton-wool” spots (see Figs. 11.9, 11.11, 11.14, and 15.12)

1. The cotton-wool spot observed clinically is a result of a microinfarct (coagulative necrosis) of the nerve fiber layer of the retina and is not a true exudate. They usually disappear from view in weeks to months.

2. They are present most commonly in the preproliferative or early part of the proliferative stage of DR, especially during a phase of rapid progression.

3. Cotton-wool spots are formed at the edges of microinfarcts of the nerve fiber layer of the neural retina (see Chapter 11) and represent backup of axoplasmic flow.

4. Cytoid bodies are the characteristic histologic counterpart of the cotton-wool spot, and they are caused by the swollen ends of ruptured axons in the nerve fiber layer in the infarcted area. They resemble a cell with its nucleus when cut in cross-section, thereby leading to the appellation “cytoid.”

Fig. 15.13 Exudates. A, Diagram shows exudates predominantly in outer plexiform (Henle fiber) layer of macula. Exudates on right contain fat-filled (lipidic) histiocytes (gitter cells). B, Diagram shows exudates in outer plexiform layer (Henle fiber layer) of fovea. In foveal area, fibers run obliquely, resulting in clinically seen star figure. C, Fundus appearance of exudates, small hemorrhages, microaneurysms, and early neovascularization of temporal disc. Note star figure in fovea, an unusual finding in diabetic patients. D, Histologic section shows exudates present in outer plexiform layer. E, Oil red-O stain shows lipid-positivity of exudates. F, Electron microscopy shows exudates filled with foamy (lipidic) histiocytes. (A and B, Modified from drawings by Dr. RC Eagle, Jr.)

Fig. 15.14 (A) Optical coherence tomography (OCT) image of diabetic retinopathy with vitreous traction on the internal limiting membrane and disruption of the retinal architecture by hemorrhages and exudates. Compare with the regular well-organized features in B. (Courtesy of retinal angiographers Mr. Timothy Bennett and Mr. James Strong.)

Fig. 15.15 Pathogenesis of diabetic macular edema. AGE, advanced glycation end products; AII, angiotensin II; DAG, diacylglycerol; ET, endothelin; LPO, lypoxygenase; NO, nitric oxide; PKC, protein kinase C; RAS, rennin–angiotensin system; VEGF, vascular endothelial growth factor. (From Bhagat N, Grigorian RA, Tutela A et al.: Diabetic macular edema: Pathogenesis and treatment. Surv Ophthalmol 54:1, 2009.)

Fig. 15.16 Exudates. Microcystoid or macrocystoid (retinoschisis) macular degeneration may occur as a result of exudation. A, Small exudates can coalesce into larger ones. B, Eventually, coalescence of exudates can result in a macrocyst (macular retinoschisis), as occurred here. Note hole (smooth edge shows it is not an artifact) in inner wall of macrocyst.

Fig. 15.17 A, Optical coherence tomography (OCT) image of diabetic retinopathy involving the macula and resulting in cystoid macular edema. Compare with the regular well-organized features in B. (Courtesy of retinal angiographers Mr. Timothy Bennett and Mr. James Strong.)

V. Hemorrhagic retinopathy (Fig. 15.18). The clinical appearance of a retinal hemorrhage is determined by the microanatomy of the retinal layer in which the hemorrhage is located.

A. Dot-and-blot hemorrhages

1. Dot-and-blot hemorrhages are relatively small hemorrhages located in the inner nuclear layer that spread to the outer plexiform layer of the neural retina.

2. In three-dimensional view, they appear serpiginous.

B. Splinter (flame-shaped) hemorrhages are small hemorrhages located in the nerve fiber layer.

C. Globular hemorrhages are caused by the spread of dot-and-blot hemorrhages in the middle neural retinal layers.

D. Confluent hemorrhages are large and involve all of the neural retinal layers.

Larger hemorrhages (globular and confluent) may herald the onset of the proliferative (malignant) phase of the disease.

E. Massive hemorrhages may break through the internal limiting membrane to extend beneath or into the vitreous body or, rarely, into the subneural retinal space.

Fig. 15.18 Hemorrhagic retinopathy. A, Dot, blot, flame-shaped, and globular hemorrhages are present in the neural retina. B, Flame-shaped or splinter hemorrhages consist of small collections of blood in the nerve fiber layer. Dot-and-blot hemorrhages are caused by small hemorrhagic collections in the inner nuclear and outer plexiform layers. C, Diagram shows dot-and-blot and globular hemorrhages in middle layers, and splinter hemorrhage in nerve fiber layer of neural retina. Large hemorrhage under internal limiting membrane (submembranous intraneural retinal hemorrhage) has broken through neural retina into the vitreous compartment. (C, Modified from a drawing by Dr. RC Eagle, Jr.)

VI. Preproliferative DR (Fig. 15.19; see also 15.12) consists of:

A. Increased neural retinal hemorrhages

B. Cotton-wool spots

C. Venous dilatation

D. Venous beading

E. Intraretinal microangiopathy

Fig. 15.19 Preproliferative retinopathy. Fundus (A) and fluorescein (B) appearance. Note numerous areas of nonperfusion. C, Trypsin digest of neural retina shows mainly nonviable capillaries. Some capillaries on left demonstrate endothelial cell proliferation and increased basement membrane deposition, representing intraretinal microvascular angiopathy. (A and B, Courtesy of Dr. GE Lang.)

VII. PDR (“malignant” stage; Figs. 15.20–15.23)

A. Classically, PDR has been characterized as a vascular response to a hypoxic neural retinal environment. Numerous other factors also contribute to its pathobiology.

1. Some of these factors include hyperglycemia, retinal arteriolar and capillary closure; hemodynamic alterations in retrobulbar circulation and microcirculation; retinal capillary basement membrane alterations; immunogenic mechanisms related to insulin; pregnancy; absence of female hormones; altered plasma proteins that cause platelet and red cell aggregation; increased blood viscosity; altered ability of the blood to transport oxygen; virus induction of DM; and abnormal metabolic pathways in the retinal capillaries.

Development of anemia in a diabetic patient may cause background retinopathy to progress rapidly to PDR. An adequate number of functioning photoreceptors appears to be required for the development of PDR because neonatal mice with hereditary retinal degeneration fail to develop reactive retinal neovascularization in a model of oxygen-induced PDR.

2. Table 15.3 lists some of the myriad vitreous and serum factors that are altered in PDR. They may be produced, in part, by retinal cellular elements and, in turn, probably help modify the behavior of these cellular retinal constituents.

3. Other putative factors implicated in PDR are advanced glycation end products and macrophages.

4. Among the mediators acting during the development of PDR, VEGF and its receptor, flt-1, play a key role.

VEGF is strongly expressed in the endothelial cells of the new blood vessels in fibrovascular membranes removed at vitrectomy for PDR. Conversely, pigment epithelium-derived factor (PEDF), which inhibits angiogenesis, is only weakly expressed in such membranes. VEGF levels are increased in the aqueous humor of diabetic patients, but PEDF levels are decreased in such individuals, particularly those with PDR. Moreover, lowered PEDF levels in aqueous humor of diabetic patients strongly predict those who will have progressive retinopathy. In a similar manner, levels of VEGF and endostatin, which is an inhibitor of angiogenesis, in aqueous humor and vitreous vary appropriately to reflect the severity of DR.

5. It is important that the constituents of PDR membranes be compared to those resulting from other forms of intraocular proliferation in order to determine the characteristics of PDR. For example, proteolytic activation appears to be involved in extracellular matrix production in PDR and in nondiabetic membranes, and neovascular membranes in retinopathy of prematurity are associated with the glucose transporter GLUT1, which is lacking in proliferative retinopathy.

6. Decreased serum insulin and high glucose levels have been postulated to contribute to decreased fibroblast growth factor-2 production in the RPE and increased glial cell activation in the diabetic retina.

7. PEDF may help protect against pericyte apoptosis. It is suppressed by angiotensin II, which may contribute to exacerbation of DR in hypertensive patients. Conversely, blockade of the renin–angiotensin system can confer retinal protection in experimental models of DR.

8. Elevated expression of matrix metalloproteinases in the diabetic retina may contribute to increased vascular permeability by a mechanism involving proteolytic degradation of the tight junction protein occludin and subsequent disruption of the tight junction complex.

9. The NH₂-terminal connective tissue growth factor fragment is increased in the vitreous in PDR and is found within myofibroblasts in active PDR membranes, suggesting a local paracrine mechanism for the induction of fibrosis and neovascularization.

10. Circulating systemic factors cannot be ignored. For example, growth hormone-sufficient diabetic patients have an increased prevalence of DR over growth hormone-deficient diabetic patients. Somatostatin analogs that block the local and systemic production of insulin-like growth factor and growth hormone may prevent DR progression to the proliferative stage. Pregnant women are at particular risk for the development and progression of DR.

11. Neovascularization in PDR tends to arise from retinal venules, usually at the edge of an area of capillary nonperfusion. Rarely, they may arise from retinal arterioles. The new retinal vessels contain both endothelial cells and pericytes.

12. Angiopoietin-2 is induced by hypoxia and plays a role in the initiation of retinal neovascularization. It is involved in pericyte recruitment and modulates intraretinal and preretinal vessel formation.

B. Neovascularization initially is intraretinal, but it usually breaks through the internal limiting membrane to lie between it and the vitreous. Endothelial cell-associated proteinases can locally disrupt basement membrane (internal limiting membrane) and facilitate angiogenesis.

1. Neovascular membranes that lie flat on the internal surface of the neural retina are called epiretinal neovascular membranes.

2. Elevated neovascular membranes are called preretinal neovascular membranes.

Vitreous shrinkage (i.e., detachment) may tear the new vessels, leading to a hemorrhage. If a subvitreal hemorrhage results (the common type of diabetic “vitreous” hemorrhage between the posterior surface of the vitreous body and the internal limiting membrane of the neural retina), it clears rapidly in weeks to a few months. If a hemorrhage extending into the formed vitreous (vitreous framework) results, it may take from many months to years to clear. In such patients, vitrectomy may be indicated.

C. Pure neovascularization is eventually accompanied by a fibrous and glial (Müller cells and fibrous astrocytes) component; it is then called retinitis proliferans.

1. The membranes are composed of blood vessels, fibrous and glial matrix tissue, fibroblasts, glial cells, scattered B and T lymphocytes, and monocytes, along with immunoglobulin, complement deposits, and class II major histocompatibility complex antigens.

2. Shrinkage of the fibroglial component often leads to a neural retinal detachment, which is usually nonrhegmatogenous (i.e., without a neural retinal tear or hole).

3. Ultimately, the whole process of PDR tends to “burn out” and become quiescent.

4. Connective tissue growth factors contributes to proliferation of the fibrous component of these membranes.

D. Once blindness develops, the average life expectancy is less than six years.

E. Cataract surgery and progression of DR (see earlier in this chapter under section Lens)

Fig. 15.20 Proliferative retinopathy. Neovascularization of optic disc. A and B, Same patient, same eye, pictures taken one year apart. Severe neovascularization of optic disc has developed. C, Moderate to severe neovascularization of optic disc. D, Histologic section of another case shows shrinkage and contracture of a preretinal fibroglial vascular membrane that had arisen from the optic disc and caused a total neural retinal detachment with fixed folds of the internal limiting membrane (see also Fig. 15.23D). Intraretinal cystic spaces are often present in long-standing detachments.

Fig. 15.21 Proliferative retinopathy. Neovascularization of neural retina. A–C, Fundus and fluorescein pictures of same eye. Nonperfusion of neural retina most marked on left side. Areas of neovascularization elsewhere (NVE) present, mainly temporal retina. D, Trypsin digest of neural retina shows nonviable capillaries (presumably corresponding to areas of nonperfusion), mainly toward the lower left corner. Surrounding capillaries show marked endothelial cell proliferation and increased basement membrane deposition, representing early intraretinal neovascularization. E, Histologic section shows usual site of origin of NVE (i.e., from a venule). (A–C, Courtesy of Dr. GE Lang.)

Fig. 15.22 Proliferative retinopathy. Neovascularization of neural retina. A, The superior venule is dilated and beaded. Neovascular tufts arise from the venules. B, A histologic section of another case shows new blood vessel arising from a retinal venule, perforating the internal limiting membrane, and spreading out on the internal surface of the retina between the internal limiting membrane and the vitreous body. In this location, the fragile new abnormal blood vessels may be subject to trauma (e.g., vitreous detachment), resulting in a subvitreal hemorrhage between the retinal internal limiting membrane and the posterior hyaloid of the separated vitreous body.

Fig. 15.23 Proliferative retinopathy. Neovascularization of optic disc and retina. A, Tuft of neovascularization arising from the optic nerve head is attached to the posterior surface of an otherwise detached vitreous body. B, Scanning electron micrograph shows blood vessels arising from the internal surface of the neural retina and attaching to the posterior surface of the partially detached vitreous. C, Periodic acid–Schiff-stained histologic section shows blood vessels originating from a retinal venule and attaching to the posterior surface of the vitreous. D, The gross specimen shows the end stage of diabetic retinopathy. Extensive neovascularization of the retina and the detached vitreous have resulted in a traction neural retinal detachment. The subneural retinal space is filled with a gelatinous material (l, lens; o, organized vitreous; n, neural retina; s, subneural retinal exudate). The absence of similar material underlying a retinal detachment in any fixed specimen should raise the suspicion that the detachment is an artifact of sectioning and was not present in vivo. (B, Courtesy of Dr. RC Eagle, Jr.)

TABLE 15.3

Vitreous and Serum Factors Altered in Human Proliferative Diabetic Retinopathy

	Proangiogenic
Increased in vitreous and/or retina	Peptide growth factors: VEGF, HGF, FGF-5, leptin, IGF-1, IGF-2, PDGF-AB, SDF-1, angiogenin
	Extracellular matrix adhesion molecules, ICAM-1, oncofetal fibronectin
	Inflammatory cytokines: IL-6, IL-8, endothelin-1, TNF-α, TGF-β₁, AGEs
	Complement: complement C(4) fragment
	Polyamines: spermine, spermidine
	Vasoactive peptides: endothelin-1, angiopoietin-2, angiotensin-2, adrenomedullin, ACE, nitrate
	Inflammatory cells: CD4 and CD8 (T lymphocytes), CD22 (B lymphocytes), macrophages, HLA-DR
	Antiangiogenic
Increased in vitreous and/or retina	Endostatin, angiostatin, PEDF, TGF-β₁
Increased in vitreous and/or retina	Undefined retinal function: α₁-antitrypsin, α₂-HS glycoprotein
Decreased in vitreous and/or retina	Angiopoietin-2, putrescine, kallistatin, chymase, TGF-β₂ activation, CD55, CD59
No change in vitreous and/or retina	ACE, C1q and C4
Increased in serum	NO, sIL-2R, IL-8, TNF-α, VEGF, angiotensin-2, renin, endothelin
Decreased in serum	Soluble angiopoietin receptor Tie2, IL-1β, IL-6

ACE, angiotensin-converting enzyme; AGE, advanced glycation end products; FGF, fibroblast growth factor; HGF, hepatocyte growth factor (scatter factor); HLA, human leukocyte antigen; ICAM, intercellular adhesion molecule; IGF, insulin-like growth factor; IL, interleukin; NO, nitric oxide; PDGF, platelet-derived growth factor; PEDF, pigment epithelium-derived factor; SDF-1, stromal-derived factor 1; sIL-2R, soluble interleukin-2 receptor; TGF-α₁, transforming growth factor α₁; TNF-β, tumor necrosis factor-β; VEGF, vascular endothelial growth factor.

(From Gariano RF, Gardner TW: Retinal angiogenesis in development and disease. Nature 438:960, 2005.)

Vitreous

I. Vitreous detachment (Fig. 15.24; see also Fig. 15.14 and Figs. 12.8 and 12.9)

A. Vitreous detachment (“contracture”) is more common in diabetic patients than in nondiabetic subjects and seems to occur at an earlier age.

1. Peripapillary vitreoretinal traction can cause optic nerve head elevation resembling edema. OCT can be helpful in confirming the diagnosis.

2. Extrafoveal vitreous traction may be associated with diffuse macular edema.

B. The proliferating fibroglial vascular tissue from the optic nerve head or neural retina usually grows between the vitreous and the neural retina (i.e., along the inner surface of the internal limiting membrane of the neural retina), along the external surface of a detached vitreous, or into Cloquet’s canal. The proliferating tissue does not grow directly into a formed vitreous. A preoptic disc canal-like structure, probably Cloquet’s canal and the area of Martegiani, is associated with PDR.

1. High levels of VEGF are present in the vitreous in PDR and proliferative vitreoretinopathy.

2. Elevated levels of other growth factors and inflammatory mediators have been found in diabetic vitreous. See Table 15.3.

3. Proteomics presents an even more complicated picture of the vitreous constituents in proliferative diabetic retinopathy and nondiabetic patients. In one study, 531 proteins were identified, with 415 and 346 proteins identified in PDR and nondiabetic vitreous humor samples, respectively.

In eyes with diffuse DME associated with vitreomacular traction and a thickened premacular cortical vitreous, ultrastructural examination demonstrates native vitreous collagen with single cells interspersed within the collagenous layer or a cellular monolayer. Eyes with tangential vitreomacular traction exhibit multilayered membranes on a layer of native vitreous collagen. The predominant cell types are fibroblasts and fibrous astrocytes, with some myofibroblasts and macrophages. Thus, the vitreomacular interface is characterized by a layer of native vitreous collagen and a varying cellular component in eyes with diffuse DME.

Fig. 15.24 Vitreous hemorrhage. A, New blood vessels (lower left) lie between internal limiting membrane of neural retina and vitreous body. Partial detachment of vitreous (upper right) has caused traction on neural retina. B, If no further detachment of the vitreous occurs, vessels may grow onto the posterior surface of the detached vitreous. C, With further vitreous detachment, the fragile new vessels can break, resulting in hemorrhage into the vitreous compartment (D).

II. Hemorrhage into vitreous compartment (Fig. 15.25; see Fig. 15.24)

A. A hemorrhage into the subvitreal space is more common than that into the vitreous body.

Vitreous hemorrhage does not seem to be related to activity. In fact, approximately 60% of vitreous hemorrhages follow sleep or resting. This fact may be related to an increased neural retinal blood flow that normally occurs in the dark (at night).

B. Organization of the hemorrhage with fibroglial overgrowth may occur, usually along the external surface of the detached vitreous.

Fig. 15.25 Vitreous hemorrhage. A, Clinical appearance of vitreous hemorrhage. B, Hemosiderin-laden macrophages and red blood cells present in vitreous compartment. C, Macrophages stain positive for hemosiderin (blue) with iron stain, but red blood cells do not.

III. Asteroid hyalosis—some studies show a correlation between asteroid hyalosis and diabetes; others do not. A review of 10,801 autopsy eyes examined during the period 1965–2000 found no correlation between the presence of asteroid hyalosis and diabetes.

Optic Nerve

I. Neovascularization (see Fig. 15.20)—the optic disc is a site of predilection for neovascularization, which often grows into Cloquet’s canal.

Disc neovascularization may respond to intravitreal injection of anti-VEGF therapy.

II. Ischemic (nonarteritic) optic neuropathy

Retrobulbar neuritis, papillitis, optic disc edema, and optic atrophy—all occurring infrequently—may be ischemic manifestations of diabetic microangiopathy in the optic nerve head when collateral circulation is inadequate.

Diabetic papillopathy (transient bilateral optic disc edema and minimal impairment of function) may develop in patients with type 1 or type 2 diabetes. Although the vision decrease tends to be quite mild, serious visual loss has been reported.

A. Diabetic papillopathy is rare. Fewer than 130 cases had been reported by 2012.

B. The condition usually resolves without treatment, although local steroid injection or treatment with bevacizumab may be helpful.

C. It should not be confused with neovascularization of the disc or central nervous system-induced papilledema.

D. It is characterized by optic disc swelling caused by vascular leakage and axonal edema around the optic nerve head. It may be accompanied by intraretinal hemorrhages and hard exudates.

E. It may be associated with small cup : disc ratio and rapid reduction in blood sugar.

Diabetic papillopathy may rarely be associated with a rapidly progressive optic disc neovascularization. Transient optic disc edema secondary to vitreous traction in a quiescent eye with PDR may mimic diabetic papillopathy. The development of bilateral nonarteritic anterior ischemic optic neuropathy from diabetic papillopathy has been reported.

III. Central retinal vein occlusion (see Chapter 11)

Based on animal studies, diabetes is a risk factor for glaucomatous optic neuropathy. Diabetes is also among the risk factors for optic disc hemorrhages in glaucoma. Nerve fiber layer is decreased, particularly in the superior segment of the retina, in diabetic patients even before the development of clinical retinopathy. Nerve fiber layer thickness further decreases with the development of DR and with impairment of metabolic regulation. This finding may impact the evaluation of nerve fiber layer in glaucomatous diabetic patients.

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Natural History

Retinal Vasculature in Normal Subjects and Diabetic Patients

Conjunctiva and Cornea

Lens

Iris

Ciliary Body and Choroid

Neural Retina

Vitreous

Optic Nerve

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