Diabetes Mellitus

Diabetes Mellitus

15   Diabetes Mellitus NATURAL HISTORY I. Diabetes mellitus (DM) is a heterogeneous group of disorders characterized by elevated blood glucose and ...

41MB Sizes 0 Downloads 10 Views

15



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 insulindependent) or type 2 (previously called noninsulindependent) 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

528

Ch. 15:  Diabetes Mellitus

2.

3.

4. 5.

6.

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. 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. 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 qualityadjusted life expectancy compared to black individuals. Factors associated with mortality are glycemic regulation, dyslipidemia, and creatinine level. Baseline factors associated with progression to blindness include the presence of maculopathy and glycemic control (HbA1 level). 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. 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.

Conjunctiva and Cornea

CONJUNCTIVA AND CORNEA o faz

A

Healthy

Diabetic Retinal capillary

Basement membrane “envelope” where pericyte nucleus had been

Endothelial call nucleus Pericyte nucleus

B

e sr

sr

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. 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.

p C

D

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).

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).

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

529 529

530

Ch. 15:  Diabetes Mellitus

A

B

C

D

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.

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

Lens

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” agerelated cataracts. Diabetic patients, however, are at an

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.

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.

531 531

532

Ch. 15:  Diabetes Mellitus

A

B

C

D

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.)

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 preexisting 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.

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.

Iris

A B

D C

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.)

E

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.

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

533 533

534

Ch. 15:  Diabetes Mellitus

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.

II. III.

IV.

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.

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

V.

is different from the “spotty” or “patchy” thickening that may be seen in nondiabetic subjects. The multilaminar basement membrane of ciliary nonpigmented epithelium (internal basement membrane of ciliary epithelium) is not affected. 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. 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. 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 contri­ butions to visual function and participates in multiple homeostatic relationships to the other cellular elements.

Neural Retina

pep

m-bm

A

ce

B

C

c

c

bm

D

el

E

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).

535 535

536

Ch. 15:  Diabetes Mellitus

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.

A

r

B 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.

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.

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

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.

Neural Retina

B A pep bm ch

ch

D

db

m C

bm

h

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.)

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-toendothelial cell ratio is 1 : 1. 2. In the diabetic retinal capillary, the pericyte-toendothelial 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,

537 537

538

Ch. 15:  Diabetes Mellitus

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.)

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

Neural Retina

A

B

m

n

m

n

C

D

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.)

TABLE 15.2  Diabetic Alterations in Retinal Cellular Elements Cell Type

Changes

Vascular

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

Glial

Microglial Neuronal

(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.)

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.

539 539

540

Ch. 15:  Diabetes Mellitus

A

B

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.

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. 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. 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 en­ toptically 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.

Neural Retina

l

A

l

B 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.

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 app­ roximately 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.

541 541

542

Ch. 15:  Diabetes Mellitus

A

B

v

av

av a

C

D

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.

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.

Neural Retina

A

B

C

D

E

F

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.)

543 543

544

Ch. 15:  Diabetes Mellitus

A

B 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.)

Sustained hyperglycemia

DAG ↑

Histamine ↑ H-receptors on the retinal blood vessels

AGE ↑

PKC ↑

ET ↑

Vasoconstriction

ET-receptors on pericytes

Hypoxia

IL-6 ↑

VEGF ↑

Phosphorylation of tight junction proteins. Disorganisation of BRB

Macula edema

RAS activation

LPO ↑ NADH/NAD+ ↑ NO ↑ Antioxidant enzymes

Oxidative damage

All ↑ Accumulation of cytokeratin and glial fibrillary acidic protien

Destabilization of vitreous. Abnormalities in collagen crosslinking ↑ activity of MMP PPVP

Vitreo-macular traction

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.)

Neural Retina

A

B

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.

A

B 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.)

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 prepro­ liferative 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.

545 545

546

Ch. 15:  Diabetes Mellitus

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 crosssection, thereby leading to the appellation “cytoid.” 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.

A

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. 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 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

B

C 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.)

Neural Retina

A

B

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.)

C

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 epitheliumderived 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 

547 547

548

Ch. 15:  Diabetes Mellitus

A

B

C

D

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.

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.

Neural Retina

A

B

C

D

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.)

E

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)

549 549

550

Ch. 15:  Diabetes Mellitus

A

B

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.

A

B

l

o n s C

D

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.)

Optic Nerve

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 Decreased in vitreous and/or retina No change in vitreous and/or retina Increased in serum Decreased in serum

Endostatin, angiostatin, PEDF, TGF-β1 Undefined retinal function: α1-antitrypsin, α2-HS glycoprotein Angiopoietin-2, putrescine, kallistatin, chymase, TGF-β2 activation, CD55, CD59 ACE, C1q and C4

NO, sIL-2R, IL-8, TNF-α, VEGF, angiotensin-2, renin, endothelin 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 epitheliumderived 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.

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. 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.

551 551

552

Ch. 15:  Diabetes Mellitus

A

B

C

D

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).

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.

Optic Nerve

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.

A

B

C

Access the complete reference list online at 

553 553

Bibliography 553.e1

BIBLIOGRAPHY Natural History Andresen AR, Christiansen JS, Jenson JK: Diagonal ear-lobe crease and diabetic retinal angiopathy [letter]. N Engl J Med 294:1182, 1976 Canataroglu H, Varinli I, Ozcan AA et al.: Interleukin (IL)-6, interleukin (IL)-8 levels and cellular composition of the vitreous humor in proliferative diabetic retinopathy, proliferative vitreoretinopathy, and traumatic proliferative vitreoretinopathy. Ocul Immunol Inflamm 13:375, 2005 Caprio S: Development of type 2 diabetes mellitus in the obese adolescent: A growing challenge. Endocr Pract 18:791, 2012 Chase HP, Garg SK, Jackson WE et al.: Blood pressure and retinopathy in type 1 diabetes. Ophthalmology 97:155, 1990 Chopra V, Varma R, Francis BA et al.: Type 2 diabetes mellitus and the risk of open-angle glaucoma: The Los Angeles Latino Eye Study. Ophthalmology 115:227, 2008 Christen U, Bender C, von Herrath MG: Infection as a cause of type 1 diabetes? Curr Opin Rheumatol 24:417, 2012 Davis MD, Hiller R, Magli YL et al.: Prognosis for life in patients with diabetes: Relation to severity of retinopathy. Trans Am Ophthalmol Soc 77:144, 1979 Deshpande AD, Harris-Hayes M, Schootman M: Epidemiology of diabetes and diabetes-related complications. Phys Ther 88:1254, 2008 Diabetes Control and Complications Trial Research Group: Early worsening of diabetic retinopathy in the Diabetes Control and Complications Trial. Ophthalmology 116:874, 1998 Dielemans I, deJong PTVM, Stolk R et al.: Primary open-angle glaucoma, intraocular pressure, and diabetes mellitus in the general population: The Rotterdam Study. Ophthalmology 103:1271, 1996 Efron N: The Glenn A. Fry award lecture 2010: Ophthalmic markers of diabetic neuropathy. Optom Vis Sci 88:661, 2011 Forlenza GP, Rewers M: The epidemic of type 1 diabetes: What is it telling us? Curr Opin Endocrinol Diabetes Obes 18:248, 2011 Frank RN: The Optic UK Lecture: Bench-to-bedside adventures of a diabetes researcher: Results past, results present. Eye (Lond) 25:331, 2011 Gale EA: Viruses and type 1 diabetes: Ignorance acquires a better vocabulary. Clin Exp Immunol 168:1, 2012 Goldstein DE, Blinder KJ, Ide CH et al.: Glycemic control and development of retinopathy in youth-onset insulin-dependent diabetes mellitus. Ophthalmology 100:1125, 1993 Grauslund J: Long-term mortality and retinopathy in type 1 diabetes. Acta Ophthalmol 88 Thesis1:1, 2010 Grauslund J, Green A, Sjolie AK: Blindness in a 25-year follow-up of a population-based cohort of Danish type 1 diabetic patients. Ophthalmology 116:2170, 2009 Grimsby JL, Porneala BC, Vassy JL et al.: Race–ethnic differences in the association of genetic loci with HbA1c levels and mortality in U.S. adults: The third National Health and Nutrition Examination Survey (NHANES III). BMC Med Genet 13:30, 2012 Grosso A, Cheung N, Veglio F et al.: Similarities and differences in early retinal phenotypes in hypertension and diabetes. J Hypertens 29:1667, 2011 Guery B, Choukroun G, Noel LH et al.: The spectrum of systemic involvement in adults presenting with renal lesion and mitochondrial tRNA(Leu) gene mutation. J Am Soc Nephrol 14:2099, 2003 Hober D, Sane F, Jaidane H et al.: Immunology in the clinic review series; focus on type 1 diabetes and viruses: Role of antibodies enhancing the infection with Coxsackievirus-B in the pathogenesis of type 1 diabetes. Clin Exp Immunol 168:47, 2012

Ido Y, Vindigni A, Chang K et al.: Prevention of vascular and neural dysfunction in diabetic rats by C-peptide. Science 277:563, 1997 Kaul K, Hodgkinson A, Tarr JM et al.: Is inflammation a common retinal–renal–nerve pathogenic link in diabetes? Curr Diabetes Rev 6:294, 2010 Klein R, Klein BEK, Moss SE et al.: The Wisconsin Epidemiologic Study of Diabetic Retinopathy: XIV. Ten-year incidence and progression of diabetic retinopathy. Arch Ophthalmol 112:1217, 1994 Klein R, Klein BEK, Moss SE et al.: The Wisconsin Epidemiologic Study of Diabetic Retinopathy: XV. The long-year incidence of macular edema. Ophthalmology 102:7, 1995 Klein R, Klein BEK, Moss SE et al.: The Wisconsin Epidemiologic Study of Diabetic Retinopathy: XVII. The 14-year incidence and progression of diabetic retinopathy and associated risk factors in type 1 diabetes. Ophthalmology 105:1801, 1998 Klein R, Knudtson MD, Lee KE et al.: The Wisconsin Epidemiologic Study of Diabetic Retinopathy: XXII. The twenty-five-year progression of retinopathy in persons with type 1 diabetes. Ophthalmology 115:1859, 2008 Klein R, Meuer SM, Moss SE et al.: Retinal microaneurysm counts and progression of diabetic retinopathy. Arch Ophthalmol 113:1386, 1995 Klein R, Meuer SM, Moss SE et al.: Incidence of retinopathy and associated risk factors from time of diagnosis of insulin-dependent diabetes. Arch Ophthalmol 115:351, 1997 Klein R, Sharrett AR, Klein BE et al.: The association of atherosclerosis, vascular risk factors, and retinopathy in adults with diabetes: The Atherosclerosis Risk in Communities Study. Ophthalmology 109:1225, 2002 Kyto JP, Harjutsalo V, Forsblom C et al.: Decline in the cumulative incidence of severe diabetic retinopathy in patients with type 1 diabetes. Diabetes Care 34:2005, 2011 Leal EC, Santiago AR, Ambrosio AF: Old and new drug targets in diabetic retinopathy: From biochemical changes to inflammation and neurodegeneration. Curr Drug Targets CNS Neurol Disord 4:421, 2005 Lind K, Huhn MH, Flodstrom-Tullberg M: Immunology in the clinic review series—Focus on type 1 diabetes and viruses: The innate immune response to enteroviruses and its possible role in regulating type 1 diabetes. Clin Exp Immunol 168:30, 2012 Lonneville YH, Ozdek SC, Onol M et al.: The effect of blood glucose regulation on retinal nerve fiber layer thickness in diabetic patients. Ophthalmologica 217:347, 2003 Lozano R, Naghavi M, Foreman K et al.: Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: A systematic analysis for the Global Burden of Disease Study 2010. Lancet 380:2095, 2013 Marshall G, Garg SK, Jackson WE et al.: Factors influencing the onset and progression of diabetic retinopathy in subjects with insulindependent diabetes mellitus. Ophthalmology 100:1133, 1993 McCollister KE, Zheng DD, Fernandez CA et al.: Racial disparities in quality-adjusted life-years associated with diabetes and visual impairment. Diabetes Care 35:1692, 2012 Miceli MV, Newsome DA: Cultured retinal pigment cells from donors with type I diabetes show an altered insulin response. Invest Ophthalmol Vis Sci 32:2847, 1991 Mitchell P, Smith W, Chey T et al.: Open-angle glaucoma and diabetes: The Blue Mountain Eye Study, Australia. Ophthalmology 104:712, 1997 Mohan R, Rajendran B, Mohan V et al.: Retinopathy in tropical pancreatic diabetes. Arch Ophthalmol 103:1487, 1985 Morris AP, Voight BF, Teslovich TM et al.: Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat Genet 44:981, 2012

553.e2 Ch. 15:  Diabetes Mellitus

Moss SE, Klein R, Klein BEK: Ten-year incidence of visual loss in a diabetic population. Ophthalmology 101:1061, 1994 Moss SE, Klein R, Meuer MB et al.: The association of iris color with eye disease in diabetes. Ophthalmology 94:1226, 1987 Sacks DA, McDonald JM: The pathogenesis of type II diabetes mellitus: A polygenic disease. Am J Clin Pathol 105:149, 1996 Sentell TL, He G, Gregg EW, Schillinger D: Racial/ethnic variation in prevalence estimates for United States prediabetes under alternative 2010 American Diabetes Association criteria: 1988–2008. Ethn Dis 22:451, 2012 Sivaprasad S, Gupta B, Crosby-Nwaobi R et al.: Prevalence of diabetic retinopathy in various ethnic groups: A worldwide perspective. Surv Ophthalmol 57:347, 2012 Takahashi H, Goto T, Shoji T et al.: Diabetes-associated retinal nerve fiber damage evaluated with scanning laser polarimetry. Am J Ophthalmol 142:88, 2006 van de Enden M, Nyengaard JR, Ostrow E et al.: Elevated glucose levels increase retinal glycolysis and sorbitol pathway metabolism: Implications for diabetic retinopathy. Invest Ophthalmol Vis Sci 36:1675, 1995 Van Leiden HA, Dekker JM, Moll AC et al.: Risk factors for incident retinopathy in a diabetic and nondiabetic population. Arch Ophthalmol 121:245, 2003 Wong TY, Cheung N, Islam FM et al.: Relation of retinopathy to coronary artery calcification: The multi-ethnic study of atherosclerosis. Am J Epidemiol 167:51, 2008 Wong TY, Klein R, Islam FM et al.: Diabetic retinopathy in a multiethnic cohort in the United States. Am J Ophthalmol 141:446, 2006 Yau JW, Rogers SL, Kawasaki R et al.: Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care 35:556, 2012 Zhang X, Saaddine JB, Chou CF et al.: Prevalence of diabetic retinopathy in the United States, 2005–2008. JAMA 304:649, 2010

Conjunctiva and Cornea Ahmed A, Bril V, Orszag A et al.: Detection of diabetic sensorimotor polyneuropathy by corneal confocal microscopy in type 1 diabetes: A concurrent validity study. Diabetes Care 35:821, 2012 Arnarsson A, Jonasson F, Sasaki H et al.: Risk factors for nuclear lens opacification: The Reykjavik Eye Study. Dev Ophthalmol 35:12, 2002 Azar DT, Spurr-Michaud SJ, Tisdale AS et al.: Decreased penetration of anchoring fibrils into the diabetic stroma. Arch Ophthalmol 107:1520, 1989 Brandt JD, Beiser JA, Kass MA et al.: Central corneal thickness in the Ocular Hypertension Treatment Study (OHTS). Ophthalmology 108:1779, 2001 Chang PY, Carrel H, Huang JS et al.: Decreased density of corneal basal epithelium and subbasal corneal nerve bundle changes in patients with diabetic retinopathy. Am J Ophthalmol 142:488, 2006 Cheung AT, Price AR, Duong PL et al.: Microvascular abnormalities in pediatric diabetic patients. Microvasc Res 63:252, 2002 Cheung AT, Ramanujam S, Greer DA et al.: Microvascular abnormalities in the bulbar conjunctiva of patients with type 2 diabetes mellitus. Endocr Pract 7:358, 2001 Dabbah MA, Graham J, Petropoulos I et al.: Dual-model automatic detection of nerve-fibres in corneal confocal microscopy images. Med Image Comput Comput Assist Interv 13:300, 2010 Edwards K, Pritchard N, Vagenas D et al.: Utility of corneal confocal microscopy for assessing mild diabetic neuropathy: Baseline findings of the LANDMark study. Clin Exp Optom 95:348, 2012 Efron N, Edwards K, Roper N et al.: Repeatability of measuring corneal subbasal nerve fiber length in individuals with type 2 diabetes. Eye Contact Lens 36:245, 2010

Fujishima H, Tsubota K: Improvement of corneal fluorescein staining in post cataract surgery of diabetic patients by an oral aldose reductase inhibitor, ONO-2235. Br J Ophthalmol 86:860, 2002 Gonzalez-Meijome JM, Jorge J, Queiros A et al.: Two single descriptors of endothelial polymegethism and pleomorphism. Graefes Arch Clin Exp Ophthalmol 248:1159, 2010 He J, Bazan HE: Mapping the nerve architecture of diabetic human corneas. Ophthalmology 119:956, 2012 Hertz P, Bril V, Orszag A et al.: Reproducibility of in vivo corneal confocal microscopy as a novel screening test for early diabetic sensorimotor polyneuropathy. Diabet Med 28:1253, 2011 Hiraoka M, Amano S, Oshika T et al.: Factors contributing to corneal complications after vitrectomy in diabetic patients. Jpn J Ophthalmol 45:492, 2001 Hugod M, Storr-Paulsen A, Norregaard JC et al.: Corneal endothelial cell changes associated with cataract surgery in patients with type 2 diabetes mellitus. Cornea 30:749, 2011 Inoue K, Kato S, Ohara C et al.: Ocular and systemic factors relevant to diabetic keratoepitheliopathy. Cornea 20:798, 2001 Jacques PF, Moeller SM, Hankinson SE et al.: Weight status, abdominal adiposity, diabetes, and early age-related lens opacities. Am J Clin Nutr 78:400, 2003 Kallinikos P, Berhanu M, O’Donnell C et al.: Corneal nerve tortuosity in diabetic patients with neuropathy. Invest Ophthalmol Vis Sci 45:418, 2004 Keoleian GM, Pach JM, Hodge DO et al.: Structural and functional studies of the corneal endothelium in diabetes mellitus. Am J Ophthalmol 113:64, 1992 Khalfaoui T, Lizard G, Ouertani-Meddeb A: Adhesion molecules (ICAM-1 and VCAM-1) and diabetic retinopathy in type 2 diabetes. J Mol Histol 39:243, 2008 Kria L, Khalfaoui T, Mkannez G et al.: Immunohistochemical study of vascular endothelial growth factor (VEGF), tumor suppressor protein (p53) and intercellular adhesion molecule (ICAM-1) in the conjunctiva of diabetic patients. J Mol Histol 36:381, 2005 Larson L-I, Bourne WM, Pach JM et al.: Structure and function of the corneal endothelium in diabetes mellitus type I and type II. Arch Ophthalmol 114:9, 1996 Lee JS, Lee JE, Choi HY et al.: Corneal endothelial cell change after phacoemulsification relative to the severity of diabetic retinopathy.  J Cataract Refract Surg 31:742, 2005 Leem HS, Lee KJ, Shin KC: Central corneal thickness and corneal endothelial cell changes caused by contact lens use in diabetic patients. Yonsei Med J 52:322, 2011 Leske MC, Wu SY, Nemesure B et al.: Risk factors for incident nuclear opacities. Ophthalmology 109:1303, 2002 Malik RA, Kallinikos P, Abbott CA et al.: Corneal confocal microscopy: A non-invasive surrogate of nerve fibre damage and repair in diabetic patients. Diabetologia 46:683, 2003 Mathew PT, David S, Thomas N: Endothelial cell loss and central corneal thickness in patients with and without diabetes after manual small incision cataract surgery. Cornea 30:424, 2011 Messmer EM, Schmid-Tannwald C, Zapp D et al.: In vivo confocal microscopy of corneal small fiber damage in diabetes mellitus. Graefes Arch Clin Exp Ophthalmol 248:1307, 2010 Midena E, Brugin E, Ghirlando A et al.: Corneal diabetic neuropathy: A confocal microscopy study. J Refract Surg 22:S1047, 2006 Mimura T, Obata H, Usui T et al.: Pinguecula and diabetes mellitus. Cornea 31:264, 2012 Mocan MC, Durukan I, Irkec M et al.: Morphologic alterations of both the stromal and subbasal nerves in the corneas of patients with diabetes. Cornea 25:769, 2006 Modis L Jr, Szalai E, Kertesz K et al.: Evaluation of the corneal endothelium in patients with diabetes mellitus type I and II. Histol Histopathol 25:1531, 2010

Bibliography 553.e3

Morikubo S, Takamura Y, Kubo E et al.: Corneal changes after smallincision cataract surgery in patients with diabetes mellitus. Arch Ophthalmol 122:966, 2004 Okamura N, Ito Y, Shibata MA et al.: Fas-mediated apoptosis in human lens epithelial cells of cataracts associated with diabetic retinopathy. Med Electron Microsc 35:234, 2002 Price MO, Thompson RW Jr, Price FW Jr: Risk factors for various causes of failure in initial corneal grafts. Arch Ophthalmol 121:1087, 2003 Saghizadeh M, Kramerov AA, Tajbakhsh J et al.: Proteinase and growth factor alterations revealed by gene microarray analysis of human diabetic corneas. Invest Ophthalmol Vis Sci 46:3604, 2005 Sani JS, Mittal S: In vivo assessment of corneal endothelial function in diabetes mellitus. Arch Ophthalmol 114:649, 1996 Schultz RO, van Horn DL, Peters MA et al.: Diabetic keratopathy. Trans Am Ophthalmol Soc 74:180, 1981 Shenoy R, Khandekar R, Bialasiewicz A et al.: Corneal endothelium in patients with diabetes mellitus: A historical cohort study. Eur J Ophthalmol 19:369, 2009 Shetlar DJ, Bourne WM, Campbell RJ: Morphologic evaluation of Descemet’s membrane and corneal endothelium in diabetes mellitus. Ophthalmology 96:247, 1989 Siribunkum J, Kosrirukvongs P, Singalavanija A: Corneal abnormalities in diabetes. J Med Assoc Thai 84:1075, 2001 Su DH, Wong TY, Foster PJ et al.: Central corneal thickness and its associations with ocular and systemic factors: The Singapore Malay Eye Study. Am J Ophthalmol 147:709, 2009 Su DH, Wong TY, Wong WL et al.: Diabetes, hyperglycemia, and central corneal thickness: The Singapore Malay Eye Study. Ophthalmology 115:964, 2008 Su F, Li B, Wang J et al.: Molecular regulation of vasculogenic mimicry in human uveal melanoma cells: Role of helix–loop–helix Id2 (inhibitor of DNA binding 2). Graefes Arch Clin Exp Ophthalmol 247:411, 2009 Sudhir RR, Raman R, Sharma T: Changes in the corneal endothelial cell density and morphology in patients with type 2 diabetes mellitus: A population-based study, Sankara Nethralaya Diabetic Retinopathy and Molecular Genetics Study (SN-DREAMS, Report 23). Cornea 31:1119, 2012 Tavakoli M, Boulton AJ, Efron N et al.: Increased Langerhan cell density and corneal nerve damage in diabetic patients: Role of immune mechanisms in human diabetic neuropathy. Cont Lens Anterior Eye 34:7, 2011 Tavakoli M, Kallinikos P, Iqbal A et al.: Corneal confocal microscopy detects improvement in corneal nerve morphology with an improvement in risk factors for diabetic neuropathy. Diabet Med 28:1261, 2011 Taylor HR, Kimsey RA: Corneal epithelial basement membrane changes in diabetes. Invest Ophthalmol 20:548, 1981 To WJ, Telander DG, Lloyd ME et al.: Correlation of conjunctival microangiopathy with retinopathy in type-2 diabetes mellitus (T2DM) patients. Clin Hemorheol Microcirc 47:131, 2011 Yoon KC, Im SK, Seo MS: Changes of tear film and ocular surface in diabetes mellitus. Korean J Ophthalmol 18:168, 2004

Lens Agte VV, Tarwadi KV: Combination of diabetes and cataract worsens the oxidative stress and micronutrient status in Indians. Nutrition 24:617, 2008 Barber AJ: A new view of diabetic retinopathy: A neurodegenerative disease of the eye. Prog Neuropsychopharmacol Biol Psychiatry 27:283, 2003

Biswas S, Harris F, Singh J et al.: Role of calpains in diabetes mellitusinduced cataractogenesis: A mini review. Mol Cell Biochem 261:151, 2004 Chung SS, Chung SK: Genetic analysis of aldose reductase in diabetic complications. Curr Med Chem 10:1375, 2003 Cunliffe IA, Flanagan DW, George NDL et al.: Extracapsular cataract surgery with lens implantation in diabetics with and without proliferative retinopathy. Br J Ophthalmol 75:9, 1991 Datiles MB, Kador PF: Type I diabetic cataract. Arch Ophthalmol 117:284, 1999 Degenring RF, Vey S, Kamppeter B et al.: Effect of uncomplicated phacoemulsification on the central retina in diabetic and non-diabetic subjects. Graefes Arch Clin Exp Ophthalmol 245:18, 2007 Fan H, Suzuki T, Ogata M et al.: Expression of PCNA, ICAM-1, and vimentin in lens epithelial cells of cataract patients with and without type 2 diabetes. Tokai J Exp Clin Med 37:51, 2012 Freel CD, al-Ghoul KJ, Kuszak JR et al.: Analysis of nuclear fiber cell compaction in transparent and cataractous diabetic human lenses by scanning electron microscopy. BMC Ophthalmol 3:1, 2003 Gardner TW, Antonetti DA, Barber AJ et al.: Diabetic retinopathy: More than meets the eye. Surv Ophthalmol 47(Suppl 2):S253, 2002 Grauslund J: Eye complications and markers of morbidity and mortality in long-term type 1 diabetes. Acta Ophthalmol 89 Thesis 1:1, 2011 Gul A, Rahman MA, Hasnain SN et al.: Could oxidative stress associate with age products in cataractogenesis? Curr Eye Res 33:669, 2008 Gul A, Rahman MA, Salim A et al.: Advanced glycation end products in senile diabetic and nondiabetic patients with cataract. J Diabetes Complications 23:343, 2009 Hayashi K, Hayashi H, Nakao F et al.: Posterior capsule opacification after cataract surgery in patients with diabetes mellitus. Am J Ophthalmol 134:10, 2002 Jaffe GJ, Burton TC, Kuhn E et al.: Progression of nonproliferative diabetic retinopathy and visual outcome after extracapsular cataract extraction and intraocular lens implantation. Am J Ophthalmol 114:448, 1992 Kim B, Kim SY, Chung SK: Changes in apoptosis factors in lens epithelial cells of cataract patients with diabetes mellitus. J Cataract Refract Surg 38:1376, 2012 Klein BEK, Klein R, Moss SE: Prevalence of cataracts in a populationbased study of persons with diabetes mellitus. Ophthalmology 92:1191, 1985 Kumamoto Y, Takamura Y, Kubo E et al.: Epithelial cell density in cataractous lenses of patients with diabetes: Association with erythrocyte aldose reductase. Exp Eye Res 85:393, 2007 Lopes de Faria JM, Katsumi O, Cagliero E et al.: Neurovisual abnormalities preceding the retinopathy in patients with long-term type 1 diabetes mellitus. Graefes Arch Clin Exp Ophthalmol 239:643, 2001 Lorenzi M, Gerhardinger C: Early cellular and molecular changes induced by diabetes in the retina. Diabetologia 44:791, 2001 Palsamy P, Ayaki M, Elanchezhian R et al.: Promoter demethylation of Keap1 gene in human diabetic cataractous lenses. Biochem Biophys Res Commun 423:542, 2012 Patel JI, Hykin PG, Cree IA: Diabetic cataract removal: Postoperative progression of maculopathy—Growth factor and clinical analysis. Br J Ophthalmol 90:697, 2006 Pollack A, Dotan S, Oliver M: Course of diabetic retinopathy following cataract surgery. Br J Ophthalmol 75:2, 1991 Rahim A, Iqbal K: To assess the levels of zinc in serum and changes in the lens of diabetic and senile cataract patients. J Pak Med Assoc 61:853, 2011 Richter GM, Choudhury F, Torres M et al.: Risk factors for incident cortical, nuclear, posterior subcapsular, and mixed lens opacities: The Los Angeles Latino eye study. Ophthalmology 119:2040, 2012

553.e4 Ch. 15:  Diabetes Mellitus

Santiago AP, Rosenbaum AL, Masket S: Insulin-dependent diabetes mellitus appearing as bilateral mature diabetic cataracts in a child. Arch Ophthalmol 115:422, 1997 Schatz H, Atienza D, McDonald HR et al.: Severe diabetic retinopathy after cataract surgery. Am J Ophthalmol 117:314, 1994 Smith R: Diabetic retinopathy and cataract surgery. Br J Ophthalmol 75:1, 1991 Tkachov SI, Lautenschlager C, Ehrich D et al.: Changes in the lens epithelium with respect to cataractogenesis: Light microscopic and Scheimpflug densitometric analysis of the cataractous and the clear lens of diabetics and non-diabetics. Graefes Arch Clin Exp Ophthalmol 244:596, 2006 Tsilimbaris M, Diakonis VF, Kymionis GD et al.: Prospective study of foveal thickness alterations after cataract surgery assessed by optical coherence tomography. Ophthalmologica 228:53, 2012 Yanoff M: Ocular pathology of diabetes mellitus. Am J Ophthalmol 67:21, 1969

Neurosensory Retina Bandello F, Berchicci L, La SC et al.: Evidence for anti-VEGF treatment of diabetic macular edema. Ophthalmic Res 48(Suppl 1):16, 2012 Baskin DE: Optical coherence tomography in diabetic macular edema. Curr Opin Ophthalmol 21:172, 2010 Beutel J, Peters S, Luke M et al.: Bevacizumab as adjuvant for neovascular glaucoma. Acta Ophthalmol 88:103, 2010 Bhagat N, Grigorian RA, Tutela A et al.: Diabetic macular edema: Pathogenesis and treatment. Surv Ophthalmol 54:1, 2009 Biro Z, Balla Z: Foveal and perifoveal retinal thickness measured by OCT in diabetic patients after phacoemulsification cataract surgery. Oftalmologia 53(2):54, 2009 Biro Z, Balla Z: OCT measurements on the foveal and perifoveal retinal thickness on diabetic patients after phacoemulsification and IOL implantation. Eye (Lond) 24:639, 2010 Ebihara Y, Kato S, Oshika T et al.: Posterior capsule opacification after cataract surgery in patients with diabetes mellitus. J Cataract Refract Surg 32:1184, 2006 Feng Y, Busch S, Gretz N et al.: Crosstalk in the retinal neurovascular unit: Lessons for the diabetic retina. Exp Clin Endocrinol Diabetes 120:199, 2012 Feng Y, vom Hagen F, Pfister F et al.: Impaired pericyte recruitment and abnormal retinal angiogenesis as a result of angiopoietin-2 overexpression. Thromb Haemost 97:99, 2007 Fletcher EL, Phipps JA, Ward MM et al.: Neuronal and glial cell abnormality as predictors of progression of diabetic retinopathy. Curr Pharm Des 13:2699, 2007 Fletcher EL, Phipps JA, Wilkinson-Berka JL: Dysfunction of retinal neurons and glia during diabetes. Clin Exp Optom 88:132, 2005 Forst T, Weber MM, Mitry M et al.: Pilot study for the evaluation of morphological and functional changes in retinal blood flow in patients with insulin resistance and/or type 2 diabetes mellitus. J Diabetes Sci Technol 6:163, 2012 Gambhir D, Ananth S, Veeranan-Karmegam R et al.: GPR109A as an anti-inflammatory receptor in retinal pigment epithelial cells and its relevance to diabetic retinopathy. Invest Ophthalmol Vis Sci 53:2208, 2012 Gustavsson C, Agardh CD, Zetterqvist AV et al.: Vascular cellular adhesion molecule-1 (VCAM-1) expression in mice retinal vessels is affected by both hyperglycemia and hyperlipidemia. PLoS One 5:e12699, 2010 Hayashi Y, Kato S, Maeda T et al.: Immunohistologic study of interleukin-1, transforming growth factor-beta, and alpha-smooth muscle actin in lens epithelial cells in diabetic eyes. J Cataract Refract Surg 31:2187, 2005

Ho AC, Scott IU, Kim SJ et al.: Anti-vascular endothelial growth factor pharmacotherapy for diabetic macular edema: A report by the American Academy of Ophthalmology. Ophthalmology 119:2179, 2012 Kakehashi A, Inoda S, Mameuda C et al.: Relationship among VEGF, VEGF receptor, AGEs, and macrophages in proliferative diabetic retinopathy. Diabetes Res Clin Pract 79:438, 2008 Koleva-Georgieva DN, Sivkova NP: Optical coherence tomography for the detection of early macular edema in diabetic patients with retinopathy. Folia Med (Plovdiv) 52:40, 2010 Lang GE: Diabetic macular edema. Ophthalmologica 227(Suppl 1):21, 2012 Meleth AD, Agron E, Chan CC et al.: Serum inflammatory markers in diabetic retinopathy. Invest Ophthalmol Vis Sci 46:4295, 2005 Miller JW, Le Couter J, Strauss EC et al.: Vascular endothelial growth factor A in intraocular vascular disease. Ophthalmology 120:106, 2013 Patel JI, Saleh GM, Hykin PG et al.: Concentration of haemodynamic and inflammatory related cytokines in diabetic retinopathy. Eye (Lond) 22:223, 2008 Sun C, Wang JJ, Mackey DA et al.: Retinal vascular caliber: Systemic, environmental, and genetic associations. Surv Ophthalmol 54:74, 2009 Verma A, Raman R, Vaitheeswaran K et al.: Does neuronal damage precede vascular damage in subjects with type 2 diabetes mellitus and having no clinical diabetic retinopathy? Ophthalmic Res 47:202, 2012 Verma A, Rani PK, Raman R et al.: Is neuronal dysfunction an early sign of diabetic retinopathy? Microperimetry and spectral domain optical coherence tomography (SD-OCT) study in individuals with diabetes, but no diabetic retinopathy. Eye (Lond) 23:1824, 2009 Wiemer NG, Dubbelman M, Hermans EA et al.: Changes in the internal structure of the human crystalline lens with diabetes mellitus type 1 and type 2. Ophthalmology 115:2017, 2008 Zeng HY, Green WR, Tso MO: Microglial activation in human diabetic retinopathy. Arch Ophthalmol 126:227, 2008 Zong H, Ward M, Madden A et al.: Hyperglycaemia-induced proinflammatory responses by retinal Muller glia are regulated by the receptor for advanced glycation end-products (RAGE). Diabetologia 53:2656, 2010

Iris Aiello LM, Wand M, Liang G: Neovascular glaucoma and vitreous hemorrhage following cataract surgery in patients with diabetes mellitus. Ophthalmology 90:814, 1983 Fine BS, Berkow JW, Helfgott JA: Diabetic lacy vacuolation of iris pigment epithelium. Am J Ophthalmol 69:197, 1970 Smith ME, Glickman P: Diabetic vacuolation of the iris pigment epithelium. Am J Ophthalmol 79:875, 1975 Yanoff M: Ocular pathology of diabetes mellitus. Am J Ophthalmol 67:21, 1969 Yanoff M, Fine BS, Berkow JW: Diabetic lacy vacuolation of iris pigment epithelium. Am J Ophthalmol 69:201, 1970

Ciliary Body and Choroid Cao J, McCeod DS, Merges CA et al.: Choriocapillaris degeneration and related pathologic changes in human diabetic eyes. Arch Ophthalmol 116:589, 1998 Fryczkowski AW, Sato SE, Hodes BL: Changes in the diabetic choroidal vasculature: Scanning electron microscopy findings. Ann Ophthalmol 20:299, 1988 Hidayat AA, Fine BS: Diabetic choroidopathy: Light and electron microscopic observations of seven cases. Ophthalmology 92:512, 1985 Rothova A, Meenken C, Michels RPJ et al.: Uveitis and diabetes mellitus. Am J Ophthalmol 106:17, 1988

Bibliography 553.e5

Yanoff M: Ocular pathology of diabetes mellitus. Am J Ophthalmol 67:21, 1969

Retina Adamis AP, Miller JW, Bernal M-T et al.: Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy. Am J Ophthalmol 118:445, 1994 Aguilar E, Friedlander MF, Gariano RF et al.: Endothelial proliferation in diabetic retinal aneurysms. Arch Ophthalmol 121:740, 2003 Aiello LP, Northrup JM, Keyt BA et al.: Hypoxic regulation of vascular endothelial growth factor in retinal cells. Arch Ophthalmol 113:1538, 1995 Alzaid AA, Dinneen SF, Melton LJ III et al.: The role of growth hormone in the development of diabetic retinopathy. Diabetes Care 17:531, 1994 Ambati J, Chalam KV, Chawla DK et al.: Elevated γ-aminobutyric acid, glutamate, and vascular endothelial growth factor levels in the vitreous of patients with proliferative diabetic retinopathy. Arch Ophthalmol 115:1161, 1997 Ashton N: Vascular basement membrane changes in diabetic retinopathy. Br J Ophthalmol 58:344, 1974 Ballantyne AJ, Lowenstein A: Diseases of the retina: I. The pathology of diabetic retinopathy. Trans Ophthalmol Soc UK 63:95, 1943 Baudouin C, Gordon WC, Fredj-Reygrobellet D et al.: Class II antigen expression in diabetic preretinal membranes. Am J Ophthalmol 109:70, 1990 Bek T: A clinicopathological study of venous loops and reduplications in diabetic retinopathy. Acta Ophthalmol Scand 80:69, 2002 Bengtsson B, Heijl A, Agardh E: Visual fields correlate better than visual acuity to severity of diabetic retinopathy. Diabetologia 48:2494, 2005 Bloodworth JMB Jr: Diabetic microangiopathy. Diabetes 12:99, 1963 Boehm BO, Lang G, Feldmann B et al.: Proliferative diabetic retinopathy is associated with a low level of the natural ocular antiangiogenic agent pigment epithelium-derived factor (PEDF) in aqueous humor: A pilot study. Horm Metab Res 35:382, 2003 Boehm BO, Lang G, Volpert O et al.: Low content of the natural ocular anti-angiogenic agent pigment epithelium-derived factor (PEDF) in aqueous humor predicts progression of diabetic retinopathy. Diabetologia 46:394, 2003 Bronson SK, Reiter CE, Gardner TW: An eye on insulin. J Clin Invest 111:1817, 2003 Brooks PC, Clark RAF, Cheresh DA: Requirement of vascular integrin for angiogenesis. Science 264:569, 1994 bu-El-Asrar AM, Dralands L, Missotten L et al.: Expression of apoptosis markers in the retinas of human subjects with diabetes. Invest Ophthalmol Vis Sci 45:2760, 2004 Chen YJ, Kuo HK, Huang HW: Retinal outcomes in proliferative diabetic retinopathy presenting during and after pregnancy. Chang Gung Med J 27:678, 2004 Chew EY, Klein ML, Ferris FL et al.: Association of elevated serum lipid levels with retinal hard exudate in diabetic retinopathy: Early Treatment Diabetic Retinopathy Study (ETDRS) report 22. Arch Ophthalmol 114:1079, 1996 Clermont AC, Aiello LP, Mori F et al.: Vascular endothelial growth factor and severity of nonproliferative diabetic retinopathy mediate retinal hemodynamics in vivo: A potential role for vascular endothelial growth factor in the progression of nonproliferative diabetic retinopathy. Am J Ophthalmol 124:433, 1997 Cogan DG, Toussaint D, Kuwabara T: Retinal vascular patterns: IV. Diabetic retinopathy. Arch Ophthalmol 66:366, 1961 Cussick M, Chew EY, Chan C-C et al.: Histopathology and regression of retinal hard exudates in diabetic retinopathy after reduction of elevated serum lipid levels. Ophthalmology 110:2126, 2003

Daria B, Maiello M, Lorenzi M: Increased incidence of micro thrombosis in retinal capillaries of diabetic individuals. Diabetes 50:1432, 2002 Diabetes Control and Complications Trial Research Group: Early worsening of diabetic retinopathy in the diabetes control and complications trial. Ophthalmology 116:874, 1998 Economopoulou M, Bdeir K, Cines DB et al.: Inhibition of pathologic retinal neovascularization by alpha-defensins. Blood 106:3831, 2005 Frank RN: On the pathogenesis of diabetic retinopathy: A 1990 update. Ophthalmology 98:586, 1991 Frank RN: Diabetic retinopathy. N Engl J Med 350:48, 2004 Fritsche P, van der HR, Suttorp-Schulten MS et al.: Retinal thickness analysis (RTA): An objective method to assess and quantify the retinal thickness in healthy controls and in diabetics without diabetic retinopathy. Retina 22:768, 2002 Funatsu H, Yamashita H, Noma H et al.: Stimulation and inhibition of angiogenesis in diabetic retinopathy. Jpn J Ophthalmol 45:577, 2001 Gargiulo P, Giusti C, Pietrobono D et al.: Diabetes mellitus and retinopathy. Dig Liver Dis 36(Suppl 1):S101, 2004 Gariano RF, Gardner TW: Retinal angiogenesis in development and disease. Nature 438:960, 2005 Giebel SJ, Menicucci G, McGuire PG et al.: Matrix metalloproteinases in early diabetic retinopathy and their role in alteration of the blood–retinal barrier. Lab Invest 85:597, 2005 Goebel W, Kretzchmar-Gross T: Retinal thickness in diabetic retinopathy: A study using optical coherence tomography (OCT). Retina 22:759, 2002 Güven D, Ozdemir H, Hasanreisoglu B: Hemodynamic alterations in diabetic retinopathy. Ophthalmology 103:1245, 1996 Hammes HP, Du X, Edelstein D et al.: Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Nat Med 9:294, 2003 Hanneken A, de Juan E Jr, Lutty GA et al.: Altered distribution of basic fibroblast growth factor in diabetic retinopathy. Arch Ophthalmol 109:1005, 1991 Helbig H, Kornacker S, Berweck S et al.: Membrane potentials in retinal capillary pericytes: Excitability and effect of vasoactive substances. Invest Ophthalmol Vis Sci 33:2105, 1992 Hellstedt T, Immonen I: Disappearance and formation rates of microaneurysms in early diabetic retinopathy. Br J Ophthalmol 80:135, 1996 Hersh PS, Green WR, Thomas JV: Tractional venous loops in diabetic retinopathy. Am J Ophthalmol 92:661, 1981 Hinton DR, Spee C, He S et al.: Accumulation of NH2-terminal fragment of connective tissue growth factor in the vitreous of patients with proliferative diabetic retinopathy. Diabetes Care 27:758, 2004 Hussain A, Hussain N, Nutheti R: Comparison of mean macular thickness using optical coherence tomography and visual acuity in diabetic retinopathy. Clin Exp Ophthalmol 33:240, 2005 Ioachim E, Stefaniotou M, Gorezis S et al.: Immunohistochemical study of extracellular matrix components in epiretinal membranes of vitreoproliferative retinopathy and proliferative diabetic retinopathy. Eur J Ophthalmol 15:384, 2005 Kador PF, Akagi Y, Takahashi Y et al.: Prevention of retinal vessel changes associated with diabetic retinopathy in galactose-fed dogs by aldose reductase inhibitors. Arch Ophthalmol 108:1301, 1990 Karacorlu M, Ozdemir H, Karacorlu S et al.: Intravitreal triamcinolone as a primary therapy in diabetic macular oedema. Eye 19:382, 2005 Klein R, Klein BEK, Moss SE et al.: Retinal vascular abnormalities in persons with type 1 diabetes: The Wisconsin Epidemiologic Study of diabetic retinopathy: XVIII. Ophthalmology 110:2118, 2003 Klein R, Meuer SM, Moss SE et al.: The relationship of retinal microaneurysm counts to the 4-year progression of diabetic retinopathy. Arch Ophthalmol 107:1780, 1989

553.e6 Ch. 15:  Diabetes Mellitus

Klein R, Meuer SM, Moss SE et al.: Retinal microaneurysm counts and progression of diabetic retinopathy. Arch Ophthalmol 113:1386, 1995 Klein R, Moss SE, Klein BEK et al.: The Wisconsin Epidemiologic Study of Diabetic Retinopathy: XI. The incidence of macular edema. Ophthalmology 96:1501, 1989 Knudsen LL, Lervang HH: Can a cilio-retinal artery influence diabetic maculopathy? Br J Ophthalmol 86:1252, 2002 Kuhn F, Kiss G, Mester V et al.: Vitrectomy with internal limiting membrane removal for clinically significant macular oedema. Graefes Arch Clin Exp Ophthalmol 242:402, 2004 Lahdenranta J, Pasqualini R, Schlingemann RO et al.: An antiangiogenic state in mice and humans with retinal photoreceptor cell degeneration. Proc Natl Acad Sci USA 98:10368, 2001 Layton CJ, Becker S, Osborne NN: The effect of insulin and glucose levels on retinal glial cell activation and pigment epithelium-derived fibroblast growth factor-2. Mol Vis 12:43, 2006 Lee VS, Kingsley RM, Lee ET et al.: The diagnosis of diabetic retinopathy. Ophthalmology 100:1504, 1993 Leto G, Pricci F, Amadio L et al.: Increased retinal endothelial cell monolayer permeability induced by the diabetic milieu: role of advanced non-enzymatic glycation and polyol pathway activation. Diabetes Metab Res Rev 17:448, 2001 Li W, Liu X, Yanoff M et al.: Cultured retinal capillary pericytes die by apoptosis after an abrupt fluctuation from high to low glucose levels: A comparative study with retinal capillary endothelial cells. Diabetologia 39:537, 1996 Li W, Tao L, Yanoff M: Agonist-induced phosphatidylinositide breakdown and mitogenesis in retinal capillary pericytes. Ophthalmic Res 26:36, 1994 Lindahl P, Johansson BR, Levéen P et al.: Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 277:242, 1997 Ljubimov AV, Caballero S, Aoki A et al.: Involvement of protein kinase CK2 in angiogenesis and retinal neovascularization. Invest Ophthalmol Vis Sci 45:4583, 2004 Lobo CL, Bernardes RC, de A Jr et al.: One-year follow-up of blood– retinal barrier and retinal thickness alterations in patients with type 2 diabetes mellitus and mild nonproliferative retinopathy. Arch Ophthalmol 119:1469, 2001 Lyons TJ, Jenkins AJ, Zhen D et al.: Diabetic retinopathy and serum lipoprotein subclasses in the DCCT/EDIC cohort. Invest Ophthalmol Vis Sci 45:910, 2004 Mansour AM, Schachat A, Bodiford G et al.: Foveal avascular zone in diabetes mellitus. Retina 13:125, 1993 Massin P, Audren F, Haouchine B et al.: Intravitreal triamcinolone acetonide for diabetic diffuse macular edema: Preliminary results of a prospective controlled trial. Ophthalmology 111:218, 2004 Matsuoka M, Ogata N, Minamino K et al.: Expression of pigment epithelium-derived factor and vascular endothelial growth factor in fibrovascular membranes from patients with proliferative diabetic retinopathy. Jpn J Ophthalmol 50:116, 2006 McFarland TJ, Zhang Y, Appukuttan B et al.: Gene therapy for proliferative ocular diseases. Expert Opin Biol Ther 4:1053, 2004 Nagaoka T, Kitaya N, Sugawara R et al.: Alteration of choroidal circulation in the foveal region in patients with type 2 diabetes. Br J Ophthalmol 88:1060, 2004 Nguyen QD, Shah SM, Van AE et al.: Supplemental oxygen improves diabetic macular edema: A pilot study. Invest Ophthalmol Vis Sci 45:617, 2004 Nicoletti VG, Nicoletti R, Ferrara N et al.: Diabetic patients and retinal proliferation: An evaluation of the role of vascular endothelial growth factor (VEGF). Exp Clin Endocrinol Diabetes 111:209, 2003 Nishiwaki H, Shahidi M, Vitale S et al.: Relation between retinal thickening and clinically visible fundus pathologies in mild nonproliferative diabetic retinopathy. Ophthalmic Surg Lasers 33:127, 2002

Noma H, Funatsu H, Yamashita H et al.: Regulation of angiogenesis in diabetic retinopathy: Possible balance between vascular endothelial growth factor and endostatin. Arch Ophthalmol 120:1075, 2002 North PE, Anthony DC, Young TL et al.: Retinal neovascular markers in retinopathy of prematurity: Aetiological implications. Br J Ophthalmol 87:275, 2003 Perrin RM, Konopatskaya O, Qiu Y et al.: Diabetic retinopathy is associated with a switch in splicing from anti- to pro-angiogenic isoforms of vascular endothelial growth factor. Diabetologia 48:2422, 2005 Poulaki V, Joussen AM, Mitsiades N et al.: Insulin-like growth factor-I plays a pathogenetic role in diabetic retinopathy. Am J Pathol 165:457, 2004 Romeo G, Liu WH, Asnaghi V et al.: Activation of nuclear factorkappaB induced by diabetes and high glucose regulates a proapoptotic program in retinal pericytes. Diabetes 51:2241, 2002 Roy S, Cagliero E, Lorenzi M: Fibronectin overexpression in retinal microvessels of patients with diabetes. Invest Ophthalmol Vis Sci 37:258, 1996 Savage HI, Hendrix JW, Peterson DC et al.: Differences in pulsatile ocular blood flow among three classifications of diabetic retinopathy. Invest Ophthalmol Vis Sci 45:4504, 2004 Schneeberger SA, Hjelmeland LM, Tucker RP et al.: Vascular endothelial growth factor and fibroblastic growth factor 5 are colonized in vascular and avascular epiretinal membranes. Am J Ophthalmol 124:433, 1997 Schröder S, Palinski W, Schmid-Schönbein GW: Activated monocytes and granulocytes, capillary nonperfusion, and neovascularization in diabetic retinopathy. Am J Pathol 139:81, 1991 Sennlaub F, Valamanesh F, Vazquez-Tello A et al.: Cyclooxygenase-2 in human and experimental ischemic proliferative retinopathy. Circulation 108:198, 2003 Sinclair SH: Macular retinal capillary hemodynamics in diabetic patients. Ophthalmology 98:1580, 1991 Siren V, Immonen I: uPA, tPA and PAI-1 mRNA expression in periretinal membranes. Curr Eye Res 27:261, 2003 Sonkin PL, Sinclair SH, Hatchell DL: The effect of pentoxifylline on retinal capillary blood flow velocity and whole blood velocity. Am J Ophthalmol 115:775, 1993 Stitt AW, Frizzell N, Thorpe SR: Advanced glycation and advanced lipoxidation: Possible role in initiation and progression of diabetic retinopathy. Curr Pharm Des 10:3349, 2004 Sugimoto M, Sasoh M, Ido M et al.: Detection of early diabetic change with optical coherence tomography in type 2 diabetes mellitus patients without retinopathy. Ophthalmologica 219:379, 2005 Tang J, Mohr S, Du YD et al.: Non-uniform distribution of lesions and biochemical abnormalities within the retina of diabetic humans. Curr Eye Res 27:7, 2003 Vinores SA, Gadegbeku C, Compochiaro PA et al.: Immunohistochemic localization of blood–retinal barrier breakdown in human diabetes. Am J Pathol 134:231, 1989 Vitale S, Maguire MG, Murphy RP et al.: Clinically significant macular edema in type I diabetes. Ophthalmology 102:1170, 1995 Vlassara H, Palace MR: Diabetes and advanced glycation endproducts. J Intern Med 251:87, 2002 Watanabe D, Suzuma K, Matsui S et al.: Erythropoietin as a retinal angiogenic factor in proliferative diabetic retinopathy. N Engl J Med 353:782, 2005 Wilkinson CP, Ferris FL, Klein RE et al.: Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales. Ophthalmology 110:1677, 2003 Wilkinson-Berka JL: Angiotensin and diabetic retinopathy. Int J Biochem Cell Biol 38:752, 2006 Witmer AN, Blaauwgeers HG, Weich HA et al.: Altered expression patterns of VEGF receptors in human diabetic retina and in

Bibliography 553.e7

experimental VEGF-induced retinopathy in monkey. Invest Ophthalmol Vis Sci 43:849, 2002 Yamagishi S, Matsui T, Nakamura K et al.: Pigment epitheliumderived factor is a pericyte mitogen secreted by microvascular endothelial cells: Possible participation of angiotensin II-elicited PEDF downregulation in diabetic retinopathy. Int J Tissue React 27:197, 2005 Yanoff M: Diabetic retinopathy. N Engl J Med 274:1344, 1966 Yanoff M: Ocular pathology of diabetes mellitus. Am J Ophthalmol 67:21, 1969 Yanoff M: Histopathogenesis of diabetic retinopathy. Acta Diabetol Lat 9:527, 1972

Vitreous Anderson B Jr: Activity and diabetic vitreous hemorrhages. Ophthalmology 87:173, 1980 Bergren RL, Brown GC, Duker JS: Prevalence and association of asteroid hyalosis with systemic disease. Am J Ophthalmol 111:289, 1991 Citirik M, Kabatas EU, Batman C et al.: Vitreous vascular endothelial growth factor concentrations in proliferative diabetic retinopathy versus proliferative vitreoretinopathy. Ophthalmic Res 47:7, 2012 Fawzi AA, Vo B, Kriwanek R et al.: Asteroid hyalosis in an autopsy population: The University of California at Los Angeles (UCLA) experience. Arch Ophthalmol 123:486, 2005 Feke GT, Zuckerman R, Green GJ et al.: Response of human retinal blood flow to light and dark. Invest Ophthalmol Vis Sci 24:136, 1983 Foos RY, Kreiger AE, Forsythe AB et al.: Posterior vitreous detachment in diabetic subjects. Ophthalmology 87:122, 1980 Foos RY, Kreiger AE, Nofsinger K: Pathologic study following vitrectomy for proliferative diabetic retinopathy. Retina 5:101, 1985 Gandorfer A, Rohleder M, Grosselfinger S et al.: Epiretinal pathology of diffuse diabetic macular edema associated with vitreomacular traction. Am J Ophthalmol 139:638, 2005 Hernandez C, Ortega F, Garcia-Ramirez M et al.: Lipopolysaccharidebinding protein and soluble CD14 in the vitreous fluid of patients with proliferative diabetic retinopathy. Retina 30:345, 2010 Hixson A, Reynolds S: Peripapillary vitreoretinal traction. Optometry 82:602, 2011 Jerdan JA, Michels RG, Glaser BM: Diabetic preretinal membranes: An immunohistochemical study. Arch Ophthalmol 104:286, 1986 Kim T, Kim SJ, Kim K et al.: Profiling of vitreous proteomes from proliferative diabetic retinopathy and nondiabetic patients. Proteomics 7:4203, 2007 Kuiper EJ, de Smet MD, van Meurs JC et al.: Association of connective tissue growth factor with fibrosis in vitreoretinal disorders in the human eye. Arch Ophthalmol 124:1457, 2006 Luxenberg M, Sime D: Relationship of asteroid hyalosis to diabetes mellitus and plasma lipid levels. Am J Ophthalmol 67:406, 1969 Nasrallah FP, Jalkh AE, Van Coppenolle F et al.: The role of the vitreous in diabetic macular edema. Ophthalmology 95:1335, 1988 Ophir A, Trevino A, Fatum S: Extrafoveal vitreous traction associated with diabetic diffuse macular oedema. Eye (Lond) 24:347, 2010 Roy MS, Podgor MJ, Bungay P et al.: Posterior vitreous fluorophotometry in diabetic patients with minimal or no retinopathy. Retina 7:170, 1987 Schwartzman ML, Iserovich P, Gotlinger K et al.: Profile of lipid and protein autacoids in diabetic vitreous correlates with the progression of diabetic retinopathy. Diabetes 59:1780, 2010 Yamakiri K, Yamashita T, Miyazaki M et al.: Fibrous proliferation of the pre-papillary canal in proliferative diabetic retinopathy: Cloquet’s

canal as a scaffold for proliferative diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 243:204, 2005 Yanoff M: Ocular pathology of diabetes mellitus. Am J Ophthalmol 67:21, 1969 Yoshimura T, Sonoda KH, Sugahara M et al.: Comprehensive analysis of inflammatory immune mediators in vitreoretinal diseases. PLoS One 4:e8158, 2009

Optic Nerve Appen RE, Chandra SR, Klein R et al.: Diabetic papillopathy. Am J Ophthalmol 90:203, 1980 Barr CC, Glaser JS, Blankenship G: Acute disc swelling in juvenile diabetes: Clinical profile and natural history of 12 cases. Arch Ophthalmol 98:2185, 1980 Bayraktar Z, Alacali N, Bayraktar S: Diabetic papillopathy in type II diabetic patients. Retina 22:752, 2002 Cankaya AB, Ozdamar Y, Ozalp S et al.: Impact of panretinal photocoagulation on optic nerve head parameters. Ophthalmologica 225:193, 2011 Giuliari GP, Sadaka A, Chang PY et al.: Diabetic papillopathy: Current and new treatment options. Curr Diabetes Rev 7:171, 2011 Ho AC, Maguire AM, Fisher YL et al.: Rapidly progressive optic disc neovascularization after diabetic papillopathy. Am J Ophthalmol 120:673, 1995 Isaacs TW, Barry C: Rapid resolution of severe disc new vessels in proliferative diabetic retinopathy following a single intravitreal injection of bevacizumab (Avastin). Clin Experiment Ophthalmol 34:802, 2006 Kim HY, Cho HK: Peripapillary retinal nerve fiber layer thickness change after panretinal photocoagulation in patients with diabetic retinopathy. Korean J Ophthalmol 23:23, 2009 Lopes de Faria JM, Russ H, Costa VP: Retinal nerve fibre layer loss in patients with type 1 diabetes mellitus without retinopathy. Br J Ophthalmol 86:725, 2002 Mallika PS, Aziz S, Asok T et al.: Severe diabetic papillopathy mimicking non-arteritic anterior ischemic optic neuropathy (NAION) in a young patient. Med J Malaysia 67:228, 2012 Mathews MK: Nonarteritic anterior ischemic optic neuropathy. Curr Opin Ophthalmol 16:341, 2005 Nakamura M, Kanamori A, Negi A: Diabetes mellitus as a risk factor for glaucomatous optic neuropathy. Ophthalmologica 219:1, 2005 Nelson K, Singh G, Boyer S et al.: Two presentations of nonarteritic ischemic optic neuropathy. Optometry 81:587, 2010 Ozdek S, Lonneville YH, Onol M et al.: Assessment of nerve fiber layer in diabetic patients with scanning laser polarimetry. Eye 16:761, 2002 Pavan PR, Aiello LM, Wafai Z et al.: Optic disc edema in juvenileonset diabetes. Arch Ophthalmol 98:2193, 1980 Regillo CD, Brown GC, Savino PJ et al.: Diabetic papillopathy: Patient characteristics and fundus findings. Arch Ophthalmol 113:889, 1995 Saito Y, Ueki N, Hamanaka N et al.: Transient optic disc edema by vitreous traction in a quiescent eye with proliferative diabetic retinopathy mimicking diabetic papillopathy. Retina 25:83, 2005 Sato T, Fujikado T, Hosohata J et al.: Development of bilateral, nonarteritic anterior ischemic optic neuropathy in an eye with diabetic papillopathy. Jpn J Ophthalmol 48:158, 2004 Soares AS, Artes PH, Andreou P et al.: Factors associated with optic disc hemorrhages in glaucoma. Ophthalmology 111:1653, 2004 Yassur Y, Pickle LW, Fine SL et al.: Optic disc neovascularisation in diabetic retinopathy: II. Natural history and results of photocoagulation treatment. Br J Ophthalmol 64:77, 1980