Diabetic Macular Ischemia

Scott E. Pautler

8.1 Introduction

Diabetic retinopathy encompasses many interrelated pathological changes that occur in the retina of diabetic patients. Retinal ischemia has received much attention as a primary risk factor for the development of proliferative diabetic retinopathy.1 Ischemia affecting the macula has received less attention in the literature likely due to difficulty in detection and lack of treatment options.2 Retinal capillary nonperfusion was first described by Ashton using India ink preparations of the diabetic retina (Fig. 8.1).3 Subsequent histological studies revealed acellular capillaries in zones of nonperfusion (Fig. 8.2).4–7 Clinically, diabetic macular ischemia is detected by fluorescein angiography as a lack of filling of the macular capillaries, which correlates well with reported histological changes.1,7–9 Although capillary obstruction occurs in the early stages of diabetic retinopathy, precapillary arteriolar and larger arteriolar occlusions become increasingly evident in more advanced stages.3 The cause and sequence of evolution are not well understood, but the risk factors for DMI are likely those of diabetic retinopathy in general. These include

degree and duration of hyperglycemia and hyper- tension.10–12 Small studies of DMI identify

increased risk of macular ischemia with diabetic macular edema, increased stage of diabetic retinopathy, and other factors that likely relate to severity

S.E. Pautler (*)

Department of Ophthalmology, University Community Hospital, University of South Florida, Tampa, FL 33607, USA

e-mail: pautlers@aol.com

of diabetes, such as age of onset.2,13,14 Prevalence data are not available as major population studies

of diabetic retinopathy are not geared to identify macular ischemia.15,16 Despite these gaps in under-

standing, diabetic macular ischemia is recognized as an important cause of visual disability and poor response to treatment of diabetic macular edema and proliferative diabetic retinopathy.7,17,18

8.2Pathogenesis, Anatomy, and Physiology

Anatomic changes in diabetic macular ischemia include a variety of cellular and extracellular abnormalities resulting in a loss of neuroretinal tissue and occlusion of the microvasculature. These anatomic changes occur in the late stages of diabetic retinopathy along with other complications of diabetic retinopathy, such as macular edema and fibrovascular proliferation. Thus, it is difficult to study macular ischemia in isolation. Furthermore, there are myriad physiological and anatomical alterations with complicated and arcane interactions that have not been fully elucidated to date.

Factors involved in the occlusion of macular capillaries include changes in the vascular lumen itself, as well as interactions with the extraluminal neurosensory retina and intraluminal blood constituents. Diabetes affects both the cellular and extracellular components of the retinal capillary wall. Among the earliest pathological abnormalities are alterations in the retinal capillary basement membrane, which represents the shared basement membrane of the pericytes and endothelial cells.

Fig. 8.1 India ink preparation demonstrating capillary loss in diabetic retinopathy. (Reprinted with permission from Ashton.3 Copyright # 1953 British Journal of Ophthalmology. All rights reserved)

Normally, the basement membrane is primarily composed of a thin, smooth deposition of type IV collagen with macromolecules, which interact with the endothelium. The basement membrane may serve as a skeleton to support cellular components, as a molecular sieve, and metabolically as an inhibitor of proliferation. In diabetic retinopathy, there is thickening of the retinal capillary basement membrane with increased type IV collagen deposition, vacuolization, deposition of fibrillar type III collagen, and decreased heparin sulfate BM-1 proteo- glycan.19–21 The alteration of macromolecules

within the basement membrane may result in direct deleterious effects on endothelial cells.20 The cause of these basement membrane changes appears to be related to the aldose reductase metabolic pathway, advanced glycation end products (AGE) for-

mation, and vascular endothelial growth factor (VEGF).19,21–25 Retinal cellular dysfunction may

result in the formation of abnormal basement membrane by the endothelium.23,26 Conversely, it is con-

ceivable that basement membrane pathology may be causally related to further subsequent cellular changes. For example, a thickened basement membrane may decrease access of nutrients and oxygen to pericytes and neurosensory retina in a manner analogous to thickening of Bruch’s membrane in age-related macular degeneration.27–29 Low oxygen tension induces the expression of VEGF and its receptors.25

Pericytes surround the abluminal capillary surface and play important roles in capillary function. As pericytes are derived from smooth muscle cell precursors, they may regulate vascular tone.30–32 Pericytes produce structural elements of the extracellular matrix and basement membrane.30 Pericytes

regulate endothelial proliferation and differentiation.30,33 They are well seen on enzymatic digest

preparations with prominent round nuclei on the outer surface of the capillary wall, and loss of pericytes is revealed as empty balloon-like spaces (Fig. 8.3).6 Pericyte apoptosis occurs early in diabetic retinopathy. Pericytes have a relatively lower rate of proliferation relative to endothelial cells, which are also lost through apoptosis. Consequently,

Fig. 8.3 Flat section reveals former pericytes as clear spaces on the outer surface of the capillary wall. (Reproduced with permission from Cogan et al.5 Copyright # 1961 American Medical Association. All rights reserved)

pathological specimens often show a greater loss of pericytes relative to endothelial cells.34 A newer concept explaining the loss of pericytes is angiopoie- tin-induced migration of pericytes from the capillary wall.35 Because pericyte loss occurs to a much greater degree in the retina than in other tissues, local retinal factors are implicated in the pathogenesis.4 Additional factors implicated in pericyte loss include impaired adhesion to abnormal basement

membrane and adverse effects of hyperglycemia on cell replication.36,37 The loss of pericytes may lead

to closure of capillary lumen though the loss of cytokine interaction with the endothelium.38 The presence of antipericyte antibodies may represent a risk factor for diabetic macular ischemia; it is unknown whether this is a cause of or a result of tissue damage.39–41

The endothelial cell plays a central role in diabetic retinopathy. The endothelium interacts with

many humoral and cellular elements, and loss of endothelial cells is associated with capillary closure. The endothelium is a continuous monocellular lining of the luminal wall of retinal capillaries and with intercellular tight junctions creates a barrier to the diffusion of macromolecules (the blood–ocular barrier). Its function is affected by surrounding ele-

ments in the capillary wall, the neurosensory retina, and the blood components.23,26,38 The molecular

mechanisms involved in endothelial damage and macular ischemia are complex and include the sorbitol pathway, AGE formation, protein kinase C, renin–angiotensin system, inflammation, oxidation,

and alterations in gene expression and in the release of numerous cytokines.42–54 There may be a balance

of angiogenic cytokines, which appear to protect against apoptosis of the endothelium, and anti-

angiogenic cytokines, which may induce apoptosis.55,56 In diabetes, factors in the blood stream

that lead to endothelial damage include increased platelet aggregation and adherence, as well as leukostasis resulting from less deformability, increased activation, and increased adhesion.57–61 Decreased red blood cell deformability and increased aggregation occur with hyperglycemia as well.62 Normal platelet–endothelial interaction maintains the endothelial vascular integrity through the release of humoral factors that stabilize the tight junctions.33 Platelets also mediate endothelial–leuko- cyte interaction and help suppress blood–ocular breakdown when the endothelium becomes damaged.63,64 The degradation of extracellular matrix in diabetic retinopathy releases fibronectin and associated fragments that stimulate endothelial cell proliferation and adhesion, likely involved in microaneurysm formation and neovascularization.65 Endothelial cell proliferation may play a role in the pathogenesis of microaneurysms, and hypertrophy may result in capillary occlusion.66 Subsequent apoptosis of the endothelium may also result in obliteration of the capillary lumen and neurosensory nonperfusion.7,9,34 Platelet–fibrin thrombi likely contribute to obliteration of the capillary lumen in association with endothelial cell loss.67 Integrin-mediated leukocyte entrapment is increasingly recognized as a cause of arteriolar occlusion and downstream damage to the capillary bed.68–71 Following acute occlusion, retinal glial cells invade and proliferate within the vascular lumen.72

There is evidence to suggest that the neurosensory retina plays a role in the evolution of retinal microangiopathy.88 Prior to the development of diabetic retinopathy, neurosensory retinal dysfunction is evident on testing with ERG, hue discrimination, and contrast sensitivity.89–97 Early functional

changes in neurotransmission are reversible and may be due to hyperglycemia or hypoxia.92,98,99

Although there is an adaptive response by the retina to hyperglycemia, over time permanent neurosen-

sory damage occurs and may lead to further microvascular changes of diabetic retinopathy.90,100–102

For example, the hypoxic retina produces VEGF,

among other cytokines, in response to hypoxia.73,103,104 VEGF production may represent

an adaptive response to metabolic stress in order to promote neuronal survival.88 VEGF protects

against apoptosis and induces endothelial proliferation, migration, and vasopermeability that may

lead to microaneurysm formation, neovascularization, and edema.53,56,105 Glutamate excitotoxic

damage may ultimately lead to neurosensory apoptosis leading to a reduction in cytokine production and resultant retinal capillary cellular apoptosis and capillary closure.89,106 In addition, lipid mediators are released from the neurosensory retina in response to oxidative stress. These prostanoids contribute to neurovascular injury and

directly induce endothelial cell death with subsequent closure of the capillary bed.67,107 Thus, a

number of pathways have been identified to support the role of neurosensory damage in contributing to capillary dropout. In addition, there are examples of retinal vasculopathy secondary to