of DME.14 The onset of diabetes in patients with type 1 disease is usually easy to define, in contrast to patients with type 2 disease. As a result, one can measure in a meaningful way the duration of type 1 diabetes before which DME is not seen; a duration of 7 years has been reported.15 Such is not possible in type 2 disease, in which it is common for patients to have the disease for years before diagnosis, and in which it is not rare to have patients present with blurred vision secondary to DME as the presenting sign that leads to the diagnosis of type 2 diabetes. The annual rate of incidence of DME has declined in recent years compared to earlier periods, perhaps as a result of tighter glycemic control. In the Wisconsin Epidemiologic Study of Diabetic Retinopathy, the annual rates of incidence of DME for the intervals 1980–1982 to 1984–1986 and 1994–1996 to 2005–2007 were 2.3 and 0.9%, respectively.16 By comparison, the mean glycosylated hemoglobin values were 10.7 and 9.4%, respectively.16

The major ocular factor associated with DME and subclinical DME is diabetic retinopathy severity. Although DME can be seen at any level of diabetic retinopathy, increasing diabetic retinopathy severity

is associated with increasing prevalence of both DME and subclinical DME.3,16,18–20 The 14-year incidence

of DME increases from 25 to 37% as baseline retinopathy severity increases from mild to moderate nonproliferative diabetic retinopathy (NPDR).18 Point estimates of 4 and 15% for prevalence of subclinical DME in mild to moderate NPDR and severe NPDR to PDR, respectively, have been reported.20

7.2 Pathophysiology and Pathoanatomy

The reader should review Chapter 1 for a more detailed discussion of the pathophysiology of diabetic retinopathy. In this section, we emphasize only those aspects relevant to an understanding of diabetic macular edema.

7.2.1 Anatomy

The capillaries in the macula are distributed in two strata within the inner retina with the exception of the single-level arrangement bordering the foveal avascular zone (Fig. 7.2). This single level of capillaries

Fig. 7.2 Light micrograph of a section from the human macula. The line indicates a capillary comprising the foveal avascular zone border. The fovea lies to the left of the line. These capillaries are contained within the ganglion cell layer. Reprinted with permission from Iwasaki et al.21

is found within the ganglion cell layer.21 Erythrocytes travel in the perifoveal capillaries in a pulsatile manner with speed in the range of 0.5–1.0 mm/s.22 Farther from the fovea, the two levels of capillaries are found within the nerve fiber–ganglion cell layer and the inner nuclear cell layer. The more superficial capillary network is closer to the arteries, and the deeper network is closer to the venules. Arising from the disk and extending within the nerve fiber layer along the superotemporal and inferotemporal vascular arcades is the radial peripapillary capillary network, which seems to have sparse connections to the superficial capillary network of the ganglion cell layer (Fig. 7.3).23 The outer retina throughout the macula is avascular and receives oxygenation by diffusion from the deeper choriocapillaris.24 The maximum distance between capillaries in the inner retina is approximately 65–100 mm and the estimated maximal diffusion distance in the human macula consistent with normal function has been estimated to be approximately half this distance or approximately

45 mm.21 Eighty percent of microaneurysms, which seem to be a microvascular response to vascular endothelial growth factor (VEGF) generated from hypoxic retinal tissue, originate in the inner nuclear layer and its border zones.25 The larger microaneurysms tend to occur in this zone and smaller ones in the nerve fiber–ganglion cell layers. Microaneurysms range in size from 13 to 136 mm.25 Microaneurysms are particularly frequent on the edges of nonperfused retina, consistent with the hypothesis that they are a secondary reaction to hypoxia and increased local vascular endothelial growth factor concentration, and not a primary change in diabetic retinopathy (Figs. 7.4 and 7.5). As defined by fluorescein angiography, microaneurysms in DME do not have a regional clustering. One study reported that, on average, 3% of the leaking microaneurysms discerned by fluorescein angiography were present in the central circular zone of 1-mm diameter, whereas the percentages in the inferior, nasal, superior, and temporal zones as defined by the Early Treatment Diabetic

Fig. 7.4 The left panel (a) illustrates the foveal avascular zone (FAZ) of a normal macula from a cynomolgus monkey which has a similar anatomy to the human macula. The right panel (b) illustrates changes induced by intravitreal injection

of VEGF. The microaneuryms resemble those seen in dia-

betic retinopathy. Reprinted with permission from Tolentino et al.26

Fig. 7.5 The circled zone shows large microaneurysms and some dot hemorrhages that border an ischemic, whitened zone of retina

Retinopathy Study (ETDRS) grid were 26, 25, 23, and 24%, respectively.27 The relationship of microaneurysms and DME is not straightforward. The retina is not necessarily thickened adjacent to micro-

aneurysms and not all microaneurysms are leaky.28,29 There is no increase in total microaneur-

ysms or leaking aneurysms per unit area in progressively more thickened retina.29 Nevertheless, abla-

tion of leaky microaneurysms clearly improves DME.4,30

In center-involved macular edema, it is common for the central macula, including the foveal vascular zone, to be thickest, an inversion of the normal relationship. Although the underlying reason has not been established, one hypothesis is based on the

Fig. 7.6 Diagram indicating one pathway for salt and water within the retina. Under the influence of higher intravascular pressure in the arterioles, salt and water pass out of the vessels (transudate) and into the extracellular space of the retina, then returning to the intravascular space in part by entering the venular side of the circulation which has a lower intravascular pressure

(RPE) pump, which may explain the greater accumulation of edema fluid and increased retinal thickness at this location (Fig. 7.7). A fundus sign of the preferential accumulation of edema fluid in the center of the macula is the appearance of the macular lipid star commonly seen in cases of DME (Fig. 7.8). As the RPE pumps salt and water from the retinal extracellular space to the choroid, lipoproteins contained in

the extracellular fluid are left behind as yellow exudates that must be cleared much more slowly by macrophages. In 15–30% of cases of DME, a serous retinal detachment is present which is usually localized under the fovea. Although the explanation for the subfoveal location of fluid is conjectural, one

possibility posits an effect of impaired subfoveal choroidal circulation in DME.31,32

Fig. 7.7 Diagram indicating the different situation of the center ofthemacula.Thereisnovenoussideofthevasculatureinthisone location in the retina, thus salt and water can exit the vascular space from the capillaries, but can only leave the extracellular spaceviatheactionoftheretinalpigmentepithelialpump,andnot via reentry into the venules which are missing in this location

Fig. 7.8 A macular lipid star is a common fundus sign in diabetic macular edema and indicates that the center of the macula is a preferential site for accumulation of extracellular fluid

Fig. 7.9 Model of the retinal pigment epithelial pumping mechanism. The RPE cells are connected by zonula occludens which restrict the extracellular flow of ions and water back from the choroid toward the retina via the intercellular space between RPE cells. The primary energy dependent pump is the apical (retina side) sodium–potassium, electrogenic pump (left side of the cell). Other active transport systems derive the energy they require to run from the

electrochemical gradients built up by this primary pump. In the apical membrane, independent sodium-bicarbonate, sodium–potassium-chloride, chloride–bicarbonate, and sodium-lactate–water transport sites have been described. In the basal membrane, a chloride–bicarbonate co-transporter exists. Passive conductance channels for potassium and chloride also exist as shown. Adapted with permission from La Cour34 and Quintyn33

Tight junctions occur between capillary endothelial cells of the retina, the basis of the inner blood– retina barrier, and between the lateral walls of RPE cells, the outer blood–retina barrier. Diabetes causes a redistribution of occludin within the tight junctions of retinal vascular endothelium which may be the histologic correlate of the altered blood–retina barrier.35 In a rat model of diabetes, the early breakdown of the blood–retinal barrier is selective for small venules and capillaries of the inner retina with sparing of the arterioles.36 The inner blood–retina barrier rather than outer blood–retina barrier (RPE layer) breakdown is considered to be more important in the mechanism of DME even though RPE lesions can be seen shortly

after induction of diabetes in the streptozotocintreated rat model of the disease.37,38 The amount

of heparin sulfate proteoglycan is increased in the vascular endothelium of diabetic eyes compared to

nondiabetic eyes. Muller cells are important in transporting water from the extracellular space into the retinal capillaries of the inner retina.39 Their density in the macaque monkey is five times greater in the parafovea than the retinal periphery.40 The colocalization of Muller cells with the retinal regions most affected by edema suggests that Muller cell dysfunction contributes to DME. Moreover, Muller cells proliferate in epiretinal membranes, which can exert traction on microvessels and possibly increase their permeability, exacerbating macular edema. Astrocytes, which wrap their end feet around microvessels, decrease their production of glial fibrillary acidic protein in diabetes, which may be important in the altered blood–retina barrier.35 Within the retina, the synaptic portion of the outer plexiform layer and the entire inner plexiform layer comprise the two highest