Fig. 7.13 Schematic summarizing the mechanisms of action of the various treatments for diabetic macular edema. The color-filled blocks represent different treatment modalities for DME. Adapted and expanded from Stefansson24

Intravitreal triamcinolone

Decreased leukostasis and ischemia

Intravitreal anti

VEGF drugs

Vitrectomy

Increased oxygen tension of inner retina

Decreased

VEGF

production

Autoregulatory arteriolar vasoconstriction

Decreased

concentration of

unblocked VEGF Decreased hydrostatic pressure in capillaries

and venules

the Muller cell but not out of it. In addition, Muller cells have a bidirectional potassium channel called Kir4.1 that allows Muller cell intracellular potassium to flow into vessels around which Muller cell processes are wrapped (Fig. 7.14). In animal models of diabetes, there is downregulation of Kir4.1. Diabetic Muller cells in these models continue to take up potassium from the extracellular space but cannot discharge the potassium into the retinal microvessels. Because water osmotically follows solute, the Muller cells swell, a situation termed intracellular edema. In addition, a dysregulated polyol pathway activated by chronic hyperglycemia in diabetes is thought to be associated with accumulation of intracellular osmotically active solutes that draw in water and cause cellular swelling.54,93 Whereas the evidence for

intracellular edema appears to be substantial in dis-

eases of the brain, models for intracellular edema in the retina have been less well investigated.92,94

7.4 Clinical Definitions

There are several definitions important for understanding the literature on diabetic macular edema.

Diabetic Macular Edema – retinal thickening within 1 disk diameter of the center of the macula or definite hard exudates in this region.4 This definition used in the Early Treatment Diabetic Retinopathy Study (ETDRS) differs from some other definitions in which the radius may be 2 disk diameters

Fig. 7.14 Schematic depicting pathways for water transport in the retina. Water is generated in the retina by oxidative synthesis of adenosine 50-triphosphate (ATP) that generates carbon dioxide and water (H2O).The Muller cell has processes that wrap around retinal microvessels. Bidirectional potassium channels called Kir4.1 are present in the Muller cell membranes abutting these microvessels. Muller cells also possess unidirectional potassium channels called Kir2.1 abutting the extracellular space that allows passage of potassium from the neuroretinal cells into the Muller cell.

Aquaporin 4 (AQ4) water channels allow the osmotic co-transport of water to follow potassium movement. The retinal pigment epithelium also actively transports potassium and chloride from the retina to the choroid with water cotransport occurring via aquaporin1 (AQ1) channels. In diabetes, the Kir4.1 channels are decreased, but not the KIR2.1 unidirectional potassium channels or the RPE potassium transport channels. The net effect is Muller cell swelling – intracellular edema. Reproduced with permission from Reichenbach and colleagues92

and in which the hard exudates criterion may be omitted. For epidemiologic purposes, some studies also classify an eye as having DME if there are macular photocoagulation scars to indicate previous treatment even if no macular thickening is present.95

Clinically Significant Macular Edema (CSME) – the situation in which at least one of the following criteria is fulfilled:

a.Retinal thickening within 500 mm of the center of the macula

b.Hard exudates within 500 mm of the center of the macula with adjacent retinal thickening

c.One disk area of retinal thickening any part of

which is within 1 disk diameter of the center of the macula4

7.5Focal and Diffuse Diabetic Macular Edema

The terms focal and diffuse are used frequently to differentiate two types of DME, although these

terms have not been defined consistently in the litera- ture.100–121 Focal edema is said to arise from micro-

aneurysms (Fig. 7.15), whereas diffuse edema is said

to arise from generally dilated and hyperpermeable capillaries throughout the macula (Fig. 7.16).122,123

The difficulty comes in translating this simple concept into an operationally reproducible methodology in clinical practice. Focal DME defined in a variety of ways has been reported to be more common than diffuse DME, but many cases of DME subjected to

these definitions have mixed features making a clear distinction difficult (Fig. 7.17).79,116,124–127 Additional

confusion may arise because the term focal is used to describe a technique of applying laser directly to microaneurysms when treating DME with focal/grid photocoagulation.4

In general, paucity of lipid exudates has been associated with diffuse edema in ophthalmoscopic

definitions, whereas presence of lipid and lipid

rings has been associated with focal edema.79,102,112,128–132 Definitions involving color

fundus photographs often involve area criteria, and the criteria vary among studies.

In the ETDRS, DME was defined clinically from stereoscopic biomicroscopy without reference to focal or diffuse descriptions of that clinical examination. However, fluorescein angiograms were analyzed by a reading center and the source of fluorescein leakage was graded categorically by proportion of leakage originating from microaneurysms for classification of edema as focal or diffuse. Eyes with 67% of leakage associated with microaneurysms were classified as focal, those with 33–66% of leakage associated with microaneurysms as intermediate, and those with <33% of leakage associated with microaneurysms as diffuse.133,134 The reproducibility of grading fluorescein angiograms for leakage source has been classified as only fair by the ETDRS authors.133 Others are less circumspect. Blair and colleagues state ‘‘it is notoriously difficult to quantify leakage on fluorescein angiograms.’’29

Fig. 7.15 (a) Focal diabetic macular edema is often described as arising from microaneurysms and having an association with lipid exudates, often in circinate rings. In this red-free photograph, lipid exudates surround a large microaneurysm temporal to the center of the macula. (b) The mid-phase fluorescein angiogram shows the

microaneurysm responsible for the exudates. The exudates are not apparent on fluorescein angiography. (c) The latephase fluorescein angiogram shows fluorescein leakage from the microaneurysm. (d) The horizontal radial line scan OCT image shows parafoveal cystoid thickening of the macula

Fig. 7.16 (a) Diffuse diabetic macular edema is often described as arising from dilated capillaries throughout the posterior pole, but not from microaneurysms, involving large areas of the macula, involving the center of the macula, and associated with few lipid exudates.The usage of the term

diffuse, however, is inconsistent in the published literature. This color fundus photograph shows few lipid exudates. (b) Relatively few microaneurysms are seen relative to the amount of fluorescein leakage shown in the late frame (see c). (c) Profuse late leakage of fluorescein is present

Optical coherence tomography (OCT) can also be used to define edema as focal or diffuse. In the false color map, isolated islands of hot colors surrounded by larger areas of cool colors give a sense of focality, but this is subjective. Some have suggested that diffuse DME be understood to imply an increasing number of elevated subfields on the map display.135 This OCT-based characterization has not proven to

explain additional variability in visual acuity over that explained by central subfield mean thickness, age, or fluorescein leakage in the inner subfields nor has it been predictive of visual acuity outcomes at 1 year after focal photocoagulation.136

When clinicians are asked to classify DME as focal or diffuse, evidence suggests that their assessments differ from classifications used by photographic

Fig. 7.17 Many eyes with diabetic macular edema have mixed characteristics with leakage from microaneurysms and dilated capillary segments, lipid exudates in some thickened areas and not others, and large areas of thickening, but not necessarily involving the center of the macula. An example is shown. (a) A lipid ring is present superotemporally but other regions of thickened macula are free of lipid. (b) A midphase frame of the fluorescein angiogram does not show more

microaneurysms in the area of the lipid ring than in other areas without lipid. (c) A frame from the late phase of the fluorescein angiogram shows an area of leaky microaneurysms inferotemporal to the center of the macula without associated lipid of note. (d) The OCT shows that the fovea is only mildly thickened, a characteristic often associated with focal edema, yet with a large area of thickened macula, a characteristic often associated with diffuse edema

reading centers. In comparing a British prospective survey of laser treatment for DME in which clinicians graded DME and a Diabetic Retinopathy Clinical Research (DRCR) network clinical trial involving two methods of laser treatment for DME in which a reading center graded DME, there was a 27% discrepancy between fractions categorized as focal by the two studies.137 Although this might reflect different samples, it could also suggest that the clinical and photographic methods capture different information about these eyes, and suggests that caution is required in implicitly comparing statements about focal DME defined in different ways.

Many authors have claimed that diffuse DME is refractory to macular photocoagulation and that diffuse DME is a prognostic factor for poorer visual acuity at follow-up, but the evidence for these

claims has not come from prospective clinical trials and is weak.115,138 In some cases, the literature has

been misquoted, most frequently by claiming that the ETDRS showed that diffuse DME showed a

poorer response to focal/grid laser than focal DME.121,139 In fact, the ETDRS looked at the

source of fluorescein leakage as a possible factor that might modify the beneficial effect of photocoagulation for DME on the development of moderate