3.1Clinical Overview

3.1.1Clinical Findings

Diabetic macular edema (DME) is stereoscopically visible as a retinal thickening from accumulation of fluid and hard exudates at the posterior pole on dilated fundus examination. Macular edema arises from the breakdown of the blood-retinal barrier, secondary to the pathophysiological mechanisms of increased capillary permeability and vascular leakage (Fig. 3.1). It can develop in both NPDR and PDR, and it represents a sight-threatening complication.

Microaneurysms are the most common macular finding and are considered as the main source of leaking fluid and lipid transudation (Fig. 3.2). Hard exudates are a typical sign of DME: clinically, their presence suggests a current or a previous DME (Fig. 3.3). The leaking fluid is composed by water, proteins, and lipids and usually collects into the outer plexiform layer (OPL) of the retina [1]. Fluid and proteins could be reabsorbed by the adjacent retinal pigment epithelium and the blood vessels, while the lipids might remain collected into the OPL and could easily be detected as hard exudates by biomicroscopy.

Vitreomacular interface abnormalities like epiretinal membrane (ERM) or vitreomacular traction (VMT) could be detected on careful biomicroscopy and then confirmed by OCT examination [2] (Fig. 3.4). The ERM is considered both an idiopathic condition and a secondary disorder due to different ocular pathologies. On fundus biomicroscopy, the ERM is identified at early stages for its typical “cellophane” morphology, which is characteristically recognized on OCT as a thin hyperreflective band just above the retinal surface. In more advanced stages, a manifest vitreomaculopathy with macular edema, retinal striae, and vessel distortion is seen.

Postsurgical cystoid macular edema is a frequent visual loss condition that happens in diabetics that had recently performed ocular surgery. Frequently, complicated cataract extraction, including the lenticular sac rupture or the intraocular lens dislocation, is implicated in this vision-threatening complication. The angiographic characteristics are similar to the DME, except for the “petalloid” appearance of macular edema and the optic disk staining.

Fig. 3.1 (a) Color fundus photography demonstrates microaneurysms situated just under the fovea and few hard exudates above the inferior-temporal vascular arcade. (b) FA of the posterior pole (early frame) shows point hyperfluorescence inferiorly to the fovea from leaking microaneurysms. (c) FA (late frame) reveals sectorial cystoid macular edema

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Fig. 3.2 (a) FA (early frame) shows the presence of multiple leaking microaneurysms scattered above and under the fovea. (b) FA (late frame) reveals perifoveal hyperfluorescence from microaneurysms’ leakage. (c) OCT coupled with infrared image shows preserved retinal thickness. The microaneurysm is clearly visualized by the OCT image as a capsular round structure (white arrow)

Chronic macular edema leads to anatomical formation of partial or complete macular hole and retinoschisis secondary to intraretinal cyst rupture and retinal pigment epithelium failure [3] (Fig. 3.5).

Summary 3.1

Biomicroscopic findings in DME include retinal thickness associated with microaneurysms and hard exudates. Vitreomacular interface abnormalities including epiretinal membrane or vitreomacular traction could also be detected. Postsurgical cystoid macular edema is characterized by a visual deterioration that happens in diabetics that had recently performed ocular surgery.

3.1.2Biomicroscopic Classification of DME

The Early Treatment Diabetic Retinopathy Study (ETDRS) defined clinically significant macular edema (CSME) as a macular edema with one of the following characteristics [4]: retinal thickening within 500 microns (μm) of the fovea; hard exudates within 500 μm of the fovea, if associated with adjacent retinal thickening; and a zone of retinal thickening of one disk area or larger, within a distance of one

Fig. 3.3 (a) Color fundus photography shows retinal thickening, associated to hard exudates and clinically significant diabetic macular edema. (b) OCT coupled with infrared image shows large intraretinal cyst situated in the inner retinal layers, with adjacent intraretinal hyperreflective dots consistent with hard exudates (arrow)

Fig. 3.4 Tractional DME associated to well-evident epiretinal membrane and intraretinal cysts

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Fig. 3.5 (a, b) Color and red-free photographs showing macular hole, associated to epiretinal membrane and vitreoretinal traction in the temporal side of the macula. (c–e) Different scans centered to the fovea can display multiple pathological alterations in the same patient. Horizontal scan (c) reveals epiretinal membrane associated to large intraretinal cysts and vitreoretinal traction in the temporal area. Vertical line (d) shows rupture of an intraretinal cyst and tractions above and under the fovea. Diagonal scan (e) clearly demonstrates the presence of a large lamellar hole, not completely visible in the previous examinations

optic disk diameter of the fovea (Table 3.1) (Fig. 3.6). The ETDRS definition of CSME was primarily made on clinical examination rather than on fluorescein angiography or visual acuity characteristics. Besides, hard exudates are considered by the ETDRS as CSME, even if retinal thickness could be absent.

Table 3.1 Modified definition of clinical significant macular edema (CSME) from the ETDRS proposed in 1985

Clinical significant macular edema (CSME) is defined if any of the following clinical findings is present

Retinal thickening at or within 500 μm of the fovea

Hard exudates at or within 500 μm of the fovea, if associated with adjacent retinal thickening A zone of retinal thickening of ≥1 disk area, within 1 disk diameter of the fovea

Fig. 3.6 (a) Color fundus photography shows clinically significant macular edema, with retinal thickening, circinate lipid temporally to the macula, juxtafoveal hard exudates, and microaneurysms. (b) OCT discloses cystoid macular edema. (c, d) FA (early and late frames) shows the breakdown of the blood-retinal barrier consistent with diffuse diabetic edema

In 2001, the American Academy of Ophthalmology proposed a new simplified classification of DME, the DME Disease Severity Scale [5]. The presence of DME is defined by the presence of any type of retinal thickening or hard exudates at the posterior pole. The gravity of DME is classified according to the topographic location of the retinal thickening and hard exudates within the center of the macula. In particular, a mild DME is defined as a retinal thickening relatively distant from the center of the macula, while, in the severe form, the thickening location is involving the macula. In the moderate DME, the location is approaching the center of the macula, even if the precise distance has been deliberately not specified (Table 3.2).

Further classifications have been proposed analyzing the DME with the diagnostic tools: fluorescein angiography and OCT (see Sect. 3.2).

Recently, a new algorithm has been presented, analyzing the different patterns of presentation of DME and suggesting the best therapeutic option in each case [6]. According to this scheme, DME could be classified by biomicroscopy into three