3.2Diagnostic Tools

b

f

Fig. 3.7 (a) Red-free photograph of the posterior pole showing multiple hard exudates in a limited area situated superiorly and temporally to the macula, microaneurysms, and hemorrhages spread along the posterior pole. (b, c) FA early (b) and late (c) frames revealing breakdown of the blood-retinal barrier consistent with diffuse macular edema. (d) Panretinal FA demonstrates increased fluorescein leakage from cystoid macular edema, limited areas of retinal non-perfusion, and pronounced hyperfluorescence from neovascularization elsewhere (NVE) in the nasal quadrant. (e, f) SD-OCT, horizontal (e) and vertical (f) scans displaying increased retinal thickness, associated to small subretinal detachment and intraretinal cysts

breakdown of the blood-retinal barrier (BRB), which causes fluid accumulation in the intraretinal layers of the macula [7]. The tight junctional complex between the endothelial vascular cells and glial cells primarily forms the inner BRB [8], while the tight junctions between retinal pigment epithelium (RPE) cells, including the desmosomes and the zonula occludens, compose the outer BRB [9]. When the rate of leaking fluid exceeds the ability of the BRB in clearing such fluid, retinal edema develops.

According with the angiographic examination, DME has been classified into two patterns: focal and diffuse. In focal DME, a well-defined, localized area of leakage, originated by microaneurysms, surrounded by adjacent hard exudates, could be noticed [10, 11] (Fig. 3.8). In diffuse DME, an extensive, non-defined retinal leakage is present, originated by a generalized breakdown of the inner BRB, without any discrete leaking microaneurysms [11] (Fig. 3.9). The angiographic analysis of the type of leakage plays a useful role in the decision of the laser treatment option (focal or grid photocoagulation) and in the final prognosis.

It was assumed that the pathogenesis of DME was firmly of retinal vascular origin. However, a different etiology has been proposed in 1975, suggesting a possible

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e

Fig. 3.8 Baseline imaging of a patient with mild NPDR. Color fundus photography (a) of the posterior pole showing hard exudates (arrow) temporally to the fovea and few microaneurysms. FA early (b) and late (c) frames revealing the presence of leaking microaneurysms associated to a focal fluorescein leakage located in the temporal side of the fovea, referring to focal macular edema. OCT (d) shows a limited increase of retinal thickness, more evident in the inferior-temporal area, associated to intraretinal fluid and hard exudates (arrow). (e) OCT scan of the same patient 1 year later, showing worsening of the macular edema, associated to the occurrence of a larger central intraretinal cyst, increasing of the intraretinal fluid located in the outer and inner nuclear layers and persistence of hard exudates

role of retinal pigment epithelium (RPE) [12]. The term non-retinovascular leakage was proposed to define an unusual form of DME, in which RPE and subretinal space play a key role. The authors suggested a form of diffuse, late-phase leakage, originated by RPE, without any cystoid spaces clearly visible on FA, associated with a breakdown of the outer blood-retinal barrier.

For a long time, traditional FA could only visualize 30° of the retina at one time. Now, with the innovative advances in the retinal imaging, new ultra-widefield fluorescein angiographs have been developed, allowing a more detailed analysis of the peripheral retina, reaching in some cases up to 200° of visualization with a single photogram [13].

FA has a unique role in the recognition of the ischemic changes, in both the macular area and periphery. Ischemic maculopathy could be noticed with FA as macular capillary non-perfusion and increase of the foveal avascular zone in the early angiograms, followed by a later leakage (Fig. 3.10). Currently, new insights in the pathophysiology of DME have highlighted a possible contributing role of the peripheral non-perfusion in the development of DME [13].

OCT clearly identifies the different pathological features in DME, like neurosensory retinal detachment, cystoid macular edema, and vitreomacular abnormalities. Furthermore, with OCT the role of vitreoretinal interface abnormalities, such as thickened and taut premacular posterior hyaloid, in the pathogenesis of diabetic retinopathy has been recognized. Spectral-domain OCT (SD-OCT) is a new technology that allowed a precise anatomical evaluation of the different layers of the retina and, if coupled with FA, gives morphological correlations between the two imaging techniques [14]. Several studies evaluated the correlation between morphology and functional changes in DME. In a recent work, assessing the angiographic and tomographic patterns of DME, the following correlations have been found: in focal DME, as seen by FA, the most frequent OCT feature is represented by outer plexiform layer (OPL) swelling, while in diffuse DME a swelling is noticed primarily in the inner nuclear layer and secondarily in the OPL [15]. In another work, the two main morphological changes seen in DME are the intraretinal cysts, situated in the outer nuclear layer (ONL), and the serous retinal detachment (SRD) [16]. OCT enables the clear identification of vitreoretinal abnormalities, such as vitreomacular tractions or thickened and taut posterior hyaloid, which are currently implicated in the pathogenesis of DME (Fig. 3.11). Besides, the new current tomographic findings recently reported are the hyperreflective foci, which have been detected within the neurosensory retina in DME in the foveal and parafoveal areas, and their presence has been correlated with photoreceptors’ integrity and visual acuity [17, 18].

Central retinal thickness (CRT) measurement is an important parameter for the quantitative measurement of DME, and it is widely used in the clinical trials for the follow-up and response to the treatment, due to its good repeatability [19]. Unfortunately, the different instruments provided a noncomparable data of the CRT measurement. With previous time-domain OCT, a normal value of CRT has been reported as a mean of 182 ± 23 μm [20], while a new concept of subclinical DME has been recently defined as an increased retinal thickness, in the absence of foveal center edema and CRT fewer than 300 μm [21]. Recently, macular micropseudocysts have been defined as small hyporeflective areas in the retinal layers in the absence of clinically significant macular edema or manifest retinal thickness on OCT [22]. The authors suggested that these early retinal abnormalities might precede DME and predict its formation.

Even if an increase in CRT is often associated with a reduction in visual acuity, other tomographic findings, in the absence of CRT augmentation, are responsible for a significant visual loss. As reported recently, a disruption of the outer retina integrity, including internal segment-outer segment (IS-OS) junction and external limiting membrane (ELM), is associated with lower visual acuity outcomes and is clearly visible with the SD-OCT imaging [23]. With regard to the macular ischemia, a reduced CRT value, associated to photoreceptors’ abnormalities, has also been identified [24] (Fig. 3.12).

Enhanced depth imaging (EDI) OCT is a new imaging modality to analyze the choroid and evaluate the choroidal thickness (CT) measurement. A choroidal thinning has been found in diabetics at different stages of diabetic retinopathy compared to nondiabetics, even in case of DME. Overall, different papers showed that a

e

Fig. 3.11 Tractional macular edema. (a) Color photography shows only few microaneurysms and retinal hemorrhages. (b) Red-free image reveals the presence of an epiretinal membrane. (c, d) FA early (c) and late (d) frames with increasing diffuse fluorescein leakage. (e) OCT clearly demonstrates the presence of an epiretinal membrane associated to increased retinal thickness and few intraretinal cysts

decreased CT was present in all groups of diabetic retinopathy, with or without diabetic maculopathy, without any differences between diabetic groups [25–27]. However, the exact role of choroid in the etiology of DME is still unknown (Fig. 3.13).

En face SD-OCT is another innovative method to analyze the retinal morphology and has evaluated the outer retina findings in DME [28].

Peripapillary retinal nerve fiber layer (RNFL) and ganglionar cell complex

(GCC), introduced for the management of the glaucoma, have been widely tested in many retinal pathologies. In DME, no significant changes in the RNFL have been identified [29], while GCC is currently under investigation.