Summary 3.3

Fluorescein angiography is a useful tool to identity the areas of increased vascular permeability and leakage and the areas of macular and peripheral ischemia. Optical coherence tomography is a noninvasive, accurate, and standardized technique for the anatomical assessment and quantitative measurement of DME.

3.3Present Therapies

3.3.1Laser Photocoagulation

The ETDRS was designed to assess the effectiveness of laser photocoagulation in DME and to give the management and procedural recommendations [4, 10, 42, 43]. The results showed a reduced risk of about 50 % of moderate visual loss (defined as a doubling of the visual angle from the beginning to the last visit) in the treated group compared to the controls. In addition, an increased chance of moderate visual gain (defined as a halving of initial visual angle) and a reduced retinal thickening were observed in the treated group (Fig. 3.14). The greatest improvement was reported in the eyes with center-involved DME, even if a significant benefit was also seen in DME without center involvement.

Nevertheless, severe side effects were registered, including visual field scotomas and enlargement of laser scars (Fig. 3.15). The results of the ETDRS, based on a halving of the risk of moderate visual loss and a low rate of complications, revealed that macular laser should be considered for CSME.

It is important to note that the baseline characteristics of the patients enrolled in the ETDRS did not include the BCVA evaluation. Patients with a BCVA of 20/20 or more were recruited and treated with macular laser photocoagulation (MLP) [4]. This fact has an influence on the reported limited visual acuity recovery. A subgroup analysis of the ETDRS revealed that patients with center-involved DME and a BCVA of 20/20 or better reduced the risk of moderate visual loss from 23 to 11 % at a 3-year follow-up. In patients without the involvement of the central macula, the risk of moderate visual loss was only 2.5 % in the treated group compared to 7 % of the untreated group [44]. Thus, macular laser photocoagulation is suggested in DME with center involvement.

Patients with reduced BCVA of less than 20/200 were not included in the study, and thus no clinical recommendations have been suggested. However, further investigations showed some benefits from laser treatment even in these cases.

The ETDRS confirmed the benefits of two treatment strategies of macular laser photocoagulation (MLP): focal or grid photocoagulation (Table 3.4). Angiographic examination has been widely used to classify the type of leakage, to choose the best

Fig. 3.15 (a) Large scars from grid laser photocoagulation. (b) Evolution of the retinal atrophy in a 3-year follow-up

Table 3.4 Laser treatments in DME

d

Fig. 3.16 (a) Red-free photography shows lipid circinate, microaneurysms, and hemorrhages located in the temporal side from the macula, consistent with focal macular edema. (b) FA (early frame) reveals hyperfluorescence from leaking microaneurysms and hypofluorescence from blocking defects due to hemorrhages. (c) FA (late frame) detects limited breakdown of the blood-retinal barrier consistent with focal DME. (d) OCT coupled with infrared image shows increased retinal thickness temporally to the fovea, corresponding to the area of leaking microaneurysms, associated to intraretinal cysts localized in the outer nuclear layer as well as hard exudates (arrow)

laser strategy, and to guide the treatment [45]. Thus, the ETDRS did not require the performance of FA before macular photocoagulation, and laser was performed based only on biomicroscopic examination.

Focal laser photocoagulation is effective to treat focal points of leakage (Fig. 3.16). A direct laser photocoagulation was designed to treat all leaky microaneurysms in an area of retinal thickness included between 500 and 300 μm. Laser parameters were defined with the following characteristics: argon-green wavelength 50 μm of spot size, exposure duration from 0.05 to 0.10 s, and an appropriate power as required to achieve a mild gray-white laser burn, without obtaining a definite whitening of the microaneurysms. A further treatment in the area included between 300 and 500 μm has also been proposed by the ETDRS in eyes with previous nonresponder laser treatment and with a lower BCVA than 20/40 [10].

Grid laser photocoagulation was described to treat a diffuse DME, applying a pattern of multiple burns in an area distant from 500 μm from the center of the macula and 500 from the optic disk (Fig. 3.17). Laser parameters were suggested as follows: a spot size included from 50 to 200 μm, a spacing of one burn width apart, and exposure time of 0.1 s or less. The power was progressively titrated to achieve barely visible gray burns.

However, the exact mechanism of action of grid laser treatment is not clearly understood. Several hypotheses have been proposed, including autoregulation of blood flow, improved retinal oxygenation, and metabolic stimulation of retinal pigment epithelium [46–48].

The ETDRS recommendations have been proved to be effective and have been used for a long time. However, the development of side effects, including the enlargement of the scar and the coalescence of multiple laser burns, encouraged the physicians to try alternative lighter treatment approaches, called modified ETDRS

Another alternative technique, called mild macular grid (MMG), was presented as a milder but potentially more extensive photocoagulation. It consisted in the application of mild laser burns, widely spaced throughout the macula, excluding the foveal region, with a reduced secondary thermal injury on the retina. Several papers compared the two techniques: mETDRS grid versus MMG. In 2007, the Diabetic Retinopathy Clinical Research Network showed that the BCVA recovery was not substantially different between the two groups, but a reduced CRT on the mETDRS group was seen. Thus, the authors concluded that the mETDRS approach should be considered as the recommended technique [49].

A “light” laser treatment has been investigated comparing to conventional or “classic” procedure with an Nd:YAG 532 nm green photocoagulator for clinically significant macular edema. This barely visible photocoagulation differed from conventional treatment in that the energy delivered was the lowest to generate barely visible spots on the RPE. The study revealed that “light” photocoagulation could be considered as effective as classic procedure [50] (Table 3.4).

“Subthreshold micropulse” laser is another less invasive strategy that has been developed recently. This technique is characterized by the delivery of ophthalmoscopically invisible laser burns, mainly obtained by reducing the exposure time [51]. The specific parameters of each type of laser photocoagulator are defined by the “duty cycle” (Table 3.4). There is evidence that the micropulse laser explicates its activity selectively on retinal pigment epithelium, delivering reduced heat conduction in the adjacent retinal layers. Recent works documented the presence of barely visible laser burns on fluorescein angiography, while they are not visible on OCT and fundus autofluorescence [33, 51]. A comparison between subthreshold micropulse laser and conventional photocoagulators has been performed and shown encouraging results, with regard to subthreshold micropulse, even if no definite conclusions can be drawn [16, 52, 53].

In 2006, a new semiautomated pattern scanning laser photocoagulator (PASCAL®; OptiMedica Corp, Santa Clara California) has been presented, which has the property of delivering, with a single foot press, several laser spots in a predetermined sequence and causes a reduced retinal damage [54]. In fact, PASCAL photocoagulator can apply “light” and “subthreshold” laser burns, reducing specifically the exposure time to 10–20 and 5–7 milliseconds (ms), respectively, and titrating progressively the power [55, 56] (Table 3.4). The result is a lower cumulative energy delivering and a minimally healing effect on the retina (Fig. 3.19). This property is confirmed by histological studies that reported not only a reduction in the enlargement of the laser burns but also a contraction of the scars over time [57]. In vivo observation of laser burns performed with SD-OCT revealed a preservation of the internal segment-outer segment (IS-OS) layer [58].

Navilas technology is a new eye-tracking photocoagulator with fundus camera integration, which has a high precision in the perifoveal area [59–61]. Starting from FA, an individualized laser grid program could be achieved reaching elevating rates of accuracy (Table 3.4). Earlier papers showed that Navilas is an effective strategy with a specifical activity on RPE.