disease [30]. A progressive decrease in macular and peripapillary CT was noted with increasing level of DR, reaching the lower levels in PDR [31].

4.2.5Perimetry

The Diabetic Retinopathy Study (DRS) evaluated the adverse effects after PRP with argon or xenon laser on visual field testing. Constricted visual field was reported in the 5 % of argon laser group [32]. Visual field sensitivity, using several threshold strategies, has been tested later for the evaluation of different laser photocoagulators, revealing some secondary effects to the laser procedure [33].

4.2.6Further Diagnostic Tools

To assess macular function, multifocal electroretinogram (mf-ERG) has been performed in the eyes with PDR before and after PRP, reporting a functional impairment following the treatment that was not predictable with BCVA and OCT measurement [34, 35].

Retinal sensitivity has been assessed in PDR using microperimetry, showing a reduction related to the extensive areas of capillary non-perfusion [36].

Other examination tools, including fundus autofluorescence and retinal vessel analyzer, with flicker procedure, have been assessed in PDR before and after PRP, revealing some changes related to the procedure [37, 38].

Summary 4.2

Fluorescein angiography is a widely used diagnostic tool for the diagnosis of PDR and its management after the treatment. Ultrasonography plays a key role in assessing the intraocular pathology when biomicroscopy is seriously limited by media opacity. Optical coherence tomography provides a better clinical understanding of PDR, especially in the study of the vitreoretinal abnormalities involving the macula.

4.3Present Therapies

4.3.1Panretinal Laser Photocoagulation

Panretinal photocoagulation (PRP) is considered the standard of care for the treatment of PDR. The aim of PRP is to prevent visual loss following vitreous hemorrhage, retinal detachment, and neovascular glaucoma, by leading to regression of neovascularization (Fig. 4.11). This evidence came from two large landmark randomized clinical trials: the Diabetic Retinopathy Study (DRS) and the Early Treatment Diabetic Retinopathy Study (ETDRS) [39–41].

c

Fig.4.11 (continued)

The DRS was a multicenter, randomized, collaborative clinical trial sponsored by the National Institutes of Health in 1971, evaluating the efficacy and safety of PRP in a 12-month follow-up. The study enrolled 1,742 patients with severe nonproliferative DR and PDR and best corrected visual acuity (BCVA) of 20/100 or more [42]. Patients were randomized in one eye to laser photocoagulation, direct or scatter, with either xenon arc or argon laser, and observation in the fellow eye. Direct photocoagulation consisted of placement of laser burns straight over the NVs, especially in case of NVE. In case of NVD, direct photocoagulation was performed only with the argon laser (Fig. 4.12). Scatter (panretinal) photocoagulation (PRP) consisted in the application of 1,200–1,600 laser burns in the retina, from the vascular arcades to the equator, excluding the macula and the optic disk, with moderate intensity and with a distribution of one-half burn width apart one from each other. Argon laser spots resulted less severe and smaller than xenon arc ones. The study showed a reduction of 50 % in severe visual loss (SVL), defined as a BCVA inferior than 5/200 at two or more consecutive visits, in the treated group [43]. In the group with high-risk PDR characteristics, more benefits from PRP were noted: a rate of SVL was reported in 26 and 11 % of both untreated and treated groups, respectively [32, 39, 40, 44]. In the non-high-risk PDR group, a reduced risk of SVL of 7 and 3 %, respectively, was reported in the control and treated arms. The greatest benefits were noted in the xenon group, even if this treatment was associated with a higher rate of visual field loss. Among the

Fig. 4.12 Regression of NVE. (a, b) Early (a) and late (b) frames of FA that demonstrate leakage from NVE located on a collateral of the superior temporal vascular arcade, requiring PRP. (c, d) Early (c) and late (d) frames of FA, showing persistence and slight increase of the leakage from the previous NVE and occurrence of more severe new vessels located on the inferior temporal vascular arcade, even after PRP. The angiograms reveal also the occurrence of macular ischemia and retinal non-perfusion located temporal to the macula. (e, f) Early (e) and late (f) frames of FA showing disappearance of the leakage, from inactive NVEs, after PRP and direct photocoagulation over the NVE. The angiograms demonstrate also persistence of macular ischemia and slight hyperfluorescence of the optic disk

subjects that underwent xenon laser procedure, 25 % of treated eyes revealed a severe visual field loss and a further 25 % a modest visual field loss; while in the argon group only the 5 % of the eyes reported a severe or modest visual field loss. Furthermore, a BCVA decrease of one line and a permanent reduction of two or more lines were recorded in the 19 and 11 % of the xenon-treated arm, possibly as

a secondary effect to laser procedure. Difficulties with driving at night and dark adaptation were described as side effects related to both xenon and argon laser. Regarding the treatment strategy, an increased risk of hemorrhage was related to the direct treatment, compared to the scatter one. Thus, the authors recommended mild to moderate scatter argon laser photocoagulation as a valuable treatment in the eyes with high-risk PDR. The authors did not provide clear suggestions between prompt and deferral photocoagulation.

Later, the ETDRS enrolled 3,711 patients with mild to severe NPDR or early PDR that were randomly assigned to prompt photocoagulation in one eye and deferral photocoagulation in the fellow eye [41, 45]. In the deferral group, in case of switch to high-risk characteristics, scatter laser photocoagulation was prompt performed. The study showed a small reduction in incidence of SVL in the early-treated eyes, compared to the deferral eyes, even if the rates of SVL were lower at the 5-year follow-up, respectively, of 2.6 and 3.7 % in both groups [46]. In the eyes with moderate-to-severe NPDR, the incidence of SVL was even lower. Thus, the study demonstrated that the benefits related to early photocoagulation were higher than side effects in the eyes with very severe NPDR or early PDR and thus PRP was recommended. In case of high-risk PDR, the results revealed that scatter PRP should be performed immediately and not delayed.

In a later analysis of the ETDRS, early PRP was suggested in severe NPDR or early PDR in case of older patients with type 2 diabetes mellitus [47].

The Preferred Practice Patterns, prescribed by the American Academy of Ophthalmology (AAO) in 2008, confirmed the role of PRP in high-risk PRP [48]. The recommendations, in case of non-high-risk PDR and severe or very severe NPDR, suggested performing PRP as approaching to the high-risk PDR, especially in type 2 patients. Besides, the AAO added that retinal specialists could evaluate the timing of PRP in some selected cases, such as patients with poor compliance, or undergoing cataract extraction, or who are pregnant, or with serious fellow-eye morbidity. In addition, even if NVE is isolated or NVI are not included in the DRS definition of high-risk PDR, the clinical practice suggested administering prompt PRP as soon as any type of PDR developed.

The exact mechanism of action of PRP in the regression of NV is not completely understood. The proposed theories suggested a role of PRP in the ablation of the ischemic retina, leading to a reduced secretion of vasoactive factors, such as VEGF [49, 50]. In addition a suppression of retinal pigment epithelium (RPE) cells and photoreceptors, consuming a discrete rate of oxygen, could reduce not only the production of VEGF but also improve the oxygenation of the retina and the release of neovascular inhibitors, which are usually found in the RPE [50–52].

The original parameters proposed by the DRS and ETDRS have been widely used in the everyday clinical practice for a long time [53]. According to the DRS, xenon arc photocoagulation is currently not recommended due to the increased risk of visual field defects, while argon laser is suggested as a valuable treatment. With regard to the wavelength’s choice, green, yellow, and red are the preferred types. The red wavelength has the advantage of penetrating deeper in case of media

c

Fig. 4.13 Regression of NVE in a patient with poor metabolic control. (a) FA with poor visualization of the posterior pole due to vitreous hemorrhage and a reduced visual acuity of only count fingers. The angiogram demonstrates preretinal hemorrhage and diffuse breakdown of the bloodretinal barrier. (b) Two months later, FA shows progressive clearing of the vitreous after PRP and improvement of the glucose control. (c) At the ninth month of follow-up, FA shows complete disappearance of the vitreous hemorrhage and macular edema, with few microaneurysms at the posterior pole. The glicometabolic control is widely and slowly improved and the visual acuity comes back to 20/20

opacities, like dense cataract or vitreous hemorrhage (Fig. 4.13). Nevertheless, it is more painful than the green one and could lead to choroidal hemorrhage. Blue light demonstrated a more toxic action to the RPE and thus is currently not considered, especially in macular laser treatment.

With regard to the proposed recommendations, laser burns of 500 μm should be applied, with a distance of up to one width apart and a power titrating to achieve moderately intense gray-white spots. The extension of a complete PRP should cover the entire retina, from the vascular arcades to beyond the equator and two disk diameters temporally to the macula (Fig. 4.14). Scatter laser photocoagulation was judged from the DRS to be effective alone in the treatment of PDR, while direct photocoagulation increased the risk of hemorrhage from the treated NV. Nevertheless, in some selected cases, such as flat and small NVE, local photocoagulation of NVs could be carefully evaluated (Fig. 4.15).

After a complete PRP, according to the ETDRS recommendations, next followup should be scheduled between 2 and 4 months, and additional treatment could be offered to the patients in case of persistent activity of NVs (Fig. 4.16). Retreatment

Fig. 4.14 Panretinal FA demonstrates few areas of hyper-fluorescence from leakage due to NVEs, associated to severe peripheral non-perfusion, preretinal hemorrhage, and inadequate laser photocoagulation. Larger laser burns should be extended throughout the four quadrants, including the far periphery to achieve the regression of the NVEs

could consist in placing additional laser burns above or between preexistent laser pots or directly on small, flat NVE [53]. It is important to note that limited residual vitreous or preretinal hemorrhages may occur also if adequate PRP has been performed and no additional laser is deemed necessary. In case of repeated and extensive vitreous hemorrhages or in case of tractional retinal detachment, vitrectomy should be considered.

The ETDRS and later studies reported an increased rate of side effects secondary to extensive sessions of laser photocoagulation, including macular edema development or progression, exudative retinal and choroidal detachment, and angle-closure glaucoma [53–55]. In particular, in case of PDR with associated DME, PRP might exacerbate the retinal thickness. Nevertheless, all these complications, including DME onset or aggravation, generally underwent to spontaneous improvement. In order to avoid these complications, in the ETDRS recommendations, the performance of a complete PRP was divided in two or more sessions, separated at least by a 2-week interval.

In a later investigation, the Diabetic Retinopathy Study Research Group evaluated the effectiveness and safety of single-session PRP compared to conventional four sessions. The study showed nonstatistically significant differences between the two modalities [54]. However, many authors suggested performing macular laser photocoagulation or intravitreal injections of anti-vascular endothelium

factor (VEGF) or steroids before or at the same time of PRP to decrease the risk of aggravating the preexistent DME and to improve the visual recovery in the short term [54, 56].

Regarding the further side effects, the DRS and ETDRS showed an increased incidence of visual field defects, color vision and dark adaptation reduction, and, in some cases, visual acuity decrease following PRP. Other complications include corneal abrasion or laser burns direct on lens or iris or iritis. In addition, a pain of variable level is reported from the patients according to the intensity of the laser power and duration and according to the topographical area, such as the site of ciliary nerves in the suprachoroidal space. Retrobulbar, sub-Tenon’s, or subconjunctival anesthesia may replace topical administration in some selected cases.

Pattern scanning laser (PASCAL, Topcon Medical Laser Systems, Santa Clara, California USA) is a new 532 nm laser photocoagulator, which enables the delivery of multiple laser burns in a predetermined configuration with a single-foot depression [57] (Fig. 4.17). This new system has the ability of delivering laser burns with a shorter exposure time (about 10–20 ms) compared to conventional photocoagulators, which resulted in a faster and less painful treatment. With PASCAL technology, reducing the exposure time, a decreased thermal injury is delivered to the retina and choroid. There is evidence that the laser burns may affect only the retinal pigment epithelium and the photoreceptors, excluding any damage to the inner retina and choroid [58]. Nevertheless, reducing the pulse duration, physicians should titrate the power to higher values to achieve the desired therapeutic effects [59]. A paper, comparing PASCAL laser to conventional argon laser, showed that both groups had favorable outcomes, in terms of NVs’ regression, but the treatment with PASCAL was associated with lesser collateral damage [33]. Evaluating the laser parameters, in the PASCAL group, significant higher power was required to achieve the same grade burns, even if the average fluence was higher in the conventional laser group. Time for sitting was statistically significant shorter in the PASCAL arm and a greater number of laser burns were performed in the same group. Pain perception during the treatment, evaluated through the visual analog scale (VAS), showed a statistically significant reduction in discomfort in the group treated with PASCAL. The authors found out also that PASCAL burns were smaller and more uniform and that laser spots were hard in coalescing than conventional argon laser. In conclusion the study revealed that, even if the power achieved is higher than conventional systems, PASCAL photocoagulator was safe, effective, and rapid and was also associated with a less discomfort.

Differently, a recent study comparing PASCAL to standard argon laser in performing a complete PRP, using conventional laser parameters, revealed a higher rate of persistence or recurrence of NVs 6 months after treatment in the PASCAL group [60]. This fact was explicated by the authors by the fact that Pascal laser scars do not enlarge over time, comparing to standard argon laser, providing less damage to the peripheral retina and in some cases a reduced activity in ablating ischemic retina. Thus, the study concluded that PASCAL photocoagulator in the setting of traditional laser parameters seemed to be less effective in the treatment of high-risk PDR and that higher power is needed to ensure the same benefits.

a

b

Fig. 4.17 (a) FA demonstrates a complete PRP performed with PASCAL photocoagulator in one session. Laser burns, delivered in a predetermined configuration, are equally spaced and have similar size. The angiogram of the posterior pole reveals also macular non-perfusion. (b) OCT vertical scan shows the presence of scarring tissue under the fovea and disorganization of the outer retinal layers, associated with poor visual prognosis

With the technology of PASCAL, single-setting PRP could be offered to the patients, even if some concerns about the safety have been raised up. However, in recent trials evaluating the safety and effectiveness of single-setting PRP did not show an increase rate of side effects compared with conventional four-setting PRP [61, 62]. Besides, the patients’ compliance was higher in the single-setting PRP group and in the future this procedure might cut down the health-care costs.

Navigated laser (Navilas®, OD-OS GmbH, Teltow, Germany) is a novel device characterized by the simultaneous presence of fundus imaging (including infrared, color photograph, fluorescein angiography) and pattern laser photocoagulator [63]. The main advantage is represented by the high precision in retina navigation and great reproducibility of the laser procedure. The touch-screen monitor