Fig. 4.22 (a–d) Baseline characteristics of a patient with high-risk PDR. (a) Fundus photography shows extensive vascularized fibrosis and retinal traction. (b, c) FA of the posterior pole and periphery demonstrates intense hyper-fluorescence from leakage due to NVD and NVE, diffuse blood-retinal barrier breakdown, and retinal non-perfusion. (d) OCT scan shows dense vitreoretinal traction above the retinal surface and increased thickness of the retina with intraretinal cysts. (e–h) Final follow-up at 12 months of the same patient after PRP and vitrectomy. (e) Fundus color photography shows complete removal of neovascularization and vitreoretinal fibrosis. Panfundus (f) and conventional (g) FAs show absence of new vessels and slight breakdown of the blood-retinal barrier. (h) OCT scan demonstrates wide reduction of the macular edema with good preservation of the fovea and increased retinal thickness in the inter-papillomacular segment. (i) OCT scan showing increased retinal thickness with intraretinal cysts 4 months later despite IV ranibizumab. (j) Final follow-up at 1 year after three more IV ranibizumab reveals the persistence of cystoid macular edema but better foveal profile

4.4Evolving Algorithms

PRP is at present the only evidence-based recommended treatment for PDR, which enables a reduction of 50 % of severe visual loss in the high-risk group, as reported by the DRS. Currently, PRP should be considered as the first-line approach in the management of PDR.

The injection of VEGF inhibitor has shown some favorable effects in the regression of neovascularization, even if the benefits are limited and a high rate of recurrence has been shown in the short term.

Nevertheless, the combination therapy of PRP and anti-VEGF injections should be offered to the patient in some selected cases, to avoid the unwanted side effects of laser alone or to achieve better results. In fact, there is evidence that a development or ingravescence of DME may occur frequently after PRP. Thus, combining PRP and anti-VEGF injection could be considered as a valuable treatment option, in such cases of both PDR and DME, to improve the effects in the near term.

Vitrectomy and other more challenging treatment strategies should be considered in case of advanced PDR, even with the option of adjunctive anti-VEGF injections (Figs. 4.23, 4.24, and 4.25).

A therapeutic algorithm has been proposed in the management of PDR (Fig. 4.26). In case of vitreous hemorrhage, the visualization of the retina and the performance of a complete PRP are deemed difficult to achieve. Thus, an echographic examination should be promptly performed to assess the integrity of the retina. If a retinal detachment is present, surgery is the first-line treatment; while if retina is completely attached, an anti-VEGF injection is suggested to promote the vitreous clearing. In fact, the addition of an injection of VEGF inhibitor prior to PRP could enable a progressive resolution of the bleeding and allow the physician to perform the laser treat-

ment before than waiting the natural spontaneous clearing of the hemorrhage.

In case of high-risk PDR, an injection of anti-VEGF should be offered to the patient before the performance of a complete PRP, in order to strengthen the therapeutic effect of laser alone and accelerate the resolution of the new vessels activity.

In case of sectorial PDR, a sectorial peripheral laser photocoagulation is recommended.

Summary 4.5

PRP is at present the only evidence-based recommended treatment for PDR. The combination therapy of PRP and anti-VEGF injections should be considered in some selected cases, to avoid the unwanted side effects of laser alone or to achieve better results.

4.5New Frontiers

Several mediators with anti-angiogenic and anti-inflammatory properties are currently under evaluation as targeted therapeutic interventions against PDR development and progression. High levels of VEGF and other cytokine, including intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), interleukine-6 (IL-6), and tumor necrosis factor-α (TNFα), have been found in the vitreous of diabetics affected by PDR compared to healthy subjects [89–91].

VEGF is the major factor involved in the pathogenesis of PDR. Currently the efficacy of IVR, IVB, and IVP is under evaluation in the treatment of naïf or recalcitrant PDR or in more severe cases of vitreous hemorrhage, associated or not with

b

c

f

g

h

Fig. 4.23 (a, b) Baseline characteristics in a case of advanced PDR. (a) FA demonstrates hyperfluorescence from NVD and NVE and hypo-fluorescence due to defects of retinal perfusion. (b) OCT scan shows increased retinal thickness associated to subretinal fluid, cystoid edema, and epiretinal membrane. (c, d) Panfundus FA (c) and OCT (d) of the same patient after PRP and IV bevacizumab show persistence of new vessels and macular edema. (e, f) FA (e) and OCT (f) after vitrectomy reveal excision of neovascularization, persistence of macular edema, and regression of subfoveal fluid. (g) OCT of the same patient after three more IVB shows complete resolution of macular edema 6 months later. (h) Final OCT follow-up discloses mild recurrence of macular edema

PDR [92–95]. Other studies are evaluating which is the best timing strategy, such as prompt PRP or IVR plus deferral PRP [96].

Aflibercept (VEGF-trap) is a fusion protein, which is able to inhibit all isoforms of extracellular VEGF, and its efficacy in the treatment of DME has been shown. Currently some randomized studies evaluating intravitreal aflibercept as monotherapy or as an adjuvant procedure in the treatment of PDR are ongoing [97, 98]. In an ongoing trial, intravitreal aflibercept will be administered every 4 weeks for the first five initial injections and later, according to two different arms, respectively every 4 or 8 weeks for a 52-week interval. In the second study, subjects with PDR requiring pars plana vitrectomy are randomly assigned to preoperative aflibercept and pars plana vitrectomy with intraoperative aflibercept injection or to standard vitrectomy in a 24-week follow-up [97].

Fig. 4.24 (a, b) Baseline imaging of a patient with severe PDR associated to NVD, massive NVE, and preretinal hemorrhage, already treated with full PRP. (c, d) Final follow-up of the same patient after vitrectomy shows removal of the fibrosis, complete regression of neovascularization, and hemorrhages

ICAM-1 is a molecule involved in leukocyte adhesion to retinal vessels, inducing inflammation and immune activation [89]. Thus, the potential of ICAM-1 as a target of therapeutic intervention has been identified for the treatment of PDR and different molecules have been studied. The use of aspirin, meloxicam, or etanercept in an animal model of PDR resulted to be effective in reducing the levels of ICAM-1 [99]. In another paper, a small-interfering RNA (siRNA) that causes a selective downregulation of ICAM-1 applied in a murine model revealed to have some effects in RDP, inhibiting leukocyte adhesion and infiltration [100]. Fasudil, a selective ROCK inhibitor, showed some potential in reducing ICAM-1 expression in diabetic rats [101]. Other agents targeting periostin, a matricellular protein with activity in cell migration and adhesion, showed some benefits in the inhibition of the fibrovascular membranes present in PDR [102].

TNFα showed some proinflammatory and proangiogenic properties, such as cytokines activation, induction of adhesion molecules, and monocyte chemotaxis [103]. Thus, targeting the soluble TNF receptors has been postulated as a potential treatment approach [104].

Transforming growth factor-ß (TGF-ß2) is an anti-angiogenic factor and studies showed that its active fraction was reduced in the vitreous of patients with PDR [105]. Plasmin, a molecule that controls the levels of TGF-ß2, has been considered as a possible target to treat PDR.