provides imaging of high contrast and sharpness, allowing the physician to plan the treatment on the screen and then apply the selected array. For PRP, a specific widefield lens is suggested, resulting in an 85-° view, even if in selected cases (such as blepharospasm or corneal irritations) treatment could be performed without contact lens. Further data regarding the treatment of PDR with the navigated laser are needed.

Summary 4.3

Panretinal photocoagulation (PRP) is currently considered the standard of care for the treatment of PDR, and this evidence came from two large landmark randomized clinical trial: the Diabetic Retinopathy Study (DRS) and the Early Treatment Diabetic Retinopathy Study. In the DRS, a reduction of 50 % of severe vision loss was reported in the high-risk PDR after PRP. Nevertheless an increased rate of side effects has been reported secondary to extensive sessions of laser photocoagulation, including macular edema development or progression, exudative retinal and choroidal detachment, and angle-closure glaucoma. At present, more recent laser photocoagulators have been introduced, providing a more accurate, faster, and less painful laser treatment, with a reduced number of side effects and sessions.

4.3.2Intravitreal Injections

Although PRP is considered the gold standard in the management of PDR, additional treatment with intravitreal injections of steroids and anti-VEGF agents have been suggested recently. This adjuvant therapy has been investigated both to prevent macular edema development or progression after PRP and to enhance laser photocoagulation in the regression of neovascularization.

4.3.2.1 Intravitreal Steroids

Intravitreal steroids have been hypothesized to provide some benefits in addition to conventional PRP in terms of BCVA improvement and CRT reduction [56, 64] (Fig. 4.18).

There is evidence that intravitreal steroids could inhibit the metabolic pathway of VEGF and have a valuable effect in the treatment of anti-inflammatory, proliferative, and neovascular diseases [65, 66]. In fact, triamcinolone acetonide showed some benefits on retinal blood flow changes and inflammation induced by retinal photocoagulation [67]. In an animal model, intravitreal steroids reduced the bloodretinal breakdown secondary to laser treatment [68].

Since exacerbation of DME has been described as a secondary effect of PRP for PDR, intravitreal triamcinolone acetonide (IVTA) combined with PRP in the treatment of PRP and macular laser photocoagulation (MPC) has been investigated. In a preliminary prospective, randomized, clinical trial, 23 subjects affected by high-risk PDR and DME underwent IVTA, 1 week before PRP and MPC in one eye and PRP

Fig. 4.18 (a, b) Baseline imaging of a female with poor visual acuity (20/200). (a) Proliferative diabetic retinopathy with NVE in the superior, nasal, and inferior sectors, associated to severe retinal nonperfusion on the full periphery and at the posterior pole. (b) OCT scan at baseline shows cystoid macular edema. (c, d) Imaging of the same patients 3 months after intravitreal injection of slow-release steroid implant and PRP. (c) Single-frame FA of the posterior pole shows an improvement of the dramatic macular ischemia. (d) OCT scan reveals regression of DME. Nevertheless the visual acuity gain was unsatisfactory

and MPC alone in the fellow eye for a 6-month interval [69]. The study did not show a significant beneficial effect of additional IVTA compared to the standard management. In a later, larger work, 345 eyes receiving both PRP and MPC were randomized to placebo or intravitreal ranibizumab (IVR) at baseline and at 4 weeks or IVTA at baseline followed by sham at 4 weeks on a 14-week follow-up [70]. The study showed more favorable results in terms of BCVA and CRT in the two adjunctive injections arms, even if a longer follow-up is needed.

4.3.2.2 Intravitreal Anti-VEGF Agents

There is evidence that VEGF is implicated in the pathogenesis of PDR and that its inhibition could prevent the neovascularization related to ischemic retina [71, 72]. Several works showed that anti-VEGF injections alone might have some favorable effects in the regression of NVs [73, 74]. Nevertheless, their action revealed to be transient and NVs recurrence appeared after a 12-week interval [75]. Since the efficacy of anti-VEGF injections in the treatment of PDR and their short duration have been clearly documented, new approaches evaluating the combination of PRP and anti-VEGF molecules are currently under investigation to increase and extend each therapeutic action.

Intravitreal ranibizumab (IVR) adjunct to PRP, as previously reported by the DRCR.net, revealed to be more effective than laser alone in a short follow-up of 14 weeks [70] (Fig. 4.19). These results were confirmed by another small,

prospective, study evaluating patients affected by high-risk PDR and randomly assigned to PRP alone or in association with one single IVR in a follow-up of 48 weeks [76]. The study showed a greater reduction in fluorescein leakage in the combination group and that IVR seemed to be protective against the visual acuity decline and macular edema aggravation secondary to laser procedure (Fig. 4.20). In a later paper of the same research group, patients treated with PRP alone were compared to patients treated with adjunctive IVR by assessing electroretinographic examination in a 48-week interval [35]. The results showed that in the association group, a less extensive PRP is needed, leading to a reduction in retinal function loss and to a greater preservation of photoreceptors activity compared to the standard laser alone.

Intravitreal bevacizumab (IVB) has been widely used in the treatment of PDR, especially in association with PRP [77–85] (Figs. 4.21 and 4.22). A significant reduction in the vitreous level of VEGF has been clearly documented 1 day after IVB and sustained through day seven [77]. Nevertheless, a meaningful increase of intraocular inflammatory cytokines, in particular of interleukin-6, has been reported immediately after IVB and later reduced at the seventh day, suggesting some inflammatory changes after IVB.

In a prospective, sham-controlled clinical trial, 80 eyes with high-risk PDR have been treated with additional IVB to PRP compared to PRP alone [81]. In the short 6-week interval, a complete regression of NVs was recorded in 87 % of the group treated with IVB compared to the 25 % of control group. However, at a 16-week follow-up, a recurrence was noted and the IVB group reached the same regression rate of control group (25 %).

The role of IVB has been assessed in the treatment of persistent actively leaking NVs refractory to PRP [75, 82]. At the 1-year follow-up, the fluorescein leakage from NVs was significantly improved and BCVA increased, after a mean of two injections.

The efficacy of IVB has been assessed also in PDR complicated by vitreous hemorrhage, revealing that IVB may induce a faster regression of vitreous hemorrhage and thus reduce the need of surgical intervention [83]. A later work confirmed the beneficial effects of the combination therapy in the short term for the management of high-risk PDR and vitreous hemorrhage [84]. Nevertheless, long-term results are still lacking.

However, an increased risk of fibrotic complications has been reported after IVB and in more advanced cases a progression of tractional retinal detachment following IVB [79, 80], even if it is still unclear if the angiofibrotic switch and the development of a tractional retinal detachment are due to the natural history or if it is related to the rapid decrease of VEGF secondary to IVB. In a recent report, the action of IVB in fibrovascular membranes has been confirmed, revealing that IVB may interfere with the vascular microenvironment, leading to vascular contraction and increasing of the rate of pericyte [85].

A direct effect of intravitreal pegaptanib sodium (IVP) upon PDR has been demonstrated. In a retrospective analysis [86] of the Macugen Diabetic Retinopathy Study [87], the effectiveness of IVP on retinal neovascularization has been assessed.

Fig. 4.19 Young female patient that has been followed for 4 years, showing a progression from NPDR to PDR, successfully treated with PRP and IV ranibizumab. (a) At baseline, moderate NPDR, with mild area of ischemia in the temporal quadrant. (b) Baseline infrared image of the posterior pole, showing the horizontal OCT scan, and (c) OCT shows well-preserved retinal anatomy, with the integrity of the photoreceptors’ complex and in the absence of macular edema. (d) Nine months later, FA shows a breakdown of the blood-retinal barrier at the posterior pole, an increase of the hemorrhages, and the persistence of the ischemia associated to mild vascular ectasia and IRMA. The patient has not been treated but he has been carefully followed for the risk of progression of the retinopathy to proliferative stage. (e) At 12-month follow-up, FA demonstrates the occurrence of NVE on the superior temporal vascular arcade and the presence of retinal non-perfusion on the periphery. The FA shows in addition the persistence of the breakdown of the blood-retinal barrier. (f) At the 18-month follow-up, after PRP, FA shows increase hyper-fluorescence from NVE, associated to a mild hyperfluorescence of the optic disk and persistence of the breakdown of the blood-retinal barrier at posterior pole. (g) The patient underwent further laser and one injection of ranibizumab. Three months later, the NVEs were inactive and an improvement of the breakdown of the blood-retinal barrier is detectable. (h) Infrared image of the posterior pole of final follow-up showing the horizontal scan. (i) OCT scan shows preserved retinal thickness, with the integrity of the photoreceptors’ complex and in the presence of few intraretinal cysts in the inner nuclear layer

The results showed a regression of NVs at week 36 on most of the eyes treated with IVP.

In a smaller, randomized, controlled exploratory study, the efficacy of IVP has been compared to PRP in the treatment of active PDR [88]. The results showed a complete regression of NVs in all the subjects treated with only IVP at the 12th week, and such results have been maintained through week 36, while in the PRP group only two eyes showed complete regression at the final end point.

In case of recurrent and non-clearing vitreous hemorrhage [89], the treatment with IVP achieved a faster resolution of the bleeding, allowing the performance of PRP and reducing the need of vitrectomy in approximately one-third of the cases.

Summary 4.4

Although PRP is considered the gold standard in the management of PDR, additional treatment with intravitreal injections of steroids and anti-VEGF agents has been suggested recently. Intravitreal triamcinolone acetonide provided some benefits in addition to conventional PRP in terms of visual improvement and macular edema reduction, due to its anti-inflammatory and anti-angiogenic properties. Injections of anti-VEGF agents (ranibizumab, bevacizumab, pegaptanib) showed some favorable effects in the regression of new vessels, even if the benefits are limited in the short term. The combination of PRP and anti-VEGF molecules is currently a therapeutic option in some cases, to strengthen the action of laser photocoagulation and reduce the side effects.

c

h i

Fig. 4.20 (a) FA of the posterior pole showing multiple hemorrhages “dot and blot” situated at the macula as well as hemorrhages located radially to the optic disk and several microaneurysms in the perifoveal region, suggesting a diffuse edema. (b) OCT scan demonstrates cystoid macular edema, with a central large intraretinal cyst, multiple small intraretinal cysts located in the inner and outer nuclear layers and subretinal fluid. (c) The patient has been treated with 3 intravitreal injections of ranibizumab and grid laser. The FA with periphery shows the occurrence of NVE on the nasal quadrant and persistence of the breakdown of the blood-retinal barrier even with the presence of grid laser treatment. The patients underwent a full PRP, grid laser treatment, and a further IVR. OCT scan (d) shows complete regression of DME, with disappearance of the intraretinal cysts and subretinal fluid and preservation of the photoreceptors’ complex. FA at final follow-up (e) showing complete regression of NVE and absence of DME

Fig. 4.21 (a–d) Baseline imaging of the right eye of a young female patient with poor metabolic control and visual acuity of 20/200. (a) Color fundus photography shows severe ischemic diabetic maculopathy, with multiple hemorrhages and hard exudates. (b) FA (early frames) of the posterior pole demonstrates a number of microaneurysms and macular ischemia. (c) Panretinal FA showing retinal non-perfusion in the periphery, breakdown of the blood-retinal barrier, and mild hyper-fluorescence of the optic disk. (d) OCT scan showing DME, with large central cysts, massive subretinal fluid, and hard exudates. (e–h) Follow-up at 3 months after sectorial laser photocoagulation, one IV bevacizumab and improvement of the metabolic control. (e) The color fundus photography shows persistence of the hemorrhages, hard exudates, and retinal whitening due to ischemia. FA (early frames) of the posterior pole (f) and panretinal FA (g) demonstrate the occurrence of NVD and NVE on the superior quadrant as well as reduction of the breakdown of the blood-retinal barrier. (h) OCT scan reveals wide reduction of the DME, with disappearance of the intraretinal cysts and less subretinal fluid. (i–k) 6-month follow-up, after full PRP. (i) FA shows a reduction of the hemorrhages at the posterior pole. (j) OCT discloses recurrence of DME, with large subretinal fluid, several intraretinal cysts, and hard exudates. (k) Panretinal FA reveals full PRP, complete regression of NVE, and persistence of the breakdown of the blood-retinal barrier, associated to macular ischemia. (l–n) Follow-up at 12 months after three more IV bevacizumab, resolution of macular edema, but unsatisfactory best corrected visual acuity recovery due to severe atrophic changes on OCT and macular ischemia. (l) The color fundus photography at the end of follow-up shows complete regression of hard exudates and hemorrhages and atrophic changes at the macula. (m) OCT shows thinning of the retina, with disorganization of the outer retina layers and few intraretinal cysts. (n) Panretinal FA reveals complete regression of the neovascularization and non-perfusion of the macula