5.1Introduction

Diabetic retinopathy (DR) is a chronic ocular complication of diabetes that is seen to some degree in virtually all diabetics. The rate of progression varies depending on the duration of the disease, glycemic control, hypertension, and genetics. Proliferative diabetic retinopathy (PDR) is diagnosed in the presence of retinal or disc neovascularization, a consequence of retinal ischemia. The Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) reported a 25-year cumulative progression prevalence of DR and PDR to be 83 and 42 %, respectively, in type I diabetics [1]. Overall, the rate of progression to PDR and severe vision loss has decreased in the last two decades, most likely due to improvement in diabetic care [1, 2].

Advanced PDR is not only characterized by retinal neovascularization and vitreous hemorrhage (VH) but also can include rubeosis iridis, neovascular glaucoma, and development of preretinal Þbrous membranes with tractional retinal detachment (TRD), macular dragging, and, sometimes, a combined traction-rhegmatogenous RD. Additional Þndings can include anterior hyaloidal Þbrovascular proliferation, which can lead to cyclitic membrane formation, RD, and hypotony. Such eyes frequently undergo pars plana vitrectomy (PPV). In some cases, antiangiogenic adjuvant pharmacologic therapy is used to treat diabetes-related VH and neovascularization.

The risk of developing advanced PDR correlates directly with markers of glycemic exposure (such as HbA1c, duration of diabetes), hypertension, cardiovascular disease events, and albuminuria and inversely with age at diabetes diagnosis and, surprisingly, smoking. The risk of developing advanced DR was found to increase by sevento ninefold, if the subject was on insulin treatment (with or without oral hypoglycemic agents) in RIACE Italian Multicenter Study [3]. Severe vision loss typically occurs in eyes with advanced PDR [4].

5.2Pathophysiology

Ocular ischemia, a result of diabetes-related microvascular injury and reduced perfusion, is the primary stimulus for retinal and iris neovascularization. Vascular endothelial growth factor (VEGF) plays an important role in the pathologic processes causing diabetic retinopathy, including macular edema and retinal neovascularization. Both VEGF-A and VEGF-B participate in angiogenesis, and their actions are mediated by three tyrosine kinase receptors: KDR (VEGFR-2), Flt-1(VEGFR-1), and Flt-4 (VEGFR-3) [5]. Hypoxia promotes the expression of VEGF-A mRNA. VEGF stimulates vascular permeability and endothelial proliferation, activates metalloproteinases that lyse the extracellular matrix, and potentiates space for growth of new vessels [5, 6].

Increased VEGF levels are present in the vitreous of eyes with PDR [6, 7]. The severity of PDR and the intravitreal concentration of VEGF are highly correlated [6]. There is considerable variation in VEGF expression among individuals, and several different gene polymorphisms occur. Polymorphism may explain individual differences in susceptibility to DR [8, 9].

In response to hypoxia, glial cells, which are the central nervous system counterpart of peripheral Þbrocytes, also undergo activation and proliferation (gliosis) with retinal neovascularization. Glial cell (e.g., astrocytes, microglia, and Muller-glial cells) proliferation leads to Þbrovascular membrane formation [10]. As these membranes contract, TRD develops. Transforming growth factor-β2 (TGF- β2), the predominant isoform in the vitreous, is overexpressed in the vitreous of PDR patients. Also, its expression correlates with the presence of intraocular Þbrosis [11]. The exact mechanism of transition from the angiogenic to the Þbrotic phase of PDR, termed the angio-Þbrotic switch, is unknown [12]. VEGF inhibition and regression of retinal neovascularization are associated with increased expression of connective tissue growth factor (CTGF) in the vitreous that leads to vitreoretinal Þbrosis. VEGF upregulates CTGF, and the VEGF-CTGF complex inhibits VEGFinduced angiogenesis. Kuiper et al. [12] hypothesize that a balance between VEGF and CTGF levels in vitreous regulates the switch from the angiogenic phase to Þbrotic phase in PDR. An acute decline in VEGF levels in an eye with neovascularization inhibits angiogenesis, causes an imbalance between VEGF/CTGF levels, and temporarily increases Þbrosis. CTGF is present in myoÞbroblasts and pericytes, which can transform into myoÞbroblasts. Activated human hyalocytes and MŸller cells can produce CTGF as well [12].

5.3Neovascular Glaucoma

Neovascular glaucoma (NVG) is a serious sequela of advanced PDR. Its incidence has decreased in the last 20 years with better management of diabetes and use of panretinal photocoagulation (PRP) laser treatment.

Diffusion of VEGF into the anterior segment is the main culprit for development of rubeosis iridis and neovascularization in the angle. Levels of VEGF are increased in the anterior chamber of eyes with rubeosis and NVG, and these levels are higher than in eyes with only PDR [13, 14]. Eyes in which the posterior capsule is compromised, either during cataract extraction or following YAG capsulotomy, are at a higher risk of anterior segment complications due to easier access of the angiogenic factors from the vitreous into the anterior chamber [15, 16]. Rubeosis may be detected on iris ßuorescein angiography (FA) much earlier than seen clinically with slit-lamp exam [17].

As diabetes-related rubeosis iridis worsens, neovascularization invariably extends into the angle and causes obstruction of trabecular meshwork and NVG. In early stages, Þne and tiny tufts of neovascularization may be seen at the pupillary border or at the edge of the peripheral iridotomy. These vessels grow radially towards the base of the iris. Neovascularization of the angle can occur irrespective of vessel growth at the pupillary margin or on the iris diaphragm; a gonioscopic examination of the angle, thus, should be performed in high-risk eyes. An extremely thin Þbrovascular membrane grows with neovascularization in the angle; IOP increases once signiÞcant portion of the trabecular meshwork is blocked by the membrane. This secondary open-angle neovascular glaucoma usually responds to