Treatment of Proliferative Diabetic Retinopathy

9.1 Introduction

Proliferative diabetic retinopathy (PDR) is an advanced stage of diabetic microangiopathy in which extensive retinal capillary occlusion results in the growth of preretinal fibrovascular tissue. The pathogenesis is not well understood. Underlying pathophysiologic changes in diabetic retinopathy include abnormal shunting of glucose via the aldose reductase pathway, formation of advanced glycation end-products, activation of protein kinase-C beta isoform, induction of vascular endothelial growth factor (VEGF), oxidative damage, and inflammation.1–5 Pathological

anatomic changes evolve with abnormal thickening of capillary basement membrane, loss of pericytes, breakdown of the blood–retinal barrier, changes in microvascular caliber, microaneurysm formation, endothelial cell loss associated with capillary occlusion, and neovascularization within the retina (intraretinal microvascular abnormalities) and in the preretinal space with varying degrees of preretinal fibrosis. PDR may cause loss of vision from edema, ischemia, intraocular hemorrhage, premacular membranes, vitreomacular traction, traction retinal detachment, traction– rhegmatogenous retinal detachment, and neovascular glaucoma.6

S.E. Pautler (*)

Department of Ophthalmology, University Community Hospital, University of South Florida, Tampa,

FL 33607, USA

e-mail: pautlers@aol.com

Neovascularization (NV) is a distinctive ocular manifestation of diabetes mellitus and develops as a

result of retinal ischemia/hypoxia in diabetic retino- pathy.13–15 NV grows from the surface of the retina

at the posterior border of retinal capillary nonperfusion, from the surface of the disk, and from

anterior sites (iris, ciliary body, and anterior retina) in eyes with increasing degrees of ischemia.13,16,17

Retinal neovascularization generally arises from retinal veins or postcapillary venules near sites of arteriovenous crossing or venous branching.18,19 The distribution of retinal NV follows a C-shaped

extramacular distribution, sparing the temporal raphe.13,18,19 Neovascularization of the disk

(NVD) is associated with extensive retinal nonperfusion.13,17 Presumably, NVD occurs as VEGF and other growth factors migrate from peripheral ischemic retina to the disk by way of vitreopapillary drainage.13,15 The neovascular tissue grows within the outer cortical vitreous and may induce overlying secondary vitreous degeneration.20–23 With time the vascular nature of the NV is associated with fibrous tissue proliferation, likely mediated by agents other than VEGF, such as connective tissue growth fac- tor.24–26 Initial contraction of the fibrous tissue may lead to retinal striae and retinal dragging.27–30

Further vitreous traction may lead to retinal detachment with or without retinal breaks.31,32 Release of

angiogenic growth factors from hypoxic retina continues until neurosensory cell death occurs (in the very late stages of natural history or following

photocoagulation) after which neovascular involution occurs.13,33 The fibrous tissue remains and vitreous traction may continue to progress.18,21,34 The

clinical presentation of proliferative diabetic retinopathy includes a wide spectrum of disease due to variability in the relative developmental stages of vascular and fibrous proliferation.

An important factor affecting the presentation of PDR is the status of the vitreous. The vitreous undergoes a number of pathological changes in diabetes, including an increase in the number of collagen crosslinks and an increase in glycation end-pro- ducts.35 These changes contribute to premature degeneration and liquefaction of the vitreous in diabetes.36 In the absence of a posterior vitreous detachment, the cortical vitreous provides a scaffold on which preretinal neovascularization proliferates.22

With continued neovascular growth, extensive areas of fibrovascular proliferation create firm attachment between the retina and the vitreous cortex.18 This is a common presentation in type 1 and early-onset type 2 diabetes mellitus as PDR develops in the environment of an intact vitreous body. The presentation of PDR in an older individual differs in large part due to the degree of vitreous degeneration and posterior separation.37,38 If incomplete PVD is present, NV may grow anteriorly from the site of attachment (e.g., the disk) within the elevated posterior vitreous cortex, but it does not create further extension of fibrovascular plaques on the surface of the retina. In the presence of complete PVD, clinically important neovascularization does not usually develop.37,39 However, anterior ocular neovascularization may become manifest (e.g., NV involving the anterior retina, ciliary body, and iris).40

Iris neovascularization (rubeosis) may occur in advanced stages of diabetic retinopathy and threatens pain and blindness from neovascular glaucoma.41,42 Rubeosis frequently begins at the superior pupillary border of the iris and trabeculum due to convection currents in the anterior chamber, which in a head-up posture results in

an upward flow of aqueous over the surface of the iris.43,44 Rubeosis progresses more slowly in

phakic than aphakic eyes, likely due to the effect of the crystalline lens as a barrier to the diffusion of neovascular growth factors into the anterior chamber.45–47 The vitreous possesses inhibitors of NV and may also be a physical barrier to vasoproliferative factors that give relative protection

against NV developing in the anterior segment.13,48 This explains the increased incidence

of neovascularization of the iris and other anterior structures following vitrectomy and lensectomy,

especially in eyes with under-treated or untreated PDR.13,40,47,49 The reader is referred to Chapter 1

for extensive review of the pathophysiology of diabetic retinopathy.