Francesco Bandello, Rosangela Lattanzio,

Ilaria Zucchiatti, and Gisella Maestranzi

Contents

4.1Clinical Overview

4.1.1Clinical Findings

Proliferative diabetic retinopathy (PDR) is a dramatic complication that occurs in almost 50 % of type 1 and 10 % of type 2 diabetic patients with 20 or 15 years of disease, respectively [1, 2]. PDR is characterized by a network of vessels or fine

F. Bandello, MD, FEBO (*) • R. Lattanzio, MD • I. Zucchiatti, MD • G. Maestranzi, MD Department of Ophthalmology, University Vita-Salute,

Scientific Institute San Raffaele, via Olgettina 60, Milan 20132, Italy e-mail: bandello.francesco@hsr.it; lattanzio.rosangela@hsr.it; ilaria.zucchiatti@gmail.com; maestranzi.gisella@hsr.it

Fig. 4.1 (a) New vessels that grow from the optic disk, neovascularization of the disk (NVD). (b) New vessels that arise on the retinal surface, neovascularization elsewhere (NVE). (c) More severe neovascularization, with extension of NVE more than 0.5 disk area. (d) NVE associated with small preretinal hemorrhage. (e) NVD associated with larger preretinal hemorrhage. (f) Subhyaloid hemorrhage in high-risk PDR

loops that arises perpendicular from the retinal surface towards the vitreous cavity along the scaffolding offered by the vitreous cortex, as a response to chronic retinal hypoxia. New vessels (NVs) may grow from the optic disk, neovascularization of the disk (NVD), or from the superficial retinal vasculature, neovascularization elsewhere (NVE) [3, 4] (Fig. 4.1a, b).

The main stimulus for the new vessels development comes from the retinal ischemia secondary to capillary occlusion, and the greatest risk occurs in severe nonproliferative diabetic retinopathy (NPDR) [5, 6]. The reduced provision in oxygen and nutrients to the non-perfused retina may trigger the release of vasoactive molecules

into the vitreous, including vascular endothelial growth factor (VEGF) [7, 8]. In normal condition, a balance between factors stimulating and factors inhibiting the neovascularization is present. When PDR occurs, this balance is shifted towards the proangiogenic stimulus as an attempt to satisfy the need of hematic supply.

Clinical identification of NVs is primarily made by biomicroscopy even if their clinical features could vary. NVs can grow and assume the typical aspect of a carriage wheel, made by a network of radiating vasculature surrounded by an external round or even an irregular disposition over the retinal layer (Fig. 4.1c). Generally NVs are composed by fibrous proliferation and may extend across both arterial and venous branches. Nevertheless, in some cases it could be difficult to differentiate NVs from intraretinal microvascular abnormalities (IRMAs). On dilated fundus examination, IRMAs are usually visible in the deeper retina, near to cotton wool spots, and rarely around the disk, often associated to other vascular signs, including venous loops [9]. In case of unusual presentation, NVs could be clearly differentiated from IRMAs using FA examination.

New vessels are very fragile, because they are made by endothelium proliferation in the absence of standard intramural pericytes. A recent study evaluating the topographical distribution of neovascularization showed that the majority of NVEs are situated along the superior vascular arcades and inferonasal to the optic disk, while NVD may privilege the upper temporal disk rim [10].

The natural history of posterior segment neovascularization is variable: new vessels could grow or assume a fibrovascular structure or rarely regress [11]. Fibrosis of retinal neovascularization is caused by the growth of fibrocytes and glial cells on the new vessels, which lay down collagen fibers to constitute a fibrovascular complex [12, 13].

In case of carriage wheel neovascularization, a first regression of the new vessels situated in the center of the configuration has been described, followed by the substitution with fibrous tissue; then the external vasculature becomes more narrow and stretch. Further vessel proliferation could originate from preexisting fibrotic vascularization that has regressed, and thus new vessels at different stages of evolution could occur on the same time.

The structure of new vessels is very subtle and fragile and could easily lead to rupture and bleeding [14, 15] (Fig. 4.1d, e). Blood could fill into the vitreous (vitreous hemorrhage) or deposit into the subhyaloid space, the virtual space included between the vitreous and retina (subhyaloid hemorrhage) (Fig. 4.1f). In case of subhyaloid hemorrhage, blood assumes the typical appearance characterized by round shape and horizontal fluid level. In case of vitreous hemorrhage, blood can remain localized or diffuse into the vitreous cavity, inhibiting the fundus exploration and causing a serious visual impairment (Fig. 4.2). Vitreous hemorrhage could spontaneously clear, even if the clearing speed is quite variable, according to the amount of blood and the gravity of the PDR, taking a few weeks or sometimes some months. Red blood cells can also diffuse to the anterior chamber and drain through the trabecular meshwork.

Fibrovascular tissue can later get into a severe scarring and contraction, creating some vitreoretinal forces and tractions, which can lead to posterior vitreous detachment [11]. Shrinking of these pathological structures could further cause vitreomacular traction, inducing retinoschisis and cystic retinal degeneration (Fig. 4.3). In addition, the fibrovascular contraction could lead to further severe complication to the posterior pole, such as macular distortion and macular hole formation (Fig. 4.4).

Fig. 4.2 (a) Fundus photography, showing poor visualization of the posterior pole from vitreous hemorrhage. (b) FA is obscured from the presence of the blood and retinal new vessels are poorly visible. Retinal ischemia and point hyper-fluorescence secondary to vascular ectasia are noticeable in the retinal areas free from the blood

Fig. 4.3 (a) Red-free photography of the posterior pole, showing vitreoretinal traction, from advanced new vessels, arising from the optic disk and reaching the inferior and superior temporal vascular arcades up to the macula. (b) Panretinal FA revealing intense hyper-fluorescence from the neovascularization and confluent hypo-fluorescence of the periphery due to severe retinal nonperfusion. (c–e) The angiographic pattern of advanced retinal new vessels, associated to vitreoretinal fibrovascular traction: fluorescein leakage is beginning on early frames showing the complex scaffold due to the neovascular structure (c), which is widely increasing on intermediate frames (d) and then showing a pronounced leakage on late phases (e). Macular ischemia and multiple points of hyper-fluorescence due to vascular ectasia are also detectable

b

Fig. 4.4 (a) Color fundus photography of the posterior pole, clearly showing extensive NVD (arrowhead) and NVE localized along the superior and inferior temporal vascular arcades (arrows), associated to large fibrovascular traction that originates from the optic disk towards the vascular arcade, above the macula, as well as macular fibrosis. (b) FA of the posterior pole revealing multiple areas of hyper-fluorescence from vascular leakage secondary to NVD and NVE above and below the macula, as well as hyper-fluorescence on the macula region, from breakdown of the blood-reti- nal barrier and macular fibrosis. (c) Panretinal FA, showing, in addition to the extensive neovascularization, several peripheral areas of retinal non-perfusion and amputation of the retinal vessels

In more advanced stages, the fibrovascular complex can grow to the vitreous cavity, creating some pathological adhesions and leading to a tractional retinal detachment, as a severe sight-threatening complication.

Neovascularization of the iris (NVI) is characterized by the growth of blood vessels on the iris surface. When the neovascularization reaches the angle, a dysregulation in the normal egress of the aqueous occurs. Anterior chamber angle closure, secondary to synechiae formation and neovascular glaucoma, may occur in more advanced forms (Fig. 4.5).

Summary 4.1

Proliferative diabetic retinopathy is characterized by a fibrovascular proliferation that arises from the optic disk (neovascularization of the disk) or from the superficial retinal vasculature (neovascularization elsewhere), as a response to chronic retinal hypoxia. New vessels could lead to rupture and bleeding and blood could fill into the vitreous (vitreous hemorrhage) or deposit into the subhyaloid space (subhyaloid hemorrhage). In more advanced stages, fibrovascular tissue contraction could lead to vitreomacular traction and tractional retinal detachment.