Cummings and Cunha-Vaz Table 4 Classiﬁcation of diabetic retinopathy Background retinopathy Capillary microaneurysms (‘dots’) Intraretinal hemorrhages (‘blots’) Hard exudates (lipid exudates) Pre-proliferative retinopathy Soft exudates (cotton wool spots, infarcts) Intra-retinal microvascular abnormalities (IRMAs) Venous abnormalities (beading, looping, and re-duplication) Proliferative retinopathy New vessels on the disc or within one disc diameter (NVD) New vessels elsewhere (NVE) Rubeosis iridis (± neovascular glaucoma) Maculopathy Edematous Exudative Ischemic Any combination of above Pericyte damage is also present, but its distribution is irregu- lar and is only made more apparent because the affected cells are encased in basement membrane and thus take longer than endothelial cells to be replaced when damaged. Fluorescein angiography conﬁrmed the histopathological ﬁndings of diabetic retinal disease in a dynamic manner. It was the ﬁrst technique to document the abnormal leakage of ﬂuorescein through the walls of the retinal vessels, demonstrating a breakdown of the blood-retinal barrier (BRB). Vitreous ﬂuorophotometry has been used to quantify the alteration of the BRB (Cunha-Vaz et al 1975). The method has conﬁrmed that alteration of the BRB. When alterations of the fundus are detected by ophthal- moscopy, it is said that non-proliferative diabetic retinopathy is present. The clinical features of non-proliferative diabetic retinopathy are: microaneurysms, intra-retinal hemorrhages, hard exudates and variable degrees of retinal edema. Retinal microaneurysms are usually the ﬁrst ophthalmoscopic sign of diabetic retinopathy. New microaneurysms are constantly being formed while older ones become occluded and the rate of formation of new microaneurysms may be the most relevant marker of disease progression. Retinal edema is a frequent ﬁnding that leads to distortion of visual images and may cause a signiﬁcantly decreased visual acuity, even in the relatively early stages of the retinopathy. Stereoscopic fundus photography and slit-lamp micros- copy have played an important role by demonstrating changes in retinal volume in the macular area, but findings are dependent on the observer’s experience, and the results do not offer a reproducible measurement of the volume change. 372 Two new techniques that make objective measurements of changes in retinal thickness have recently become available: optical coherence tomography (OCT) and the retinal thickness analyzer (RTA) (Zeimer et al 1989; Puliaﬁto et al 1995). It is now possible to measure changes in retinal thick- ness and identify macular edema using non-invasive instrumentation in a clinical setting. Diabetic macular edema may now be identiﬁed by its type and distribution, evolution, pathophysiology, and by the degree of involvement of the central macular area (Cunha-Vaz 2006) (see Table 5). Pre-proliferative diabetic retinopathy is an intermediate stage between non-proliferative and proliferative retinopathy. Widespread and increasing capillary closure is the fundamental feature of the pre-proliferative retinopathy stage. There are also soft exudates, venous beading and intra- retinal microvascular abnormalities (IRMA). In addition, proliferative retinopathy is characterized by the presence of new vessels that may arise from the optic disk or from the retina periphery. These new vessels initially lie in the plane of the retina, but quickly pierce the internal limiting membrane and become pre-retinal, forming adhesions with the overlying vitreous. The presence of the new vessels leads to retraction of the vitreous. This pulling effect causes the progressive complications associated with retinal neovascularization, such as vitreous hemorrhage, progressive visual distortion and traction retinal detachment. Neovascularization always develops in eyes that show generalized and widespread capillary non-perfusion, again conﬁrming that it is a direct consequence of generalized ischemia. Neovascular age-related macular degeneration Age-related Macular Degeneration (AMD) occurs in two main forms: early (ie, dry) AMD and late (ie, neovascular/ exudative/wet) AMD (Ambati et al 2003). Table 5 Diabetic macular edema – characterization Characteristics Focal Diffuse Chronicity Not chronic Chronic Foveal involvement Fovea preserved Partial foveal involvement BRB (inner) No leakage Open BRB BRB (outer [RPE]) No RPE dysfunction RPE dysfunction OCT cysts None OCT cysts present Traction None Traction present Ischemia (FAZ) None Ischemia present HbA1c HbA1c 8% HbA1c 8% Blood pressure (BP) BP 130/80 mmHg BP 130/80 mmHg Abbreviations: BRB,blood-retinal barrier;RPE,retinal pigment epithelium;FAZ,foveal vascular zone; HbA1c, glycated hemoglobin; OCT, optical coherence tomography. Clinical Ophthalmology 2008:2(2)