Clinical description

Figure 1

The earliest histological signs of DR are basement membrane thickening and smooth muscle cell (pericyte) loss in intraretinal capillaries. Breakdown of the blood-retinal barrier may ensue and manifests clinically as small intraretinal haemorrhages, lipid/protein exudates, microaneurysms, and edema. These findings comprise nonproliferative diabetic retinopathy (NPDR), which is typically more prominent in the central retina, or macula, and so is detectable with the hand-held ophthalmoscope (Figure 1A).

Figure 2

With progression of DR, capillaries occlude and micro-infarcts appear as 'cotton wool spots' (Figure 1B). Ischaemia and hypoxia may follow and elicit an angiogenic response in which neovessels grow from the intraretinal vasculature into the vitreous cavity. Abnormal vascular growth, also visible ophthalmoscopically (Figure 2A), is the hallmark of proliferative diabetic retinopathy (PDR). Retinal neovessels are prone to rupture and bleed into the vitreous cavity (Figure 2B), causing rapid and sometimes profound loss of vision. Moreover, neovessels may acquire a fibrotic component that exerts traction on and detaches the underlying retina (Figure 2C).

Retinal specialists typically use binocular ophthalmoscopic techniques that afford a wider-angle retinal view than the hand-held ophthalmoscope and facilitate detection of macular oedema. Fluorescein angiography images the retinal vasculature using a nonradioactive dye. It demonstrates retinal vascular leakage, capillary nonperfusion, and neovessels and may guide aspects of laser therapy. Optical coherence tomography (OCT) provides cross-sectional views of the retina that rival histological microscopic sections (Figure 1C). OCT is highly useful to detect subtle changes not evident on physical examination and quantifies macular oedema and its response to therapy (Figure 1D). Ocular ultrasonography is used to evaluate the retina when dense vitreous haemorrhage or other media opacity precludes visualization.

Pathogenesis

Several mechanisms are proposed to link hyperglycemia with microvascular complications.¹⁰ Sugars may bind to proteins and other cellular components that then undergo additional reactions to produce advanced glycation end products (AGEs) that compromise protein function. Prolonged hyperglycemia also alters expression of selected genes that may initiate the pathologic changes of early retinopathy. Finally, hyperglycemia promotes oxidative stress mediated by free radicals, peroxides and other oxidative byproducts. AGEs and glucose-induced gene expression further exacerbate the hyperoxidative milieu.

Early investigations suggested a hormonal role in DR based on exacerbation of DR in pregnancy, rarity of DR prior to puberty and occasional resolution of DR after pituitary apoplexy. More than 50 years ago, growth hormone was determined to underlie these findings and hypophysectomy and pituitary ablation emerged as partly successful though highly risky therapies for DR. An essential role for growth hormone in development of retinal neovascularization was confirmed in transgenic mice expressing a growth hormone antagonist.¹¹

We now understand that the vascular pathology of DR results from a complex interplay of numerous cellular and molecular factors.¹² A major role is played by vascular endothelial growth factor (VEGF), an endothelial cell mitogen that also promotes vascular permeability. It is upregulated by local tissue hypoxia and increases in the retina under ischaemic conditions. VEGF likely promotes blood-retinal-barrier dysfunction early in DR as well as later angiogenic complications. Anti-VEGF therapy is rapidly emerging as an important therapeutic option for DR.

Diabetic retinopathy is not an exclusively vascular disease. Retinal neuronal degeneration and glial activation occur in DR and indeed, may appear prior to vascular lesions. A new paradigm is emerging that considers inflammatory factors and neurodegenerative processes not only as reactive mechanisms subsequent to vascular damage, but also as primary pathogenetic events in DR. This evolving model points to anti-inflammatory and neuroprotective therapies for DR.¹³

Management

Retinal oedema secondary to vascular hyperpermeability and exudation is the most frequent cause of visual impairment in NPDR. When macular oedema involves or threatens the central macula (fovea) it is clinically significant macular oedema (CSME). CSME is typically associated with mild or moderate loss of vision (e.g., between 20/20 and 20/200), but occasionally legal blindness (<20/200 in the better eye) occurs. CSME is most often treated with a light laser treatment to the macula that aims to seal leaking microaneurysms and promote resorption of intraretinal exudation. Laser treatment reduces the risk of subsequent vision loss by 50%.¹⁴

However, macular laser improves vision in relatively few patients with CSME and provides little benefit for patients with diffuse macular leakage. In these patients, the long-acting depot steroid triamcinolone acetonide (kenalog) given by intravitreal or periocular injection may reduce oedema and improve vision,¹⁵ but its use is limited by the need for repeated injections and the common side effects of cataract and glaucoma. Intravitreal injections of anti-VEGF antibodies ranibizumab (Lucentis) and bevacizumab (Avastin) are now in clinical use for patients with CSME, though their precise role is under investigation.¹⁶ Anti-VEGF therapy also requires frequent repeated injections, and alternative means to inhibit VEGF activity (e.g., RNA silencing, gene transfer, and small-molecule antagonists) are under development.

The presence of neovessels does not affect vision, but the complications of vitreous haemorrhage and fibrosis are the most common causes of more severe vision loss among diabetic patients. The mainstay of therapy for PDR is a destructive laser procedure known as panretinal photocoagulation (PRP). Although the exact mechanism for PRP is uncertain, it is thought that destruction of peripheral retina decreases retinal metabolic activity, thereby relieving ischaemia-induced hypoxia, which is the stimulus for abnormal retinal angiogenesis. PRP is highly effective for regression of neovessels (Figure 2D) and prevention of severe vision loss,¹⁷ but is sometimes painful and may reduce peripheral vision. Anti-VEGF agents are useful in situations where rapid though temporary regression of neovessels is desired.

Vitreous haemorrhage is initially managed by observation alone since blood often spontaneously resorbs over several weeks. Anti-VEGF agents may accelerate clearing by reducing neovessels and their tendency to bleed. For eyes that do not clear, surgical evacuation (posterior vitrectomy) is recommended to restore clarity and to allow intraoperative placement of PRP.

Tractional retinal detachments due to epiretinal fibrovascular proliferation present a formidable surgical challenge. Meticulous removal of contractile tissues and intraocular tamponade with inert gases or silicone oil often achieves anatomic and functional success, but recurrent detachment is common and visual results may be disappointing. Pharmacologic prevention of intraocular fibrosis is not currently available.

Diabetic patients are at risk from several ocular conditions in addition to retinopathy. Widely fluctuating blood glucose levels cause osmotic gradients across the lens epithelium, transient lens swelling and blurring. Cataract is more common and presents at a younger age in diabetics. Diplopia may result from cranial nerve palsies. Retinal vein occlusions are associated with diabetes. Finally, severe ocular ischaemia in DR may elicit neovascularization in the iris, where it can obstruct aqueous humor outflow and elevate intraocular pressure. This 'neovascular glaucoma' is often painful, difficult to treat, and may rapidly result in permanent loss of vision.