Introduction Ophthalmic complications of diabetes • Common ○ Retinopathy. ○ Iridopathy (minor iris transillumination defects). ○ Unstable refraction. • Uncommon ○ Recurrent styes. ○ Xanthelasmata. ○ Accelerated senile cataract. ○ Neovascular glaucoma (NVG). ○ Ocular motor nerve palsies. ○ Reduced corneal sensitivity. • Rare. Papillopathy, pupillary light-near dissociation, Wolfram syndrome (progressive optic atrophy and multiple neurological and systemic abnormalities), acute-onset cataract, rhino-orbital mucormycosis. Prevalence The reported prevalence of diabetic retinopathy (DR) in diabetics varies substantially between studies, even amongst contemporary populations in the same country, but is probably around 40%. It is more common in type 1 diabetes than in type 2 and sightthreatening disease is present in up to 10%. Proliferative diabetic retinopathy (PDR) affects 5–10% of the diabetic population; type 1 diabetics are at particular risk, with an incidence of up to 90% after 30 years. Risk factors • Duration of diabetes is the most important risk factor. In patients diagnosed with diabetes before the age of 30 years, the incidence of DR after 10 years is 50%, and after 30 years 90%. DR rarely develops within 5 years of the onset of diabetes or before puberty, but about 5% of type 2 diabetics have DR at presentation. It appears that duration is a stronger predictor for proliferative disease than for maculopathy. • Poor control of diabetes. It has been shown that tight blood glucose control, particularly when instituted early, can prevent or delay the development or progression of DR. However, a sudden improvement in control may be associated with progression of retinopathy in the near term. Type 1 diabetic patients appear to obtain greater benefit from good control than type 2. Raised HbA1c is associated with an increased risk of proliferative disease. • Pregnancy is sometimes associated with rapid progression of DR. Predicating factors include greater pre-pregnancy severity of retinopathy, poor pre-pregnancy control of diabetes, control exerted too rapidly during the early stages of pregnancy, and pre-eclampsia. The risk of progression is related to the severity of DR in the first trimester. If substantial DR is present, frequency of review should reflect individual risk, and can be up to monthly. Diabetic macular oedema usually resolves spontaneously after pregnancy and need not be treated if it develops in later pregnancy. • Hypertension, which is very common in patients with type 2 diabetes, should be rigorously controlled (<140/80 mmHg). Tight control appears to be particularly beneficial in type 2 diabetics with maculopathy. Cardiovascular disease and previous stroke are also predictive. • Nephropathy, if severe, is associated with worsening of DR. Conversely, treatment of renal disease (e.g. renal transplantation) may be associated with improvement of retinopathy and a better response to photocoagulation. • Other risk factors include hyperlipidaemia, smoking, cataract surgery, obesity and anaemia. Pathogenesis DR is predominantly a microangiopathy in which small blood vessels are particularly vulnerable to damage from high glucose levels. Direct hyperglycaemic effects on retinal cells are also likely to play a role. Many angiogenic stimulators and inhibitors have been identified; vascular endothelial growth factor (VEGF) appears to be of particular importance in the former category. Classification The classification used in the Early Treatment Diabetic Retinopathy Study (ETDRS – the modified Airlie House classification) is widely used internationally. An abbreviated version is set out in Table 13.1, in conjunction with management guidelines. The following descriptive categories are also in widespread use in clinical practice: • Background diabetic retinopathy (BDR) is characterized by microaneurysms, dot and blot haemorrhages and exudates. These are generally the earliest signs of DR, and persist as more advanced lesions appear. • Diabetic maculopathy strictly refers to the presence of any retinopathy at the macula, but is commonly reserved for significant changes, particularly vision-threatening oedema and ischaemia. • Preproliferative diabetic retinopathy (PPDR) manifests with cotton wool spots, venous changes, intraretinal microvascular anomalies (IRMA) and often deep retinal haemorrhages. PPDR indicates progressive retinal ischaemia, with a heightened risk of progression to retinal neovascularization. • PDR is characterized by neovascularization on or within one disc diameter of the disc (NVD) and/or new vessels elsewhere (NVE) in the fundus. • Advanced diabetic eye disease is characterized by tractional retinal detachment, significant persistent vitreous haemorrhage and neovascular glaucoma. Signs Microaneurysms Microaneurysms are localized outpouchings, mainly saccular, of the capillary wall that may form either by focal dilatation of the capillary wall where pericytes are absent, or by fusion of two arms of a capillary loop (Fig. 13.2A). Most develop in the inner capillary plexus (inner nuclear layer), frequently adjacent to areas of capillary non-perfusion (Fig. 13.2B). Loss of pericytes (Fig. 13.2C) may also lead to endothelial cell proliferation with the formation of ‘cellular’ microaneurysms (Fig. 13.2D). Microaneurysms may leak plasma constituents into the retina as a result of breakdown in the blood–retinal barrier, or may thrombose. They tend to be the earliest sign of DR. • Signs. Tiny red dots, often initially temporal to the fovea (Fig. 13.3A); may be indistinguishable clinically from dot haemorrhages. • Fluorescein angiography (FA) allows differentiation between dot haemorrhages and non-thrombosed microaneurysms. Early frames show tiny hyperfluorescent dots (Fig. 13.3B), typically more numerous than visible clinically. Late frames show diffuse hyperfluorescence due to leakage. Retinal haemorrhages • Retinal nerve fibre layer haemorrhages arise from the larger superficial pre-capillary arterioles (Fig. 13.4A) and assume their characteristic shape (Fig. 13.4B) because of the architecture of the retinal nerve fibre layer.

• Intraretinal haemorrhages arise from the venous end of capillaries and are located in the compact middle layers of the retina (see Fig. 13.4A) with a resultant red ‘dot/blot’ configuration (Fig. 13.4C). • Deeper dark round haemorrhages (Fig. 13.4D) represent haemorrhagic retinal infarcts and are located within the middle retinal layers (see Fig. 13.4A). The extent of involvement is a significant marker of the likelihood of progression to PDR. Exudates Exudates, sometimes termed ‘hard’ exudates to distinguish from the older term for cotton wool spots – ‘soft’ exudates, are caused by chronic localized retinal oedema; they develop at the junction of normal and oedematous retina. They are composed of lipoprotein and lipid-filled macrophages located mainly within the outer plexiform layer (Fig. 13.5A). Hyperlipidaemia may increase the likelihood of exudate formation. • Signs ○ Waxy yellow lesions (Fig. 13.5B) with relatively distinct margins arranged in clumps and/or rings at the posterior pole, often surrounding leaking microaneurysms. ○ With time the number and size tend to increase (Fig. 13.5C), and the fovea may be involved. ○ When leakage ceases, exudates absorb spontaneously over a period of months, either into healthy surrounding capillaries or by phagocytosis.

○ Chronic leakage leads to enlargement and the deposition of crystalline cholesterol (Fig. 13.5D). • FA will commonly show hypofluorescence only with large dense exudates, as although background choroidal fluorescence is masked, retinal capillary fluorescence is generally preserved overlying the lesions (Fig 13.6). Diabetic macular oedema (DMO) Diabetic maculopathy (foveal oedema, exudates or ischaemia) is the most common cause of visual impairment in diabetic patients, particularly type 2. Diffuse retinal oedema is caused by extensive capillary leakage, and localized oedema by focal leakage from microaneurysms and dilated capillary segments. The fluid is initially located between the outer plexiform and inner nuclear layers; later it may also involve the inner plexiform and nerve fibre layers, until eventually the entire thickness of the retina becomes oedematous. With central accumulation of fluid the fovea assumes a cystoid appearance – cystoid macular oedema (CMO) that is readily detectable on optical coherence tomography (OCT) (Fig. 13.7A) and assumes a central flower petal pattern on FA (Fig. 13.7B). • Focal maculopathy: well-circumscribed retinal thickening associated with complete or incomplete rings of exudates (Fig. 13.8A). FA shows late, focal hyperfluorescence due to leakage, usually with good macular perfusion (Fig. 13.8B). • Diffuse maculopathy: diffuse retinal thickening, which may be associated with cystoid changes; there are typically also scattered microaneurysms and small haemorrhages (Fig. 13.9A). Landmarks may be obscured by oedema, which may render localization of the fovea impossible. FA shows mid- and late-phase diffuse hyperfluorescence (Fig. 13.9B), and demonstrates CMO if present.

Ischaemic maculopathy • Signs are variable and the macula may look relatively normal despite reduced visual acuity. In other cases PPDR may be present. • FA shows capillary non-perfusion at the fovea (an enlarged FAZ) and frequently other areas of capillary non-perfusion (Fig. 13.10) at the posterior pole and periphery. Clinically significant macular oedema Clinically significant macular oedema (CSMO) is detected on clinical examination as defined in the ETDRS (Fig. 13.11): • Retinal thickening within 500 µm of the centre of the macula (Fig. 13.11, upper left). • Exudates within 500 µm of the centre of the macula, if associated with retinal thickening; the thickening itself may be outside the 500 µm (Fig. 13.11, upper right). • Retinal thickening one disc area (1500 µm) or larger, any part of which is within one disc diameter of the centre of the macula (Fig. 13.11, lower centre).

Cotton wool spots Cotton wool spots are composed of accumulations of neuronal debris within the nerve fibre layer. They result from ischaemic disruption of nerve axons, the swollen ends of which are known as cytoid bodies, seen on light microscopy as globular structures in the nerve fibre layer (Fig. 13.12A). As cotton wool spots heal, debris is removed by autolysis and phagocytosis. • Signs. Small fluffy whitish superficial lesions that obscure underlying blood vessels (Fig. 13.12B and C). They are clinically evident only in the post-equatorial retina, where the nerve fibre layer is of sufficient thickness to render them visible.

• FA shows focal hypofluorescence due to local ischaemia and blockage of background choroidal fluorescence. Venous changes Venous anomalies seen in ischaemia consist of generalized dilatation and tortuosity, looping, beading (focal narrowing and dilatation) and sausage-like segmentation (Fig. 13.13). The extent of the retinal area exhibiting venous changes correlates well with the likelihood of developing proliferative disease. Intraretinal microvascular abnormalities Intraretinal microvascular abnormalities (IRMA) are arteriolar– venular shunts that run from retinal arterioles to venules, thus bypassing the capillary bed and are therefore often seen adjacent to areas of marked capillary hypoperfusion (Fig. 13.14A).

• Signs. Fine, irregular, red intraretinal lines that run from arterioles to venules, without crossing major blood vessels (Fig. 13.14B). • FA shows focal hyperfluorescence associated with adjacent areas of capillary closure (‘dropout’) but without leakage. Arterial changes Subtle retinal arteriolar dilatation may be an early marker of ischaemic dysfunction. When significant ischaemia is present signs include peripheral narrowing, ‘silver wiring’ and obliteration, similar to the late appearance following a branch retinal artery occlusion.

Proliferative retinopathy It has been estimated that over one-quarter of the retina must be non-perfused before PDR develops. Although preretinal new vessels may arise anywhere in the retina, they are most commonly seen at the posterior pole. Fibrous tissue, initially fine, gradually develops in association as vessels increase in size. • New vessels at the disc (NVD) describes neovascularization on or within one disc diameter of the optic nerve head (Fig. 13.15). • New vessels elsewhere (NVE) describes neovascularization further away from the disc (Fig. 13.16); it may be associated with fibrosis if long-standing. • New vessels on the iris (NVI – Fig. 13.17), also known as rubeosis iridis, carry a high likelihood of progression to neovascular glaucoma (see Ch. 10).

• FA (see Fig. 13.15C) highlights neovascularization during the early phases of the angiogram and shows irregular expanding hyperfluorescence during the later stages due to intense leakage of dye from neovascular tissue. FA can be used to confirm the presence of new vessels (NV) if the clinical diagnosis is in doubt, and also delineates areas of ischaemic retina that might be selectively targeted for laser treatment.