Arterial system

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  The central retinal artery , an end artery, enters the optic nerve approximately 1 cm behind the globe. It is composed of three anatomical layers:

  
  
  
  
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    The intima, the innermost, is composed of a single layer of endothelium resting on a collagenous zone.

    
    
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    The internal elastic lamina separates the intima from the media.

    
    
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    The media consists mainly of smooth muscle.

    
    
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    The adventitia is the outermost and is composed of loose connective tissue.

  
  
  
  
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  Retinal arterioles arise from the central retinal artery. Their walls contain smooth muscle, but in contrast to arteries the internal elastic lamina is discontinuous.

Capillaries

Retinal capillaries supply the inner two-thirds of the retina, with the outer third being supplied by the choriocapillaris. The inner capillary network (plexus) is located in the ganglion cell layer, with an outer plexus in the inner nuclear layer. Capillary-free zones are present around arterioles ( Fig. 13.1A ) and at the fovea (foveal avascular zone – FAZ). Retinal capillaries are devoid of smooth muscle and elastic tissue; their walls consist of the following ( Fig. 13.1B ):

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  Endothelial cells form a single layer on the basement membrane and are linked by tight junctions that form the inner blood–retinal barrier.

  
  
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  The basement membrane lies beneath the endothelial cells with an outer basal lamina enclosing pericytes.

  
  
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  Pericytes lie external to endothelial cells and have multiple pseudopodial processes that envelop the capillaries. Pericytes have contractile properties and are thought to participate in autoregulation of the microvascular circulation.

Normal retinal capillary bed. (A) Periarteriolar capillary-free zone – flat preparation of Indian ink-injected retina; (B) endothelial cells with elongated nuclei and pericytes with rounded nuclei – trypsin digest preparation

(Courtesy of J Harry and G Misson, from Clinical Ophthalmic Pathology , Butterworth-Heinemann 2001)

Venous system

Retinal venules and veins drain blood from the capillaries.

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  Small venules are larger than capillaries but have a similar structure.

  
  
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  Larger venules contain smooth muscle and merge to form veins.

  
  
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  Veins contain a small amount of smooth muscle and elastic tissue in their walls and are relatively distensible. Their diameter gradually enlarges as they pass posteriorly towards the central retinal vein.

Ophthalmic complications of diabetes

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  Common

  
  
  
  
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    Retinopathy.

    
    
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    Iridopathy (minor iris transillumination defects).

    
    
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    Unstable refraction.

  
  
  
  
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  Uncommon

  
  
  
  
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    Recurrent styes.

    
    
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    Xanthelasmata.

    
    
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    Accelerated senile cataract.

    
    
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    Neovascular glaucoma (NVG).

    
    
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    Ocular motor nerve palsies.

    
    
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    Reduced corneal sensitivity.

  
  
  
  
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  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 sight-threatening 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

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  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.

  
  
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  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.

  
  
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  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.

  
  
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  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.

  
  
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  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.

  
  
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  Other risk factors include hyperlipidaemia, smoking, cataract surgery, obesity and anaemia.

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.

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  Signs. Tiny red dots, often initially temporal to the fovea ( Fig. 13.3A ); may be indistinguishable clinically from dot haemorrhages.

  
  

  
  

  
  

  

  
  

  
  

  Microaneurysms. (A) Microaneurysms and dot/blot haemorrhages at the posterior pole; (B) FA shows scattered hyperfluorescent spots in the posterior fundus

  
  

  
  

  

  
  
  
  
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  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.

Microaneurysms – histopathology. (A) Two arms of a capillary loop that may fuse to become a microaneurysm – flat preparation of Indian ink-injected retina; (B) an area of capillary non-perfusion and adjacent microaneurysms – flat preparation of Indian ink-injected retina; (C) eosinophilic (dark pink) degenerate pericytes – trypsin digest preparation; (D) microaneurysm with endothelial cell proliferation (cellular microaneurysm) – trypsin digest preparation

(Courtesy of J Harry and G Misson, from Clinical Ophthalmic Pathology , Butterworth-Heinemann 2001 – figs A and C; J Harry – figs B and D)

Retinal haemorrhages

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  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.

  
  

  
  

  
  

  

  
  

  
  

  Retinal haemorrhages. (A) Histology shows blood lying diffusely in the retinal nerve fibre and ganglion cell layers and as globules in the outer layers; (B) retinal nerve fibre layer (flame) haemorrhages; (C) dot and blot haemorrhages; (D) deep dark haemorrhages

  
  

  (Courtesy of J Harry and G Misson, from Clinical Ophthalmic Pathology , Butterworth-Heinemann 2001 – fig. A)

  
  

  
  

  

  
  

  
  

  

  
  

  
  

  

  
  
  
  
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  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 ).

  
  
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  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.

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  Signs

  
  
  
  
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    Waxy yellow lesions ( Fig. 13.5B ) with relatively distinct margins arranged in clumps and/or rings at the posterior pole, often surrounding leaking microaneurysms.

    
    
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    With time the number and size tend to increase ( Fig. 13.5C ), and the fovea may be involved.

    
    
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    When leakage ceases, exudates absorb spontaneously over a period of months, either into healthy surrounding capillaries or by phagocytosis.

    
    
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    Chronic leakage leads to enlargement and the deposition of crystalline cholesterol ( Fig. 13.5D ).

  
  
  
  
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  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 ).

  
  

  
  

  
  

  

  
  

  
  

  FA of exudates. (A) Clinical appearance; (B) exudates not shown on FA

  
  

  
  

  

  
  

Exudates. (A) Histology shows irregular eosinophilic deposits mainly in the outer plexiform layer; (B) small exudates and microaneurysms; (C) more extensive exudates, some associated with microaneurysms; (D) exudates involving the fovea, including central crystalline cholesterol deposition – focal laser has recently been applied superotemporal to the fovea

(Courtesy of J Harry – fig. A; S Chen – figs C and D)

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 ).

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  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 ).

  
  

  
  

  
  

  

  
  

  
  

  Focal diabetic maculopathy. (A) A ring of hard exudates temporal to the macula; (B) FA late phase shows focal area of hyperfluorescence due to leakage corresponding to the centre of the exudate ring

  
  

  
  

  

  
  
  
  
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  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.

  
  

  
  

  
  

  

  
  

  
  

  Diffuse diabetic maculopathy. (A) Dot and blot haemorrhages – diffuse retinal thickening is present; (B) late-phase FA shows extensive hyperfluorescence at the posterior pole due to leakage

  
  

  (Courtesy of S Chen – fig. B)

  
  

  
  

  

  
  

Cystoid macular oedema. (A) OCT shows retinal thickening and cystoid spaces; (B) FA shows leaking microaneurysms and central diffuse hyperfluorescence with a flower-petal configuration – same patient as Fig. 13.6

Ischaemic maculopathy

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  Signs are variable and the macula may look relatively normal despite reduced visual acuity. In other cases PPDR may be present.

  
  
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  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.

  
  

  
  

  
  

  

  
  

  
  

  Ischaemic diabetic maculopathy. FA venous phase shows hypofluorescence due to capillary non-perfusion at the central macula and elsewhere

  
  

  (Courtesy of S Chen)

  
  

Clinically significant macular oedema

Clinically significant macular oedema (CSMO) is detected on clinical examination as defined in the ETDRS ( Fig. 13.11 ):

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  Retinal thickening within 500 µm of the centre of the macula ( Fig. 13.11 , upper left).

  
  
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  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).

  
  
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  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).

Clinically significant macular oedema

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.

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  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.

  
  
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  FA shows focal hypofluorescence due to local ischaemia and blockage of background choroidal fluorescence.

Cotton wool spots. (A) Histology shows cytoid bodies in the retinal nerve fibre layer; (B) clinical appearance; (C) red-free photography showing differing appearance of cotton wool spots and haemorrhages, the latter appearing black – the smaller well-defined white lesions are exudates

(Courtesy of J Harry – fig. A)

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.

Venous changes. (A) Looping; (B) beading; (C) severe segmentation

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 ).

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  Signs . Fine, irregular, red intraretinal lines that run from arterioles to venules, without crossing major blood vessels ( Fig. 13.14B ).

  
  
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  FA shows focal hyperfluorescence associated with adjacent areas of capillary closure (‘dropout’) but without leakage.

Intraretinal microvascular abnormalities. (A) Histology shows arteriolar-venular shunt and a few microaneurysms within a poorly perfused capillary bed – flat preparation of Indian ink-injected retina; phase contrast microscopy; (B) clinical appearance

(Courtesy of J Harry – fig. A)

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.

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  New vessels at the disc (NVD) describes neovascularization on or within one disc diameter of the optic nerve head ( Fig. 13.15 ).

  
  

  
  

  
  

  

  
  

  
  

  Disc new vessels. (A) Mild; (B) severe; (C) FA shows leaking disc vessels, with extensive peripheral capillary dropout and a small focus of leaking vessels elsewhere

  
  

  (Courtesy of S Chen – fig. B)

  
  

  
  

  

  
  

  
  

  

  
  
  
  
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  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 elsewhere. (A) Mild; (B) severe; (C) associated with fibrosis

  
  

  
  

  

  
  

  
  

  

  
  
  
  
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  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 ).

  
  

  
  

  
  

  

  
  

  
  

  New vessels on the iris (rubeosis iridis)

  
  

  (Courtesy of C Barry)

  
  
  
  
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  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.

General

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  Patient education is critical, including regarding the need to comply with review and treatment schedules in order to optimize visual outcomes.

  
  
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  Diabetic control should be optimized.

  
  
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  Other risk factors , particularly systemic hypertension (especially type 2 diabetes) and hyperlipidaemia should be controlled in conjunction with the patient’s diabetologist.

  
  
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  Fenofibrate 200 mg daily has been shown to reduce the progression of diabetic retinopathy in type 2 diabetics and prescription should be considered; the decision is independent of whether the patient already takes a statin.

  
  
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  Smoking should be discontinued, though this has not been definitively shown to affect retinopathy.

  
  
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  Other modifiable factors such as anaemia and renal failure should be addressed as necessary.

Treatment of diabetic macular oedema

Until recently laser photocoagulation was the mainstay of treatment for DMO, reducing the risk of visual loss by 50% overall compared with observation. The availability of newer treatment modalities and increasing evidence for their efficacy has dramatically altered the approach to management over recent years. However, options should always be discussed fully with the patient. In particular, patients with good vision who otherwise meet criteria for treatment might prefer observation once the risks of various interventions are taken into account.

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  Laser photocoagulation (modified ETDRS focal/grid treatment).

  
  
  
  
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    Focal ( Figs 13.18A and B ). Diode or argon burns are applied to leaking microaneurysms 500–3000 µm from the foveola; spot size 50–100 µm, duration 0.05–0.1 s with sufficient power to obtain a greyish reaction beneath the microaneurysm.

    
    

    
    

    
    

    

    
    

    
    

    Laser for clinically significant macular oedema. (A) Prior to focal laser treatment; (B) immediately following focal laser; (C) prior to modified macular grid laser treatment; (D) patient in (C) immediately post-grid laser; (E) appearance 2 months following a limited laser grid; (F) dense macular grid – the fovea is spared

    
    

    (Courtesy of S Chen – figs A, B and F; R Bates – figs C–E)

    
    

    
    

    

    
    

    
    

    

    
    

    
    

    

    
    

    
    

    

    
    

    
    

    

    
    
    
    
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    Grid ( Figs 13.18C–F ). Burns are applied to macular areas of diffuse retinal thickening, treating no closer than 500 µm from the foveola and 500 µm from the optic disc using a spot size of 50–100 µm and duration 0.05–0.1 second, with power adjusted to give a mild reaction. A ‘modified’ grid includes focal treatment to foci of leakage, usually microaneurysms.

  
  
  
  
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  Subthreshold micropulse diode laser. This modality uses very short (microsecond order) laser pulse duration combined with a longer interval (e.g. 5% duty cycle) allowing energy dissipation, minimizing collateral damage to the retina and choroid whilst stimulating the retinal pigment epithelium (RPE). Research to date indicates that similar results are achieved to those of conventional thermal laser.

  
  
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  Intravitreal anti-VEGF agents. Following substantial clinical studies, intravitreal VEGF inhibitors (see also Ch. 14 ) have been adopted as a critical element of the management of diabetic maculopathy. Most current studies have looked at ranibizumab or bevacizumab.

  
  
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  Intravitreal triamcinolone. In pseudophakic eyes intravitreal triamcinolone steroid injection followed by prompt laser is comparable to ranibizumab with regard to visual improvement and reducing retinal thickening. However, there is a significant risk of an elevation of intraocular pressure (IOP) and this must be monitored carefully. No benefit above laser has consistently been shown for phakic eyes, which have a substantially increased risk of cataract. Sustained-release intravitreal steroid implants have also demonstrated promising results.

  
  
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  Pars plana vitrectomy (PPV – Fig. 13.19 ) may be indicated when macular oedema is associated with tangential traction from a thickened and taut posterior hyaloid (see Ch. 14 – vitreomacular traction syndrome). It has also been suggested that some eyes without a taut posterior hyaloid may also benefit from vitrectomy. Clinically, a taut thickened posterior hyaloid is characterized by an increased glistening of the pre-macular vitreous face. FA typically shows diffuse leakage and prominent CMO, but OCT is usually the definitive assessment. There are several other indications for PPV in the management of diabetic eye disease (see later).

  
  

  
  

  
  

  

  
  

  
  

  Pars plana vitrectomy including macular grid in diabetic maculopathy. (A) Preoperative appearance; (B) appearance several weeks postoperatively; (C) and (D) pre- and postoperative macular OCT scans

  
  

  (Courtesy of S Chen)

  
  

  
  

  

  
  

  
  

  

  
  

  
  

  

  
  
  
  
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  Specific recommendations

  
  
  
  
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    CSMO not involving the macular centre should be treated with photocoagulation (see Fig. 13.18 ), or with micropulse laser if available.

    
    
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    CSMO involving the macular centre but with normal or minimally affected vision, perhaps 6/9 or better, can either undergo laser (micropulse may carry a lower risk of foveolar damage) or be observed if leakage arises very close to the fovea. If laser is performed, it is prudent to treat no closer than 500 µm from the perceived macular centre.

    
    
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    CSMO involving the macular centre and with reduced or reducing vision (6/9–6/90) and significant foveolar thickening on OCT should be considered for intravitreal anti-VEGF treatment, with initial induction using monthly injections for 3–6 months. An as-needed approach can subsequently be adopted. It is possible that combining anti-VEGF treatment with laser – probably deferred until completion of the induction phase – offers advantages, particularly in terms of reducing the frequency of injections, and investigation is ongoing.

    
    
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    Pseudophakic eyes with CSMO involving the macular centre and 6/9–6/90 vision should be considered for either the regimen above or intravitreal preservative-free triamcinolone followed soon afterwards by laser.

    
    
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    Options in resistant cases include intravitreal steroid: intravitreal triamcinolone – optimally preservative-free – or a sustained-release intravitreal steroid implant. Pars plana vitrectomy may be considered, particularly if vitreomacular traction is present.

    
    
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    Eyes with markedly reduced vision due to DMO generally have a poor prognosis, and optimal management is not determined. Depending on circumstances, observation or any of the interventions discussed above may be considered.

  
  

Laser treatment for proliferative retinopathy

Scatter laser treatment (panretinal photocoagulation – Fig. 13.20 ) continues to be the mainstay of PDR treatment, with intravitreal anti-VEGF injection and other modalities remaining adjunctive. The Diabetic Retinopathy Study (DRS) established the characteristics of high-risk proliferative disease and demonstrated the benefit of panretinal photocoagulation (PRP); for instance, severe NVD without haemorrhage carries a 26% risk of visual loss at 2 years that is reduced to 9% with PRP.

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  Informed consent. Patients should be advised that PRP may occasionally cause visual field defects of sufficient severity to legally preclude driving a motor vehicle; they should also be made aware that there is some risk to central vision, and that night and colour vision may be affected.

  
  
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  Co-existent DMO. If actual or imminent CSMO is also present, laser for this should preferably be carried out prior to PRP or at the same session; the intensity and amount of PRP should be kept to the lowest level likely to be effective, and may be spread over multiple sessions; adjunctive intravitreal steroid or an anti-VEGF agent may improve the outcome.

  
  
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  Lens. A contact lens is used to provide a stable magnified fundus view. A panfundoscopic lens is now generally preferred to a three-mirror lens, as it is more difficult to inadvertently photocoagulate the posterior pole through the former. Some practitioners prefer to use a higher-magnification/smaller area contact lens (e.g. Mainster®, Area Centralis®) for the more posterior component of treatment. It is essential to constantly bear in mind that an inverted and laterally reversed image is seen.

  
  
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  Anaesthesia. The amount of treatment it is possible to apply during one session may be limited by patient discomfort; this tends to be least at the posterior pole and greatest in the periphery and over the horizontal neurovascular bundles. It tends to worsen with successive sessions. Topical anaesthesia is adequate in most patients, although sub-Tenon or peribulbar anaesthesia can be administered if necessary.

  
  
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  Laser parameters

  
  
  
  
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    Spot size. A retinal burn diameter of 400 µm is usually desired for PRP. The diameter selected at the user interface to achieve this depends on the contact lens used and the operator must be aware of the correction factor for the particular lens chosen. As an approximation, with panfundoscopic-type lenses the actual retinal spot diameter is twice that selected on the laser user interface; 200 µm is typically selected for PRP, equating to a 400 µm actual retinal diameter once relative magnification is factored in. With the Mainster and Area Centralis, the retinal diameter equates closely to the interface selection, so 400 µm may be selected.

    
    
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    Duration depends on the type of laser: 0.05–0.1 s was conventionally used with the argon laser, but newer lasers allow much shorter pulses to be used and 0.01–0.05 s (10–50 ms) is the currently recommended range. Multispot strategies available on some machines utilize a combination of short pulse duration (e.g. 20 ms), very short intervals and pre-programmed delivery arrays to facilitate the application of a large number of pulses in a short period (see Fig. 13.20D ). True micropulse PRP is also under investigation and shows promising results. Shorter pulse duration seems to require a greater total number of burns for an adequate response, and may be slower to achieve regression.

    
    
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    Power should be sufficient to produce only a light intensity burn.

    
    
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    Spacing. Burns should be separated by 1–1.5 burn widths.

    
    
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    Extent of treated area. The initial treatment session should consist of 1500 burns in most cases, though more may be applied if there is a risk of imminent sight loss from vitreous haemorrhage. The more extensive the treatment at a single session, the greater the likelihood of complications. Reported figures vary, but 2500–3500 burns are likely to be required for regression of mild PDR, 4000 for moderate PDR and 7000 for severe PDR. The number of burns offers only approximate guidance, as the effective extent of treatment is dependent on numerous variables.

    
    
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    Pattern of treatment. Treatment is generally restricted to the area outside the temporal macular vascular arcades; it is good practice to delineate a ‘barrier’ of laser burns temporal to the macula early in the procedure to help to reduce the risk of accidental macular damage. Many practitioners leave two disc diameters untreated at the nasal side of the disc, to preserve paracentral field. In very severe PDR it is advisable to treat the inferior fundus first, since any vitreous haemorrhage will gravitate inferiorly and obscure this area, precluding further treatment. Areas of vitreoretinal traction should be avoided.

  
  
  
  
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  Review is dependent on PDR severity and the requirement for successive treatment applications; initial treatment should be fractionated over 2–3 sessions. Once an adequate number of burns have been applied review can be set for 4–6 weeks.

  
  
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  Indicators of regression include blunting of vessel tips, shrinking and disappearance of NV, often leaving ‘ghost’ vessels or fibrosis ( Fig. 13.21 ), regression of IRMA, decreased venous changes, absorption of retinal haemorrhages, disc pallor. Contraction of regressing vessels or associated induction of vitreous separation can precipitate vitreous haemorrhage. Significant fibrous proliferation can lead to tractional retinal detachment (see below). Patients should remain under observation, as recurrence can occur with a requirement for additional PRP.

  
  

  
  

  
  

  

  
  

  
  

  Treatment of proliferative diabetic retinopathy. (A) Severe proliferative disease; (B) 3 months later the new vessels have regressed – there is residual fibrosis at the disc

  
  

  (Courtesy of S Milewski)

  
  

  
  

  

  
  

(A) Limited panretinal photocoagulation, with fresh retrohyaloid haemorrhage; (B) more extensive treatment; (C) retinal appearance several weeks after laser; (D) composite image of ‘pattern scan’ multispot array treatment

(Courtesy of C Barry – fig. C; S Chen – fig. D)

VEGF inhibition for proliferative retinopathy

Intravitreal anti-VEGF injection has an adjunctive role in the treatment of PDR. Indication can include attempted resolution of persistent vitreous haemorrhage (with prior B-scan ultrasono­graphy to exclude retinal detachment) with the aim of avoiding vitrectomy, the initial treatment of rubeosis iridis (see below and Ch. 10 ) whilst a response to PRP is realized, and possibly the rapid control of very severe PDR to minimize the risk of haemorrhage.

Targeted retinal photocoagulation (TRP)

Wide-field fluorescein angiography allows accurate delineation of peripheral capillary non-perfusion ( Fig. 13.22 ). Selective treatment of these areas with scatter laser has been reported as effectively leading to regression of NV whilst minimizing potential complications.

Wide-field FA showing widespread areas of capillary non-perfusion – the arrow indicates a well-defined example

(Courtesy of S Chen)

Clinical features

• •
  

  Haemorrhage may be preretinal (retrohyaloid), intragel or both ( Figs 13.23A and B ). Intragel haemorrhages usually take longer to clear than preretinal because the former are usually more substantial. In some eyes, altered blood becomes compacted on the posterior vitreous face to form an ‘ochre membrane’. Ultrasonography is used in eyes with dense vitreous haemorrhage to detect the possibility of associated retinal detachment.

  
  

  
  

  
  

  

  
  

  
  

  Advanced diabetic eye disease. (A) Retrohyaloid and small amount of intragel haemorrhage; (B) more substantial intragel bleeding; (C) tractional retinal detachment

  
  

  (Courtesy of S Chen – figs B and C)

  
  

  
  

  

  
  

  
  

  

  
  
  
  
• •
  

  Tractional retinal detachment ( Fig. 13.23C ) is caused by progressive contraction of fibrovascular membranes over areas of vitreoretinal attachment. Posterior vitreous detachment in eyes with PDR is often incomplete due to the strong adhesions between cortical vitreous and areas of fibrovascular proliferation; haemorrhage often occurs at these sites due to stress exerted on NV.

  
  
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  Rubeosis iridis (iris neovascularization – NVI) may occur in eyes with PDR, and if severe may lead to neovascular glaucoma (see Ch. 10 ). NVI is particularly common in eyes with severe retinal ischaemia or persistent retinal detachment following unsuccessful pars plana vitrectomy.

Indications for pars plana vitrectomy

Vitrectomy in diabetic retinopathy is typically combined with extensive endolaser PRP. Visual results depend on the specific indication for surgery and the severity of pre-existing disease.

• •
  

  Severe persistent vitreous haemorrhage that precludes adequate PRP is the most common indication. In the absence of rubeosis iridis, vitrectomy has traditionally been considered within 3 months of the initial vitreous haemorrhage in type 1 diabetics and in most cases of bilateral haemorrhage. However, the outcome may be better with earlier surgery, and the availability of intravitreal anti-VEGF therapy may further modify the approach.

  
  
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  Progressive tractional RD threatening or involving the macula must be treated without delay. However, extramacular tractional detachments may be observed, since they often remain stationary for prolonged periods.

  
  
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  Combined tractional and rhegmatogenous RD should be treated urgently.

  
  
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  Premacular retrohyaloid haemorrhage ( Fig 13.24A ), if dense and persistent should be considered for early vitrectomy because, if untreated, the internal limiting membrane or posterior hyaloid face may serve as a scaffold for subsequent fibrovascular proliferation and consequent tractional macular detachment or macular epiretinal membrane formation. Dispersion with YAG laser (hyaloidotomy) is often successful ( Figs 13.24B and C ).

  
  

  
  

  
  

  

  
  

  
  

  Large premacular retrohyaloid haemorrhage. (A) Before and (B, C) after Nd : YAG laser hyaloidotomy

  
  

  (Courtesy of S Chen)

  
  

  
  

  

  
  

  
  

  

  
  

All patients

• •
  

  Blood pressure (BP).

  
  
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  Erythrocyte sedimentation rate (ESR) or plasma viscosity (PV).

  
  
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  Full blood count (FBC).

  
  
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  Random blood glucose. Further assessment for diabetes if indicated.

  
  
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  Random total and high-density lipoprotein (HDL) cholesterol. Additional lipid testing may be considered.

  
  
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  Plasma protein electrophoresis. To detect dysproteinaemias such as multiple myeloma.

  
  
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  Other tests. Some authorities advocate routine investigation for systemic end-organ damage related to the cardiovascular risk factors commonly found in patients with RVO. This is intended to help the prevention of further non-ocular damage, as well as facilitating systemic management to reduce the risk of recurrent ocular venous occlusion. Research is conflicting, some studies suggesting that cardio- and cerebrovascular mortality is not elevated above that of the general population in patients with RVO and others finding the converse.

  
  
  
  
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    Urea, electrolytes and creatinine to detect renal disease associated with hypertension; chronic renal failure is also a rare cause of RVO.

    
    
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    Thyroid function testing. There is a higher prevalence of thyroid disease in RVO patients.

    
    
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    Electrocardiography (ECG). Left ventricular hypertrophy is associated with hypertension.

  
  

Selected patients according to clinical indication

These tests might be considered in patients under the age of 50, in bilateral RVO, patients with previous thromboses or a family history of thrombosis, and some patients in whom investigation for the common associations is negative. Evidence of a causative link for many of these is limited.

• •
  

  Chest X-ray. Sarcoidosis, tuberculosis, left ventricular hypertrophy in hypertension.

  
  
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  C-reactive protein (CRP). Sensitive indicator of inflammation.

  
  
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  Plasma homocysteine level. To exclude hyperhomocysteinaemia, for which there is reasonable evidence of an increased RVO risk.

  
  
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  ‘Thrombophilia screen’. By convention this refers to heritable thrombophilias; tests might typically include thrombin time, prothrombin time and activated partial thromboplastin time, antithrombin functional assay, protein C, protein S, activated protein C resistance, factor V Leiden mutation, prothrombin G20210A mutation, lupus anticoagulant and anticardiolipin antibody (IgG and IgM); the last may be the most important of these.

  
  
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  Autoantibodies. Rheumatoid factor, antinuclear antibody (ANA), anti-DNA antibody, antineutrophil cytoplasmic antibody (ANCA).

  
  
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  Serum angiotensin-converting enzyme (ACE). Sarcoidosis.

  
  
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  Treponemal serology. See Chapter 11 .

  
  
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  Carotid duplex imaging to exclude mimicking ocular ischaemic syndrome.

Diagnosis

• •
  

  Symptoms if the central macula is involved consist of the sudden painless onset of blurred vision and metamorphopsia. Peripheral occlusion may be asymptomatic.

  
  
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  VA at presentation is very variable. Historically 50% of untreated eyes retain 6/12 or better in the long term, but about a quarter only achieve 6/60 or worse.

  
  
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  Iris neovascularization (NVI) and neovascular glaucoma (NVG) are much less common in BRVO – 2–3% at 3 years – than in CRVO.

  
  
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  Fundus

  
  
  
  
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    Dilatation and tortuosity of the affected venous segment, with flame-shaped and dot/blot haemorrhages, principally in the retinal area drained by the thrombosed vein though an occasional haemorrhage may be identified elsewhere; cotton wool spots and retinal oedema may be absent but are often prominent ( Fig. 13.27A ).

    
    

    
    

    
    

    

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