Ординатура / Офтальмология / Английские материалы / Clinical Ophthalmology A Systematic Approach 7th Edition_Kanski, Bowling_2011

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Fig. 14.44 Tear of the RPE. (A) A pale triangular area with surrounding blood and an adjacent darker area; (B) FA late phase shows relative hypofluorescence of the folded flap with adjacent hyperfluorescence where the RPEis absent; (C) OCTshows hyperreflectivity adjacent to the fold

(Courtesy of Moorfields Eye Hospital – figs A and B; C Barry – fig. C)

Choroidal neovascularization

Pathogenesis

1Causative factors. Wet AMD is associated with CNV which comprises abnormal growth of a blood vessel complex through Bruch membrane from the choriocapillaris. The following interactive factors are thought to be important.

•The integrity of Bruch membrane and the RPE, inflammatory pathway components, localized hypoxia and the accumulation of metabolic products.

•The importance of locally-active cytokines involved with the promotion and inhibition of vessel growth has been realized, with particular attention focusing on vascular endothelial growth factor (VEGF), which binds to endothelial cell receptors, promoting angiogenesis and vascular leakage.

•Complement factor H (CFH) is also thought to play a key role, as may the anti-angiogenic pigment epithelium-derived factor (PEDF).

2Morphology. CNV membranes that remain sub-RPE are termed type 1, and when growth extends subretinally are known as type 2.

Clinical features

1Presentation is with relatively rapid onset (often over days) of painless blurring of central vision including metamorphopsia. A positive scotoma may be described, particularly if haemorrhage has occurred.

2Signs. Although the CNV itself can on occasion be visualized as a grey-green or pinkish-yellow lesion, most signs are caused by complications as follows:

•Localized subretinal fluid and occasionally CMO.

•Intraand subretinal lipid deposition, sometimes extensive (Fig. 14.45A).

•Haemorrhage (Fig. 14.45B) which may be subretinal, preretinal, vitreous and associated with PED.

•Retinal and subretinal cicatrization ('disciform scar’ – Fig 14.45C) in an evolved or treated lesion.

•Exudative retinal detachment which may be extensive (Fig. 14.45D), resulting in total visual loss.

•The prognosis of untreated CNV is often very poor, with reduction of vision to the ‘hand movements’ level not uncommon.

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Fig. 14.45 Complications of choroidal neovascularization. (A) Extensive lipid deposition; (B) bleeding; (C) ‘disciform’ scarring; (D) extensive exudative retinal detachment in end-stage disease

Fluorescein angiography

FA is used primarily to confirm a suspected diagnosis of CNV prior to committing the patient to anti-VEGF treatment. Precise localization is now much less important and the distinction between classic and occult CNV membranes less relevant than formerly. Monitoring now consists predominantly of serial retinal thickness or volume assessment with OCT. The terminology commonly used to describe the FA appearances of CNV is derived from the Macular Photocoagulation Study (MPS) as follows:

1Classic CNV is a well-defined membrane which fills with dye in a ‘lacy’ pattern during the early phases of dye transit (Fig. 14.46B), fluoresces brightly during peak dye transit (Fig. 14.46C), and then leaks into the subretinal space and around the CNV over 1

–2 minutes. The fibrous tissue within the CNV then stains with dye exhibiting late hyperfluorescence (Fig. 14.46D). It is typically seen when CNV is subretinal rather than sub-RPE. Classic CNV is classified topographically according to its relation to the centre of the FAZ on FA as follows:

•Extrafoveal; 200–1500 µm from the centre.

•Juxtafoveal; 1–200 µm.

•Subfoveal (see Fig. 14.46); most membranes are subfoveal at presentation.

2Occult CNV is used to describe CNV when its limits cannot be fully defined on FA (Fig. 14.47), typically when growth is between the RPE and Bruch membrane. Variants distinguished in the MPS classification are fibrovascular PED (see above) and ‘late leakage of an undetermined source’ (LLUS), areas of leakage in the late phase of the angiogram without classic CNV or fibrovascular PED. CNV may be said to be ‘predominantly’ or ‘minimally’ classic when the classic component is greater or less than 50% of the total lesion. The MPS classification also refers to ‘components’ of the lesion such as adjacent blood, serous PED or pigment which may be obscuring part of the CNV, and which are counted as part of the total lesion.

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Fig. 14.46 FA of classic subfoveal CNV. (A) A few specks of blood at the fovea; (B) FA arteriovenous phase shows ‘lacy’ hyperfluorescence; (C) venous phase shows more intense hyperfluorescence; (D) late phase shows persistent hyperfluorescence due to staining

Fig. 14.47 FA of occult CNV. (A) Specks of blood at the fovea; (B–D) FA shows diffuse hyperfluorescence but the limits of the membrane cannot be defined

Indocyanine green angiography

ICGA demonstrates CNV as a focal hyperfluorescent ‘hot spot’ or ‘plaque’, and can be an extremely useful adjunct to FA for the following reasons:

•Increased sensitivity in the detection of CNV, for instance when the presence of low-density haemorrhage, fluid or pigment precludes adequate FA visualization (Fig. 14.48A–D).

•The distinction of CNV from other diagnoses having a similar clinical presentation, particularly PCV, retinal angiomatous proliferation (RAP) and central serous chorioretinopathy (CSR).

•The delineation of occult CNV is now much less important since the introduction of anti-VEGF treatment. It may still have utility for combined modality treatment, and for patients who refuse intravitreal therapy.

•The identification of vascular feeder complexes supplying areas of CNV, again less important with the advent of anti-VEGF treatment.

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•The management of RAP, when the identification of feeder vessels may facilitate their photoablation.

•The management of PCV, especially the localization of vascular complexes.

Fig. 14.48 ICGA of CNV. (A) Blood and fluid at the macula surrounded by hard exudates; (B–D) shows a small area of increasing hyperfluorescence (‘hot spot’) fromunderlying CMV

Optical coherence tomography

The major use of OCT in the management of CNV is in monitoring the response to treatment, for which it provides an accurate quantitative assessment. OCT has to date been of limited help in the diagnosis of CNV, though ongoing improvements in structural definition with newer high resolution devices, including three-dimensional imaging and the ability to construct separate images of different retinal layers, is likely to lead to increasing utility. Typically, CNV is shown as a thickening and fragmentation of the RPE/choriocapillaris high-reflectivity band.

Subretinal and sub-RPE fluid (Fig. 14.49A), blood and scarring (Fig. 14.49B) are demonstrated.

Fig. 14.49 OCT. (A) CNV and subretinal fluid; (B) subretinal scarring

(Courtesy of C Barry)

Treatment with anti-VEGF agents

1Principles. These agents prevent the VEGF-A form of the cytokine interacting with the relevant receptors on the endothelial cell surface and so retard or reverse CNV. They have become the predominant means of treatment for CNV, dramatically improving the

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visual prognosis. Intravitreal injection is the standard method of administration, notable risks including retinal detachment, damage to the lens, RPE tears and endophthalmitis. Elevated intraocular pressure and sterile uveitis may also occur. Systemically, there is a suggestion of a slightly increased incidence of stroke.

2Indications. Predominantly classic, minimally classic and occult CNV subtypes all respond to anti-VEGF therapy, but benefit is only likely in the presence of active disease. Evidence for active CNV includes fluid or haemorrhage, leakage on FA, an enlarging CNV membrane, or deteriorating vision judged likely to be due to CNV activity. An eye with almost any level of vision may benefit, although better VA at the outset is associated with a better final VA and patients with only ‘hand movements’ should be assessed on an individual basis.

3Contraindications. The presence of a fibrotic disciform scar makes treatment extremely unlikely to be useful, even in the presence of active CNV. RPE tears may be a relative contraindication.

Ranibizumab (Lucentis)

Ranibizumab is a humanized monoclonal antibody fragment developed specifically for use in the eye. It non-selectively binds to and inhibits all isoforms of VEGF-A. The optimal timing of intravitreal injections is not yet clearly defined. The usual dose is 0.5 mg in 0.05 mL. Three main treatment strategies are currently adopted:

1Regular monthly injection is the regimen adopted in initial major trials. Overall, around 95% of patients maintain vision regardless of lesion type, and 35–40% significantly improved, most markedly during the first 3 months.

2Three initial monthly injections followed by monthly review with re-injection when deterioration occurs as assessed by VA (e.g. loss of 5 letters or more) and OCT (e.g. retinal thickness increase of 100 µm or more).

3'Treat and extend’ entails administering three initial injections at monthly intervals and then gradually increasing the period between injections until deterioration is evident. If possible a tailored interval is determined for each patient.

Bevacizumab (Avastin)

In contrast to ranibizumab, bevacizumab (Avastin) is a complete antibody and is very much cheaper; at present its use for AMD is ‘off label’.

Limited results suggest that it is effective – perhaps comparably to ranibizumab – and safe for intravitreal injection and trials are ongoing to compare the two. As bevacizumab is a larger molecule than ranibizumab, it may be retained in the vitreous for a longer period, so may need to be given less frequently. Speculatively it might also be associated with fewer systemic side-effects, at least in comparison with the

0.5 mg dose of ranibizumab; the bevacizumab 1-year stroke rate is around 0.5%, similar to the normal population rate. The dose of bevacizumab is usually 1.25 mg/0.05 mL or 2.5 mg/0.1 mL.

Pegaptanib (Macugen)

Pegaptanib sodium was the first anti-VEGF agent approved by regulatory authorities for ocular treatment. Although offering visual outcomes superior to photocoagulation, the results are similar to outcomes with PDT (see below), and use of pegaptanib is considerably less widespread than other anti-VEGF agents.

Technique of intravitreal injection

1Preparation

a The environment should be appropriate: an operating room or dedicated ‘clean room’ with adequate illumination.

bThe procedure and its risks should be explained to the patient and appropriate consent obtained.

cTopical anaesthetic and mydriatic agents are instilled. Subconjunctival lidocaine 1% may be used to supplement the topical agent, particularly if a wider-gauge needle is used (no larger than 27-gauge).

dSome authorities recommend pre-injection topical antibiotics, typically for 3 days.

eFive per cent povidone iodine is applied to the ocular surface and at least three minutes allowed prior to injection (if allergic to iodine an alternative such as chlorhexidine can be used).

f Hands are washed using a standard surgical procedure, and sterile gloves donned.

gThe periocular skin, eyelids and lashes are cleaned with 5–10% povidone iodine.

hAs for other forms of intraocular surgery, an adhesive clear plastic sterile drape may be advisable, though is not universally used.

iA sterile speculum is placed in the eye.

2Technique

aThe patient is instructed to look away from the injection site – this is most commonly inferotemporal because of ease of access.

b A gauge is used to mark an injection site 3.5–4.0 mm posterior to the limbus (pars plana).

cThe sterile pouch containing a pre-prepared syringe is opened, or a sterile syringe is used to draw up the appropriate volume of drug from a vial of ready-prepared drug. A needle (typically 30-gauge) on the syringe is primed to expel any air.

dForceps can be used to stabilize the eye (and if wished to apply anterior traction to the conjunctiva so that the hole in the conjunctiva does not overlie the scleral injection site; a sterile cotton applicator is an alternative for this purpose).

eThe needle is advanced perpendicularly through the sclera towards the centre of the eyeball, and the required volume of drug (0.5–1.0 mL) is slowly injected into the vitreous cavity. For larger gauge needles, stepping the entry site should be considered.

fThe needle is removed and discarded. To minimize reflux including vitreous prolapse (‘vitreous wick syndrome’), a sterile cotton-tipped applicator can be rolled over the entry site as the needle is withdrawn.

gBroad-spectrum antibiotic drops are instilled immediately after the injection, and continued four times daily for at least 3 days.

hElevated IOP can occlude the central retinal artery, and it is important routinely to ensure this remains perfused after the procedure by checking the patient's vision (subjectively is adequate), directly visualizing the artery, or checking the IOP; the latter should always be considered in glaucoma patients. If the artery occludes, urgent paracentesis should be carried out; it may be helpful for the patient to lie down as this may improve blood flow.

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Patients should be able to return to normal activity after 24 hours, but should be warned to seek advice urgently should they experience any deterioration in their vision or symptoms of inflammation.

Photodynamic therapy (PDT)

1Principles. Verteporfin (Visudyne®) is a light-activated compound that is preferentially taken up by dividing cells including neovascular tissue. It is injected intravenously and is then activated focally by illumination with relatively low-energy light from a diode laser source at a peak absorption wavelength of the compound, leading to thrombosis. The main advantage of PDT is its sparing of healthy tissue (Fig. 14.50). The availability of anti-VEGF treatments has been associated with a dramatic reduction in the use of PDT. However, it remains useful in certain circumstances such as patient refusal of intravitreal treatment and as a component of combination therapy (see below).

2Indications. In eyes with subfoveal predominantly classic CNV not larger than 5400 µm and a visual acuity of 6/60 or better. Other categories, particularly small occult and larger predominantly classic lesions, may also stabilize with PDT.

3Technique involves the intravenous infusion of verteporfin (6 mg/kg body weight) over 10 minutes, followed 5 minutes later by laser to an area 1000 µm larger than the greatest dimension of the CNV membrane for 83 seconds. Re-treatment is applied to areas of persistent or new leakage at 3-monthly intervals, with a mean of about five treatments in the first 2 years.

4Side-effects include transient lower backache during infusion, transient decrease in vision, injection site reaction, and sensitivity to bright light for 24–48 hours. Preceding PDT with intravitreal steroid injection may confer an improved outcome.

Fig. 14.50 Photodynamic therapy. (A) Small dirty grey lesion at the fovea surrounded by blood; (B) FA venous phase shows hyperfluorescence fromclassic subfoveal CNV surrounded by a hypofluorescent ring; (C) greatest linear dimension of the lesion; (D) FA 3 months following successful treatment shows hypofluorescence at the site of the lesion

(Courtesy of S Milewski)

Combination therapies

Although anti-VEGF therapy has revolutionized the management of CNV, further investigation is attempting to achieve outcomes which are better still. A principal goal is a reduction in the frequency of intravitreal injections, in view particularly of the rare but potentially severe adverse effects. It is hoped that the use of more than one treatment modality in combination will facilitate this. Regimens include the combination of PDT with antiVEGF, PDT with intravitreal steroid, steroid and anti-VEGF and ‘triple therapy’: with steroid/anti-VEGF/PDT.

Argon laser photocoagulation

Thermal laser ablation of CNV is now rarely used, though may still be suitable for treatment of classic extrafoveal membranes and some cases of PCV and RAP.

Experimental treatments

A range of additional treatment modalities are under investigation. Examples include:

•Brachytherapy with low-intensity strontium-90.

•VEGF Trap-Eye: an inhibitor binding all forms of VEGF-A to D as well as Placental Growth Factor, given intravitreally.

•Inhibitors of other cytokines such as platelet-derived growth factor and integrin.

•Small interfering RNAs using gene-specific RNA strands to modify gene expression.

•VEGF receptor tyrosine kinase inhibitors.

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•Sustained-release anti-VEGF systems, including microsphere encapsulation.

•Gene therapy utilizing adenoviral vectors; it is envisaged that delivery via this method would obviate the need for repeated intravitreal injections.

•Artificial retina implants.

Haemorrhagic AMD

The visual prognosis for most eyes with extensive subretinal or sub-RPE haemorrhage is poor, although the following should be considered.

1Stop coumarin anticoagulant therapy, if appropriate, after liaising with the prescribing physician. Antiplatelet agents usually do not need to be discontinued.

2Intravitreal anti-VEGF injection may be beneficial in some patients with thin (<1 mm) haemorrhage.

3For massive haemorrhage in an eye with previously good vision, options include:

•Observation.

•Intravitreal anti-VEGF alone.

•Intravitreal recombinant tissue plasminogen activator (rTPA) and pneumatic (e.g. SF6 gas) haemorrhage displacement, with or without intravitreal VEGF inhibitor.

•Vitrectomy with subretinal rTPA combined with the above.

Retinal angiomatous proliferation

Retinal angiomatous proliferation (RAP) is a variant of exudative AMD in which the major component of the neovascular complex is initially located within the retina. The process may originate within the deep retinal capillary plexus or within the choroid, in the latter case with the early formation of retinal–choroidal anastomoses (RCA) without an underlying type 1 neovascular membrane. The disease is often bilateral and symmetrical and visual deterioration can be rapid and profound.

Diagnosis

1Presentation is similar to that of AMD but PED and exudate are more common. Haemorrhages are also more common and tend to be superficial and multiple.

2Stages

aStage I shows intraretinal neovascularization (IRN) – intraretinal angiomatous proliferation. Dilated retinal vessels develop, typically accompanied by intra-, suband preretinal haemorrhage, oedema and exudate (Fig. 14.51A).

bStage II manifests subretinal neovascularization (SRN) – proliferation extends posteriorly into the subretinal space and is associated with increasing oedema and exudate. An RCA and serous PED may be present.

cStage III in which CNV is clearly evident clinically or angiographically. A vascularized PED (V-PED), RPE tear or demonstrable RCA may be present. A disciform scar will often form.

3OCT demonstrates the neovascularization as a hyper-reflective area. There will typically be cystoid macular oedema, subretinal fluid, and underlying elevation of the RPE.

4 FA is usually similar to purely occult or minimally classic CNV (Fig. 14.51B), but may show focal intraretinal hyperfluorescence.

5ICGA is diagnostic in most cases, showing a hot spot in mid or late frames (Fig. 14.51C), and sometimes a characteristic ‘hairpin loop’.

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Fig. 14.51 Retinal angiomatous proliferation. (A) Macular drusen and a small intraretinal haemorrhage at the macula; (B) FA early venous phase shows faint hyperfluorescence froma small frond of intraretinal neovascularization; (C) ICGA late phase shows hyperfluorescence of the frond (‘hot spot’)

(Courtesy of Moorfields Eye Hospital)

Treatment

Optimal management has yet to be determined. VEGF has been identified in excised RAP lesions, suggesting a useful role for anti-VEGF therapy, and reports to date show promising results. Limited success has been reported for other treatments including focal photocoagulation of the intraretinal component, PDT, intravitreal steroid and surgical section of supplying vessels. The condition may occasionally resolve spontaneously.

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Polypoidal choroidal vasculopathy

Overview

Polypoidal choroidal vasculopathy (PCV), also known as posterior uveal bleeding syndrome, is an idiopathic choroidal vascular disease characterized by a dilated network of inner choroidal vessels with multiple terminal aneurysmal protuberances. It is more common in patients of African and East Asian ethnic origin than in whites and more common in women than men (5 : 1). The disease is often bilateral but asymmetrical in severity.

Diagnosis

1Presentation is usually in late middle age (average age 60) with sudden onset unilateral visual impairment.

2Signs

•Terminal swellings are frequently visible as reddish-orange nodules beneath the RPE in the peripapillary or macular area, and less commonly the periphery.

•Multiple recurrent serosanguineous retinal and RPE detachments (Fig. 14.52A).

•Deterioration can be slow with intermittent bleeding and leakage, resulting in macular damage and visual loss.

•Up to 50% may have a favourable outlook, with eventual spontaneous resolution of exudation and haemorrhage.

3ICGA is essential for diagnosis.

•Early stages show a network of large choroidal vessels with surrounding hypofluorescence.

•Polyp-like swellings (Fig. 14.52B and C) then appear on the larger vessels and rapidly begin to leak.

•The previously darker surrounding region becomes hyperfluorescent by the late phase (Fig. 14.52D).

•A cluster of grapes-like lesion may carry a higher risk of severe visual loss.

4Differential diagnosis is mainly with AMD; the two conditions sometimes coexist.

Fig. 14.52 Polypoidal choroidal vasculopathy. (A) Haemorrhagic RPEdetachment and macular exudate; (B–C) ICGA shows blockage by blood and hyperfluorescence of a polyp-like frond nasal to the fovea; (D) late hyperfluorescence due to staining

Treatment

The favourable prognosis without treatment in a substantial proportion of cases should be borne in mind.

•Asymptomatic polyps should usually be observed without treatment.

•Anti-VEGF agents appear to be less effective than in the CNV of AMD.

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•PDT is more effective in PCV than AMD, although recurrence is common.

•Laser photocoagulation of feeder vessels or leaking polypoidal lesions may be effective in selected cases.

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