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

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Age-related macular degeneration

Introduction

Age-related macular degeneration (AMD), also known as age-related maculopathy (ARM), is a degenerative disorder affecting the macula. It is characterized by the presence of specific clinical findings including drusen and RPE changes as early features with no evidence the signs are secondary to another disorder. Later stages of the disease are associated with impairment of vision.

Classification

1Conventionally AMD is divided into two main types:

aDry (non-exudative) AMD is the most common form, comprising around 90% of diagnosed disease; geographic atrophy (GA) is the advanced stage of dry AMD.

bWet (exudative) AMD is much less common than dry, but is associated with more rapid progression to advanced sight loss. The main manifestations are (CNV) and pigment epithelial detachment (PED). Occasionally, the dry form can develop into the wet.

2The International Age-Related Maculopathy Epidemiological Study Group (IARMESG) published guidance in 1995 in an attempt to standardize terminology, including referring to all signs of age-related macular change as age-related maculopathy (ARM), but usage continues to vary.

aEarly AMD (‘early ARM’ in the IARMESG classification) is characterized by medium-large drusen, RPE hyperpigmentation and/or hypopigmentation. This stage is frequently known simply as ‘ARM’.

bAdvanced AMD (IARMESG: ‘late ARM’ or just ‘AMD’) is more severe, with GA and/or CNV.

Epidemiology

•AMD is the most common cause of irreversible visual loss in industrialized countries. In the USA, it is responsible for around 54% of severe sight loss (better eye worse than 6/60) in Caucasian, 14% in Hispanic and 4% in black individuals. The prevalence increases with age and symptoms are rare in patients less than 50 years of age.

•In the UK, significant visual impairment (binocularly 6/18 or worse) from AMD affects about 4% of the population aged over 75 years and 14% of those over 90, with 1.6% over 75 having binocular acuity of less than 6/60.

•Patients with advanced AMD (late ARM) in one eye, or even moderate vision loss due to non-advanced AMD in one eye, have about a 50% chance of developing advanced AMD in the fellow eye within 5 years.

Risk factors

AMD is multifactorial in aetiology, and is thought to involve a complex interaction between genetic and environmental factors.

1Age is the major risk factor.

2Race. Late ARM is more common in Caucasians than other races, despite a similar prevalence of early ARM.

3Heredity. Family history is important. Variants in many genes have been implicated in AMD risk and protection such as chromosome 1q32 for complement factor H (CFH), which helps to protect cells from complement-mediated damage, the hemicentin gene on 1q24-25, and the ABCR gene on chromosome 1p (also important in Stargardt disease/fundus flavimaculatus).

4Smoking roughly doubles the risk of AMD.

5Hypertension and other cardiovascular risk factors are likely to be associated.

6Dietary factors. High fat intake and obesity may promote AMD, with high antioxidant intake having a protective effect in some groups (see below).

7Other factors such as cataract surgery, blue iris colour, high sunlight exposure, and female gender are suspected, but their influence remains less certain.

Drusen

Histopathology

1Definition. Drusen (singular: druse) are extracellular deposits located at the interface between the RPE and Bruch membrane. The material of which they are composed has a broad range of constituents, and is thought to be derived from immune-mediated and metabolic processes in the RPE.

2Role in pathogenesis of AMD is unclear. Age-related drusen are rare prior to the age of 40, but are common by the 6th decade. The distribution is highly variable, and they may be confined to the fovea, may encircle it or form a band around the macular periphery. They may also be seen in the peripheral and mid-peripheral fundus.

3A distinction between ‘hard’ and ‘soft’ drusen is useful clinically and evident histopathologically (Fig. 14.36), although the underlying pathophysiological processes may be similar. Features associated with an increased risk of subsequent visual loss include large soft and/or confluent drusen, and associated focal hyperpigmentation of the RPE.

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Fig. 14.36 Histology of drusen. (A) Hard drusen are discrete, homogeneous, eosinophilic nodular deposits lying between the RPEand the inner collagenous layer of Bruch membrane; (B) soft drusen are non-homogeneous, eosinophilic deposits with ill-defined margins

(Courtesy of J Harry)

Clinical features

1Hard drusen are well-defined and less than half a retinal vein width (< 63 µm) in diameter (Fig. 14.37A). Their presence as the only

finding probably carries little increased risk of visual loss, and so they frequently are not included in definitions of ARM.

2Soft drusen are less distinct and generally substantially larger than hard drusen (Fig. 14.37B). It has been suggested that the presence of more than five soft drusen might be taken as a defining feature of ARM. As soft drusen enlarge and become more numerous, they may coalesce giving a localized elevation of the RPE, a ‘drusenoid RPE detachment’ (Fig. 14.37C) – see below. Dystrophic calcification may develop in both types of drusen (Fig. 14.37D).

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Fig. 14.37 Drusen. (A) Hard drusen; (B) soft drusen; (C) coalescence of soft drusen; (D) calcified drusen

Fluorescein angiography

Fluorescein angiographic findings depend on the state of the overlying RPE and on the affinity of the drusen for fluorescein. Hyperfluorescence can be caused by a window defect due to atrophy of the overlying RPE, or by late staining (Fig. 14.38). Hypofluorescent drusen masking background fluorescence are hydrophobic, with a high lipid content, and tend not to stain.

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Fig. 14.38 (A) Soft drusen; (B) FA shows late hyperfluorescence

Lesions related to drusen

A number of conditions feature lesions similar to age-related drusen, and at least some may have a similar pathophysiological basis.

1Doyne honeycomb retinal dystrophy (malattia leventinese, autosomal dominant radial drusen) is an uncommon condition in which drusen appear during the 2nd–3rd decades (see Ch. 15); the genetic basis has been established for the majority of cases.

2‘Cuticular’ drusen, also known as ‘grouped early adult-onset’ or ‘basal laminar’ drusen (not to be confused with basal linear deposits, nodular thickenings of Bruch membrane seen in ARM), tend to be seen in relatively young adults. The lesions consist of small (25–75 µm) yellowish nodules (Fig. 14.39A) which tend to cluster and increase in number with time and can progress to serous PED. FA may give a ‘stars in the sky’ appearance (Fig. 14.39B). The condition has been linked to a variant of the CFH gene.

3Type 2 membranoproliferative glomerulonephritis is a chronic renal disease that occurs in older children and adults. A minority of patients develop bilateral diffuse drusen-like lesions. The CFH gene has again been implicated.

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Fig. 14.39 (A) Cuticular drusen; (B) FA shows hyperfluorescent spots – ‘stars in the sky’ appearance

(Courtesy of C Barry)

Prophylactic antioxidant supplementation in AMD

There is substantial evidence, notably from the Age-Related Eye Disease Study (AREDS), that taking high dose antioxidant vitamins and minerals on a regular basis can decrease the risk of AMD progression.

Recommendations for use

The recommendation was made in AREDS that individuals aged over 55 should undergo examination for the following high risk characteristics, and if one or more are present should consider antioxidant supplementation:

•Extensive intermediate-sized drusen.

•At least one large (≥ 125 µm) druse.

•Geographic atrophy in one or both eyes.

•Advanced AMD in one eye (greatest benefit in AREDS).

The reduction in risk of progression to further visual loss at 5 years is in the order of 25% for those taking supplements with the more advanced of these signs at baseline; supplements did not discernibly reduce progression in those with early or no AMD.

Regimen

The regimen used in AREDS is set out below:

•500 mg of vitamin C.

•400 IU of vitamin E.

•15 mg of beta-carotene.

•80 mg of zinc, with 2 mg of copper (cupric oxide) to prevent zinc-induced copper deficiency.

Other considerations

Although supplementation is generally very safe, possible adverse effects include an increased risk of lung cancer with beta-carotene in smokers and ex-smokers, genitourinary tract problems with high zinc intake, and heart failure in people with vascular disease or diabetes (vitamin E).

•Macular xanthophylls (lutein and zeaxanthin) and omega-3 fatty acids may also be of benefit and many of the preparations available commercially now contain these. Trials such as AREDS2 are ongoing to try to establish the optimal nutrient combination.

•A liberal green leafy vegetable intake confers a lower risk of AMD, and for individuals with a strong family history of AMD and those with early AMD who do not meet the AREDS criteria, this may be a prudent lifestyle choice.

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•Cessation of smoking should definitely be advised in these circumstances, and protective measures against exposure to excessive sunlight might be considered.

Non-exudative (dry) AMD

Diagnosis

1Symptoms consist of gradual impairment of vision over months or years. Both eyes are usually affected, but often asymmetrically. Vision may fluctuate, and is often better in bright light.

2Signs in approximately chronological order:

•Numerous intermediate-large soft drusen (Fig. 14.40A) which can become confluent.

•Focal hyperand/or hypopigmentation of the RPE.

•Sharply circumscribed areas of RPE atrophy associated with variable loss of the retina and choriocapillaris (Fig. 14.40B and C).

•Enlargement of atrophic areas, within which larger choroidal vessels may become visible and pre-existing drusen disappear (GA; Fig. 14.40D). Visual acuity may be severely impaired if the fovea is involved. Rarely, CNV may develop in an area of GA.

•'Drusenoid’ RPE detachment (see below). Many authorities regard the development of any form of PED as defining conversion to ‘wet’ AMD, regardless of evidence of CNV.

3FA of atrophic areas shows a window defect due to unmasking of background choroidal fluorescence (Fig. 14.40E and F), if the underlying choriocapillaris is still intact. Exposed sclera may exhibit late staining.

Fig. 14.40 Atrophic age-related macular degeneration. (A) Drusen and mild RPEchanges; (B) drusen and moderate retinal atrophy; (C) drusen and geographic atrophy; (D) geographic atrophy and disappearance of drusen; (E) FA arteriovenous phase shows slight hyperfluorescence; (F) FA late phase shows intense hyperfluorescence (window defects)

Management

1Prophylaxis

•Antioxidant supplementation if indicated.

•Treatable risk factors should be addressed such as smoking, assessment of cardiovascular and dietary considerations, ocular sun protection measures and possibly a higher threshold for cataract surgery.

2An Amsler grid should be provided for home use, with advice to self-test on a regular basis (perhaps weekly), seeking appropriate

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professional advice urgently in the event of any change.

3Provision of low vision aids, and for patients with significant visual loss, certification as visually impaired where this is available may facilitate access to social and financial support.

4Experimental surgery

•Miniature intraocular telescope implantation may be of benefit in selected cases.

•Retinal translocation surgery involving 360° retinotomy with retinal rotation, in conjunction with extraocular muscle surgery to correct torsion. There is a high risk of subsequent retinal detachment complicated by PVR. Accelerated degeneration of the ‘new’ macula may occur.

5Laser photocoagulation of drusen leads to their disappearance, but does not seem to reduce the risk of progression to AMD.

Retinal pigment epithelial detachment

Pathogenesis

Pigment epithelial detachment (PED) from the inner collagenous layer of Bruch membrane is caused by disruption of the physiological forces maintaining adhesion. The basic mechanism is thought to be the reduction of hydraulic conductivity of a thickened and dysfunctional Bruch membrane, thus impeding movement of fluid from the RPE towards the choroid. Immune-mediated processes may also be important. The different types are discussed below.

Serous PED

1Symptoms consist of blurred central vision and metamorphopsia. In some cases the former may be partly due to induced hypermetropia.

2Signs

•An orange dome-shaped elevation with sharply delineated edges, often with a paler margin of subretinal fluid (Fig. 14.41A). Multiple lesions of diverse size may occur.

•A pigment band on the dome is thought to indicate chronicity.

•Associated subretinal fluid in an irregular distribution raises the suspicion of underlying CNV, as does the presence of chorioretinal folds.

•Sub-RPE or subretinal blood and retinal lipid are particularly suggestive of CNV.

•If no drusen are seen, polypoidal choroidal vasculopathy (PCV – see below) should be suspected.

3FA shows a well demarcated oval area of hyperfluorescence which increases in intensity but not in area with time: ‘pooling’ (Fig. 14.42B, and see Fig. 14.26). A notch in the circumscribed area may signify the presence of CNV.

4ICGA demonstrates an oval area of hypofluorescence with a faint ring of surrounding hyperfluorescence (Fig. 14.42C). CNV is detected in more than 90% of cases as focal CNV (‘hot spot’) or diffuse ‘plaque’ CNV, or a combination of both.

5OCT shows separation of the RPE from Bruch membrane by an optically empty area (Fig. 14.42D). CNV may be indicated in a serous PED by a notch between the main elevation and a second small mound.

6Natural course

•Patients over the age of 60 tend to have a worse prognosis. The eventual outcome tends to be poor (acuity 6/60 or less) whatever the specific course, although the speed of visual loss varies.

•RPE tear formation (see below) is associated with particularly rapid visual loss, as is haemorrhage from CNV.

•Chronicity with increasing atrophy and gradually worsening vision, or spontaneous resolution leaving an area of GA can occur.

•Spontaneous resolution without significant permanent visual loss is more common in younger patients.

•Up to about a third of patients develop clinical CNV within 2 years of diagnosis, although a much larger proportion has CNV on angiography.

7Management

•Observation may be appropriate in patients without detectable CNV, especially those younger than 60 years of age.

•Intravitreal injection of vascular endothelial growth factor (VEGF) inhibitors, particularly ranibizumab and bevacizumab, may stabilize vision and improve the morphological features of vascularized PED, although this carries about a 10% risk of RPE tear formation.

•Combined PDT and intravitreal anti-VEGF has also been effective at stabilizing vision, though the RPE tear risk persists at around 10%.

•Combined photodynamic therapy (PDT) and intravitreal triamcinolone injection (IVTA) may be beneficial in some cases.

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Fig. 14.41 Detachment of the RPE. (A) Clinical appearance; (B) FA shows hyperfluorescence; (C) ICGA shows hypofluorescence with a faint ring of surrounding hyperfluorescence; (D) OCTshows separation of the RPEfromBruch membrane

(Courtesy of P Gili – figs A and B; fig. C – A Bolton; C Barry – fig. D)

Fig. 14.42 Drusenoid detachment of the RPE. (A) Clinical appearance; (B) FA late phase shows moderate hyperfluorescence due to staining

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Fibrovascular PED

By definition (Macular Photocoagulation Study classification) fibrovascular PED represents a form of ‘occult’ CNV (see below).

1Signs. The PED is much more irregular in outline and elevation than in serous PED.

2 FA shows markedly irregular granular or ‘stippled’ hyperfluorescence, with uneven filling of the PED, leakage and late staining.

3ICGA demonstrates CNV more effectively.

4OCT will demonstrate the PED, which will be optically denser than a serous PED in places, fibrous proliferation being shown as deeper scattered reflections. Subretinal fluid will be demonstrated.

5Management is essentially as for serous PED with CNV.

Drusenoid PED

Drusenoid PED develops from confluent large soft drusen (Fig. 14.42A).

1Signs. Shallow elevated pale areas with irregular scalloped edges that are often bilateral.

2FA shows early diffuse hypofluorescence with patchy relatively faint early hyperfluorescence, progressing to moderate irregular late staining (Fig. 14.42B).

3ICGA shows predominantly hypofluorescence.

4OCT shows homogeneous hyperreflectivity within the PED, in contrast to the optically empty appearance of a serous PED. There will usually be no subretinal fluid.

5Natural course. The outlook is usually better than other forms of PED, with only gradual visual loss, though probably around 75% still progress to develop GA and 25% CNV by 10 years from diagnosis. They often remain stable for long periods: at 3 years, only about one-third will have GA or CNV.

6Management consists of observation in most cases, with no evidence to support the efficacy of any intervention.

Haemorrhagic PED

Virtually all eyes with haemorrhagic PED have underlying CNV or polypoidal choroidal vasculopathy (PCV): consider the latter if no drusen are seen.

1Symptoms consist of sudden impairment of central vision.

2Signs

•Elevated dark red dome-shaped lesion with a well-defined outline (Fig. 14.43A).

•The blood may break through into the subretinal space assuming a more diffuse outline and a lighter red colour (Fig. 14.43B).

3 FA exhibits dense masking of background fluorescence, but overlying vessels are visible.

4Management of large haemorrhagic lesions is described below (‘haemorrhagic AMD’) but the prognosis for central vision is generally poor. CNV associated with a small haemorrhagic PED can be managed conventionally (see below for management of PCV).

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Fig. 14.43 (A) Haemorrhagic detachment of the RPE; (B) blood has broken through into the subretinal space

Retinal pigment epithelial tear

1Pathogenesis. An RPE tear may occur at the junction of attached and detached RPE if tangential stress becomes sufficient. Tears may occur spontaneously, following laser photocoagulation or PDT of a PED or associated CNV, or after intravitreal injection of antiVEGF agent or steroid for any form of wet AMD. Older patients and large, irregular PEDs associated with CNV are at higher risk for this complication.

2 Presentation when the fovea is involved is with sudden worsening of central vision.

3Signs. A crescent-shaped pale area of RPE dehiscence is seen, next to a darker area corresponding to the retracted and folded flap (Fig. 14.44A).

4FA late phase shows hypofluorescence over the flap due to the thickened folded RPE, with adjacent hyperfluorescence over the exposed choriocapillaris where the RPE is absent. The two areas are separated by a well-defined linear border (Fig. 14.44B).

5OCT shows loss of the normal dome-shaped profile of the RPE in the PED, with hyper-reflectivity adjacent to the folded RPE (Fig. 14.44C).

6The prognosis in subfoveal tears is poor although a minority of eyes maintain good visual acuity, particularly if the fovea is spared.

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