age-related macular degeneration: diagnosis and management

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Age-related macular degeneration: diagnosis

and management

H. L. Cook, P. J. Patel, and A. Tufail

Moorfields Eye Hospital, City Road, London EC1V 2PD, UK

Background: Age-related macular degeneration (AMD) is a leading cause of

blind registration in Western Europe and the third leading cause of blindness

worldwide.

Methods: The management of AMD is discussed with a review of current and

new treatments.

Results: Although there is no treatment for advanced dry AMD (geographicatrophy), there have been considerable advances in the management of

neovascular AMD (nAMD). Established therapies for nAMD include laser

photocoagulation and photodynamic therapy (PDT), but these have largely been

superseded by agents which block the action of vascular endothelial growth

factor (anti-VEGF agents). Current preventative strategies involve cessation of

smoking and use of specific nutritional supplements to reduce the risk of

developing nAMD.

Conclusions: There have been exciting advances in the treatment of nAMD and

increased understanding of the genetics and pathogenic mechanisms involved

will hopefully lead to the development of new therapies in the future.

Keywords: age-related macular degeneration/treatment/diagnosis/prophylaxis

Introduction

Age-related macular degeneration (AMD) is the leading cause of blindness and visual disability in patients aged 60 years in Europeand North America.1 Worldwide, AMD is the third leading cause of

blindness, behind cataract and glaucoma, causing 8.7% of all legalblindness.2 The clinical spectrum of AMD encompasses drusen, hyper-plasia of the retinal pigment epithelium (RPE), geographic atrophy andchoroidal neovascularization (CNV). These changes affect the maculaof the retina and subsequently may affect central or reading visualacuity.

AMD has been classified in one of the two ways. It can be dividedinto two broad clinical categories depending on whether there is a

British Medical Bulletin 2008; 85: 127–149

DOI:10.1093/bmb/ldn012

& The Author 2008. Published by Oxford University Press.

All rights reserved. For permissions, please e-mail: [email protected]

Accepted: January 10,

2008

Correspondence to

Mr A. Tufail

Moorfields Eye Hospital

City Road

London

EC1V 2PD

E-mail: adnan.tufail@

moorfields.nhs.uk

Published Online xx, 2008


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presence of abnormal neovascularization: neovascular (synonymouswith exudative or wet) and dry AMD. A second classification is useddepending on the extent of visual impairment; late AMD, whichincludes neovascular AMD and an advanced dry form called geo-graphic atrophy and early AMD that includes all other forms (Fig. 1).

Early (dry) AMD is more prevalent than neovascular AMD in the UKand USA. However, patients with neovascular AMD account for75% of cases of severe visual impairment secondary to AMD.3

Patients with early (dry) AMD consisting of drusen and hyperplasiaof the RPE may have no visual difficulties (Fig. 2). A minority of patients with early (dry) AMD may progress to geographic atrophy.Geographic atrophy is gradually progressive, and may involve thecentre of the fovea causing central visual loss (Fig. 3). Geographicatrophy accounts for 25% of patients with severe visual loss second-ary to AMD.3

It is believed that the changes in Bruch’s membrane and RPE thatoccur in dry AMD may give rise to a state where blood vessels maysprout off existing choriocapillaris (pro-angiogenic state). These vesselsthen break through the normal level of Bruch’s membrane into thesub-RPE or sub-retinal spaces. Neovascular AMD is defined by thedevelopment of CNV. The patient will often report a sudden worseningof their central vision, often with distortion. Clinically, the CNV pro-duces haemorrhage, exudative retinal detachment or serous or haemor-rhagic pigment epithelial detachments (Fig. 4). In end-stage disease,this results in a fibrovascular or atrophic macular scar and subsequentpermanent damage to the central vision.

Fig. 1 Classification of age-related macular degeneration.

H. L. Cook et al.

128 British Medical Bulletin 2008;85


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Fig. 2 Fundus photograph showing an eye with drusen and RPE hyperplasia.

Fig. 3 Fundus photograph showing an eye with advanced geographic atrophy (dry AMD).

Age-related macular degeneration

British Medical Bulletin 2008;85 129


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Prevalence/demographics

Friedman et al.4 found that AMD occurs in patients over the age of 55 years. Prevalence increases substantially with increasing age. Theyalso estimated that AMD affects .1.75 million individuals aged 40years in the USA. Owing to the rapidly ageing population, this figure isprojected to rise to almost 3 million by 2020. Furthermore, 10–15%of patients with AMD have severe loss of central vision.

The prevalence of AMD varies between racial groups with higherprevalence in European-descended populations. Pooled data from threelarge epidemiological studies showed that drusen were stronglyage-related in the black population, and that sight-threatening AMDwas less prevalent than in a white population.4 Hispanic and LatinAmerican populations seem to have a lower incidence of advanced andneovascular AMD than European-descended white populations.1,5

There is little data available on other population groups.

Risk factors for the development of AMD

There have been a number of studies investigating risk factors for thedevelopment of AMD. However, there have been conflicting results for

Fig. 4 Fundus photograph showing an eye with neovascular age-related macular

degeneration.

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many risk factors in different study populations.6 The only consistentlypositive associations are smoking and a genetic component.

SmokingThere is a strong epidemiological association between smoking and thedevelopment of advanced AMD. Current smokers have an increasedrisk of developing dry and neovascular AMD relative to non-smokerswith an odds ratio (OR) of 2.83 and 2.35, respectively. Past smokershave an OR of 2.80 and 1.82, respectively, when compared with non-smokers.7 Cigarette smoking confers an increased risk of developingAMD in addition to known genetic associations8 (see Geneticssection). The benefit of smoking cessation to prevent second eyedisease has not been evaluated.

Genetics

Both Beaver Dam and Rotterdam studies found an increased risk of AMD developing in relatives of affected individuals. The OR for asibling of an affected individual developing neovascular AMD after5-year follow-up in the Beaver Dam study was 10.3.6 In the Rotterdamstudy, there was an OR of 6.6 for signs of early AMD in the offspringof affected individuals when compared with offspring of non-affectedindividuals.6

Three studies have found an association between a polymorphism incomplement factor H (a control protein involved in the regulation of the alternative pathway of the complement cascade) and AMD.9–11

The relative risk of developing AMD with the common polymorphismT ! C substitution in exon 9 of the complement factor H gene isabout 2.3 –2.7 for heterozygotes and 3.5 –7.4 for homozygotes.9–11

This finding has been subsequently supported by findings in otherpopulation groups.12–15 Another member of the complement system,factor B, has also been shown to have both high-risk and protectivevariants associated with the development of AMD.16 A third gene

(LOC387715) found on chromosome 10, whose gene product has afunction yet to be fully elucidated, has an independent effect on AMDalmost as strong as that of the Factor H gene.17,18 Interestingly, boththe high-risk variants of Factor H and LOC387715 interact with ciga-rette smoking to confer an increased risk of developing AMD thaneach factor alone.8 These exciting discoveries should lead to improvedunderstanding of the pathogenesis of AMD and the development of novel therapies.




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Natural history

Approximately 90% of the white population aged 40 years will haveone or two small hard drusen (,63 mm in diameter) in the macula of either eye. There is almost no risk of progression to advanced AMD in

these eyes. However, in eyes with .8 small hard drusen (Fig. 2), thereis a 2–3-fold increased risk of developing large soft drusen (125 mmin diameter, where 125 mm is approximately the width of a retinal veinat the optic nerve head) and pigmentary changes after 10 years. Largesoft drusen are associated with a 6–7-fold increased risk of progressionto advanced AMD. Large numbers of small hard drusen are alsoassociated with progression to geographic atrophy.6 Patients with neo-vascular AMD in one eye have an 50% risk of second eye CNV at 7years follow-up.3,53

Diagnosis

History

Patients usually present with distortion, blurring or a scotoma (blackor grey patch) in their central vision, which is rapid in onset in neo-vascular AMD and more gradually progressive in geographic atrophy.Patients with dry AMD in both eyes or unilateral neovascular AMDmay be asymptomatic or just complain of mild distortion in theirvision and be detected as an incidental finding at a routine opto-

metric assessment. Patients with vision loss from late AMD (definedas presence of CNV or GA) in both eyes can develop visual halluci-nations (Charles Bonnet syndrome). Visual hallucinations may beunformed (coloured lights or patterns) or formed (animals, peopleand scenes). Many patients will not volunteer these symptoms unlessdirectly asked.

Clinical examination

Patients with drusen and mild pigmentary changes alone may have avisual acuity within the normal range. Patients with late AMD usually

have reduced visual acuity in the affected eye. An area of central distor-tion or scotoma may be mapped out by the patient on an Amsler grid.Examination of the fundus, preferably using a stereoscopic viewingmethod (slit-lamp biomicroscopy), shows the presence of drusen, pig-mentary, exudative, haemorrhagic or atrophic changes affecting themacula. Non-stereoscopic examination (direct ophthalmoscopy orfundal photography) may miss retinal thickening or elevation due toneovascular AMD.

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Additional tests

Fluorescein angiography is used to confirm the presence and nature of neovascular AMD. Sodium fluorescein dye is injected intravenously.Fundus photographs are then taken through a barrier filter as the fluor-escent dye fills the choroidal and retinal circulations. CNV can be

defined either by its anatomical location relative to the centre of thefovea or by its filling characteristics. Treatment is often determinedbased on an understanding of these two angiographic findings.‘Classic’ CNV membranes fill with dye in the arterial phase, are welldefined and leak fluorescein dye beyond the borders in later shots.Lesions that leak in a less clearly demarcated pattern in later shots, butnot in the early shots, are termed ‘occult’ lesions. CNV may be predo-minately classic (greater than 50% classic component) or minimallyclassic (50% or less classic component). Currently, the determinationof the type of neovascular AMD is essential in order to assess the suit-ability for treatment modalities such as laser photocoagulation andphotodynamic therapy (PDT), but pharmacologic therapies (anti-VEGFagents) are effective in treating all subtypes of CNV.

Lesions are also divided into extrafoveal, juxtafoveal or subfovealtypes depending on their location. The location of the lesion influencestreatment options.

† Extrafoveal lesions: 200–2500 mm from the fovea

† Juxtafoveal lesions: 1–199 mm from the fovea

† Subfoveal lesions involve the centre of the fovea.

Optical coherence tomography may also be a useful adjunctive diag-nostic tool. This device produces a cross-sectional image through theretina, RPE and choroid, and can measure macular thickness and thetissue plane of fluid collections. This can be helpful in determiningthe presence of pigment epithelial detachments and in patients withallergy to sodium fluorescein.

Differential diagnosis of CNV

CNV can occur secondary to other disease processes that alter theintegrity of the Bruch’s membrane/RPE complex, such as pathologicalmyopia (short-sightedness greater than 26 dioptres). Myopic patients

can develop atrophic or neovascular changes that are similar to AMD,but may appear at a younger age and have a different natural historyand response to treatment. Some inflammatory eye diseases result inCNV, but there are usually signs of active or previous uveitis thatwould not be present in AMD. Some inherited macular dystrophiesmay look similar to dry AMD. However, these are usually very sym-metrical, there may be a family history and onset is usually at anearlier age.




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Management

If neovascular AMD is present, the type and location of CNV must bedetermined by fluorescein angiography, ideally within a few days of onset of symptoms, as treatment options and response to treatment andsubsequently final visual outcome are better in early disease. For thisreason, at risk patients with known dry AMD are asked to regularlycheck the vision in the fellow eye using an Amsler grid or similar targetand to seek urgent ophthalmic review if they develop new visual symp-toms. Table 1 gives an overview of treatments for neovascular AMDand there is more detailed discussion below.

At present, there is no proven treatment for patients with dry AMDprogressing to atrophy, although the cessation of smoking and the useof high-dose antioxidant vitamins may reduce the risk of CNV devel-oping (see below).

Conventional laser treatment

Argon laser photocoagulation can be used to ablate the area of activeCNV in patients with neovascular AMD. The MacularPhotocoagulation study established that laser photocoagulation pre-vented severe loss of vision (loss of six or more lines of visual acuity) inextrafoveal CNV secondary to AMD.19 This randomized, controlledtrial (RCT) terminated recruitment to the extrafoveal arm at 18months as 60% of untreated eyes but only 25% of treated eyes hadsevere visual loss.19 A 5-year follow-up data showed that 64% of untreated eyes developed severe visual loss compared with 46% of

treated eyes at 5 years.20 However, there is a 54% recurrence rate at 5years after treatment. Approximately 75% of recurrences occur withinthe first year.

Patients with juxtafoveal CNV fared less well than extrafoveal CNV.At 5-year follow-up, 55% of treated patients had experienced severevisual loss compared with 65% controls.21 A sub-group analysis foundthat classic CNV without an occult component benefited from treat-ment and that juxtafoveal lesions with an occult component did notbenefit from laser photocoagulation.

Patients with treated subfoveal CNV were less likely to have severe

visual loss at 4-year follow-up than untreated eyes (23 versus 45%).22

However, this treatment is rarely performed as there is a significantrisk of immediate worsening of vision in treated patients (20% chanceof severe visual loss within 3 months in the treated group versus 11%of controls) and there are now available other treatments for subfoveallesions.

Only a minority (13% in a series by Freund et al.) of patients pre-senting with neovascular AMD fulfil the treatment criteria for argon

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Table 1 Table comparing different treatment modalities available for neovascular AMD.

Treatment Trial name Trial

method

CNV Lesion Type Number in trial (eyes) Total follow-up

(years)

Visual outco

Treatment

group (eyes)

Control

group

(eyes)

Treatment g

(eyes)

Medical

Argon laser

photocoagulation

MPS RCT New subfoveal 77 83 4 SVL 22%

Juxtafoveal 138 138 5 SVL 52%

Extrafoveal 119 117 5 SVL 46%

PDT TAP RCT All subfoveal with

some classic

component

402 207 2 MVL or bett

53%

SVL, 18%

Predominately classic 159 83 2 MVL, 46%

SVL, 19%

Minimally classic 202 104 2 MVL, 53% SVL, 26%

Classic, no occult 93 49 2 MVL or bett

70%

VIP RCT Subfoveal occult no

classic CNV

166 92 2 MVL in 55%

Pegaptanib

(Macugenw)

VISION RCT Subfoveal classic and

occult

890 (3

subgroups with

different doses)

296 1 SVL 10% wi

0.3 mg dose

Ranibizumab

(Lucentisw)

MARINA RCT Su bfoveal occult/

minimally classic

240 (0.5 mg

subgroup)

238 2 90% lost ,

33% gained

letters

ANCHOR RCT Subfoveal

predominantly classic

140 (0.5 mg

subgroup)

143 PDT

treated

1 96% lost ,

40% gained

letters

B r i t i s h M e d i c al B ul l e t i n2 0 0

8 ; 8 5

1 3 5

b y g u e s t o n A p r i l 7 , 2 0 1 6 h t t p : / / b m b . o x f o r d j o u r n a l s . o r g / D o w n l o a d e d f r o m

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Table 1 Continued

Treatment Trial name Trial

method

CNV Lesion Type Number in trial (eyes) Total follow-up

(years)

Visual outco

Treatment

group (eyes)

Control

group

(eyes)

Treatment g

(eyes)

Bevacizumab

(Avastinw)

Spaide

et al.35PCS Subfoveal CNV 266 0 Variable (2

month data

available for 222

eyes)

31% had vis

improvemen

2-month fol

Intravitreal TCA

(single dose)

Gillies

et al.34RCT Subfoveal CNV with

any classic component

73 70 1 SVL 35%.

PDT plus intravitreal

TCA 25 mg

Augustin

et al.55PCS All CNV 184 (148

subfoveal, 19

juxta-, 17 extra)

0 Variable Mean visua

improved by

Snellen line

Anecortave acetate(15 mg dose)

D’Amicoet al.36

RCT Subfoveal CNV (25 eyeswith predominately

classic CNV)

33 eyes 30 eyes 1 79% lost ,

3% SVL

Anecortave acetate Slakter

et al.37RCT Subfoveal

predominantly classic

263 267 1 45% lost ,

Surgical

Macular

translocation

Aisenbrey

et al.45PCS Subfoveal CNV 90 0 1 27% increas

by 15 lette

Limited macular

translocation

Fujii et al.48 RCS 86 0 1 40.7% achie

visual acuity

100 or bette

CNV, choroidal neovascularization; MPS, Macular Photocoagulation Study; RCT, randomized controlled trial; SVL, severe visual loss (lo

MVL, moderate visual loss; RR, relative risk; PDT, photodynamic therapy; TAP, Treatment of Age-Related Macular degeneration with Ph

Verteporfin in Photodynamic Therapy Study; VISION VEGF, Inhibition Study in Ocular Neovascularization; MARINA, Minimally classic/o

Ranibizumab In the treatment of Neovascular AMD (presented but not published); ANCHOR, ANti-VEGF Antibody for the Treatment o

Neovascularization in AMD (presented but not published); TCA, triamcinolone acetonide; BCVA, best corrected visual acuity; PCS, pros

case series.

1 3 6

B r i t i s h M e d i c al B ul l e t i n2 0 0 8 ; 8 5

b y g u e s t o n A p r i l 7 , 2 0 1 6 h t t p : / / b m b . o x f o r d j o u r n a l s . o r g / D o w n l o a d e d f r o m

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laser therapy.23 Current recommendations are that conventional lasertreatment is an option for patients with extrafoveal CNV or juxtafovealclassic no-occult CNV where the lesion is outside the foveal avascularzone or juxtafoveal classic no-occult CNV when PDT is unavailable.Patients are counselled that they will have a dense scotoma in the

location of the treatment but that the aim of the treatment is to pre-serve central vision and minimize the final size of the scotoma.However, newer treatment options (anti-VEGF agents) avoid scotomaand offer the prospect of visual improvement.

PDT with Verteporfin

PDT utilizes a 10-min intravenous infusion of Verteporfin (a photosen-sitising drug) followed by application of a diode laser (689 nm) to theaffected area in the retina 15 min after the start of the infusion. Light isabsorbed by the photosensitizer molecules, which causes an oxidationprocess in lipid membranes and proteins. This leads to disruption of cellular structures and subsequent thrombosis and vascular occlusion inactive CNV. Verteporfin is relatively contraindicated in patients withliver disease or a history of porphyria. Patients should avoid sunlightexposure for 48 h after treatment.

A systematic review of two RCTs, the Treatment of AMD withPhotodynamic therapy (TAP) Study and Verteporfin in PhotodynamicTherapy (VIP) Study, found that PDT with Verteporfin significantlyreduced the risk of moderate and severe visual loss at 24 months com-pared with placebo (moderate visual loss: OR, 0.77; severe visual loss:

OR, 0.62) in eyes with subfoveal CNV measuring 5400 mm causedby AMD.24 Two-year follow-up data showed that 77% of eyes with100% classic lesions lost less than 15 letters after PDT treatment com-pared with 31% in the placebo group.25 Two-year follow-up data forpredominately classic lesions showed 59% of eyes lost less than 15letters of visual acuity compared with 31% of the placebo group.25

Patients with 100% occult lesions respond relatively well to PDT treat-ment (51% of treated patients lost ,15 letters versus 25% controls at2 years).26 A controversial sub-group analysis found maximal benefitin smaller lesions and those with poor initial vision. Patients with mini-

mally classic lesions or occult classic CNV were not shown to benefitfrom PDT in randomized trials. Most practitioners would not use PDTfor these indications and would instead treat with available anti-VEGFagents (see later section).

Patients usually require a course of treatment at three monthly inter-vals (mean number of treatments is 5 over 2 years). There is an 1%risk of sudden permanent worsening of the vision following the treat-ment with PDT (5% in patients with occult lesions).




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Anti-angiogenic drugs

There is currently extensive research into modulating the angiogenicresponse in AMD.

Anti-vascular endothelial growth factor

There is extensive in vitro and in vivo evidence that VEGF is implicatedin retinal angiogenesis and vascular permeability. There has beenintense laboratory and clinical research in this area, and researchershave developed agents that block VEGF activity some of which arealready in clinical use:

1. Pegaptanib Sodium (Macugenw)Pegaptanib (Macugenw, Eyetech Pharmaceuticals, NY, USA) is a selec-

tive anti-VEGF oligonucleotide conjugated with a polyethylene glycol thatbinds to the major human soluble VEGF isoform (VEGF165). A phase IIIRCT comparing intravitreal doses of 0.3, 1.0 and 3.0 mg and sham injec-tion showed that with six weekly injections over a 48-week period therewas a significant reduction in moderate visual loss (,15 letters lost) at 54weeks follow-up. In the 0.3 mg treatment group, there was a statisticallysignificant increase in the proportion of patients with stable visionwith 70% losing ,15 letters versus 55% in the sham treatment group(P, 0.001).27 Side-effects included endophthalmitis (0.16%), lens trauma(0.7%) and retinal detachment (0.6%).27,28 Pegaptanib has now beenlicensed for clinical use in the USA and Europe.

2. Ranibizumab (Lucentisw)A recombinant anti-VEGF monoclonal antibody fragment that binds to

all isoforms of VEGF-A (Ranibizumab, Lucentisw; Genentech, CA, USA)

has been developed. Recent published Phase III data show a benefit fromtreatment for all lesion types and sizes with ranibizumab with repeatedfour weekly intravitreal injections. The ANCHOR study29 randomized423 patients with predominantly classic neovascular AMD to monthlyinjections of Lucentisw at two different doses or to conventional treat-ment with verteporfin PDT. The 12-month results showed 94.3% of patients treated with 0.3 mg Lucentisw and 96.4% treated with 0.5 mglost ,15 letters on visual acuity testing compared with 64.3% in thePDT-treated group. In addition, visual acuity improved by 15 letters in35.7% of the 0.3 mg Lucentisw-treated group and 40.3% of the0.5 mg-treated group with only 5.6% of PDT-treated patients improving

vision. The average visual acuity change was a gain of 8.5 letters in the0.3-mg group and 11.3 letters in the 0.5-mg group compared with adecrease of 9.5 letters in the PDT-treated group at 12 months. TheMARINA study30 randomized 716 patients with minimally classic oroccult neovascular AMD to monthly injections of Lucentisw at two differ-ent doses or to sham treatment. The 24-month results showed 92% of patients treated with 0.3 mg Lucentisw and 90% treated with 0.5 mg lostfewer than 15 letters on visual acuity testing compared with 52.9% in thesham-treated group. In addition, visual acuity improved by 15 letters in

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26.1% of the 0.3 mg Lucentisw-treated group and 33.3% of the 0.5-mgtreated group compared with only 3.8% of sham injection group. Theaverage visual acuity change was a gain of 5.4 letters in the 0.3-mg groupand 6.6 letters in the 0.5-mg group compared with a decrease of 14.9letters in the sham injection group at 24 months. The risk of endophthal-mitis in the two studies was 1.4% over 2 years (0.05% per intravitrealinjection). Further studies have investigated the efficacy of as requiredranibizumab intravitreal injections in treating neovascular AMD in orderto explore the possibility of reducing the number of intravitreal treatmentswhile maintaining efficacy. The PIER study31 was a prospective, multi-centre, randomized, controlled trial of 184 patients with subfoveal CNVdue to AMD received either ranibizumab (0.3 or 0.5 mg) or sham treat-ment once a month for 3 months and followed by doses every once every3 months for a total of 24 months in a 1:1:1 ratio. At the 12 months,patients with quarterly treatment gained a mean of 2.9 ETDRS letters(0.3 mg group) or 4.3 letters (0.5 mg group) compared with a mean lossof 8.7 letters for the sham group with 12% (0.3 mg group) and 13%

(0.5 mg group) gaining 15 letters or more. This study suggests that theefficacy of ranibizumab is reduced if given as a quarterly treatment. Theresults from the PrONTO study,32 which was a prospective open-labelinterventional case series of neovascular AMD patients with subfovealCNV treated with three consecutive monthly intravitreal injections of rani-bizumab (0.5 mg) with further injections if clinically indicated, supportthis treatment strategy. At month 12, the mean visual acuity improved by9.3 letters (P, 0.001) and the mean OCT central retinal thicknessdecreased by 178mm (P, 0.001). Visual acuity improved 15 or moreletters in 35% of patients. These visual acuity and OCT outcomes wereachieved with an average of 5.6 injections over 12 months. This small

study suggests visual acuity outcomes similar to the Phase III clinicalstudies, may be achieved with fewer intravitreal injections.

3. Bevacizumab (Avastinw)Initially developed for use in oncology (licensed for use in colorectal

cancer), bevacizumab (Avastinw) has been increasingly used as an intra-vitreal injection to treat neovascular AMD. Bevacizumab is a full-length,humanized, monoclonal antibody binding all forms of VEGF-A. Severalpublished case series have suggested efficacy similar to that of Lucentisw,but as yet there have been no prospective, randomized, controlled trialspublished. The largest retrospective case series of 266 eyes with follow-upof 2 months (data available for 222 eyes) showed visual acuity improve-

ment in 31.1% with a statistically significant reduction in mean centralmacular thickness.33 The evidence for the efficacy of intravitreal bevacizu-mab in treating neovascular AMD is from interventional case series withno reports from multi-centre, randomized, controlled trials. However,despite the availability of a licensed alternative treatment (ranibizumab),there is widespread, worldwide ‘off-label’ use of bevacizumab for thisindication as Lucentis, is significantly more expensive than Avastin and asAvastin was available prior to the licensing of Lucentis. This has given rise




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to the highly unusual situation of a drug (Avastin) used for an unlicensedindication despite robust clinical trials supporting the safety and efficacyof a licensed alternative (Lucentis) in treating wet AMD.

Intravitreal VEGF inhibitors appear to be relatively free from systemicside-effects and complications although systemic VEGF-A inhibition

may predispose to thrombo-embolic complications and an excess riskof thrombo-embolic complications was reported in the first year of follow-up in the ranubizumab (Lucentisw) randomized, controlledtrials which diminished in the second year of follow-up. The SAILOR(Safety Assessment of Intravitreal Lucentis for AMD) study is anongoing phase IIIb study with patients randomized to 0.3 or 0.5 mg of Lucentis. A planned interim safety analysis from this study reported ahigher risk of cerebrovascular accidents in the 0.5 mg group (1.2%)compared with the 0.3 mg group (0.3%). The results of further clinicaltrials are awaited, and other VEGF or VEGF receptor blocking drugs

are also under development.Selected treatments still undergoing evaluation

Transpupillary thermotherapy

Transpupillary thermotherapy (TTT) involves the use of a long-pulsediode laser (810 nm) to occlude CNV. A formal RCT (TTT4CNVTrial) did not show any benefit in treating subfoveal occult CNV sec-ondary to AMD compared with sham (presented at ARVO AnnualMeeting 2005 by Reichel et al.).

SteroidsA number of different steroids have been evaluated and different deliv-ery vehicles including depot preparations are in development.However, published data are limited to triamcinolone acetonide andanecortave acetate.

Triamcinolone

Triamcinolone acetonide is a glucocorticoid and if injected into thevitreous, it may have an effect for up to 4–6 months. A RCT toevaluate a single dose of 4 mg intravitreal triamcinolone acetonide

versus placebo in the treatment of 151 eyes with CNV with a classiccomponent found no difference in risk of severe visual loss betweentreatment and control groups at 1 year.34 A number of small, non-randomized trials have been performed using repeated doses of triamci-nolone 25 mg; however, there is no robust data to show a benefit overnatural history. Currently, no good RCT data exist to support its useyet either alone or in combination with other therapies although thereis a suggestion of enhanced efficacy in combination with PDT.35

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Several RCTs are ongoing, including one using a preservative freeversion of triamcinolone that may have less associated ocular morbidityand combination with other treatment.

Anecortave acetate

Anecortave acetate is a synthetic angiostatic steroid that has no glu-cocorticoid activity and a good ocular safety profile. It prevents vas-cular growth by inhibiting proteases necessary for endothelial cellmigration. A RCT of 128 patients investigated the use of sixmonthly juxtascleral (injection into the tissue plane between theTenon’s sheath and sclera rather than into the vitreous cavity) injec-tion of anecortave acetate at 3, 15 and 30 mg doses versusplacebo.36 At 1-year follow-up, patients in the 15 mg treatmentgroup did significantly better than the control group in mean

change from baseline visual acuity (P ¼ 0.01), stabilization of visualacuity (P ¼ 0.03) and prevention of severe visual loss (P ¼ 0.02).There were no significant safety issues. A phase III equivalencystudy between 15 mg anecortave against PDT did not reach itsprimary endpoint of equivalency despite similar outcomes betweenthe two groups37 (see Table 1). The authors felt that the outcomeof anecortave was limited by reflux during delivery and furthertrials are ongoing with modification of the delivery technique.Anecortave has received a license for use in neovascular AMD inAustralia in 2006.

Medical treatments not shown to be beneficial by RCTs

Radiotherapy

Low doses of ionizing radiation can inhibit vascular endothelial cellproliferation in vitro and prevent angiogenesis in vivo. A systematicreview of 11 trials of teletherapy (external beam radiotherapy) foundgreat variability in the treatment methods and was unable to draw anyfirm conclusions about the efficacy of radiotherapy.38

Alpha-interferon treatment

A large RCT evaluating alpha-interferon as a treatment in wet AMDfound no statistically significant benefit from treatment (three differentdosages) compared with placebo over a 1-year period.39 Therefore,alpha-interferon is not recommended as a treatment in wet AMD.




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Surgical treatments

There are a number of surgical techniques available in the managementof wet AMD. These techniques are only performed by a limitednumber of surgeons.

Excision of choroidal neovascular membranes

This involves performing a pars plana vitrectomy then removing theCNV via a retinotomy incision. This method theoretically preservesfoveal retinal photoreceptors and is suitable for occult lesions as theprecise anatomical boundaries of the CNV do not need to be deli-neated. A multi-centre RCT of 454 eyes found no statistical differencebetween the treatment group and controls at 24 months.40 There wasan increased risk of retinal detachment in the treatment group com-

pared with controls.

Retinal pigment epithelial cell transplantation

Exogenous RPE transplantation

It is thought that the reason for poor visual acuity outcomes followingCNV excision is removal of RPE cells with the excised CNV complex.This leads to choriocapillaris atrophy and subsequent loss of photo-receptor function due to ischaemia. New techniques using RPE cell

transplantation aim to overcome this issue. Early studies using humanfoetal RPE cell transplants gave disappointing results due to the devel-opment of chronic cystoid macular oedema which affected centralvisual acuity.

Autologous RPE transplantation

Recent studies using autologous RPE transplantation have had morepromising results. A consecutive patient case series of 53 patients withsubfoveal CNV found a statistically significant improvement in readingvisual acuity between the group with CNV excision and autologousRPE transplantation when compared with the group with CNV exci-sion only.41 However, the complication rate is too high currently to usethis approach outside research studies.42

Evacuation of submacular haemorrhage

Large submacular haemorrhage secondary to wet AMD carries apoor visual prognosis due to the development of subretinal fibrosis.

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Early surgical removal of haemorrhage has been advocated to preventpermanent visual loss. Mechanical removal of clot results in extensiveiatrogenic damage. A large RCT investigating surgery for haemorrhagicCNV (lesions composed of .50% haemorrhage) found that there wasno difference in the risk of loss of two or more lines of visual acuity at

2 years between the treatment and control groups (56% of treatedcases versus 59% of controls).43 However, the risk of severe visual losswas less in the surgery group (36% control group versus 21% surgerygroup, P ¼ 0.004). A newer technique using tissue plasminogen activa-tor (tPA) without the need for a vitrectomy has been described.However, the numbers of patients treated are small and no RCT hasbeen performed.44 Combined evacuation of blood with retinal translo-cation is described below.

Macular translocationThis procedure aims to relocate the fovea to an adjacent area of healthy RPE in eyes with subfoveal CNV. There are two main methodsfor relocating the fovea.

36088888 Retinotomy and macular translocation

A pars plana vitrectomy is performed followed by a 3608 retinotomy.The retina is then artificially detached, rotated around the optic nerveand re-attached. The largest case series to date presented by Aisenbreyet al.45 found that 24/90 (27%) had three or more line gain on the

ETDRS chart at 12 months and that 32% had three or more line lossof vision. The complication rate was high in initially reported series(retinal detachment in 29% mainly due to proliferative vitreoretinopa-thy, CNV recurrence in 22% and cystoid macular oedema in 52%),but is reducing in more recent series.46 A recent pilot RCT comparingsurgery to PDT reported a higher proportion of patients improvingvision after macular translocation surgery at 1 year follow-up.47

Additional strabismus surgery is required and some patients have per-sistent diplopia. The surgery is complex and the operation is lengthy,but has potential in very selected cases to restore vision.

Limited macular translocation

Limited macular translocation involves a chorioscleral shortening pro-cedure to move the fovea to a healthy area of RPE. This can beachieved by infolding or outpouching of the sclera, which createsredundancy of the retinal tissue which can then be displaced 1–2 mm.There are no RCTs of this technique. The largest retrospective caseseries to date reported outcomes on 102 eyes; of which, 1-year




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follow-up was achieved in 86.48 This study found that 39.5% had atwo or more lines of improvement in visual acuity. However, there wasa 34.6% CNV recurrence rate; of which, 65% of recurrences were sub-foveal and resulted in loss of visual acuity.

The arrival of anti-VEGF agents has restricted the use of surgery to

selected cases in specialist centres.

Combination therapy

The use of anti-VEGF agents with intensive patient follow-up andrepeated intravitreal injections every 4–6 weeks has led to an interestin combination therapies both to reduce retreatment rates and toimprove outcomes. Numerous case series and retrospective studies havebeen published evaluating combination therapies in wet AMD but atpresent, there is no clear data on the usefulness of combination thera-pies although there is a suggestion of benefit from combining PDT andintravitreous triamcinolone. There are, however, several RCTs under-way to investigate the role of combination therapies with the prospectof reducing the frequency of anti-VEGF therapy.

Prophylaxis

Nutritional supplements

A large RCT of 3640 patients [Age-related Eye Disease Study

(AREDS)] investigated four nutritional treatments for the prevention of advanced AMD (development of CNV or geographic atrophy).49 Thesetreatments were placebo, zinc (80 mg plus copper 2 mg/daily), antioxi-dants (vitamin C 500 mg plus vitamin E 400 IU plus beta-carotene15 mg/daily) and zinc plus antioxidants. Overall, it was found thatcompared with placebo, zinc plus antioxidants significantly reducedthe proportion of patients progressing to advanced AMD (OR, 0.72;99% CI, 0.52– 0.98) or moderate visual loss (OR, 0.73; 99% CI,0.54–0.99) over a 6-year period.

The visual benefit is greatest, and was statistically significant in

people with late AMD in one eye and early AMD in the other. There isno benefit in patients with no signs of AMD or those with bilateral,advanced AMD. These high doses of zinc and anti-oxidants cannot beachieved from diet alone. There was little evidence of harm in thisstudy although some patients developed yellowing of the skin second-ary to anti-oxidant ingestion and increased admission for genitourinarycomplications secondary to zinc ingestion. There is good evidence fromother studies that the beta-carotene component increases the risk of

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lung cancer in smokers, and this treatment is currently not rec-ommended in smokers or ex-smokers. There are currently no RCTs onother nutritional supplements such as lutein or doses of anti-oxidantsother than those used in the RCT described above.

Laser to drusenTwo RCTs have investigated the use of laser to eyes with drusen toprevent subsequent development of advanced AMD50,51,54. The studyby Olk et al.50 in 229 eyes found a statistically significant increase invisual acuity in eyes with drusen treated with diode laser comparedwith eyes with no treatment at 2 years (improvement of 2 lines in11% with laser versus 0% with no treatment; 95% CI, 6– 25).However, a second RCT by the Choroidal NeovascularizationPrevention Trial Research Group found that in the subgroup of peoplewith unilateral drusen, laser significantly increased the incidence of

CNV compared with no treatment [estimated 12-month incidence17% with laser versus 3% with no treatment (P, 0.05)].51,54 In viewof the increased risk of CNV, laser treatment for drusen is not currentlyrecommended.

Anecortave acetate

A multi-centre RCT is currently underway to evaluate the use of jux-tascleral injection of anecortave acetate as a prophylactic treatment infellow eyes of patients with unilateral advanced wet AMD.

Supportive measures

Low vision aids and eccentric fixation methods

Treatment may or may not be possible in patients with AMD, but mostwill benefit from supportive measures. These include simple advice onadequate lighting in the home and for near-vision tasks. Formal assess-ment for low visual aids by a trained optometrist will enable thepatient to optimize the use of the vision that he or she has. Closedcircuit television (CCTV) aids are useful for some patients to enlargetext, but are expensive to purchase.

Some patients can be trained to use eccentric fixation in order toimprove their visual acuity. This technique involves the patient lookingjust to one side of the object of interest rather than directly at theobject. Healthier juxtafoveal retina can then be used to produce animage. No good RCTs exist to determine the effectiveness of lowvisual aids yet.

Formal partial-sighted or blind registration also enables patients toaccess social support and practical advice on modifications to the




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home and the provision of other aids. Many patients also benefit fromcounselling either formally or informally through patient supportgroups.

Implantable miniature telescope

In addition to standard low-vison aids, newer approaches to visualrehabilitation have included the implantable miniature telescope.52

This is a monocular-fixed focus telescopic device implanted into thepatients eye during cataract surgery which provides magnification of the central vision at the expense of the field of view. There have beenencouraging results in clinical trials with further trials ongoing.

Current treatment recommendations for wet AMD

The introduction of anti-VEGF agents has revolutionized the manage-ment of wet AMD. In a rapidly changing field, our current recommen-dations for management include:

1. Pan-anti-VEGF blockade using ranibizumab. The use of Avastin remainscontroversial, but potentially very cost-effective.

2. Argon laser ablative therapy restricted to small, well-defined extra-fovealCNV.

3. The role of PDT may be in combination therapy and is subject to furtherstudy at present.

4. Surgical macular translocation may be considered in selected cases includ-ing second affected eyes not suitable for anti-VEGF therapy (includingRPE.rips involving the macula).

5. Preventative measures including cessation of smoking and use of AREDSnutritional supplements.

Summary

AMD is an increasing health burden throughout the world and is thethird commonest cause of visual impairment worldwide. There are a

number of established treatment options as well as promising therapiesand surgical approaches under evaluation to stabilize vision in wetAMD. It is, therefore, important that patients with symptoms of impaired central vision should be seen and assessed promptly by anophthalmologist in order that appropriate investigations can be per-formed to assess suitability for treatment. All patients should also haveaccess to supportive measures and appropriate advice on lighting, etc.The role of prophylactic treatments is also important in order to

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preserve central vision. The increasing understanding of the geneticsand pathogenesis of AMD may lead to the development of morespecific and effective therapies in the future.

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age-related macular degeneration: diagnosis and management

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