Age-related macular degeneration: diagnosis and management

Transcription

Published Online xx, 2008
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
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 (geographic
atrophy), 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superseded by agents which block the action of vascular endothelial growth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
Accepted: January 10,
2008
Correspondence to
Mr A. Tufail
Moorfields Eye Hospital
City Road
London
EC1V 2PD
E-mail: adnan.tufail@
moorfields.nhs.uk
Age-related macular degeneration (AMD) is the leading cause of
blindness and visual disability in patients aged 60 years in Europe
and North America.1 Worldwide, AMD is the third leading cause of
blindness, behind cataract and glaucoma, causing 8.7% of all legal
blindness.2 The clinical spectrum of AMD encompasses drusen, hyperplasia of the retinal pigment epithelium (RPE), geographic atrophy and
choroidal neovascularization (CNV). These changes affect the macula
of the retina and subsequently may affect central or reading visual
acuity.
AMD has been classified in one of the two ways. It can be divided
into two broad clinical categories depending on whether there is a
British Medical Bulletin 2008; 85: 127–149
DOI:10.1093/bmb/ldn012
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Background: Age-related macular degeneration (AMD) is a leading cause of
blind registration in Western Europe and the third leading cause of blindness
worldwide.
H. L. Cook et al.
Fig. 1 Classification of age-related macular degeneration.
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British Medical Bulletin 2008;85
presence of abnormal neovascularization: neovascular (synonymous
with exudative or wet) and dry AMD. A second classification is used
depending on the extent of visual impairment; late AMD, which
includes neovascular AMD and an advanced dry form called geographic atrophy and early AMD that includes all other forms (Fig. 1).
Early (dry) AMD is more prevalent than neovascular AMD in the UK
and USA. However, patients with neovascular AMD account for
75% of cases of severe visual impairment secondary to AMD.3
Patients with early (dry) AMD consisting of drusen and hyperplasia
of 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 the
centre of the fovea causing central visual loss (Fig. 3). Geographic
atrophy accounts for 25% of patients with severe visual loss secondary to AMD.3
It is believed that the changes in Bruch’s membrane and RPE that
occur in dry AMD may give rise to a state where blood vessels may
sprout off existing choriocapillaris ( pro-angiogenic state). These vessels
then break through the normal level of Bruch’s membrane into the
sub-RPE or sub-retinal spaces. Neovascular AMD is defined by the
development of CNV. The patient will often report a sudden worsening
of their central vision, often with distortion. Clinically, the CNV produces haemorrhage, exudative retinal detachment or serous or haemorrhagic pigment epithelial detachments (Fig. 4). In end-stage disease,
this results in a fibrovascular or atrophic macular scar and subsequent
permanent damage to the central vision.
Age-related macular degeneration
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).
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H. L. Cook et al.
Prevalence/demographics
Friedman et al. 4 found that AMD occurs in patients over the age of
55 years. Prevalence increases substantially with increasing age. They
also estimated that AMD affects .1.75 million individuals aged 40
years in the USA. Owing to the rapidly ageing population, this figure is
projected 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 higher
prevalence in European-descended populations. Pooled data from three
large epidemiological studies showed that drusen were strongly
age-related in the black population, and that sight-threatening AMD
was less prevalent than in a white population.4 Hispanic and Latin
American populations seem to have a lower incidence of advanced and
neovascular 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 the
development of AMD. However, there have been conflicting results for
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Fig. 4 Fundus photograph showing an eye with neovascular age-related macular
degeneration.
many risk factors in different study populations.6 The only consistently
positive associations are smoking and a genetic component.
Smoking
Genetics
Both Beaver Dam and Rotterdam studies found an increased risk of
AMD developing in relatives of affected individuals. The OR for a
sibling of an affected individual developing neovascular AMD after
5-year follow-up in the Beaver Dam study was 10.3.6 In the Rotterdam
study, there was an OR of 6.6 for signs of early AMD in the offspring
of affected individuals when compared with offspring of non-affected
individuals.6
Three studies have found an association between a polymorphism in
complement 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 polymorphism
T ! C substitution in exon 9 of the complement factor H gene is
about 2.3– 2.7 for heterozygotes and 3.5–7.4 for homozygotes.9 – 11
This finding has been subsequently supported by findings in other
population groups.12 – 15 Another member of the complement system,
factor B, has also been shown to have both high-risk and protective
variants associated with the development of AMD.16 A third gene
(LOC387715) found on chromosome 10, whose gene product has a
function yet to be fully elucidated, has an independent effect on AMD
almost as strong as that of the Factor H gene.17,18 Interestingly, both
the high-risk variants of Factor H and LOC387715 interact with cigarette smoking to confer an increased risk of developing AMD than
each factor alone.8 These exciting discoveries should lead to improved
understanding of the pathogenesis of AMD and the development of
novel therapies.
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There is a strong epidemiological association between smoking and the
development of advanced AMD. Current smokers have an increased
risk of developing dry and neovascular AMD relative to non-smokers
with an odds ratio (OR) of 2.83 and 2.35, respectively. Past smokers
have an OR of 2.80 and 1.82, respectively, when compared with nonsmokers.7 Cigarette smoking confers an increased risk of developing
AMD in addition to known genetic associations8 (see Genetics
section). The benefit of smoking cessation to prevent second eye
disease has not been evaluated.
H. L. Cook et al.
Natural history
Diagnosis
History
Patients usually present with distortion, blurring or a scotoma (black
or grey patch) in their central vision, which is rapid in onset in neovascular AMD and more gradually progressive in geographic atrophy.
Patients with dry AMD in both eyes or unilateral neovascular AMD
may be asymptomatic or just complain of mild distortion in their
vision and be detected as an incidental finding at a routine optometric assessment. Patients with vision loss from late AMD (defined
as presence of CNV or GA) in both eyes can develop visual hallucinations (Charles Bonnet syndrome). Visual hallucinations may be
unformed (coloured lights or patterns) or formed (animals, people
and scenes). Many patients will not volunteer these symptoms unless
directly asked.
Clinical examination
Patients with drusen and mild pigmentary changes alone may have a
visual acuity within the normal range. Patients with late AMD usually
have reduced visual acuity in the affected eye. An area of central distortion or scotoma may be mapped out by the patient on an Amsler grid.
Examination of the fundus, preferably using a stereoscopic viewing
method (slit-lamp biomicroscopy), shows the presence of drusen, pigmentary, exudative, haemorrhagic or atrophic changes affecting the
macula. Non-stereoscopic examination (direct ophthalmoscopy or
fundal photography) may miss retinal thickening or elevation due to
neovascular AMD.
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Approximately 90% of the white population aged 40 years will have
one 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), there
is a 2 –3-fold increased risk of developing large soft drusen (125 mm
in diameter, where 125 mm is approximately the width of a retinal vein
at the optic nerve head) and pigmentary changes after 10 years. Large
soft drusen are associated with a 6– 7-fold increased risk of progression
to advanced AMD. Large numbers of small hard drusen are also
associated with progression to geographic atrophy.6 Patients with neovascular AMD in one eye have an 50% risk of second eye CNV at 7
years follow-up.3,53
Additional tests
†
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 diagnostic tool. This device produces a cross-sectional image through the
retina, RPE and choroid, and can measure macular thickness and the
tissue plane of fluid collections. This can be helpful in determining
the presence of pigment epithelial detachments and in patients with
allergy to sodium fluorescein.
Differential diagnosis of CNV
CNV can occur secondary to other disease processes that alter the
integrity of the Bruch’s membrane/RPE complex, such as pathological
myopia (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 history
and response to treatment. Some inflammatory eye diseases result in
CNV, but there are usually signs of active or previous uveitis that
would not be present in AMD. Some inherited macular dystrophies
may look similar to dry AMD. However, these are usually very symmetrical, there may be a family history and onset is usually at an
earlier age.
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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 fluorescent dye fills the choroidal and retinal circulations. CNV can be
defined either by its anatomical location relative to the centre of the
fovea or by its filling characteristics. Treatment is often determined
based on an understanding of these two angiographic findings.
‘Classic’ CNV membranes fill with dye in the arterial phase, are well
defined and leak fluorescein dye beyond the borders in later shots.
Lesions that leak in a less clearly demarcated pattern in later shots, but
not in the early shots, are termed ‘occult’ lesions. CNV may be predominately classic (greater than 50% classic component) or minimally
classic (50% or less classic component). Currently, the determination
of the type of neovascular AMD is essential in order to assess the suitability for treatment modalities such as laser photocoagulation and
photodynamic therapy (PDT), but pharmacologic therapies (anti-VEGF
agents) are effective in treating all subtypes of CNV.
Lesions are also divided into extrafoveal, juxtafoveal or subfoveal
types depending on their location. The location of the lesion influences
treatment options.
H. L. Cook et al.
Management
Conventional laser treatment
Argon laser photocoagulation can be used to ablate the area of active
CNV in patients with neovascular AMD. The Macular
Photocoagulation study established that laser photocoagulation prevented severe loss of vision (loss of six or more lines of visual acuity) in
extrafoveal CNV secondary to AMD.19 This randomized, controlled
trial (RCT) terminated recruitment to the extrafoveal arm at 18
months as 60% of untreated eyes but only 25% of treated eyes had
severe 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 5
years after treatment. Approximately 75% of recurrences occur within
the first year.
Patients with juxtafoveal CNV fared less well than extrafoveal CNV.
At 5-year follow-up, 55% of treated patients had experienced severe
visual loss compared with 65% controls.21 A sub-group analysis found
that classic CNV without an occult component benefited from treatment and that juxtafoveal lesions with an occult component did not
benefit 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 significant
risk of immediate worsening of vision in treated patients (20% chance
of severe visual loss within 3 months in the treated group versus 11%
of controls) and there are now available other treatments for subfoveal
lesions.
Only a minority (13% in a series by Freund et al.) of patients presenting with neovascular AMD fulfil the treatment criteria for argon
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If neovascular AMD is present, the type and location of CNV must be
determined by fluorescein angiography, ideally within a few days of
onset of symptoms, as treatment options and response to treatment and
subsequently final visual outcome are better in early disease. For this
reason, at risk patients with known dry AMD are asked to regularly
check the vision in the fellow eye using an Amsler grid or similar target
and to seek urgent ophthalmic review if they develop new visual symptoms. Table 1 gives an overview of treatments for neovascular AMD
and there is more detailed discussion below.
At present, there is no proven treatment for patients with dry AMD
progressing to atrophy, although the cessation of smoking and the use
of high-dose antioxidant vitamins may reduce the risk of CNV developing (see below).
Table 1 Table comparing different treatment modalities available for neovascular AMD.
Treatment
Medical
Argon laser
photocoagulation
PDT
Trial name
MPS
TAP
Trial
method
RCT
RCT
RCT
Pegaptanib
(Macugenw)
VISION
RCT
Ranibizumab
(Lucentisw)
MARINA
RCT
Number in trial (eyes)
Total follow-up
(years)
Visual outcome
Treatment group
(eyes)
Control
group (eyes)
4
SVL 22%
SVL 47%
P ¼ 0.002
138
5
SVL 52%
SVL 61%
119
117
5
SVL 46%
SVL 64%
RR 1.2
(P ¼ 0.04)
RR 1.5
(P ¼ 0.001)
All subfoveal with
some classic
component
402
207
2
MVL or better in
53%
Predominately classic
159
83
2
Minimally classic
202
104
2
Classic, no occult
93
49
2
Subfoveal occult no
classic CNV
Subfoveal classic and
occult
166
92
2
MVL in 55%
MVL or
better in
38%
SVL 30%
MVL 78%
SVL 43%
MVL 56%
SVL 30%
MVL or
better in
29%
MVL in 68%
890 (3
subgroups with
different doses)
240 (0.5 mg
subgroup)
296
1
SVL 10% with
0.3 mg dose
238
2
90% lost ,15 letters
Treatment
group (eyes)
Control
group
(eyes)
New subfoveal
77
83
Juxtafoveal
138
Extrafoveal
Subfoveal occult/
minimally classic
SVL, 18%
MVL, 46%
SVL, 19%
MVL, 53%
SVL, 26%
MVL or better in
70%
33% gained 15
letters
ANCHOR
RCT
Statistical
significance
Subfoveal
predominantly classic
140 (0.5 mg
subgroup)
143 PDT
treated
1
40% gained 15
letters
SVL 22%
with 0.3 mg
dose
53% lost
,15 letters
4%
gained 15
letters
64% lost
,15 letters
6% gained
15 letters
RR 0.61
P ¼ 0.58
P . 0.05
P , 0.001
P , 0.001
P , 0.01
P , 0.01
P , 0.01
P , 0.01
Continued
135
VIP
CNV Lesion Type
H. L. Cook et al.
136
Table 1 Continued
Treatment
Trial name
Trial
method
CNV Lesion Type
Number in trial (eyes)
Treatment
group (eyes)
Control
group
(eyes)
70
0
Variable
30 eyes
1
Mean visual acuity
improved by 1.22
Snellen lines
267
1
3% SVL
90
0
1
86
0
1
PCS
Subfoveal CNV
266
0
Intravitreal TCA
(single dose)
PDT plus intravitreal
TCA 25 mg
Gillies
et al. 34
Augustin
et al. 55
RCT
Subfoveal CNV with
any classic component
All CNV
73
Anecortave acetate
(15 mg dose)
D’Amico
et al. 36
RCT
Anecortave acetate
Slakter
et al. 37
RCT
Aisenbrey
PCS
et al. 45
Fujii et al. 48 RCS
184 (148
subfoveal, 19
juxta-, 17 extra)
Subfoveal CNV (25 eyes 33 eyes
with predominately
classic CNV)
Subfoveal
263
predominantly classic
Subfoveal CNV
Treatment group
(eyes)
31% had visual
improvement at
2-month follow-up
Spaide
et al. 35
Surgical
Macular
translocation
Limited macular
translocation
Visual outcome
Variable (2
month data
available for 222
eyes)
1
Bevacizumab
(Avastinw)
PCS
Total follow-up
(years)
SVL 35%.
Statistical
significance
Control
group (eyes)
P , 0.001
SVL 35%
P , 0.01
53% lost
,15 letters
23% SVL
49% lost
,15 letters
P ¼0.0323
P ¼ 0.0224
P ¼ 0.43
27% increased BCVA
by 15 letters
40.7% achieved
visual acuity of 20/
100 or better
CNV, choroidal neovascularization; MPS, Macular Photocoagulation Study; RCT, randomized controlled trial; SVL, severe visual loss (loss of six or more lines of visual acuity);
MVL, moderate visual loss; RR, relative risk; PDT, photodynamic therapy; TAP, Treatment of Age-Related Macular degeneration with Photodynamic Therapy Study; VIP,
Verteporfin in Photodynamic Therapy Study; VISION VEGF, Inhibition Study in Ocular Neovascularization; MARINA, Minimally classic/occult trial of the Anti-VEGF antibody
Ranibizumab In the treatment of Neovascular AMD (presented but not published); ANCHOR, ANti-VEGF Antibody for the Treatment of Predominantly Classic CHORoidal
Neovascularization in AMD (presented but not published); TCA, triamcinolone acetonide; BCVA, best corrected visual acuity; PCS, prospective case series; RCS, retrospective
case series.
laser therapy.23 Current recommendations are that conventional laser
treatment is an option for patients with extrafoveal CNV or juxtafoveal
classic no-occult CNV where the lesion is outside the foveal avascular
zone 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 preserve central vision and minimize the final size of the scotoma.
However, newer treatment options (anti-VEGF agents) avoid scotoma
and offer the prospect of visual improvement.
PDT with Verteporfin
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PDT utilizes a 10-min intravenous infusion of Verteporfin (a photosensitising drug) followed by application of a diode laser (689 nm) to the
affected area in the retina 15 min after the start of the infusion. Light is
absorbed by the photosensitizer molecules, which causes an oxidation
process in lipid membranes and proteins. This leads to disruption of
cellular structures and subsequent thrombosis and vascular occlusion in
active CNV. Verteporfin is relatively contraindicated in patients with
liver disease or a history of porphyria. Patients should avoid sunlight
exposure for 48 h after treatment.
A systematic review of two RCTs, the Treatment of AMD with
Photodynamic therapy (TAP) Study and Verteporfin in Photodynamic
Therapy (VIP) Study, found that PDT with Verteporfin significantly
reduced the risk of moderate and severe visual loss at 24 months compared with placebo (moderate visual loss: OR, 0.77; severe visual loss:
OR, 0.62) in eyes with subfoveal CNV measuring 5400 mm caused
by AMD.24 Two-year follow-up data showed that 77% of eyes with
100% classic lesions lost less than 15 letters after PDT treatment compared with 31% in the placebo group.25 Two-year follow-up data for
predominately classic lesions showed 59% of eyes lost less than 15
letters of visual acuity compared with 31% of the placebo group.25
Patients with 100% occult lesions respond relatively well to PDT treatment (51% of treated patients lost ,15 letters versus 25% controls at
2 years).26 A controversial sub-group analysis found maximal benefit
in smaller lesions and those with poor initial vision. Patients with minimally classic lesions or occult classic CNV were not shown to benefit
from PDT in randomized trials. Most practitioners would not use PDT
for these indications and would instead treat with available anti-VEGF
agents (see later section).
Patients usually require a course of treatment at three monthly intervals (mean number of treatments is 5 over 2 years). There is an 1%
risk of sudden permanent worsening of the vision following the treatment with PDT (5% in patients with occult lesions).
H. L. Cook et al.
Anti-angiogenic drugs
There is currently extensive research into modulating the angiogenic
response in AMD.
Anti-vascular endothelial growth factor
There is extensive in vitro and in vivo evidence that VEGF is implicated
in retinal angiogenesis and vascular permeability. There has been
intense laboratory and clinical research in this area, and researchers
have developed agents that block VEGF activity some of which are
already in clinical use:
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 from
treatment for all lesion types and sizes with ranibizumab with repeated
four weekly intravitreal injections. The ANCHOR study29 randomized
423 patients with predominantly classic neovascular AMD to monthly
injections of Lucentisw at two different doses or to conventional treatment 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 mg
lost ,15 letters on visual acuity testing compared with 64.3% in the
PDT-treated group. In addition, visual acuity improved by 15 letters in
35.7% of the 0.3 mg Lucentisw-treated group and 40.3% of the
0.5 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 the
0.3-mg group and 11.3 letters in the 0.5-mg group compared with a
decrease of 9.5 letters in the PDT-treated group at 12 months. The
MARINA study30 randomized 716 patients with minimally classic or
occult neovascular AMD to monthly injections of Lucentisw at two different 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 lost
fewer than 15 letters on visual acuity testing compared with 52.9% in the
sham-treated group. In addition, visual acuity improved by 15 letters in
138
1. Pegaptanib Sodium (Macugenw)
Pegaptanib (Macugenw, Eyetech Pharmaceuticals, NY, USA) is a selective anti-VEGF oligonucleotide conjugated with a polyethylene glycol that
binds to the major human soluble VEGF isoform (VEGF165). A phase III
RCT comparing intravitreal doses of 0.3, 1.0 and 3.0 mg and sham injection showed that with six weekly injections over a 48-week period there
was a significant reduction in moderate visual loss (,15 letters lost) at 54
weeks follow-up. In the 0.3 mg treatment group, there was a statistically
significant increase in the proportion of patients with stable vision
with 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 been
licensed for clinical use in the USA and Europe.
3. Bevacizumab (Avastinw)
Initially developed for use in oncology (licensed for use in colorectal
cancer), bevacizumab (Avastinw) has been increasingly used as an intravitreal injection to treat neovascular AMD. Bevacizumab is a full-length,
humanized, monoclonal antibody binding all forms of VEGF-A. Several
published case series have suggested efficacy similar to that of Lucentisw,
but as yet there have been no prospective, randomized, controlled trials
published. The largest retrospective case series of 266 eyes with follow-up
of 2 months (data available for 222 eyes) showed visual acuity improvement in 31.1% with a statistically significant reduction in mean central
macular thickness.33 The evidence for the efficacy of intravitreal bevacizumab in treating neovascular AMD is from interventional case series with
no 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 this
indication as Lucentis, is significantly more expensive than Avastin and as
Avastin was available prior to the licensing of Lucentis. This has given rise
139
26.1% of the 0.3 mg Lucentisw-treated group and 33.3% of the 0.5-mg
treated group compared with only 3.8% of sham injection group. The
average visual acuity change was a gain of 5.4 letters in the 0.3-mg group
and 6.6 letters in the 0.5-mg group compared with a decrease of 14.9
letters in the sham injection group at 24 months. The risk of endophthalmitis in the two studies was 1.4% over 2 years (0.05% per intravitreal
injection). Further studies have investigated the efficacy of as required
ranibizumab intravitreal injections in treating neovascular AMD in order
to explore the possibility of reducing the number of intravitreal treatments
while maintaining efficacy. The PIER study31 was a prospective, multicentre, randomized, controlled trial of 184 patients with subfoveal CNV
due to AMD received either ranibizumab (0.3 or 0.5 mg) or sham treatment once a month for 3 months and followed by doses every once every
3 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 loss
of 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 the
efficacy of ranibizumab is reduced if given as a quarterly treatment. The
results from the PrONTO study,32 which was a prospective open-label
interventional case series of neovascular AMD patients with subfoveal
CNV treated with three consecutive monthly intravitreal injections of ranibizumab (0.5 mg) with further injections if clinically indicated, support
this treatment strategy. At month 12, the mean visual acuity improved by
9.3 letters (P , 0.001) and the mean OCT central retinal thickness
decreased by 178 mm (P , 0.001). Visual acuity improved 15 or more
letters in 35% of patients. These visual acuity and OCT outcomes were
achieved with an average of 5.6 injections over 12 months. This small
study suggests visual acuity outcomes similar to the Phase III clinical
studies, may be achieved with fewer intravitreal injections.
H. L. Cook et al.
to the highly unusual situation of a drug (Avastin) used for an unlicensed
indication despite robust clinical trials supporting the safety and efficacy
of a licensed alternative (Lucentis) in treating wet AMD.
Selected treatments still undergoing evaluation
Transpupillary thermotherapy
Transpupillary thermotherapy (TTT) involves the use of a long-pulse
diode laser (810 nm) to occlude CNV. A formal RCT (TTT4CNV
Trial) did not show any benefit in treating subfoveal occult CNV secondary to AMD compared with sham ( presented at ARVO Annual
Meeting 2005 by Reichel et al.).
Steroids
A number of different steroids have been evaluated and different delivery vehicles including depot preparations are in development.
However, published data are limited to triamcinolone acetonide and
anecortave acetate.
Triamcinolone
Triamcinolone acetonide is a glucocorticoid and if injected into the
vitreous, it may have an effect for up to 4 –6 months. A RCT to
evaluate a single dose of 4 mg intravitreal triamcinolone acetonide
versus placebo in the treatment of 151 eyes with CNV with a classic
component found no difference in risk of severe visual loss between
treatment and control groups at 1 year.34 A number of small, nonrandomized trials have been performed using repeated doses of triamcinolone 25 mg; however, there is no robust data to show a benefit over
natural history. Currently, no good RCT data exist to support its use
yet either alone or in combination with other therapies although there
is a suggestion of enhanced efficacy in combination with PDT.35
140
Intravitreal VEGF inhibitors appear to be relatively free from systemic
side-effects and complications although systemic VEGF-A inhibition
may predispose to thrombo-embolic complications and an excess risk
of thrombo-embolic complications was reported in the first year of
follow-up in the ranubizumab (Lucentisw) randomized, controlled
trials which diminished in the second year of follow-up. The SAILOR
(Safety Assessment of Intravitreal Lucentis for AMD) study is an
ongoing phase IIIb study with patients randomized to 0.3 or 0.5 mg of
Lucentis. A planned interim safety analysis from this study reported a
higher 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 clinical
trials are awaited, and other VEGF or VEGF receptor blocking drugs
are also under development.
Several RCTs are ongoing, including one using a preservative free
version of triamcinolone that may have less associated ocular morbidity
and combination with other treatment.
Anecortave acetate
Medical treatments not shown to be beneficial by RCTs
Radiotherapy
Low doses of ionizing radiation can inhibit vascular endothelial cell
proliferation in vitro and prevent angiogenesis in vivo. A systematic
review of 11 trials of teletherapy (external beam radiotherapy) found
great variability in the treatment methods and was unable to draw any
firm conclusions about the efficacy of radiotherapy.38
Alpha-interferon treatment
A large RCT evaluating alpha-interferon as a treatment in wet AMD
found no statistically significant benefit from treatment (three different
dosages) compared with placebo over a 1-year period.39 Therefore,
alpha-interferon is not recommended as a treatment in wet AMD.
141
Anecortave acetate is a synthetic angiostatic steroid that has no glucocorticoid activity and a good ocular safety profile. It prevents vascular growth by inhibiting proteases necessary for endothelial cell
migration. A RCT of 128 patients investigated the use of six
monthly juxtascleral (injection into the tissue plane between the
Tenon’s sheath and sclera rather than into the vitreous cavity) injection of anecortave acetate at 3, 15 and 30 mg doses versus
placebo.36 At 1-year follow-up, patients in the 15 mg treatment
group did significantly better than the control group in mean
change from baseline visual acuity (P ¼ 0.01), stabilization of visual
acuity (P ¼ 0.03) and prevention of severe visual loss (P ¼ 0.02).
There were no significant safety issues. A phase III equivalency
study between 15 mg anecortave against PDT did not reach its
primary endpoint of equivalency despite similar outcomes between
the two groups37 (see Table 1). The authors felt that the outcome
of anecortave was limited by reflux during delivery and further
trials are ongoing with modification of the delivery technique.
Anecortave has received a license for use in neovascular AMD in
Australia in 2006.
H. L. Cook et al.
Surgical treatments
There are a number of surgical techniques available in the management
of wet AMD. These techniques are only performed by a limited
number of surgeons.
Excision of choroidal neovascular membranes
Retinal pigment epithelial cell transplantation
Exogenous RPE transplantation
It is thought that the reason for poor visual acuity outcomes following
CNV excision is removal of RPE cells with the excised CNV complex.
This leads to choriocapillaris atrophy and subsequent loss of photoreceptor function due to ischaemia. New techniques using RPE cell
transplantation aim to overcome this issue. Early studies using human
foetal RPE cell transplants gave disappointing results due to the development of chronic cystoid macular oedema which affected central
visual acuity.
Autologous RPE transplantation
Recent studies using autologous RPE transplantation have had more
promising results. A consecutive patient case series of 53 patients with
subfoveal CNV found a statistically significant improvement in reading
visual acuity between the group with CNV excision and autologous
RPE transplantation when compared with the group with CNV excision only.41 However, the complication rate is too high currently to use
this approach outside research studies.42
Evacuation of submacular haemorrhage
Large submacular haemorrhage secondary to wet AMD carries a
poor visual prognosis due to the development of subretinal fibrosis.
142
This involves performing a pars plana vitrectomy then removing the
CNV via a retinotomy incision. This method theoretically preserves
foveal retinal photoreceptors and is suitable for occult lesions as the
precise anatomical boundaries of the CNV do not need to be delineated. A multi-centre RCT of 454 eyes found no statistical difference
between the treatment group and controls at 24 months.40 There was
an increased risk of retinal detachment in the treatment group compared with controls.
Macular translocation
This procedure aims to relocate the fovea to an adjacent area of
healthy RPE in eyes with subfoveal CNV. There are two main methods
for relocating the fovea.
36088 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 nerve
and re-attached. The largest case series to date presented by Aisenbrey
et 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 loss
of vision. The complication rate was high in initially reported series
(retinal detachment in 29% mainly due to proliferative vitreoretinopathy, CNV recurrence in 22% and cystoid macular oedema in 52%),
but is reducing in more recent series.46 A recent pilot RCT comparing
surgery to PDT reported a higher proportion of patients improving
vision after macular translocation surgery at 1 year follow-up.47
Additional strabismus surgery is required and some patients have persistent 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 procedure to move the fovea to a healthy area of RPE. This can be
achieved by infolding or outpouching of the sclera, which creates
redundancy of the retinal tissue which can then be displaced 1 –2 mm.
There are no RCTs of this technique. The largest retrospective case
series to date reported outcomes on 102 eyes; of which, 1-year
143
Early surgical removal of haemorrhage has been advocated to prevent
permanent visual loss. Mechanical removal of clot results in extensive
iatrogenic damage. A large RCT investigating surgery for haemorrhagic
CNV (lesions composed of .50% haemorrhage) found that there was
no 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 treated
cases versus 59% of controls).43 However, the risk of severe visual loss
was less in the surgery group (36% control group versus 21% surgery
group, P ¼ 0.004). A newer technique using tissue plasminogen activator (tPA) without the need for a vitrectomy has been described.
However, the numbers of patients treated are small and no RCT has
been performed.44 Combined evacuation of blood with retinal translocation is described below.
H. L. Cook et al.
follow-up was achieved in 86.48 This study found that 39.5% had a
two or more lines of improvement in visual acuity. However, there was
a 34.6% CNV recurrence rate; of which, 65% of recurrences were subfoveal 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
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 These
treatments were placebo, zinc (80 mg plus copper 2 mg/daily), antioxidants (vitamin C 500 mg plus vitamin E 400 IU plus beta-carotene
15 mg/daily) and zinc plus antioxidants. Overall, it was found that
compared with placebo, zinc plus antioxidants significantly reduced
the 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 is
no benefit in patients with no signs of AMD or those with bilateral,
advanced AMD. These high doses of zinc and anti-oxidants cannot be
achieved from diet alone. There was little evidence of harm in this
study although some patients developed yellowing of the skin secondary to anti-oxidant ingestion and increased admission for genitourinary
complications secondary to zinc ingestion. There is good evidence from
other studies that the beta-carotene component increases the risk of
144
The use of anti-VEGF agents with intensive patient follow-up and
repeated intravitreal injections every 4 –6 weeks has led to an interest
in combination therapies both to reduce retreatment rates and to
improve outcomes. Numerous case series and retrospective studies have
been published evaluating combination therapies in wet AMD but at
present, there is no clear data on the usefulness of combination therapies although there is a suggestion of benefit from combining PDT and
intravitreous triamcinolone. There are, however, several RCTs underway to investigate the role of combination therapies with the prospect
of reducing the frequency of anti-VEGF therapy.
lung cancer in smokers, and this treatment is currently not recommended in smokers or ex-smokers. There are currently no RCTs on
other nutritional supplements such as lutein or doses of anti-oxidants
other than those used in the RCT described above.
Laser to drusen
Anecortave acetate
A multi-centre RCT is currently underway to evaluate the use of juxtascleral injection of anecortave acetate as a prophylactic treatment in
fellow 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 most
will benefit from supportive measures. These include simple advice on
adequate lighting in the home and for near-vision tasks. Formal assessment for low visual aids by a trained optometrist will enable the
patient to optimize the use of the vision that he or she has. Closed
circuit television (CCTV) aids are useful for some patients to enlarge
text, but are expensive to purchase.
Some patients can be trained to use eccentric fixation in order to
improve their visual acuity. This technique involves the patient looking
just to one side of the object of interest rather than directly at the
object. Healthier juxtafoveal retina can then be used to produce an
image. No good RCTs exist to determine the effectiveness of low
visual aids yet.
Formal partial-sighted or blind registration also enables patients to
access social support and practical advice on modifications to the
145
Two RCTs have investigated the use of laser to eyes with drusen to
prevent subsequent development of advanced AMD50,51,54. The study
by Olk et al. 50 in 229 eyes found a statistically significant increase in
visual acuity in eyes with drusen treated with diode laser compared
with eyes with no treatment at 2 years (improvement of 2 lines in
11% with laser versus 0% with no treatment; 95% CI, 6 –25).
However, a second RCT by the Choroidal Neovascularization
Prevention Trial Research Group found that in the subgroup of people
with unilateral drusen, laser significantly increased the incidence of
CNV compared with no treatment [estimated 12-month incidence
17% with laser versus 3% with no treatment (P , 0.05)].51,54 In view
of the increased risk of CNV, laser treatment for drusen is not currently
recommended.
H. L. Cook et al.
home and the provision of other aids. Many patients also benefit from
counselling either formally or informally through patient support
groups.
Implantable miniature telescope
In addition to standard low-vison aids, newer approaches to visual
rehabilitation have included the implantable miniature telescope.52
This is a monocular-fixed focus telescopic device implanted into the
patients eye during cataract surgery which provides magnification of
the central vision at the expense of the field of view. There have been
encouraging results in clinical trials with further trials ongoing.
The introduction of anti-VEGF agents has revolutionized the management of wet AMD. In a rapidly changing field, our current recommendations for management include:
1. Pan-anti-VEGF blockade using ranibizumab. The use of Avastin remains
controversial, but potentially very cost-effective.
2. Argon laser ablative therapy restricted to small, well-defined extra-foveal
CNV.
3. The role of PDT may be in combination therapy and is subject to further
study at present.
4. Surgical macular translocation may be considered in selected cases including second affected eyes not suitable for anti-VEGF therapy (including
RPE.rips involving the macula).
5. Preventative measures including cessation of smoking and use of AREDS
nutritional supplements.
Summary
AMD is an increasing health burden throughout the world and is the
third commonest cause of visual impairment worldwide. There are a
number of established treatment options as well as promising therapies
and surgical approaches under evaluation to stabilize vision in wet
AMD. It is, therefore, important that patients with symptoms of
impaired central vision should be seen and assessed promptly by an
ophthalmologist in order that appropriate investigations can be performed to assess suitability for treatment. All patients should also have
access to supportive measures and appropriate advice on lighting, etc.
The role of prophylactic treatments is also important in order to
146
Current treatment recommendations for wet AMD
preserve central vision. The increasing understanding of the genetics
and pathogenesis of AMD may lead to the development of more
specific and effective therapies in the future.
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Age-related macular degeneration: diagnosis and management

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