Nov 2016

with
Prof Charles McGhee
& A/Prof Dipika Patel
Series Editors
Age-related macular
degeneration: update
Background
Age-related macular degeneration (AMD) is the
leading cause of blindness or severe irreversible
visual impairment in people over 50, in the
developed world. As of 2009, 49% of the current
blind foundation registrations in New Zealand
were for AMD 1 . The incidence, prevalence and
progression of AMD increases with age and
varies by ethnicity. In the Beaver Dam Eye
Study, a primarily Caucasian population, the
prevalence of AMD was 10% in individuals aged
55 to 64 year rising to 46% for those aged ≥
75 2 . The prevalence of AMD in Asians over 55 is
estimated 6.8% 3 . AMD is comparatively rare in
the Asian subcontinent and Hispanic populations
and is virtually unknown in African, Maori and
Polynesian populations. The subtype of AMD
that is seen clearly differs between ethnicities.
Whilst classical AMD is seen most commonly in
Causasians, polypoidal choriovasculopathy (PCV)
is the commonest type of AMD seen in Asians. In
2014, the prevalence of AMD in New Zealanders
aged 45-85 year age group was estimated to
be 184,000, numbers which are projected to
increase markedly to 208,200 by 2026 4 . With the
impending demographic shift towards an aging
population, AMD represents a significant and
increasing burden on the health care provision in
New Zealand in the coming years.
Risk Factors and pathophysiology
It has long been recognised that the likelihood of
an individual developing AMD is the result of a
complex interplay of genetic and environmental
risk factors; factors which are probably
cumulative with respect to the risk of developing
the disease. Whilst the genetics of AMD are
beyond the scope of this article it is clear that
certain genetic anomalies carry a significant
risk for affected individuals, the classic example
being complement factor H polymorphisms.
Gene products for CFH play an important role
in the regulation of the host immune system
and individuals who carry a CFH polymorphism
therefore posses a dysfunctional and “over active”
immune system. This risk is not insignificant, for
example individuals who are homozygous for
the Y420H risk allele of CFH are known to be 7x
more likely to develop AMD compared to normal
controls. These results suggest that inflammation,
plays a significant although as yet ill understood
role in the development of AMD. Apart from age,
ethnicity and genetics – strong non-modifiable
risk factors – numerous studies have identified
cigarette smoking to increase the risk of
developing AMD. Smoking significantly increases
AMD risk in a dose response relationship with
the relative risk increasing in proportion to
the number of pack years 5 . Smoking cessation
reduces the risk of progression and thus smoking
cessation remains the single most effective
population intervention to reduce the burden
that AMD represents.
The conventional hypothesis for the
development of AMD holds that the primary
event in the development of AMD is dysfunction
of the RPE, with build-up of drusen, RPE
atrophy, ischaemia of the outer retina and
ultimately the production of VEGF and subretinal
neovascularization. However this conventional
hypothesis ignores the role of the choroid and in
particular the role that the choriocapillaris plays
in the maintenance of the Bruchs/ RPE complex
and the outer retina. What is now clear is that
irrespective of the mechanism a thin choroid, and
in particular a thin inner choroid is a significant
risk factor for the development of “classical” AMD.
How “risk” CFH polymorphisms and smoking fits
into this story remains a matter of conjecture
but it is highly likely that inflammation plays
a key role in the loss of the choroicapillaris.
Whether this is the primary event, or the end
game of AMD needs further study but the answer
to this question has huge implications for the
development of new therapeutic targets in both
dry and wet AMD.
DAVID SQUIRRELL AND PAVANI KURRA*
Classification and natural history
Most readers will be familiar with the classification
of AMD and recognise that AMD encompasses
a wide spectrum of disease. Dry AMD is
characterised by the presence of one or more of
the following: presence of at least intermediate
size drusen (63 microns or larger in diameter),
retinal pigment epithelium (RPE) abnormalities,
reticular pseudodrusen and/or of geographical
-atrophy (GA) of RPE. Wet AMD is characterised
by the development of subretinal and intraretinal
neovascularisation. Soft drusen and pigmentary
abnormalities increase with age and strongly
predict progression towards advanced AMD.
The risk of progression of AMD also seems
to accelerate the more advanced the disease
becomes. Whilst approximately 15% of patients
with early AMD developed large drusen at 10
years the risk of advanced AMD developing over
this time period was low. However if a patient has
Intermediate AMD the five year risk of developing
advanced AMD increases steeply to near 20%. It
is also noteworthy that patients with reticular
pseudodrusen have a particularly high propensity
to develop advanced AMD. The risk of a patient
who has advanced AMD in one eye, developing
advanced AMD in the other eye is approximately
50% at five years. In all cases the risk of progression
to advanced AMD, is inversely associated with
choroidal thickness.
Prevention
By far and away the single most effective
preventative strategy for the development of
advanced AMD is to stop smoking. The large and
hugely influential AREDS studies demonstrated
that antioxidant supplements may slow the
progression of moderate AMD (soft drusen
and pigmentary changes) to wet AMD but the
therapeutic effects are sometimes overstated.
Although the relative risk reduction for patients
taking antioxidant supplements was around 25%
in real terms the more important absolute risk
reduction was smaller at around 8%. There have
also been concerns raised by some that, in a small
sub-set of patients, antioxidant supplements may
actually accelerate AMD. However, generally one
would still advocate antioxidant supplements in
all patients with moderate AMD. There is currently
no evidence to suggest AREDS supplements help in
halting progression of dry AMD.
The reported ability of lutein, xeothanine and
mesoxanthine supplementation to increase the
density of macular pigments is interesting and
the results emerging from the clinical trials with
subjects on these supplements report better
subjective and objective measures of visual
functioning compared to controls. However
whether such interventions actually reduce the
risk of the development of AMD remains uncertain
and at the present time one can only say that their
role is unknown.
The drug treatment of dry AMD remains an
exciting area of research with a number of
neuroprotective and inflammatory modulating
agents the subject of large clinical trials. The
technologies underpinning stem cell transplants
also continue to improve and show great promise,
but at the time of writing the drug treatment of
dry AMD remains a story of unfulfilled promises.
Wet AMD treatment
It is perhaps not too much of an exaggeration to say
that the use of antiVEGF agents in ophthalmology
has been one of the single greatest advances in
modern medicine. Certainly the advent of the
antiVEGF era has transformed the outcome of
wet AMD with the improvement in visual acuity
observed in the key note ANCHOR and MARINA
trials extending out to five years and beyond 6,7 . The
question of which antiVEGF agent to use (Avastin,
Lucentis or Eylea) remains the subject of debate
and the choice of which drug is used in which
country may have as much to do with politics and
economics as it does evidence. The key note trials
demonstrated that regardless of the drug used,
most patients with classical
wet AMD did well and,
at a population level at
least, there was little to
choose between the agents.
However as always there
are nuances; not every
patient responds equally
well to each drug and the
treating clinician needs
to be prepared to switch
drugs early if the agent used
proves to be ineffective. One
exception is that Aflibercept
is more effective than the
other two agents at treating
patients who have the PCV
variant of AMD. Currently in
New Zealand avastin is the
first line treatment for wet
AMD, Lucentis being the
funded second line agent.
In November, Pharmac will
announce the results of
their long-awaited review
of antiVEGF agents and it
is anticipated that they will
add Eylea to this list. The
drug treatment of wet AMD
continues to evolve at a fast
pace and whilst it is not
possible to “pick a winner”
at this time, what is certain
is that new, longer-acting
treatments will enter the
market over the coming
years.
Putting the excitement of
emerging drug treatments
to one side, currently the
greatest challenge for
clinicians, particularly
those in the public sector,
is to provide the treatment
patients need. Despite
innervations such as
utilising trained nursing
staff to deliver injections,
most public eye clinics are
struggling to provide the
treatments their patients need. In Auckland alone,
we are now providing about 20,000 appointments
annually to treat wAMD, a growth in demand that
has not been matched by increased resources. It is
widely accepted that under treatment of wet AMD
is associated with worse outcomes and MDNZ and
others continue to lobby central government and
local DHBs for more resources.
In summary the outlook for our patients with AMD
has never looked better. Challenges do however
remain. Early detection and treatment is crucial and
MDNZ and others continue to work hard raising
awareness of AMD. Once diagnosed patients,
optometrists and general practitioners need an easily
accessible “fast track” referral process to ensure
treatment is delivered promptly. The availability of
these “fast track” services are patchy and patients
often have to rely on the private sector in the first
instance to get prompt treatment. Thereafter, eye
clinics need the resource to provide capacity for the
ongoing review and treatment of what is a chronic
disease. Our score card for the management of wet
AMD in New Zealand remains “heading in the right
direction, but could do better” ▀
About the authors
* Dr David Squirrell
David is a specialist whose primary interest is medical retina
and AMD. David has severed as the principle investigator for
numerous studies in AMD, including the key note IVAN trial.
David works at Greenlane Clinical centre and Milford Eye clinic
Auckland.
* Dr Pavani Kurra
Pavani is currently working as a junior clinical fellow
in medical retina at the University of Auckland and
Greenlane Clinical Centre. She also spent time undertaking
ophthalmology electives at L. V. Prasad Eye Institute and in
Alice Springs prior to her fellowship in New Zealand.
Fig 1. (a) Colour photograph, (b) fluorescein angiogram and (c) OCT of patient with classic wet AMD.
Fig 2. (a) Colour photograph, (b) infrared image and (c) OCT of a patient with reticulo-pseudodrusen.
Note there are very few drusen seen on fundoscopy but marked changes are seen on the infrared
image. The OCT image is characteristic with focal subretinal protrusions and a thin choroid
Fig3. Five year outcome data from the CATT trial revels that patients maintain their vision into year 5
with appropriate and timely treatment
References:
1. Blind Foundation. Blindness by cause among New
Zealanders aged 50 or over. . (Blind Foundation
New Zealand, Auckland, 2009).
2. Klein, R., Klein, B. & Linton, K. Prevalence of agerelated
maculopathy: The Beaver Dam Eye Study.
Ophthalmology 99, 933-943 (1992).
3. Kawasaki, R., et al. The prevalence of AMD in
Asians: A systematic review and meta-analysis.
OPhthalmology 117, 921-927 (2010).
4. Worsley, D. & Worsley, A. Prevalence predictions for
age-related macular degeneration in New Zealand
have implications for provision of health care
services. New Zealand Medical Journal 128, 44-55
(2015).
5. Khan, J., Thurlby, D., Shahid, H. & etal. Smoking
and age related macular degeneration: the
number of pack years of smoking is a major
determinant of risk for both geographic atrophy
and choroidal neovascularisation. British Journal of
Ophthalmology 90, 75-80 (2006).
6. Brown, D., Kaiser, P., Michels, M., Soubrane, G. &
Schenider, S. Ranibizumab versus verteporfin for
nAMD (ANCHOR study). New England Journal of
Medicine 355, 1432-1444 (2006).
7. Rosenfeld, P., et al. Ranibizumab for neovascular
AMD. The New England Journal of Medicine 355,
1419-1431 (2006).
Dr David Squirrell
Dr Pavani Kurra
24 NEW ZEALAND OPTICS November 2016