Age related macular degeneration (AMD
Transcript Age related macular degeneration (AMD
Current Perspectives in Age Related
• Degeneration is the change of a tissue to a less functionally
active form. Until recently the syndrome was referred to as
Senile Macular Degeneration, a name given to the condition by
Haab as early as 1885, the terminological change reflecting
contemporary sensibility regarding diseases in ageing
• Age related macular degeneration has recently been
comprehensively morphologically classified by Professor AC
Bird and his co-workers who formed the International ARM
Epidemiological Study Group.The disorder is either referred to
as age related maculopathy (ARM) or age related macular
• Prevalence in UK about 1.64% of Population (Melton Mowbury )
• 50,000 people may have end stage ARMD
Age Related Maculopathy
• The International Epidemiological Study
Group defines Age Related Maculopathy
(ARM) as a disorder of the macular area,
most often clinically apparent after 50 years
of age, characterised by:
• discrete whitish-yellow spots identified as
• increased pigment or hyperpigmentation
associated with drusen.
• sharply demarcated areas of depigmentation
or hypopigmentation of the retinal pigment
epithelium and associated drusen.
Common manifestations of macular
The key lesion of ARM is the druse (pleural drusen) an aggregation of hyaline material located
between Bruch’s membrane and the RPE. It is associated with atrophy and depigmentation of the
overlying RPE. Certain types of drusen are associated with sight threatening pathology. Small,
hard drusen are referred to simply as drusen, soft drusen over 63 microns in diameter are statistically
associated with visual pathology and are termed early ARM.
Non Exudative Macular Degeneration Dry or non exudative ARM is due to a slow and progressive
degeneration of the photoreceptors and the RPE with gradual failure of central vision.
Geographic atrophy consists of one or more areas of RPE hypopigmentation with clearly visible
choroidal vessels. It is the severest form of the non exudative ARM representing a zone of RPE
atrophy 175 microns or greater in diameter with exposure of the underlying choroidal vessels.
Exudative Macular Degeneration This type of macular degeneration may have rapid and
devastating effects upon vision. By contrast with patients with non -exudative retinal degeneration in
whom impairment of vision is gradual, central vision may be lost over the course of a few days.
The pathology of neovascular AMD is choroidal neovascularisation with the formation of a
subretinal neovascular membrane. (SRNVM) The SRNVM lead to haemorrhage and disciform
scarring. PEDs also form a part of the description.
• Age related macular degeneration (AMD) accounts for almost
50% of those registered as blind or partially sighted. The
development of management strategies is limited by the diverse
nature of the age related changes and a lack of a clear
understanding of the process of visual loss in the elderly.
• Effective treatment is limited to the management of sub-retinal
neovascularisation (SRNV) in selected cases).
• Despite early expectations that laser treatment might provide
significant benefit in preventing blindness, recurrent disease and
progressive visual failure limit the final outcome.
• Early recognition and prevention of potential disease is not as
yet applicable to disease other than that related to SRNV.
The macula subserves high resolution central and colour vision. It is
horizontally oval, 5mm in diameter. The foveola forms the central floor. It has
a diameter of 0.35mm. It is the thinnest part of the retina. Its entire thickness
consists only of cone photoreceptors and it subserves the most acute vision.
The retinal pigment epithelium (RPE) is a single layer of hexagonally shaped
cells They reach out to the photoreceptor layer of the inner retina. Bruch's
membrane separates the RPE from the vascular choroid.
Ultrastructurally it is composed of five elements and througout life can
accumulate metabolic debris related to the build up of lipofuscin from the
RPE. The functions of the RPE include the maintenance of the photoreceptors,
absorbtion of stray light, formation of the outer blood retinal barrier,
phagocytosis and regeneration of visual pigment.
The macula has the highest concentration of photoreceptors and is the the area
where the RPE is most metabolically active and as a consequence most likely
to suffer the consequence of enzymatic failure over time with the accumulation
of metabolic debris and lipofuscin .
• Major epidemiological studies have centred
on preventive aspects of the condition.
These studies indicate, however, that the
condition may not be as responsive to
lifestyle modification as are other diseases of
the elderly, for example, as is ischaemic
heart disease, it is imperative that however
that any relationship between AMD and
treatable or preventable pathology be fully
Prevalence of AMD
• The first major epidemiologic study was the Framingham
Eye Study ( FES ). (5) The Framingham study , it will be
recalled, had investigated a study population in the town
of Framingham Massachusetts for the risk factors of
coronary artery disease since 1948. In the Eye Study
(1977) 2675 of the 3977 still living members of the initial
study were given an eye examination.
• This study showed that a prevalence of AMD of 11% for
those aged 65-74 years and 28% for those aged 75-85
years . A total prevalence in the population aged between
52-85 of 8.8% was recorded. By contrast, the prevalence
of age related cataract was 15.5 % and that of open angle
glaucoma 3.3%. Other studies also show the disease to be
extremely comon in the elderly.
Blue Mountains Eye Study (1995)
• provides an accurate estimate for the age specific
prevalence of ARM. End stage macular degeneration was
present in 1.9% of the elderly population studied and was
bilateral in 56% of this group. It was more frequently of
the neovascular type ( ratio neovascular: atrophic 2:1)
• ARM rose in prevalence from 0% among people younger
than 55 years to 18.5% among those 85 years or older.
Soft drusen were found in 13.3% of the surveyed
population and retinal pigment abnormalities in 12.6%.
• The sex ratio was 1.34 indicating a marked female
• The Beaver Dam Study disclosed a relationship between the
development of exudative lesions and a history of current cigarette
smoking.The relative odds for exudative macular degeneration , in
females was 2.5 times increased risk (95% confidence interval 1.016.20) compared with those who are ex smokers or never smokers. For
males it was 3.2 ( 95% confidence interval 1.03- 10.50)
• The Eye Case Control Group also found smoking increases the risk
of the exudative type of AMD 2.8 times in those who are current
smokers. Smoking cessation lowers the relative risk of AMD
Several studies have described the beneficial effects of dietary
carotenoids in slowing the course of the disease.Vitamin A, C or E
supplimenters had no demonstrable reduced risk of developing
AMD. Dietary zinc supplements did not have any beneficial effect
and the use of dietary vitamin supplements was not identified as a
strategy likely to prevent AMD in those who have good general
nutrition. The current recommendation is the consumption of foods
rich in dietary carotenoids, namely spinach and collard greens.
• Exogenous Post Menopausal Oestrogen
• The use of exogenous supplements in post menopausal women
lowered risk of AMD in a study performed by the Eye Case Control
• Genotype and Ethnic Origin
• Studies in siblings and probands support the belief that genetic factors
influence age related changes in Bruch’s membrane more than do
Postulated risk factors for macular
The Beaver Dam Study disclosed a relationship between the development of
exudative lesions and a history of current cigarette smoking.
Several studies have described the beneficial effects of dietary carotenoids in
slowing the course of the disease.
Exogenous Post Menopausal Oestrogen
The use of exogenous supplements in post menopausal women lowered risk of
AMD in a study performed by the Eye Case Control Study Group.
Genotype and Ethnic Origin
Cardiovascular Risk factors
There was no statistically significant relationship between hypertension, or
history of cardiovascular disease and ARM.
The recent Blue Mountains Eye Study disclosed no relationship between light
Clinical Characteristics• Age related macular degeneration has recently been
comprehensively morphologically classified by
Professor AC Bird and his co-workers who formed
the International ARM Epidemiological Study
Group.The disorder is either referred to as age
related maculopathy (ARM) or age related macular
Bird AC, Bressler NM, Bressler SB, Chisholm IH, Coscas G, Davis MD, de Jong
PTVM, Klaver CCW, Klein R, Mitchell P, Sarks SH, Soubrane G ,Taylor HR ,
Vingerling JR , An International Classification and Grading System for AgeRelated Maculopathy and Age Related Macular Degeneration Special Article,
Survey of Ophthalmology (1995 ) ; 39 :367-374
• The key lesion of ARM is the druse (pleural drusen) most people over
the age of 40 years have at least one druse.
The druse is an aggregation of hyaline material located between
Bruch’s membrane and the RPE. It is associated with atrophy and
depigmentation of the overlying RPE. Certain types of drusen are
associated with sight threatening pathology. Small, hard drusen are
referred to simply as drusen, soft drusen over 63 microns in diameter
are statistically associated with visual pathology and are termed early
• Hyper or hypopigmentation of the RPE also constitutes part of the
description of ARM.
Basal laminar drusen.
Drusen and CNV.
Non Exudative ( Dry ) Macular
• Dry or non exudative ARM is due to a slow and
progressive degeneration of the photoreceptors and
the RPE with gradual failure of central vision. It is
also known as atrophic ARM. RPE changes, as
manifested by hypo or hyperpigmentation may be
present. There may be thinning of the overlying
• Geographic atrophy consists of one or more areas of
RPE hypopigmentation with clearly visible choroidal
vessels. It is the severest form of the non
exudative ARM representing a zone of RPE atrophy
175 microns or greater in diameter with exposure of
the underlying choroidal vessels.
Non Exudative ( Dry ) Macular
• As yet, there is still no proven effective therapy for the
non-neovascular form of AMD.
• Several modalities for the prevention or treatment of
AMD are being investigated, including nutritional
supplements, angiogenesis inhibitors, submacular
surgery, external beam radiation therapy and macular
• Statins may help.
Exudative Macular Degeneration ( Wet
or Neovascular AMD )
• The pathology of neovascular AMD is choroidal
neovascularisation with the formation of a subretinal
neovascular membrane. (SRNVM) The SRNVM lead to
haemorrhage and disciform scarring.
• Age related Bruch’s membrane change may be especially
important in exudative macular degeneration, this change
includes thickening of Bruch’s membrane, drusen and
other metabolic accuminata such as lipids and loss of basal
connections with the RPE.
• Pigment epithelial detachment may occur in relation to
Bruch’s membrane change.
Pigment epithelial detachment.
• Pigment epithelial detachment in patients
under the age of 55 years is not usually
associated with significant visual loss but
occurring in those over 55 is likely to result in
visual loss within 4 years in the majority of
• Such loss may reflect the presence of
neovascularisation under the detachment.
• Sub-retinal neovascularisation can occur throughout the fundus
but rarely gives rise to complications save in the macular area
where it is associated with visual loss. Angiographically well
defined neovascular systems lying away from fixation may on
occasions be modified by treatment. If untreated, visual loss
may be rapid with neovascular extension under fixation in 75%
of cases within a year such that 60% develop severe visual loss
within 3 years.
• Less well defined neovascularisation is considered untreatable
and grows more slowly, but still 40% develop severe visual loss
within 2 years.
• Juxta papillary lesions tend to extend towards the macula but
do not invariably cause visual loss as they grow more slowly and
may involute spontaneously.
• Classic – Early leakage from edge of
membrane, lacy pattern. Ealy transit
phase- some late leakage
• Occult type 1, probably fibrovascular
PED, shows stippling, leakage at end of
• Occult type 2- Undetermined late
• The location and angiographic characteristics of
neovascular systems are used in determining the
approach to management. Away from the macula
they are described as peripheral or juxtapapillary. In
the macula, but lying more than 200 microns from
fixation, they are defined as extrafoveal. They are
juxtafoveal or subfoveal when immediately adjacent
to, or under, the foveola. Neovascular systems with
well defined leakage seen on fluorescein angiography
are described as classical and those with ill defined
leakage are considered occult. Some complexes are
mixed with both classical and occult components.
• With AMD-related visual loss affecting one
eye the risk of losing vision in the fellow eye
increases to between 7 and 10% annually.
• The five year risk is lowest in the absence of
large drusen or pigment hyperplasia but
increases with one of these risk factors to
30% or with both to over 50%.
• The highest risk is for those with a pigment
epithelial tear in one eye for whom the
annual risk of second eye involvement is
closer to 40%.
Endstage Disciform, Summary of risk
factors for progression in other eye
Large drusen, close to fixation
• Progression rates over 80%
• The value of routine screening, given the lack of effective
treatment, is unproven. There may be a case for self
assessment, using an Amsler Grid, in those patients with high
risk of neovascular disease which includes those with large soft
drusen and pigment hyperplasia and those with established
exudative AMD in one eye.
• Prophylactic Laser studies ( Bird, Guymer )
• Mild low risk disease (ARM) requires no special management
and, coming on slowly, can be managed in the community.
Optometrists would seem to be well placed to carry out routine
examinations and offer advice about the value of magnification
and lighting. Optometrists can reassure patients with minimal
symptoms or signs of ARM and should not refer further. Referral
from the primary sector usually occurs when visual impairment
begins to interfere with normal lifestyle. Referral is indicated
• General practitioners and optometrists need to be aware of the
urgent nature of referrals for patients with recent onset of
distortion and visual loss (less than a month) and who still have
reasonably good vision (6/12 or better).
• Such patients may still have treatable disease and should be
referred urgently to either the ophthalmic casualty department
or to the outpatient clinic following discussion with the local
ophthalmologist. This is particularly true for the second eye
when the other eye is already involved.
• In the elderly population with AMD concurrent ophthalmic
disease, such as cataract and glaucoma, may also frequently
occur and needs to be identified and treated appropriately.
• Good control of hypertension may favourably influence the
surgical treatment of neovascular membranes.
Investigation and Therapy
• Diagnosis and assessment of macular disease including
angiography and exclusion of other treatable causes of visual
• Treatment by laser photocoagulation or otherwise as
• Rehabilitation including:
• a) provision of suitable optical aids in the primary or secondary
sector and training in their use.
• b) Completion when appropriate of the form BD8 (BP1 in
Scotland, A 655 in Northern Ireland) and referral to Social
Services (Appendix 2).
• c) Counselling and rehabilitation within the hospital and
statutory or voluntary services in the community.
• Colour photography is routinely
undertaken with angiography. It helps
to determine the nature of changes
seen of the angiogram particularly in
defining exudative change and the
cause of blocked fluorescence due to
haemorrhage, pigment or other cause.
Drusen are sometimes much more
visible on angiography than colour
photography and vice versa.
• Angiography should be available with a minimum of
delay particularly given the rapid growth potential of
any neovascular lesion. As the angiographic features
may progress rapidly, laser treatment should be
undertaken within 48 hours of the latest angiogram if
at all possible. Stereoscopic angiography is
• Indocyanine angiography has a role in the
assessment of vascular systems under the pigment
epithelium which may be ill defined on fluorescein
angiograph, and in the assessment of the particular
condition of polypoidal choroidopathy. How far it
results in benefit in terms of management remains
• Hot spots, plaques
• Choroidal neovascularisation is a major cause of
visual loss in AMD and one that, when well defined,
may be amenable to treatment. Effective treatment
protocols for laser photocoagulation have been
• Pending the confirmed results of the current
prospective treatment trials of radiation and
photodynamic therapy (PDT), and their approval for
use if appropriate, the mainstay of interventional
treatment is that of laser photocoagulation.
Photocoagulation ( MPS ) Study
• In 1982 three studies showed treatment benefit from argon
laser photocoagulation when a well defined neovascular
complex lay outside 200 microns from fixation. 5-7 This is most
likely to be the case when the visual acuity is still good (6/12 or
better) and the duration of symptoms short (less than a month).
• Such situations are, however, rare and occur in only 5-10% of
• Despite the initial hopes of treatment it is now recognised that
continued growth of the membrane and recurrent disease are
major limiting factors for success and occur in about 50% within
5 years after initial successful treatment.
Pigment pigment epithelial detachments
• Pigment epithelial detachments do not usually
benefit from laser treatment
• Treatment is frequently complicated by rapid
visual loss associated with a pigment
epithelial tear or rapid progression of an
unrecognised neovascular response.
• A few neovascular lesions outside the
detachment itself or within the 'notch' have
been shown to respond favourably to focal
Pigment pigment epithelial detachments
• The recommended treatment protocol usually
• Heavy confluent laser photocoagulation (514nm or
577nm) covering the whole of the angiographic
lesion and a margin of 100 microns around it.
• Laser power setting and duration to achieve an
intense white coagulum.
• A planned sequence of burns around and onto the
lesion avoiding other structures.
• Location of the initial burns to minimise the risk of
movement causing an exclamation mark burn up to
Photo-Coagulation of CNV.
Macular Photocoagulation Study
• Macular Photocoagulation Study Group. Laser
photocoagulation for juxtafoveal choroidal
neovascularization. Five year results from randomized
clinical trials. Arch Ophthalmol 1994; 112:500-9.
• Photodynamic therapy ( PDT ) uses
photoporphyrin dye to induce closure of choroidal
new vessels (CNV). CNV immediately below the
central macula can now be treated..
• The procedure utilises a laser to activate the dye.
The dye, Visudyne ( verteporfin ), is extremely
expensive and several treatments may be
necessary to thrombose the membrane. Five
treatments over two years may become standard
Verteporfin, a photosensitizer or light-activated drug,
was approved patients with predominantly classic
subfoveal CNV caused by AMD.
• Photodynamic therapy (PDT) is a combination drug
and device treatment process, which involves
verteporfin, or another photosensitizer, and a laser
• This activation of the drug creates free radical
formation, which causes cellular damage and
eventually results in thrombosis of the vessels and
slowing of the progression of CNV.
• A phase 1 and 2 investigation showed that a single
treatment of PDT with verteporfin could stop
fluorescein leakage from CNV for 1-4 weeks in
patients with classic subfoveal CNV
• PDT for AMD is a two stage process
comprising a 10 minute intravenous infusion
of 6mg/kg verteporfin followed by activation
5 minutes later by 689nm diode laser for 83
seconds at 50J/cm2.
• The photosensitive verteporfin is selectively
taken up by rapidly proliferating endothelial
cells within the target CNV reaching its peak
concentration at 15 minutes.
• Cytotoxic reactive oxygen intermediates
damage cellular proteins and cause
• The recent publication of the Treatment
of Age-related Macular Degeneration
(TAP) report and Verteporfin in
Photodynamic Therapy (VIP) trials
• For predominantly classic lesions the
frequency of stable/improved vision
was: 12 months - 67% treated, 39%
TAP (Treatment of AMD with
• Two 24-month randomized, double-masked, placebo-controlled Phase
III trials known as the TAP (Treatment of AMD with Photodynamic
therapy) Investigation were published in the October 1999 issue of
Archives of Ophthalmology.
• Photodynamic therapy with verteporfin achieved short-term cessation
of fluorescein leakage from CNV without loss of vision or growth of
classic CNV in some patients with age-related macular degeneration.
Except for nonperfusion of neurosensory retinal vessels at a light dose
of 150 J/cm, no other adverse events were of concern.
• The primary finding of these trials showed that in 243 patients with
predominantly classic CNV, vision remained stable or improved in
67% of patients treated with Visudyne therapy compared to 39% of
patients on placebo (p is less than 0.001).
TAP Study Group. Photodynamic Therapy of subfoveal choroidal neovascularisation in age-related macular degeneration with verteporfin. One year
results of 2 randomized clinical trials. TAP report 1. Arch. Ophathmol., 1999;117:1329-45.
• Provision of low vision aids.
• Visual handicap registration.
• Training and coping strategies.
Explaining the management of AMD requires patience and sympathy.
Patients with AMD greatly benefit from continuing support and
information about their condition and all patients losing vision need
hope and encouragement.
• Statutory and voluntary support
services in the community.
The BD8 Form ( 1948 National
Assistance Act )
• Blindness- ‘cannot do any work for which eyesight is
• Partial Sight- ‘substantially and permanently
handicapped by defective vision.’
• ( The WHO definition of blindness is vision less than 3/60
in the better eye with best available spectacle correction )
The leading cause of blindness and
partial sightedness registrations in the
UK is now AMD.
Despite this, with ancillary help, many
of the sufferers of AMD manage to live
independent and fulfilling lives.
Treatment remains supportive for most
patients with macular degeneration
although a minority will benefit from
macular laser photocoagulation.
Photodynamic therapy ( PDT ) may
offer new therapeutic possibilities for
those with subretinal membranes who
have not yet lost their central vision.