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Age related macular degeneration
1. AGE-RELATED MACULAR
DEGENERATION
AJAY KUMAR SINGH
•Department of Ophthalmology
•King George‘s Medical University,
Lucknow (INDIA)
2. INTRODUCTION
Age- macular
degenerati
related on
• DEFINITION:
– A common chronic degenerative
disorder of unknown pathogenesis that
affects older individuals and features
central visual loss. .
3. EPIDEMIOLOGY
• An epidemic of “ageing” is impending in
the Western world. According to the latest
predictions released by the United Nations
the increase in population aged over 80 is
expected to be more than five fold, from
69 million in 2000 to 379 million by 2050.
• One major implication of this demographic
change is the emergence of conditions that
are directly related to ageing.
Ref: BMJ 2003; 326: 485-8
4. AMD: TERMINOLOGY
• Referred as senile macular degeneration, a
name given by Haab as early as 1885.
• Age-related macular degeneration has recently
been named by Professor A C Bird and
coworkers who performed the International
ARM Epidemiological study group.
• The disorder is either referred to age related
maculopathy (ARM) or age-related macular
degeneration (AMD).
5. AMD: PREVALANCE
• The UN estimates the number of people
with AMD are about 20-25 million
worldwide.
• WHO’s estimate is 8 million people with
severe visual impairment.
• AMD was found to be second only to
cataract as the cause of severe visual loss.
• Prevalence of AMD in >75 year age group
varies from 1.2% to 29.3% in different
Ref: BMJ 2003; 326: 485-8
populations.
6. AMD: PREVALANCE
• 3 population based studies; the Beaver
Dam Eye Study, Blue Mountain Eye Study
and the Rotterdam study report the over-
all prevalence rates to be 1.7% in US, 1.4%
in Australia and 1.2% in Netherlands
respectively.
• In South India, the prevalence is 1.1%
whereas, another study from North India
reports the prevalence rate to be 4.7%.
1. Invest Ophthalmology vis. Sci 2001; 42: 2237-41
2. Am J. Epidemiology 1977; 106: 133
7. POSTULATED RISK FACTORS FOR
AMD
• Ageing
– The Framingham Eye study (1976) showed
the prevalence
– 65-74 years- 11%
– 75-85 years- 28%
• Gender
– Blue Mountains study (2002) suggests that 5-
year incidence of neovascular AMD among
women is double that of men.
• Smoking
– The Beaver Dam Study (1992) disclosed a
relationship between the development of
8. POSTULATED RISK FACTORS FOR
AMD
• Cardiovascular Risk factors
– Hypertension: Rotterdam study
(2003) suggests positive
correlation between high blood
pressure and increased
incidence of AMD.
• Light
– Initially postulated hypothesis:
UV-damage by photo-oxidative
damage via reactive oxygen
intermediates.
– The Blue Mountains Eye Study
(2002) disclosed no relationship
between light and AMD.
9. POSTULATED RISK FACTORS FOR
AMD
• Nutrition
– Several studies
(including AREDS) have
described the
beneficial effects of
dietary carotenoids,
anti-oxidants, Zn and
omega-3 fatty acid in
slowing the course of
the disease.
• Exogenous Post
Menopausal Oestrogen
– The use of exogenous
supplements in post
10. GENETICS
• Family history of macular degeneration:
– Autosomal dominant with variable penetration
– In first degree relative with macular
degeneration, chances is about 2.5 times.
• Macular Degeneration Gene:
– Few studies* have described the increased risk
of AMD associated with polymorphisms of
complement factor H (HF1/CFH)
– single nucleotide polymorphisms on 1q32, 6p21,
and 10q26 are the risk for development of AMD
– The odds of developing macular degeneration
are increased by about 2.5 to 5.5 times if one
*Moshfeghi DM, Blumenkranz MS, Retina. 2007 Mar;27(3):269-75
has the CFH gene variant.
12. AMD: SYMPTOMS
Initial symptoms:
• Straight lines appear wavy
• Blurry vision
• Distorted vision
• Objects may appear as the wrong shape or size
• A dark empty area in the centre of vision
13. AMD: SYMPTOMS
• Patient’s ability
to perform
normal daily
tasks such as
reading,
sewing, telling
the time,
driving are
greatly
impaired.
16. RETINAL PIGMENT EPITHELIUM
The retinal pigment
epithelium (RPE) is a
single layer of
hexagonally shaped cells
& attached to the
photoreceptor layer.
Functions -
1.Maintain the
photoreceptors
2.Absorption of stray light
3.Formation of the outer
blood retinal barrier
4.Phagocytosis and
regeneration of visual
pigment
17. • Bruch’s membrane separates the RPE from
vascular choroid.
• Function of Bruch’s membrane is to
provide support to the retina.
• Choroid capillaries are a layer of fine blood
vessels that nourishes the retina and
provides O2.
20. DRY AMD
• Accounts for about 90% of all cases
• Also called atrophic, non-exudative or
drusenoid macular degeneration
• Clinically , dry AMD may manifest-
Stage of drusen and/or hyperpigmentation
Stage of incipient atrophy (non geographic
atrophy)
Stage of geographic atrophy
22. DRY AMD
Insufficient oxygen and nutrients
damages photoreceptor molecules
With ageing, the ability of RPE cells to digest
these molecules decreases
Excessive accumulation of residual metabolic
debris and hyaline material (drusen)
RPE membrane and cells degenerate and
atrophy sets in and central vision is lost
23. DRY AMD
Drusen:
• Drusen are aggregation of hyaline material
located between Bruch’s membrane and
RPE.
• Drusen are composed of metabolic waste
products from photoreceptors.
• Hypo/hyper pigmentation of RPE may be
present.
24. • Types:
– Small: <63 µ
– Intermediate: 63-124 µ
– Large: >125 µ
– Hard:
• generally small (<63 µ), bright yellow, solid
appearing drusen with well defined margins
• may be asymptomatic
– Soft:
• larger (>63 µ), pale yellow, ill defined, fluffy
margins
• High risk for neovascular AMD
25. • Soft Drusen:
– Membranous:
• 63-175 µ
• Pale, shallow appearing drusens
– Granular:
• About 250 µ
• Solid appearing drusens
– Serous:
• >500 µ
• Have pooled serous fluid
• blister like appearance
• May result in serous PED
26. HISTOPATHOLOGY
• Drusen appear as focal areas of the eosinophilic
material between the basement membrane of RPE
& BM.
• Deposits on the internal side of RPE basement
membrane called –basal laminar deposits & on its
external aspects called – basal linear deposits.
• Basal linear deposits are believed to form soft
drusen with the passage of time & are more
common in eyes effected by neo-vascular AMD.
Drus
en
27. • Diagnostic criteria*
• Degenerative disorder in persons >50
years, characterized by the presence of
any of the following:
– Soft drusen (>63 µ)
– RPE abnormalities- areas of
hypo/hyperpigmentation (excluding
pigment surrounding small, hard
drusen)
– Visual acuity (VA) is not a criterion for
the diagnosis
*International Epidemiological Age-related Maculopathy
study Group
31. DRY AMD: COURSE AND VISUAL
PROGNOSIS
• Patients with only drusen not have much
loss of vision, but require additional
magnification of the text and more intense
lighting to read small points.
• Presence of large drusen (>63 microns in
diameter) is associated with a risk of the
late form of the disease like CNV.
• Geographic atrophy- severest form of the
dry AMD, RPE atrophy >175 microns with
exposure of the underlying choroidal
vessels.
32. EXUDATIVE MACULAR
DEGENERATION
( WET OR NEOVASCULAR AMD )
• Accounts for about 10%
• The pathology of neovascular AMD is
choroidal neovascularisation with the
formation of a subretinal/choroidal
neovascular membrane (SRNVM/CNVM)
The CNVM lead to haemorrhage and
fibrovascular proferation and subsequent
scarring.
• Age related Bruch’s membrane change may
be especially important in exudative
macular degeneration, this change
includes thickening of Bruch’s membrane,
33. WET AMD
Photoreceptors and pigment epithelium send
a distress signal to choriocapillaries to
make new vessels
New vessels grow behind the macula
Breakdown in the Bruch’s membrane
Blood vessels are fragile
Leak blood and fluid
Scarring of macula
Potential for rapid and
35. WET AMD
• Diagnostic criteria*
• persons >50 years, characterized by the
presence of any of the following:
– choroidal neovascularization
– serous retinal pigment epithelial
detachment
– hemorrhagic retinal pigment epithelial
detachment
– fibrotic scar in the macula
*Takahashi K et al.Nihon Ganka Gakkai Zasshi. 2008
Dec;112(12):1076-84.
38. WET AMD
• CNV lesion is well demarcated & its
location may be determined by closest
point to the FAZ.
• Lesion location is classified
angiograpically as follows:-
1. Subfoveal: under the centre of FAZ
2. Juxtafoveal: 1-199 µm from the centre of FAZ
3. Extrafoveal: >200 µm & <2500 µm from the
centre of FAZ
• Types:
– Type I: CNV beneath RPE
– Type II: CNV above RPE
45. RPE TEAR
• Spontaneously or on
photocoagulation of CNV.
• Visual acuity abruptly fall
• Angiogram shows CNV in
early & in late phase
shows hypofluorescence
corresponding to heaped-
up RPE with
hyperfluorescence over
the torn area.
47. VARIATION
• Retinal angiomatosis proliferans
– Has been termed Type-III CNVM
– Characterized by predominantly
intraretinal neovascularization
– 3 Stages:
• Stage 1
– Intraretinal neovascularization
• Stage 2
– Subretinal neovascularization
• Stage 3
– CNV clearly determined
clinically/angiographically.
– RCA (retino-choroidal anastamoses) seen
as “Hair-pin” appearance on FFA.
48. WET AMD: COURSE AND VISUAL
PROGNOSIS
• Leakage of blood or serum in CNV may occur
precipitously and associated with the abrupt
loss of vision.
• Patients with CNV shows rapid decline in vision
(20/200) within weeks.
• Once CNV has developed in one eye, the other
eye is at relatively high risk for the same
change.
• More frequently, visual acuity deteriorates more
slowly and stabilizes within 3 years.
49. AMD: STAGING
• AREDS Categories:
– No AMD (AREDS category 1)
• No or a few small (<63 micrometres in diameter)
drusen.
– Early AMD (AREDS category 2)
• Many small drusen or a few intermediate-sized (63-
124 micrometres in diameter) drusen, or macular
pigmentary changes.
– Intermediate AMD (AREDS category 3)
• Extensive intermediate drusen or at least one large
(≥125 micrometres) drusen, or geographic atrophy
not involving the foveal centre.
– Advanced AMD (AREDS category 4)
• Geographic atrophy involving the foveal centre
(atrophic, or dry, AMD)
51. AMD: DIAGNOSTIC TOOLS
• Visual acuity
• Amsler grid test: Assesses
distorted or reduced vision
and small irregularities in
the central field of vision.
• Ophthalmoscopy: to detect
drusen, as well as
neovascularization
• Fluorescein and ICG
angiography: Determines
the presence and location
of neovascularization.
• Aided by optical
coherence tomography.
52. AMD: MANAGEMENT
• Role of Antioxidants:
• AREDS-1 study- use of high dose of
multivitamins & antioxidants decreases the
risk of progression of ARM in those with
high risk characteristics.
• Combination of antioxidants and zinc
(AREDS-1 Formula)-
– Vitamin C: 500 milligrams (mg)
– Vitamin E: 400 international units (IU)
– Beta carotene: 15 mg (equivalent to Vit.A 25000
IU)
– Zinc: 80 mg
– Copper (cupric oxide): 2 mg
53. AMD: MANAGEMENT
• AREDS-2 Study:
– Lutein & zeaxanthin antioxidants
micronutrients found in human macula.
– Diet rich in these give some protection
against the disease.
– omega-3 fatty acids, docosahexaenoic acid
(DHA) and eicosapentaenoic acid (EPA) have
also been shown to help with AMD.
– AREDS-2 Formula-
• Vitamin C - 500 mg
• Vitamin E - 400 IU
• Beta-Carotene - 15 mg
• Zinc - 80 mg
• Copper - 2 mg
• Lutein - 10 mg
55. ANTI ANGIOGENICS
• Anti-VEGFs:
– reduce the growth of new blood vessels,
decrease the leakage through them.
• Bevacizumab (Avastin)
• Ranibizumab (Lucentis)
• Pegaptanib sodium (Macugen)
• Aflibercept (VEGF Trap-Eye)
56. • Bevacizumab (Avastin)-
– Full-length monoclonal
antibody (150 kD)
– Binds all isoforms of
VEGF
– Has FDA approval for i.v.
use in metastatic
colorectal, metastatic
breast and non-small cell
carcinoma of lung
– Is being used off-label for
choroidal
neovascularization based
on results of short-term
57. • Ranibizumab (Lucentis )
– Recombinant humanized
immunoglobulin G1, kappa
isotype, antibody fragment
(Fab) (48 kD)
– Binds to all isoforms of
VEGF.
– Dose- First 3 injections of
0.5 mg (0.05 mL) four
weekly & further on
physician's assessment.
•
58. • Pegaptanib sodium
(Macugen)
– 28 base ribonucleotide
aptamer
– Binds to Heparin-binding
domain of VEGF-A
– Inactivates VEGF-A
165,189 and 206 isoforms
– Given 0.3 mg dose six
weekly minimum for two
years.
– VISION (VEGF Inhibition
Study in Ocular
Neovascularization)
(2002) has shown that
59. • Aflibercept (VEGF Trap-
Eye)
– a fusion protein of key
binding domains of
human VEGFR-1 and 2
combined with a human
IgG Fc fragment
– blocks all isoforms of
VEGF-A
– Also blocks placental
growth factors-1 and 2
– Two Phase III clinical
trials (VIEW-1 and VIEW-
2) comparing aflibercept
to ranibizumab are
61. PHOTODYNAMIC THERAPY (PDT)
• PDT helps to selectively close off subretinal new
vessels.
• Two stage treatment:
• Injecting the photosensitiser drug
(Verteporfin)
• Applying cold laser (689 nm) to activate the
drug
– Releases the singlet oxygen molecule that
damages the endothelium
– Thrombosis of the capillaries
– New PDT drug under phase-3 trial: Purlytin
(SnE2)
– PDT with ICG has also been evaluated* using
diode laser (805 nm).
*Chang Kyoon Yoon et al. Korean J Ophthalmol. 2007
62. • Many studies have shown that
ranibizumab is superior to placebo/PDT
for treatment of neovascular AMD.
– MARINA (Minimally classic/occult trial of the Anti-
VEGF antibody Ranibizumab In the treatment of
Neovascular AMD) (2007)
– ANCHOR (Anti-VEGF antibody for the treatment of
predominantly classic Choroidal neovascularization
in AMD) (2009)
– PIER (Phase III-b, multicentre, randomized, double-
masked, sham injection controlled study of the
efficacy and safety of ranibizumab in subjects with
sub-foveal neovascularization with or without
classic CNV) (2008)
– PrONTO (Prospective OCT Study with Lucentis for
63. LASER PHOTOCOAGULATION
• Macular Photocoagulation Study (MPS) (1993):
– A series of prospective randomized multicenter
clinical trials
– To determine the efficacy of laser photocoagulation
surgery in CNV caused by AMD, ocular
histoplasmosis, and idiopathic causes.
• Modality for juxtafoveal & extrafoveal CNV
associated with AMD.
• Beneficial in CNV lesions with well demarcated
boundaries, <6.5 MPS disc area (1 MPS disc
area= 2.54 mm2)
• Well-circumscribed new blood vessels
identified on the fluorescein angiogram and
lasered.
• Disadvantages-
– Immediate significant fall in central vision
65. TRANSPUPILLARY THERMOTHERAPY (TTT)
• First described by Oosterhuis et al. in 1998
for treatment of choroidal melanoma.
• The goal of TTT is to create and maintain
tissue hyperthermia.
• The diode laser (810 nm, near infrared):
– low absorption in xanthophyll, minimising nerve
fibre layer damage
– poorly absorbed by haemoglobin, allowing
treatment through preretinal and subretinal
blood
– mainly absorbed in the choroid, enabling
effective treatment of choroidal lesions.
• In ongoing trials: 3 mm spot, 800 mW, 60
sec.
66. RADIATION THERAPY
• TELETHERAPY (EBRT):
– Studies have shown equivocal results.
– Adverse effects: Cataract, keratoconjunctivitis
siccs, epiphora
• BRACHYTHERAPY (Plaque Radiotherapy):
– Published reports include use of Palladium-103
(103 Pd)1, Strontium-90 (90 Sr)2 and Ruthenium-
106 (106 Ru)3
– These studies have shown less vision loss in
study group than controls.
– 1. Finger et effects: Radiation induced vasculitis,
Adverse al. 2003
2. Jaakkola et al 1998 and 2005,of adjacent tissue
retinal edema, necrosis Finger et al 1999
3. Berta et al. 1995
68. Diagnosis Recommended
Treatment
No clinical signs of AMD Observation with no
(AREDS category 1) medical or
surgical therapies
Early AMD
(AREDS category 2)
Advanced AMD with bilateral subfoveal
geographic atrophy or disciform scars
Intermediate AMD Antioxidant vitamin and
(AREDS category 3) mineral
supplements as
recommended
Advanced AMD in one eye in the AREDS reports
(AREDS category 4)
69. Diagnosis Recommended
Treatment
Subfoveal CNV Ranibizumab/Bevaci
zumab intravitreal
injection
Subfoveal CNV, new or recurrent, for Pegaptanib sodium
predominantly classic lesions <12 MPS disc intravitreal
area in size injection
Minimally classic, or occult with no classic
lesions where the entire lesion is
<12 disc areas in size, subretinal hemorrhage
associated with CVN comprises <50% of
lesion, and/or there is lipid present, and/or
the patient has lost
15 or more letters of visual acuity during the
previous 12 weeks
Subfoveal CNV, new or recurrent, where the PDT with verteporfin
classic component is >50% of the lesion and
the entire lesion is <5400 microns in greatest
linear diameter
70. Diagnosis Recommended Treatment
Extrafoveal classic CNV, new or Thermal laser photocoagulation
recurrent, surgery as recommended in the
May be considered for MPS reports
juxtapapillary CVN
American Academy of
Ophthalmology Summary
72. EMERGING TREATMENTS FOR AMD
• Retaane® (Anecortave acetate)
– modified steroid promising in reducing the risk
of vision loss due to the growth of unhealthy
blood vessels in wet AMD.
• AdPEDF : Adenovirus-based Pigment
Epithelium Derived Factor
– a gene that leads to the production of the
protein PEDF, which helps keep photoreceptors
healthy, thereby preserving vision.
• siRNA (Bevasiranib)
– silences the genes that lead to the growth of
unhealthy, vision-robbing blood vessels under
the retina.
– safety and efficacy established in a Phase II
study
73. EMERGING TREATMENTS FOR AMD
(Contd.)
• ATG3 (mecamylamine)
– a topical formulation that inhibits the
nicotinic acetylcholine receptors
– Currently undergoing phase II human study
• EVIZON™ (squalamine lactate)
– aminosterol with anti–angiogenic activity
– Derived from the liver of the dogfish shark,
administered intravenously (no eye
injection)
– in a Phase III human study for the treatment
of wet AMD
• OT-551 (antioxidant eye drops)
– supplement the eye’s natural defense
74. EMERGING TREATMENTS FOR AMD
(Contd.)
• Encapsulated Cell Technology (ECT)
– Developed by Neurotech,
– tiny capsule (6 mm) implanted into the eye,
contains retinal cells that produce a vision-
preserving protein ,Ciliary Neurotrophic Factor
(CNTF)
– keep photoreceptors alive and healthy,
preserving vision.
– currently in a Phase II human clinical trial for
people with dry AMD.
75. REHABILATATION
• Low vision aids-
– Individual who
experiences
untreatable visual
loss & effects the
daily life.
– Reading lamps &
simple magnifiers
may be beneficial.
– Closed circuit
television & scanning
devises are also
77. CONCLUSIONS
• AMD continues to be one of the leading
causes of visual loss in aged people.
• New therapeutic strategies continue to be
developed & tested.
• Anti-angiogenic drugs remain the mainstay of
current treatment.
• Advancement in pharmacology, bio-
technology and genetic engineering may
dramatically change the treatment protocol
with better outcome in near future.
• And, refinements in advanced surgical
techniques may offer better results in
future………..
