DR WANI'S TALK ON AMD FOR RESIDENTS 30 March 2020.pptx

Age Related
Macular
Degeneration
Dr.Vivek Wani MS FRCSEd
Consultant Vitreoretina Surgeon
KLES DR. Prabhakar Kore Hospital
and MRC
Belagavi
India
3/30/2020
1
DR WANI 's online class for KLE Ophthal
PGs

I) AMD-Definition
There is no agreed definition of AMD
No agreed age and agreed criteria to diagnose
However the clinical classification of AMD in to
DRY(non-neovascular) and WET(neovascular)
is universally accepted
3/30/2020
2
DR WANI 's online class for KLE Ophthal PGs

Age Related Macular Degeneration
(ARM) or AMD
International classification and grading system for age related maculopathy and age
related macular degeneration.
 ARM- is a degenerative disorder of persons 50 years of age or older that is
characterized by the following abnormalities of macula:
 Soft drusen 63microns or larger
 Hyperpigmentation and /or hypopigmentation of RPE
 RPE and associated neurosensory detachment
 Peri retinal hemorrhages
 Geographic atrophy of RPE, or
 Peri retinal fibrous scarring in absence of other retinal vascular disorders
 VA is not a factor in the disease definition and classification
(Bird et al Surv Ophthalmol 1995;39:367-374)
3/30/2020
3

II) Epidemiology
 Leading cause of blindness in the world after cataract and
glaucoma
 Age-related macular degeneration accounts for more than 54%
of all vision loss in the white population in the USA (2004)
 6.4% of 65-74 years group had signs of AMD v/s 19.7% of
patients aged 75 years or more
 In India Early AMD was seen in up to 21% and late AMD was
seen 2.3% of individuals aged 60 years and above
http:/www.who.int/blindness/causes/priority (2012)
The Eye Diseases Prevalence Research Group. Causes and prevalence of visual impairment
among adults in the United States. Arch Ophthalmol 2004; 122: 477–85.
Framingham Eye Study Surv Ophthalmol.1980;24(Suppl):335-610
Smith W et al Ophthalmology 2001; 108: 697–704.
Raman R et al Eye. 2016 ;30(5):688-97.
3/30/2020
4

Epidemiology
 Dry AMD is more common than neovascular AMD
 Dry AMD(geographic atrophy) -20% of blindness
due to AMD
 Wet AMD (neovascular) -80% of blindness due to
AMD
 However dry AMD may be a cause of moderate
visual loss in much greater number of individuals
 Ref-Ferris et al Arch Ophthalmol.1984; 102: 1640-2
 Ref-Ryan et al. Retina vitreous macula Volume I
3/30/2020
5

III) Risk factors for AMD
 Age is the strongest risk factor –after 60 years the incidence
increases
 Positive family history
 Genetic factors
 Smoking (very strong)
 Hypertension
 Cardiovascular disease
 Hyperopic eyes
 Race (Caucasians>Africans)
 Low dietary intake of vitamin A, zinc, lutein and omega 3 fatty
acids
Protective factors are – Diet rich in green leafy vegetables, fish
(Meditararian diet )
Lim et al Lancet 2012; 379: 1728–38
Sui et al BJO 2013;97:389-394
3/30/2020
6

Genetics and AMD
Genes suspected to play a
role in AMD
• CFH (complement factor H;
chr 1)
LANCET 2012
• CFB (complement factor B
[properdin]; chr 6)
• C2 (complément component
2; chr 6)
• ARMS2/HTRA1 (HtrA-
serinepeptidase1; chr 10)
• APOE (apolipoprotein E; chr
19) protective gene
• TIMP3 (tissue inhibitor of
metalloproteinase 3; chr 22)
3/30/2020
7

CFH
CFH is a protective protein that prevents
uncontrolled complement activation and
inflammation
CFH mutations will lead to increased
complement activation and inflammation
3/30/2020
8

IV) Pathogenesis
A-Important structures involved in the AMD are
 Photoreceptors
 RPE
 Bruch’s membrane
 Choriocapillaris
Highly active area
60-70% of blood supply to eye is from choroidal
circulation
Oxygen concentration is maximum in macular area
than anywhere else in the body
3/30/2020
9

Parmeggiani et al , Mediators of inflammation
2012
3/30/2020
10

RPE functions
3/30/2020
11

Bruch’s membrane- 5 layered
3/30/2020
12
1. Basement membrane of RPE-collagen IV-
0.15 mu
2. Inner collagen layer-collagens I, III and V,
proteoglycans chondroitin sulfate and
dermatan sulfate-1.4microns
3. Middle elastin layer—0.8microns thick-
elastin fibers, collagen VI, fibronectin, and
other proteins, and collagen fibers from
the ICL and outer collagenous layer (OCL)
can cross the EL. The EL confers
biomechanical properties, vascular
compliance, and anti-angiogenic barrier
functions

Bruch’s membrane
3/30/2020
13
4)Outer collagen layer—1 micron -same
like inner collagen layer
5) Basal lamina of Choriocapillaris –
collagen IV may be discontinuous
In normal physiology, BrM appears to
function as a robust barrier against
neovascularization
Allows passage of oxygen, h2O, nutrients
through it

Bruch’s membrane
 Bruch's membrane thickness 2 µm in first decade
4.7 µm 80 years later
 This thickening is caused by the deposition of
waste products of the RPE, such as oxidized lipids
and proteins
 However the elastic layer reduces in thickness
with age
 A thickened Bruch’s membrane in old age may be
barrier for passage of oxygen, H2O and other
nutrients
3/30/2020
14

Choriocapillaris
 The density and diameters of the
choriocapillaris capillaries decreases with
age, and this decrease is even greater in
patients with AMD-hypoxia
 The overall loss appears most marked in
regions of geographic atrophy
3/30/2020
15

B) Processes of Pathogenesis of
AMD
 Multifactorial disease
 Only 10% of individuals over 75 years are
affected –so age alone is not a risk factor
 Genetic-not all with a defective gene develop
severe AMD
 Age, environmental factors and genetic
factors play a complex role in its development
3/30/2020
16

Pathogenesis of AMD
i)Lipofuscinogenesis(with its linkage to oxidative
stress
ii)Drusen formation or drusenogenesis
iii) Alterations in the Bruch’s membrane
iii)Local inflammation
iv) Cell death –RPE in dry AMD
iv)Neovascularization (in the case of wet form)
From Novak 2006
3/30/2020
17

1) Lipofuscinogenesis in RPE
 Aged RPE has less efficiency in processing
phagocytosed photoreceptors
 So there is progressive accumulation of degraded
products of photoreceptors which are called lipofuscin
granules in RPE
 Lipofuscin are made up of lipids 50% and proteins
44%
 They contain fluorophores which are responsible for
increased reflectivity seen on FAF
 One fluorophore is A2E which is made up of two
vitamine A aldehyde molecules and one ethanolamine
molecule
3/30/2020
18

LIPOFUSCINOGENESIS
 These lipofuscin are altered by oxidative stress
from visible and ultraviolet light and high oxygen
concentration (the O2 concentration in outer retina
is the maximum in the body)
 Radical oxygen molecules produced
 Lipofuscins in RPE cells may induce apoptosis
 A2E inhibits lysosomal functions, induces
photosensitization and apoptosis , can start
complement system of immunity
 RPE cells may show depigmentation, migration,
atrophy and death
3/30/2020
19

2 )Drusenogenesis
Drusens result from dysfunction of the
RPE due to age and lipofuscin
accumulation
The drusen material mostly from the
RPE slowly starts accumulating
between basement of RPE and inner
collagen layer of Bruch’s membrane
Seen clinically when they achieve a
particular size
3/30/2020
20

Drusenogenesis
Drusens are made up of
 Photoreceptor remnants
 Glycoproteins
 Amyloid beta proteins
 Immune associated elements-immunoglobulins, class II antigens
 Vitronectin, apolipoprotein B and E, alpha-crystallin and lipids
 Components of complement cascade
(Including the H -CFH, terminal pathway components including Membrane
attack complex)
Lipids –unesterified cholesterol form >40% of the drusens
 Apolipoproteins E and amyloid beta are deposits in brain seen in
Alzheimer disease –they have proinflammatory and angiogenic properties
3/30/2020
21

3/30/2020
DR WANI ‘s online class for KLE Ophthal PGs
22

Basal laminar and Basal linear
deposits –NOT CLINICAL entities
They are histological findings
BA LAM DE- is between RPE plasma membrane
and basement membrane of RPE
 IT IS MADE up of long spaced collagen and is
basement membrane material
Basal linear deposits
 Thin layer of deposits situated between BM of
RPE and inner collagen layer of Bruch’s
membrane
 Is same material as soft drusen and continuous
with drusens when present
3/30/2020
23

3/30/2020
24
From Khan et al Progress in Retinal and eye research 2016

Alterations in Bruch’s membrane
 Bruch’s membrane thickens with age
 Apolipoproteins and other lipids accumulate in
Bruchs membrane and these probably come
from Sub RPE space and RPE
 Less permeable to passage of oxygen, water
and nutrients across it
 Bruch’s membrane calcification - fracture can
occur
3/30/2020
25

Inflammation-chronic in nature
 The drusen has many proinflammatory proteins which
set up inflammatory reactions
 Macrophages, microglia are recruited in the
inflammation and many cytokines like IL8, IL18 are
produced
 Inflammosomes are multiprotein complexes that
assemble at the site of inflammation and have been
found in AMD
 ALU RNA is a RNA that induces apoptosis of RPE as
consequence of inflammation
 Complement system is an important part of the
inflammatory cycle
3/30/2020
26

Complement system
 C3 protein when enters the complement cascade reaction forms
a final product called C5b 9 which is a membrane attack complex
-MAC
 Many of the components of the drusen promote the C3 activation
 Complement factor H constantly prevents C3 entering the
cascade reaction and controls the formation of membrane attack
complex
 CFH gene variant lacks the capacity to block C3 entering the
cascade reaction and hence promotes complement reaction
induced inflammation
 Membrane attack complex can lead to RPE cell death,
dissolution of Bruch’s membrane leading to CNV
3/30/2020
27

Angionesis
 IS the growth of new vessels from choriocapillaris in to
the subRPE place or subretinal place
 Requires break in Bruch’s membrane
 Inflammatory or mechanical weaknesses lead to break
in the Bruch’s membrane
 VEGF secreted by RPE cells or by macrophages
recruited during inflammation stimulate new vessels to
grow from choriocapillaris to sub RPE space and some
times through the RPE layer in to the subretinal space
3/30/2020
28

From Miller Am J Ophthalmol
2013
3/30/2020
29

3/30/2020
30

3/30/2020
31

V) AMD- Clinical features
3/30/2020
32
A -Symptoms
 Initially none
 Difficulty in dark
adaptation
 Inability to read, missing
words
 Scotoma or black spots
 Metamorphopsia-very
important symptom
 Decreased vision –
sudden or gradual

3/30/2020
33
DR WANI /s online class for KLE Ophthal PGs

AMD –Clinical features
Dry AMD OR Non neovascular -
includes early, intermediate and
dry type of advanced AMD
Wet AMD or Neovascular AMD
includes only neovascular AMD
and its manifestations
3/30/2020
34

DRY AMD
A -Symptoms
 Initially none
 Difficulty in dark adaptation
 Inability to read, missing words
 Scotoma or black spots
 Decreased vision
3/30/2020
35

V) B- Dry or non neovascular
AMD Fundus appearance
 Drusens-present in both Dry and Wet
 RPE Hypopigmentation or hyperpigmenation
 Geographic atrophy- RPE and underlying
choriocapillaris atrophy making large
choroidal vessels visible
3/30/2020
36

Drusens
 They are seen as round whitish grey or yellow
lesions located at the level of RPE within the
macula
 Vary in number, size, shape and degree of
elevation and associated RPE changes
 They are rarely present <45 yrs of age
 Not uncommon between 45-60 yrs
 Universally present after 60 yrs age
3/30/2020
37

Drusens-size
 Small <63 microns not a sign of AMD may be
present in patients aged<45 yrs
 Intermediate-63-124 microns
 Large >/= 125 microns
 Very large>250microns
 A drusen’s smallest diameter is compared to
retinal vein at the edge of disc which is roughly
124 microns
 We make an estimation of the size of the drusen
3/30/2020
38

Small or hard drusens
 Small drusens are –discrete, well
demarcated, yellowish white
 They occur with ageing but alone are not
enough to classify as AMD
3/30/2020
39

Small or Hard Drusens
 FFA –they appear as pin point window defects
 Histopathologically –single enlarged RPE
cells with lipid accumulation or sub RPE
deposit
 The risk to progression to advanced AMD of
1.3% only over five years
 No treatment is advised only FU after a year
3/30/2020
40

Hard Drusen
3/30/2020
41

Soft drusens
 Soft drusens >63 microns
 Situated between RPE basement membrane and inner
collagenous layer of Bruch’s membrane
 Intermediate sized 64-124 microns
 large drusens >124 mu and
 very large drusens>250mu
 Ill defined borders, greyish white or yellowish white
 Vary in size and shape
 Decreasing density of the drusen from center to the
margins
 Tendency to cluster and merge with one another –
coalescence
3/30/2020
42

Soft drusens FFA
 FFA-hyperfluorescence early and fade or
stain in late phase
 Persistent staining is due to pooling of dye in
focal detachment of RPE membrane or
staining of diffuse drusen material
 In fact many large drusens are focal
detachments of RPE
 The RPE cells over the soft drusens are hypo
pigmented or atrophic
3/30/2020
43

3/30/2020
44

OCT OF DRUSENS
3/30/2020
45

3/30/2020
46

LARGE DRUSENS
3/30/2020
47

SOFT drusens
 Their number increases with age
 They may spontaneously regress or
disappear over period of time-leaving RPE
atrophy
 Eyes with soft drusens are at increased risk of
developing RPE abnormality, Geographic
atrophy and CNV
3/30/2020
48

Large and small drusens
3/30/2020
49

RE
3/30/2020
50

LE
3/30/2020
51

RISKS OF advanced AMD in
large drusens
Eyes with bilateral large drusens
 Risk of CNV is 18% in at least one eye in
three years
 Risk of Geographic atrophy-8%
Eyes with large drusens with CNV in one eye
 Large drusen present -46% risk of CNV in
good eye in 5 yrs
 If no large drusens 10% risk only
3/30/2020
52

SPECIAL TYPES OF
DRUSEN
 Cuticular drusen
 Psuedodrusen or subretinal drusen or
subretinal drusenoid deposits
Read about them in article by Spaide et al in
Survey of Ophthalmol 2018
3/30/2020
53

Cuticular drusens
 Are small like hard drusens but are more numerous
than hard drusens and extend beyond arcades up to
midperiphery
 Are between RPE basement membrane and Inner
collagenous layer of the Bruch’s membrane
 Many are small like hard drusens but may be large
 FFA-starry night appearance due to the RPE atrophy
over the druse
 FAF- mild decrease in FAF over the druse
 OCT-shows triangular or saw-tooth appearance

3/30/2020
54

Figure from Balaratnasingam et
al Ophthalmology 2018
3/30/2020
55

Subretinal drusenoid deposits
 Pseudo drusens or Reticular drusens
 Located internal to the RPE between RPE and
sensory retina
 Their composition is like soft drusens
 APPEAR AS whiter or blue and better seen with
blue light-Blue light is not filtered by RPE AS
THEY ARE ABOVE THE RPE
 A network like appearance seen –reticular
 More in PERIFOVEA
3/30/2020
56

3/30/2020
57

3/30/2020
58

3/30/2020
59

AMD
 Early ADM-soft drusens
 Intermediate AMD- soft drusens +RPE
changes- Hyperpigmentation and /or
hypopigmentation
 Late AMD
 GA invovling the fovea, RPE detachment,
CNV and disciform scar
3/30/2020
60

RE LARGE DRUSENS
3/30/2020
61

The LE of patient with large
drusens
3/30/2020
62

SO SOFT drusens = danger
 Soft drusens are not soft on vision!
 Need regular follow up
 Educate the patient and we will discuss the
treatment later
3/30/2020
63

Changes in RPE in Non-neovascular
AMD
 Pigment mottling
 Stippled hypopigmentation
 Focal hyperpigmentation
 Geographic atrophy
3/30/2020
64

Changes in RPE in Non
neovascular AMD
Pigment mottling and Stippled hypopigmentation
 These occur when the neurosensory retina
thins over the abnormal RPE area
 These abnormalities may precede the GA
 RPE overlying the drusens shows
hypopigmenation
3/30/2020
65

neovascular AMD
Focal hyperpigmenation
 Clinically evident pigment clumping at the level of
outer retina or subretinal space
 May be punctate, linear, or reticular in shape
 Present in 3-12% of adults >50 yrs
 Significance-increased chances of soft drusens,
GA, CNV
 Higher risk of CNV if focal hyperpigmentation and
soft drusens are present and if the other eye has
CNV -58-73% within 5 years
3/30/2020
66

3/30/2020
67

3/30/2020
68

Focal hyperpigmentation
3/30/2020
69

GEOGRAPHIC ATROPHY
 Advanced form of Dry AMD when it involves the
fovea
 RPE atrophies in well defined round area with
atrophy of underlying choriocapillaris -- so large
choroidal vessels seen easily
 These areas start as round areas often ringing the
fovea and then coalesce and enlarge and
ultimately involve the fovea
 Up to 20% of cases of legal blindness due to AMD
are due to GA
3/30/2020
70

Geographic atrophy
 The area of GA has atrophic RPE and
choiocapillaris and hence the photoreceptor layer
atrophies and hence has scotoma
 If it involves fovea then VA can drastically
decrease
 GA then becomes advanced form of AMD
 They are at risk of developing CNV at the edge of
GA
 FFA –RPE window defect
3/30/2020
71

Geographic atrophy LE
3/30/2020
72

3/30/2020
73

GA
 GA arises from three situations
1. Area of confluent large drusens may regress and
leave irregularly shaped areas of GA. These areas
may coalesce with other areas and ring the fovea
2. Small foci of pigmentary mottling areas may coalesce
and progress to a single area of GA that then spreads
contiguously to surround the fovea in a horseshoe
manner and then encircle it
3. Spontaneous flattening of the RPE detachment may
result in GA
3/30/2020
74

GA
 It spreads slowly 139 microns per year in one
dimension
 Around 0.7 Disc area/year
 Older patients have faster progression of the
disease
3/30/2020
75

GA and FFA
3/30/2020
76

GA
3/30/2020
77

3/30/2020
78

GEOGRAPHIC ATROPHY
 RPE atrophy causes increased choroidal reflectivity
 Thin retina (Survey Ophthalmol 2012)
3/30/2020
79

Dry AMD and Fundus
Autoflourescence
3/30/2020
80

FAF
 The prominent source of fluorophores are the
A2E in lipofuscin granules which are by
product of incomplete degradation of the
photoreceptor outer segments
3/30/2020
81

FAF in GA that shows the
progression of the lesion
3/30/2020
82

neovascular AMD
 Clinically evident pigment clumping at the level of
outer retina or subretinal space
 May be punctate, linear, or reticular in shape
 Present in 3-12% of adults >50 yrs
 Significance-increased chances of soft drusens,
GA, CNV
 Higher risk of CNV if focal hyperpigmentation and
soft drusens are present and if the other eye has
CNV -58-73% within 5 years
3/30/2020
83

Treatment of non-neovascular
AMD or Dry AMD
 Nutritional supplement-intermediate AMD or worse
 Health education
 Low visual aids
 PIGGY BACK IOL FOR near vision (Sharioth IOL)
 Photocoagulation of drusens
 Intravitreal injection of lampalizumab a complement
factor d antibody failed the clinical trial
 Intravitreal inj of brimonidine(neuroprotection) and
zimura( inhibits splitting of c5) are under trial
3/30/2020
84

3/30/2020
85

3/30/2020
86
EARLY
INTERMEDIAT
E
ADVANCED
NORMAL AGING
/NO DISEASE

3/30/2020
87

AREDS conclusions
Who should take vitamin supplements AREDS
 Intermediate disease
 Advanced disease in one eye
 The risk of progression to advanced AMD is
reduced by about 25%
Arch Ophthalmol 2001
3/30/2020
88

3/30/2020
89

Health education
 CNV and its early symptoms-metamorpopsia, scotoma or
decreased vision
 Amsler grid in high risk cases- now there are online better
facilities
 Need to check each eye separately to be told to the patient
 Need to take nutritional supplement on long term basis
 Avoid smoking
 Dietary habits
 Need for regular eye examinations
 Avoid UV light (use dark glasses and avoid excessive sun
exposure)
3/30/2020
90

Neovascular AMD
The hall mark of wet AMD is
CNV
3/30/2020
91

Symptoms of Wet AMD
 Metamorphopsia
 Decreased vision –sudden or gradual
 Scotoma
 Asymptomatic in some cases
3/30/2020
92

3/30/2020
93
JULY 2019
SEPTEMBER 2019

Wet AMD
3/30/2020
94
 The growth of new vessels
from choriocapillaris through
the Bruch’s membrane
 Break in the Bruch’s
membrane is a trigger for
CNV
 Buds of neovascular tissue
from choriocapillaris
perforate the outers aspect of
Bruch’s membrane
 Fibroblasts accompany the
new vessels

Types of CNV –TYPE I
 TYPE I CNV –occult
 The FV complex proliferates between the BM
of RPE and inner collagen layer of Bruch’s
membrane
 This FV complex can destroy the normal
architecture of choriocapillaris, Bruch’s
membrane and RPE
3/30/2020
95

Type I CNV in sub RPE space
 May leak fluid under the RPE causing its detachment
 Fluid may accumulate below the RPE lifting it up from
Bruch’s membrane
 CNV can bleed causing the hemorrhagic RPE
detachment
 Fluid may appear in the sub-retinal space –serous
retinal detachment clinical or OCT
 Sub RPE Blood may break in to subretinal space and
rarely break in to vitreous –subhyaloid hg and vitreous
hg
 The FV may scar and form disciform scar
3/30/2020
96

Type II CNV
3/30/2020
97
 It can grow through
RPE and reach
subretinal space-
Type II CNV

Type I and Type II CNV
membranes
3/30/2020
98

3/30/2020
99

Signs of wet AMD
 Presence of SRF-serous retinal detachment in the
macula-shallow elevation with indistinct borders
 Presence of serous RPE detachment-well demarked
elevated round or oval shaped darker mound of RPE
 Irregular elevation of RPE-fibroascular RPE
detachment
 RPE detachment ---hemorrhagic RPE detachment
appears darker
 Subretinal blood- appears bright red
 Subretinal or intraretinal lipids
3/30/2020
100

3/30/2020
101

3/30/2020
102

3/30/2020
103

Signs of wet AMD
 Subretinal pigment ring
 Subretinal gray white lesion –type I
 Cystoid macular edema
 Sea fan pattern of subretinal small vessels-
type II
 RPE rip
 Disciform scar
3/30/2020
104

3/30/2020
105

Type III CNV RAP lesion
 Retinal angiomatous proliferation RAP or type
III CNV
 intraretinal hemorrhages +
 intraretinal exudates and anastomosis
between subretinal/sub RPE and intraretinal
new vessels
3/30/2020
106

Wet AMD
 Diagnosis is straight forward in most cases
who are appropriate age
 INVESTIGATIONS
 FFA-gold standard
 OCT- is mostly replacing FFA
 OCT angiography- nonivasive imaging of
vascular pathology –cost
 ICG useful in occult CNVs IPCV type of AMD
3/30/2020
107

FFA in wet AMD
 Diagnosis-type of CNV if +
 Location and extent of CNV
 Follow up
 The earliest frame where leakage starts
defines the CNV lesion-type I or II
 Each CNV type is evaluated for presence,
proximity to the center of the macula and area
involved
3/30/2020
108

Classic CNV –seen in Type II
CNV
 A well-demarcated area of intense
hyperfluorescence appearing early and has lacy
pattern and shows progressive leakage
 Leakage obscures the margins of CNV
 Fl most intense at the perimeter of the CNV
 At the edge of CNV hypoflourescence is
commonn due to blood or pigment
 The center may show hypofluorescence
 Seen in a minority of eyes with AMD
 Many a times occult component will also be seen
3/30/2020
109

LE post phaco one yr ago
Disturbed vision -5 days LE 20/25
3/30/2020
110

3/30/2020
111
FFA LE

RE Wet AMD
3/30/2020
112

RE CLASSIC CNV
3/30/2020
113

Classic CNV
3/30/2020
114

Classic CNV
3/30/2020
115

Classic CNV
 Measure the size of CNV in early frame
 Measure its border’s distance from the foveal
center
3/30/2020
116

3/30/2020
117

Classic CNV according to the
location
 Subfoveal- any part of the lesion is located
below the center of the fovea
 Juxtafoveal-the edge of the CNV is more than
1 micron from the center of the FAZ and
within 200 microns
 Extrafoveal –the central border of the CNV is
beyond 200 microns from center of FAZ
3/30/2020
118

OCCULT CNV-FFA
 Two forms
A. PED –Fibrovascular Pigment epithelial
detachment
B. Late leakage of an undetermined origin
3/30/2020
119

PED
 Fibrovascular PED
 Irregular elevation of RPE with stippled or
granular irregular fl first seen usually by 1-2
minutes after dye inj
 It is best seen with stereo angiogram
 Progressive leakage occurs and causes a
stippled hyperfl that is not intense like the
classic type
3/30/2020
120

Occult CNV
3/30/2020
121

3/30/2020
122

3/30/2020
123

3/30/2020
124

Classic and occult mixed
3/30/2020
125

3/30/2020
126

Angiographic Subtypes of CNV
In eyes with a combination of CNV, three angiographic
subtypes are identified:
1. Classic subtype has classic components >50 percent
of the total lesion area
2. Minimally classic has 1 to 50 percent of the total lesion
area comprising a classic subtype.
3. Occult with no classic--- has no classic component in
it
These were important consideration for PDT
3/30/2020
127

RPE RIP
3/30/2020
128

End result of AMD
3/30/2020
129

3/30/2020
130
DISCIFORM SCAR

3/30/2020
131

Facts about CNV
 Most angiographic lesions are subfoveal and
occult
 20% of the subfoveal lesions are
predominantly classic
 Approximately half of juxtafoveal and
extrafoveal lesions are predominantly classic
3/30/2020
132

Uses of differentiation of CNV
lesions
 Classic and occult- response to laser
treatment is better in classic –MPS study-
obsolete
 Predominantly classic vs minimally
classic – for PDT treatment -benefits have
been shown only in predominantly classic
or purely occult
3/30/2020
133

OCT
 It has become an important tool of
investigation for AMD
3/30/2020
134

OCT signs of CNV activity
 It is nonivasive, detects SRF, intraretinal
fluid, location of CNV
 Helps to monitor response to treatment
 Intraretinal cyst
 Subretinal fluid
 RPE detachment
 Subretinal blood
 Subretinal tissue
3/30/2020
135

3/30/2020
136

3/30/2020
137

3/30/2020
138

3/30/2020
139

3/30/2020
140
Keane et al Survey Ophthalmol 2012

3/30/2020
141

3/30/2020
142
FROM de Carlo et al International journal of retina and vitreous 2015
OCT angiography

ICG
 Longer infra red wavelength can penetrate RPE
and choroid and are less absorbed by Hg
So it is useful in cases of
 Occult CNV or poorly defined CNV
 CNV with overlying hg or fluid or exudate
 Distinguish serous from vascularized portions of
fibrovascular PED
 Useful in diagnosis of IPCV identifies polyps and
BVN
3/30/2020
143

TREATMENT OF WET AMD
 Laser ablation –MPS study in 1990s- no more used
 Photodynamic therapy with Verteporfin- visual gains are
less limited to nonresponding to ANTi VEGF
 Intravitreal injection of steroids –mostly in recalcitrant
cases very rare
 Intravitreal injection of Anit-VGEF drugs mainstay of
treatment
 Combined treatment –PDT+STEROIDS+anti VEGF
 Surgical treatment of CNV now rarely used
 Anti oxidants to protect the other eye
 Low visual aids in cases with poor vision and end stage
disease
3/30/2020
144

1) Laser ablation
 No treatment was available about 30 years
ago for wet AMD
 Argon laser treatment was established as the
treatment of choice by a RCT in 1980s by
Macular Photocoagulation Study(MPS)
 It classified the CNV due to AMD in to
a. Extrafoveal
b. Juxta foveal
c. Subfoveal
3/30/2020
145

3/30/2020
146

3/30/2020
147

1) MPS
 Recommended treatment for only Classic types of CNV IN
JUXTAFOVEAL AND EXTRAFOVEAL
 HENCE many lesions remained ineligible for treatment
 Subfoveal network to be treated after informing patients that there will be
immediate loss of vision
 The CNV has to ablated by argon laser by confluent burns with treatment
of 100 microns around the margin of CNV
 So it is a destructive treatment
 The laser burn should not Involve the center of FAZ
 The treatment was done under the guidance of FFA pictures
 There were benefits for juxtafoveal and extrafoveal CNV compared to no
treatment but recurrences and persistence of CNV was common
 NOW it is recommended for selective extrafoveal networks only
3/30/2020
148

2) Photodynamic therapy with
vertporfin
 PDT became the first treatment that was shown to be
effective for CNV due to AMD
 It involves injecting IV verteporfin (6mg/kg body wt) – a
light activated compound which is picked up by CNV
vessels only-dividing cells
 Then the area of CNV is irradiated by diode laser source
(689 nm)
 Drug molecules when irradiated by laser produce oxygen
radical molecules and destroy the CNV
 The light selectively damages the CNV which has picked
up the drug
 The energy level required for this is less than that used in
MPS study so it spares the normal tissue
3/30/2020
149

Recommendations are from two
studies TAP AND VIP
 TAP Study-(treatment of ARMD with
photodynamic therapy)
 Vertoporfin In Photodynamic (VIP)therapy
trial; AMD and pathologic myopia
3/30/2020
150

Indications for treatment
 Subfoveal predominantly classic CNV and
classic CNV>50% of the lesion
 Subfoveal occult with no classic CNV and
lesion is </=4 DD, CNV>50% OF lesion, PDT
if recent disease progression
 NO BENEFIT in minimally classic CNV, lesion
any size <or >4 DD
 IPCV used with intravitreal ANTI VEGFS
3/30/2020
151

2) PDT-V
 Retreatments every 3 months are needed
 There is usually no visual improvement in
cases treated but chances of visual loss are
reduced
 4% of patients may lose vision immediately
after treatment
 Needs special laser
 Drug is photosensitive so patients should
avoid sunlight for 24 hours at least
3/30/2020
152

Side effects of the injection
 Transient visual disturbances
 injection-site adverse events
 transient photosensitivity reactions
 infusion-related low back pain
3/30/2020
153

3) Steroid injection for AMD
 Triamcinolone acetonoid intravitreal inj has been used
in treating uveitis, diabetic macular edema
 It has anti inflammatory, anti angiogenic and anti fibrotic
properties
 However it has not been shown to reduce the risk of
visual loss in cases of CNV due to AMD
 It has also been used in conjunction with PDT and Anti
VEGFs
 However there is no good clinical evidence so far
to include it in treatment of CNV due to AMD
3/30/2020
154

4)Anti VEGFs in AMD
 CNV occurs due to up regulation of VEGF in
AMD due to inflammatory process
 Presently they have become the mainstay of
treatment of CNV due to AMD
 They are effective in all types-classic and
occult and all locations
 Pts with nAMD show improvement in vision
with anti VEGF treatment which was not seen
with previous treatments
3/30/2020
155

3/30/2020
156

4)About VEGF
 VEGF exists as four isoforms: VEGF-121, VEGF-
165, VEGF-189, and VEGF-206
 VEGF-121 has been shown to persist for at least
14 days, whereas VEGF-165 is short lived
 This might explain why pegaptanib, a drug
specifically targeting VEGF-165, has been less
successful in treating CNV
 Ranibizumab or bevacizumab target all isoforms
3/30/2020
157

Anti VEGF drugs
A. Pegaptanib –Macugen is a
pegylated oligonucleotide that selectively binds
VEGF165 and is administered every 6 weeks by
intravitreal injection
B. Ranibizumab- Lucentis
C. Bevacizumab –Avastin
D. Aflibercept- VEGF trap eye
E. Broculizumab approved in 2020
F. Many others in pipeline
3/30/2020
158

4) A. Pegaptanib –Macugen
 Macugen was the first Anti VEGF drug to be
approved by the FDA
 It is a synthetic oligonucleotide
 Pegaptanib is a pegylated modified
oligonucleotide that binds with high specificity
and affinity to extracellular Vascular
Endothelial Growth Factor (VEGF isoform
165) inhibiting its activity
3/30/2020
159

3/30/2020
160

3/30/2020
161

4) A. Pegaptanib
 V.I.S.I.O.N study showed that macugen
reduced the risks of vision loss compared to
placebo treatment
 All types of CNV were treated
 Repeated injections are needed (dose 0.3mg)
 No more used
3/30/2020
162

C. Ranibizumab Lucentis
 It is FDA approved anti VEGF for AMD, CRVO
and BRVO treatment and DME and myopic CNV
 It is a humanized monoclonal antibody fragment
(Fab) that inhibits all isoforms of VEGFs
 MARINA study-minimally classic and Occult
CNV(Rosenfeld et al N Engl J Med 2006;355:1419-31)
 ANCHOR study- predominantly classic CNV(Brown
et al N Engl J Med 2006;355:1432-44.)
3/30/2020
163

C. Ranibizumab
 First drug to show that the treated patients not
only had reduced risk of losing vision but also
improved vision
 Monthly injections are needed
 Dose used 0.05 ml containing o.5mg
 Costly treatment
 Well tolerated
3/30/2020
164

4D. Bevacizumab –Avastin
 It is used in ophthalmology as an OFF LABEL
drug as it is not approved for intraocular use but
approved for systemic administratino in Ca colon
 Availableas a vial so it needs to be prepared in OT
under strict aseptic precautions to avoid
contamination
 Cluster of endophthalmitis cases have occurred
due to mistakes in pharmacies dispensing the
drug (US-Florida)
3/30/2020
165

CATT study
 Comparison of Age related macular
degeneration treatment trial (CATT)
 Compared Avastin with Lucentis
 2 year follow up reported in Ophthalmology
2012
 Both are equally effective in terms of
prevention of loss of vision, gain in vision and
side effects
CATT research group . N Engl J Med 2011;364:1897-908
3/30/2020
166

3/30/2020
167
CATT STUDY- CATT study group Ophthalmology 2012

Aflibercept-VEGF trap
 2 mg in 0.05 ml
 It is a decoy protein that binds to VEGF and inactivates it
 Domain 2 of VEGF receptor 1 and Domain 3 of VEGF receptor 2
are attached to Fc portion of the human antibody IgG
 It has more affinity for VEGF than ranibizumab
 It is needed every 6-8 weeks instead of every month
 VIEW study compared aflibercept with ranibizumab and was
found to be giving equally good results with 8 weekly injections
Heier et al Ophthalmology 2012;119:2537–2548
3/30/2020
168

3/30/2020
169
VIEW STUDY –Heier et al Ophthalmology 2012

New anti VEGF-Brolucizumab
 Low molecular weight, single-chain antibody fragment vascular
endothelial growth factor (VEGF) inhibitor
 Because it is smaller molecule penetrates better and has
increased duration of action
 HAWK and Harrier trials proved that it is vision recovery were
comparable between Brolucizumab and aflilbercept
 The injections were needed every 3 months in 50% patients
FDA has approved it for n AMD
 Dugel P et al Ophthalmology 2019
3/30/2020
170

Anti VEGF treatment strategies
 Monthly injections indefinitely- not practical
 PRN-loading monthly doses till the activity of CNV
stops and then as needed OCT and VA
 Treat and Extend- Stabilize by monthly injections
 Then treat after 6 weeks instead of 4 weeks. Then call
after 8 weeks and give injection thus extend treatment
interval to 12 weeks if the condition is stable.
 Treatment burden is huge for the patients and hospitals
 VA usually reduces over time sometimes due to GA
developing
3/30/2020
171

When to stop treatment
 If VA is stable and no intraretinal fluid AND No
activity +
 If FFA shows no progression
 If VA <0.05
 If disciform scar develops
3/30/2020
172

3/30/2020
173

De Jong PT. Age-related macular degeneration. NEnglJMed.;
2006;355(9827):1728–38.
3/30/2020
174

3/30/2020
175

Other Anti VEGF drugs
 Anti Platelet derived growth factor Anti PDGF
 Combining this drug with Lucentis have
shown better visual acuity gains
 Also less need for repeated injections
3/30/2020
176

Anti VEGFs
 Also given in massive subretinal massive
hemorrhage involving the fovea along with
gas injection +/- tpa injection
3/30/2020
177

Surgical treatment
 Submacular surgery to remove the CNV
 Submacular surgery to remove subretinal
blood-massive hg
 Massive subretinal hg can be toxic to the
photoreceptors so it is tried in desperate
cases
 Macular translocation
3/30/2020
178

Other treatments
 Anti oxidants as already explained
 Low visual aids
3/30/2020
179

IPCV
 Characterized by CNV which has branching
network of vessels with dilated end bulbs
 Characterized by serous and hemorrhagic
RPE detachment, subretinal hgs, serous RPE
detachment and more common in east asian
and african patients
3/30/2020
180

3/30/2020
181

3/30/2020
182

3/30/2020
183

3/30/2020
184

3/30/2020
185

3/30/2020
186
Palkar et al Taiwan J Ophthalmol 2019

Treatment of IPCV
 More difficult
 Anti VEGF versus anti VEGF+PDT
 Anti VEGF only therapy was found to be
better in LAPTOP study, PLANET study
(ranibizumab and aflibercept)
3/30/2020
187

Retinal angiomatous proliferation
( RAP)
 Type III CNV of AMD
 Three stages
 1st stage- intraretinal NV- with hgs and hard
exudates
 2nd stage –subretinal NV with serous RD and
subretinal blood
 3rd Stage- choroidal CNV with anastomosis
between retinal and choroidal NV
 Treatment remains anti VEGF
3/30/2020
188

3/30/2020
189

3/30/2020
190

References
 Khan, K.N., et al., Progress in Retinal and
Eye Research (2016)
 Miller J Am J Ophthalmol 2013;155:1–35.
 Klein et al Arch
Ophthalmol. 2011;129(12):1543-1550
 AREDS research group .Arch Ophthalmol.
2005 ; 123(11): 1570–1574
 J Nowak et al Pharmacology reports 2006
3/30/2020
191

THANKS FOR YOUR
ATTENTION
3/30/2020
192

DR WANI'S TALK ON AMD FOR RESIDENTS 30 March 2020.pptx

Recommended

Recommended

More Related Content

Similar to DR WANI'S TALK ON AMD FOR RESIDENTS 30 March 2020.pptx

Similar to DR WANI'S TALK ON AMD FOR RESIDENTS 30 March 2020.pptx (20)

More from vbwani

More from vbwani (12)

Recently uploaded

Recently uploaded (20)

DR WANI'S TALK ON AMD FOR RESIDENTS 30 March 2020.pptx