Wet AMD is caused by the growth of abnormal blood vessels under the retina (choroidal neovascularization, or CNV). There are three types of CNV based on their origin: type 1 from the choroid, type 2 between the RPE and retina, and type 3 from the deep retinal vessels. CNV causes leakage and bleeding that can damage the retina. Diagnosis involves imaging like OCT, FFA, and ICG to detect fluid, leaking vessels, or scarring. Treatment focuses on inhibiting CNV through anti-VEGF injections or photodynamic therapy.

1. Wet AMD …
DR: SAMEERA
MMJEI,HUBLI

4. Hard Exudates Drusens
 small white or yellowish white deposits with sharp
margins
 appear waxy, shiny, or glistening
 They are located in the outer layers of the retina,
deep to the retinal vessels
 arranged as individual dots, confluent patches,
sheets, or in rings or crescents surrounding zones of
retinal edema or groups of microaneurysms
 Non –refractile
 Extracellular lipids  leakage from precapillary
arterioles
 More orange appearance
 Softer around edges
 B/L
 May not b associated with DR
 Regular appearance
 Located more deeper, at Bruchs
 Glowing
 Metabolic debris from RPE

5. The RPE in a young retina has a homogenous distribution
of the melanin granules, a BM without deposits, and a
preserved function
In dry AMD, the RPE melanin
granules are localized
basally lipofuscin granules
increase in number  disks
digestion reduces 
formation of drusen between
the basement membrane of
the RPE and the inner
collagen layer of the BM and
the
thickened BM

6. In wet AMD, CNV develops, and an
inflammatory response develops
with an influx of lymphocytes and
macrophages to the scene  fragile
new vessels leak and lead to
subretinal hemorrhage

7. Drusens…
Histologically :
 this material corresponds to the abnormal thickening of the inner aspect of
the Bruch membrane
Ultrastructurally,:
 basal laminar deposits (granular, lipid-rich material and widely spaced
collagen fibers between the plasma membrane and basement
membrane of the RPE cell)
 basal linear deposits (phospholipid vesicles and electron-dense granules
within the inner collagenous zone of the Bruch
membrane)

8. Drusens…Types..

9. Hard drusen:
 round, discrete yellow-white spots,measure less than 63 μm
 not age-related and do not carry an increased risk for development of
neovascularization
Soft drusen :
 ill defined, with nondiscrete borders, measuring 63 μm or greater
 age-related and associated with a higher risk for development of
advanced AMD with the development of neovascularization

10. Confluent drusens
 Soft drusens progresses 
pigmentary changes  Drusenoid
PED
 “High risk drusen”

11. Reticular drusen
 subretinal drusenoid deposits with
components similar to classical AMD
drusen
 located between the RPE and the
photoceptor inner segment/outer
segment junction
 High risk factor

12. FFA - DRUSEN
 Typically, small hard drusen hyperfluoresce early in FA studies because of a
window defect
 larger soft and confluent drusen and drusenoid PEDs slowly and
homogenously stain late because of pooling of the fluorescein dye in the
sub-PED compartment

13. OCT :drusen
 SD-OCT imaging of small and large
drusen typically reveals sub-RPE
nodular elevations / small RPE
detachments with a notable absence
of intraretinal and subretinal fluid
 Reticular pseudodrusen are identified
above the RPE and beneath the inner
segment ellipsoid layer
 Enhanced depth imaging (EDI) of the
choroid : Choroidal thickness typically
normal or reduced in non
neovascular AMD

14. Abnormalities of the RPE
 focal hyperpigmentation
 nongeographic atrophy
 geographic atrophy
 Increased pigmentation at the level of the outer retina corresponds to
focal hyperpigmentation of the RPE.
 On FA, these areas typically show blockage
 SD-OCT, show hyperreflective outer retinal foci
The incidence of focal hyperpigmentations increases with age, and their
presence indicates greater risk of progression to the more advanced forms
of AMD.

15. AREDS ???
 Age-Related Eye Disease Study (AREDS)
 prospective multicenter randomized clinical trial
 In 1992 and 2006 designed to assess the natural course and risk factors for
age-related cataract and AMD
 effects of antioxidant vitamins and minerals on these two ocular conditions
were studied
 AREDS 1 ,2

16. Classification
 No AMD (AREDS category 1)  the control group; it is characterized by no or few small
drusen (<63 µm in diameter).
 Early AMD (AREDS category 2)  a combination of multiple small drusen, few
intermediate drusen (63–124 µm in diameter), or mild RPE abnormalities.
 Intermediate AMD (AREDS category 3)  any of the following features:
----- Numerous intermediate drusen
----- At least one large drusen (125 µm or larger in diameter)
----- Geographic atrophy (a sharply demarcated, usually round or oval, of
atrophy of the RPE not involving the center of the fovea)

17. Advanced AMD (AREDS category 4)
 One or more of the following (in the absence of other causes) in one eye:
--- Geographic atrophy of the RPE involving the foveal center
--- Neovascular maculopathy that includes the following:
 - Choroidal neovascularization (CNV) : pathologic angiogenesis originating from the
choroidal vasculature that extends through a defect in Bruch’s membrane
 - Serous and/or hemorrhagic detachment of the neurosensory retina or RPE
 - Retinal hard exudates (a secondary phenomenon resulting from chronic intravascular
leakage)
 - Subretinal and sub-RPE fibrovascular proliferation
 - Disciform scar (subretinal fibrosis)

18. Nongeographic atrophy
 atrophy that does not cover a contiguous area and may appear as an area
of mottling or depigmentation.
 When the area of absent or attenuated RPE is contiguous, the condition is
termed geographic atrophy of the RPE.

19. Dry AMD
 Non-exudative AMD with large
drusen
 No signs of subretinal fluid or
CNVM. Foveal contour is intact.
Hyper reflective “mounds” that displace the
retinal tissue

20. Geographic atrophy
 Geographic atrophy often spares the fovea until late
 It may first present as one or more noncontiguous patches of atrophy
around the fovea  enlarge and coalesce later
 good visual acuity (VA) until late  when the fovea becomes progressively
atrophic, leading to severe loss of visual acuity
 Although not all eyes with drusen or PED will develop atrophy, the
incidence of atrophy appears to increase with age. Twelve to 20% of
patients with GA have severe vision loss

21. Geographic atrophy
 The unmasked choroidal vessels are more readily
visible, the overlying outer retina may appear thin,
and choriocapillaris is attenuated or atrophied.
 On FA, GEOGRAPHIC ATROPHY shows well-
circumscribed round to oval window defects
 SD-OCT: loss of the RPE and the overlying inner
segment ellipsoid and photoreceptor layer can be
seen
 Dense hypoautofluorescence occurs in areas of GA
 Fundus autofluorescence is a practical and
noninvasive tool to monitor progression of GA

22.  non-exudative AMD with geographic atrophy--
loss of outer retinal layers
 Bruch's membrane and choroidal capillaries is
visible due to the overlying outer retinal
atrophy.

23. Macular Atrophy
Hyporeflective RPE allows increased penetration of light into the choroid
The reflectivity is increased because light absorption is reduced at the retina
and the RPE

24. AREDS
 first established the benefit of vitamin and zinc supplementation in
reducing the risk of vision loss in patients with nonexudative AMD
 supplementation with the antioxidant vitamins C (500 mg) and E (400
IU), beta carotene (15 mg), and the micronutrient zinc (80 mg zinc
oxide and 2 mg cupric oxide to prevent zinc-induced anemia) in patients
with intermediate or stage 3 nonneovascular AMD
 demonstrated a 25% risk reduction for progression to advanced AMD and
a 19% risk reduction in rates of moderate vision loss (≥3 lines of visual
acuity) at 5 years

25. AREDS2 study
 designed to test whether these observations could be confirmed in a prospective trial
 4000 participants
 confirmed the overall risk reduction found in the original AREDS study
 lutein and zeaxanthin had similar effects to beta carotene
 80 mg of zinc  appropriate dose for AMD prophylaxis
 Furthermore, LCPUFAs ( Omega 3 fatty acids) were not found to decrease the rate of
progression to advanced AMD
 increased rate of lung cancer among current and former smokers using beta carotene
replace beta carotene with lutein and zeaxanthin and not to add LCPUFAs

26. ARMD

27. DISEASE DEFINITION
Disorder of the macula characterized by one or more of the following
 Presence of at least intermediate-size drusen (63 µm or larger in diameter)
 Retinal pigment epithelium (RPE) abnormalities such as hypopigmentation or
hyperpigmentation
 Reticular pseudodrusen
 Presence of any of the following features:
- geographic atrophy of the RPE,
- choroidal neovascularization (exudative, wet)
- polypoidal choroidal vasculopathy
- retinal angiomatous proliferation

28. Facts..
 50 years or older, with or without visual symptoms
 under 50 years of age : consider the possibility of other hereditary macular
dystrophies in patients who have clinical features that resemble AMD.
 estimated 80% of AMD patients have non-neovascular or atrophic AMD
 the neovascular form is responsible for nearly 90% of the severe visual
acuity loss (20/200 or worse) from AMD

29. Risk factors
 increasing age, ethnicity, and genetics
 cigarette smoking (dose response relationship)
 low systemic levels of antioxidants
 complement factor H (CFH) Y402H polymorphism with a higher risk of
AMD
 Obesity
 Sunlight exposure
 Dietary fat intake
 HT,IHD

30. Neovascular AMD
 The hallmark :presence of CNV
 Degenerative changes in the Bruch membrane  accumulation of drusen 
progressive thickening of membrane  nonneovascular AMD
 associated with a pro angiogenesis neovascularization that originates from the
choriocapillaris and perforates the outer aspect of the Bruch membrane
 New vessels accompanied by fibroblasts, resulting in a fibrovascular complex 
leak and bleed and may disrupt and destroy the normal RPE–photoreceptor
complex  hypertrophic fibrotic disciform scar

31. Signs and symptoms
 sudden onset of decreased vision, metamorphopsia, and/or paracentral
scotomata
 Clinical signs : subretinal or intraretinal fluid, exudate and/or blood, a
pigment ring or gray-green membrane, irregular elevation of the RPE or
a PED, an RPE tear, and/or a sea fan pattern of subretinal vessels
 Intra retinal blood and cystoid macular edema (CME)
may indicate the presence of type 3 neovascularization, which originates
from the deep capillary plexus of the retinal circulation

32. Investigations
 SD-OCT
 FFA
 ICG
 FAF
 OCTA
 Microperimetry
 Adaptive optics

33. Anatomical classification
Three types of CNV
 Type 1  new vessels originating from the choriocapillaris grow through
a defect in the Bruch membrane into the sub–pigment epithelial space
 Leakage and bleeding can lead to the development of a vascularized
serous or fibrovascular PED. The fibrovascular PEDs are often seen to
have an irregular surface contour.

34.  Type 2  between the RPE and the
outer segments of the retina
 On examination, the membrane will
appear as a lacy or gray green lesion
 less common than type 1
neovascularization

36. Types of CNVM
Classic/Type 2 CNVM located above the
RPE with SRF adjacent to the lesion
Fibrovascular pigment epithelial detachment secondary to a
CNVM Type 1

37.  Type 3  results from new blood vessels sprouting from the deep
capillary plexus of the retina and growing downward toward the RPE.
 Because of their intraretinal growth, these lesions were originally termed
retinal angiomatous proliferations (RAP)
 On examination, they appear as a small area
of red discoloration, often associated with
retinal exudate

38. Types -CNV
Intra retinal Type 3
RPE and photoreceptors Type 2
Choriocapillaries Type 1

39. Neovascular AMD -Classification
Angiographically as :
 classic
 occult
 predominantly classic
 minimally classic
 or mixed lesions
Serous and/or hemorrhagic detachment of the neurosensory retina or the
RPE, and/or various stages of an elevated, fibrovascular disciform scar

40. FFA patterns of CNV
FA patterns of CNV may include classic or occult CNV or
combinations of both
 Classic CNV is an area of bright, lacy, and well-defined
hyperfluorescence that is identified in the early phase and progressively
leaks by the late phases
 Occult CNV consists of 2 forms:
(1) PED, either fibrovascular PED or vascularized serous PED
(2) late leakage from an undetermined source

41. Classic CNVM
Early lacey hyperF “classic” increases thru’
out transit phase
HypoF “halo” – blood &/or macula
pigment
Late leak, blurred margins & apparent ↑ in
size
Extra/Juxta/Sub : foveal

42. •Subfoveal : when the centre of the FAZ is involved either by extension
from an extrafoveal area or by originating directly under the centre of
fovea.
•Juxtafoveal : when the CNVM is closer than 200microns from the centre
of the FAZ but does not involve it
•Extrafoveal : CNVM is more than 200microns from the centre of the
foveal avascular zone(FAZ).

43. Late leaks – Occult CNV
Type I – FVPED –
Irregular elevation of the RPE with
stippled hyperF seen by 2 minutes and
persistent staining or leaking into the
sensory subretinal space by 10 minutes

44. Occult CNVM
 the PED may pool dye  ground-
glass pattern that is consistent with a
serous PED
 a notch, or hot spot, indicating
vascular tissue in the PED—a
vascularized serous PED

45.  A fibrovascular PED is an irregular elevation of
the RPE that has accompanying stippled
heterofluorescence
 even hypofluorescence early in the angiogram,
with progressive late leakage in the later stages
of the angiogram
FVPED

46. Type II – late leak of undetermined
source –
LLUS
Hyperfluorescence with pooling of dye into the
sensory subretinal space at 2 to 5 minutes in the
absence of a visualized source is considered late
leakage of unknown origin.
Late leaks – Occult CNV

47. ICG in Wet AMD
 presence of thick blood, pigment, scar tissue, or a PED may block
fluorescence and obscure any underlying CNV
 ICG  employs a dye that is almost fully protein bound and has a longer
wavelength nearer the infrared spectrum
 Penetrates heme and pigment to allow identification of the CNV

48. < 1DD size

49. > 1DD size

50. SD-OCT : CNV
 Type 1 CNV: elevation of the RPE / PED on SD-OCT
serous PED  sharply elevated, dome-shaped lesion with hollow internal
reflectivity and typically no associated subretinal or intraretinal fluid
 fibrovascular PED : sharply elevated and typically demonstrates a lacy or
polyp like hyperreflective lesion on the undersurface of the RPE, with or
without signs of contraction
 chronic fibrovascular PED : multilayered appearance, and a complex
fibrovascular scar may be appreciated in sub PED compartment, with or
without associated subretinal and/or intraretinal fluid

51. SD-OCT :CNV
 Type 2 CNV: hyperreflective band or plaque in the subneurosensory
space, with associated subretinal and/or intraretinal fluid.
 Type 3 CNV: hyperreflective focus emanating from the deep capillary
plexus of the retina, with or without associated CME and PED.

52. Drusenoid PED (DPED)
 pigment epithelial detachments as
well-defined drusen at least 350
microns in the narrowest diameter *
 High rate of progression to both
geographic atrophy (GA) and
neovascular AMD.
*AREDS Report number 28

54. Fibrovascular PED

55. RPE Tear Notched PED

57. OCTA

58. CNV in OCTA
Evidence of a hyperintense decorrelation signal
Precise evaluation of morphology / extend / type
Naive patients:
Branches with a main feeder trunk
Rounded / tree/octopus/cart wheel /lacy wheel like/sea fan
Peripheral anastomosis may be evident

59. CNV -Type 1 Neovascularization
SD-OCT → irregularity of RPE and
ellipsoid zone with drusen. Mild
subretinal fluid +
No CNV is detected above the RPE
OCTA of the choroid slab → blood
flow in a neovascular net

60. Type 2 CNV
OCTA: Superficial retina slab → no
abnormal vascular flow
Lower border of tissue slab set just
above the RPE and the
segmentation thickness reduced to
20 μm → small subretinal CNV
OCT angiography of the outer retina
and RPE slab shows CNV

61. Type 3 CNV Hyper-fluorescent spot
and proliferative intraretinal capillary in
the inner retina

62. Geographic Atrophy
OCTA : larger choroidal vessels displaced into the areas of
decreased choriocapillaries
Choriocapillaries loss precedes the RPE atrophy
Diagnostic use in the future for monitoring the progression

63. Differential diagnosis
Any disorder that is associated with disruption of
the Bruch complex and secondary CNV.
 The subretinal fluid of CSR can be confused with subretinal fluid or edema
associated with CNV and AMD.
( younger /no SRH unless a secondary CNV has developed)
geographic or gutterlike gravitational configuration on wide-field
angiographic or autofluorescent imaging
a thick choroid in EDI

64. Differential Diagnoses
• Angioid Streaks
• Central Serous Chorioretinopathy
• Choroidal Melanoma
• Choroidal Rupture
• Exudative Retinal Detachment
• Macular Dystrophy
• Multifocal Choroidopathy Syndromes
• Myopic Degeneration
• Pattern Dystrophy
• Presumed Ocular Histoplasmosis Syndrome

65. Management
 Thermal lasers
 Anti VEGFs
 Intravitreal Steroids
 PDT
 MPLT
 Surgical

66. Laser photocoagulation -MPS
(thermal laser)
 Classic extrafoveal CNV with well-defined boundaries
 Poor outcomes
 high recurrence rates
T T T (Transpupillary thermotherapy)

67. Photodynamic therapy ( PDT)
 systemic administration of a photosensitizing drug (Verteporfin)
 application of light of a particular wavelength to the affected tissue to
incite a localized photochemical reaction
 reaction generates reactive oxygen species, leading to capillary endothelial
cell damage & vessel thrombosis
 slowed progression but did not prevent significant vision loss
 Recent trends  recalcitrant cases or eyes with PCV

68. Anti VEGFs- Main Rx
 Pegaptanib Sodium (Macugen)
 Bevacizumab (Avastin)
 Ranibizumab (Lucentis)
 Biosimilars
 Aflibercept (Eylea)

69. Trials –Wet AMD
 Marina
 Anchor
 PrONTO
 CATT
 Horizon
 Sustain
 Sailor
 IVAN
 VIEW 1 and 2 …………………………………………………

70. MARINA Trial

71. ANCHOR Trial

72. PrONTO
 a Ranibizumab study
 Prospective OCT Imaging of Patients with Neovascular AMD Treated with Intraocular
Ranibizumab
 Explored whether dosing based on the presence of fluid in the macula as detected by OCT
could result in fewer injections but achieve visual acuity outcomes similar to the results
obtained with monthly dosing
 three consecutive monthly injections with intravitreal ranibizumab (0.5 mg). Then, from
month 3 through month 24, patients were examined monthly with OCT and additional
injections were performed only if certain OCT-based criteria were fulfilled
 retreatment  loss of five letters of VA,
new-onset hemorrhage or CNV
increase of central retinal thickness of more than 100 μm
documented with OCT, or intraretinal fluid

73. CATT trial

75.  “treat-and-observe”  regular treatment is administered until
the macula is dry by clinical and OCT-determined criteria, followed by
treatment only for signs of recurrent exudation during the maintenance
 “treat-and-extend”  treat-and extend regimen, in which regular
monthly treatment is continued until the macula is dry, after which treatment
continues at gradually increasing intervals
 The follow-up between injections is lengthened by 1 to 2 weeks until
recurrence of fluid is observed. If recurrent fluid is detected on a follow-up
visit, the treatment interval is reduced to the previous interval

76. RISK OF TEAR
 Fibrovascular PEDs may be at increased risk for the development of an RPE
tear after anti-VEGFs
 Risk may be especially significant with PEDs greater than 600 μm
 mechanism : contraction of the type 1 neovascular membrane beneath the
PED that occurs as a result of the anti-VEGF injection

77. MPLT

78. Intravitreal steroids along with
AntiVEGFs /PDT

79. Surgical…
 Sub foveal CNVM removal
 Macular translocation
 Submacular hemorrhage removal …
( necrosis of the underlying retina)

81. To complete…
 Low vision aids
 Vision Rehabilitation
 Genetic counselling
 IMPACT study  Squalamine eye drops
 siRNA (RNA agents)
 Strontium Beta radiations

82. Charles Bonnet Syndrome…!!!
 people who have decreased vision see complex, vivid, repetitive images
that are not real.
 macular degeneration, diabetes and glaucoma
 not due to psychiatric conditions

83. Thank you….

84. Polypoidal lesions (asterisk) are attached to the back
surface of the higher PED, and a BVN exists in the lower
PED which is recognized as ‘double layer sign' (open
arrowheads). Subfoveal choroidal thickness is remarkably
increased (bidirectional arrows

85. Polypoidal choroidal vasculopathy
 Polypoidal choroidal vasculopathy (PCV), initially described as posterior
uveal bleeding syndrome, is a variant of choroidal neovascularization
(type 1) and is characterized by multiple, recurrent serosanguineous RPE
detachments. A network of polyps with associated feeder vessels, similar
in appearance to a string of pearls, can be identified with SDOCT
adherent to the RPE monolayer of the fibrovascular PED—hence
designation of type 1 neovascularization

86. INTRODUCTION
 Age-related macular degeneration (AMD) : leading cause of irreversible
visual impairment among the elderly worldwide
 affecting 30–50 million individuals. progressive degeneration of the
photoreceptors, retinal pigment epithelium (RPE), and choriocapillaris
although the earliest manifestation of the disease appears
histopathologically as abnormalities within Bruch’s membrane. advanced
form of disease is characterized by macular neovascularization,
geographic atrophy (atrophy of the RPE, choriocapillaris, and
photoreceptors), or both

87. Occult CNVM
 Fibrovascular PED refers to an irregular elevation of the RPE with
progressive, stippled leakage on FA. AlternativelyLate leakage from an
undetermined source refers to regions of fluorescence at the level of the
flat RPE that are ill defined early and best appreciated in the late phases of
the angiographic study. The angiographic description of occult CNV may
be anatomically related to type 1 neovascularization, whereas that of
classic CNV may be related to type 2 neovascularization; this relation is not
a hard-and-fast rule, however Type 3 neovascularization, or RAP, may be
signaled by the presence of a spot of retinal hemorrhage in the macula

88.  FA and indocyanine green (ICG) angiography may demonstrate a focal hot
spot and late CME; associated pooling into a PED may also be present.,
which may appear as a hot spot.

89.  n the MPS, classification of neovascular AMD with CNV was based on
fluorescein angiography. Classic CNV (Gass Type 2 membrane) is defined
as a well-demarcated hyperfluorescence in the early phase of the
angiogram, with progressive leakage of dye into the overlying
subneurosensory retinal space during the late phases of the angiogram.
Occult CNV (Gass Type 1 membrane) is characterized by either a
fibrovascular pigment epithelial detachment (PED) or late leakage of
undetermined source.. An occult lesion with late leakage of undetermined
source is not elevated yet shows a similar pattern of late leakage (usually
after 1 minute). Other clinical subtypes or features of neovascular AMD
may include the follow

90.  Retinal PED
 Idiopathic polypoidal choroidal vasculopathy,133,134 which should be
suspected in patients with orange polypoid lesions and especially in
patients of African or Asian descent. The lesions are often located in the
peripapillary region. An indocyanine green (ICG) angiogram is often useful
in confirming the diagnosis.
 Retinal angiomatous proliferation (RAP

91.  Once advanced AMD develops in one eye, there is an increased likelihood
of having geographic atrophy or neovascularization in the fellow eye
 established to assess the risk of converting to advanced AMD. Large
drusen, any pigment changes, and the disease state of the fellow eye were
particularly predictive for developing advanced AMD.

92. Sub Retinal Drusen

93. Complement pathway (complement factor 2[43],
complement factor 3[44], complement factor B[45],
complement factor H, complement factor
I)[46][47][48][49][50]
Extracellular matrix function, cellular anchoring (Fibulin
5[51] and 6[52][53])
Innate immunity (Toll-like receptor 3 and
4)[54][55][56][57][58]
Proteolysis/Drusen metabolism (HTRA1, serine
protease)[59][60]
DNA repair (ERCC6)[61]
DNA transcription (RAX2)[62]
Lipid signaling/metabolism (transporter protein,
ABCA4)[63][64][65][66]
Other (LOC387715, hypothetical gene)[67][68]