ARMD should be detected and prevention should be tried , and wet armd treated with anti vegf drugs .

1. ARMD
MANAGEMENT 2016
Indoredrishti.wordpress.com

2. DR DINESH MITTAL DR SONALEE MITTAL
DRISHTI EYE HOSP VIJAYNAGAR INDORE

5. ARMD

6. INTRODUCTION
• Age-related macular degeneration (AMD) is the leading
cause of irreversible visual impairment among the elderly
worldwide affecting 30–50 million individuals. Loss of
visual acuity typically results from 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 .

7. • This definition of early ARM excluded small, hard drusen
alone, pigment changes alone, and even pigment
changes surrounding small, hard drusen for two reasons:
• (1) hard drusen become an almost constant finding in the
fifth decade; and
• (2) a number of diverse processes can cause pigment
abnormalities that may not be possible to distinguish
from early ARM, so the inclusion of soft drusen makes
the definition more specific to ARMD.
• However, eyes with numerous small, hard drusen or
eyes with pigment abnormalities in the absence of
obvious drusen can also progress to soft drusen.

8. Age-Related Macular
Degeneration
• Age-related macular degeneration (AMD) is the leading
cause of blindness in the developed world in people over
50 years of age. It is estimated that among North
Americans, 15 million (85%–90% of all AMD patients)
currently have “dry” (nonneovascular, or nonexudative)
AMD and 1.7 million people (10%–15% of all AMD patients)
have “wet” (neovascular) AMD. An estimated 200,000 new
cases of neovascular AMD develop each year in North
America.

9. ARMD
• The disease nearly always begins as the non-
neovascular or dry form of AMD and may progress to
geographic atrophy or the neovascular (wet) form in
one or both eyes. When neovascularization occurs,
there is commensurate accumulation of fluid,
hemorrhage, and lipid exudation within the macula that
can culminate in fibrosis referred to as a disciform
scar. A patient can have advanced dry AMD in both
eyes, advanced wet AMD in both eyes, or dry AMD in
one eye and wet AMD in fellow eye. It is controversial
whether the wet and dry forms of AMD represent two
distinct disease entities or end-stage manifestations of
the same disease

10. OVERVIEW
• Once advanced AMD develops in one eye, there is an
increased likelihood of having geographic atrophy or
neovascularization in the fellow eye. A simplified severity
scale based on fundus appearance was 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. The cause of AMD is multifactorial and
influenced by age, ethnic background, and a combination
of environmental and genetic factors. There is no cure;
however, vitamin supplementation, good nutrition, and
cessation of smoking can slow the progression of the dry
form of AMD while drugs that inhibit vascular endothelial
growth factor-A (VEGF-A) have been successful in
converting the wet form of AMD back to the dry form

11. Epidemiology and Risk Factors
for ARMD
• The only proven treatment available for the dry or
nonexudative forms of this disease, comprising 85% of
cases, is an antioxidant/mineral supplement which can
slow the progression of the disease by 25% over 5
years. For the wet form of the disease, anti-vascular
endothelial growth factor (VEGF) treatments have been
very effective in preventing severe vision loss. Still,
preventive measures are needed to reduce the burden
of this disease. Smoking is the most consistently
identified modifiable risk factor. Obesity, sunlight
exposure, & nutritional factors including antioxidants
and dietary fat intake may also affect AMD incidence
and progression.

12. • Within the past 5 years new and improved treatments for
the neovascular form of advanced AMD have been adopted
throughout the developed world. Therefore, in the years
ahead the overall burden of vision loss associated with
AMD is anticipated to decline substantially. The same
progress has not been made for treatment of advanced
non-neovascular AMD (GA); as such, the importance of
atrophic AMD as a leading cause of vision impairment is
expected to increase. The advanced forms of AMD are
those that are frequently associated with visual acuity loss
and they are divided into non neovascular atrophic (dry)
type and neovascular (wet) type. In atrophic AMD, gradual
disappearance of the retinal pigment epithelium (RPE)
results in one or more patches of atrophy that slowly
enlarge and coalesce. Affected areas have no visual
function, since loss of RPE is associated with fallout of
photoreceptors. Gass applied the term “geographic
atrophy of the retinal pigment epithelium” to this
presentation, which is the natural end-result of AMD in the
absence of clinical evidence of choroidal neovascularization
(CNV).

14. A. The RPE in a
young retina has a
homogenous
distribution of the
melanin granules,
a BM without
deposits, and a
preserved function

15. B. In dry AMD, the RPE
melanin granules are
localized basally, and
lipofuscin granules increase
in number while the efficacy
of the disks digestion
reduces. Note the formation
of drusen between the
basement membrane of the
RPE and the inner collagen
layer of the BM and the
thickened BM

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

17. Nonneovascular AMD
• The prototypical lesion of the nonneovascular form
of AMD is the druse. Other indicators are
abnormalities of the RPE, including
hyperpigmentation and atrophy.

20. Drusen
• Clinically, drusen are small, round, yellow lesions
located at the level of the RPE, mostly in the
• postequatorial retina . 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) and basal linear deposits (phospholipid
vesicles and electron-dense granules within the inner
collagenous zone of the Bruch membrane) are present

21. Drusen
• Drusen in an extramacular location are of no
known visual consequence. Typical drusen
deposits are located between the RPE and
• Bruch’s membrane and vary widely in number, size,
shape, and distribution. Most drusen are 20–100 μm
in diameter and are characterized as hard or soft
as well as small (< 63 μm), intermediate (> 63 μm
but < 125 μm) or large (≥ 125 μm).

22. Hard drusen vs soft drusen
• Hard drusen, which appear as round, discrete yellow-white
spots,measure less than 63 μm. These drusen are
commonly identified in many populations; they are not age-
related and do not carry an increased risk for development
of neovascularization, with 80% of the general population
older than 30 years manifesting at least one. In contrast,
soft drusen are ill defined, with nondiscrete borders,
measuring 63 μm or greater . Different population based
studies and clinical trials have indicated that large, soft,
confluent drusen are age-related and associated with a
higher risk for development of advanced AMD with the
development of neovascularization. After the age of 70
years, 26% of individuals have large or soft drusen, and
17% have confluent drusen .

27. FA OF DRUSEN
• Typically, small hard drusen hyperfluoresce early in FA
studies because of a window defect, whereas 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. However,
there is some variability in how drusen appear on FA.

28. OCT of drusen
• SD-OCT imaging of small and large drusen typically
reveals sub-RPE nodular elevations or even 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
• and are graded according to their degree of elevation .
• Enhanced depth imaging (EDI) of the choroid using OCT
has permitted more detailed analysis of the choroid in
AMD. Choroidal thickness values are typically normal or
reduced in nonneovascular AMD.

29. Abnormalities of the RPE
• Several patterns of RPE abnormalities characterize
nonneovascular AMD, including focal hyperpigmentation,
nongeographic atrophy, and 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, and on 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.

30. Abnormalities of the RPE
• Nongeographic atrophy refers to 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. In areas of GA, 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,
whereas on 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

33. Geographic atrophy
• Geographic atrophy often spares the fovea until late in
the course of the disease. It may first present as one or
more noncontiguous patches of atrophy around the fovea.
These patches enlarge and coalesce and may be
associated with a dense paracentral scotoma, thereby
limiting tasks such as reading. Patients with GA may
demonstrate good visual acuity (VA) until late in the
course of the disease, when the fovea becomes
progressively atrophic, leading to severe visual acuity
decline from central blindness and forcing the patient to
use noncentral retina and eccentric fixation to read and
perform other visual tasks

34. • 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 .

35. Management of nonneovascular
AMD
• Education and follow-up Eyes with soft drusen and RPE
hyperpigmentation are at increased risk of developing GA
and CNV. As such, patients with nonneovascular AMD
should be educated about the symptoms of advanced
AMD and instructed to contact an ophthalmologist
promptly should these symptoms occur. If reduced visual
acuity or reduced vision function (difficulty reading
despite good measured visual acuity) is noted, a low
vision evaluation should be considered. Periodic
examinations are advised to monitor for concurrent,
treatable eye disease (eg, cataract, glaucoma) and to re
evaluate low vision needs.

36. Amsler grid
• The Amsler grid is a test card for patient home-monitoring
use; it contains white grid lines on a black background
and a central dot for fixation. Each eye is tested
individually with reading glasses and at reading distance
to check for any new metamorphopsia, scotoma, or other
significant changes in central vision. Any changes noted
by the patient should be evaluated urgently .

37. MICRONUTRIENTS
• 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.

38. AREDS
• Intermediate AMD was defined as the presence of at least
1 large druse (>125 μm) or nonsubfoveal GA, and
advanced unilateral AMD was defined as vision loss due
to neovascular AMD or GA in 1 eye. At 10 years, 44% of
placebo recipients compared with 34% of the supplement
recipients had advanced AMD (a 27% risk reduction).
Among participants with no AMD or only early AMD (a few
small drusen), there was no measurable benefit. There
was no increased mortality among patients taking the
AREDS formula

39. AREDS
• A simplified 4-point grading scale was developed by
AREDS for classifying the severity of AMD and predicting
the disease course based on the following findings:
• presence of 1 or more large (>125-μm diameter) drusen
(1 point)
• presence of any pigment abnormalities (1 point)
• for patients with no large drusen, presence of bilateral
intermediate (63–124 μm) drusen (1 point)
• presence of neovascular AMD (2 points)

40. AREDS

41. • Large population-based studies suggest that
supplementation with the xanthophylls lutein & zeaxanthin
as well as omega-3 long-chain polyunsaturated fatty acids
(LCPUFAs: docosahexaenoic acid [DHA] and
eicosapentaenoic acid [EPA]) may also help reduce AMD
progression.

42. AREDS2 study
• The AREDS2 study was designed to test whether these
observations could be confirmed in a prospective trial.
Among the 4000 participants, the study confirmed the overall
risk reduction found in the original AREDS study, concluded
that lutein and zeaxanthin had similar effects to beta
carotene, and found 80 mg of zinc to be the appropriate dose
for AMD prophylaxis. Furthermore, LCPUFAs were not found
to decrease the rate of progression to advanced AMD. A
nonocular effect detected was an increased rate of lung
cancer among current and former smokers using beta
carotene, a finding other nonophthalmic studies had
previously reported. As a result, study’s recommendations
for AREDS supplementation were to replace beta carotene
with lutein and zeaxanthin and not to add LCPUFAs .

44. Lifestyle changes
• With increasing evidence that environment and health
habits influence the development and progression of AMD,
patients should be counseled to alter behaviors that put
them at risk. Of particular importance are smoking
cessation, obesity reduction, and blood pressure control.
Cataract surgery has not been linked consistently to the
progression of AMD, nor is there strong evidence linking
UV (UV-A or UV-B) light exposure to the progression of
AMD. It should be noted, however, that there are no
negative effects of wearing UV-protective glasses .

45. Neovascular AMD
• The hallmark of the neovascular form of AMD is the
presence of CNV. Degenerative changes in the Bruch
membrane—such as the accumulation of drusen and the
progressive thickening of membrane’s inner aspect that
characterize nonneovascular form of AMD—can be
associated with a proangiogenic environment, including
neovascularization that originates from the
choriocapillaris and perforates the outer aspect of the
Bruch membrane. These new vessels are accompanied by
fibroblasts, resulting in a fibrovascular complex that can
leak and bleed and may disrupt and destroy the normal
architecture of the RPE–photoreceptor complex,
ultimately leading to the formation of a hypertrophic
fibrotic disciform scar.

49. Signs and symptoms of
neovascular AMD
• Patients with neovascular AMD describe the sudden onset
of decreased vision, metamorphopsia, and/or paracentral
scotomata. Amsler grid self-testing by patients is highly
effective for early detection of neovascular AMD. Clinical
signs of CNV may include 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.
• Intraretinal 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.

50. Anatomical classification of CNV
• Three types of CNV are now recognized. In type 1
neovascularization, 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.

51. • In type 2 neovascularization, the CNV occupies the
subneurosensory compartment between the RPE and
the outer segments of the retina . On examination, the
membrane will appear as a lacy or graygreen lesion; in
AMD, this finding is less common than is type 1
neovascularization.

61. CNVM
• Type 3 neovascularization 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.

62. • Ultimately, if untreated, these neovascular processes
may evolve into a hypertrophic, fibrotic, disciform scar.
The retina overlying the scar loses its normal outer
retinal architecture, which can lead to severe, permanent
central vision loss.

63. Fluorescein angiographic
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, and
• (2) late leakage from an undetermined source

65. OCCULT CNVM
• Fibrovascular PED refers to an irregular elevation of the
RPE with progressive, stippled leakage on FA.
Alternatively, the PED may pool dye rapidly in a
homogenous ground-glass pattern that is consistent with
a serous PED but has a notch, or hot spot, indicating
vascular tissue in the PED—a vascularized serous PED

67. Late leakage from an
undetermined source
• Late 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.

68. • FA and indocyanine green (ICG) angiography may
demonstrate a focal hot spot and late CME; associated
pooling into a PED may also be present. The presence of
thick blood, pigment, scar tissue, or a PED may block
fluorescence and obscure any underlying CNV. ICG
angiography, which employs a dye that is almost fully
protein bound and has a longer wavelength nearer the
infrared spectrum, may be valuable in penetrating heme
and pigment to allow identification of the CNV, which may
appear as a hot spot.

69. SD-OCT patterns of CNV
• Type 1 neovascular membranes demonstrate elevation of
the RPE and a PED on SD-OCT. A serous PED appears as a
sharply elevated, dome-shaped lesion with hollow
internal reflectivity and typically no associated subretinal
or intraretinal fluid. A fibrovascular PED may or may not
be sharply elevated and typically demonstrates a lacy or
polyplike hyperreflective lesion on the undersurface of
the RPE, with or without signs of contraction. A chronic
fibrovascular PED has a multilayered appearance, and a
complex fibrovascular scar may be appreciated in sub
PED compartment, with or without associated subretinal
and/or intraretinal fluid.

70. SD-OCT patterns of CNV
• Type 2 neovascular membranes appear as a
hyperreflective band or plaque in the subneurosensory
space, with associated subretinal and/or intraretinal fluid.
Type 3 neovascular membranes are best appreciated with
SD-OCT as a hyperreflective focus emanating from the
deep capillary plexus of the retina, with or without
associated CME and PED. Recognition of these SD-OCT
patterns is crucial for the diagnosis and classification of
CNV. Also, SD-OCT is a noninvasive procedure as well as
the most important and practical modality for monitoring
the response of therapy by assessing regression of the
neovascular membrane and resolution of subretinal and
intraretinal fluid.

71. 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.

72. Polypoidal choroidal
vasculopathy
• It is now believed to occur in women and men of all
races and to be a variant of neovascular AMD, with
same genetic profile. The areas of serosanguineous
detachment are often peripapillary and multifocal but
may be peripheral, and associated nodular, orange,
subretinal lesions may be appreciated. Vitreous
hemorrhage may occur more frequently than in classic
AMD, and the typical soft drusen of AMD may or may
not be present. The natural history and visual acuity
outcomes of PCV may be better than those of CNV
associated with AMD . ICG angiography and SD-OCT
are important techniques for identifying the polyps.

74. Differential diagnosis of
neovascular AMD
• A variety of conditions can mimic the neovascular changes
of AMD and typically include any disorder that is associated
with disruption of the Bruch complex and secondary CNV.
• The subretinal fluid of central serous chorioretinopathy can
be confused with subretinal fluid or edema associated with
CNV and AMD. However, patients with CSC are usually
younger and usually do not have associated subretinal
hemorrhage unless a secondary CNV has developed. CSC
can be further differentiated by characteristic signs
including patches of RPE mottling that may assume a
• geographic or gutterlike gravitational configuration on wide-
field angiographic or autofluorescent imaging and a thick
choroid best visualized with EDI-OCT.

75. Management of neovascular AMD
• If neovascular AMD is suspected on clinical grounds,
FA and OCT studies can be obtained. SD-OCT is most
efficient and reliable tool in diagnosing and
distinguishing types 1, 2, & 3 neovascularization and in
monitoring response to therapy.

76. Laser photocoagulation
(thermal laser)
• From the 1980s through 2000, laser therapy was primary
treatment for classic extrafoveal CNV with well-defined
boundaries. However, outcomes were poor because of
high recurrence rates, as demonstrated in the Macular
Photocoagulation Studies. The use of thermal laser
treatment is now rare except to treat extrafoveal lesions
that are sufficiently far from the foveal center to have
minimal risk of iatrogenic foveal laser damage and a
lower rate of recurrence.

77. Photodynamic therapy PDT
• Photodynamic therapy PDT was introduced in 2000 as a
less-destructive modality for treating CNV than thermal
laser and entails the systemic administration of a
photosensitizing drug followed by an application of light
of a particular wavelength to the affected tissue to
incite a localized photochemical reaction. This reaction
generates reactive oxygen species, leading to capillary
endothelial cell damage & vessel thrombosis. Studies
showed that PDT slowed progression but did not prevent
significant vision loss in eyes with CNV that had certain
lesion characteristics. Use of PDT in the management of
exudative AMD is now rare except in recalcitrant cases
or eyes with PCV.

78. Vascular endothelial
growth factor (VEGF) is
a homodimeric
glycoprotein that is
secreted in response to
hypoxia and ischemia.
VEGF induces
angiogenesis and
vascular permeability.
Arrows show the
binding site VEGFR

79. Antiangiogenic therapies
• Angiogenesis—the formation of new blood vessels that
occurs via sprouting or splitting from existing vessels—is
characterized by a complex cascade of events. The first
step in the cascade involves vasodilation of existing
vessels and increased vascular permeability. This process
is followed by degradation of the surrounding extracellular
matrix, which facilitates migration and proliferation of
endothelial cells. The endothelial cells join together to
form a lumen, which becomes a new capillary. The vessels
subsequently mature and undergo remodeling to form a
stable vascular network. The successful execution of this
cascade requires a balanced interplay of growth-promoting
and growth-inhibiting angiogenic factors.

80. Antiangiogenic therapies
• Identified activators of angiogenesis include vascular
endothelial growth factor (VEGF), fibroblast growth factor
(FGF), transforming growth factor α (TGF-α) and TGF-β,
angiopoietin-1, and angiopoietin-2. Inhibitors of
angiogenesis include thrombospondin, angiostatin,
endostatin, and pigment epithelium–derived factor
(PEDF).

81. Antiangiogenic therapies
• The majority of recent antiangiogenesis research has
focused on the inhibition of VEGF. VEGF expression is
increased in pigment epithelial cells during the early
stages of AMD, suggesting that VEGF plays a causal role
in the initiation of neovascularization. In addition, high
concentrations of VEGF have been observed in excised
CNV and vitreous samples from AMD patients. VEGF is a
homodimeric glycoprotein that is a heparin-binding growth
factor specific for vascular endothelial cells. It can induce
angiogenesis, vascular permeability, and
lymphangiogenesis and may act as a survival factor for
endothelial cells by preventing apoptosis. There are at
least 4 major VEGF isoforms, of which VEGF165 is
thought to be the most dominant in AMD.

82. Pegaptanib
• Pegaptanib, an RNA oligonucleotide ligand (or
aptamer) that binds human VEGF165 with high
affinity and specificity, was the first intravitreal
anti-VEGF therapy approved by the US FDA , in
2004. Studies showed that it slowed vision loss, but
it has since been supplanted by far more effective
agents.

83. Ranibizumab
• Ranibizumab is a recombinantly produced, humanized antibody
fragment (Fab) that binds VEGF. Unlike pegaptanib,
ranibizumab binds to and inhibits all active isoforms of VEGF-A
and their active degradation products. Two studies, MARINA
(Minimally Classic/Occult Trial of the Anti-VEGF Antibody
Ranibizumab in the Treatment of Neovascular AMD) and
ANCHOR (Anti-VEGF Antibody for the Treatment of
Predominantly Classic CNVM in AMD), demonstrated that, at
12 months, 95% of ranibizumab-treated patients experienced
vision stabilization or improvement compared with 62% of
sham-treated patients and 64% of patients treated with PDT,
respectively. More important, approximately 30%–40% of
ranibizumab-treated patients experienced vision improvement
of 15 letters or more compared with control participants in
each study, with an average letter gain of approximately 10
letters . Almost 80% of patients maintained or improved vision
after 24 months.

87. Present status
• Sixty-five AMD patients from the MARINA, ANCHOR, and
HORIZON studies were evaluated approximately 7 years
after baseline recruitment. Of these patients, 23%
achieved a best-corrected visual acuity (BCVA) of 20/40
or better, while 37% had BCVA of 20/200 or worse, and
almost one-half (43%) of eyes had an unchanged or
improved letter score versus baseline. Active fluid was
detected by SD-OCT in 68% of study eyes, and macular
atrophy, the area of which correlated with vision loss,
was detected by fundus autofluorescence in 98% of eyes.

88. TREAT AND OBSERVE / EXTEND
• treatment effect declined in the ranibizumab
recipients during quarterly dosing (ie, every 3
months) but not with monthly dosing intervals.
These data clarified that quarterly treatment
appears to be suboptimal. In general, there are 2
accepted treatment schemes that deviate from the
FDA-approved labeling of monthly injections: “treat-
and-observe,” or “as-needed,” and “treat-and-
extend” approaches to anti-VEGF therapy.

89. “treat-and-observe,” or “as-needed,”
and “treat-and-extend”
approaches to anti-VEGF therapy
• In the treat-and-observe method, 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
phase. This approach is in contrast to the treat-and
extend regimen, in which regular monthly treatment is
continued until the macula is dry, after which
treatment continues at gradually increasing intervals.
In this second approach, injections are administered
even with inactive CNV. The goal of this therapy is to
cautiously extend the time between injections as far
apart as tolerated as long as there are no signs of
recurrence.

90. MONTHLY INJECTIONS NEEDED
ONLY FOR THREE MONTHS &
• Several clinical trials have evaluated as-needed
approaches to anti-VEGF therapy: PrONTO (Prospective
Optical Coherence Tomography Imaging of Patients With
Neovascular AMD Treated With Intraocular Ranibizumab),
SAILOR (Study to Evaluate Ranibizumab in Subjects With
Choroidal Neovascularization Secondary to AMD),
SUSTAIN (Study of Ranibizumab in Patients with Subfoveal
Choroidal Neovascularization Secondary to AMD), and
HORIZON (Open-Label Extension Trial of Ranibizumab for
Choroidal Neovascularization Secondary to AMD). All of
these studies utilized 3 monthly injections followed by
various as-needed treatment regimens, determined on the
basis of clinical and OCT-guided criteria, and all showed
vision and OCT outcomes that were comparable to or
reduced from those obtained with MARINA and ANCHOR.

91. Safety data
• Safety data have been favorable for intravitreal
ranibizumab therapy. Intravitreal injections are
occasionally associated with minor local complications
such as subconjunctival hemorrhage and local
irritation. However, the incidence of severe, visually
compromising complications such as vitreous
hemorrhage, retinal detachment, or endophthalmitis is
exceedingly low across numerous trials including those
just described. Systemic arteriothrombotic events can
arise during the course of ranibizumab therapy, but no
study has conclusively determined an increased
incidence of these events related to injection of the
drug.

92. RISK OF TEAR
• Eyes with fibrovascular PEDs may be at increased
risk for the development of an RPE tear after anti-
VEGF therapy, and this risk may be especially
significant with PEDs greater than 600 μm in height.
The mechanism of the tear may relate to contraction
of the type 1 neovascular membrane beneath the PED
that occurs as a result of the anti-VEGF injection.

95. PROTOCOLS OF TREATMENT:
RETREATMENT ALGORITHMS AND
MAINTENANCE THERAPY
• Fixed Monthly Injections
• Initially, there was no clear consensus on retreatment strategies.
In the MARINA and ANCHOR studies of ranibizumab, patients
received monthly intravitreal injections during 2 years, so each
patient received a total of 24 injections. Today, the fixed monthly
ranibizumab retreatment schedule has not been widely accepted
. Patients were at first treated with three monthly injections of
ranibizumab, termed the “loading phase,” followed by a quarterly
injection regimen. The results observed were positive but did not
equal the MARINA and ANCHOR results. In fact, patients showed
less mean gain in VA, and fewer patients experienced 15 or more
letters of visual gain. Additionally, if after the loading phase there
was a gain in VA, it was not maintained during the study .

96. As-Required Injections
• PrONTO study introduced a dosing regimen characterized by three consecutive monthly
intravitreal injections followed by as-needed retreatment based upon signs of recurrence,
ophthalmoscopy, OCT, or fluorescein angiography, called the as-needed or PRN protocol . It
seems that the PRN dosing regimen is the most widely used today. Ranibizumab was used
in PrONTO study, and the dosing regimen was OCT guided and variable. Patients received
three monthly intravitreal injections, and retreatment was based upon 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. In the first year of PrONTO study, patients
received an average of 5.6 injections of ranibizumab. The results of PrONTO study suggest
that 70% of the patients treated with intravitreal ranibizumab showed resolution of edema
within 1 month after the first injection, and 90% of the patients showed resolution of fluid
after the loading phase .
• The CATT study compared ranibizumab and bevacizumab using monthly and as-required
retreatment schedules (67). In this study, bevacizumab administered monthly led to a gain
of 8.0 letters at 12 months, and bevacizumab administered as-required led to a gain of 5.9
letters. Similarly, ranibizumab administered monthly led to a gain of 8.5 letters at 12
months, and ranibizumab in as-required schedule led to a gain of 6.8 letters. It is clear that
a monthly retreatment schedule showed greater gain in VA, but the differences were
“inconclusive” for the bevacizumab groups and were not significant for the ranibizumab
groups. These studies follow up patients for 12 months, but other studies with longer follow-
ups, such as HORIZON and SUSTAIN, have shown that significant visual gain is achieved
with monthly injections and the as-required schedule is not as effective as the monthly
fixed schedule.

97. Treat and Extend
• Other retreatment schedules are used, in order to
minimize the number of injections and visits to the
hospital. In the treat-and-extend schedule, the patients
are treated with monthly injections until macula is dry
and without fluid seen with OCT. 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. Treatment schedule is variable and
subject to change at every visit, but the time between
visits in individualized based on each patient's response
to treatment

98. PrONTO
• a ranibizumab study known as PrONTO (Prospective
OCT Imaging of Patients with Neovascular AMD Treated
with Intraocular Ranibizumab). This phase I/II study
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.130 The study
design mandated 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 .

99. PrONTO
• After one year, the mean improvement in visual acuity from
baseline was 9.3 letters (P < 0.001), and at two years it was
11.1 letters (P < 0.001). More than one-third of eyes (35%) in
PrONTO gained at least 15 letters of visual acuity at one year
and 43% gained at least 15 letters at two years. These visual
acuity outcomes were comparable to the outcomes in the
MARINA and ANCHOR trials. Moreover, these visual acuity
outcomes were achieved with an average of 5.6 out of a
maximum of 13 monthly injections the first year and 9.9
injections out of a maximum of 25 monthly injections over two
years. The PrONTO study also demonstrated that the onset of
action for ranibizumab was rapid with an average decrease in
OCT central retinal thickness of about 50 μm at one day, 100
μm at one week, and 150 μm at one month after the first
injection .

100. • Compared with the MARINA and ANCHOR outcomes in
which monthly injections were mandated, the OCT-guided
retreatment strategy appeared to result in similar visual
acuity outcomes with far fewer intravitreal injections.
Another OCT-based retreatment strategy known as ‘treat
and extend’ has also been proposed, trying to reduce
number of injections and number of visits, with visual
acuity improvement . Whether it is the PrONTO-style
retreatment strategy known as ‘treat and observe’ or the
‘treat and extend’ regimen, the visual acuity outcomes are
probably very similar to the outcomes achieved with
monthly injections but fewer injections are required.
Other studies have explored the ‘treat and observe’
strategy with similar favorable results.

105. Bevacizumab
• Bevacizumab is a full-length monoclonal antibody against
VEGF that was approved by the FDA in 2004 for the treatment
of metastatic colorectal cancer. It has been described for
“offlabel” use via intravitreal and intravenous administration
for the treatment of AMD. Both bevacizumab and ranibizumab
are manufactured by the same pharmaceutical company, and
there are important differences between the drugs:
bevacizumab is larger and has 2 antigen-binding domains
compared with the single domain for ranibizumab, and cost
differences between them are substantial, potentially
affecting access to treatment for some patients. Because
fragment antibodies in general have shorter systemic half-
lives than those of full-length antibodies (2.2 hours for
ranibizumab vs ~21 days for bevacizumab), intravitreal
injections of ranibizumab have a shorter systemic half-life
than intravitreal injections of bevacizumab.

106. Bevacizumab
• Because of the 50-fold lower cost and the purported
similar efficacy of bevacizumab compared with
ranibizumab, several comparative efficacy studies have
been conducted. These studies include CATT (Comparison
of Age-Related Macular Degeneration Treatments Trials)
in the United States, IVAN (Randomised Controlled Trial of
Alternative Treatments to Inhibit VEGF in Age-Related
Choroidal Neovascularisation) in the United Kingdom,
MANTA (Randomized Observer and Subject Masked Trial
Comparing the Visual Outcome After Treatment With
Ranibizumab or Bevacizumab in Patients With
Neovascular Age-Related Macular Degeneration
Multicenter Anti-VEGF Trial in Austria), and GEFAL
(Groupe d’Evaluation Français Avastin vs Lucentis) in
France .

107. Bevacizumab
• CATT was the first and largest multicenter, randomized
clinical trial to compare the relative safety and efficacy of
ranibizumab with bevacizumab for the treatment of
neovascular AMD. The trial was funded by the US National Eye
Institute and studied 1208 patients. Results showed that
bevacizumab was noninferior to ranibizumab therapy in
monthly or as-needed delivery schedules over 2 years. Mean
letters gained from baseline did not differ statistically among
the 4 arms of the study: 8.8 letters in the ranibizumab-
monthly group, 7.8 letters in the bevacizumab-monthly group,
6.7 letters in the ranibizumab as-needed group, and 5.0 letters
in the bevacizumab as-needed group . Systemic adverse
events were significantly greater in the bevacizumab (39.9%)
than in the ranibizumab (31.7%) group, but death and
arteriothrombotic events were not statistically different
between the 2 drugs .

108. AVASTIN

109. The preparation
of individual
syringes
requires a strict
aseptic
technique with
adequate
sterilization
procedures

110. NEEDLE GAUGE AND TECHNIQUE
• complications described are
temporary increase in
intraocular pressure and reflux
of bevacizumab with the
formation of a subconjunctival
bleb . Some ophthalmologists
have adopted different
intravitreal injection
techniques in order to
decrease the incidence of
reflux taking into
consideration intraocular
pressure . Some patients may
experience elevation of
intraocular pressure 30
minutes after the injection.

112. TREATMENT OF DME VS ARMD
• It is important to distinguish wet AMD from
DME—these are, indeed, two very different
diseases. For patients with wet AMD, we are
treating choroidal neovascularization with
exudation. For patients with DME, we are
only treating edema, the source of which is
retinovascular incompetence. While we are
trying to get that macula to a satisfactory
dry status, the burden over time tends to fall
off in DME.

113. TREATMENT OF DME VS ARMD
•In wet AMD, there is more of a
continuous burden year after year for
an indefinite time frame in most
patients. In DME, studies with
discontinuous or P.R.N. style therapy
such as Protocol I and Protocol T,
many patients were eventually able to
cease therapy .

114. TREATMENT OF DME VS ARMD
•With wet AMD, whether it is P.R.N. or TREAT-
AND-EXTEND (TAE), the mean number of
treatments will typically reach a plateau after
the first year. It does not tend to decrease
much thereafter. But with DME, P.R.N.
studies that we have seen, Protocol I in
particular, started with a mean of eight to
nine injections in year 1, then three to four in
year 2, two to three in year 3 and by years 4
and 5, many had no further treatment .

115. Low vision therapies
• Despite the success of intravitreal anti-VEGF
pharmacotherapy, a significant number of patients with
AMD will ultimately develop bilateral central blindness
for which few therapeutic options exist. Recently, an
implantable miniature telescope was approved by the
FDA that can provide magnification up to a factor of
2.7; in pivotal FDA trials, its use resulted in 2 lines of
vision gained in 90% of patients. Eyes need to be
monitored carefully for corneal decompensation
caused by endothelial cell loss; the corneal transplant
rate is projected to be close to 5% at 5 years after the
implantation surgery.

116. Low vision therapies
• Low vision rehabilitation Vision loss of any degree has a profound
effect on a patient’s activities of daily living including driving and
reading. Although the patient and doctor may be focused on therapies,
sufficient attention should be given to low vision strategies that
improve function and quality of life. Severe vision loss and central
blindness resulting from AMD can be devastating, but low vision
rehabilitation and the use of optical and nonoptical devices can
improve the patient’s functional status and quality of life . Even
patients who have undergone successful anti-VEGF therapy may
sustain reduced visual acuity in the 20/50–20/70 range and can benefit
from low vision interventions such as use of magnification (eg, high-
plus lenses, closedcircuit television), improved lighting, and enhanced
contrast. Training and visual rehabilitation to use eccentric foci
shifted outside of the central scotoma caused by the disciform scar
may also be very helpful. To accomplish some of these rehabilitation
strategies and best meet patients’ needs, clinicians are encouraged
to consider referring patients for low vision consultation and to local
low vision centers or state services for the blind.

117. Light is transmitted through the
anterior segment of the eye to reach
the posterior elements and reaches
the electrodes at either the subretinal
or epiretinal layer.

120. CONCLUSION
• AMD continues to be the leading cause of irreversible
visual acuity loss worldwide among the elderly. Vitamin
supplementation, dietary modifications, and smoking
cessation appear to be the most useful strategies to slow
the progression of dry AMD. For the treatment of wet AMD,
ranibizumab, bevacizumab, and aflibercept have
revolutionized the prognosis for patients. For the first time,
patients can be treated with the expectation that their
vision may improve. However, not all patients improve with
10% losing 15 letters or more over two years as shown in
the phase 3 ranibizumab trials, and this vision loss is likely
caused by the progression of the underlying dry AMD once
the neovascularization has been arrested and the wet AMD
has been converted back to dry AMD .

121. CONCLUSION
• With the result from the CATT showing that monthly dosing
with anti-VEGF drugs increases the incidence of GA, it seems
reasonable to avoid monthly dosing and provide personalized
treatment strategies using either the ‘as-needed’ or ‘treat and
extend’ regimens. For this reason, the future of AMD therapy
rests in developing treatments for the dry form of the disease.
The need for effective treatments to prevent the progression
of dry AMD is paramount as the prevalence of AMD is
expected to double in the coming decades. Genetics offers
the best hope in identifying pathways that can be targeted
using pharmacotherapies so that visual acuity loss from AMD
can be prevented. Although the promise of embryonic stem
cells remains eternal as a strategy to recover lost vision, the
best strategy to treat AMD will continue to be prevention of
vision loss.

122. THANK
YOU
DR DINESH
DR SONALEE