AMD Year Book 2012 - Théa Pharma

AMD YEAR BOOK 2012
Anita Leys
salomon-yves Cohen
Francesco BAndeLLo

Age-related macular degeneration (AMD) is the leading cause of blindness in patients over
the age of 60 in industrialized countries. It is divided in two different groups: non exudative
or atrophic AMD and exudative or neovascular AMD. The first form is more common, but the
second is responsible of 90% of the visual impairment related to AMD.
If untreated, the end stage of non-exudative AMD is geographic atrophy (GA), a circumscribed
area of macular atrophy. On the other hand, exudative AMD progresses to form an organized
fibrous scar (disciform scar) which results in irreversible central visual loss.
Therefore the impact of AMD on quality of life and patients’ autonomy can be devastating.
During the last decade, the approach to these forms of AMD has changed.
Epidemiological studies have revealed the risk factors associated with AMD such as age, sex,
diet, nutritional status, smoking, hypertension and genetic markers and many pathogenic
mechanisms have been identified. New imaging instrumentation can help ophthalmologists
to obtain an early diagnosis and to carefully manage the patient. Finally new therapeutic
approaches to AMD are available and others are emerging and experimental treatments are
on the horizon.
The aim of this AMD Year Book 2012 is to summarize the new information about AMD that were
presented during the last 8 months in international meetings.
Today we are happy to present the second edition of the AMD Year Book 2012, which includes
new data from recent literature as well as information obtained during EVER 2011 and AAO 2011
in part 1 and during the ARVO meeting 2012 in part 2.
We are grateful for the contribution of the European practitioners who covered the congresses.
As usual every part has a first chapter covering epidemiology and risk factors, pathogenic
mechanisms and genetics. The second chapter points to improved and new imaging
techniques and repercussion on the treatment of the patient. In the last chapter new and
emerging treatment options are discussed.
We hope you will enjoy this synthesis of new data in the field of AMD.
ANITA LEYS
YVES COHEN
FRANCESCO BANDELLO
Introduction
AMD YEAR BOOK 2012
1

Part. 1
AMD YEAR BOOK 2012
3

Acknowledgments
to the European practitioners
Dr Anne ALEX (Germany)
Dr Luisa COLACO (Portugal)
Dr Umberto DE BENEDETTO (Italy)
Dr Elisa DE NOVA (Spain)
AMD YEAR BOOK 2012
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Chapter 1
Chapter 2
Chapter 3
Contents
Epidemiology and risk factors.
Pathogenic mechanisms and genetics
AAO 2011 and EVER 2011
Anita LEys, MD, PhD
The evolving imaging of AMD for diagnosis and
monitoring the disease progression
salomon-yves COhEN, MD, PhD
Disease management and treatment
Francesco BANDELLO, MD, FEBO
AMD YEAR BOOK 2012
p. 9
p. 31
p. 47
7

Anita LEys, MD, PhD
Medical Retina, Ophthalmology, University Hospitals Leuven.
Capucijnenvoer 33. 3000 Leuven, Belgium
Anita LEYS is a medical retina specialist at the University
Hospitals Leuven.
She is the author of a thesis entitled
Oogfundusaandoeningen bij Nieraandoeningen
(KU Leuven, 1993) and the author or co-author of a total
of 100 publications and of book chapters on AMD,
radiation retinopathy, eye and renal diseases,
and eye and systemic diseases.
AMD YEAR BOOK 2012
9

Chapter 1
Epidemiology and risk factors.
Pathogenic mechanisms and genetics.
AAO 2011 and EVER 2011
Professor Anita LEys (Belgium)
1
2
3
4
5
6
7
8
9
Progression of geographic atrophy in the AREDs1 study ...................................................... p. 13
Reticular pseudodrusen as a risk factor for advanced AMD in AREDs2........ p. 15
hypovitaminosis D as a risk factor in AMD ........................................................................................................ p. 17
Gene testing and AMD: are we ready to start? .......................................................................................... p. 19
Emerging role of biomarkers for AMD ....................................................................................................................... p. 21
Lipids and AMD ...................................................................................................................................................................................................... p. 23
6.1 Lecerf JM: Plasma cholesterol and lipid metabolism ................................................................................................................ p. 23
6.2 Bretillon L: Cholesterol in retina and RPE ................................................................................................................................................ p. 23
6.3 Rudolf M: Cholesterol, drusen and AMD .................................................................................................................................................. p. 24
Recent data on apolipoprotein ε (APOε) ............................................................................................................ p. 25
Amyloidβ accumulation in Alzheimer’s disease and AMD.
how to reduce amyloidβ accumulation? ........................................................................................................... p. 27
Bibliography ............................................................................................................................................................................................................ p. 29
AMD YEAR BOOK 2012
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1
Progression of geographic atrophy
in the AREDs1 study
Chew E. Retina Subspeciality Days AAO 2011
Although geographic atrophy (GA) is considered to be an endstage of AMD, the whole process
from age-related precursor lesions leading to GA is progressive and the atrophic lesion itself
is growing with time.
The progression of GA in the AREDS1 Study has been analysed in 95 eyes of 77 participants who
developed GA at least 4 years following enrollment in the study. The average time from baseline
to initial identification of GA was 6.6 years (Figure 1). The early precursor lesions of GA included
large and confluent drusen, then hyperpigmentation, drusen regression, and in 25% of cases
highly refractile deposits, then hypopigmentation leading to GA. The mean time for progression
from large drusen to GA was 5.9 years and for progression from hyperpigmentation and
refractile deposits to GA 2.5 years. The growth rate of the geographic atrophy lesion was
2 mm 2 at 1 year, nearly 4 at 2 years, nearly 6 at 3 years or 1.78 mm 2 /year overall. VA loss was
3.7 letters at first documentation of GA, and by 22 letters at year 5.
Figure 1:
Large and confluent macular drusen, and foci of hyperpigmentation in a 74 years-old patient
(left), and progression to drusen regression, refractile deposits and GA at age 79 (right).
AMD YEAR BOOK 2012
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2
Reticular pseudodrusen as a risk
factor for advanced AMD in AREDs2
Domalpally A. Late breaking developments.
Retina Subspeciality Days AAO 2011.
An intermediate analysis of the AREDS2 Study has identified reticular pseudodrusen in 25%
of participants. Further analysis showed that reticular pseudodrusen are a risk factor for GA
(Figure 2), but not for neovascular AMD.
Figure 2:
Reticular pseudodrusen and geographic atrophy in a 82 year-old pseudophakic patient. VA is
20/80. The reticular pseudodrusen are imaged with blue light (upper left), are also evident
on the colour images (upper right), and are identified on the Spectralis OCT as a strongly
hyperreflective band with an irregular surface at the inner side of the RPE (bottom). The area
of geographic atrophy is parafoveal and deeply autohypofluorescent (upper left). The fovea
is relatively spared of atrophic changes. The outer border of the geographic atrophic lesion
has banded autohyperfluorescence.
AMD YEAR BOOK 2012
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3
hypovitaminosis D as a risk factor
in AMD
Mauget-Faÿsse EVER 2011 (3215)
Hypovitaminose D is frequent in the older age group. In a case-control study conducted in Lyon
and Angers, France, 37/65 participants had hypovitaminose D (serum 25-hydroxyvitamin
D < 50 nmol/ml). The mean age of the participants was 76 years. Of the total of 65 participants
31 were AMD patients treated in Lyon. From a geriatric center in Angers, 34 patients without
AMD were prospectively recruited as controls. Subjects with hypovitaminose D had more often
AMD than those without hypovitaminose, and the association was significant (p = 0.029). Oddsratios
(OD) were 3.10 for increased risk of AMD and 3.50 for risk of advanced AMD.
These data and the reports of Parech et al. (1) , and Millen et al. (2) , suggest a role for vitamin D in
AMD and show a correlation between reduced serum vitamin D levels and risk for AMD. In the
third National Health and Nutrition Examination Survey1 7752 adults were evaluated to access
a possible association of serum vitamin D and early and advanced AMD. Levels of serum vitamin
D were inversely associated with early but not advanced AMD. OR was 0.64 for early AMD in
the highest versus the lowest quintile of serum 25-hydroxyvitamin D. Millen et al. (2) confirmed
the association of increased serum vitamin D and decreased OR of early AMD. Seddon et al.
(3) studied twin pairs with discordant AMD phenotypes and detected higher dietary vitamin D
intake in the twin with less severe AMD compared with the co-twin. On the other hand, Golan
et al. (4) found no association of vitamin D plasma levels and AMD in a large cross section study
of AMD and non AMD participants.
Recent reports have shed light in mechanisms of interaction of vitamin D with AMD. Lee et al. (5)
demonstrated that vitamin D administration for 6 weeks in aged mice significantly impacts on
the aging process. Treated mice showed significant reductions in retinal inflammation, in levels
of amyloid β accumulation, and in retinal macrophage numbers and showed improvement in
visual function. The protection of vitamin D against age-related macular degeneration, suggested
in epidemiologic studies, could be due to rejuvenating action of vitamin D in the aging eyes by
reducing inflammation and clearing amyloid β.
Moreover, a genetic association between vitamin D metabolism and AMD risk has been
demonstrated (6) . In an initial study extremely phenotypically discordant sibling pairs were used
to evaluate the association of neovascular AMD and vitamin/sunlight-related epidemiological
factors. After controlling for established AMD risk factors (polymorphisms CFH and ARMS2/
HTRA1, smoking) the study team found that ultraviolet irradiance was protective for neovascular
AMD (p = 0.001). Serum vitamin D levels were higher in unaffected individuals than in their
affected siblings (statistically not significant). Genetic studies were performed in the initial
cohort and replicated in the extended family cohort, and in unrelated case-control cohorts with
a total of 2.528 individuals.
AMD YEAR BOOK 2012
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Hypovitaminosis D as a risk factor in
AMD
These genetic studies resulted in the identification of single point variants in CYP24A1
(the gene encoding the catabolizing enzyme of the vitamin D pathway) that influence the
AMD risk after controlling for smoking, sex and age in all populations, both separately and
in a meta-analysis.
The problem of vitamin D deficiency is prevalent among elderly, because of diminished ability to
produce vitamin D with advanced age. Moreover, hypovitaminosis is not restricted to the elderly.
As of 2005, approximately 40% of men and 50% of women aged over 18 from the USA were
estimated to have inadequate levels of serum 25-hydroxy vitamin D (7) . Recommendations for
vitamin D intake (sun exposure, milk, supplements) are important to maintain adequate serum
25-hydroxyvitamin D levels, taking into account the requirement of vitamin D for bones, CNS, and
other organs and the protective role in many diseases, including protection for AMD.
AMD YEAR BOOK 2012

4
Gene testing and AMD:
are we ready to start?
Kim I. Retina Subspeciality Days AAO 2011
AMD is a complex genetic disorder. Alleles and haplotypes (combinations of alleles at a given
locus that are inherited together) on chromosome 1 in complement Factor H (CFH) and on
chromosome 10 in Age-Related Maculopathy Susceptibility 2 (ARMS2) have large influences
on risk for all AMD subtypes in populations of various ethnicities (8) . However, the combination of
these genes alone is insufficient to correctly predict the development and progression of AMD.
Genome wide scans and genome wide association studies have revealed a number of other
genes associated with AMD or candidate genes, including lipid metabolism genes. AMD genes
intervene in the alternative complement pathway (CFH, C2, CFB, C3 and CFI), in the high-density
lipoprotein (HDL) cholesterol pathway (LIPC,A ABCA1 and CETP),in the extracellular matrix
pathway (TIMP3, COL10A1, and COL8A1) and angiogenesis pathway (VEGFA). The function of
ARMS2/HTRA1 is still not confirmed. HDL genes seem to play important roles in drusen initiation
in the early stages of AMD. As drusen accumulate between RPE and Bruch’s membrane, genes
in the complement pathway are activated (9) . Complete characterization of alleles that influence
AMD, also including those with a weaker association, will be necessary for optimal and accurate
determination of an individual’s overall genetic risk of developing advanced disease as well
as further understanding of the pathogenesis of AMD and identification of new targets for
therapeutic intervention.
Currently recognized genes and environmental factors may help to identify patients
most susceptible to AMD. Risk assessment models for development of advanced AMD are
available (10-11) and are useful for designing clinical trials and for AMD surveillance.
Genetic testing for individuals is becoming widely available (Macular Risk, RetinaGene, deCODE
genetics, 23 and me or ARUP Laboratories), but are we ready and willing to start? A first concern
is the value of the test. Gene testing should be evaluated by ACCE. ACCE Model Project is the
first public-available analytical process for evaluating scientific data on emerging genetic tests.
The ACCE framework has been adopted by various entities worldwide for evaluating genetic
tests. ACCE takes its name from the four main criteria for evaluating a genetic test: Analytic
validity, Clinical validity, Clinical utility and associated Ethical, legal and social implications. In
clinical validity, AMD current models achieve area under the receiver-operating curve (AUC) near
0.80. In clinical utility, correlations between genotype and response to anti-VEGF treatment have
been inconsistent. On the other hand, there are some suggestions of decreased benefits from
AREDS supplements in patients with CFH Y402H risk allele.
Another concern is the added value of genetic testing of an individual. In a recently published
Seminar in ophthalmology (8) , the authors explain in detail the current concepts in the field of
genetics of AMD and genetic testing. Lack of specific efficacious preventative treatments
severely limits the utility of genetic testing for individuals without any signs of disease. For
those already affected by some degree of AMD, retinal findings remain the strongest predictor
of advanced AMD, with genotype adding minimally to risk prediction. For those who develop
advanced AMD, no consistent correlations have been made with respect to treatment response
and genotype.
The authors conclude that while genetic studies should be an integral aspect of clinical
studies of AMD, routine genotyping of AMD patients may not yet be indicated.
AMD YEAR BOOK 2012
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5
Emerging role of biomarkers for
AMD
Sternberg P. Jr. Retina Subspeciality Days AAO 2011
A biomarker is a naturally occurring molecule, gene, clinical feature or characteristic that
is objectively measured and evaluated as an indicator of normal biologic and pathogenic
processes, or pharmacologic responses to a therapeutic intervention.
AMD biomarkers are important in the prediction of the disease. They can be classified in:
1. Morphologic Predictors of AMD and clinical/phenotypic predictors of treatment response.
Drusen size and number can predict the development of AMD. AREDS severity study has a
9-step scale, which associates drusen and pigmentary abnormality with risk. The AREDS
simplified scale is designed for clinical practice. Size of AMD lesion is a predictor, with poor
prognosis of large lesions. Angiographic characteristics of CNV are indicative for prognosis
and treatment response.
2. Genetic predictors of AMD include mitochondria DNA polymorphisms and somatic mutations
with increased risk for carriers of at risk alleles. Complement factor H (CFH) at 1q31 and
ARMS2/HTRA1/LOC387715 at 10q26, and other complement cascade genes - C2/BF, C3 and
CFI - are genetic predictors of disease. Besides, CFH Y402H and LOC387715 are genetic
predictors of progression of disease. CFH is a genetic predictor of treatment response for
antioxidants and zinc therapy. CFH Y402H CC carriers proved to have poorer outcome with
bevacizumab and were more likely to need reinjection with ranibizumab. However, correlations
between genotype and response to anti-VEGF treatment have been inconsistent. In CATT, no
correlation was demonstrated between genotype and response to anti-VEGF treatment.
3. Systemic quantitative AMD predictors include inflammatory markers, oxidative stress
markers and lipid profiles.
• A significant elevation of Apo B levels has been demonstrated in serum of AMD patients (15a) .
In AMD decreased HDL and increased LDL have been observed in one study (15) , but other
studies showed conflicting results.
• Inflammatory markers are CRP, IL-6, Fas Ligand, and complement components and fragments.
• Oxidative stress markers include carboxyethylpyrroles (CEPs), malondialdehyde (MDA),
homocysteine, and thiol redox status in plasma, and 8-OHdG in aqueous (12-14) .
Salomon et al. (13) , in a review article in Chemical Research in Toxicology, demonstrated the
importance of CEP-oxidative protein modification of DHA in AMD. In the outer retina oxidative
cleavage occurs of docosahexaenate (DHA)-containing phospholipids derived from old
photoreceptor disc membranes. This process is associated with production of CEPs. CEPs
modify proteins and CEP-modified proteins accumulate in DHA-rich photoreceptor outer
segments of retina, endocytosis occurs in RPE, and accumulate in drusen. CEP-modified
protein levels are elevated in AMD retina, drusen, RPE, and blood. CEP-modified proteins induce
phagocytosis of rod outer segments, induce angiogenesis (CNV) and induce immune response.
The autoimmune tissue destruction results in atrophy (GA).
AMD YEAR BOOK 2012
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Emerging Role of Biomarkers for
AMD
Weismann et al., in a report in Nature (14) , has focused attention on malondialdehyde.
Malondialdehyde (MDA) and its condensation products are reliable markers for oxidative stress
and have been associated with many disorders including atherosclerosis and AMD. Drusen
have been shown to contain MDA. Complement factor H binds MDA and protects from oxidative
stress, can block uptake of MDA-modified proteins by macrophages, and can block MDA-induced
proinflammatory effects. The CFH polymorphism H402Y, which is strongly associated with AMD
markedly reduces the ability of CFH to bind MDA, indicating a causal link to disease etiology.
AMD YEAR BOOK 2012

6 Lipids and AMD
SIS EVER 2011: Cholesterol and Retina
6.1 - Lecerf JM: Plasma cholesterol and lipid metabolism
Plasma cholesterol is carried in blood by lipoproteins. Lipoproteins contain free and esterified
cholesterol, triglycerids, phospholipids and apolipoproteins. Very low-density lipoproteins
are liver derived and contain triglycerides and cholesterol. Low-density lipoproteins contain
cholesterol and apolipoprotein B. High-density lipoproteins are involved in the reverse transport
of cholesterol. Lipoproteins deliver cholesterol to gonads, adrenal glands, liver and other tissues.
Triglycerides are transported and stored in adipose tissue and are a source of energy for
muscles.
The plasma lipid metabolism is complex. Genetic factors control apolipoprotein synthesis,
control proteins for transfer and exchanges, and control receptors. Diet and abdominal
adiposity modulate the lipid metabolism.
Statins do not reduce risk of AMD (16) .
In the recently published PIMAVOSA Study, macular pigment density was associated not
only with plasma lutein and zeaxantin but also with omega-3 long-chain PUFAs, particularly
with EPA and DPA (17) .
6.2 - Bretillon L: Cholesterol in retina and RPE
Cholesterol in the neuroretina derives from biosynthesis and from the circulation. RPE cells
express lipoprotein and scavenger receptors that allow identification of cholesterol-rich
lipoprotein, and enhance uptake of cholesterol in neuroretina. The neuroretina and RPE cells
express proteins that can remove cholesterol.
Deposits of free cholesterol and cholesterol esters at the basement of Bruchs’ membrane
are hallmarks of aging and of AMD.
AMD YEAR BOOK 2012
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Lipids and AMD
6.3 - Rudolf M: Cholesterol, drusen and AMD
The authors propose a biochemical model of AMD (18) .
• RPE secretes apolipoprotein B-lipoprotein particles of unusual composition, resulting in
drusen formation and accumulation into Bruchs’ membrane eventually forming a lipid wall,
a precursor of basal laminar deposit.
• In addition, apolipoprotein B-lipoprotein particles are perhaps partially delivered from nutrients
and lipophylic recycling system.
• Constituents of these eye lesions interact with reactive oxygen species to form proinflammatory
peroxidised lipids that elicit neovascularisation.
Directions for research and therapeutic strategies should be based on the oil-spill in
Bruchs’ membrane and taking into account associations between AMD and previously
identified CFH, C2, C3, CFB, CFI, APOε and ARMS/HTRA1 genes/regions and the novel
genes LIPC, CETP, ABCA1 in the HDL cholesterol pathway (19-21) .
AMD YEAR BOOK 2012

7
Recent data on Apolipoprotein ε
(APOε)
Apolipoprotein ε is a lipid transport protein involved in low-density cholesterol modulation.
A pooled analysis (22) of 15 studies showed an association of late AMD and APOε. Following
adjustment for age, sex, and smoking, the APOε 4 haplotype was protective for AMD with an
OR of 0.72 per haplotype and the APOε 2 haplotype was a risk factor for AMD with an OR of
1.83 for homozygote carriers.
Ever smokers had a significant increased risk relative to never smokers for both CNV
and GA but not early AMD implicating smoking as a major contributing factor to disease
progression from early signs to late AMD.
AMD YEAR BOOK 2012
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8
Amyloidβ accumulation in
Alzheimer’s disease and AMD. how
to reduce amyloidβ accumulation?
T helper 2 inducing dendritic cell vaccine against A-β
(EVER 2011 p. 3432, Possemiers et al.)
In addition to age as a risk factor, Alzheimer’s disease and AMD have many characteristics in
common, including amyloid in senile plaques of the Alzheimer’s disease brain and in drusen of
AMD patients (23) . To reduce amyloid β accumulation several research projects are ongoing.
• Based on previous studies that have shown that T helper 2 responses are effective in degrading
amyloidβ Possemiers et al. want to develop a T helper 2 inducing dendritic cell vaccine against
amyloidβ.
• The monoclonal antibody against A-β Ponezumab (PF-04360365) had a significant therapeutic
effect in mouse model of AMD (24) , and is used in a phase 2 trial for Alzheimer’s disease.
• Synthetic apolipoprotein mimetics are used in animal models and early human clinical trials,
based on the fact that apolipoproteins naturally regulate lipid transport within the bloodstream.
These synthetic apolipoprotein mimetics have anti-inflammatory properties and are highly
effective for binding lipids, for clearance of plasma cholesterol, and to remove lipid accumulation
in vessel walls. 4F (oral apolipoprotein A-I mimetic peptide D-4F), used in a mouse model of
Alzheimer’s disease, inhibited amyloid β deposition and improved cognitive function. 4F
intravitreal injection, used in an animal model of AMD, reduced the lipid deposition and the
thickness of Bruchs’ membrane and structural remodeling was obtained without adverse
events (25) . Apparently, 4F accepts lipids from accumulated lipoproteins in Bruchs ’membrane
and facilitates removal.
AMD YEAR BOOK 2012
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9
Bibliography
1. Parekh N, Chappell RJ, Millen AE et al. Association between vitamin D and age-related macular degeneration
in the thirs national health and nutrition examination survey, 1988 through 1994. PMID 17502506. Arch
Ophthalmol 2007, 125: 661-69.
2. Millen AE, Voland E, Sondel SA et al. Vitamin D status and early age-related macular degeneration in
postmenopausal women. PMID 21482873. Arch Ophthalmol. 2011; 129: 481-93.
3. Seddon JM, Reynolds R, Shah HR, Rosner B. Smoking, dietary betaine, methione, and vitamin D in monozygotic
twins with discordant macular degeneration: epigenetic implications. PMID 21620475. Ophthalmology 2011;
118: 1386-94.
4. Golan S, Shalev V, Treister G et al. Reconsidering the connection between vitamin D levels and age-related
macular degeneration. PMID 21818133. Eye 2011; 25; 1122-9.
5. Lee V, Rekhi E, Kam JH and Jeffery G. Vitamin D rejuvenates aging eyes by reducing inflammation, clearing
amyloid beta and improving visual function. PMID 22217419. Neurobiol Aging 2012.
6. Morisson MA, Silveira AC, Huynh N et al. Systems biology-based analysis implicates a novel role for vitamin D
metabolism in the pathogenesis of age-related macular degeneration. PMID 22155603. Hum Genomics 2011;
5: 538-68.
7. Zadshir A, Tareen N, Pan D et al. The prevalence of hypovitaminosis D among US aduls: Data from the NHANES III.
Ethn. Dis. 2005; 15, suppl 5, S5-97-S5-101.
8. De Angelis MM, Silveira AC, Carr EA, Kim IK. Genetics of age-related macular degeneration: current concepts,
future directions. Seminars of Ophthalmology 2011; 26: 77-93.
9. Yu Y, Reynolds R, Rosner B et al. Prospective assessment of genetic effects on progression to different
stages of AMD using multistate Markov models. Invest Ophthalmol Vis Sci 2012; 53: 1548-56.
10. Seddon JM, Reynolds R, Yu Y et al. Risk models for progression to advanced age-related macular degeneration
using demographic, environmental, genetic and ocular factors. Ophthalmology, 2011; 118: 2203-11.
11. Klein ML, Francis PJ, Ferris FL et al. Risk ssessment model for development of advanced age-related macular
degeneration. Arch Ophthalmol 2011; 129:1543-50.
12. Brantley MA, Osborn MP, Sanders BJ et al. Plasma biomarkers of oxidative stress and genetic variants in
age-related macular degeneration. Am J Ophthalmol 2012; 153: 460-7.
13. Salomon RG, Hong L, Hollyfield JG. Discovery of carboxyethylpyrroles (CEPs): critical insights into AMD, autism,
cancer, and wound healing from basic research on the chemistry of oxidized phospholipids. Chem Res Toxicol
2011; 24: 1803-1816.
14. Weismann D, Hartvigsen K, Lauer N et al. Complement factor H binds malondialdehyde epitopes and protects
from oxidative stress. Nature 2011; 478, 76-81.
15. Van Leeuwen R, Klaver CC, Vingerling JR et al. Cholesterol and age-related macular degeneration: is there a
link? Am J Ophthalmol 2004; 137: 750-2.
15 a . Fauser S, Smailhodzic D, Caramoy A, Van de Ven JP et al. Evaluation of serum lipid concentrations and genetic
variants at high-density lipoprotein metabolism loci and TIMP3 in age-related macular degeneration. Invest
Ophthalmol Vis Sci. 2011; 52; 5525-5528.
16. Shalev V, Sror M, Goldstein I et al. Statin use and the risk of age-related macular degeneration in a large
health organization in Israel. Ophthalmic Epidemiol 2011; 18: 83-90.
AMD YEAR BOOK 2012
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Bibliography
17. Delyfer MN, Buaud B, Korobelnik JF et al. Association of macular pigment density with plasma omega-3 fatty
acids: the PIMAVOSA Study. Invest Ophthalmol Vis Sci 2012; 53: 1204-10.
18. Cursio CA, Johnson M, Rudolf M, Huang JD. Oil spil in ageing Bruchs membrane. Br J Ophthalmol 2011; 95: 1638-
1645.
19. Neale BM, Fagerness J, Reynolds R et al. Genome-wide association study of advanced AMD identifies a role
of the hepatic lipase gene (LIPC). Proc Natl Acad Sci USA 2010; 107: 7395-400.
20. Chen W, Stambolian D, Edwards AO et al. Genetic variants near TIPM3 and high-density lipoprotein-associated
loci influence susceptibility to AMD. Proc Natl Acad Sci USA 2010; 107: 7401-6.
21. Yu Y, Reynolds R, Fagerness J et al. Association of variants in the LIPC and ABCA1 genes with intermediate
and large drusen and advanced AMD. Invest Ophthalmol Vis Sci 2011; 52: 4663-70.
22. McKay GJ, Patterson CC, Chakravarthy U et al. Evidence of association of APOε with AMD: a pooled analysis
of 15 studies. Hum Mutat. 2011; 32: 1407-16.
23. Ohno-Matsui K. Parallel findings in age-related macular degeneration and Alzheimer’s disease. Prog Retn >
Eye Res 2011; 30: 217-38.
24. Ding JD, Johnson LV, Herrmann R et al. Anti-amyloid therapy protects against retinal pigment epithelium
damage and vision loss in a model of age-related macular degeneration. PMID 21690377. Proc Natl Acad Sci
USA 2011; 108: E279-87.
25. Rudolf M, Clark ME, Messinger JD et al. Apo-AI mimetic peptide reduces lipid deposition in Murine Bruch’s
membrane after intravitreal injection. Invest Ophthalmol Vis Sci 2010; 51: 2984.
AMD YEAR BOOK 2012

salomon-yves COhEN, MD, PhD
Centre Ophtalmologique d’Imagerie et de Laser,
11 rue Antoine Bourdelle, 75015 Paris
Resident and Fellow, Medical Retina, University of Creteil
(Pr Coscas).
In Charge of the AMD clinics, Lariboisière Hospital, Paris
(Pr Gaudric).
Master in Biology of Vessels, PhD in Neurosciences.
Member of the European Board of Ophthalmology.
Author of textbooks on Fluorescein Angiography,
Indocyanine Green Angiography, AMD, Low-Vision
Rehabilitation.
Author of more than 80 papers published in peer
reviewed journals.
Achievement award 2003, American Academy of
Ophthalmology.
AMD YEAR BOOK 2012
31

Chapter 2
The evolving imaging of AMD for diagnosis and
monitoring the disease progression
Doctor salomon-yves COhEN (France)
1
2
Disease progression ................................................................................................................................................................................ p. 35
Imaging AMD ............................................................................................................................................................................................................. p. 37
2.1 FAF imaging .............................................................................................................................................................................................................................. p. 37
2.2 OCT ..................................................................................................................................................................................................................................................... p. 38
2.3 Indocyanine green angiography ..................................................................................................................................................................... p. 40
2.4 Adaptative optics ................................................................................................................................................................................................................ p. 41
3
Future developments of imaging in AMD ............................................................................................................. p. 45
AMD YEAR BOOK 2012
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1
Disease progression
Progression of Geographic Atrophy in the Age-Related Eye Disease Study (AREDS) was reported
by EY Chew (Subspeciality day, AAO).
Geographic atrophy (GA) associated with AMD remains a major cause of vision loss with no
proven effective therapy. Regulatory agencies have accepted structural changes, such as
growth of atrophic lesions, as reasonable outcome measurements in clinical trials. The growth of
lesions associated with GA was measured in the AREDS Study. AREDS is a randomized, controlled
trial of high-dose antioxidants and zinc to reduce progression of AMD.
AREDS participants who had developed GA at least 4 years following enrolment in the study were
included in the analysis and followed for a median of 10 years. Retrospectively, annual fundus
photographs were evaluated prior to the development of GA to identify specific fundus lesions.
Ninety-five eyes of 77 participants developed GA at least 4 years following enrolment in the
study, where average time from baseline to initial GA was 6.6 years. Large drusen formation
was initially detected, followed by hyperpigmentation, drusen regression, and then hypopigmentation,
which lead to GA.
The developing GA was found in drusen (100%), drusen > 125 μm (96%), confluent drusen
(94%) and hyperpigmentation (82%). Time from lesion appearance to GA onset varied from
large drusen (5.9 years) to hyperpigmentation and refractile deposits (2.5 years). The
study also measured the growth rate of the lesions: 2.03 mm 2 at 1 year, 3.78 mm 2 at 2 years,
5.93 mm 2 at 3 years and 1.78 mm 2 per year overall. Median time to developing central GA after
any GA diagnosis was 2.5 years. Average visual acuity decreased by 3.7 letters at first
documentation of central GA, and by 22 letters at year 5.
Thus, AREDS data confirmed that eyes with AMD usually develop GA following the
regression of pre-existing large and confluent drusen. Regression of these large drusen
is associated first with hyperpigmentation, followed by hypopigmentation. It is also
often accompanied by deposition of refractile deposits and terminates in some cases
with GA. These AREDS data will contribute to our knowledge of the natural history of GA
development associated with AMD.
AMD YEAR BOOK 2012
35

2
Imaging AMD
It is a challenge for the imaging devices to achieve a resolution, which is able to detect the very
early changes in the macula, predicting the occurrence of ARM/AMD. Commonly used or new
devices imaging techniques for diagnosis of ARM/AMD are:
1. Fundus color photography and fundus autofluorescence (FAF) imaging
2. Optical coherence tomography (OCT)
3. Fluorescein angiography (FA)
4. Indocyanine green angiography (ICGA)
5. Adaptative optics
2.1 - FAF imaging
Fundus autofluorescence gives information about changes especially important for early
GA detection. Widefield autofluorescence (e.g. Optos 200Tx widefield instrument) is a further
development (SR Sadda, subspeciality day, AAO). It contains a simultaneous phase SLO
technology, which permits additional autofluorescence imaging. It is able to image up to a 200-
degree field of view without medical mydriasis of the pupils, but one has to accept peripheral
distortion. Indeed, it was discovered that central retinal fundus autofluorescence (FAF) changes
are accompanied with FAF changes in the periphery in retinal degeneration, inflammatory
diseases and AMD. In AMD patients, over 60% of patients showed such peripheral FAF changes.
The OPERA substudy and AREDS2 trial will study these changes and their importance more
detailed, especially for neovascular AMD. They may aid in the diagnosis and pathogenesis of
disease. Meanwhile, the presence of FAF changes were reported in a second study, recently
released (Reznicek L et al. Peripheral Fundus Autofluorescence is Increased in Age-related
Macular Degeneration. Invest Ophthalmol Vis Sci. 2012 Mar 12). In this study, consecutive
series of 71 normal eyes, 71 eyes with neovascular AMD having received anti-VEGF treatment
and 43 eyes with untreated AMD were investigated. In all subjects, wide-field FAF imaging was
performed applying a wide-field scanning laser ophthalmoscope (Optomap® Panoramic 200Tx,
Optos). Fundus autofluorescence increased with age not only in the perifoveal retinal area, but
also in the retinal periphery. For age corrected measurements peripheral FAF was significantly
increased for both, treated and untreated AMD groups compared to normal subjects.
AMD YEAR BOOK 2012
37

Imaging AMD
2.2 - OCT
Huang et al. first introduced the optical coherence tomography (OCT) in 1991 “as a high resolution,
noninvasive, in vivo ophthalmic imaging technique with low coherence interferometry to detect
echo time delays of light, as opposed to sound“. Originally, time-domain (TD) OCT was used.
The reference arm moves mechanically. About 400 A-Scans/second were achieved. The
spectral-domain OCT (SD-OCT; fourier domain technique) has a stationary reference arm, a
high-speed spectrometer and a charge coupled device (CCD) camera to detect light echoes
simultaneously. With this technique, the acquisition speed was increased to 25.000 to 27.000
A-Scans/second and the axial resolution was enhanced to 3-7 µm.
Two main technical improvements allow to visualizing the choroid (R Spaide, subspeciality day,
AAO); this is of importance because imaging the choroid has become more important to analyze
pathogenic pathways of AMD, but also to evaluate the treatment success of anti-VEGF therapy.
Enhanced depth imaging (EDI; available mode in SD-OCTs), at least enables to measure choroidal
thickness. The peak sensitivity is shifted to the choroidal scleral junction and therefore images
of deeper layers can be taken. This works through zero delay inversion and A-Scan averaging
with a wavelength of 840 nm.
The swept-source OCT (SS-OCT; Carl Zeiss Meditec) is equipped with a light source that only
produces a single wavelength (1050 nm) of light at any instance and the output of light is swept
across a range of frequencies. A photodiode serves as detector, which detects signals faster
than a commonly used CCD (charge coupled device) in the SD-OCT. Scattering is reduced and
deeper tissue penetration is possible. The scan rates are higher (up to 300.000 A-Scans/
second) in the SS-OCT. The scan depth is about 5 mm due to less sensitivity loss. The peak
sensitivity is similar to that in the SD-OCT. Simultaneous imaging of the vitreous, the retina
and the choroid becomes possible. Choroidal thickness can also be measured.
With these OCT improvements, choroidal thinning was frequently observed in AMD patients. In
examinations of healthy eyes, regional variations of choroidal thickness with inter-individual
differences were observed and have to be considered when measuring choroidal thickness
in diseased patients. In normal eyes, the choroid is thickest subfoveally and decreases rapidly
nasally and less temporally.
A recent paper also showed the improvements in OCT technology to monitor the course of
drusen and their evolution towards RPE atrophy (Yehoshua et al. Natural history of drusen
morphology in age-related macular degeneration using spectral domain optical coherence
tomography. Ophthalmology 2011; 118: 2434-41). The authors report the results of a prospective,
and longitudinal study of 143 eyes of 100 patients. They used a custom software to quantify
volumetric changes in drusen over a period of ≥ 6 months. On average, drusen volume and
drusen area increased over time with the magnitude of the increase dependent on the length
of follow-up (p = 0.001, 3 mm circle). However, drusen volume decreased in 12% of eyes, with
occurrence of RPE atrophy.
AMD YEAR BOOK 2012

Thus, OCT is now used as a routine tool to quantify lesions which were previously only qualitative.
For example, an eye with small areas of RPE atrophy could be imaged with autofluorescence
pictures, that give information about the location of RPE atrophy, and its future development;
and with OCT which allows to observe thinning of the choroids, and to quantify the course of
progression of the geographic atrophy (Figure 1).
A B
C
Figure 1:
Geographic atrophy imaged with red-free pictures in October 2011 (a), and in March 2012
(b). Improvements of imaging allowed to better visualize geographic atrophy in March 2012,
thanks to the auto-fluorescence fundus photograph (c ) , showing the limits of the atrophy
and the surrounding hyperfluorecencent areas, in which geographic atrophy is likely to
extend. Furthermore, it was possible to automatically measure the area involved by atrophy
in March and, retrospectively, 5 months before, showing, in this case, a growth rate of 96%,
and a diminution of the closest distance to fovea of 50%.
(Image Dr S.Y. Cohen)
D
AMD YEAR BOOK 2012
Sub-RPE Slab
RPE Profile TM
October 2011 March 2012
39

Imaging AMD
Recently, it has been shown that eyes with reticular pseudodrusen also have a thin choroid, as
measured by EDI-OCT (Querques G. Choroidal changes associated with reticular pseudodrusen.
Invest Ophthalmol Vis Sci 2012; 53: 1258-1263). The authors compared 22 consecutive patients
(22 eyes) with reticular pseudodrusen, and without medium/large drusen, with 21 age and
sex-matched subjects (21 eyes) with early age-related macular degeneration (AMD), and
without pseudodrusen. The mean subfoveal choroidal thickness was significantly reduced
in the group with reticular pseudodrusen compared with that in the control group (174.6 ± 10.1
and + 241.4 ± 16.5, respectively; p < 0.001).
With the Fourier-domain mode locking (FDML), the tuning speed of the laser light source is
improved and up to 370.000 A-Scans/second can be achieved. Further software modifications
improve the resolution (e.g. with eye tracking). Internal choroidal structures can be visualized
and provide information for a better understanding of pathophysiological processes in ocular
diseases.
2.3 - Indocyanine green angiography
The role of indocyanine green angiography (ICGA) in management of AMD seems to decrease
significantly in the last years. This is pointed out in a recent review (SY Cohen et al. Is indocyanine
green still relevant ? Retina 2011; 31: 209-221. In 1992, Yannuzzi et al. showed that late frames
of ICGA allowed visualization of the entire choroidal neovascular membrane, and ICGA-guided
photocoagulation of occult CNV became part of standard care in exudative AMD without classic
CNV, i.e. in occult CNV, especially when the latter was located inside or at the margin of a pigment
epithelial detachment (PED). Anti-VEGF therapy was available in France in 2007, and inaugurated
a new era in the management of exudative AMD. This method of treatment differs radically from
laser photocoagulation or verteporfin PDT, because there is no longer any point in limits of the
CNV, since it is sufficient simply to inject the anti-VEGF drug into the vitreous. Thus, precise
delineation of the CNV membrane is obviously less important than before, and this may explain
the marked reduction in the use of ICGA in AMD. However, there are useful indications of ICGA
in AMD, especially when diagnosis associated polypoidal choroidal vasculopathy is considered.
Recently, a retrospective study analysed the charts of 44 consecutive patients (55 eyes) with
newly diagnosed occult CNV secondary to AMD treated by intravitreal ranibizumab (Querques
G. et al. Anatomic response of occult choroidal neovascularization to intravitreal ranibizumab:
a study by indocyanine green angiography. Graefes Arch Clin Exp Ophthalmol 2012; 250: 479-
484). In all patients, optical coherence tomography (OCT) and ICGA were performed at baseline,
after 3 months and 12 months. The mean follow-up was 20.3 ± 6.2 months. Central macular
thickness (CMT) significantly improved during follow-up (229.0 ± 54.7 μm vs 281.0 ± 61.3 μm
at baseline, p = 0.003). An overall stabilization was observed on ICGA in both the lesion area
(5.27 ± 3.9 mm 2 at baseline vs 4.60 ± 3.5 mm 2 at month 12, p = 0.4), and greatest linear
dimension (GLD 2.66 ± 1.2 mm at baseline vs 2.55 ± 1.0 mm at month 12, p = 0.3). Thus, the study
suggests that functional outcomes after intravitreal ranibizumab were related to CMT
reduction rather than CNV regression. ICGA does not seem to be useful in the follow-up of
patients treated with anti-VEGF therapy.
AMD YEAR BOOK 2012

2.4 - Adaptative optics
Adaptive optics (AO) enables the approach of retinal imaging on a single cell level (M Ching,
subspeciality day, AAO). It can be distinguished between rods and cones due to a high resolution
of the retina (transverse resolution of about 2 microns). Optical aberrations are measured by
a wavefront sensor and corrected by a deformable mirror. It is even possible to differentiate
between the three different subtypes of cones. Thereby, a different cone mosaic was detected
in patients with color vision deficiency.
Several combinations were attained with adaptive optics and already existing techniques.
Fluorescence AO (FAO) combines adaptive optics with scanning laser ophthalmoscopy (SLO).
Intracellular lipofuscin is used to detect single retinal pigment epithelial cells (RPE cells)
simultaneously to the overlaying cones. A quantitative analysis is possible. Every single cell can
be labeled by software features and counted. The measurement of cone density (foveal cones),
rod imaging, RNFL imaging or the illustration of retinal eccentricity is feasible. The application for
pharmaceutical testing, stem cell implants etc. is also feasible. This device can be meaningful
for monitoring in diseases of photoreceptor degenerations, macular telangiectasia, geographic
atrophy, and for the evaluation of therapeutic efficiency.
The combination of SD-OCT with a confocal microscopy developed an AO-OCT with an resolution
of 3.5 x 3.5 x 3.5 µm (Imagine Eyes rtx1 TM). The area of interest can be marked and scanned.
Quantitative analysis of cells/area and retinal vessel wall analysis is possible. The limitations
of the device are achieved through eye movements and visual pathway opacities. Besides, it
produces large datasets and operator skills are more important again than in other modern
imaging devices.
AMD YEAR BOOK 2012
41

Imaging AMD
Adaptative optics (AO) is currently used at the Institut de la Vision, Paris, to analyze Geographic
Atrophy (GA) (Paques M. et al. ARVO 2012). In this study, the authors examined eight eyes of
eight patients with GA, which underwent 850 nm AO imaging (rtx1, Imagine Eyes, France)
of the macula. Results were compared to reflectance and autofluorescence scanning laser
ophthalmoscope imaging and to optical coherence tomography. Compared to the other imaging
modalities, AO allowed a better delineation of GA limits (Figure 2) and showed more details
about melanin redistribution within and around GA areas. The authors conclude that AO imaging
imaging may provide novel biomarkers for detecting the earliest stages, documenting the retinal
pathology and monitoring progression of GA.
A B
Figure 2:
Geographic atrophy imaged with autofluorescence fundus photography (a), and adaptative
optics, performed on the paracentral atrophic area (b). Note the disappearance of photo-
receptors and black dots corresponding to melanine clumps.
Courtesy Pr Michel Paques, Institut de la Vision, Paris.
AMD YEAR BOOK 2012

New imaging of geographic atrophy could thus include adaptative optics, fundus photography,
and OCT (Figure 3).
A B
C
Figure 3:
Geographic atrophy imaged with adaptative optics (a), fundus photography and horizontal
scan of the OCT. The area of photoreceptors loss correspond to the area of RPE atrophy.
Courtesy Dr Massamba, Department of Ophthalmology of Pr Souied, Creteil, France).
AMD YEAR BOOK 2012
43

3
Future developments of imaging
in AMD
The polarization sensitive OCT (PS-OCT) is based upon a depth-resolved tissue birefringence.
Thereby, a better tissue-specific contrast between the retinal nerve fiber layer (RNFL) and retinal
tissue is achieved due to their individual interactions with light. Retinal layers, e.g. the retinal
pigment epithelium, can be displayed individually.
Meanwhile, retinal blood flow imaging can be performed with OCT. So far, angiography
(qualitative), doppler ultrasound (inaccurate) and the laser doppler flow meter (time consuming)
were the only possibilities to visualize retinal blood flow. The Doppler-OCT measures the retinal
blood flow velocity due to light reflectivity changes over a period of time. A double circular
scan of the optic nerve head scans all retinal branch vessels during the same time in different
distances to their origin (6 times per second) over a short time period. For quantification, a
special retinal circulation software is used. With the color Doppler-OCT (CD-OCT), real time blood
flow visualization is possible and discrimination between arteries and veins can be made. In
C-Mode imaging, microstructures and anatomic relationships can be visualized. At the present,
usefulness of these developments for imaging chorioretinal diseases, and especially AMD, is
not clear.
However, with these further developments, early disease detection, monitoring of disease
progression and therapy experience a huge improvement. The diversity of applications is
augmented. OCT is no longer a simple diagnostic tool, but can get access to intraoperative
use. Moreover, an OCT biomicroscopy is conceivable. A binocular OCT, integrated in a “normal”
slit lamp, could be used in the examination routine. The applications of the optical coherence
tomography pass beyond the identification of macular edema, subretinal fluid, RNFL thickness,
macular thickness and longitudinal measurements in glaucoma, AMD and diabetes. Quantification
of eye motility measurements could be possible and used for the detection of strabismus and
ocular alignment. Also, visual field testing is feasible with binocular OCT.
The rising knowledge of disease development and progression and the continuing
development of imaging techniques to higher scanning speed and higher resolution on
single-cell level, lead to a stage of diagnosis standard and treatment control, on which we
have never been before. The variety of treatment options can be compared and optimal
treatment intervals evaluated. This in turn leads to a good effectiveness and reduction
of costs. Additionally, treatment can interfere earlier in the pathologic pathway and thus
result in a better outcome of visual acuity. It is obvious that we have reached a new area of
diagnosis and imaging in ophthalmology.
AMD YEAR BOOK 2012
45

Francesco BANDELLO, MD, FEBO
Professor and Chairman Department of Ophthalmology
University Vita-Salute, Scientific Institute San Raffaele, Milano, Italy
Dr BANDELLO is Full Professor of Ophthalmology and
Chairman at the Department of Ophthalmology - University
Vita Salute, Scientific Institute San Raffaele of Milano.
Dr BANDELLO is member of the Academia Ophthalmologica
Internationalis and member and Vice President of the
Academia Ophthalmologica Europea.
Dr BANDELLO serves as a NEI (NIH - U.S.A) Peer Reviewer for
grant applications since 2006.
Dr BANDELLO is a fellow of the European Leadership
Development Programme (EuLDP) of the American Academy
of Ophthalmology.
Dr BANDELLO is former executive committee member of the
Macula Society and member of the “Accademia Nazionale di
Medicina”.
Dr BANDELLO was elected as a member of the Advisory
Board of the Italian Society of Ophthalmology for 9 years
and scientific coordinator of the annual meeting of the
Society for 7 years.
Dr BANDELLO was the scientific coordinator of the
Ophthalmology Monographs of the Italian Society of
Ophthalmology for 12 years.
Dr Bandello was Vice-President of the European Board of
Ophthalmology and chairman of the Recidency Review
Committee of the same association.
AMD YEAR BOOK 2012
47

Dr BANDELLO was the General Secretary and Treasurer of
the Italian Society of the Retina.
Dr BANDELLO is former member of the International
Executive Committee Michaelson Symposium and former
member of the Subcommittee for Michaelson Award.
Dr BANDELLO is former board member of Club Jules Gonin.
Dr BANDELLO is president elect of the European Society of
Retina Specialists (EURETINA).
Dr BANDELLO is president of the Italian Society of the Retina.
Dr BANDELLO is member of the Scientific Advisory Board
Panel of AMD Alliance International.
Dr BANDELLO is Vice-President of EUROLAM (Europe and
Latin-America Society of Ophthalmology).
Dr BANDELLO is member of the Panel Discussion (tavolo
oftalmologico) of AIFA (Italian Agency for Drug).
Dr BANDELLO is member of the Steering Committee of the
Osservatorio Malattie Rare (O.Ma.R).
Dr BANDELLO is Chair of the Committee for revision of the
curricula for Vitreoretinal Diseases section of the
International Council of Ophthalmology (ICO).
Dr BANDELLO is member of the Scientific Committee of
Vision+ Onlus.
Dr BANDELLO is Novartis Ophthalmology Vision Award (NOVA)
Committee Member.
Dr BANDELLO is Member of the Grants Review and Awards
Committee (GRAC) of the Bayer Ophthalmology Awards
Program (BOAP).
Dr BANDELLO is candidate for Membership of American
Ophthalmological Society (AOS).
In 1984 Dr BANDELLO attended the Department of
Ophthalmology of the University of Creteil (Paris XII)
(France) (Chairman: Pr Gabriel Coscas) and became
“Assistant Etranger” at the Faculty of Medicine of the same
University.
AMD YEAR BOOK 2012

Dr BANDELLO is Associate Editor of the European Journal
of Ophthalmology, which is indexed in Current Contents/
Clinical Medicine, Science Citation Index, Expanded ISI
Alerting Service, Index Medicus, MEDLINE, EMBASE/Excerpta
Medica, Ocular Resources Computer-Scan, Pascal Data Base
of INIST.
Dr BANDELLO is Co-Editor of Developments in Ophthalmology,
Karger, Basel, Switzerland.
Dr BANDELLO is Editorial Board member of Case Reports in
Ophthalmology.
Dr BANDELLO is Editorial Board member of the journal
“Retinal Physician”.
Dr BANDELLO is former Editorial Board member for the
Journal of Ocular Pharmacology and Therapeutics.
Dr BANDELLO is Associate Editor of Ophthalmologica.
Dr BANDELLO is Editorial Board member for the “Giornale
Italiano di Vitreoretina”.
Dr BANDELLO is Editorial Board member of “ISRN
Ophthalmology” (International Scholarly Research
Network).
Dr BANDELLO is Editorial Board member of the Springer
Healthcare journal “Combination Products in Therapy”.
Dr BANDELLO is Advisory Board Member of “Ophthalmology
and Therapy”.
Dr BANDELLO served as trained principal investigator in
several clinical trials performed following ICH/GCP and
mainly concerning age-related macular degeneration and
diabetic retinopathy.
Dr BANDELLO is co-author of five books. He has published
165 Pub-Med papers. He presented well over hundreds
of presentations at different meetings. These primarily
relate to retinal diseases; diabetic retinopathy; age-related
macular degenerations; fluorescein and indocyanine green
angiographies of different retinal vascular disorders.
AMD YEAR BOOK 2012
49

Chapter 3
Disease management and treatment
Professor Francesco BANDELLO (Italy)
1
2
Non exudative AMD ..................................................................................................................................................................................... p. 53
1.1 New therapeutic perspectives ........................................................................................................................................................................... p. 54
Neovascular AMD ............................................................................................................................................................................................ p. 57
2.1 Combined treatments .................................................................................................................................................................................................. p. 58
2.2 New therapeutic approach ..................................................................................................................................................................................... p. 58
2.2.1 Radiation Therapy....................................................................................................................................................................................... p. 58
2.2.2 VEGF Trap ............................................................................................................................................................................................................... p. 61
2.2.3 Anti-VEGF and anti PDGF-B .................................................................................................................................................................. p. 61
2.2.4 Anti-VEGF and Anti-Endothelial Cell drug combinations ................................................................................... p. 62
AMD YEAR BOOK 2012
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1
Non exudative AMD
The aim of non exudative AMD treatment is to restore loss of visual function. However the
realistic goal of available treatments is its preservation. New therapies that modulate risk
factors such as incorrect diet and nutritional status are currently available. However, these are
able to prevent the development or progression of the pathology but do not completely cure
patients affected by AMD.
The Age Related Eye Disease Study (AREDS), a multi-center, randomized, controlled clinical trial
demonstrated that oral supplementation of a combination of vitamin C (500 mg), vitamin E
(400 UI), beta-carotene (15 mg), zinc oxide (80 mg) and cupric oxide (2 mg) in patients with
intermediate or advanced AMD in one eye had a 25% relative risk reduction over 5 years of
developing advanced AMD in the other eye. The risk of vision loss of three or more lines was
reduced by 19% with this treatment.
Deficiencies of Essential fatty acids (docosahexaenoic acid, DHA) have been implicated in AMD
onset, and long chain omega-3 fatty acids may also help to prevent the oxidative, inflammatory
and age-related retinal damage that occurs during AMD development.
Hyperhomocysteinemia is responsible for vascular damage and is also implicated in neovascular
AMD. Vitamin B12 and folate are involved in reducing blood homocysteine concentration. The
WAFACS Study showed that the patients treated with vitamin B12 and folate had a statistically
significant 35% to 40% decreased risk of developing AMD.
Macular pigment is composed primarily of the xanthophylls lutein and zeaxanthin, also members
of the carotenoid family. Their antioxidant properties, as well as their ability to filter shortwavelength
light, may help to protect the outer retina and RPE from oxidative stress and aid in
cell membrane stability.
Several epidemiologic studies demonstrated that carotenoid intake reduced the risk for
advanced AMD and that lutein and zeaxanthin based diet may protect against intermediate
AMD in female patients.
In conclusion, the published papers are not sufficient to recommend routine nutritional
supplementation for primary prevention of AMD. However, patients with intermediate risk
of AMD or advanced AMD in one eye are recommended to take AREDS type supplements,
because this formulation is able to reduce the risk of progression to advanced AMD. Also
the dietary intake of additional nutrients such as carotenoids and omega-3 fatty acids
could be helpful to slow AMD progression.
AMD YEAR BOOK 2012
53

Non exudative AMD
1.1 - New therapeutic perspectives
During the last years, the molecular mechanisms and pathophysiology of nonexudative AMD
has been discovered, so new therapeutic strategies have been developed.
The aim of neuroprotective therapy is to tip the balance in favor of cell survival by blocking
cell death signals and enhancing cell survival signaling. Because of the slow progression
of cell apoptosis in AMD, ongoing studies are testing drug delivery implants characterized by
progressive controlled release of neuroprotective agents.
Currently 3 different drugs are being tested in patients affected by geographic atrophy (GA):
• Neurotech encapsulated cell technology which releases ciliary neurotrophic factor (CNTF).
• Allergan biodegradable brimonidine drug delivery system.
• Alimera Iluvien fluocinolone acetonide drug delivery implant.
Neurotech managed to create a new intraocular implant (NT-501) that contains live human RPE
cells encapsulated in a particular membrane that allows cellular CNTF and other metabolites to
enter the retina, protecting the implant itself from rejection by the host immune system. The
principal characteristic of this implant is that it does not release a primary stored drug, but
produces the therapeutic drug directly in situ. The resulting vitreous CNTF levels are consistent
over time and are effective in photoreceptor preservation and visual acuity stabilization.
It is well known that brimonidine protects the human retina from degeneration secondary to a
variety of mechanic, ischemic or toxic insults, modulating different cellular pathways involved
in cellular apoptosis. Brimo PS DDS® consists in a drug delivery system composed by a
biodegradable polymer matrix containing brimonidine tartrate. It is intravitreally injected and
the drug is released slowly, degrading itself completely. The results of a phase 2 clinical trial
that is evaluating the effects of this delivery system in patients affected by GA are pending.
Inflammation has been demonstrated to have role in the ethiopathogenesis of AMD and in vivo
studies have documented the positive effects of fluocinolone acetonide in rat’s retina. Alimera
has developed Iluvien (sustained release of fluocinolone acetonide) for diabetic macular edema
and is starting a trial to evaluate the effects of steroids in the development of GA. This study is
ongoing and enrollment is still opened.
Experimental findings suggest that certain molecular compounds of lipofuscin (LF), derived from
the chemically modified residues of incompletely digested photoreceptor outer segment discs,
may interfere with normal cell function leading to photoreceptor apoptosis. This is the basis of a
new therapeutic approach to dry AMD that consists in modulating the visual cellular cycle.

4-Hydroxy (phenyl) retinamide (Fenretinide, Sirion Therapeutics, Tampa, FL) is a synthetic
retinoid that strongly binds to excess vitamin A, thus decreasing the amount of retinol available
in the visual cycle and inhibiting the production of toxic metabolites in RPE cells. The safety of
this drug has already been documented. A reduction in lesion growth was documented, but
the results were not statistically different from the placebo group. However, a difference was
reported if the patient received fenretide with a smaller particle size. New studies, with a larger
number of enrolled patients, are necessary to clarify the effects of this new therapeutic approach.
Inflammation, particularly via the complement system, plays an important role in the
ethiopathogenesis of AMD. Since 2005, different genetic polymorphisms in the complement
factor H (CFH) gene, complement component 3 (C3) gene and complement factor B/complement
component 2 loci have been associated with the ethiopathogenesis of AMD. Later, a similar
association was also reported for the complement factor 1 gene.
Therefore new approaches that interfere with different pathways of the complement cascade
are being tested.
POT-4, a compstatin derivative, targets reversibly C3 (a point of convergence for all three
pathways of complement activation). A phase 1 dose escalation trial is ongoing, and a phase
2 study is being organized to also investigate the anti-VEGF properties of POT-4.
Complement inhibition with Eculizumab for the treatment of Non exudative age related macular
degeneration (COMPLETE) study is a phase 2 study that is testing the safety and the efficacy of
Eculizumab (humanized monoclonal antibody that specifically binds C5, blocking the activation
of complement) for the treatment of dry AMD.
The most innovative field regarding the treatment of Dry AMD is stem cell transplantation.
It is very interesting because, when it will be a concrete therapeutic approach, it could
completely replace the dead cells that characterize many retinal diseases such as GA or
retinitis pigmentosa. Preclinical studies demonstrate the efficacy of using embryonic stem
cells for treating retinal degenerative disease. However, the use of these cells in clinical
practice is currently limited by many aspects such as the immunogenicity and stability of
the cells and the propensity to form tumors in situ.
AMD YEAR BOOK 2012
55

2
Neovascular AMD
In the last decade, the role of VEGF and neoangiogenesis in the pathogenesis of neovascular
AMD was stressed. Consequently, the advent of intravitreous VEGF inhibitors has revolutionized
the management of this disease.
The first anti-VEGF agent used in AMD treatment was pegaptanib sodium. Other anti-VEGF drugs
are ranibizumab and bevacizumab.
Today, on the basis of results from the pivotal phase 3 clinical trials, ranibizumab dosed monthly
represents the reference product to which all other therapeutic regimens are to be compared.
Recently new trials are testing the possibility to reduce the number of intravitreal injections
administered to the patient (PRN or treat and extend approaches) without reducing the positive
effects of anti-VEGF therapy.
PRN (Pro Re Nata “as needed“) approach consists in regular monthly follow up visits and
retreatment decided on the basis of the presence of retinal exudation. Unlike traditional PRN,
a treat and extend approach initially involves regular and frequent treatment until the macula
is dry, followed by a gradual extension of the treatment interval and corresponding follow-up
visit. Treatment is rendered at every visit and this extension continues until there are signs of
recurrence, at which point the treatment interval is then reduced.
About this topic, a formal head-to-head comparison of bevacizumab and ranibizumab is being
conducted by the National Eye Institute of the National Institute of Health in the Comparisons
of Age-Related Macular Degeneration Treatment Trials (CATTs). The CATT Study design includes
four treatment arms: either bevacizumab or ranibizumab on a variable schedule and either
bevacizumab or ranibizumab on a fixed monthly schedule for 1 year followed by random
assignment to either continued monthly injections or a variable schedule based on the
treatment response. The primary outcome measure is mean change in BCVA; secondary
outcome measures include number of treatments, anatomical changes in the retina, adverse
events, and cost.
During the last AAO Meeting, Daniel Martin reported the results of this study*:
• Bevacizumab and ranibizumab were equivalent for visual acuity at all time points when
administered at the same dose regimen.
• PRN dosing with monthly evaluation produced average gain that was 2 letters less than
monthly dosing, but overall results still excellent.
• PRN dosing resulted in 4-5 fewer injections over 1 year than monthly dosing.
• Both drugs produced an immediate and substantial decrease of fluid.
• Neither drug eliminated fluid in the majority of eyes (although more eyes were completely
dry with monthly ranibizumab).
* Martin DF, Comparison of AMD treatments trials (CATT): Bevacizumab-ranibizumab trial. AAO 2011.
AMD YEAR BOOK 2012
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Neovascular AMD
2.1 - Combined treatments
The establishment of new guidelines for the administrations of anti-VEGF drugs to minimize
the side effects and the number of injections is still opened. It is well known that AMD is a
multi-factorial disease, however all the available drugs are able to only interfere with a single
pathogenetic mechanism. It is possible that the ongoing studies regarding the incorporation of
different treatments will be capable of obtaining better results and potentially reach in treating
also non responder patients.
Verteporfin PDT controls the progression of CNV in a particular way. It induces the occlusion of
the microvasculature within the lesion, blocking its progression. The combination of this therapy
with anti-VEGF injections may be positive compared with either modality alone, yielding longer
treatment-free intervals and requiring fewer intravitreal injections.
Contrasting data regarding this combined therapy led to the initiation of two different
large long term clinical trials: DENALI and MONT BLANC trials. These randomized, doublemasked,
controlled, multicenter studies were designed to assess the efficacy and
safety outcomes of ranibizumab and verteporfin PDT compared with ranibizumab alone
for any type of subfoveal CNV due to AMD. Both trials aim to show the non inferiority
of combination therapy with respect to mean change in BCVA from baseline at month
12. Data released showed an average of 2.5 letters of VA improvement with combination
therapy compared with 4.4 letters with monotherapy alone.
2.2 - New therapeutic approach
2.2.1 - Radiation Therapy
Radiation has the ability to destroy different tissues with two principal mechanisms: producing
DNA damage (directly or indirectly via H2O molecule’s damage, producing OH- free-radicals) and
releasing vasoactive substances resulting in additional tissue damage and vessel closure.
It is well known that endothelial cells in newly formed vessels are more sensitive than mature
vessels or fibroblasts to radiation therapy. This is the basis of the employment of radiation in
exudative AMD therapy.
It was demonstrated that this treatment has anti-angiogenic, anti-inflammatory and anti-fibrotic
effects if addressed against CNV. The first two effects are secondary to the destruction of
neovascular tissue, which is a characteristic of this promising therapy and that differentiates
it from the effects of anti-VEGF therapy which is effective in limiting the increased vascular
permeability, but doesn’t lead to CNV regression. Finally the anti fibrotic effect is secondary to
the direct inhibition of CNV metaplasia, leading targeted endothelial cells to apoptosis.

Two different types of radiotherapy have been employed in the treatment of neovascular AMD:
external beam radiation in which the radiation source is outside the patient’s body and is
directed against a particular tissue; and brachytherapy, which consists in the placement of a
radiation source inside the body, near or adjacent to the target tissue.
In brachytherapy the radioactive plaque is sewn directly into the sclera, posterior to the macula
and this allows a reduced variability of the radiation dose. This type of radiation has a favorable
physical characteristic: the rapid decline of the dose with increasing distance from the source
(approximating 10% for every 0.1 mm away from the target). Unfortunately this type of therapy
requires surgical removal of the plaque and is complicated in a major percentage of cases by
cataract formation.
• The MERITAGE Study (Macular EpiRetinal Brachyteraphy in Treated Age-Related Macular
Degeneration Patients) is a multicenter, non-randomized phase 2 study that is evaluating
the effects of a single intraocular treatment with 24 Gy radiation (strontium-90) followed by
intravitreal ranibizumab injections in patients with predominantly classic or occult (with no
classic) CNV secondary to AMD.
• At 6 months, the mean number of injections was 1.8. At 6 months follow-up, about 50 % of
patients lost fewer than 15 letters, and 5.7% gained at least 15 letters. One patient lost more
than 30 letters. Twenty-eight patients (52.88%) gained 0 or more letters.
• The study results pointed to a favorable trend with respect to a reduced number of anti-VEGF
injections at 12 months following delivery of Epimacular Brachytherapy (mean of 3.9) versus
the period of time leading up to Epimacular Brachytherapy intervention (mean of 12.3). In
addition, 25% of patients remained injection-free at 12 months following the Epimacular
Brachytherapy procedure.
Study results at one year also suggest that a single procedure of Epimacular Brachytherapy
can stabilize visual acuity in a majority of this patient population (79%) while decreasing
the number of anti-VEGF injections required. Most importantly, 47% of patients enrolled
in the study experienced some improvement in their visual acuity while 10% of patients
gained 15 or more letters of visual acuity at 12 months.
AMD YEAR BOOK 2012
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Neovascular AMD
• CABERNET is a phase 3 trial comparing the effects of epiretinal strontium-90 radiation combined
with ranibizumab, to that of ranibizumab alone. In this study, patients were randomized in two
different arms: in arm A patients received a one-time treatment of strontium-90 and two
ranibizumab injections (the first following surgery and the second during the 1 month follow
up visit). Subjects enrolled in arm B received 3 monthly ranibizumab intravitreal injections
followed by quarterly injections for 2 years.
This study demonstrated the non inferiority of radiation therapy compared to ranibizumab
treatment in eyes losing 15 or more ETDRS letters and a superiority in eyes which gained
15 or more ETDRS letters.
• Oraya therapeutics (Newark, CA). More recent studies are examining the efficacy of radiotherapy
for wet AMD utilizing a new divergent technique: the external, non-surgical, orthovoltage
X-Ray IRayTM therapy (Oraya Therapeutics, Inc., Newark, CA).
• The IRay system is a stereotactic radiosurgical device designed specifically to treat diseases
of the eye. This instrumentation incorporates eye tracking, lesion targeting through coupling
to OCT and A-scan ultrasound and gating.
• The IRay is a robotically controlled, noninvasive, low-energy X-ray irradiation therapeutic
platform that delivers highly collimated beams through the inferior pars plana that overlap at
the macula to deliver precise doses of 16 to 24 Gy to a 4 mm spot size on the macula. The entire
patient treatment process requires only a topical anesthetic, and patients are able to leave the
hospital within 15 to 20 minutes of receiving treatment.
• In a Phase 1 study, both treatment-naïve and previously treated patients were enrolled at sites
in Mexico. In total, 3 radiation doses and 4 treatment strategies were employed:
• Ranibizumab at Day 0, 16-Gy IRay treatment between days 1 and 14, ranibizumab at Day 30, and
then monthly evaluation with OCT and quarterly fluoresecein angiography.
• Ranibizumab at Day 0, 24 Gy IRay treatment between days 1 and 14, ranibizumab at Day 30, and
then monthly evaluation with OCT and quarterly fluoresecein angiography.
• Ranibizumab at Day 0, 11 Gy IRay treatment between days 1 and 14, ranibizumab at Day 30, and
then monthly evaluation with OCT and quarterly fluoresecein angiography.
• 16 Gy treatment followed by monthly evaluation with OCT and quarterly fluorescein angiography.
AMD YEAR BOOK 2012

2.2.2 - VEGF Trap
Vascular endothelial growth factor Trap-Eye (VEGF Trap-Eye) is a potent, specific VEGF antagonist
that binds and inactivates circulating VEGF in the extravascular space. It consists of extracellular
portions of VEGF receptors 1 and 2 fused to the Fc portion of human immunoglobulin G. VEGF
Trap-Eye may bind both VEGF-A or PlGF to form an inert 1:1 complex with one of the growth
factors. Thus, VEGF Trap-Eye has broader anti-VEGF activity compared to pegaptanib, which
binds only the VEGF-A165 isoform and ranibizumab, which neutralizes all active isoforms of
VEGF-A, but not PlGF. Moreover, VEGF Trap-Eye has a longer half-life in the eye after intraocular
injection and it binds other members of the VEGF family including placental growth factors 1 and
2, which have been shown to contribute to excessive vascular permeability.
Heier JS, at the last AAO meeting, presented the 1 year results of the CLEAR-IT 2 trial. It is a
multicenter, randomized, double-masked trial designed to evaluate visual and anatomical
outcomes, injection frequency, and safety during the PRN treatment phase of a study evaluating
a 12-week fixed dosing period followed by PRN dosing to week 52 with VEGF Trap-Eye for
neovascular AMD.
The study demonstrated that:
• All VEGF Trap-eye dosing groups were non inferior and clinically equivalent to ranibizumab
dosing monthly for the primary end point on maintenance of vision.
• VEGF Trap-eye dosed 2 mg every two months demonstrated similar efficacy and safety to
ranibizumab monthly dosed.
2.2.3 - Anti-VEGF and anti PDGF-B
PDGF-B regulates the recruitment of pericytes which are required for vessel maturation.
E10030 (Ophthotech) is an antiplatelet derived growth factor aptamer. A phase 1 study
demonstrated the safety of the combination ranibizumab/E10030. This study also showed
a main gain of 14 letters at week 12 in treated patients and that 59% of the enrolled patients
gained 15 or more letters. All patients showed vascular regression. Currently, a phase 2 trial is
recruiting patients with AMD complicated by classic CNVM to test a possible synergistic effect.
AMD YEAR BOOK 2012
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Neovascular AMD
2.2.4 - Anti-VEGF and Anti-Endothelial Cell drug combinations
1. Integrins αυβ3 e α5β1 are upregulated in angiogenesis and integrin α5β1 is also upregulated
in the RPE, macrophages and fibroblasts. Volociximab (Ophthotech) is a human/murine
chimeric monoclonal antibody of α5β1. A phase 1 study is evaluating the safety and efficacy
of the combination ranibizumab/volociximab in the treatment of CNV. At 8 weeks follow-up,
treated patients gained 9.1 letters and mean retinal thickness reduction from 361 to 246 µm.
Authors reported that 23% of patients gained 15 letters or more.
2. Sphingolisine-1 phosphate inhibition by monoclonal antibodies results in inhibition of retinal
neovascularization and CNV in animals with a subsequent reduction of inflammation and
fibrosis.
3. The inhibition of the Nicotin acetylcholine receptor has been demonstrated to successfully
control laser induced CNV in animal models. A phase 1 trial developed to study the effects of
ATG003 (mecamylamine) in combination with ranibizumab is ongoing.
AMD YEAR BOOK 2012

Part. 2
AMD YEAR BOOK 2012
63

Acknowledgments
to the European practitioners
Dr Gabrielle BUITENDIJK (The Netherlands)
Dr Violaine CAILLAUX (France)
Dr Miguel CAsTILLA (Spain)
Dr Valentina sARAO (Italy)
AMD YEAR BOOK 2011
65

Chapter 1
Chapter 2
Chapter 3
Contents
Epidemiology and risk factors of AMD.
Pathogenic mechanisms and genetics.
ARVO 2012
Anita LEys, MD, PhD
AMD: disease progression and imaging.
ARVO 2012
salomon-yves COhEN, MD, PhD
New therapeutic perspectives and
disease management and treatment.
Francesco BANDELLO, MD, FEBO
AMD YEAR BOOK 2012
p. 69
p. 121
p. 143
67

Anita LEys, MD, PhD
Medical Retina, Ophthalmology, University Hospitals Leuven.
Capucijnenvoer 33. 3000 Leuven, Belgium
Anita LEYS is a medical retina specialist at the University
Hospitals Leuven.
She is the author of a thesis entitled
Oogfundusaandoeningen bij Nieraandoeningen
(KU Leuven, 1993) and the author or co-author of a total
of 100 publications and of book chapters on AMD,
radiation retinopathy, eye and renal diseases,
and eye and systemic diseases.
AMD YEAR BOOK 2012
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Chapter 1
Epidemiology and risk factors of AMD.
Pathogenic mechanisms and genetics.
ARVO 2012
Professor Anita LEys (Belgium)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Prevalence of AMD in Japan ................................................................................................................................................... p. 73
Distinct phenotype of AMD identified in AREDS .................................................................................... p. 75
Risk factors for AMD in the Us population .................................................................................................... p. 77
Risk factors of geographic atrophy in the Australian population ................... p. 79
Risk of aspirin use and AMD .................................................................................................................................................. p. 81
subclinical atherosclerosis and AMD ..................................................................................................................... p. 83
Coronary heart disease and AMD ................................................................................................................................. p. 85
Protective role for vitamin D in AMD ........................................................................................................................ p. 87
Lipid metabolites and AMD ......................................................................................................................................................... p. 89
Complement factor h gene in the 1q31-32 chromosomal region
and AMD risk ...................................................................................................................................................................................................... p. 91
ARMs2 gene in the 10q26.13 chromosomal region and AMD risk ..................... p. 93
CX3CR1 fractalkine receptor gene and AMD ................................................................................................ p. 95
AMD susceptibility genes in the Blue Mountains study ...................................................... p. 97
Genome-wide association study identifies 19 loci associated
with AMD ...................................................................................................................................................................................................................... p. 99
Genome-wide environmental interaction study shows that CFD
is implicated in increased risk of AMD in women who have never
taken hormone replacement therapy ............................................................................................................. p. 101
Biomarkers in combination with genomic markers and AMD ............................ p. 103
AMD and protein carriers to transport metals, vitamins and lipids
across Bruch’s membrane .................................................................................................................................................... p. 105
Alu RNA, DICER1 and geographic atrophy ...................................................................................................... p. 107
Genetic determinants of macular pigment optical density ....................................... p. 109
Pharmacogenetics of anti-VEGF therapy .................................................................................................... p. 111
Pharmacogenetics of oral DhA supplementation....................................................................... p. 113
The emergence of translational epidemiology: from scientific
discovery to population health impact ........................................................................................................... p. 115
Bibliography .................................................................................................................................................................................................... p. 117
AMD YEAR BOOK 2012
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1
Prevalence of AMD in Japan
Prevalence of AMD in the Japanese: The Nagahama Study [1]
The Nagahama cohort project has evaluated the prevalence data and AMD characteristics
for 3194 Japanese aged 50 years or older.
Each image was graded using the AREDS severity scale.
The mean age of the population was 62.7 years of which 64.2% was female. Early and late
AMD were present in 21.3% and 0.22% of the population. In 6.6% of the population pigmentary
abnormalities were present.
Soft drusen were present in 41.5% in at least one eye, which were significantly less present
(16.3%, p = 3.18 x 10 -8 ) in high myopia (axial length > 26.0 mm or spherical equivalent = < -6.0 D).
AMD YEAR BOOK 2012
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2
Distinct phenotype of AMD identified
in AREDs
The development of AMD in participants with no or small drusen in
the Age-Related Eye Disease Study (AREDS) [2]
To understand the complex pathophysiology of AMD, investigating the different stages
and subtypes of AMD might provide new insights. The AREDS Study has investigated the
characteristics of study participants with the lowest AMD grade at baseline.
Study participants without any drusen (AREDS category 1) or only small drusen (AREDS
category 2) have a low risk of developing advanced AMD. At baseline, participants with AMD
grade category 1 and category 2 developed large drusen in 6.1% and 22.4% respectively.
After ten years of follow-up 0.54% in the category 1 and 0.66% of the category 2 participants
developed neovascular AMD. No category 1 subjects developed central geographic atrophy,
while 1.22% of the category 2 subjects did develop central geographic atrophy. Participants
who progressed to end-stage AMD demonstrated peripapillary atrophy (30.4% category 1,
20% category 2) and hyperpigmentary changes (17.4% category 1, 40% category 2). This
phenotype is distinctly different from the usual pathway of AMD progression through large
drusen and pigmentary change.
Genotyping will be conducted to determine the role of genetic susceptibility.
AMD YEAR BOOK 2012
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3
Risk factors for AMD in the Us
population
Risk factors for age-related macular degeneration in the US
population: results from the National Health and Nutrition Examination
Survey (NHANES) 2005-2008 [3]
AMD status for population aged 40 or older was determined: of 5604 participants 0.98 %
had late AMD and 6.9% had early AMD.
In the NHANES 2005-2008 data significant association of any AMD was observed with
age, body mass index, systolic and diastolic blood pressure, LDL, total cholesterol,
c-reactive protein, current smoking status, and history of cardiovascular disease
(history of myocardial infarction, stroke, congestive heart failure, coronary heart
disease and angina).
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4
Risk factors of geographic atrophy
in the Australian population
Risk characteristics associated with development of geographic
atrophy: the Blue Mountains Eye Study Cohort [4]
In the Blue Mountains Eye Study n = 3654 were free of geographic atrophy (GA) at baseline.
Incident pure GA (excluding neovascular cases) was confirmed in 61 participants with an
overall 15-year incidence of 3.8%. Risk factors identified within this study were age (OR 1.2;
CI 1.2-1.3), current smoking (OR 4.8; CI 2.0-11.6), the CFH (OR 1.6; CI 1.0-2.6 per risk allele) and
ARMS2 Genes (OR 2.6; CI 1.5-4.4 per risk allele).
Soft drusen predicted the highest GA risk of all early AMD lesion characteristics.
AMD YEAR BOOK 2012
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5 Risk of aspirin use and AMD
The association of aspirin use with age-related macular
degeneration in AREDS2 [5]
The EUREYE Study recently published an association of aspirin use with advanced AMD. [6]
Frequent aspirin use was associated with early AMD and wet AMD and ORs rose with increasing
frequency of consumption. For daily aspirin users the ORs adjusted for potential confounders
showed a steady increase with increase of severity of AMD grades. ORs were in grade 1 1.26
(p < 0.001), in grade 2 1.42 and in wet AMD 2.22. In the AREDS2 Study the association of aspirin
use with AMD was recently evaluated in 4.188 participants with complete data (gradable fundus
photographs and status of aspirin use). Of these 2046 (48.8%) are taking aspirin at least 5
times a week. Participants with the AREDS Simple Scale Score of 0.1 and 2 were grouped together
(n = 661) as the control group. Participants with AREDS Simple Scale Score of 3 (SSS-3) (bilateral
large drusen or pigmentary change in one eye; n = 692), 4 (SSS-4) (bilateral large drusen and
bilateral pigmentary changes; n = 1369), and 5 (advanced AMD in one eye with bilateral large
drusen and pigmentary changes; n = 1466) were compared with the control group. Analysis
showed an inverse relationship between the stages of AMD with aspirin use (table 1); SSS-
3 OR 0.82 (0.65-1.02); SSS-4 OR 0.86 (0.70-1.05); advanced AMD OR 0.62 (0.50-0.76) adjusted
for all potential confounders. Both neovascular as central geographic atrophy were inversely
associated with aspirin use; OR 0.61 (0.49-0.75) and OR 0.62 (0.42-0.94) respectively. There
was a significant protective effect found for aspirin use and advanced AMD in the AREDS2 Study.
Table 1: Association aspirin use and AMD status in the AREDs2 study
AMD status
Odds ratios (95% Confidence intervals)
Adjusted age and sex Adjusted potential confounders*
AREDS simple scale score 3
0.84 (0.68-1.05)
0.82 (0.65-1.02)
AREDS simple scale score 4
0.87 (0.72-1.06)
0.86 (0.70-1.05)
AREDS simple scale score 5
0.70 (0.57-0.84)
0.62 (0.50-0.76)
Neovascular AMD
0.70 (0.57-0.85)
0.61 (0.49-0.75)
Central geographic atrophy
0.71 (0.49-0.91)
0.62 (0.42-0.94)
* potential confounders are: age, sex, smoking, cardiovascular disease, other medication use
E. Chew concluded at ARVO 2012 that the findings from the EUREYE Study could not
be replicated in data of AREDS1 and AREDS2. As previous studies have demonstrated
inconsistent results of the association, future analysis of the incident of advanced AMD
in AREDS2 is useful to provide further insight into this area. In the discussion of the
paper, P. Mitchell confirmed that a recent and unpublished analysis of aspirin use in
the Blue Mountains Study pointed to similar findings as EURETINA with aspirin-AMD
association.
AMD YEAR BOOK 2012
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6 subclinical atherosclerosis and AMD
The relationship of carotid artery intima-media layer thickness and
plaque to the 10-year incidence of age-related macular degeneration
in a population-based study [7]
Klein et al. has found an association of subclinical atherosclerosis with 10-year incident early
AMD and late AMD, independent of systemic and genetic risk factors.
There was no association with history of angina, myocardial infarction or stroke. Further
research could focus on interventions of lipid or inflammatory pathways associated
with the pathogenesis of atherosclerosis protects against developing AMD.
AMD YEAR BOOK 2012
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7
Coronary heart disease and AMD
Age-related macular degeneration and coronary heart disease:
evaluation of genetic and environmental associations [8]
Keilhauer-Strachwitz et al. studied the association of coronary heart disease and AMD in a
case-control study.
They found that a history of coronary heart disease (CHD) was inversely associated with the
onset age of AMD: AMD patients with a history of CHD developed AMD-symptoms significantly
later in life than those without a history (p = 0.015). History of stroke or hypertension was
not associated with the age of onset of AMD. AMD patients with homozygous variations in CFH
and ARMS2 variants and smokers < 20 pack/years were significantly earlier affected by AMD
(CFH hom: p = 0.019; ARMS2 hom: p = 0.00063; smokers: p = 0.00001) than patients without
these risk factors.
AMD YEAR BOOK 2012
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8
Protective role for vitamin D in AMD
Vitamin D reduce retinal inflammation and clears amyloid beta
[9, 10]
systemically in aged mice
Vitamin D has been linked epidemiologically to protection against AMD [11, 12] . To understand
the mechanisms, experiments have been done in aged wild type mice treated with vitamin D3
[9, 10] . The aged mice treated for 6 weeks with vitamin D showed significant reductions in retinal
inflammation, in levels of amyloid beta accumulation, and in retinal macrophage numbers with
shifts in their morphology. Moreover, significant improvement in visual function was observed
compared to non-treated mice.
The photoreceptor outer segments appeared clean with a relatively regular alignment (figure 1).
Figure 1:
Scanning electron microscopy of outer
segments debris accumulation.
Debris of accumulation on outer segments
was lower in vitamin D3 treated
mice. RPE orientated top.
Scale = 2 μm.
AMD YEAR BOOK 2012
CTRL Vit. D3
Immunohistochemistry revealed that levels of a pro-inflammatory cytokine, TNF-alpha, were
significantly reduced in the treated animals. The amyloid-beta levels in blood vessels both in
retina and aorta were reduced in the vitamin D3 treated mice.
The authors conclude that vitamin D3 has a protective effect on inflammation and
supplementation may be helpful in reducing the risk of developing AMD especially in
patients with vitamin D insufficiency.
87

Protective role for vitamin D in AMD
Vitamin D insufficiency in neovascular versus non-neovascular
age-related macular degeneration [13]
Itty et al. have retrospectively studied serum vitamin D levels of all patients who had levels
measured and were diagnosed with either neovascular AMD (n = 71) or non-neovascular AMD
(n = 80) between 1996 and 2011. Vitamin D levels demonstrate a trend towards lower mean
levels in patients with neovascular AMD compared to non neovascular AMD.
Vitamin D insufficiency was noted more commonly in the neovascular AMD group. Clinically
significant vitamin D insufficiency (25-hydroxy vitamin D in serum < 20 ng/ml) was significantly
more prevalent in the neovascular AMD group (p = 0.004).
The authors suggest a potential interest for vitamin D testing and supplementation in
patients with AMD.
Correlation of osteoporosis and incidence of skin cancers and AMD
grade in the Irish Nun Eye Study population [14]
The Irish Nun Eye Study (INES) has investigated the relationship of osteoporosis (marker of
low vitamin D levels and potential UV exposure), skin cancer (marker for high UV exposure),
type of therapy for osteoporosis and AMD grade [12] .
No significant correlation (p = 0.56) for AMD severity and markers of low vitamin D levels
(osteoporosis) were found. There was also no correlation of AMD grade with the presence of
skin cancer (p = 0.642) and AMD grade with type of therapy for osteoporosis (p = 0.55).
AMD YEAR BOOK 2012

9
Lipid metabolites and AMD
Lipid metabolites in the pathogenesis and treatment of neovascular
eye disease [15]
The biological role of lipids and lipid metabolism is not restricted to energy storage and
membrane structure. Results from animal studies and clinical trials suggest that lipid-based
mediators are likely to emerge as a novel group of modifiable variables in neovascular disease.
In AMD and diabetes, dysregulation of lipid metabolism is closely associated with disease
onset and progression. In the same diseases, some lipids and their metabolites can exert
beneficial effects. Excess dietary intake of omega-6 PUFAs seems to be associated with
an increased risk of neovascular AMD, and omega-3 PUFAs appear to be associated with a
reduced risk of AMD.
According to the authors, whether the optimal approach for effective lipid-based
treatments will lie in supplementation of beneficial substrates such as omega-3 PUFAs
or rather in the selective use of beneficial lipid metabolites or enzyme inhibitors will
largely depend on ongoing research aimed at identifying the specific lipid metabolites
that convey beneficial effects in retinopathy. Lipid mediators can play important roles
in both pathogenesis and treatment of neovascular disease.
Plasma omega-3 fatty acids and the risk for AMD: the ALIENOR Study
[16, 17]
In this prospective population-based study on nutrition and AMD, an inverse association of
late AMD with plasma omega-3 PUFA was observed, consistent with previous observations
concerning dietary intakes. [14]
Adjustment was done for potential confounders (age, gender, smoking, education, physical
activity, plasma HDL-cholesterol, plasma triglycerides, fruit consumption, CFH Y402H, apoE4
and ARMS2 A69S polymorphisms and follow-up time).
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10
Complement factor h gene in the
1q31-32 chromosomal region and
AMD risk
Does age modify associations with complement factor H in agerelated
macular degeneration? [18]
Complement factor H shows very strong association with AMD.
Recent data suggest that multiple causal variants are associated with disease [19] . Common
and rare deletions, duplications, and rearrangements are complex phenomena mediating
susceptibility and protection. Moreover, risk may change during life according to data of
Adams et al. In their study, differences were seen in genotype frequency for five tested
SNPs (Single Nucleotide Polymorphism) in the CFH gene, across different age groups. In
controls without AMD (48-86 years) increasing prevalence of the wild type without risk
was observed with increasing age. In AMD associations were strongly modified by age group
with for some SNP inverse relationship and for other SNP positive relationship. Odds ratios
for risk homozygotes for each SNP ranged from 0.37 to 0.48 in younger age groups, and from
1.87 to 2.8 in older age groups.
The authors concluded that the reversal of genetic associations with increasing age has
important implications for predictive models for AMD. So far, these models extrapolated
risks from older cohorts, and did not stratify by age, as they assumed homogeneity of
risk across all age groups, which in fact may not exist.
Genetic association of glucose transporter type 1 variants with
age-related macular degeneration and its direct interaction with
complement factor H at the protein level [20]
Glucose transporter type 1 (GLUT1/SLC2A1) is the key glucose transporter of the blood-retina
barrier and has been identified as a binding partner of complement factor H (CFH) and engages
CFH in the retinal pigment epithelium cells.
Genetic association of GLUT1 polymorphisms (SNP rs3768029) with AMD (n = 1.888 AMD and
n = 954 controls) showed ORs of 1.339 (95% CI 1.113-1.611; p = 00.001) and 1.344 (95% CI
1.067-1.694; p = 0.01) for the CT and TT carrier genotypes compared with the CC reference
genotype.
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11
ARMs2 gene in the 10q26.13
chromosomal region and AMD risk
The ARMS2 A69S variant and bilateral advanced AMD [21]
To identify genetic associations between specific risk genes and bilateral advanced AMD a
retrospective, observational case study was conducted with 173 patients with GA in at least
one eye and 830 patients with CNV in at least one eye. In this series, in patients with GA or
CNV in at least one eye, the ARMS2 A69S substitution was strongly associated with GA or CNV
in the fellow eye.
The authors conclude that ARMS2 A69S substitution may serve as a marker for bilateral
AMD.
Heritability and genome-wide association study to assess genetic
differences between advanced AMD subtypes [22]
A sibling correlation study and genome-wide association study (GWAS) has been conducted to
investigate whether CNV and GA segregate separately in families and to identify which genetic
variants are associated with these 2 subtypes of AMD.
For the sibling correlation study, 209 sibling pairs with advanced AMD were included. For the
GWAS, 2594 participants with advanced AMD subtypes and 4134 controls were included.
Replication cohorts included 5383 advanced AMD participants and 15240 controls. For the
GWAS, genome-wide genotyping was conducted and 6036699 single nucleotide
polymorphisms (SNPs) were imputed. The most significant associations were evaluated in
independent cohorts. In siblings of probands with CNV or GA, the same advanced subtype is
more likely to develop (p = 4.2 x 10-5).
Conclusion of the GWAS Study was that the ARMS2/HTRA1 locus (rs 10490924) confers
increased risk for both advanced AMD subtypes but imparts greater risk for CNV than
for GA (OR 1.38; p = 7.4 x 10-14).
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ARMS2 gene in the 10q26.13
chromosomal region and AMD risk
ARMS2 association with the mitochondrial outer membrane is
reduced in RPE cells exposed to oxidative stress and in AMD [23]
The ARMS2 locus in the 10q26.13 chromosomal region has been consistently associated with
AMD. The localization of the ARMS2 protein has been controversial and since it is only expressed
in primates functional characterization has been difficult.
Boulton et al. investigated normal and AMD donor eyes and immunolabeled the tissues for
ARMS2 [24] . Immunohistochemistry and immunoelectron microscopy showed that AMRS2 was
primarily localized to the mitochondrial outer membrane and also located in the cytosol of the
RPE cells. The distribution of ARMS2 showed cell to cell variation; in normal tissue approximately
85% of the mitochondria were positive for ARMS2, while the remaining mitochondria had no
AMRS2 association.
AMD tissue showed no overall change in ARMS2 expression in the RPE cells, but there
were a decreased amount of positive mitochondria for AMRS2. The investigators also
studied primary human RPE cultures: exposure of cultured RPE cells to acute oxidative
stress resulted in reduced ARMS2 expression and like in AMD there was a reduced
association of ARMS2 with mitochondria.
AMD YEAR BOOK 2012

12
CX3CR1 fractalkine receptor gene
and AMD
A prospective study of common polymorphisms in CX3CR1 and risk
of age-related macular degeneration (AMD) [24]
The CX3CR1 fractalkine receptor genes have been implicated as a candidate for AMD. Abnormal
RPE cells, drusen-like accumulation, photoreceptor atrophy and choroidal neovascularization
have been reported in the Ccl2/Cx3cr1-deficient mouse [25] . The Ccl2 gene encodes the proinflammatory
chemokine Ccl2 (MCP-1), which is responsible for chemotactic recruitment
of monocyte-derived macrophages to sites of inflammation. The CX3CR1 gene encodes the
fractalkine receptor CX3CR1 and is required for accumulation of monocytes and microglia
recruited via CCL2. Chemokine-mediated inflammation is implicated in retinal degenerative
diseases including AMD.
Schaumberg et al. could not find an association for AMD with common variants in CX3CR1 gene,
but identified significant interactions for neovascular AMD between CX3CR1 variants (T280M,
V249I or rs2669845) and C3, ARMS2 and, obesity [20] .
The T280M polymorphism of the CX3CR1 has also been tested in a large French case-control
study by Zerbib et al. [26] .
In this population there was no association between the risk variant and exudative AMD.
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13
AMD susceptibility genes in the
Blue Mountains study
Age-related macular degeneration susceptibility genes in an older
Australian population: comparison of distributions and clinical
significance of two major genes with other known genes [27]
The investigators of the Blue Mountains Study compared distribution and clinical significance
between the 3 single nucleotide polymorphisms (SNPs) of the CFH and ARMS2 (major) genes
and 9 SNPs of other reported AMD related (non-major) genes (COL8A1, CFI, C2FB, VEGFA, COL10A1,
TNFRSF10A, LIPC, CETP, SYN3) in an older Australian population (n = 2534). Over 70% of this
general population had 2+ risk alleles in the major susceptibility genes CFH and ARMS2, and
over 90% 4+ risk alleles in the known non-major genes.
Risk for developing late AMD was robust for the major susceptibility carriers, but not
significant for the non-major gene carriers.
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14
Genome-wide Association study
identifies 19 loci associated with
AMD
Meta-analysis of genome-wide association studies identifies 19 loci
associated with AMD risk [28]
In an AMD gene meta-analysis, including 7.650 advanced cases and 51.812 controls from 15
study samples of European and Asian ancestry, 19 loci were confirmed with evidence of
genome-wide significance (p-values ranging from 4 x 10 -540 - 2 x 10 -8 ). Of these 19 loci, 12
were previously established AMD risk loci which were confirmed in this study and revealed
7 other loci: COL8A1/FILIP1L (p = 4 x 10 -13 ), IER3/DDR1 (p = 2 x 10 -11 ), SLC16A8 (p = 3 x 10 -11 ),
TGFBR1 (p = 3 x 10 -11 ), RAD51B (p = 9 × 10 -11 ), MIR548A2 (p = 5 x 10 -9 ) and B3GALTL (p = 2 x 10 -8 ).
Pathway analysis of the 19 loci revealed a significant over-representation of pathways
regulating complement system activity, lipid metabolism and inhibition of angiogenesis.
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15
Genome-wide environmental
interaction study shows that CFD is
implicated in increased risk of AMD
in women who have never taken
hormone replacement therapy
Genome-wide Interaction Analysis of exogenous estrogen in agerelated
macular degeneration (AMD) implicates CFD [29]
Previous studies found that women who take exogenous estrogen in the form of hormone
replacement therapy (HRT) have reduced risk of AMD. In a genome-wide interaction study the
investigators aimed to detect novel genes for AMD by accounting for interactions with estrogen.
For women who have never taken HRT, a suggestive association with AMD was found for
Complement Factor D (CFD, rs3826945: OR = 0.30, p = 4.39 x 10 -5 ).
CFD is a member of the alternative complement pathway, but its association with AMD has
been equivocal. It was recently reported that associations for CFD SNPs and AMD or CFD plasma
concentrations were mostly restricted to women [30] .
The results of this genome-wide interaction study support this finding and suggest
exogenous estrogen as a mediator of CFD’s effect. This also demonstrates how genomewide
environmental interaction studies can implicate additional genes for complex traits
that have been missed in studies of genetic main effects.
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16
Biomarkers in combination with
genomic markers and AMD
Carboxymethyllysine and pentosidine with genotype as predictors
of AMD [31]
Genomic markers alone are insufficient for prognosis, as many carriers of AMD risk genotypes
never develop AMD. Biomarkers may help us predict which person will develop AMD. In
combination, genomic markers and the biomarkers carboxymethyllysine (CML), pentosidine,
and carbocyethypyrrole (CEP) significantly improve AMD risk predictions. When plasma levels
of CEP, CML or pentosidine are combined with genotype of CFH Y402H, ARMS2 A69S, C3 R80G and
HTRA rs11200638, the risk of developing AMD was more precise. Risks were 2-5 times higher
using data on these biomarkers than based on genotype alone (p < 0.001).
Metabolic Profiling Can Distinguish AMD Patients from Controls [32]
The study team investigated if metabolic profiles can distinguish patients with neovascular agerelated
macular degeneration (NVAMD) from similarly-aged controls.
Metabolic profiling, a technique in which thousands of metabolites are simultaneously quantified
and grouped by biochemical pathway, provides a comprehensive analysis of an individual’s
environmental exposures. The investigators compared the metabolic profile from 26 NVAMD
patients and 19 controls. All participants were genotyped for rs1061170 (Y402H) in complement
factor H (CFH), a known genetic risk factor for AMD. Ninety-four distinct features were significantly
different between NVAMD patients and controls. Linear discriminant analysis showed the ability
to separate metabolites related to NVAMD from those related to controls with 99.1% accuracy.
Additionally, 34 of the NVAMD-related metabolites were associated with either CFH CC (n = 18) or
CFH TC+TT (n = 16) genotypes. The study results suggest that a panel of individual metabolites
may be differentially regulated in AMD patients and controls. This type of comprehensive,
quantitative analysis strengthens the ability to evaluate environmental contributions to AMD risk.
The authors conclude that the combination of metabolic and genotype data holds
significant promise for the identification of clinically-relevant biomarkers for AMD.
Serum biomarkers of inflammation and age-related macular
degeneration severity [33]
S100B has been identified as a potential biomarker for AMD. It was significantly associated
with AMD stage (p = < 0.001) and correlated with sRAGE. S100B-RAGE interactions have
been demonstrated to play a role in inflammation-mediated outer retinal pathology and
angiogenesis.
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17
AMD and protein carriers to
transport metals, vitamins and
lipids across Bruch’s membrane
Albumin diffusion across human Bruch’s membrane: modulation by
ginseng compound [34]
Most metals, vitamins and lipids are carried across Bruch’s membrane bound to protein carriers
similar in size to the albumin molecule.
Ageing is associated with a decline in macromolecule transport. The potential use of ginseng
compounds to improve the macromolecular transport pathway has been assessed by Kang
et al.
The investigators have shown that ginseng compounds can improve the trafficking of
carrier sized protein molecules like albumin across Bruch’s membrane.
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18
Alu RNA, DICER1 and geographic
atrophy
Alu elements are the most common small interspersed repetitive elements in the human genome.
Alu repeats affect the genome in several ways, causing insertion mutations, recombination
between elements, gene conversion and alterations in gene expression [35] .
J. Ambati and his team reported that in the RPE Alu RNA accumulation is implicated in geographic
atrophy and that the accumulation is due to deficit of the microRNA-processing enzyme DICER.
[36] . The RNase DICER1 maintains RPE cells healthy by regulating the expression of toxic Alu RNA
transcripts. DICER1 dysregulation induces Alu RNA accumulation and thereby leads to RPE cell
degeneration in geographic atrophy.
The mechanism of Alu RNA-induced toxicity and RPE cell degeneration has recently been
investigated by this team [37] . In mice, DICER1 deficit or Alu RNA exposure activates the NLRP3
inflammasome and triggers MyD88 signaling via IL18 in the RPE. Genetic or pharmacological
inhibition of inflammasome components (NLRP3, Pycard, Caspase-1), MyD88, or IL18 prevents
RPE degeneration induced by DICER1 loss or Alu RNA exposure. In human GA, RPE cells contain
elevated amounts of NLRP3, PYCARD and IL18 and there was increased activation of Caspase-1
and MyD88. The combined data from mice and humans, provide a rationale for targeting this
pathway in GA.
At ARVO 2012 different aspects of this study were discussed:
• Reactive oxygen species and P2X 7 receptors are critical for Alu RNA induced RPE degeneration
by NLRP3 inflammasome [38] .
• Dicer protects RPE cells by regulating Caspase-1 and Myd88 activation [39] .
• Alu-RNA-induced cytotoxicity in age-related macular degeneration is mediated by Myd88,
but not by a variety of RNA [40] .
• Dicer dysregulation, Alu RNA accumulation and inflammasome activation in human GA eye.
• Dicer protects RPE cells by regulaiong Caspase-1 and Myd88 activation [41] .
• Alu RNA induces RPE degeneration via Il18-Myd88-Caspase-3 signaling [42] .
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19
Genetic determinants of macular
pigment optical density
Genetic determinants of macular pigment optical density in the
Carotenoids in Age-Related Eye Diseases Study CAREDS Study [43]
The investigators of the CAREDS Study identified in their participants variation in genes related
to the metabolism or uptake of carotenoids and to lipoprotein trafficking.
These variations predicted inter-individual variation in macular pigment optical density in the
postmenopausal women of their study, and was independent of dietary intake of lutein and
zeaxantine. These genetic variants could explain, in part, the variation in retinal response to
dietary lutein and zeaxantin, and could increase the risk for AMD.
The six genes associated with macular pigment optical density were: 3 genes (5 SNPs)
related to HDL levels or cholesterol transport (ABCA1, ABCG5, LIPC), the gene SCARB1
(3 SNPs), which encodes a plasma membrane scavenger lipoprotein receptor which
has been related to carotenoid uptake, the gene RPE65 (2 SNPs), which encodes a
retinoid binding protein in the retinoid visual cycle, and the gene BCMO1 (4 SNPs), which
encodes a pro-vitamin A carotenoid clevage enzyme.
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20
Pharmacogenetics of anti-VEGF
therapy
Pharmacogenetics of anti-VEGF therapy in the Comparison of AMD
Treatments Trials (CATT) [44]
The pharmacogenetic relationship was evaluated between genotypes of single nucleotide
polymorphisms (SNPs) known to be associated with AMD and response to treatment with
ranimizumab or bevacizumab for neovascular AMD.
In the CATT trials, there was no evidence that specific alleles for CFH, ARMS2, HTRA1 and
C3 predict response to anti-VEGF therapy.
Cumulative effect of high risk alleles in CFH, ARMS2 and VEGF
on response to ranibizumab treatment in age-related macular
degeneration [45]
The investigators evaluated the impact of high-risk alleles in CFH and ARMS2 and SNPs in
VEGF, VEGF receptor KDR and genes involved in angiogenesis (LRP5, FZD4) on response to
ranibizumab treatment and on the age of treatment onset. In contrast to previous studies,
they stratified the data according to the number of high-risk alleles to enable to study the
combined effects of these genotypes. After ranibizumab treatment, AMD patients without
high-risk alleles in CFH and ARMS2 genes demonstrated a mean VA improvement of 10.5 ETDRS
letters while no VA gain was observed in the carriers of all four CFH and ARMS2 high risk
alleles (p = 0.009). Carriers of 4 risk alleles in the CHF and ARMS2 genes were also
significantly younger at the onset of treatment than the carriers of 3 high-risk alleles
(p = 0.008) and 5.3 years younger than the AMD carriers of 1 or 2 risk alleles (p < 0.0001).
Adding VEGF SNP to the model demonstrated a significant decrease of the age at treatment
onset. The mean age at which the first ranibizumab treatment was carried out among the
carriers of all 6 high-risk alleles in CHF, ARMS2 and VEGF was 70.2 years versus 80.2 years
in the AMD carriers of none or one high-risk allele (p < 0.0001). Compared to the carriers of
0.1 risk allele, carriers of all 6 risk alleles demonstrated a mean visual loss of 20.5 ETDRS
letters (p < 0.0001).
The authors claim to have evaluated the largest pharmacogenetic AMD cohort and they
conclude that a cumulative effect of high-risk alleles in CFH, ARMS2 and VEGF may lead to
a younger age of onset in combination with bad response rates to ranibizumab treatment
and thus to a more aggressive form of AMD.
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21
Pharmacogenetics of oral DHA
supplementation
The NAT-2 Study: genetic analysis [46]
Oral DHA (840 mg/day) had the same effect on 3-year CNV incidence as placebo (olive oil) in
the NAT-2 (Nutritional AMD treatment-2) Study.
However, CNV incidence appeared markedly reduced in DHA supplemented patients with the
highest EPA-DHA index.
A significant effect of DHA was observed in patients without CFH at risk allele. No
differences were found with the ARMS2 polymorphism.
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22
The emergence of translational
epidemiology: from scientific discovery
to population health impact
Translational research in AMD [47]
Epidemiology has the role to provide data to help translate initial basic discoveries into clinical
and public health applications.
This translation implies an integrative genomics approach to efficiently identify AMD-associated
targets (receptors, transporters, and enzymes) impacted by bioactive molecules (nutrients,
FDA-approved drugs, and their metabolites).
Translational research in AMD for development or evaluation of molecules requires
feasibility for streamlined testing in model systems and clinical populations.
AMD YEAR BOOK 2012
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23
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370: Program number 3807-A421.
2. Shih G.C, Nigam E, Agron E, Chew EY. The development of AMD in participants with no or small drusen in the
Age-Related Eye Disease Study (AREDS). ARVO 2012; 125: Program number 847-D785.
3. Wagley S, Gautam S, Arroyo JG. Risk factors for age-related macular degeneration in the US population:
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4. Joachim N. Mitchell P, Kifley A, Wang JJ. Risk characteristics associated with development of geographic
atrophy: The Blue Mountains Eye Study Cohort. ARVO 2012; 215: Program number 1327.
5. Chew EY, Clemons TE, Gensler G, Age-Related Eye Disease Study 2 (AREDS2) Research Group. The association
of aspirin use with age-related macular degeneration in AREDS2. ARVO 2012; 215: Program number 1325.
6. De Jong PT, Chakravarthy U, Rahu M, et al. Associations between aspirin use and aging macula disorder:
the European Eye Study. Ophthalmology 2012; 119: 112-8.
7. Klein R, Cruckshanks KJ, Myers C, et al. The relationship of carotid artery intima-media layer thickness and
plaque to the 10-year incidence of age-related macular degenration in a population-based study. ARVO 2012;
215: Program number 1326.
8. Keilhauer-Strachwitz, CN,Al-Khaled K, Menger JF et al. Age-related macular degeneration and coronary heart
disease: Evaluation of genetic and environmental associations. ARVO 2012; 316: Program number 2933-A378.
9. Lee V, Hoh Kam L, Jeffrey G. Vitamin D reduce retinal inflammation and clears amyloid beta systemically in
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10. Lee V, Rekhi E, Kam JH, Jeffery G. Vitamin D rejuvenates aging eyes by reducing inflammation, clearing
amyloid beta and improving visual function. Neurobiol Aging 2012; PMID 22217419.
11. Seddon JM, Reynolds R, Shah HR, Rosner B. Smoking, dietary betaine, methionine, and vitamin D in monozygotic
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12. Morrison MA, Silveira AC, Huynh N et al. Systems biology-based analysis implicates a novel role for vitamin D
metabolism in the pathogenis of AMD. Hum Genomics 2011; 5: 538-68.
13. Itty S, Vajzovic I, Day S, Mruthynjaya P. Vitamin D insufficiency in neovascular versus non-neovascular age-
related macular degeneration. ARVO 2012; 465: Program number 5182-D1235.
14. Moore E, Silvestri V, Stevenson M, Silvestri G. Correlation of osteoporosis and incidence of skin cancer and
AMD grade in the Irish Nun Eye Study population. ARVO 2012; 547: Program number 6516-A518.
15. Stahl A, Krrohne TU, Sapieha P et al. Lipid metabolites in the pathogenesis and treatment of neovascular eye
disease. Br J Ohthalmol 2011; 95: 1496-1501.
16. Merle B, Delyfer MN, Korobelnik JF, et al. Dietary omega-3 FA and the risk for ARM: the ALIENOR Study. IOVS
2011; 52: 6004-11.
17. Merle B, Delyfer MN, Korobelik JF, et al. Plasma omega-3 fatty acids and the risk for age-related macular
degeneration: the ALIENOR Study. ARVO 2012; 370: Program number 3813-A427.
18. Adams MK, Simpson JA, Robman L, et al. Does age modify associations with complement factor H in age-
related macular degeneration? ARVO 2012; 215: Program number 1324.
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macular degeneration. PloS one 2011; 6: e25598.
20. Kortvely E, Den Hollander AI, Gorza M, et al. Genetic association of glucose transporter type 1 variants with
age-related macular degeneration and its direct interaction with complement factor H at the protein level.
ARVO 2012; 546: Program number 6483-A409.
21. Schwartz SG, Agarwal A, Kovach JL et al. The ARMS2 A69 S variant and bilateral advanced AMD. Retina 2012;
PMID 22481475.
22. Sobrin L, Ripke S, Yu Y, et al. Heritability and genome-wide association study to assess genetic differences
between advanced AMD subtypes. Ophthalmology 2012; PMID 22705344.
23. Boulton ME, Qi X, Kanda A, et al. ARMS2 association with the mitochondrial outer membrane is reduced in
RPE cells exposed to oxidative stress and in AMD. ARVO 2012; 476: Program number 5301.
24. Schaumberg DA, et al. A prospective study of common polymorphisms in CX3CR1 and risk of age-related
macular degeneration (AMD). ARVO 2012; 215: Program number 1321. 8.
25. Zhou Y, Sheets KG, Knott EJ, et al. Cellular and 3D optical coherence tomography assessment during the
initiation and progression of retinal degeneration in the Ccl2/Cx3cr1-deficient mouse. Exp Eye Res 2011; 93:
636-4.
26. Zerbib J, Puche N, Richard F, et al. No association between the T280M polymorphism of the CX3CR1 gene
and exudative AMD. Experimental Eye Research 2011; 93: 382-386.
27. Wang JJ, Rochtchina E, Attia J, et al. Age-related macular degeneration susceptibility genes in an older
Australian population: comparison of distributions and clinical significance of two major genes with other
known genes. ARVO 2012; 215: Program number 1322.
28. Shu MC, Chen W, Fritsche LG, et al. Meta-analysis of genome-wide association studies identifies 19 loci
associated with AMD risk. ARVO 2012; 278: Program number 2259.
29. Courtenay MD, Naj AC, Cade WH, et al. Genome-wide interaction analysis of exogenous estrogen in age-
related macular degeneration (AMD) implicates CFD.
30. Stanton CM, Yates JR, den Hollander AI, et al. Complement factor D in age-related macular degeneration. IOVS
2011; 52: 8828-34.
31. Crabb JW, Jang GF, Zhang L, et al. Carboxymethyllysine and pentosidine with genotype as predictors of
AMD. ARVO 2012; 304: Program number 2715.
32. Brantley MA, Osborn MP, Park Y, et al. Metabolic profiling can distinguish AMD patients from controls. ARVO
2012; 280: Program number 2270.
33. Hogg RF, Glenn J, Dasari S, et al. Serum biomarkers of inflammation and age-related macular degeneration
severity. ARVO 2012; 316: Program number 2929-A374.
34. Kang MY, Sim CM, Seok JH, et al. Albumin diffusion across human Bruch’s membrane: modulation by
ginseng compounds. ARVO 2012; 215: Program number 1595-A548.
35. Batzer MA, Deininger PL. Alu repeats and human genomic diversity. Nat. Rev genet 2002; 3: 370-9.
36. Kaneko H, Dridi S, Tarallo V, et al. DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration.
Nature, 2011; 471: 325-30.
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37. Tarallo V, Hirano Y, Gelfand BD, et al. DICER1 loss and Alu RNA induce age-related macular degeneration via
the NLRP3 inflammasome and MyD88. Cell 2012; 149: 847-59.
38. Kerur N, Tarallo V, Hirano Y, et al. Reactive oxygen species and P2X7 receptors are critical for Alu RNA induced
RPE degeneration by NLRP3 inflammasome. ARVO 2012;546: Program number 6491-A417.
39. Fowler BJ, Hirano Y, Tarallo V, et al. Dicer protects RPE cells by regulating Caspase-1 and Myd88 activation.
ARVO 2012; 304: Program number 2718.
40. Hirano Y, Tarallo V, Gelfand B, et al. Alu-RNA-induced cytotoxicity in age-related macular degeneration is
mediated by Myd88, but not by a variety of RNA. ARVO 2012; 292: Program number 2588-D966.
41. Dridi S, Tarallo V, Gelfand F, et al. Dicer dysregulation, Alu RNA accumulation and inflammasome activation in
human GA eye. ARVO 2012; 231: Program number 1606-A559.
42. Tarallo V, Hirano Y, Gelfand BD, et al. Alu RNA indudec RPE degeneration via Il18-Myd88-Caspase-3 signaling.
ARVO 2012. Program number 6471-A397.
43. Meyers KJ, Johnson EJ, Iyengar SK, et al. Genetic determinants of macular pigment optical density in the
Carotenoids in Age-Related Eye Diseases Study. ARVO 2012; 215: Program number 1323.
44. Hagstrom SA, Ying GS, Pauer GJ, et al. Pharmacogenetics of anti-VEGF therapy in the Comparison of AMD
Treatments Trials (CATT). ARVO 2012; 364: Program number 3682.
45. Smailhodzic D, Muther P, Chen JC. Cumulative effect of high risk alleles in CFH, ARMS2 and VEGF on response
to ranibizumab treatment in age-related macular degeneration. ARVO 2012; 316: Program number 2934.
46 Souied EH, Delcourt C, Puche N, et al. The NAT-2 Study: genetic analysis. ARVO 2012; 364: Program number 368.
47. SanGiovanni JPP. Translational research in AMD. ARVO 2012; 255: Program number 1744.
AMD YEAR BOOK 2012
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salomon-yves COhEN, MD, PhD
Centre Ophtalmologique d’Imagerie et de Laser,
11 rue Antoine Bourdelle, 75015 Paris
Resident and Fellow, Medical Retina, University of Creteil
(Pr Coscas).
In Charge of the AMD clinics, Lariboisière Hospital, Paris
(Pr Gaudric).
Master in Biology of Vessels, PhD in Neurosciences.
Member of the European Board of Ophthalmology.
Author of textbooks on Fluorescein Angiography,
Indocyanine Green Angiography, AMD, Low-Vision
Rehabilitation.
Author of more than 80 papers published in peer
reviewed journals.
Achievement award 2003, American Academy of
Ophthalmology.
AMD YEAR BOOK 2012
121

Chapter 2
AMD:
disease Progression and Imaging: ARVO 2012
Age-Related Maculopathy (ARM) - soft Drusen
Doctor salomon-yves COhEN (France)
1
Age-Related Maculopathy (ARM) - soft Drusen ................................................................................. p. 125
1.1 What’s new in natural history of soft drusen? ............................................................................................................................ p. 125
1.2 Towards multimodal imaging of soft drusen? .............................................................................................................................. p. 125
2
Age-Related Maculopathy-Reticular Pseudodrusen .................................................................. p. 127
2.1 How is the choroid in reticular pseudodrusen, and what implications
concerning their origin? ......................................................................................................................................................................................... p. 127
2.2 What are the relationships between reticular pseudodrusen and geographic atrophy?.......... p. 127
3
Geographic Atrophy ................................................................................................................................................................................. p. 129
3.1 What are the general and local risk factors for geographic atrophy? .............................................................. p. 129
3.2 How does Geographic Atrophy progress? ........................................................................................................................................ p. 129
3.3 Is Near Infrared useful in Geographic Atrophy? .......................................................................................................................... p. 132
3.4 Are the measurements of enlargement of GA reliable? .................................................................................................... p. 132
4
Exudative AMD .................................................................................................................................................................................................... p. 133
4.1 What are the best tools for diagnosis and follow-up of exudative AMD? ...................................................... p. 133
4.2 What are the risk factors of RPE tears? .............................................................................................................................................. p. 133
4.3 What do we know about RPE atrophy occurring in exudative AMD? .................................................................... p. 134
4.4 What do we know about ocular retinal tubulations? .............................................................................................................. p. 134
5
New Imaging modalities .................................................................................................................................................................. p. 137
5.1 Towards non invasive diagnosis of exudative AMD? ............................................................................................................. p. 137
5.2 What’s new In adaptative optics? ............................................................................................................................................................... p. 139
5.3 Should we measure choroidal thickness in routine practice? ................................................................................... p. 139
6
Conclusion ................................................................................................................................................................................................................ p. 141
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1
Age-Related Maculopathy (ARM) -
soft Drusen
1.1 - What’s new in natural history of soft drusen?
Soft drusen usually coalesce to form drusenoid pigment epithelial detachments (PEDs).
The course of the material is considered as a slow increase in the drusen volume. However,
quantification of the phenomenon and its course has not been fully studied. Two studies
focused on the natural history of drusenoid PEDs secondary to AMD using SD-OCT imaging.
They proposed that the subtle changes in area and volume measurements would provide
a convenient quantifiable way to monitor disease progression in eyes with dry AMD. One of
them showed that drusenoid PEDs increased or remained stable over time with an associated
slight decrease in visual acuity while the second one revealed a dynamic growth pattern, with
a tendency for drusenoid PEDs to increase in volume and area before progressing to CNV or
GA. (3823/ Thanos D. Papakostas, Natural History Of Drusenoid Pigment Epithelium Detachments
In Age-related Macular Degeneration Using Spectral Domain Oct); 2908/ Renata Portella Nunes,
Natural History Of Drusenoid Retinal Pigment Epithelial Detachments Using SDOCT Imaging).
Relationships between soft drusen and AMD have been studied for many years. On the contrary,
occurrence of severe AMD in eyes without drusen or with only small drusen is not a known
condition. Studying the development of AMD in participants with No (AREDS category 1) or Small
Drusen (category 2) in the Age-Related Eye Disease Study (AREDS), a phenotype distinctly
different from the usual pathway of AMD progression through large drusen and pigmentary
changes was observed. Progressive development of pigmentary changes and peripapillary
atrophy was observed among eyes proceeding to advanced AMD, particularly in those that did
not develop large drusen prior to development of advanced disease. The authors propose this
may signify unique susceptibilities and disease processes in category 1 and 2 progressors.
(847/ Grace C. Shih, The Development of AMD in Participants with No or Small Drusen in the Age-
Related Eye Disease Study (AREDS)). This peculiar phenotype warrants further studies.
1.2 - Towards multimodal imaging of soft drusen?
In addition to color fundus photographies (CFP), many studies report the usefulness of
fundus autofluorescence (FAF) imaging and spectral domain optical coherence tomography
(SD-OCT) to document the different stages of ARM/AMD. Multimodal imaging revealed a broad
spectrum of microstructural findings that may indicate different drusen development stages
and/or soft drusen phenotypes, as observed in a study to determine FAF signal variability
and corresponding microstructural alterations on SD-OCT in areas of funduscopically
visible drusen associated with AMD. A total of 73 soft drusen were analyzed showing similar
appearance of yellowish-white deposits in CFP, while variable corresponding alterations were
present on both FAF and SD-OCT scans. In all cases, SD-OCT scans showed an elevation of
bands 1-4 by sub-RPE material. Focal hyper-reflectivity above band 4 up to the outer nuclear
layer (ONL) was most frequently correlated with increased FAF. ONL thinning and choroidal
hyper-reflectivity were associated with decreased FAF (845/ Arno P. Goebel, In-vivo Mapping
Of Drusen By Fundus Autofluorescence And Spectral-domain Optical Coherence Tomography).
There is no doubt that confrontation of FAF and SD-OCT data will bring new informations
concerning drusen and other components of ARM.
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2
Age-Related Maculopathy-Reticular
Pseudodrusen
Reticular pseudodrusen correspond to deposits located above the RPE and thus have also be
termed drusenoid subretinal deposits; recently, others have decided to refer to the condition
as to reticular macular disease. We will use these terms indifferently.
2.1 - how is the choroid in reticular pseudodrusen, and what implications
concerning their origin?
Reticular pseudodrusen are often associated with typical ARM/AMD. Choroidal analysis
in eyes with reticular pseudodrusen with indocyanine green angiography and enhanced
depth imaging spectral domain optical coherence tomography (EDI SD-OCT) found an overall
thinned choroid, compared to eyes with early AMD without pseudodrusen, supporting
the hypothesis that the derangement of the retinal pigment epithelium by the underlying
atrophy and fibrosis of the choroid, could lead to the accumulation of subretinal debris (2904/
Giuseppe Querques, Choroidal Changes Associated With Reticular Pseudodrusen).
Interestingly, in this study, the choroid of eyes with reticular pseudodrusen appeared thicker
at 3000-µm superior to the fovea compared with all measurement points. We recall that
pseudodrusen are mainly located in the area around the superior temporal arcade. Another study
also compared choroidal thickness in eyes with AMD with or without reticular pseudodrusen.
Similarly, it showed an overall significant thinner choroid in eyes with pseudodrusen than
in eyes without pseudodrusen. Thereby, there appears to be a significant morphological
association between pseudodrusen and choroidal thinning. The underlying hypothesis is that
reticular pseudodrusen could be a choroid vascular occlusive disease (2901/ Divya L. Nigam,
Characterization of Reticular Drusen and Association with Age Macular Degeneration through
Multiple Imaging Modalities).
2.2 - What are the relationships between reticular pseudodrusen and
geographic atrophy?
It is well known that reticular pseudodrusen may progress to geographic atrophy. In a study
evaluating the progression of primary geographic atrophy in patients with age-related macular
degeneration, Marsiglia et al. found a high correlation between primary geographic atrophy
and the presence of reticular pseudodrusen. Indeed, among 121 eyes with geographic atrophy,
95% has reticular pseudodrusen, as diagnosed by the means of fundus autofluorescence
and near infrared images, that may imply a common pathway. In these eyes, expanding
of geographic atrophy occurred in areas previously involved by reticular pseudodrusen,
suggesting that reticular pseudodrusen may correspond to the beginning of retinal atrophy
(849/ Marcela Marsiglia, Progression of Primary Geographic Atrophy in Patients with Age-
Related Macular Degeneration and Relation to Reticular Macular Disease).
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Age-Related Maculopathy-Reticular
Pseudodrusen
In eyes with geographic atrophy associated with reticular pseudodrusen, we also note, over
time, that the retinal area involved by reticular pseudodrusen increases. Furthermore, density
of reticular pseudodrusen increases. They can become coalescent in the center of the macula,
while their density gradually decreases with increasing eccentricity. Continuous enlargement of
reticular pseudodrusen area indicates progression of this phenotypic characteristic associated
with geographic atrophy in age-related macular degeneration. Systematic recording of reticular
pseudodrusen expansion could provide a new relevant prognostic marker in dry age-related
macular degeneration (848/ Julia S. Steinberg, Longitudinal Analysis Of Reticular Drusen
Associated With Geographic Atrophy In Age-related Macular Degeneration).
On the contrary, the multifocal ERG performed in eyes with Subretinal Drusenoid Deposits did not
identifying any significant decrease in retinal response in the areas where SDD were present
compared to non-affected areas (2900/ Florian Alten, Multifocal Electroretinogram in Eyes with
Subretinal Drusenoid Deposits).
AMD YEAR BOOK 2012

3
Geographic atrophy
3.1 - What are the general and local risk factors for geographic atrophy?
The risk characteristics associated with development of GA in The Blue Mountains Eye Study
Cohort were baseline age (OR 1.2, CI 1.2-1.3 per year older), current smoking (OR 4.8, CI 2.0-11.6),
the CFH (OR 1.6, CI 1.0-2.6 per risk allele) and ARMS2 genes (OR 2.6, CI 1.5-4.4 per risk allele).
Baseline early AMD lesion characteristics that predicted higher GA risk included drusen type
(soft indistinct: OR 46.0, CI 14.9-141.9; and reticular drusen: OR 13.3, CI 3.9-45.0); central drusen
location within 500 µm radius of the fovea (OR 9.8, CI 4.4-21.5); drusen area greater than
375 µm in diameter (OR 8.0, CI 2.8-22.6), the presence of retinal pigment epithelial
depigmentation (OR 6.9, CI 2.5-19.1) and hyperpigmentation (OR 11.9, CI 5.5-25.5), referenced
to the group with none or hard drusen only (1327/ Nichole D. Joachim. Risk Characteristics
Associated with Development of Geographic Atrophy: The Blue Mountains Eye Study Cohort).
3.2 - how does geographic atrophy progress?
Progression of GA is often monitored using color fundus and AF imaging. An investigation
developed a computer-based image segmentation method as a means of standardizing the
quantification of GA in color and AF fundus photographs (4086/ David J. Ramsey. Automated
Image Alignment and Segmentation to Follow Progression of Geographic Atrophy in AMD).
Other group evaluated a parameter based upon an indirect measure of the extent to which the
shape of an area of GA in an eye departs from that of a circle, the Non-Circularity Index (NCI),
as a risk factor for rate of GA expansion in a sample of AREDS eye. They found NCI was strongly
associated with progression rate of GA and postulate it as a useful predictor for use in clinical
trial eligibility. This association also suggests that future rate of enlargement of GA in an eye
may be more related to the junctional zone of RPE at risk rather than simply to area of GA
(2054/ Ronald P. Danis, Index of Non-Circularity of Areas of Geographic Atrophy (GA) Is Related
to Progression Rate).
The confocal Scanning Laser Ophthalmoscopy Fundus AutoFluorescence (cSLO FAF) have
been used to evaluate the topographic progression of Geographic Atrophy (GA) in patients
with AMD, finding that the distribution and progression of existing GA patches depend both on
the eccentricity from the center and total GA size; appearing the central macula areas more
susceptible for the occurrence and expansion of GA (850/ Steffen Schmitz-Valckenberg,
Longitudinal Analysis Of The Topographic Progression Of Geographic Atrophy Secondary To Agerelated
Macular Degeneration).
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Geographic atrophy
Also in the evaluation of features associated with progression of GA, finding that the area of
abnormal AF surrounding the GA, presence of halo and changes in background AF were
associated with a more rapid progression of GA on AF. More precisely, in a study of 156 eyes
with GA followed-up for 2 years, Domalpally et al. found three features associated with a more
rapid progression of GA on fundus autofluorescence: large area of abnormal autofluorescence
surrounding GA, presence of halo and presence of background autofluorescence changes
(Figure 1).
Figure 1:
Fundus autofluorescence of a left eye presenting geographic atrophy.
The dotted line shows the area of AF abnormalities surrounding GA. The
lesion is unifocal with halo and presence of background AF changes.
(Amitha Domalpally et al., ref above).
The baseline area measurements of GA did not correlate with progression rate. Fundus
autofluorescence imaging may provide predictive information on the progression of GA (2053/
Amitha Domalpally et al. Features Associated with Progression of Geographic Atrophy (GA)
from Autofluorescence (AF) Images).
AMD YEAR BOOK 2012

A study joining FAF imaging with high-resolution Spectral Domain Optical Coherence
Tomography (SD-OCT) identified morphologic alterations in eyes with GA due to AMD that
correlate with the area of atrophy, rate of progression, and the presence of unifocal or multifocal
patches of atrophy.
Morphologic alterations that were more prevalent in large areas of GA than in small areas of
GA included dome-shaped elevations of the outer retina in the perilesional zone (p < 0.0001),
irregular elevations of the outer retinal layers within the area of atrophy (p = 0.0012), debris
beneath these elevations (p = 0.076), and outer retinal tubulations within the area of atrophy
(p = 0.072).
Hyperreflective plaques in the outer retina, both at the junction between GA and non atrophic
retina as well as in the atrophic region itself, were commonly seen in eyes with multifocal GA
but appeared infrequently in eyes with unifocal GA (p = 0.039).
Morphologic alterations that occurred more commonly in faster progressing lesions than in
slower ones included irregular elevations of the outer retinal layers within the area of atrophy
(p < 0.0001) as well as outer retinal tubulations within the area of atrophy (p = 0.0055).
When square root transformations were applied to the lesion area, separation of the outermost
hyperreflective band occurred more frequently in faster progressing lesions than in smaller
ones (p = 0.0055) (852/ Kareem Moussa, Impact of Spectral-Domain Optical Coherence
Tomography (SD-OCT)-Determined Morphology in Geographic Atrophy Due to Age-Related
Macular Degeneration on Lesion Size, Rate of Progression, and the Presence of Multifocal or
Unifocal Lesions).
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Geographic atrophy
3.3 - Is near infrared useful in geographic atrophy?
According to Querques et al., mean retinal sensitivity, as measured by SD-OCT with integrated
microperimetry, was decreased in areas showing increased near-infrared autofluorescence
(NIA) (Figure 2). More precisely, Mean retinal sensitivity in case of increased NIA was
significantly reduced compared with normal NIA (7.15 ± 2.38 dB) (p = 0.002). Thus, this new
tool could bring both anatomical and functional information concerning geographic atrophy
(2685/ Lea Querques, Functional Correlates Of Autofluorescence And Optical Coherence
Tomography Imaging In Dry Age-related Macular Degeneration).
Figure 2:
Comparison of data given by microperimetry (left), fundus autofluorescence (center), and
near-infrared autofluorescence (right). Areas of increased infrared autofluorescence were
associated with decreased retinal sensitivity.
(Courtesy Dr Querques, Ref above, Department of Ophthalmology Pr Souied, Creteil, France)
3.4 - Are the measurements of enlargement of GA reliable ?
Enlargement rates of GA can be determined by measuring the area of GA during follow-up using
different imaging modalities. Giovanni Gregori et al. showed that areas of GA measured using
autofluorescence and fluorescein angiography were smaller than when using SD-OCT images,
meaning that each modality measures a different property of GA (2050/ Giovanni Gregori,
Comparison Of SDOCT, Autofluorescence, And Fluorescein Angiography Imaging Of Geographic
Atrophy).
Whether these different imaging modalities yield similar enlargement rates remains to be
determined. This is a very important issue for future therapeutic randomized trial.
AMD YEAR BOOK 2012

4
Exudative AMD
There is no more study of natural history of exudative AMD, thanks to the efficient available
therapies. Studies focussed on the best imaging for diagnosis of subtypes of choroidal
neovascularization or treatment monitoring, on occurrence of specific complications such
as retinal pigment epithelial (RPE) tears, or on evaluation of atrophic areas in patients with
exudative AMD.
4.1 - What are the best tools for diagnosis and follow-up of exudative
AMD?
SD-OCT is the most used tool for evaluating the course of exudative AMD treated with anti-
VEGF. However, the role of fluorescein and indocyanine green angiography remains discussed
during follow-up. A study compared different imaging techniques evaluated individually (optical
coherence tomography (OCT), infrared (IR), fundus autofluorescence, fluorescein angiography,
indocyanine green angiography) with the gold standard (defined as decision based upon all
the imaging techniques) to determine the subtypes of choroidal neovascularization (CNV) as
well as the decision of retreatment, in patients affected by exudative AMD. The results showed
that OCT and IR evaluations of CNV activity were reproducible and strongly associated with
the gold standard. By contrast, fluorescein angiography evaluation was associated with the
gold-standard, but it showed poor reproducibility. Non-invasive diagnostic methods seem to
supersede invasive gold standard techniques both for the diagnosis and for the follow-up of the
disease (2653/ Vittoria Ravera, Comparison Among Different Diagnostic Methods In The Study
Of Type And Activity Of Choroidal Neovascular Membranes In Age-Related Macular Degeneration).
SD-OCT is a very useful tool for monitoring the course of exudative AMD and the effect of treatment.
SD-OCT can also offer a prognostic value for visual function in patients with exudative AMD, as
investigated by Berisha et al. Indeed, the authors found a significant correlation between the
extent of photoreceptor defects in the macular region and vision loss, independently of retinal
thickness (2920/ Fatmire Berisha, Spectral-Domain OCT Evaluation of Photoreceptor Defects in
Patients with Exudative Age Related Macular Degeneration).
4.2 - What are the risk factors of RPE tears?
A study trying to determine the factors and long-term outcomes of RPE tear after intravitreal
anti-VEGF and photodynamic therapy (PDT) for exudative AMD concluded that a tall fibrovascular
pigment epithelium detachment (PED) may have a high risk of RPE tear [5145/D1198].
Other, retrospectively studying the progression of RPE tears secondary to AMD observed
that continuing or initiating anti-VEGF therapy after RPE tears may help stabilize the Far Visual
Acuity (FVA) to some extent and slow down scar formation. In the long term pro re nata
anti-VEGF treatment cannot influence the worsening of Reading Visual Acuity (RVA). Retracting
RPE remains unsolved with anti-VEGF treatment (5147/ Albert Caramoy, Retrospective Analysis
Of Retinal Pigment Epithelium Tears With And Without Pro Re Nata Anti-VEGF Treatments).
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Exudative AMD
4.3 - What do we know about RPE atrophy occurring in exudative AMD?
The FAF have been also used to determine the prevalence, progression, and factors related
to progression of retinal pigment epithelial (RPE) atrophy in eyes with choroidal neovascularization
(CNV) secondary to AMD. The factors significantly correlated with expansion
rate were the area of confluent atrophy at baseline (p < 0.0001) and the follow-up interval
(p = 0.008). An additional 23 eyes (55.3% of the remaining eyes in the follow-up group)
developed confluent hypoautofluorescence over the follow-up period.
The visual acuity at final follow-up was correlated with the area of confluent hypoautofluorescence
(p < 0.001) at that time. The change in visual acuity over the follow-up period
was correlated to the change in area of the confluent hypoautofluorescence (p = 0.015).
(867/ Nishant Kumar, Prevalence and Progression of Retinal Pigment Epithelial Atrophy in
Patients with Neovascular Age-Related Macular Degeneration treated with Intravitreal Anti-VEGF
Injections).
4.4 - What do we know about ocular retinal tubulations?
Outer retinal tabulation (ORT) is an interesting finding observed with SD-OCT, particularly in
eyes with wet AMD treated by anti-VEGF. They were first described in SD-OCT by Zweifel and
coll. (Ach Ophthalmol 2009).
They appear as multiple round or oval hyporeflective spaces with hyper-reflective doublelayered
borders, usually overlying areas of pigment epithelial alterations or subretinal fibrosis. A
retrospective study of 247 eyes treated with intravitreal ranibizumab for wet AMD documented
the incidence of ORT in wet AMD. ORT were identified in 6.07% of eyes during a 25 months
follow-up. The authors suggest that ORT should be ruled out in advanced wet AMD eyes to
avoid unnecessary interventions (5143/ Minas G. Georgopoulos, Outer Retinal Tubulation (ORT)
in Wet Age Related Macular Degeneration).
When considering eyes with exudative AMD treated with anti-VEGF agents and presenting
fibrous scar formation, the incidence of ORT grows to 26% (804/ Michelle C. Liang, Persistent
Retinal Cysts in Exudative Age-Related Macular Degeneration).
According to the authors, most cysts were located directly over the area of pathology. These
structures are unlikely to represent a sign of active choroidal neovascularization as they are
not affected by further treatment with anti-VEGF agents. Again, their presence should not be an
indication for retreatment.
AMD YEAR BOOK 2012

Wolff et al. analyzed outer retinal tubulations (ORT) in AMD with “en-face” OCT. In “enface”
OCT, they appeared as a branched network organized around a central starting point
(“pseudodendritic”). In cases of geographic atrophy, the tubular network was located at the
edge of the retinal thinning, along the ring of elevated autofluorescence when compared to
fundus autofluorescence (Figure 3).
Figure 3:
“En-face” OCT image showing outer retinal tubulations (ORT) in a patient
presenting geographic atrophy. Tubular network is located at the edge
of the retinal thinning, and invaginations of ORT inside the atrophic area
are observed.
(Courtesy Dr Benjamin Wolff et al., ref above, Department of Ophthalmology
Pr Sahel, Paris, France).
ORT viewing by this technique demonstrated the extent of outer retinal layers alterations
in AMD (2656/ Benjamin Wolff et al. En-face OCT Imaging For The Diagnosis Of Outer Retinal
Tubulations In Age-related Macular Degeneration).
AMD YEAR BOOK 2012
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5
New imaging modalities
5.1 - Towards non invasive diagnosis of exudative AMD?
The improvements made in non-invasive imaging tools put them in the first line imaging
techniques for the diagnosis, classification and monitoring of treatment in age-related macular
degeneration (AMD). Spectral domain optical coherence tomography (SD-OCT) is an imaging
technique that has become one of the reference examination methods for the diagnosis and
follow-up of patients with wet AMD. “En-face” is an emerging imaging technique derived from
SD-OCT. It produces frontal sections of retinal layers, also called “C-scan OCT”. OCT scans of the
macula are performed using a SD-OCT device and analyzed using “en-face” technique.
Neovascularization in fibro-vascular pigment epithelial detachment (PED) in AMD was also
analyzed with “en-face” OCT by Coscas et al. The technique allowed direct visualizing of
choroidal neovascularization (CNV), as a hyper-reflective neovascular network within the
hyporeflective fibrovascular PED (Figure 4).
Figure 4:
Visualization of the choroidal neovascular network without any dye, thanks to “en
face” SD-OCT. (Gabriel J Coscas, ref above)
The contours and the shape of the PED where also visualized, as well as fluid accumulation
around the PED and behind the CNV, signing CNV activity. The pattern of CNV was correlated
and confirmed on SLO-ICG images. This technique allows direct visualization of CNV network
and activity without any dye injection (2919/ Gabriel J. Coscas, En Face OCT And Fibrovascular
Pigment Epithelium Detachment In AMD).
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New imaging modalities
“En-face” OCT can also be useful in early stages of the disease, by identifying the presence
and distribution of intraretinal pigment clumps derived from retinal pigment epithelial cell
migration (2667/ Jyoti R. Dugar, Qualitative Analysis Of Intraretinal Pigment Using en-face
SDOCT Imaging).
“En-face” OCT seems to be a highly valuable new non-invasive tool for the diagnosis and
follow-up of macular diseases such as AMD. It also contributes to improve our understanding
of their physiopathogenic mechanisms.
Furthermore, in the future, novel imaging techniques allowing non-invasive vascular imaging
of exudative retinal diseases could replace all invasive diagnostic methods. High-penetration
Doppler optical coherence angiography (HP-D-OCA) is a non-invasive tool developed based on
a 1 µm swept-source optical coherence tomography to investigate choroidal vasculature. Two
Doppler scanning modes: fast (FDM) and slow (SDM), are employed to image bidirectional blood
flow and vascular structures, respectively. Non-invasive visualization of ocular vasculature
patterns using HP-D-OCA is well correlated with that of fluorescein and indocyanine green
angiography, without any contrast agent injection. In addition, this technique allows to obtain
depth location of vessels relative to the tissue structure (Figure 5). (1152/ Young-Joo Hong et
al. Non-invasive Vascular Imaging of Exudative Macular Disease by High Penetration Doppler
Optical Coherence Angiography).
Figure 5:
Left, center and right columns represent
ICG angiography, slow Doppler mode
(SDM) en-face projection and OCT intensity
cross-section image, respectively.
Top, middle and bottom rows represent
predominantly classic CNV, treated predominantly
classic CNV and polypoidal
choroidal vasculopathy.
SDM en-face images show similar
vascular structure with that of ICG
angiography. In the cross-sectional
images, OCT intensity (gray) and Doppler
signal (red) are combined and
their locations are indicated by red
arrow-pairs on SDM images. Abnormal
Doppler signals clearly appear in sub-retinal
region and beneath pigment epithelium
detachment as indicated by yellow
circles.
(Young-Joo Hong et al., ref above).
AMD YEAR BOOK 2012

5.2 - What’s new in adaptative optics?
The interest of adaptative optics (AO) imaging in geographic atrophy (GA) was studied by
Nakashima et al. AO imaging allowed a better delineation of GA limits and showed more details
about melanin redistribution within and around GA areas, compared to usual imaging modalities
(reflectance and autofluorescence scanning laser ophthalmoscope imaging, optical coherence
tomography). Extension of GA areas was associated to melanin redistribution within and outside
GA areas. The precise mapping of the redistribution of melanin-like pigments in AO imaging
allows a fine characterization of lesion extension and progression. Therefore AO imaging may
provide novel biomarkers for detecting the earliest stages, documenting the retinal pathology
and monitoring progression of GA (2052/ Kiyoko Nakashima et al. Adaptive Optics Imaging of
Geographic Atrophy). Images of this study have been reported in the AMD 2012 year book Part 1.
The contours and the shape of the PED where also visualized, as well as fluid accumulation
around the PED and behind the CNV, signing CNV activity. The pattern of CNV was correlated
and confirmed on SLO-ICG images. This technique allows direct visualization of CNV network
and activity without any dye injection (2919/ Gabriel J. Coscas, En Face OCT And Fibrovascular
Pigment Epithelium Detachment In AMD).
5.3 - should we measure choroidal thickness in routine practice?
Some studies evaluating the choroidal status in patients with AMD observed a decreased
choroidal thickness in different situations, relating it with a longer duration of exudative AMD
and greater number of anti-VEGF injections. (871/ David Xu, Choroidal Area after Anti-VEGF
Therapy in Exudative Age-related Macular Degeneration; 5172/ Leticia F. Barroso, The Effect
of Anti-VEGF Therapy in Choroidal Thickness in Patients with Exudative Age-related Macular
Regeneration).
A study was performed to investigate the correlation between subfoveal choroidal thickness
and dry AMD. Choroidal thickness was measured manually using enhanced depth imaging
protocol with SD-OCT in eyes with drusen and in eyes with geographic atrophy (GA).
Eyes with GA demonstrated thinner choroids (194.1 µm, SD = 115.3) than eyes with drusen
(274.6 µm, SD = 87.0, p < 0.001). This may reflect the fact that eyes with GA have a more
advanced disease, or suggest that eyes with drusen represent a stage of disease that has
active choroidal inflammation (2048/ Raquel Goldhardt et al. Correlation Between Choroidal
Thickness At Baseline And Disease Progression In Eyes With Dry AMD: the COMPLETE Study).
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6
Conclusion
As always, the ARVO proved to be the most interesting meeting for basic and clinical research
in Ophthalmology. The fields covered seem to be without limit. However, some tendencies may
be observed:
- The multimodal imaging of ARM/AMD, combining the data obtained with fundus photographies,
autofluorescence imaging, angiographies, and OCT
- A better knowledge of natural history and progression of geographic atrophy; these studies
would be very useful when therapies of atrophy will be available
- A step forward to the non-invasive diagnosis of exudative AMD, i.e. without angiography.
- A great interest in non-invasive analysis of the choroid in the different subtypes of
ARM/AMD.
AMD YEAR BOOK 2012
141

Francesco BANDELLO, MD, FEBO
Professor and Chairman Department of Ophthalmology
University Vita-Salute, Scientific Institute San Raffaele, Milano, Italy
Dr BANDELLO is Full Professor of Ophthalmology and
Chairman at the Department of Ophthalmology - University
Vita Salute, Scientific Institute San Raffaele of Milano.
Dr BANDELLO is member of the Academia Ophthalmologica
Internationalis and member and Vice President of the
Academia Ophthalmologica Europea.
Dr BANDELLO serves as a NEI (NIH - U.S.A) Peer Reviewer for
grant applications since 2006.
Dr BANDELLO is a fellow of the European Leadership
Development Programme (EuLDP) of the American Academy
of Ophthalmology.
Dr BANDELLO is former executive committee member of the
Macula Society and member of the “Accademia Nazionale di
Medicina”.
Dr BANDELLO was elected as a member of the Advisory
Board of the Italian Society of Ophthalmology for 9 years
and scientific coordinator of the annual meeting of the
Society for 7 years.
Dr BANDELLO was the scientific coordinator of the
Ophthalmology Monographs of the Italian Society of
Ophthalmology for 12 years.
Dr Bandello was Vice-President of the European Board of
Ophthalmology and chairman of the Recidency Review
Committee of the same association.
AMD YEAR BOOK 2012
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Dr BANDELLO was the General Secretary and Treasurer of
the Italian Society of the Retina.
Dr BANDELLO is former member of the International
Executive Committee Michaelson Symposium and former
member of the Subcommittee for Michaelson Award.
Dr BANDELLO is former board member of Club Jules Gonin.
Dr BANDELLO is president elect of the European Society of
Retina Specialists (EURETINA).
Dr BANDELLO is president of the Italian Society of the Retina.
Dr BANDELLO is member of the Scientific Advisory Board
Panel of AMD Alliance International.
Dr BANDELLO is Vice-President of EUROLAM (Europe and
Latin-America Society of Ophthalmology).
Dr BANDELLO is member of the Panel Discussion (tavolo
oftalmologico) of AIFA (Italian Agency for Drug).
Dr BANDELLO is member of the Steering Committee of the
Osservatorio Malattie Rare (O.Ma.R).
Dr BANDELLO is Chair of the Committee for revision of the
curricula for Vitreoretinal Diseases section of the
International Council of Ophthalmology (ICO).
Dr BANDELLO is member of the Scientific Committee of
Vision+ Onlus.
Dr BANDELLO is Novartis Ophthalmology Vision Award (NOVA)
Committee Member.
Dr BANDELLO is Member of the Grants Review and Awards
Committee (GRAC) of the Bayer Ophthalmology Awards
Program (BOAP).
Dr BANDELLO is candidate for Membership of American
Ophthalmological Society (AOS).
In 1984 Dr BANDELLO attended the Department of
Ophthalmology of the University of Creteil (Paris XII)
(France) (Chairman: Pr Gabriel Coscas) and became
“Assistant Etranger” at the Faculty of Medicine of the same
University.
AMD YEAR BOOK 2012

Dr BANDELLO is Associate Editor of the European Journal
of Ophthalmology, which is indexed in Current Contents/
Clinical Medicine, Science Citation Index, Expanded ISI
Alerting Service, Index Medicus, MEDLINE, EMBASE/Excerpta
Medica, Ocular Resources Computer-Scan, Pascal Data Base
of INIST.
Dr BANDELLO is Co-Editor of Developments in Ophthalmology,
Karger, Basel, Switzerland.
Dr BANDELLO is Editorial Board member of Case Reports in
Ophthalmology.
Dr BANDELLO is Editorial Board member of the journal
“Retinal Physician”.
Dr BANDELLO is former Editorial Board member for the
Journal of Ocular Pharmacology and Therapeutics.
Dr BANDELLO is Associate Editor of Ophthalmologica.
Dr BANDELLO is Editorial Board member for the “Giornale
Italiano di Vitreoretina”.
Dr BANDELLO is Editorial Board member of “ISRN
Ophthalmology” (International Scholarly Research
Network).
Dr BANDELLO is Editorial Board member of the Springer
Healthcare journal “Combination Products in Therapy”.
Dr BANDELLO is Advisory Board Member of “Ophthalmology
and Therapy”.
Dr BANDELLO served as trained principal investigator in
several clinical trials performed following ICH/GCP and
mainly concerning age-related macular degeneration and
diabetic retinopathy.
Dr BANDELLO is co-author of five books. He has published
165 Pub-Med papers. He presented well over hundreds
of presentations at different meetings. These primarily
relate to retinal diseases; diabetic retinopathy; age-related
macular degenerations; fluorescein and indocyanine green
angiographies of different retinal vascular disorders.
AMD YEAR BOOK 2012
145

Chapter 3
New therapeutic perspectives and
disease management and treatment
Professor Francesco BANDELLO (Italy)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
New therapeutic perspectives and disease management
and treatment ................................................................................................................................................................................................... p. 149
New perspectives treatments in wet AMD ................................................................................................. p. 151
New treatment regimens ............................................................................................................................................................ p. 153
LUMINOUs study ............................................................................................................................................................................................. p. 155
CATT study ............................................................................................................................................................................................................... p. 157
IVAN study ................................................................................................................................................................................................................. p. 163
VIEW study ............................................................................................................................................................................................................. p. 165
hARBOR study ................................................................................................................................................................................................... p. 167
New perspectives treatments in dry AMD .................................................................................................... p. 169
ACU-4429 .................................................................................................................................................................................................................. p. 171
New studies on AMD supplementation ............................................................................................................... p. 173
Embryonic Cell Transplantation ....................................................................................................................................... p. 177
Integrin Peptide Therapy .............................................................................................................................................................. p. 179
Photobiomodulation Therapy ............................................................................................................................................. p. 181
Bibliography ......................................................................................................................................................................................................... p. 183
AMD YEAR BOOK 2012
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1
New therapeutic perspectives
and disease management and
treatment
Age-related macular degeneration (AMD) is the leading cause of severe visual loss in adults
aged over 50 years in developed countries. AMD is a term used to summarize two different
pathological age-related changes of the macula, namely choroidal neovascularization (CNV)
(wet or neovascular form) and geographic atrophy (dry form). Currently, vascular endothelial
growth factor (VEGF) is a pivotal target for the treatment of neovascular AMD and prognosis of
this condition has improved considerably after the introduction of VEGF inhibitors. VEGF inhibition
has permitted to obtain functional and morphological results never seen before. The anti-VEGF
drugs currently available are pegaptanib sodium, ranibizumab, bevacizumab and aflibercept.
Pegaptanib sodium (Macugen; Eyetech Pharmaceuticals, Inc., New York, NY, and Pfizer Inc,
New York, NY) is a 28-base ribonucleic acid aptamer designed to bind to and block with high
specificity and affinity the activity of the 165-amino acid isoform of extracellular VEGF. Functional
positive results observed in patients who were randomized to receive therapy with intravitreal
pegaptanib compared with those treated with standard care led to the US Food and Drug
Administration (FDA) and European Medicine Agency (EMA) approval of the compound for the
treatment of neovascular AMD [1] .
Ranibizumab (Lucentis; Genentech Inc, San Francisco, CA, and Novartis AG, Basel, Switzerland) is
a fragment of a recombinant, humanized, monoclonal antibody Fab that binds to and inhibits
all the biologically active forms of VEGF-A. Ranibizumab is FDA and EMA approved for treating
neovascular AMD and it has become the standard of care for the therapy of neovascular AMD.
Clinical evidence from landmark trials indicates that monthly dosing of ranibizumab produces
superior vision outcomes compared to a less frequent dosing schedule [2, 3] .
FDA label recommends to administer ranibizumab monthly. It also indicates that although less
effective, treatment may be reduced to one injection every three months after the first three
injections if monthly injections are not feasible. EMA label indicates that treatment is given
monthly and continued until maximum visual acuity is achieved; thereafter patients should be
monitored monthly for visual acuity. Treatment is resumed when monitoring indicates loss of
stability due to neovascular AMD.
Bevacizumab (Avastin; Genentech, and Roche, Basel, Switzerland) is a full-length recombinant
humanized monoclonal antibody that binds to and inhibits all isoforms of VEGF-A. Bevacizumab
was the first drug approved by the US FDA for inhibition of angiogenesis in malignant solid
tumors. While awaiting approval of ranibizumab by the FDA, retinal physicians began using offlabel
bevacizumab because the drug had target specificity similar to that of ranibizumab and
was available at low cost. Bevacizumab rapidly became the most commonly used drug for the
treatment of neovascular AMD, despite the absence of data from randomized clinical trials
supporting its use.
AMD YEAR BOOK 2012
149

New therapeutic perspectives
and disease management and
treatment
Aflibercept (Eylea, previously known as VEGF-Trap Eye; Regeneron Pharmaceuticals, Tarrytown,
NY, USA, and Bayer HealthCare, Berlin, Germany) is a novel anti-VEGF agent that recently
gained FDA approval for the treatment of neovascular AMD.
It is a fully human recombinant fusion protein composed of the second Ig domain of VEGFR1
and the third Ig domain of VEGFR2, fused to the Fc region of human IgG1. Aflibercept was
designed by linking the amino acid sequences from the principal binding domains of the two
human VEGF receptors onto a human IgG-1 Fc framework.
Aflibercept shows an affinity for binding VEGF higher than ranibizumab offering a longer
interval between necessary treatments.

2
New perspectives treatments
in wet AMD
Research on ranibizumab is highlighted in more than 200 abstracts at the 2012 Association
for Research in Vision and Ophthalmology (ARVO) Annual Meeting.
Research continues to improve our understanding of the long-term efficacy and safety
profile of ranibizumab as well as the benefits of an individualized treatment regimen.
AMD YEAR BOOK 2012
151

3
New treatment regimens
At the poster session Ceklic et al. have presented an independent, retrospective, interventional
case series in which 316 patients with wet AMD received treatment with ranibizumab 0.5 mg
administered either monthly or quarterly according to a disease-activity-guided monitoring and
treatment algorithm.
The authors showed that at 36 months, patients have achieved a mean gain of approximately
8 letters in visual acuity with a mean total of only 16 ranibizumab injections over the three years
of follow-up [4] .
Although recent trials with a PRN regimen (HARBOR Study, CATT) have proven that an
aggressive individualized treatment can provide visual acuity gain similar to the monthly
regimen, there is the need to explore alternative treatment regimens such as the
treat-and-extend ones which may further reduce the burden of treatment and patient
evaluation duting the course of the follow-up.
AMD YEAR BOOK 2012
153

4
LUMINOUs study
The LUMINOUS Study [5] . confirms the safety profile of ranibizumab. The purpose of this
observational study is to provide additional long-term evidence on the efficacy and safety
profile of the use of ranibizumab for the treatment of neovascular AMD in a real-world setting.
This retrospective analysis on nearly 4.500 patients affected by wet AMD showed no new
safety risks after ranibizumab injections and confirmed its well known safety profile.
During the 12-month follow-up the incidence of adverse events was 0.11% endophthalmitis,
0.07% intraocular inflammation, 0.23% cataract, 0.50% elevated intra-ocular pressure, 0.14%
reduced retinal blood flow, 0.02% retinal tear, 0.02% retinal detachment, 0.61% retinal pigment
epithelial tear, 0.18% vitreous hemorrhage, 0.18% hypersensitivity, 0.16% hypertension, 0.11%
non-ocular hemorrhage, 0.11% myocardial infarction, 0.59% arterio-thromboembolic events,
and 0.11% venous thromboembolic events. The mean number of ranibizumab injections ranged
from 4.3 to 5.7 over 12 months.
The prospective arm of the Luminous Study is an ongoing global five year non-interventional,
multicenter trial and will recruit patients from clinics across Asia, Australia, Europe, North and
South America.
The LUMINOUS Study highlights the importance of post-marketing surveillance, which
may be pivotal to further assess the safety of a licensed drug. This additional safety
evaluation is not available for unlicensed drug used off-label.
AMD YEAR BOOK 2012
155

5
CATT study
The two year data from the Comparison of Age-Related Macular Degeneration Treatments
Trials (CATT) which compared bevacizumab (Avastin) and ranibizumab (Lucentis)
intravitreal injections for the treatment of neovascular AMD have been reported at the 2012
ARVO Annual Meeting [6] (Figure 1).
Ranibizumab
0.5 mg, mti.
Ranibizumab 0.5 mg
Ranibizumab
0.5 mg, PRN
Randomized 300 patients in
each of the 4 arms
Bevacizumab
1.25 mg, mti.
Bevacizumab 1.25 mg
Bevacizumab
1.25 mg, PRN
Figure 1:
Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research
Group. Ranibizumab and bevacizumab for treatment of neovascular Age-Related Macular
Degeneration. Two year results.
Paper presented at 2012 ARVO Annual Meeting, Fort Lauderdale, FL, USA.
The purpose of this prospective, randomized study was to assess the relative efficacy of
ranibizumab and bevacizumab and to determine whether an as-needed regimen would
compromise long-term visual acuity, as compared with a monthly regimen. Patients were
randomly assigned to four groups after the first mandatory intravitreal injection: 0.5 mg of
ranibizumab every 4 weeks (ranibizumab monthly) for one year and then randomization to
ranibizumab monthly or to PRN dosing; 1.25 mg of bevacizumab every 4 weeks (bevacizumab
monthly) for one year and then randomization to bevacizumab monthly or to PRN dosing;
0.5 mg of ranibizumab only when signs of active neovascularization were present (ranibizumab
as needed), and 1.25 mg of bevacizumab only when signs of active neovascularization were
present (bevacizumab as needed).
AMD YEAR BOOK 2012
Monthly treatment
50% to PRN
50% remain on mti.
One dose at the beginning then PRN, monthly follow-up
Primary end point,
after 1 year
Monthly treatment
50% to PRN
50% remain on mti.
One dose at the beginning then PRN, monthly follow-up
2 years
157

CATT Study
After the initial treatment, the patients were evaluated monthly and re-treated based on
signs of lesion activity. This was a non-inferiority study, with a 5-letter limit. Non-inferiority
trials are intended to show that the effect of one treatment (in this case bevacizumab) is not
worse than an active control (ranibizumab) by more than a pre-specified margin (five letters
in this specific study). Secondary endpoints include a 3-line visual acuity change (15 letters),
anatomical changes, numbers of injections required in each PRN group, and adverse events.
In this study 1030 patients affected by newly diagnosed wet AMD were enrolled from 47 clinical
sites throughout the USA.
Data have shown that mean visual acuity at baseline did not significantly differ between the
four study arms. Most of the change in mean visual acuity occurred during year 1, with relatively
little change during year 2.
At two years, the mean increase in letters of visual acuity from baseline was 8.8 in the
ranibizumab-monthly group, 7.8 in the bevacizumab-monthly group, 6.7 in the PRN ranibizumab
group, and 5.0 in the PRN bevacizumab group (Figure 2).
Mean change in visual acuity score from baseline
(no. of letters)
15
14
13
12
11
10
9
8
7
6
5
4
3
2
Ranibizumab monthly
Bevacizumab monthly
Ranibizumab as needed
Bevacizumab as needed
1
0
4 12 24 36 52 64 76 88 104
N (146, 135, 287, 270) (145, 135, 285, 270)
Follow-up weeks
(134, 129, 264, 251)
Figure 2:
Mean change in visual acuity at 24 months
AMD YEAR BOOK 2012

The difference in mean improvement for patients treated with bevacizumab
relative to those treated with ranibizumab was -1.4 letters. The difference in mean
improvement for patients treated by an as-needed regimen relative to those treated
monthly was -2.4 letters. In the monthly-treatment arms the proportion of patients
who experienced a gain in visual acuity of 15 letters or more was 32.8% for ranibizumab
and 31.8% for bevacizumab during 24 months of follow up, and was respectively 30.7%
and 28.3% in the PRN treatments regimens.
Patients recruited in the monthly ranibizumab and bevacizumab treatment regimens received
a mean of 22.4 and 23.4 injections, respectively (Figure 3).
Efficacy
endpoint
Mean change in visual
acuity at month 24
versus baseline (letters)
Number of injections
≥ 15-letter gain in visual
acuity
Change in subretinal
and intraretinal fluid on
OCT (µm)
% patients with no fluid
on OCT**
Figure 3:
Efficacy results at 24 months
Ranibizumab
monthly
n = 134
8.8 ± 15.9
22.4 ± 3.9
32.8%
-190 ± 172
45.5%
Bevacizumab
monthly
n = 129
7.8 ± 15.5
23.4 ± 2.8
31.8%
-180 ± 196
30.2%
* p-value for the comparison between ranibizumab and bevacizumab
** p-value for the comparison between monthly and PRN regimens
comparison between PRN regimens only
The number of injections for the PRN bevacizumab arm was 14.1 compared to 12.6 for the
ranibizumab as needed arm. On average, the decrease in central retinal thickness (CRT) was
greater in the ranibizumab monthly group compared with the other regimens.
AMD YEAR BOOK 2012
Ranibizumab
PRN
n = 264
6.7 ± 14.6
12.6 ± 6.6
30.7%
-166 ± 190
22.3%
Bevacizumab
PRN
n = 251
5.0 ± 17.9
14.1 ± 7.0
28.3%
-153 ± 189
13.9%
P
value
0.21*
0.046**
0.01
-
0.38*
0.08**
0.0003*
< 0.0001**
159

CATT Study
The mean ± SD change in CRT was -91 ± 152 µm for monthly ranibizumab, -84 ± 133 µm for
monthly bevacizumab, -78 ± 131 µm for PRN ranibizumab and -84 ± 145 µm for PRN bevacizumab
Figure 4).
Mean change in total foveal
thickness from baseline (µm)
0
-50
-100
-150
-200
0 4 8 12 24 52 76 104
Follow up (weeks) Follow up (weeks)
Figure 4:
Mean change in total retinal thickness at fovea at 24 months
0
-50
-100
-150
AMD YEAR BOOK 2012
Ranibizumab monthly
Ranibizumab switched
Ranibizumab PNR
Bevacizumab monthly
Bevacizumab switched
Bevacizumab PNR
-200
0 4 8 12 24 52 76 104
The proportion of eyes with absence of fluid on OCT was 45.5% in patients treated with
monthly injection of ranibizumab, 30.2% of those treated with monthly bevacizumab, 22.3%
with PRN ranibizumab and 13.9% with PRN bevacizumab. Absence of angiographic leakage
was observed in ranibizumab and bevacizumab monthly regimens and in PRN ranibizumab
and bevacizumab arms at a percentage of 76.1%, 75.2%, 69.3%,64.1%, respectively.
The mean visual acuity among patients assigned to continue monthly treatment changed little
during year 2, whereas the mean changes in the groups switched from monthly to treatment as
needed were -1.8 letters in ranibizumab-treated group and -3.6 letters in bevacizumab-treated
patients.
For both drugs, mean change in visual acuity at two years was similar in the originally assigned
to as-needed regimen and the groups that switched from monthly to as-needed treatment.
Among switched patients, the mean number of injections was 5.0 for ranibizumab-treated
patients and 5.8 for bevacizumab-treated arm.

The mean ± SD change in CRT was -31 ± 78 µm for switched ranibizumab arm and -19 ± 114 µm
for switched bevacizumab group. The proportions of patients without fluid on OCT were similar
in the two switched groups (19.2% for ranibizumab and 18.0% for bevacizumab arm) and were
substantially higher in the monthly-treatment arms.
Over the two years of follow up, the rates of serious events were similar for patients who
received either drug. As occurred in year one, the second year results showed a higher rate
of non-specific serious adverse events in patients treating with bevacizumab compared to
ranibizumab (40% versus 32%, respectively). The proportion of gastrointestinal disorders
(hemorrhage, hernia, nausea, and vomiting), were significantly higher in bevacizumab group
(4.8%) compared with ranibizumab arm (1.8%) (p = 0.005).
The CATT Study outcomes, although the study design and statistical analysis at year-2 are
sub-optimal have shown that there may be a clinical equivalence between ranibizumab
and bevacizumab. However, not only visual acuity results were usually worse when
bevacizumab was used as compared to ranibizumab but also other parameters such
as angiographic leakage, absence of fluid and CNV extension were less favorable in the
bevacizumab arms as compared to ranibizumab. Also, safety signals present at year-1
for bevacizumab were confirmed at year-2 highlighting the possibility that the safety
profile of bevacizumab might be inferior to ranibizumab.
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161

6
IVAN study
The efficacy and the safety of different treatment regimens of bevacizumab and ranibizumab
were also examined in a randomized controlled trial of alternative treatments to Inhibit VEGF
in Age-related choroidal Neovascularisation (IVAN Study) [7] (Figure 5).
Ranibizumab
0.5 mg, monthly
Ranibizumab 0.5 mg
Ranibizumab
0.5 mg, PRN
Randomized 150 patients to
each of the 4 arms
Bevacizumab
1.25 mg, monthly
Bevacizumab 1.25 mg
Bevacizumab
1.25 mg, PRN
Figure 5:
IVAN Study design
3 month treatment (upload), then continuation with monthly treatment, monthly follow-up
3 month treatment (upload), then treatment stop and PRN with cluster of 3 fixed consecutive
monthly injections, monthly follow-up
3 month treatment (upload), then continuation with monthly treatment, monthly follow-up
3 month treatment (upload), then treatment stop and PRN with cluster of 3 fixed consecutive
monthly injections, monthly follow-up
AMD YEAR BOOK 2012
1 year
Primary end point,
after 2 years
One year preliminary results of this multicenter, noninferiority factorial trial were presented
during a special session at the ARVO annual meeting.
The primary outcome measure was best corrected visual acuity (BCVA). The noninferiority
limit was 3.5 letters. Secondary outcomes included generic health-related quality of life
assessment, contrast sensitivity, near visual acuity, reading index and incidence of adverse
events. In this study 610 patients affected by newly diagnosed wet AMD were enrolled from
23 clinical sites throughout the United Kingdom. Patients were randomly assigned to one of
4 combinations of the 2 treatment factors: intravitreal injections with ranibizumab 0.5 mg or
bevacizumab 1.25 mg and continuous or discontinuous regimens. All patients initially received
three monthly injections of anti-VEGF.
163

IVAN Study
Participants randomized to the continuous regimen were treated monthly thereafter.
Participants randomized to the discontinuous regimen were retreated at physician’s discretion
based on OCT, visual acuity and angiographic findings. If re-treatment was needed, a further
cycle of 3 doses delivered monthly was required. In the statistical analysis, continuous and
discontinuous arms comprised both patients treated with bevacizumab and ranibizumab.
Data have shown that mean visual acuity at baseline did not significantly differ between the
four study arms. The difference between drugs (bevacizumab minus ranibizumab) was
-1.99 letters and between treatment regimens (discontinuous minus continuous) was
-0.35. The comparison by drug was inconclusive: bevacizumab was neither inferior nor
equivalent to ranibizumab using the 3.5 letter limit. Discontinuous treatment was equivalent
to continuous treatment. There were reported no significant differences between drugs or
regimens for secondary measures of visual function or generic quality of life. Angiographic
and OCT findings favored continuous treatment, but there were no differences between the
drugs. Serum VEGF levels were also measured after administration of either drug during the
follow-up at different time-points. At one year, bevacizumab significantly decreased VEGF levels
to about 50%. No changes in VEGF levels were found after ranibizumab treatment. In contrast
with CATT Study, this study have shown a slightly higher rate of arteriothromboembolic events
(mainly heart attacks and strokes) or heart failure among people treated with ranibizumab
than bevacizumab. However, when the results of the two trials were combined no difference
in heart attacks or strokes was observed among the two drugs.
Both studies showed no difference in mortality between the groups receiving different drugs
in the elderly study populations, but found a slightly higher rate of other serious adverse
events in those who received bevacizumab.
The IVAN Study has great limitations in the study design that was conceived in order to
overcome the limited number of patients enrolled. As a consequence it’s very difficult
to interpret its outcomes and translate them in clinical recommendations. Apparently,
treatment with ranibizumab and bevacizumab were clinically similar, although strictly
statistically different. The second year of the study may further highlight differences in
visual acuity outcomes between the two drugs. Very importantly, the study has shown
that bevacizumab significantly decreases VEGF serum levels. This may have relevant
implications in terms of sistemic safety of this specific drug.
AMD YEAR BOOK 2012

7
VIEW study
VIEW 1 and VIEW 2 were two large, phase III, parallel trials in which patients were randomized
to one of four treatment groups: 0.5 mg ranibizumab monthly, 0.5 mg aflibercept monthly,
2 mg aflibercept monthly, or 2 mg aflibercept dosed every 2 months after an initial loading
dose of 3 monthly injections [8] .
At week 96, outcomes included the proportion of patients who maintained visual acuity (defined
as a loss of fewer than 15 ETDRS letters) and mean change from baseline in BCVA. Prevention
of moderate vision loss after 96 weeks of treatment was achieved in 91% to 92% in all arms.
Vision improved by 7.9 letters in the 0.5 mg monthly ranibizumab arm, 7.6 letters in the 2 mg
monthly aflibercept arm, 7.6 letters in the 2 mg aflibercept every 2 months arms, 6.6 letters
in the 0.5 mg monthly aflibercept.
This study proved that a fixed treatment strategy (bimonthly) with VEGF-TRAP-Eye might
be feasible and result in visual acuity improvements similar to ranibizumab monthly.
There may be theoretical advantages in using a bimonthly-fixed regimen in terms of
reduction of burden although this may expose patients to over or under-treatment
because of the lack of an individualized approach.
AMD YEAR BOOK 2012
165

8
hARBOR study
To compare the efficacy and safety of 2 doses of ranibizumab, 1097 patients with subfoveal
wet AMD were randomized to ranibizumab injections (either 2.0 mg or 0.5 mg) dosed monthly
or on an as-needed (PRN) basis after 3 loading doses [9] .
At 12 months, all 4 treatment groups had significant and clinically meaningful increases in
BCVA. Patients randomized to 0.5 mg ranibizumab monthly gained 10.1 letters, those randomized
to 2.0 mg monthly gained 9.2 letters, those randomized to 0.5 mg PRN gained 8.2 letters
(with an average of 7.7 injections), and those randomized to 2.0 mg PRN gained 8.6 letters
(with an average of 6.9 injections). The proportion of patients who lost more than 15 letters
from baseline in the 4 groups was similar: 97.8% for 0.5 mg monthly; 93.4% for 2.0 mg
monthly; 94.5% for 0.5 mg PRN and 94.9% for 2.0 mg PRN. The mean change from baseline
in CRT was -172.0 µm, -163.3 µm, -161.2 µm and -172.4 µm for 0.5 mg monthly, 2.0 mg monthly,
0.5 mg PRN and 2.0 mg PRN, respectively.
This study has shown that high-dose of ranibizumab does not provide better visual acuity
than standard-dose in newly diagnosed AMD. However, a very short non-inferiority margin
was chosen (4 letters).
Although this study proves that there is no recommendation in using higher doses of
ranibizumab, it shows that PRN regimens with an aggressive re-treatment strategy
provide as good results as monthly regimens with ranibizumab.
AMD YEAR BOOK 2012
167

9
New perspectives treatments in dry
AMD
Currently, there is no proven drug treatment for dry AMD. However, the cessation of smoking
and treatments based on nutritional recommendations and supplements can slow disease
progression.
Several different strategies are proposed to the treatment of dry AMD.
These strategies have targeted three major therapeutic areas of investigation: preservation
of photoreceptors and the RPE (neuroprotection), prevention of oxidative damage, and
suppression of inflammation. Scientists and pharmaceutical companies continue to search
for effective ways to stop incidence and progression of dry AMD.
Several early-stage clinical trials have been discussed at the 2012 ARVO annual meeting.
AMD YEAR BOOK 2012
169

10
ACU-4429
ACU-4429 (Acucela, Bothell, WA) is a small nonretinoid molecule that functions as a modulator
of the isomerase (RPE65) required for the conversion of all transretinol to 11-cis-retinal in
the RPE. By modulating isomerization, ACU-4429 slows the visual cycle in rod photoreceptors
and decreases the accumulation of retinal fluorophore A2E [10] .
Phase 1 trial, single center, randomized, double-masked, placebo-controlled, dose-escalation
study has shown that this drug is safe and well tolerated. EnVIsIOn (Evaluating a novel VIsIOn
Treatment for AMD) is a phase 2, randomized, double-masked, placebo-controlled Clarity Trial
evaluating the effect of ACU-4429 or placebo on rod function in patients with advanced dry
AMD/geographic atrophy. In this 90-day, dose-escalation safety study, 56 subjects with
geographic atrophy received either ACU-4429 (2, 5, 7, or 10 mg) or placebo orally once per day.
Then, electroretinogram (ERG) measurements were recorded at multiple time points after
three minutes of exposure to a bright, bleaching light. Results at day 14 are presented in the
table 1 below. Similar results are achieved between day 14 and 90.
Table 1: Degree of Rod ERG suppression on day 14
Placebo 2 mg 5 mg 7 mg 10 mg
n = 14 n = 12 n = 12 n = 12 n = 6
Slope 2.52 1.77 1.00 0.98 0.34
% suppression* 0 29.9 60.7 61.3 86.4
* (slope of placebo-slope of ACU-4429/slope of placebo) x 100
Overall, these interim data show that subjects receiving ACU-4429 had a dose-dependent
response and that rod visual cycle was modulated, as measured by ERG, for doses up
to 10 mg. ERGs returned to baseline by 2 weeks after the final dose.
AMD YEAR BOOK 2012
171

11
New studies on AMD
supplementation
In AMD, oxidative stress and the depletion of essential micronutrients are considered to be
driving forces in disease progression. This condition seems to be caused by a lifelong exposure
to free radicals combined with exposure to environmental toxins, such as those derived from
smoking and inadequate levels of antioxidants. Support for this nutrient-based paradigm
was provided by the AREDS trial. This multicenter, randomized study evaluated the effect of
pharmacological doses of zinc and/or a formulation containing nutrients with antioxidant
properties (vitamin C, vitamin E, and beta-carotene) on the rate of progression to advanced
AMD and on visual acuity. The use of these vitamins and micronutrients reduced the risk
of developing advanced AMD by about 25%. The overall risk of moderate vision loss was
reduced by 19% at five years.
The AREDS2 trial is designed to evaluate the efficacy of dietary xanthophylls (lutein/
zeaxanthin) and/or omega-3 long-chain polyunsaturated fatty acids (LCPUFA), known as
docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), on the progression to advanced
AMD. These micronutrients are believed to function not only as antioxidants, but also as antiinflammatory
and antiangiogenic agents, according to epidemiologic and laboratory studies.
In addition, AREDS2 will investigate the effects of eliminating betacarotene and the effects of
reducing zinc in the original AREDS on the development and progression of AMD.
An interesting poster session about the last update about micronutrition was presented at
ARVO 2012:
• Omega-3 Supplementation Influences Vitreal Levels of Vascular Endothelial Growth Factor in
Exudative Age-Related Macular Degeneration (Rezende, Lapalme, et al. Poster: 2938/A383).
This study aimed to examine the influence of omega-3 long-chain poly-unsaturated fatty
acids (LCPUFAs) supplementation on vitreal levels of VEGF in exudative AMD. Patients with
active exudative AMD undergoing intravitreal injections of 1.25mg/0.05 ml of bevacizumab are
enrolled. Fourteen patients receiving daily omega-3 supplementation (200 mg of
docosahexaenoic acid and 400 mg of eicosapentaenoic acid) for at least 2 months were
compared with 5 patients not receiving supplements. Vitreous levels of VEGF, central foveal
thickness (CFT) and collected data on number of previous anti-VEGF injections and time
elapsed since last injection were recorded. Results: Vitreous levels of VEGF in people receiving
omega-3 supplements were 6-fold lower than those in people not receiving omega-3
supplements (p = 0.0308). CFT was significantly decreased by 25% in the supplemented
group (p = 0.0138). No complications related to the biopsy procedure were noted.
This is the first study to demonstrate that omega-3 supplementation protocols can
decrease VEGF levels in the vitreous of patients with exudative AMD undergoing anti-
VEGF treatment.
AMD YEAR BOOK 2012
173

New studies on AMD
supplementation
• JUNCTION Study: SD-OCT Shows Shrinking And Disappearing Of Drusen In Nonexudative AMD
Eyes Treated With AREDS2 Supplements Plus A Complex Containing The Natural Compounds
Curcumin, Omega-3 DHA/EPA and Phospholipids (Bayer et al. Poster: 448/D1125). To evaluate
safety and efficacy of Ayurveda’s anti-inflammatory and anti-oxidative natural compound
Curcumin in the treatment of dry AMD. Preliminary results of the Justification for the Use of
Natural Compounds in the Treatment of Inflammatory, Ophthalmic and Neurodegenerative
diseases Study (JUNCTION Study) are presented. In this study 126 patients with
nonexudative AMD with large drusen in both eyes (AREDS category 3) were randomized
to the AREDS2 supplements 1000 mg, omega-3 and 10 mg lutein / 2 mg zeaxanthin alone
or to these supplements in addition to 1000 mg CuromTM (complex of curcumin, omega-3
DHA/EPA and phospholipids). SD-OCT and fundus photography were performed at baseline
and after 6 months.
• Results: The treatment with CuromTM shows very good 24-hours bioavailabilities. In the
66 patients treated with AREDS2 plus CuromTM, there was a highly significant reduction
of drusen size between baseline and after 6 months (p < 0.0001). In the 132 eyes of these
66 patients, a disappearing of one or more drusen in 109 eyes was found. There was only
a non-significant change of drusen size in the eyes of the 60 patients who were treated
with AREDS2 supplements alone. Tolerance of AREDS2 supplements was slightly better than
of AREDS2 supplements plus CuromTM. There were 5 out of the 66 patients who were treated
with AREDS2 supplements plus CuromTM, who complained about diarrhea and/or a dull
stomach. Biomarkers of atherosclerosis improved significantly in patients who were
treated with AREDS2 supplements plus CuromTM (p < 0.05).
In conclusion CuromTM may be a powerful natural complex able to treat high-risk
dry AMD. The anti-inflammatory agent Curcumin may be part of any treatment of
nonexudative AMD. CuromTM could be able to reduce the risk of progression of
high-risk dry AMD (AREDS category 3) to exudative AMD and/or Geographic Atrophy
(AREDS category 4).
AMD YEAR BOOK 2012

• Short Term Ocular Safety Assessment Of High Dose Oral Omega-3 Fatty Acid Supplementation
for Age-Related Macular Degeneration (Gerstenblith, Baskin et al. Poster: 2936/A381). The
purpose of this prospective, non-randomized, non-comparative, interventional case series
is to evaluate the short term ocular safety of high dose oral omega-3 fatty acid
supplementation in dry AMD. Thirty-four eyes of 17 patients at least 50 years of age with
early to intermediate AMD received oral supplementation with 4 grams of omega-3-fatty
acids daily (840 mg EPA/2.520 mg DHA) for 6 months. Early Treatment Diabetic Retinopathy
Study (ETDRS) BCVA was measured at baseline and at each of the 1, 3, and 6 months follow
up visits. Multifocal ERG (mfERG) testing was performed and serum omega-3 index was
drawn at baseline and at the end of the study. Systemic and ocular adverse event data
were collected at each follow up visit.
• Results: Patients were Caucasian (100%) and predominantly women (71%), with an average
age of 69 years (range 56-89). Average ETDRS BCVA letter score at baseline was 77 letters
(Snellen equivalent of 20/32). Serum omega-3 index increased by an average of 7.6% over
the course of the study (p < 0.0001). There were no statistically significant changes in visual
acuity or retinal function by mfERG testing over the course of this short-term study. There
were no reported systemic or ocular adverse events.
Visual acuity in patients with dry AMD taking daily oral supplementation with 4 grams of
omega-3 fatty acids did not significantly change over 6 months. Additionally, there was
no significant change in retinal function as assessed by mfERG. These results argue
against any retinal or other ocular toxicity of high-dose oral omega-3 supplementation.
Additionally, dietary supplementation can increase serum omega-3 index in patients
with dry AMD.
AMD YEAR BOOK 2012
175

12
Embryonic Cell Transplantation
Advanced Cell Technology Inc. (Advanced Cell Technology, santa Monica, CA) received FDA
approval to initiate a phase 1/2 multicenter study using human embryonic stem cell (hEsC)-
derived RPE cells to treat patients with Stargardt macular dystrophy (sMD). Advanced Cell
Technology also recently filed an investigational new drug with the FDA to initiate a phase
1/2 multicentre study using hEsC-derived RPE cells to treat patients with AMD. The phase I/II
trial is a prospective, open-label study designed to determine the safety and tolerability of
the hESC-derived RPE cells following sub-retinal transplantation into patients with dry AMD.
The trial will ultimately enroll 12 patients, with cohorts of three patients each in an ascending
dosage format.
In animal studies, a significant improvement in visual performance was observed over untreated
animals, and no adverse effects were reported.
In extending these studies to human patients, there is a hope that injected RPE cells will
rescue photoreceptors and slow, if not stop, the progression of macular degeneration.
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13
Integrin Peptide Therapy
Integrin Peptide Therapy [11] is an emerging new class of treatment for vascular eye diseases.
By utilizing a small molecule discovered by Allegro Ophthalmics, ALG-1001 interferes with
multiple pathways of the angiogenic cascade beyond current anti-VEGF treatments by binding
to multiple integrin-receptor sites known to be implicated in both choroidal and pre-retinal
neovascularization.
A phase 1b/2a study for the treatment of Wet AMD is ongoing. This study follows the successful
phase 1 study establishing safety and efficacy in the treatment of diabetic macular edema in
humans.
The endpoints of this dose-ranging, six-month phase 1b/2a Wet AMD Study are safety and
efficacy as measured by improvement in best-corrected visual acuity (BCVA), reduction of
central macular thickness, and reduction in the area of choroidal neovascularization.
The study includes a loading dose of three monthly injections, with subject follow-up four
months off-treatment.
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14
Photobiomodulation therapy
Results from the Toronto and Oak Ridge Photobimodulation Study in AMD (TORPA) have been
presented at the last ARVO Annual Meeting.12 This study aimed to assess Photobimodulation
(PBM) as a safe and effective treatment in dry AMD.
This is the first study for the treatment of AMD utilizing devices that produce light from Light
Emitting Diodes (LEDs). The primary outcome measures are visual acuity, contrast sensitivity
and fixation stability. Eighteen eyes are enrolled and treated 18 times over a six week period
with two devices: Warp10 (Quantum Devices) and Gentlewaves (Light Bioscience). Treatment
parameters were: Warp10: 670 nm +/- 15 nm at 50-80 mW/cm 2 , 4-7.68 J/cm 2 , for 88 +/- 8
seconds;
Gentlewaves: 590 nm +/- 8 nm at 4 mW, 790 nm +/- 60 nm at 0.6 mW, for 30 seconds. There are
clinically and statistically significant improvements in both visual acuity and contrast sensitivity.
Fixation stability does not show a statistically significant change. There are no significant
adverse events recorded over the study period of one year. It appears that PBM could be an
important safe and effective treatment for dry AMD and the results warrant further evaluations
with a double blind placebo controlled larger study.
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15
Bibliography
1. Singerman LJ, Masonson H, Patel M, Adamis AP, Buggage R, Cunningham E, Goldbaum M, Katz B, Guyer D:
Pegaptanib sodium for neovascular age-related macular degeneration: third-year safety results of the VEGF
Inhibition Study in Ocular Neovascularisation (VISION) trial. Br J Ophthalmol 2008; 92: 1606-1611.
2. Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, Kim RY, MARINA study Group: Ranibizumab
for neovascular age-related macular degeneration. N Engl J Med 2006; 355: 1419-1431.
3. Brown DM, Michels M, Kaiser PK, Heier JS, Sy JP, Ianchulev T, ANCHOR Study Group: Ranibizumab versus
verteporfin photodynamic therapy for neovascular age-related macular degeneration: two-year results of
the ANCHOR Study. Ophthalmology 2009; 116: 57-65.
4. Ceklic L, Framme C, Schnurrbusch-Wolf U, Sebastian Wolf. Three Year Results of Visual Outcome with Disease-
Activity-Guided Ranibizumab Algorithm for the Treatment of Exudative Age-Related Macular Degeneration.
Poster: 438/D1115. May 06, 2012 ARVO annual meeting 2012, Fort Lauderdale, FL, USA.
5. Bandello F, Holz F, Gillies M, Koh A, Mitchell P, LUMINOUS group.Safety, Efficacy, And Treatment Patterns Of
Ranibizumab Therapy For Neovascular Age-Related Macular Degeneration: The LUMINOUS Studies. Poster: 2031/
D1049. May 07, 2012 ARVO annual meeting 2012, Fort Lauderdale, FL, USA.
6. Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group. Ranibizumab
and Bevacizumab for Treatment of Neovascular Age-Related Macular Degeneration. Two-Year Results. Paper
presented at 2012 ARVO Annual Meeting, Fort Lauderdale, FL, USA.
7. The IVAN Study Investigators. Ranibizumab versus Bevacizumab to Treat Neovascular Age-related Macular
Degeneration. One-Year Findings from the IVAN Randomized Trial. Paper presented at 2012 ARVO Annual
Meeting, Fort Lauderdale, FL, USA.
8. Jeffrey S. Heier, VIEW 1 and VIEW2 Investigators. 96 Weeks Results from the VIEW 1 and VIEW 2 Studies:
Intravitreal Aflibercept Injection versus Ranibizumab for Neovascular AMD Shows Sustained Improvements
in Visual Acuity. Paper presented at 2012 ARVO Annual Meeting, Fort Lauderdale, FL, USA.
9. Suner I, Yau L, Lai P. 1 HARBOR Study: One-Year Results of Efficacy and Safety of 2.0 mg versus 0.5 mg
Ranibizumab in Patients with Subfoveal Choroidal Neovascularization Secondary to Age-Related Macular
Degeneration. Paper presented at 2012 ARVO Annual Meeting, Fort Lauderdale, FL, USA.
10. Birch D, Chandler J, Reaves A, Koester J, Kubota R. Prolonged Rod Visual Cycle Suppression with ACU-4429
in Patients with Geographic Atrophy. Poster: 2044/D1062. May 07, 2012 ARVO annual meeting 2012, Fort
Lauderdale, FL, USA.
11. Boyer D, Quiroz-Mercado H, Kuppermann B. Integrin Peptide Therapy: A New Class of Treatment for Vascular
Eye Diseases - The First Human Experience in DME. Paper presented at 2012 ARVO Annual Meeting, Fort
Lauderdale, FL, USA.
12. Merry G, Dotson R, Devenyi R. Photobiomodulation as a New Treatment for Dry Age Related Macular
Degeneration. Results from the Toronto and Oak Ridge Photobimodulation Study in AMD (TORPA) Poster:
2049/D1067. May 07, 2012, Fort Lauderdale, FL, USA.
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This brochure is produced under the sole responsibility of the authors, Laboratoires Thea are not involved in the writing
of this document. This brochure may contain MA off-label and/or not validated by health authorities information.
Collection Librairie Médicale Théa
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63017 Clermont-Ferrand cedex 2 - France
Tel. 33 4 73 98 14 36 - Fax 33 4 73 98 14 38
AMD YEAR BOOK 2012
NUT AMD 1012