Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2589_Библиотеки_им_академика_М_И_Перельмана
.pdf
Macular Degeneration,
https://t.me/medicina_free
Geographic Atrophy, andInherited
Retinal Disorders
13
13.1 Introduction
Many disorders that lead to primary retinal atrophy affect the retina bilaterally and involve either
the macula, the peripheral retina, or both the
macula and the peripheral retina. The most common of these is dry age-related macular degeneration (AMD) which leads to irreversible loss of
central vision and is a signicant public health
concern in the fast-growing ageing populations in
the developed and developing regions of the
world. The incident late AMD signicantly
impacts the vision-related quality of life regarding reading, mobility, and emotional well-being
[1]. Several inherited retinal disorders (IRD)
affect the macula or the peripheral retina. These
have a variable age of onset and lead to irreversible loss of either central or peripheral vision.
The most typical example of IRD is retinitis pigmentosa (RP) which affects millions of children
worldwide and makes them blind in their youth.
Till recently, none of these could have been
treated. Rapid strides in cell biology, biotechnology, and genetics in the past few decades have led
to remarkable progress in understanding the
pathophysiology of these disorders. Often
labelled orphan diseases, many IRDs have
remained neglected because of their rarity.
However, innovative therapeutic interventions
are being developed to treat these hitherto blinding disorders and should be available in the foreseeable future. Among the rst FDA-approved
gene therapies is Luxturna for RP, and its benecial results have been sustained through almost 5
years of follow-up. For those patients who have
lost photoreceptors, a new eld of optogenetics
has made it possible to express the opsin gene
(the protein involved in phototransduction) in
inner retinal cells, and the rst human trials have
already started. Cell-based therapies have been
initiated to replace theretinal pigment epithelium
(RPE). This chapter will not discuss secondary
retinal atrophies and degenerations secondary to
the involvement of the retina, choroid or optic
nerve by diabetes mellitus, vascular occlusions,
inammation, infections, drug toxicities, cancerassociated retinopathies, and trauma.
13.2 Anatomical Considerations
The neurosensory retina (NSR)is a highly organized multilayered tissue consisting of highly
organized neural cells and their bres, namely
the photoreceptors rods and cones (rst neuron),
bipolar cells (second neuron), horizontal cells,
amacrine cells, and the retinal ganglion cells
(third neuron). The glial cells include the Muller
glial cells spanning the entire NSR, microglia,
and astrocytes. The retinal cells are post-mitotic
and do not regenerate once they undergo degeneration. The processes of the Muller cells and
the microglia (up to the inner nuclear layer) and
astrocytes only in the supercial capillary
© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023
A. Gupta et al., Ophthalmic Signs in Practice of Medicine,
https://doi.org/10.1007/978-981-99-7923-3_13
351
352
https://t.me/medicina_free
13 Macular Degeneration, Geographic Atrophy, andInherited Retinal Disorders
plexus form very intimate contact with pericytes, capillary endothelial cell, and neural cells
(the neuro- glia- vascular unit) that maintains the
metabolic and immune homeostasis of the retina. The photoreceptor outer segments are in
intimate contact with the microvilli of the RPE
cells. Each RPE cell receives the photoreceptor
outer segments from 20 to 30 rods and cones.
The RPE phagocytose the rod and cone outer
segment membranes. The rod visual pigment is
recycled in the RPE cells, whereas the Muller
cell bodies recycle the cone visual pigment. The
RPE cell layer is a single layer of post-mitotic
cells that do not regenerate once they degenerate. The RPE layer is vital for the survival of the
photoreceptors.
The visual impulse is generated when the light
falls on the photoreceptors, where the visual pigment is split into opsin and all-trans-retinal, the
process known as phototransduction. The visual
signal is transmitted from the photoreceptors to
the visual cortex via the visual pathways, involving the rst three neurons in the retina and their
synapses. The axons of the ganglion cells exit the
eye to form the optic nerve, which conducts the
signals up to the lateral geniculate nucleus, where
the fourth neuron is located. The optic radiation
from the geniculate body further transmits signals to the visual cortex located in the occipital
lobe, where the signals are perceived as the image
of the objects.
The NSR, up to the inner third of the outer
plexiform layer, receives its oxygen and micronutritional requirements from the capillary
plexus derived from the retinal vessels. The
RPE and the outer retina are avascular and get
their oxygen and micro-nutritional requirements
from the choroidal blood supply through a single layer of closed-fenestrated wide lumen capillaries 10–30μm in thickness. Compared to the
retinal capillaries, the choriocapillaris (ChC)
offers less resistance to blood ow and ensures
oxygen and metabolic substrate supply to the
outer retina [2]. The ChC’s closed-fenestrations
(which are covered with a diaphragm) are larger
than the capillaries elsewhere in the body and
face the Bruch’s membrane(BM), which separates them from the RPE cells. Unlike the sinu-
soidal capillaries in the liver, these closed
fenestrations do not allow blood plasma to pass
into the interstitial tissue. The ChC allows diffusion of small-sized macromolecules but does
not allow larger macromolecules to enter interstitial space. The scleral side of the endothelial
cells has gap junctions and discontinuous tight
junctions [2].
The choroid has the highest blood ow in the
body and very high oxygen saturation, which is
only 2–3% less than the arterial blood. A high
gradient of oxygen saturation ensures efcient
diffusion of oxygen into the outer retina [3].
The blood ow in ChC is vital for sustaining
the RPE and the photoreceptors. The innermost
layer of the ve-layered BMis constituted by
the basement membrane of the RPE cells, followed by the inner collagenous layer, the middle elastic layer, an outer collagenous layer, and
the outermost layer by the basement membrane
of the endothelial cells of the ChC. The BM
allows only the passive transport of molecules
between the ChC and the RPE by diffusion,
concentration gradient, and hydrostatic pressure. It does not allow the movement of cells
across it.
13.3 Complement Pathway-Basics
Complement pathways are essential in the pathogenesis of AMD. Complements are small proteins manufactured in the liver by hepatocytes
and circulate in the blood as precursors.
Complement pathways are an integral component of the innate immune defence system. In the
past, their role was limited to the opsonization of
the invading bacteria for their elimination by
phagocytosis. Later it was realized that complement pathways also play a signicant role in
eliminating the stressed tissue cells in the body.
Regulatory failure of complement factor H can
amplify the inammatory reaction.
The complement (C) pathways involve the
action of the proteolytic enzymes on substrates
generated by the degradation of cells. There are
mainly three mechanisms which activate the
complement pathways. The classical pathway
13.4 Age-Related Changes intheRetina
https://t.me/medicina_free
353
(CP) is through the binding of C1q, a fragment of
C1, with an antigen-antibody complex or substrates. The microglia and macrophages express
the C1q in RPE and outer photoreceptors [4].
Additionally, there may be leakage and deposition of systemic complements in the ocular
tissues.
In the retina, various substrates like C-reactive
proteins, phosphatidyl serine and other phospholipids, clustered IgG, amyloid, and hydroxyapatite are generated from the phagocytosis of the
photoreceptor outer segments, and the lysosomal
degradation of their cell membranes. These are
opsonized by C1q to initiate the CP [4].
In the Lectin pathway (LP), instead of the
C1q, mannose-binding lectin (MBL) binds to the
carbohydrate residues on the organism’s surface
and activates serine proteases like the CP. The
alternate pathway (AP) involves spontaneous
hydrolysis of C3, which maintains a low-level
activity at all times and does not require binding
to specic receptors.
All three pathways of complement activation
lead to the formation of complement convertase
C3bBb, which cleaves C3 to C3a and C3b. Factor
B binds with C3b to form C3bB. Factor B is
cleaved by factor D to form Bb, which binds to
C3b to form C3 convertase C3bBb. C3b enters
into an amplication loop with increasing
amounts of the C3 convertase formation, which
cleaves C5 to C5a and C5b. Fragments C3a and
C5a are anaphylatoxins chemoattractants for the
microglia and the macrophages. Factor C5b combines with C6–C9 to form a membrane attack
complex (MAC) which disrupts the cell walls’
bilipid layer, resulting in the cell death of RPE
cells, photoreceptors, and the endothelial cells of
the ChC [5].
Increased complement activity also leads to
the release of anaphylatoxins C3a and C5a,
whichalso recruit inammatory cells, microglial,
and macrophages in the subretinal space. The
phagocytes recognize the opsonization of the
stressed target cells (photoreceptors, RPE cells,
and ChC endothelial cells) by the complement
fragments such as C3b, iC3b, and C4b [5]. There
is some evidence that the C1q fragment, the initiating molecule in the classic pathway, maybe a
signicant pathway in AMD pathogenesis. C1q
activating ligands are present at the photoreceptor synapses, outer segments of photoreceptors,
RPE, and drusen. The microglia and macrophages also express C1q in these locations [4].
In normal circumstances, the complement
activity should cease once the substrate has
been completely removed. However, in GA,
waste products are produced continuously in the
drusen and the stressed cell membranes, resulting in continuous complement activation and
inammasome activation within the RPE cells.
These lead to the recruitment of microglia and
macrophages, cell wall lysis, and phagocytic
activity [4].
The protein Properdin increases the survival
time of C3 convertase and plays a role in promoting inammation. On the contrary, Factor H is a
regulatory protein for blocking the C3b fragment
cleaved from C3 and thus plays a signicant role
in containing innate inammatory activity [5].
Patients with the Factor H variant gene and who
did not develop the disease were found to lack
Factor B, another critical component required for
generating C3 convertase [6].
There needed to be more information on the
exact transcriptome-wide associations or the
gene expressions directly responsible for the causation of AMD pathology [7]. Only recently have
transcriptome studies been done on RPE cells
derived from the induced pluripotent stem cells
(iPSC) developed from the geographic atrophy
patients’ broblasts. These derived RPE cells
have all ve signicant protein quantitative loci
that regulate protein expression in mitochondrial
biology and neurodegeneration, suggesting a role
for mitochondrial dysfunction in GA [8].
13.4 Age-Related Changes
intheRetina
Signicant changes occur in the retina with ageing. More signicant changes occur in the outer
retina compared to the inner retina. The density
of cones in the macular area is reduced closer to
the foveal centre, although their thickness
increases [9]. There is thinning of the ChC,
354
https://t.me/medicina_free
13 Macular Degeneration, Geographic Atrophy, andInherited Retinal Disorders
which is compensated by increased passive
transfers between the outer retina and the
Choroid [2]. Histological studies of eyes from 6
to 100years old have shown an increase in the
thickness of BM from 2 to 4.7μm and a decrease
in the ChC density by 47%. The thickening of
BM is related only to age and not to AMD [10].
The decrease in the ChC density with ageing
corresponds to a similar loss of the rod photoreceptors. There is a loss of hydraulic conductivity due to the deposition of lipids in the
BM. With ageing, there is a signicant reduction in the size of the macromolecules that can
pass through the BM [2].
13.5 Age-Related Macular
Degeneration (AMD)
13.5.1 Epidemiology
Age-related macular degeneration (AMD) is a
major public health challenge with signicant ethnic and racial differences. Globally, 196 million
people are estimated to have AMD, likely reaching
288 million by 2040 [11]. Nearly 8.7% of persons
above 30 had any documented AMD, with 8%
having an early and 0.37% having a late AMD.Any
stage AMD is more common in Europeans
(11.2%) compared to Asians (6.8%) and Africans
(7.2%). Geographic atrophy (GA) was noted in
1.11% of Europeans versus 0.21% of Asians,
0.16% of Hispanics, and 0.14% of Africans [11].
13.5.2 Role ofComplement Pathways
inAMD
In a signicant breakthrough, a single-point
mutation in the genes coding for complement
factor H was rst reported in 2005. This discovery rst pointed out the role of genetics in the
causation of AMD [12–14]. The discovery of
many components of the alternative complement
pathway in drusen, a precursor of AMD, has
strongly suggested a role for innate inammation
in AMD [15].
In addition to the mutations in the complement factor H, single nucleotide polymorphisms
(SNPs) in rs10490924, in the ARMS2 gene
located on Chromosome 10, is highly associated
with AMD. This gene mediates the opsonization
of necrotic and apoptotic cells [16, 17]. A deciency of the normal ARMS2 protein may be
responsible for drusen formation [17].
A two-level model hypothesis recently suggested that the primary insult in the AMD is due
to local oxidative stress in the outer retina modulated by an unbridled inammatory response due
to SNPs in the complement factor H.Hence the
treatment strategies to control AMD target the
involved complement pathways [18].
13.5.3 Risk Factors forAMD andIts
Pathogenesis
The retina is a tissue with the highest metabolic
rate in the body and is highly vulnerable to oxidative stress. Ageing results in a decrease in the
choroidal blood ow and thinning of the choroid,
thickening of the BM with a consequent slowdown of the exchange of oxygen, metabolic substrates, and waste products between the choroid
and the photoreceptors. Rozing et al. [18] have
reviewed the subject extensively.
AMD is a complex multifactorial disease with
signicant genetic and environmental risk factors.
Besides ageing, several preventable risk factors such
as family history, hypertension, smoking, obesity,
and a sedentary lifestyle are common between AMD
and cardiovascular diseases. These cause systemic
low-grade chronic inammation and increased oxidative stress [19]. The Mediterranean diet recommended for preventing CVD, consisting of leafy
vegetables, fruits, sh, and legumes, has also been
shown to reduce the incidence of late AMD by
almost 40% [20]. Additionally, prospective population-based cohorts have shown benecial effects of
high levels of physical activity in preventing the
occurrence of early AMD [21]. Obesity and smoking in people who show SNPs in CFH Y402H and
ARMS 2 (LOC387715 A69S) genes raise the risk of
progressive AMD by 19-fold [22].
13.5 Age-Related Macular Degeneration (AMD)
https://t.me/medicina_free
355
In a large European cohort, nearly two-third of
the patients with late AMD had risk allele
rs3750486 at the ARMS2/HTRA1 locus.
Homozygous carriers had an odds ratio of 8.6 for
geographic atrophy and 11.2 for neovascular
AMD (nAMD). The lifetime risk of developing
advanced AMD was 4.4 for non-genotype, 9.4
for heterozygous, and 26.8 for homozygous carriers. The homozygotes also had the onset of late
AMDalmost 10 years earlier. This gene variant
plays the role of a strong catalyst in patients with
early changes of AMD [23].
In ageing RPE, there is an accumulation of
lipid peroxidation products which are deposited
between the basement membrane of RPE and
BM. It has been proposed that environmental factors with defective innate and adaptive immune
mechanisms in aged people due to their genetic
predisposition lead to low-grade systemic inammation, which in the eye leads to AMD. The
same factors also lead to systemic atherosclerosis, which explains the high risk of CVD in
patients with AMD.
The cellular debris is deposited under the
retina in the BM as well-dened hard drusen,
ill- dened soft drusen, or densely packed small
reticular drusen. On the other hand, subretinal
drusenoid deposits (SDD), earlier known as
pseudo reticular drusen, are deposited under the
NSRand above the RPE.The latter differs from
the classical drusen in their location and lipid
composition. The SDD may breach the ellipsoid
zone (EZ) and extend into the NSR.The SDD is
associated with type 3 new vessels and geographic atrophy [24]. The site where the drusen
will appear does not appear to be a random phenomenon but relates to the areas of choroidal
ischaemia. Although histopathological studies
in the past had shown thinning of ChC in the
AMD eyes, more recently, imaging studies
using OCT angiography have shown signicant
ow decits in ChC underlying the existing drusen, expanding drusen or even those that will
appear in future, suggesting that choroidal ischaemia is a critical event in the development of
AMD [25]. Age- related thickening of BM,
deposition of advanced glycosylated end products (AGE) and extracellular debris as basal
laminar deposits, and increased expression of
VEGF from the RPE and microglia in an ischaemic microenvironment lead to the formation
of pathological new vessels that grow most
commonly under the RPE (type1), less commonly under the NSR(type 2) or even from the
retina (type 3). These vessels do not have tight
endothelial junctions and leak uid and blood
under the macula.
13.5.4 Epigenetic Factors inDry AMD
The allele variants associated with AMD are regulatory proteins and not structural proteins.
Smoking, nutritional, and other environmental
factors are strong epigenetic factors for the
expression of regulatory proteins and increase the
risk for the development of AMD in carriers of
these alleles.
In the rst 10 years since the original studies
in 2005, large genome-wide association studies
discovered 52 independent common and rare
gene variants distributed across 34 loci [26]; at
present, the number has gone up to 90 allele variants spread over 55 independent loci [8]. Most of
the loci discovered in AMD are involved in either
complement-mediated inammation or lipid
metabolism.
13.5.5 Clinical Diagnosis ofAMD
The non-exudative AMD is asymptomatic in the
early and intermediate stages. It gets diagnosed in
patients who may visit an ophthalmology/optometry clinic for a routine examination/screening for
cataracts and glaucoma. The non- exudative AMD
is a symmetric bilateral disease, and 90% of
patients do not progress to an exudative stage.
Drusen are the hallmark of AMD and vary in size
from <63μ to nearly 1000μm. Small drusen,
<63μ, are seen in the macula as yellow- white discrete dot lesions and are commonly seen in older
people (Fig.13.1). These are called drupelets and
usually are not seen on fundus uorescein angiography (FFA). These stay unaltered for several
years and may show mineralization. On structural
356
ab
https://t.me/medicina_free
13 Macular Degeneration, Geographic Atrophy, andInherited Retinal Disorders
c
Fig. 13.1 Right eye shows (a) hard drusen (blue arrows),
and the left eye (b) shows hard drusen (blue arrows) along
with a subretinal haemorrhage (red arrow) suggestive of a
CNVM. OCT shows sub-RPE drusenoid deposits (blue
OCT, these appear as tiny nodular elevations over
the BM.These do not progress further to the GA
or predispose to choroidal neovascular membrane
(CNVM) formation. Soft drusen are made of a
similar lipoproteins debris but are larger than 63μ,
are pale yellow and have indistinct borders. The
presence of soft drusen <125μ is labelled as early
AMD (Fig. 13.2). These may become conuent
over time and increase in numbers. More than 20
soft drusen >63–124μ or multiple small with a
single large soft druse >125μ is classied as an
intermediate stage of AMD (Fig. 13.3).
Pigmentary changes may accompany the soft drusen. Both hyper and hypopigmentation may be
d
arrows) in the right eye (c), and a CNVM complex (red
arrow) with subretinal uid (blue arrow) in the left eye
(d). (Images courtesy of Dr Anita Agarwal, West Coast
Retina Medical Group, San Francisco, CA)
RPE. These were characterized only after the
availability of the structural OCT.These may be
best seen on blue light reectance images rather
than colour fundus photographs or IR reectance
images [24].
Gass [27] rst showed the development of
nAMD in 18% of eyes with drusen at an average
age of 75 years and an average follow-up of
nearly 5 years. These eyes were characterized by
the development of sub-RPE and subretinal exudation through either an intact BMor the growth
of new vessels through breaks in the BMcausing
exudative and haemorrhagic detachment of the
RPE and theNSR [27].
seen. The soft drusen are mound-like deposits
over the BM on structural OCT. On autouorescence, some of these may show a central hypoau-
13.5.6 Classication ofAMD
touorescence with a ring of hyperautouorescence.
A thin layer of basilar linear deposits connects the
soft drusen. The most signicant type of drusen is
the SDD under the NSR and overlie the
AMD is mainly of two types. More than 90% of
the cases have a gradually progressive nonexudative or dry type of AMD, and 10% have an
13.5 Age-Related Macular Degeneration (AMD)
https://t.me/medicina_free
357
a
b
Fig. 13.2 Early AMD: a 59-year-old female presented
with 6/24 vision and distortion of images in left eye.
Fundus examination (a) revealed soft drusens (blue
arrows) in the macula, seen as pale yellow lesions with
indistinct borders. Optical coherence tomography (b)
showed mound-like deposits over the Bruch’s membrane
(red arrows)
immediate vision-threatening wet type of neovascular AMD (nAMD). The hallmark of the
AMD is the development of drusen, which are
extracellular deposits of metabolic waste products between the basement membrane of the
RPE and the BM. These also get deposited
between the RPE and the NSR as SDDand have
been termed reticular pseudodrusen. A macular
research committee reached the following
consensus classication to bring uniformity in
investigators’ usage of various AMD stages
[28].
No apparent ageing changes: If there are no dru-
sen or pigmentary changes. Pigmentary
changes are considered signicant only if
associated with medium or large drusen.
Normal ageing changes: Drusen <63μm in size
without any pigmentary changes. These are
called drupelets.
Early AMD: Medium drusen >63 μm but
≤125μm and no pigmentary changes.
Intermediate AMD: Large drusen >125μm or any
pigmentary changes associated with medium
or large drusen.
Late AMD: Geographic atrophy and/or neovascu-
lar AMD.
13.5.6.1 Geographic Atrophy (GA)
Geographic atrophy (GA) is a late stage of nonexudative AMD and causes irreversible loss of
central vision. It manifests as complete loss of
the choriocapillaris (ChC), RPE, and the overlying photoreceptors. It is dened as sharply
demarcated area/s of atrophy of RPE, minimum
one-eighth optic disc size, with baring of the
large choroidal vessels without any new choroidal vessels [29]. There is a sharp demarcation of
the normal and atrophic retina (Fig. 13.4). For
this reason, it can be accurately measured on both
colour fundus pictures (CFP), fundus autouorescence (FAF), and OCT.On SD-OCT, the border of the GA is marked by a sharp descent of the
external limiting membrane (ELM)and piling up
of the RPE cells and the SDDs(Fig. 13.5). The
gap between the hypoautouorescent region on
FAF and the OCT marks the junctional zone, the
next area to degenerate [30]. Recently, based on
OCT characteristics, GA has been classied into
two stages, an incomplete RPE and outer retinal
atrophy (iRORA) and a complete RPE and outer
retinal atrophy (cRORA). For diagnosing,
iRORA, three OCT signs include vertically
aligned increased light signal transmission into
the choroid, RPE attenuation or disruption, with
overlying photoreceptor degeneration and subsidence of the INL, OPL, and ONL. If these
changes are at least 250 μm in size, these will
qualify for the diagnosis of cRORA [31].
AMD is a progressive disease, and irrespective of the successful use of intravitreal injection
of anti-VEGF to regress the new vessels, there is
no proven therapy to arrest the progression of the
GA.Notably, the macular atrophy progression in
eyes with macular new vessels (MNV) is signicantly slower than the GA in eyes without MNV,
highly suggestive of a protective role for MNV in
preventing macular atrophy [32].
358
ab
cd
https://t.me/medicina_free
13 Macular Degeneration, Geographic Atrophy, andInherited Retinal Disorders
Fig. 13.3 Intermediate AMD: a 75-year-old male presented with large, conuent, soft drusen in the macula,
seen as pale-yellow lesions in both eyes (a, b). Optical
coherence tomography showed large, mound-like deposits over Bruch’s membrane in both eyes (c, d)
ab
Fig. 13.4 Geographic atrophy: a sharply demarcated area (black arrow) of RPE atrophy with baring (blue arrow) of the
large choroidal vessels (a), seen as a dark hypoautouorescent area (red arrow) on fundus autouorescence (b)
Macular atrophy is distinct from GA. The
macular atrophy develops in about one-fourth of
the patients receiving anti-VEGF therapy over
12–24 months. By 7–8 years of follow-up, in
MNV patients, who continue to receive antiVEGF therapy, 100% of eyes may show macular
atrophy. The persistence of a shallow subretinal
uid >25μm appears protective against macular
atrophy development [33, 34].
Among the patients with GA, a new clinical
phenotype has been identied, which occurs in
relatively younger patients. They do not have
drusen and show features of pachychoroid and
hyperpermeability of choroidal vessels. The risk
13.5 Age-Related Macular Degeneration (AMD)
https://t.me/medicina_free
a b
359
Fig. 13.5 OCT of geographic atrophy: through the dark
hypoautouorescent area (blue arrow) of geographic atro-
allele ARMS2A69S was less frequent in these
patients than in conventional GA.These patients
have associated pachychoroid pigment epitheliopathy and may even have pachychoroid neovasculopathy. Unlike inherited retinal dystrophies,
these are asymmetric [35].
13.5.6.2 Progression ofDry AMD
toGA
The risk factors for progression from intermediate AMD to GA at 2 years include drusen volume, SDD, intraretinal hyperreective dots,
hyporeective core of drusen, and a thin double
layer sign observed on volume scans on OCT
[36].
For any interventional studies, the outcome
measure in GA is the rate of progression of
GA. In the age-related eye disease study
(AREDS2), 6.2% of eyes had pre-existing GA,
which was either central (33%) or non-central
(67%). The conguration was small (36%), unifocal (26%), multifocal (24%), horseshoe (9%),
or indeterminate (6%). Of those who did not
have GA at the onset, the 5-year incident rate of
GA was 19%. The 4-year risk of central involvement was 57% for those eyes that started with
non- central GA.The rate of progression of GA,
phy (a), the OCT shows complete loss (blue arrows) of
outer retinal layers and RPE (b). The border of GA is
marked by a sharp descent of ELM (red arrow)
irrespective of pre-existing or incident GA, was
~0.28mm2/year. The signicant risk factors for
progression were non-central lesions, bilaterality, and multifocality of the lesions. The progression was faster in the ARMS2 risk genotype and
C3 non-risk and APOE non-risk genotypes [29].
The ARMS2 allele and the reticular pseudodrusen are strong yet independent risk factors for
progression. The subretinal drusenoid deposits
(reticular pseudodrusen) are a signicant risk
factor for the fast progression of non-central GA
[37]. Patients with no reticular pseudodrusen and
no ARMS2 risk allele have the lowest risk of GA
progression [37].
In a large multicentric cohort, 4.5–16.5% of
patients with AMD showed progression over a
minimum follow-up of 2 years. Patients with
early or intermediate AMD in both eyes at presentation progressed to GA at 2/100 person-years
and nAMD 3.2/100 person-years. However, if
they already had GA in one eye, they progressed
at 11.2/100 person-years. In the presence of the
nAMD eye and early/intermediate AMD in the
other eye, they progressed at 4.1/100 personyears. If they had mixed GA+nAMD in one eye
and early/intermediate AMD in the fellow eye,
they progressed at 7.8/100 person-years. The
360
https://t.me/medicina_free
13 Macular Degeneration, Geographic Atrophy, andInherited Retinal Disorders
major risk factor for progression to GA was the
presence of GA in the fellow eye [38]. A prospective natural history study of patients with at least
>125μm2 area of GA measured progression by
FAF, CFP, or both. The GA progressed by
0.88mm2 at 6 months, 1.85mm2 at 12months,
and 3.14mm2 at 18months. When measured by
the CFP, the corresponding rates were 0.78, 1.57,
and 3.17mm2, respectively. The main risk factor
for progression was the presence of multifocal
areas of GA [39]. A similar progression
(3.85mm2) was noted at 2 years in a prospective
multicentric global observation study if both eyes
had GA at the onset. The progression rate was
3.55 mm2 if the fellow eye had nAMD and
2.96 mm2 if the fellow eye had intermediate
AMD [40].
Even before the RPE atrophy, there is a loss of
the EZ beyond the borders of RPE atrophy and
thinning of the outer segments, which can be
quantied on SD-OCT and predict future progression [41].
13.5.6.3 Treatment ofGA
Nutritional Supplement
Consumption of the Mediterranean diet, whole
fruits, a greater proportion of monounsaturated
fats, and alcohol intake within dened intervals
of g/day led to a signicant decrease in the progression of the GA.On the other hand, red meat
consumption was associated with a faster progression of GA [42]. Increasing consumption of
lutein and zeaxanthin-containing green leafy
vegetables and sh oil reduces the risk of AMD,
whereas supplementary calcium may increase the
risk of AMD [43].
Role ofAMD Genotyping
Genotyping is not recommended in patients with
AMD for several reasons, including the nonavailability of any genotyping-based treatment.
Patients with no AMD with genetic variants and
AMD clinical phenotypes with strong correlations for progression have little value added by
genotyping [43]. Genotyping remains as yet a
research tool. A genetic risk score can be calculated by adding up the weighted value (depend-
ing upon the strength of association) of the
presence of the gene variants [43].
Complement Inhibition inAMD
Many complement factors have been targeted to
halt the progression of GA. The most common
complement fragments targeted in clinical phase
1/2 trials are C3 and C5. Although successful in a
phase 2 trial, the factor D blocking agent,
Lampalizumab, in two parallel phase 3 trials
failed to halt the progression of GA over 48weeks
of follow-up [44].
Pegcetacoplan is a C3 inhibitor and blocks all
complement pathways. In a phase 2b study, the
use of intravitreal (IVT) injection of 15 mg
Pegcetacoplan every month or every other month
led to a signicant decrease (29%) in the progression of geographic atrophy. Every month treatment was more effective than every other month.
However, nearly 20% of the monthly treated eyes
developed new-onset exudative AMD at
12months versus 1.2% of the sham-treated eyes.
The safety and efcacy of this therapy need further evaluation in phase 3 studies [45].
A C5 inhibitor drug Avacincaptad pegol
(Zimura, Iveric bio), was tested in a phase 2/3
trial among 286 patients of GA. It showed a
27–28% reduction in progression rates of GA at
12 months compared to the sham group [46].
However, at the 18-month follow-up, 8–16% in
the treatment group developed exudative AMD
compared to 2% in the sham group. A post hoc
analysis revealed the presence of pre-existing
macular new vessels in the fellow eyes and the
double layer sign in the study eye as signicant
risk factors for developing exudative AMD in the
Pegcetacoplan-treated eyes [47]. In any case,
anti-VEGF treatment was highly effective in controlling the exudative AMD in these eyes.
Earlier, Eculizumab, a systemic inhibitor of
complement C5 although well tolerated for 6
months, was ineffective in preventing geographic
atrophy’s expansion [48].
Monoclonal antibodies to block Properdin
failed in the phase 2 clinical trial, and the trial
was stopped. Several trials are underway or have
been completed to study the efcacy of blocking
various complement pathways in AMD [49].
Соседние файлы в папке Библиотека им академика М.И. Перельмана