35
tially the blood flow through the neovascular network is
sluggish and there is little or no exudation. This is a pe-
riod of occult neovascularization and the overlying RPE
and neuroretina may be minimally affected
(5)
. With an
increase of blood flow through the network, the endo-
thelium decompensates and exudation extends into the
subpigment epithelial space creating in some cases RPE
detachments. The exudation may also extend through
the RPE and detach the overlying retina.
In type II CNV the new vessels extend from the choroid
through defects in Bruch´s membrane enters the space
between the photoreceptors and RPE cells and grow lat-
erally in the subretinal space
(5)
. This is usually accom-
panied by varying amounts of subretinal exudates and/
or blood.
Macrophages have been documented both morphologi-
cally and functionally in neovascular AMD
(42,43)
. Acti-
vated macrophages and microglia may secret cytokines
and chemokines that promote cellular damage and an-
giogenesis
(44)
.
Involution of CNV eventually occurs and is associated
with varying degrees of subretinal scar tissue, reactive hy-
perplasia of the RPE and/or atrophy, and can partially
or totally replace the neuroretina
(19)
. The outer nuclear
layer can be severely attenuated with a reduction of pho-
toreceptor length of almost 70%
(45)
. Often anastomosis
between the retinal circulation and the underlying cho-
roidal circulation develops within these old disciforme
scars
(29,46)
.
Other factors like complement factor H, that down-
regulates the alternative complement pathway
(47)
, HtrA1
– a secretory protein and an inhibitor of transforming
growth factor ß (TGF-ß)
(48)
- and ARMS2
(49)
play a role
in development of AMD. However its specific role and
relevance in development and progression to neovascular
and atrophic forms of age-related macular degeneration
are discussed in others chapters of this book.
Pathogenic Mechanisms
ment clumping at the level of the outer retina or sub-retinal
space, increases the risk of progression to the late phases of
the disease
(31,33,37).
The primary clinical characteristic of late dry AMD is the
appearance of geographic atrophy (GA) of RPE. On mi-
croscopy, GA is seen as abnormal RPE cells with hypotro-
phy, atrophy, hypertrophy, hypopigmentation, hyperpig-
mentation, migration, loss of photoreceptors, attenuation
of Bruch’s membrane and choriocapillaris degenera-
tion
(38,39)
. Geographic atrophy is clinically characterized
by roughly oval areas of hypopigmentation that allows the
increase visualization of the underlying choroidal vessels
and is the consequence of RPE cell loss. Loss of RPE cells
leads to gradual degeneration of photoreceptors and thin-
ning of the retina that may extend to the outer plexiform
and inner nuclear layers
(6,24)
. Compensatory RPE cell pro-
liferation leads to hyperpigmentary changes frequently
observed at the periphery of the hypopigmented areas
(6)
.
The atrophy of RPE is usually more severe than the loss of
choriocapillaris but the choriocapillaris seem to be highly
constricted in areas of complete RPE cell loss
(38)
.
In neovascular AMD early choroidal neovasculariza-
tion occurs under the RPE
(40)
and eventually breaks
through
(41)
, leading to accumulation of lipid-rich fluid
under the retinal pigment epithelium or neuroretina. In
haemorrhagic forms blood breaks through the RPE into
the subretinal space and sometimes through the retina
and into the vitreous
(32)
.
The pattern of growth of CNV often simulates that of a
sea fan with radial arterioles and venules supplying and
draining a circumferential dilated capillary sinus
(5)
.
As neovascularization of the sub-RPE space occurs, ini-
3. Late AMD
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