Ocular perfusion and age-related
macular degeneration
Thomas A. Ciulla, Alon Harris and Bruce J. Martin
Indiana University School of Medicine, Indianapolis, Indiana, USA
ABSTRACT.
Purpose: To review the role of ocular perfusion in the pathophysiology of agerelated macular degeneration (AMD), the leading cause of irreversible blindness
in the industrialized world.
Methods: Medline search of the literature published in English or with English
abstracts from 1966 to 2000 was performed using various combinations of relevant key words.
Results: Vascular defects have been identified in both nonexudative and exudative AMD patients using fluorescein angiographic methods, laser Doppler
flowmetry, indocyanine green angiography, and color Doppler imaging.
Conclusion: Although these studies lend some support to the vascular pathogenesis of AMD, it is not possible to determine if the choroidal perfusion abnormalities play a causative role in nonexudative AMD, if they are simply an association with another primary alteration, such as a primary RPE defect or a
genetic defect at the photoreceptor level, or if they are more strongly associated
with one particular form of this heterogeneous disease. Further study is warranted.
Key words: age-related macular degeneration – ocular perfusion – blood flow – choriod – choriocapiIlaris – retinal circulation.
Acta Ophthalmol. Scand. 2001: 79: 108–115
Copyright c Acta Ophthalmol Scand 2001. ISSN 1395-3907
A
ge related macular degeneration
(AMD) is the leading cause of irreversible visual loss in the United States,
occurring in over 10% of the population
aged 65 to 74 years and over 25% of the
population over the age of 74 years (Leibowitz et al. 1980). There are two types of
macular degeneration. The nonexudative
form involves atrophic and hypertrophic
changes in the retinal pigment epithelium
(RPE) underlying the central retina or
macula, drusen. Patients with nonexudative AMD can progress to the exudative
form of AMD, in which choroidal neovascular membranes (CNVM) develop
under the retina, leak fluid and blood,
and ultimately cause a blinding ‘‘disciform’’ scar in and under the retina. Nonexudative AMD occurs in approximately
27% of patients over 75 years, and exudative AMD occurs in nearly 5% of this
group (Klein et al. 1992). Overall, ap-
108
proximately 10–20% of patients with
nonexudative AMD progress to the exudative form, which is responsible for
most of the estimated 1.2 million cases of
severe visual loss from AMD (Hyman et
al. 1993; Tielsch et al. 1995). Also, it
should be noted that AMD is a bilateral
disorder; CNVM develop in over onefourth (26%) of fellow eyes that are initially free of exudative AMD over a fiveyear period (MPS 1993). As the population in the United States ages, visual loss
from AMD will become even more prevalent.
Nonexudative AMD is much more
common than exudative AMD and is
usually a precursor of exudative AMD.
The nonexudative form involves a variety
of presentations including hard drusen,
soft drusen and geographic (areolar)
atrophy of the RPE. Hard drusen are associated with localized dysfunction of the
RPE, while soft drusen are associated
with diffuse dysfunction of the RPE
(Bressler et al. 1988). Although more typically associated with exudative AMD, severe visual loss can occur from nonexudative AMD, particularly when geographic atrophy of the RPE develops in
the fovea to cause a central scotoma (Ciulla et al. 1998). Unfortunately, there is
no widely accepted treatment modality
for this devastating form of AMD, although some investigators have suggested
a protective effect from various micronutrients and vitamins and other investigators are studying laser treatment
of drusen (Ciulla et al. 1998).
Although the exudative form is treatable, treatment efficacy is currently low.
Currently, the only well-studied and
widely-accepted method of treatment is
laser photocoagulation of the CNVM as
demonstrated in several well designed
clinical trials, including the Macular
Photocoagulation Study (MPS), a group
of multicenter, randomized, controlled
clinical trials of laser photocoagulation
of choroidal neovascularization in patients with AMD, the presumed ocular
histoplasmosis syndrome, or in idiopathic
cases. The MPS showed that photocoagulation effectively prevented large decreases in visual acuity compared to observation. However, only 13–26% of patients with exudative AMD show welldemarcated ‘‘classic’’ CNVM (recognized
on fluorescein angiography as discreet
early hyperfluorescence with late leakage)
amenable to laser treatment and at least
half of these patients suffer from persistent or recurrent CNVM formation within
two years. Patients with poorly demarcated (due to subretinal hemorrhage, for
example) or ‘‘occult’’ CNVM (recognized
on fluorescein angiography as a fibrovascular pigment epithelial detachment
or late leakage of undetermined source)
make up the majority of patients with exudative AMD and are not eligible for
Fig. 1. According to the traditonal theory, primary genetic, dietary, or
photo-oxidative stress leads to RPE dysfunction, which consequently
leads to choriocapillaris atrophy and choroidal perfusion defects.
laser photocoagulation (Freund et al.
1993; Moisseiev et al. 1995; MPS 1982;
MPS 1986; MPS 1991).
Pathogenesis of AMD
Traditional theory
Several theories of pathogenesis have
been proposed and these include primary
RPE and Bruch’s membrane senescence,
primary genetic defects, and primary
ocular perfusion abnormalities. Oxidative insults have also been proposed as a
contributing factor. Traditionally, investigators have felt that senescence of the
RPE, which metabolically supports and
maintains the photoreceptors, leads to
AMD (Eagle 1984; Young 1987). It has
been felt that the senescent RPE accumulates metabolic debris as remnants of incomplete degradation from phagocytosed
rod and cone membranes and that progressive engorgement of these RPE cells
leads to drusen formation with subsequent progressive further dysfunction
of the remaining RPE (Eagle 1984;
Young 1987). (Figs. 1 & 2).
Bruch’s membrane, thickened with
drusen, could be predisposed to crack
formation (Green et al. 1985; Sarks
1976). Calcification and fragmentation of
Bruch’s membrane is more prominent in
eyes with exudative AMD, and it is
thought that these defects in Bruch’s
membrane could facilitate development
of CNVM (Spraul & Grossniklaus 1997).
This theory is supported by findings in
Fig. 2. According to the traditional theory, senescent RPE is susceptible
to genetic, dietary, or photo-oxidative stress, which in turn leads to
failure to metabolize photoreceptor outer segments that are constantly
being shed. This leads to drusen formation. In addition, RPE dysfunction or atrophy leads to choriocapillaris atrophy.
myopic degeneration and angioid streaks
in which CNVM develop through breaks
in Bruch’s membrane. The well-known
primate-laser model, developed by Ryan,
may also support this theory for CNVM
(Ishibashi et al. 1995, 1985, 1987; Miller
et al. 1990; Nishimura et al. 1990; Ohkuma & Ryan 1982, 1983; Ryan 1979,
1982). In this model, high intensity laser
burns are used to create ruptures in
Bruch’s membrane/RPE complex to initiate a repair process in the fundus that
results in the development of subretinal
neovascularization (Miller et al. l990).
The exact stimulus for CNVM formation
is unclear; it is possible that macrophages
involved in the initial response to Bruch’s
membrane injury secrete angiogenic
growth factors (Ishibashi et al. 1985; Nishimura et al. 1990).
Another potential mechanism by
which CNVM could develop in response
to fragmentation of Bruch’s membrane
could relate to matrix metalloproteinases
(MMP) which are extracellular matrix
degrading enzymes that may play a key
role in angiogenesis and CNVM formation (Steen et al. 1998). Bruch’s membrane has been shown to contain tissue
inhibitor of metalloproteinases (TlMP)-3
(Faris et al. 1997) and eyes with AMD
have been shown to have abnormal levels
of TIMP-3 compared to normal agematched control eyes (Kamei & Holleyfield 1999); calcification and fragmentation observed in Bruch’s membrane
may represent a breach in this antiangiogenic barrier, facilitating CNVM devel-
opment. Whatever the initial stimulus for
CNVM formation, it is clear that angiogenic growth factors are ultimately involved. Surgically excised and post mortem CNVM tissue, as well RPE cells, have
been shown to be immunoreactive for
various growth factors thought to be
angiogenic, including vascular endothelial growth factor (VEGF), transforming growth factor-beta (TGF-b),
platelet derived growth factor (PDGF)
and basic fibroblast growth factor (FGF)
(Amin et al. 1994: Kvanta 1995; Lopez et
al. 1996; Reddy et al. 1995).
Genetic Defects
Yet another theory involves genetic defects. A variety of genes have been suggested. For example, some investigators
recently reported that 16% of AMD patients in their study had a genetic defect
in a gene encoding a retinal rod protein,
the ABCR gene, which has also been
found to be defective in Stargardt’s disease (Allikmets et al. 1997). However,
there have been two more recent publications suggesting that the ABCR mutations might not be linked to AMD (De
La Paz et al. 1999; Stone et al. 1998).
There have also been recent reports of a
genetic association between AMD and
apolipoprotein E, a protein that plays a
role in central nervous system lipid
homeostasis (Klaver et al. 1998; Souied et
al. 1998). Investigators are also studying
other hereditary dystrophies with some
109
features similar to AMD, such as Malattia Leventinese and Doyne’s Honeycomb
retinal dystrophy, which are characterized
by drusen and have been associated with
a single mutation in the gene for EGFcontaining fibrillin-like extracellular matrix protein 1 (Stone et al. 1999). Sorsby’s
dystrophy, an autosomal dominant disorder that presents in the fifth decade,
shows several similarities to AMD, including submacular exudates and hemorrhages initially followed by cicatrization,
and a point mutation on the TIMP-3
gene has been reported (Weber et al.
1994). Another group, however, found no
evidence of linkage or association between the TIMP-3 gene in 38 multiplex
families with AMD (De La Paz et al.
1997).
group of investigators showed correlation
between the regions of sparring in annular maculopathy and the spatial distribution of macular pigments (Weiter et al.
1988). Furthermore, factors known to
decrease macular pigment optical density
(MPOD) levels, such as cigarette smoking (Hammond et al. 1996), light iris
color (Ciulla et al. 2000; Hammond et al.
1996), and female gender (Hammond et
al. 1996), have also been implicated to increase the risk of AMD in epidemiologic
studies; this parallel is directional, with
factors that decrease MPOD leading to
increased risk of AMD and factors that
increase MPOD leading to decreased risk
of AMD, consistent with a potential protective role of macular pigments in AMD.
Oxidative Insults
Ocular Perfusion Defects
in AMD
Oxidative insults have also been proposed
as a contributing factor and this may involve the macular pigments, lutein and
zeaxanthin, which are primarily obtained
from dark green, leafy vegetables and account for the yellow pigmentation of the
macula lutea (Bone et al. 1993, 1985).
Macular pigment is of dietary origin as
humans and non-human primates do not
synthesize carotenoids de novo (Malinow
et al. 1980; Neuringer et al. 1999). Macular pigment has been hypothesized to
play a protective role against the development of AMD through the limitation of
oxidative insults (Katz et al. 1982;
Schalch 1992; Seddon & Hennekens
1994; Snodderly et al. 1984) by filtering
out harmful wavelengths of light (Bone et
al. 1985) or by the antioxidant properties
of its components (Katz et al. 1982;
Schalch 1999).
A recent study showed that primates
raised on carotenoid-depleted diets had a
significantly increased incidence of angiographic transmission defects in the macular regions (Neuringer et al. 1999). Previous studies have shown that a higher
dietary intake of L and Z has been associated with a lower risk for AMD (Seddon
et al. 1994; West et al. 1994). Another
link between macular pigment and AMD
derives from observations of atrophic
AMD. The central fovea, which contains
the highest concentrations of macular
pigment, is often spared from atrophy
until late in progression, causing some investigators to postulate that macular pigments account for the relative resistance
of this area to degenerative change; one
110
With regard to the role of choroidal perfusion defects, it is well known that the
choriocapillaris supplies the metabolic
needs of the retinal pigment epithelium
and the outer retina; a primary perfusion
defect in the choriocapillaris could account for some of the physiologic and
pathologic changes in AMD. For example, both acute ischemia and the subsequent reperfusion of the brain are associated with CNS cell death (Chen et al.
1997; Gillardon et al. 1996; Leib et al.
1996; Macaya 1996; Nickells 1996; Quigley et al. 1995). Cell death after ischemia
occurs primarily by apoptosis, especially
when the insult is mild (Chen et al. 1997;
Gillardon et al. 1996; Leib et al. 1996;
Macaya 1996). Mild ischemia is postulated to provoke precisely such a cellular
event in retinal ganglion cells in glaucoma (Chen et al. 1997; Gillardon et al.
1996; Harris et al. 2000; Leib et al. 1996;
Macaya 1996; Nickells 1996; Quigley et
al. 1995), which is characterized by slow
loss of these cells over years, and some
forms of AMD (such as geographic atrophy of the RPE characterized by progressive loss of RPE cells) could have a
similar pathogenesis to glaucoma.
In the vascular model for AMD pathogenesis proposed by Friedman, it is
theorized that lipid deposition in sclera
and Bruch’s membrane leads to scleral
stiffening and impaired choroidal perfusion, which would in turn adversely affect metabolic transport function of the
retinal pigment epithelium (Friedman
1997; Friedman et al. 1995). The im-
paired RPE cannot metabolize and transport material shed from the photoreceptors, leading to accumulation of metabolic debris and drusen (Friedman 1997;
Friedman et al. 1995). (Figs. 3–5). This
theory is supported by studies demonstrating an association between increased
scleral rigidity and AMD (Friedman et
al. 1989). In addition, AMD, with its
widely varying clinical presentations,
may actually represent several distinct
disorders that have yet to be more clearly
differentiated on a pathogenic basis; it is
possible that RPE senescence represents
the primary derangement in some subforms, choroidal perfusion defects represent the primary derangement in other
subforms, and perhaps specific genetic
defects represent the primary defect in yet
other subforms. Epidemiological risk
factors, such as tobacco use (Christen et
al. 1996; Seddon et al. 1996), blue light
or sunlight exposure (Cruickshanks et al.
1993) and nutritional factors (MaresPerlman et al. 1995; Seddon et al. 1994)
could represent environmental influences
that exert a detrimental secondary effect
on individuals with any of the underlying
primary derangements noted above. Of
note, many of the risk factors for AMD
are similar to those for cardiovascular
disease, including tobacco use, hypertension, and nutritional factors, lending
further support for a vascular role in
AMD.
The vascular theory is supported by
studies demonstrating delayed choroidal
filling in AMD using conventional angiographic techniques (Boker et al. 1993; Remulla et al. 1995; Zhao et al. 1995). Delayed choroidal filling may have histologic significance as it may correlate with
diffuse thickening of Bruch’s membrane
(Pauleikhoff et al. 1990). This sign also
has functional significance as eyes with
this sign harbor discrete areas of increased threshold on static perimetry
(Chen et al. 1992) and are at risk for loss
of vision (Piguet et al. 1992). Specifically,
in one study, 38% of 32 eyes with this sign
lost two or more lines of vision by two
years compared to 14% of 64 eyes without this sign (Piguet et al. 1992). This difference was related to the greater incidence of geographic atrophy in the patients with delayed choroidal filling;
significantly, the incidence of CNVM was
similar in each group of patients (Piguet
et al. 1992).
It is very difficult to quantify choroidal
blood flow angiographically given the
overlying retinal circulation and multilay-
Fig. 3. According to the vascular theory, primary choroidal perfusion
abnormalities lead to RPE dysfunction and then to AMD.
Fig. 5. Decreased choroidal perfusion impairs RPE transport function
as the RPE must pump against a higher osmotic gradient. The photoreceptor outer segments, which are constantly being shed, are not properly metabolized by the RPE, which leads to drusen formation.
Fig. 4. Choroidal perfusion abnormalities arise as lipid is deposited in
the sclera and Bruch’s membrane, which then leads to collagen and
elastic degeneration, causing scleral stiffening. The increase in scleral
rigidity leads to decreased compliance and increased resistance in the
choroid, which then leads to decreased choroidal perfusion.
Fig. 6. According to the vascular model as proposed by Friedman
(Friedman 1997; Freidman et al. 1995), there is a generalized stiffening
and increase in resistance, not only in the choroidal vasculature, but
also in the cerebral vasculature. If the choroidal resistance increases
more that the cerebral vascular resistance, there is a decrease in choroidal perfusion with an increase in the osmotic gradient against which
the RPE must pump, leading to an accumulation of metabolic debris
in the form of drusen. If the choroidal resistance increases less than the
cereoral vascular resistance, there is higher choroidal perfusion pressure, which facilitates CNVM development.
ered choroidal circulation that complicates analysis. Recently, however, new
technologies have been employed to
corroborate the existence of choroidal
perfusion anomalies in AMD, including
ICG angiography, laser Doppler flowmetry, and color Doppler imaging
(Harris et al. 1999).
One group recently used a new analysis
technique based on indocyanine green
angiography to compare the choroidal
circulation in patients with AMD to a
control group. ICG facilitates study of
the choroidal circulation for several reasons. First, ICG better delineates the
choroidal circulation than fluorescein because the near-infrared light absorbed by
ICG penetrates the retina pigment epithelium better than the shorter wavelength absorbed by fluorescein. Also, unlike fluorescein, ICG is strongly bound to
plasma proteins, which prevents diffusion
of the compound through the fenestrated
choroidal capillaries, and permits better
delineation of choroidal details. This
study showed a statistically significant increased frequency of presumed macular
watershed filling (PMWF), which was described as ‘‘characteristic vertical, angled,
or stellate-shaped zones of early-phase
indocyanine green videoangiographic hypofluorescence, assumed to be hypoperfusion, which disappeared in the early
phase of the angiogram’’ (Ross et al.
l998). The investigators noted that 55.4%
of 74 patients with AMD versus 15.0%
111
of 20 normal control patients exhibited
PMWF. They also note that 59.0% of the
61 patients with AMD-associated choroidal
neovascularization
exhibited
PMWF and that the CNVM arose from
the PMWF zone in 91.7% of these cases.
This analysis approach provides valuable
insight into abnormalities of choroidal
circulation in AMD, although this
method requires subjective assessment for
the presence and location of PMWF.
Another more objective approach has
been employed using a new, area dilution
analysis technique applied to ICG angiography (Ciulla et al. 1998; Harris et al.
1998). Scanning laser ophthalmoscope
angiograms in 21 nonexudative AMD
subjects were compared to 21 agematched control subjects (Ciulla et al.
2000). After correction for eye movements, the digital image analysis system
recorded mean intensity levels at each
area over time. Four areas around the
macula and two areas in the temporal
peripapillary retina were evaluated. Fluorescence density in each block was averaged over time, graphed, and analyzed
for dye appearance time and maximal
fluorescence. In addition, intensity curves
were analyzed by quantifying the slope of
the filling portion of the curves, the
amount of time required to rise 10% and
63% above baseline by graphing intensity
of fluorescence of each area over time. Although the exact concentration of ICG in
each region cannot be determined, simultaneous acquisition of dye dilution curves
from these regions within the choroid facilitates comparison of relative concentrations between these regions. Since the
six analysis regions are identically positioned on each subjects angiogram, the
resulting analysis represents a very objective evaluation of choroidal perfusion
characteristics and does not rely on subjective assessment. This technique showed
statistically significant delayed and heterogeneous filling within the choriocapillaris of nonexudative AMD patients
when compared to normal age-matched
controls, and these changes showed some
macular-region specificity (Ciulla et al.
2000). In addition, the localized choroidal perfusion defects correlated in a
statistically significant fashion with visual
acuity and severity of non-exudative agerelated macular degeneration.
Another group used a new technique
called laser Doppler flowmetry in subjects with nonexudative AMD to show
that the choroidal blood flow was decreased at the center of the fovea com-
112
pared to a control group (Grunwald et al.
1998). This technique cannot be readily
applied outside the foveal center as the
overlying retinal circulation would
Doppler shift the reflected light from the
laser and prevent analysis of the choroid.
Nevertheless, this study and the ICG angiogram studies were consistent in that
this prior study showed alterations in
choroidal flow in the foveal center and
the ICG angiogram studies confirmed
alterations with some macular-region
specificity, although the foveal center itself was not measured.
Color Doppler imaging has been used
to evaluate the retrobulbar vasculature in
AMD; two groups have found statistically significant differences in the central
retinal and posterior ciliary arteries in
patients with AMD compared to controls
(Ciulla et al. 1999; Friedman 1995, 1997).
Critics of the vascular theory point to
literature that suggests that healthy RPE
necessary for maintenance of the choroid
and choriocapillaris (Del Priore et al.
1995, 1996; Henkind & Gartner 1983;
Korte et al. 1984; Nasir et al. 1997; Pollack et al. 1996; Takeuchi et al. 1993) and
that the vascular changes found in AMD
are secondary to primary RPE dysfunction. In primate eyes, in which the RPE
was selectively damaged by intravitreal
ornithine (Takeuchi et al. 1993) and in
porcine eyes in which the RPE was debrided surgically, the choriocapillaris degenerated by two months and one week,
respectively (Del Priore et al. 1995, 1996).
Another group obtained a similar result
in a rabbit model in which the RPE was
damaged by intravenous sodium iodate,
and they also observed absence of the
choriocapillaris histopathologically in
human eyes with retinitis pigmentosa;
they postulated the existence of a diffusable vascular modulation factor, produced by the RPE and responsible for
choriocapillaris fenestrae formation and
maintenance (Henkind & Gartner 1983;
Korte et al. 1984). Some reports suggest
that surgical removal of the RPE in
humans (during removal of choroidal
neovascular membranes) leads to abnormal perfusion of the choriocapillaris, although it is not possible to rule out preexisting atrophy or intraoperative damage (Nasir et al. 1997; Pollack et al.
1996).
Although it may not be possible to definitively determine it the vascular derangements found in AMD are primary
or secondary, findings from color Doppler imaging may support primary vascular
dysfunction. Specifically, it is intriguing
to elicit perfusion deficits in the central
retinal artery of AMD subjects, as one
would not necessarily anticipate a vascular derangement beyond the posterior ciliary arteries, which supply the choroid.
These results suggest that there may be a
more generalized perfusion defect beyond
the choroid in patients with AMD. In addition, the vascular model could account
for development of both the nonexudative and exudative forms of AMD. According to the vascular model, there is a
generalized stiffening and increase in resistance, not only in the choroidal vasculature, but also in the cerebral vasculature (Friedman 1997; Friedman et al.
1995). If the choroidal resistance increases more than the cerebral vascular
resistance, there is a decrease in choroidal
perfusion with an increase in the osmotic
gradient against which the RPE must
pump, leading to an accumulation of
metabolic debris in the form of drusen. If
the choroidal resistance increases less
than the cerebral vascular resistance,
there is higher choroidal perfusion pressure, which facilitates CNVM development. This mechanism could partially account for the development of CNVM in
the presence of Bruch’s membrane senescence or cracks.
Therapies Based on
Blood Flow
It is unclear if improving macular perfusion would lead to improved function
in nonexudative AMD or delayed disease
progression. Friedman originally proposed a clinical study that involves lamellar scleral resection as a means of decreasing scleral rigidity to enhance choroidal perfusion and in turn arrest the
progression of the disease. However, this
proposition generated significant controversy, given the invasive nature of this
procedure and the unsettled role of ocular perfusion defects in the many presentations and types of AMD. Nevertheless,
several currently available topical ophthalmic and systemic pharmaceutical
agents have been shown to enhance ocular blood flow in normal and glaucomatous eyes and these agents could have a
potential role in AMD. In healthy individuals, for example, three different topical beta-blockers, including both Beta1selective and nonselective agents (levobunolol, betaxolol, and timolol) each re-
duced the intraocular pressure (IOP), decreased the retinal arteriovenous passage
time, and increased macular capillary and
epipapillary passage time, without altering superior temporal arterial or venous diameters (Harris et al. 1995). These
results suggest enhanced perfusion of the
retina. In a subsequent comparison of timolol and betaxolol in normal tension
glaucoma, there was a dissociation between IOP alterations and blood flow
changes, with timolol (but not betaxolol)
significantly lowering IOP, while betaxolol (but not timolol) increasing end-diastolic velocities and reducing resistance indices in the average of four different
retrobulbar vessels (Harris et al. 1995).
These results suggest that betaxolol can
enhance ocular perfusion via a non-IOP
lowering mechanism.
Another pharmaceutical agent that
can enhance ocular perfusion is topical
dorzolamide. In 11 healthy subjects, dorzolamide reduced IOP decreased arteriovenous passage time, and increased
macular and superficial optic nerve head
capillary transit velocities, without altering the diameter or the superior temporal artery or vein. It did not alter flow
velocities or resistance indices in four
retrobulbar vessels on color Doppler imaging (Harris et al. 1996). Similar results
have been obtained in studies involving
subjects with normal tension glaucoma,
with a 24% decrease in retinal arteriovenous passage time after dorzolamide
treatment despite no significant alteration
in retrobulbar flow velocities (Harris et
al. 1996).
Another category of agents includes
calcium channel blockers. In one study,
there was a correlation between the mean
visual field defect and central retinal artery resistance index in 14 subjects with
normal tension glaucoma who were
treated with calcium channel blockers
(Pillanat et al. 1994, 1995). This study
also showed that those patients with the
greatest initial central retinal artery resistance index experienced the greatest improvement in mean visual field defect
(Pillanat et al. 1994, 1995). Another
study showed an improvement in mean
contrast sensitivity and alterations in
ophthalmic artery peak systolic and enddiastolic velocities in 16 of 21 normal tension glaucoma patients treated with oral
nifedipine (Harris et al. 1997). These
findings corroborate the idea that ocular
perfusion and ophthalmic visual function
are correlated.
Consequently, it is apparent that modu-
lation of ocular blood flow is possible
using currently available topical ophthalmics (glaucoma therapy) and systemic
agents (calcium channel antagonists).
These agents may improve visual function
as measured by contrast sensitivity and
visual field assessment. Further study of
these agents in nonexudative age-related
macular degeneration is warranted.
Conclusion
In summary, there appears to be a specific derangement in the choroidal circulation in patients with AMD. Specifically,
vascular defects have been identified in
both nonexudative and exudative AMD
patients using fluorescein angiographic
methods, laser Doppler flowmetry, indocyanine green angiography, and color
Doppler imaging. Although these studies
lend some support to the vascular pathogenesis of AMD, it is not possible to determine if the choroidal perfusion abnormalities play a causative role in nonexudative AMD, if they are simply an
association with another primary alteration, such as a primary RPE defect or a
genetic defect at the photoreceptor level,
or if they are more strongly associated
with one particular form of this heterogeneous disease. Specific issues to be addressed in future studies include correlation of perfusion defects with various
subtypes of nonexudative AMD, further
correlation of perfusion defects with severity of the disease process within these
subtypes, correlation of perfusion defects
with disease progression, and assessment
of currently-available vasoactive pharmaceutics in improving macular perfusion
and function in nonexudative AMD or to
slow disease progression in this disorder.
Acknowledgement
Supported, in part, by grants from Research to
Prevent Blindness, Inc.; and N.I.H. grant
EY10801. Dr. Ciulla is a recipient af a career
development award from Research to Prevent
Blindness, Inc., New York.
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Received on August 18th, 2000.
Accepted on August 25th, 2000.
Corresponding author:
Alon Harris, Ph.D.
702 Rotary Circle, IUMC
Indianapolis, IN, 46260
USA
Phone: 317 278 0134
115