Pulsatile ocular blood flow in asymmetric age-related macular degeneration

Abstract

Ocular perfusion abnormalities have been proposed in the pathogenesis of age-related macular degeneration (AMD) with differences in pulsatile ocular blood flow (POBF) in eyes with asymmetric AMD in Japanese and Taiwanese patients. The purpose of our study was to observe POBF difference in the fellow eyes of Caucasians with asymmetric AMD.
This was a cross-sectional study comparing POBF in three groups of patients with asymmetric AMD in the fellow eyes: Group 1 (n=21) with drusen and active choroidal neovascularisation (CNV); Group 2 (n=18) with drusen and disciform scar; Group 3 (n=8) with CNV and disciform scar. The POBF was adjusted for intraocular pressure (IOP), pulse rate (PR), and axial length using multiple regression analysis. Generalised estimation equation model was used to include both eyes in each group.
The geometric mean (95% confidence interval) POBF values were as follows: Group 1 with drusen 1097.9 microl/min (957.0, 1259.7) in one eye and the fellow eye with CNV 1090.1 microl/min (932.3, 1274.7); Group 2 with drusen 946.0 microl/min (794.2, 1126.7) and disciform scar 966.2 microll/min (780.3, 1196.4); Group 3 with CNV 877.1 microl/min (628.3, 1224.6) and disciform scar 767.2 microl/min (530.5, 1109.7). Adjusting for differences in axial length, pulse rate and intraocular pressure, no statistically significant difference in POBF was found between fellow eyes in the same subject.
POBF is not different between fellow eyes of Caucasian patients with asymmetric AMD.

Full text

Pulsatile ocular
blood flow in
asymmetric age-
related macular
degeneration
R Sandhu
1
, S Sivaprasad
1
, SP Shah
2
, T Adewoyin
1
and NV Chong
1
Abstract
Purpose Ocular perfusion abnormalities
have been proposed in the pathogenesis of
age-related macular degeneration (AMD) with
differences in pulsatile ocular blood flow
(POBF) in eyes with asymmetric AMD in
Japanese and Taiwanese patients. The purpose
of our study was to observe POBF difference
in the fellow eyes of Caucasians with
asymmetric AMD.
Methods This was a cross-sectional study
comparing POBF in three groups of patients
with asymmetric AMD in the fellow eyes:
Group 1 (n¼21) with drusen and active
choroidal neovascularisation (CNV); Group 2
(n¼18) with drusen and disciform scar; Group
3(n¼8) with CNV and disciform scar. The
POBF was adjusted for intraocular pressure
(IOP), pulse rate (PR), and axial length using
multiple regression analysis. Generalised
estimation equation model was used to
include both eyes in each group.
Results The geometric mean (95% confidence
interval) POBF values were as follows: Group 1
with drusen 1097.9 ll/min (957.0, 1259.7) in one
eye and the fellow eye with CNV 1090.1 ll/min
(932.3, 1274.7); Group 2 with drusen 946.0
ll/min (794.2, 1126.7) and disciform scar
966.2 ll/min (780.3, 1196.4); Group 3 with
CNV 877.1 ll/min (628.3, 1224.6) and
disciform scar 767.2 ll/min (530.5, 1109.7).
Adjusting for differences in axial length,
pulse rate and intraocular pressure, no
statistically significant difference in POBF was
found between fellow eyes in the same
subject.
Conclusions POBF is not different between
fellow eyes of Caucasian patients with
asymmetric AMD.
Eye (2007) 21, 506–511. doi:10.1038/sj.eye.6702242;
published online 3 February 2006
Keywords: pulsatile ocular blood flow;
asymmetric age-related macular degeneration;
choroidal blood flow
Introduction
Age-related macular degeneration (AMD) is the
leading cause of severe visual loss in patients
above the age of 50 years in industrialised
countries.
1–3
It is a heterogenous disorder and is
broadly classified into nonexudative or dry
type, and exudative or wet type. Despite its
high prevalence and public health impact, the
aetiology of AMD remains largely unknown.
Various studies have investigated the possible
aetiological mechanisms of pathogenesis of
AMD, suggesting genetic predisposition,
4–6
retinal pigment epithelial (RPE) senescence,
7,8
oxidative stress,
9
local inflammation or
immunological stimuli,
10,11
and haemodynamic
abnormalities.
12,13
Ocular perfusion abnormalities in relation to
AMD have been studied in the past using
various techniques. Pulsatile ocular blood flow
(POBF) reflects the total pulsatile component of
ocular blood flow. The pulsatile component of
the total blood flow ranges from 50 to 80%.
14
As
most of the ocular blood volume is present in
the choroid, the retina contributes very little to
the pulsatile component, which is thought to
mainly represent the choroidal circulation. It is
measured by a pneumotonometer based on a
pressure volume relationship as demonstrated
originally by the Langham OBF System.
15
This
provides a noninvasive, reliable, reproducible,
and inexpensive method of calculating the
average POBF from the IOP. POBF may be
influenced by various factors such as age, sex,
blood pressure, scleral rigidity, refractive error,
and axial length. However, a recent study
evaluating these factors found axial length to be
Received: 19 July 2005
Accepted in revised form:
28 November 2005
Published online: 3 February
2006
This work has been
presented as a poster at the
European association for
Vision and Eye Research,
Vilamoura, Portugal in
September 2004
1
Retinal Research Unit,
Department of
Ophthalmology, King’s
College Hospital, Denmark
Hill, London, UK
2
Clinical Research Unit,
London School of Hygiene
and Tropical Medicine,
London, UK
Correspondence:
NV Chong,
Retinal Research Unit,
Department of
Ophthalmology, Normanby
Building,
King’s College Hospital,
London SE5 9RS, UK
Tel: þ44 7346 4548;
Fax: þ44 7346 3738;
E-mail: victor@
eretina.org
Eye (2007) 21, 506–511
&2007 Nature Publishing Group All rights reserved 0950-222X/07 $30.00
www.nature.com/eye
CLINICAL STUDY

the only statistically significant factor influencing POBF
in normal subjects.
16
A group-wise comparison between exudative AMD,
nonexudative AMD and age-matched controls in a
Japanese cohort showed significant decrease in POBF in
exudative AMD.
17
In addition, significant difference in
POBF was found between eyes in asymmetric AMD in a
Taiwanese group.
18
The POBF was found to be higher in
eyes with choroidal neovascularisation (CNV) than in
fellow eyes with drusen, suggesting a role for
haemodynamic abnormalities in the development and
progression of AMD. However, it is well documented
that there are racial variations in the risk factors
19
and
prevalence
20,21
of AMD. The aim of our study was to
determine whether ocular blood flow disturbances in
fellow eyes with asymmetric AMD, using the POBF
method, in Caucasian subjects play a significant role in a
racially different sample population, and to correlate
these changes with disease activity.
Materials and methods
Methods
The study subjects underwent assessment of best
corrected logmar visual acuity, slit-lamp biomicroscopy,
fundus photography, fluorescein angiography, and axial
length measurements using the IOL Master (Zeiss) based
on the principle of laser interferometry.
POBF was measured using the OBF Analyser (Ocular
Blood Flow Analyser, Dicon Diagnostics, Paradigm,
USA). Subjects were assessed in the sitting position by
the same examiner who was masked to the diagnosis in
each eye. The measurements were taken with a mounted
probe after instillation of topical anaesthetic (0.5%
proxymetacaine). POBF values were calculated and
expressed as a mean of measurements taken from five
representative pulses.
This study was ethically approved by the Central
Office for Research and Ethics Committees (COREC),
UK. All procedures adhered to the tenets of the
Declaration of Helsinki.
Patients
The inclusion criteria were as follows: age Z50 years;
Caucasian; evidence of asymmetric AMD. Exudative
AMD included active CNV and disciform scar. The
International Classification and Grading of AMD
nomenclature
22
was used for the definition of active
CNV, disciform scar, and age-related maculopathy (stage
2a–3 as per Rotterdam study criteria).
23
The CNV lesions
were defined as classic, occult, or mixed as per TAP
study criteria.
24
Grading of the digital colour photographs and
fluorescein angiograms was performed by two
independent graders from King’s College Hospital.
Double grading for intraobserver and interobserver
variability was performed. Discrepancies were resolved
by the senior author.
The patients were divided into three groups based on
the findings of slit-lamp biomicroscopy, fundus
photography, and fluorescein angiography:
(a) Group 1, patients with early age-related
maculopathy (ARM) that is, drusen in one eye and
active CNV in the fellow eye.
(b) Group 2, ARM (drusen) in one eye and disciform
scar in the fellow eye.
(c) Group 3, active CNV in one eye and disciform scar in
the fellow eye.
Exclusion criteria were as follows: high myopia,
history of any associated ocular conditions such as
coexistent glaucoma, diabetic retinopathy, vascular
disorders including hypertensive retinopathy, and veno-
occlusive disease.
Statistical analysis
There was good intergrader agreement as assessed by
Cohen’s kappa statistics (k¼0.8). The distribution of
POBF values was assessed and found to be positively
skewed. Log transformation normalised the data
(Shapiro Wilks test for normality P¼0.37). Geometric
means and confidence intervals (CI) were calculated.
Paired Student’s t-test was used to compare differences
in geometric means of POBF between fellow eyes of the
same subject. Multivariate linear regression analysis with
log transformed POBF as the dependant variable was
used to adjust for differences in axial length, IOP, and PR.
To allow for dependence in the data because of the study
of two eyes in one subject, a generalised estimation
equation model of variance analysis was used. Tests are
two-sided with CI quoted at 95%.
Results
In total, 47 subjects with asymmetric AMD in the fellow
eye were included in the study. The demographic details
of subjects are given in Table 1. No statistically significant
difference in age or sex was noted between the groups.
The geometric mean POBF (CI) in the three groups is
shown in Table 2. After adjusting for the differences in
IOP, PR, and axial length, there was no statistically
significant difference between fellow eyes in the three
groups. Although the active CNV lesions were defined as
classic, occult, or mixed, further subgroup analysis did
Pulsatile ocular blood flow in asymmetric AMD
R Sandhu et al
507
Eye

not show a statistically significant difference in POBF
between these three subgroups.
Figures 1-3 show POBF values in the fellow eyes in
each of the three groups with asymmetric AMD.
Discussion
The results of our study show that there is no significant
difference in POBF between fellow eyes in asymmetric
AMD. We were particularly interested in the Groups 1
and 2 as a difference in POBF between fellow eyes in
these groups would aid in early detection of cases with
an increased risk for developing CNV. When looking at
the unadjusted values, differences in Group 3 achieved
statistical significance. However, this difference was not
significant after differences in IOP, PR, and axial length
were taken into account. The major drawback is
relatively few numbers in this particular group.
However, this group has little implication for clinical
usefulness in terms of disease management as both eyes
had progressed to the advanced stage of the disease.
Therefore, despite small patient numbers, further
recruitment for study purposes was not deemed
appropriate.
Two studies have investigated ocular haemodynamic
abnormalities in AMD using the POBF technique. The
results of both these studies are difficult to compare.
Mori et al
17
compared POBF between single eyes of
Japanese subjects with exudative AMD (11 eyes) ,
nonexudative AMD (10 eyes), and age-matched healthy
controls (69 eyes). The results were expressed as median,
with POBF being significantly lower in exudative as than
in nonexudative AMD (P¼0.02) and healthy controls
(P¼0.01). No significant difference was noted between
nonexudative AMD and controls.
0
01 23
500
1000
1500
2000
2500
Disease
Pulsatile ocular blood flow (ul/min)
Drusen Exudative lesions
Figure 1 Pulsatile ocular blood flow in patients with drusen
and CNV.
Table 1 Patient demographics
Characteristics Group 1 CNV/drusen Group 2 disciform/drusen Group 3 CNV/disciform P-value
No. of patients 21 18 8
Mean age years (SD) 80 (7.87) 80.05 (6.2) 82.25 (3.2) 0.694
Sex (M/F) 8/13 6/12 5/3 0.953
Table 2 Geometric mean values in patients with asymmetric AMD (n¼47)
IOP (mmHg(SD)) PA (mmHg(SD)) PV (ml(SD)) PR (/min(SD)) POBF (ml/min(CI))
Group 1 (n ¼21)
Drusen 11.7(3.4) 3.2(1.0) 8.1(2.8) 69.9(10.6) 1097.9 (957.0, 1259.7)
CNV 12.3 (4.6) 3.2(0.9) 8.2(3.2) 70.3(9.7) 1090.1 (932.3, 1274.7)
P¼0.307 P ¼0.820 P ¼0.688 P ¼0.524 P ¼0.846
*P ¼0.689
Group 2 (n ¼18)
Drusen 13.8(3.4) 3.0(0.7) 6.8(2.4) 72.9(9.9) 946.0 (794.2, 1126.7)
Disciform scar 13.3(3.4) 3.0(0.9) 7.0(2.7) 71.8(10.9) 966.2 (780.3, 1196.4)
P¼0.442 P ¼0.965 P ¼0.503 P ¼0.202 P ¼0.671
*P ¼0.120
Group 3 (n ¼8)
CNV 14.9(2.1) 3.3(1.4) 6.4(2.3) 69.0(7.7) 877.1 (628.3, 1224.6)
Disciform scar 16.0(3.1) 2.9(1.2) 5.8(2.6) 69.3(7.5) 767.2 (530.5, 1109.7).
P¼0.164 P ¼0.057 P ¼0.120 P ¼0.392 P ¼0.047
*P ¼0.740
IOP ¼intraocular pressure; PA ¼pulse amplitu de; PV ¼pulse volume; PR¼pulse rate; POBF¼pulsatile ocular blood flow.
*P-values adjusted for IOP, PR, and axial length.
Pulsatile ocular blood flow in asymmetric AMD
R Sandhu et al
508
Eye

Whereas this study made a group-wise interindividual
comparison, Chen et al
18
used a paired sample
comparison and investigated POBF difference in a
Taiwanese cohort with asymmetric AMD between fellow
eyes of the same subject, thus eliminating high
interindividual variation in POBF.
25
As the methodology
was similar to this study, it enabled us to compare the
blood flow characteristics in the two racial groups:
Caucasians vs Taiwanese. In the Taiwanese cohort, the
mean value of POBF, after adjusting for IOP and PR, was
significantly lower in the eyes with drusen than in fellow
eyes with CNV but higher than that in fellow eyes with
disciform scar. However, despite the methodology of this
study being similar to ours, no correction of POBF for
axial length was made. Although the comparison of these
two studies seems reasonable at first, this limitation must
be taken into account before the interpretation of results.
The results are also in contrast to the findings of our
study in which the mean POBF, although not statistically
significant, was found to be higher in eyes with drusen
than in fellow eyes with CNV, but lower than that in
fellow eyes with disciform scar. There may not actually
be a difference between the Chen study and this one,
given the difference in analysis in the studies (axial
length correction).
Interestingly, several epidemiological studies
26
have
observed significant variation in the prevalence of AMD
among different racial/ethnic groups and in different
parts of the world. Oshima et al reported a lower
prevalence of early and late stage ARM among Japanese
than among Caucasians, whereas late stage ARM was
found to be more common among Japanese than among
Afro-Caribbeans. Another study by Uyama et al
evaluated the incidence of CNV and predisposing
findings for the development of CNV in the second eye of
Japanese patients with unilateral exudative AMD. There
was a variation in the prevalence of soft drusen and
pigmentary change, and a low incidence of the
development of CNV in the fellow eye as compared to
that in the white population. This may explain the
difference in our results as the Taiwanese group had
lower mean POBF in the drusen eyes as than in the
fellow eyes with CNV. This is in contrast to a higher
mean POBF found in Caucasian eyes with drusen than in
fellow eyes with CNV. This would arguably be in
keeping with the observation of a higher incidence of the
development of CNV in the second eyes of Caucasians as
observed by previous studies.
Previous studies have suggested morphological
changes in the choroidal vasculature with a reduction in
blood flow, in subjects with various stages of AMD, with
most of them suggesting focal choroidal perfusion
abnormalities in both non-neovascular and neovascular
AMD. Whereas 37% decrease in subfoveal choroidal
blood flow compared to that of a control group has been
demonstrated in non-neovascular AMD using laser
Doppler flowmetry (LDF),
12
studies on neovascular
AMD by Schmetterer et al,
27
have shown lower topical
fundus pulsation amplitudes in patients with CNV using
the laser interferometric method.
27
The authors
postulated this to be because of focal choroidal perfusion
abnormalities. A recent study also suggested a
decreasing trend in the choroidal blood flow with
increasing severity of the disease. Grunwald
28
compared
foveolar choroidal blood flow in three groups according
to increasing risk for the development of CNV. Group 1
drusen 463 min the study eye and no CNV in the fellow
eye; Group 2 drusen 463 mand RPE hypertrophy in the
study eye and no CNV in the fellow eye; Group 3 eyes
with CNV in the fellow eye. Subfoveal choroidal blood
flow was assessed using the laser Doppler flowmeter. A
systematic decrease in choroidal circulatory parameters
was observed with an increase in severity of AMD
features associated with a risk for development of CNV.
0
200
400
600
800
1000
1200
1400
1600
012
3
Disease
Pulsatile ocular blood flow (ul/min)
CNV Disciform
Figure 3 Pulsatile ocular blood flow in patients with CNV and
disciform lesions.
0
01
2
3
200
400
600
800
1000
1200
1400
1600
1800
2000
Disease
Pulsatile ocular blood flow (ul/min)
Drusen Disciform lesions
Figure 2 Pulsatile ocular blood flow in patients with drusen
and disciform lesions.
Pulsatile ocular blood flow in asymmetric AMD
R Sandhu et al
509
Eye

This study again looked at focal changes in the foveolar
blood flow.
As mentioned previously, POBF reflects the total
pulsatile component of ocular blood flow and most of
this blood volume is present mainly in the choroid.
Therefore, the POBF technique estimates the average
global choroidal blood flow. As our study used this
technique, a plausible explanation for similar POBF
values in fellow eyes with asymmetric AMD may be that
global alterations in ocular perfusion in AMD may not be
significant in the pathogenesis and progression of this
severely sight threatening disease.
Conclusion
The result of our study demonstrated no significant
difference of POBF in the fellow eyes of Caucasian
patients with asymmetric AMD, particularly with early
ARM in one eye and exudative AMD in the fellow eye.
Further studies on POBF comparing racial groups and
use of techniques aimed at assessing focal choroidal
blood flow may help improve our understanding of
ocular haemodynamic abnormalities and their
implications in the development and progression of
AMD.
Acknowledgements
The authors did not receive any additional financial
support from public or private sources.
The authors have no proprietary interest in this study.
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