PERSPECTIVE
Blood Pressure, Perfusion Pressure, and Glaucoma
JOSEPH CAPRIOLI AND ANNE L. COLEMAN, ON BEHALF OF THE BLOOD FLOW IN GLAUCOMA
DISCUSSION GROUP
● PURPOSE: To provide a critical review of the relation-
ships between blood pressure, ocular blood flow, and
glaucoma and the potential for glaucoma treatment
through modulation of ocular perfusion.
● DESIGN: Summaries of the pertinent literature and
input from glaucoma researchers and specialists with
relevant experience.
● METHODS: Review and interpretation of selected liter-
ature and the results of a 1-day group discussion involv-
ing glaucoma researchers and specialists with expertise in
epidemiology, blood flow measurements, and cardiovas-
cular physiology.
● RESULTS: Accurate, reproducible, and clinically rele-
vant measurements of blood flow within the optic nerve
head and associated capillary beds are not fully achievable
with current methodology. Autoregulation of blood flow
in the retina and optic nerve head occurs over a large
range of intraocular pressures and blood pressures. Reg-
ulation of choroidal blood flow is provided by a mix of
neurohumoral and local mechanisms. Vascular factors
may be important in a subgroup of patients with primary
open-angle glaucoma, and particularly in patients with
normal-tension glaucoma and evidence of vasospasm.
Low ocular perfusion pressure and low blood pressure are
associated with an increased risk of glaucoma in popula-
tion-based studies. The physiologic nocturnal dip in
blood pressure is protective against systemic end-organ
damage, but its effects on glaucoma are not well elabo-
rated or understood. Large-scale longitudinal studies
would be required to evaluate the risk of glaucomatous
progression in non-dippers, dippers, and extreme noctur-
nal blood pressure dippers.
● CONCLUSIONS: Decreases in perfusion pressure and
blood pressure have been associated with glaucoma. How-
ever, there is no evidence to support the value of increasing
a patient’s blood pressure as therapy for glaucoma. Such
recommendations are not currently warranted, since we
lack crucial information about the microvascular beds in
which perfusion is important in glaucoma, and the appro-
Accepted for publication Jan 8, 2010.
From the Jules Stein Eye Institute, David Geffen School of Medicine at
UCLA, Los Angeles, California.
Inquiries to Joseph Caprioli, UCLA David Geffen School of Medicine,
Department of Ophthalmology, 2-118 Jules Stein Eye Institute, Los
Angeles, CA 90095; e-mail: Caprioli@ucla.edu
704 © 2010 BY ELSEVIER INC. ALL
priate methods to evaluate their blood flow. There are also
cardiovascular safety concerns associated with treatments
designed to increase ocular perfusion pressure and blood
flow by increasing blood pressure, especially in elderly
patients. For these reasons and with present evidence it is
unlikely that safe and effective glaucoma treatments based
on altering optic nerve perfusion will soon be available.
(Am J Ophthalmol 2010;149:704 –712. © 2010 by
Elsevier Inc. All rights reserved.)
G
LAUCOMA IS A FAMILY OF OPTIC NEUROPATHIES
having in common a characteristic cupping of the
optic nerve head and a distinctive pattern of visual
field loss for which increased intraocular pressure (IOP) is an
important risk factor. From the time of its earliest recognition,
there has been a debate about its etiology and preferred
treatment. Elevated IOP has long been thought to increase
the risk of glaucoma by causing abnormalities of the optic
nerve head at the level of the lamina cribrosa, affecting the
intracellular transport within the retinal ganglion cell axons
or by causing vascular abnormalities that lead to ischemic
damage. When von Graefe introduced iridectomy as a suc-
cessful treatment for acute glaucoma in the mid-1800s, he
postulated that it was helpful because it reduced aqueous
production and IOP, while Jaeger believed that it was helpful
because it altered ocular blood flow to improve nutrition and
decrease inflammation.
The role of IOP as a risk factor for glaucoma is now well
established, and current treatment of glaucoma aims to
reduce IOP to a target pressure low enough to prevent or
significantly slow progression.1 The role of optic nerve and
retinal blood flow and ischemia in glaucoma is not clear.2
In the 1990s, Hayreh, Drance, and others raised the
important issues of systemic hypotension and nocturnal
blood pressure dips in the progression of glaucoma and the
desirability of accurate clinical measurements of ocular
blood flow. Interest in these topics has resurged in light of
recent epidemiologic data concerning low blood pressure
and low calculated “ocular perfusion pressure” as risk
factors for the development and progression of glaucoma.
The purpose of this Perspective is to critically evaluate the
current evidence for reduced blood flow in the pathology of
glaucoma, its measurement, and its iatrogenic perturbation
as a means of treatment for glaucoma.
RIGHTS RESERVED. 0002-9394/10/$36.00
doi:10.1016/j.ajo.2010.01.018
 ANATOMY AND CLINICAL
MEASUREMENTS OF OCULAR
BLOOD FLOW
THE OCULAR CIRCULATION IS COMPOSED OF A COMPLEX
arterial supply and an even more complex venous drainage
system. The ophthalmic artery and its tributaries, the
posterior ciliary arteries and the central retinal artery,
provide arterial blood flow to the posterior segment. The
short posterior ciliary arteries from the choroid mainly
supply the prelaminar portion of the optic nerve, with a
minor contribution to the surface of the disc from fine
branches of the central retinal artery.3
A variety of techniques have been used to measure
ocular blood flow.4 Fluorescein angiography can be used to
estimate the arteriovenous transit time, but such estimates
do not represent a robust measure of regional blood flow.5
The perfusion of microvascular beds can be evaluated
qualitatively with this technique.6,7
The microsphere technique has been used since the
early 1970s to measure ocular blood flow in animals. The
advent of fluorescent microspheres simplified the tech-
nique, and recent refinement of the optimal dose and size
of microspheres may provide more accurate estimates of
regional optic nerve head blood flow.8 The technique is
limited by the need to euthanize the animal to harvest the
tissues and provides a limited number of “snapshot”
measurements.
Laser Doppler velocimetry (LDV) determines the veloc-
ity of blood cells in the larger retinal blood vessels.9
Volumetric blood flow to or from the retinal area served by
the artery or vein can be calculated if the velocity is
combined with measurements of vessel diameter at the
same site. LDV cannot be used to measure optic nerve
head blood flow.
Laser Doppler flowmetry (LDF) or laser speckle flowg-
raphy (LSFG) measures flux (mean velocity times the
number of moving cells) based on the Doppler shift
imparted to light scattered by blood cells moving in the
microcirculation of a laser-illuminated tissue. Both tech-
niques are used to measure microcirculatory perfusion in
the optic nerve head in animals and humans.10 The
techniques require skill and ideal subjects (eg, clear media
and perfect fixation). They cannot be used to measure flow
in large vessels, and neither provides measurements in
absolute units. Moreover, the depth to which LDF and
LSFG measurements penetrate the optic nerve head is still
being resolved and probably varies with differences in
tissue light scattering elements between subjects (eg, a
normal versus a cupped disk). Consequently, there is some
uncertainty regarding which vascular beds are actually
being measured and whether those are the vascular beds
relevant in glaucoma.
Color Doppler imaging (CDI) evaluates erythrocyte
velocity in the large ophthalmic vessels (the ophthalmic
artery, central retinal artery, and short posterior ciliary
VOL. 149, NO. 5 PRESSURE AND
arteries). CDI provides the peak systolic velocity (PSV),
the end diastolic velocity (EDV), and the mean velocity.
The resistive index ([PSV-EDV]/PSV) is often calculated,
but for the central retinal artery, it correlates poorly with
direct measures of retinal vascular resistance.11 Velocity
measurements in the ophthalmic artery are also difficult to
interpret since much of blood flow in the ophthalmic
artery does not perfuse the eye, so velocity does not change
when IOP is raised as high as 45 mm Hg.12 Several studies
have suggested that erythrocyte velocity measured with
color Doppler imaging may predict the risk of glaucoma
progression, but such findings among various studies have
not been in the same vessels or for the same measures.10
The large variation in measurements among individuals,
probably attributable in part to differences in tissue density
and vascular organization, complicates the interpretation
of color Doppler imaging. The measurements are also
highly variable and dependent on probe placement. There
is evidence that erythrocyte velocity measurements may
underestimate blood flow, and instantaneous measure-
ments may not provide an accurate estimation of either
flow or change in flow over longer, more relevant periods
of time.
The limitations of these techniques have made it diffi-
cult to determine the fundamental characteristics of ocular
blood flow in glaucoma and in normal controls. The
measurements in humans are in general quite noisy, or
variable. There is currently no widely accepted consensus
regarding which techniques should be used to evaluate
blood flow or how the results should be interpreted. None
of the methods used to estimate blood flow have been
standardized or externally validated for humans. Ocular
blood flow measurements are not currently used in the
diagnosis or management of patients with glaucoma.
PHYSIOLOGY AND
AUTOREGULATION OF OCULAR
BLOOD FLOW
THE DRIVING FORCE FOR OCULAR BLOOD FLOW IS THE
ocular perfusion pressure (OPP), defined as the ocular
arterial pressure minus the IOP. A relationship between
OPP and ocular blood flow has been demonstrated in
several animal models, where arterial pressure can be
precisely controlled.13,14 In this model, choroidal blood
flow ceases when the OPP is zero, indicating the ear artery
pressure is a reasonable estimate of the arterial pressure
entering the choroid. However, in humans and other
species lacking an artery for surrogate measurement, arte-
rial pressure is measured at a distant site (eg, the brachial
artery) and corrected for the hydrostatic column effect to
obtain an estimated ophthalmic artery pressure. Oph-
thalmodynametric measurements in humans of the IOP at
which retinal blood flow ceases indicate this is reasonable
for the central retinal artery. It should not be assumed that
GLAUCOMA 705
this holds for the arteries supplying the other ocular
circulations. For example, rat ophthalmodynamometric
measurements indicate that the pressure is approximately
10 mm Hg lower in the short posterior ciliary arteries than
in the central retinal artery. Qualitatively similar results
are reported for humans with fluorescein angiography
during acute IOP elevation.
In clinical studies, brachial arterial pressure has been
used as a surrogate for the ocular arterial pressure in the
calculation of OPP. They are not equivalent because when
an individual is sitting or standing, the ocular arterial
blood pressure is lower than the brachial arterial pressure
because of the effect of gravity (the hydrostatic column
effect). Therefore, the OPP calculated with the uncor-
rected brachial artery blood pressure is not the actual
physiologic OPP. Also, we cannot assume that the differ-
ence between the ocular and brachial arterial pressures is
the same in normal and diseased vascular beds.
Blood flow is determined not only by OPP, but also by
vascular tone (resistance). Regulation of blood flow may
occur through changes in vascular resistance (vasocon-
striction or vasodilation) independently of changes in the
OPP. Although the physics of ocular blood flow are
the same in nonprimate animal models and in humans, the
regulation of ocular blood flow is likely to vary among
species because of anatomic differences. For example, in
contrast to humans, the rabbit retinal circulation is negli-
gible and the retina is nourished mostly from the choroid.
Other differences between animal models and humans,
including postural changes from a 4-legged position to
upright and differences in circadian activity, may also
make it difficult to extrapolate findings concerning the
regulation of blood flow from one species to another.
Autoregulation of ocular blood flow is designed to match
the metabolic needs of ocular tissues to maintain consis-
tent blood flow despite changes in the OPP. In the retinal
circulation, blood flow autoregulation is desirable because
retinal metabolic activity and the consequent need for
oxygen, nutrients, and waste removal are blood flow
dependent. Because the choroidal vascular bed is a high
flow bed, with the smallest arteriovenous oxygen difference
of any in the body, the extent to which metabolic
autoregulation of choroidal blood flow occurs is not clear.
However, measurements of the retinal PO2 gradient in
primates show that normal choroid blood flow provides
adequate oxygen delivery to the photoreceptor inner
segments under light-adapted conditions and marginal
oxygen delivery under dark-adapted conditions.15 Thus,
despite the low arteriovenous oxygen difference, the cho-
roid is not over-perfused for retinal oxygen delivery, and
even mild reductions in choroidal blood flow can render
the photoreceptor inner segments hypoxic. Efficient auto-
regulation of choroidal blood flow over defined ranges of
ocular arterial pressure and IOP has been observed in
rabbits.14 In contrast, in cats and primates in which the
radioactive microsphere technique was used to measure
706 AMERICAN JOURNAL
ocular blood flow, induction of ocular hypertension re-
sulted in decreased blood flow through the choroid while
retinal blood flow remained at normal levels, suggesting a
marked difference in autoregulatory capacity between the
choroidal and retinal vascular beds.3,16 A more recent
primate study with laser speckle flowgraphy to measure
blood flow demonstrated autoregulation of optic nerve
head blood flow at some levels of blood pressure.17
Studies with laser Doppler flowmetry in humans also
indicate optic nerve head autoregulation when IOP is
increased stepwise with a suction cup.18,19 Moreover,
the optic nerve head hyperemic response to flicker light
stimulation in animals and humans indicates efficient
autoregulatory neurovascular coupling to match metab-
olism and perfusion.20
Autoregulation of both the retinal and choroidal blood
flow may make it difficult to modify ocular circulation for
therapeutic benefit. Moreover, there may be unforeseen
adverse consequences. For example, in a rabbit model,
administration of vasodilators to increase blood flow causes
an increase in ocular blood volume, which leads to a large,
transient spike in IOP that could damage an already
diseased optic nerve.21
ISCHEMIA AND GLAUCOMA
OCULAR NERVE HEAD CUPPING IS A HALLMARK OF GLAU-
coma. Although multiple factors are likely to be involved
in the etiology of glaucoma, IOP is the best recognized.
Laminar cupping may result from the mechanical stress of
IOP that causes deformation of the optic nerve head, while
prelaminar cupping may result from retinal ganglion cell
loss and changes in glial architecture.22 Other possible
etiologic factors in glaucoma include vascular factors,
genetic factors, autoimmunity, loss of normal stress re-
sponses, and inflammation; furthermore, all of these factors
may interact. Glaucomatous optic nerve head damage does
not resemble ischemic damage, which is usually character-
ized by initial pallor of the optic nerve head rather than
cupping. Elevated IOP often associated with glaucoma
could cause microangiopathy and decreased ocular blood
flow. Blood velocity measurements have typically shown a
difference between primary open-angle glaucoma patients
and normal controls. It is difficult to know, however,
whether the decreased blood flow is actually involved in
the etiology of glaucoma, or whether it is secondary from a
loss of retinal ganglion cells and a decrease in the corre-
sponding metabolic demand for oxygen and nutrients. In
other words, is it the cause or the effect?
Findings of elevated concentrations of the vasoconstric-
tor endothelin-1 (ET-1) in the aqueous humor of glaucoma
patients have supported a possible role for optic nerve
ischemia in the pathophysiology of glaucoma.23 The role of
ischemia in glaucoma has been investigated in rat, rabbit,
and primate models in which ET-1 is administered to
OF OPHTHALMOLOGY MAY 2010
chronically decrease optic nerve blood flow. In the rat
model, ET-1 administration caused retinal ganglion cell
axonal loss, but in vivo imaging showed no optic nerve
head cupping characteristic of glaucoma.24 Optic nerve
head cupping does occur in the rat model when IOP is
elevated, despite the absence of a well-developed lamina
cribrosa. The related question of whether ischemia might
increase susceptibility to pressure-mediated damage is dif-
ficult to address experimentally and remains to be an-
swered. Inter-species differences also add to difficulties
with the interpretation of experimental findings.
The loss of retinal ganglion cells in ET-1 animal models
has fueled the hypothesis that ischemia may be involved in
glaucoma. However, the damage to retinal ganglion cells
in the ET-1 rat model does not appear to be mediated by
the vascular effects of ET-1, as no change in blood flow was
measured at concentrations of ET-1 that caused death of
retinal ganglion cells.25 Evidence suggests that the death of
retinal ganglion cells is mediated by effects of ET-1
independent of, or in addition to, ischemia, including the
possibilities of astrocyte proliferation and effects from
changes in endothelin B receptor expression.25
CLINICAL EVIDENCE OF ISCHEMIC
PATHOPHYSIOLOGY IN GLAUCOMA
IN AN EARLY CASE-SERIES STUDY OF 29 NORMAL-TENSION
glaucoma patients, 10 had a history of a severe hemody-
namic crisis.26 This led to concern that overtreatment of
systemic hypertension might exacerbate glaucoma. Nine of
these patients did not progress, however, so they may
have been patients with ischemic damage rather than
progressive glaucoma. Subsequent studies have found
little or no relationship between glaucoma and either
symptomatic hypotensive episodes or systemic antihy-
pertensive treatment.27
Vascular spasticity and dysregulation of ocular blood
flow are hypothesized to be involved in at least some cases
of the normal-tension variety of primary open-angle glau-
coma (NTG). A case-control study showed a higher
occurrence of migraine in NTG patients compared to
controls.28 In many studies of NTG patients, the percent-
age of patients with a history of migraine is low, and
cross-sectional population-based prevalence studies have gen-
erally found no significant association between migraine and
glaucoma. However, migraine was identified as an indepen-
dent risk factor for progression in the Collaborative Normal-
Tension Glaucoma Study (CNTGS).29
No clinical studies have reported a significant associa-
tion between Raynaud’s syndrome and glaucoma, but
Raynaud’s syndrome is relatively rare. In the Canadian
Glaucoma Study, a prospective study that followed pa-
tients with open-angle glaucoma, peripheral vasospasm
was measured objectively, and there was a trend toward
more visual field progression in patients with vasospasm.30
VOL. 149, NO. 5 PRESSURE AND
The overall effect was small, but in some patients, vaso-
spasm may be an important risk factor for progression at
relatively “normal” IOPs. Although studies typically
have not shown a significant relationship between
migraine or Raynaud’s syndrome and glaucoma, there
may be a real relationship in a small subset of patients
and this may represent a subtype of glaucoma with a
vascular component.
Epidemiologic data have shown that while high IOP is
the major and strong risk factor for glaucoma, low OPP is
also a strong and consistent risk factor, with some studies
also finding associations with low blood pressure. Large
cross-sectional prevalence studies in different populations
(the Baltimore Eye Survey, the Egna-Neumarkt Study, the
Proyecto VER, and the Barbados Eye Study) found a
significant association between low diastolic OPP and the
prevalence of open-angle glaucoma.27 In the Barbados Eye
Study, a longitudinal population-based study representing
the best research design for identifying risk factors for the
development of glaucoma, low mean, systolic, and diastolic
OPP were significantly associated with an increased inci-
dence of glaucoma (relative risk ⫽ 2.6 for mean OPP over
9 years of follow-up). Higher IOP and lower systolic blood
pressure were also significant risk factors for the develop-
ment of glaucoma in that study.
Since measuring the relevant arterial pressure in the eye
is not currently feasible, epidemiologic and other studies
calculate OPP from the brachial artery blood pressure and
IOP. In interpreting the epidemiologic data, however, it is
difficult to determine whether the risk factor of OPP is
more than just the sum of the 2 important independent
risk factors: higher IOP and lower blood pressure.
Clinical trial data have suggested that low OPP, again
measured as the difference between brachial blood pressure
and IOP, may also increase the risk of progression in glau-
coma. In the Early Manifest Glaucoma Trial, patients with
systolic OPP ⱕ 125 mm Hg had significantly increased risk of
progression over a follow-up of up to 11 years.27 Higher
systolic blood pressure (⬎160 mm Hg) appeared to be
protective against progression.27 The greater incidence of
progression in patients with lower blood pressure, seen mainly
in patients with lower IOP, suggests a vascular risk factor for
progression independent of IOP.31
It now seems clear that low OPP (not necessarily the
physiologic OPP, but the surrogate measured with bra-
chial blood pressure) is a risk factor for glaucoma and its
progression, but its potential relationship to decreased
ocular blood flow has not been determined. Further, it is
possible that the IOP component of OPP is the impor-
tant driving force, rather than blood flow. High IOP is
a significant risk factor across population-based and
clinical studies in all patient subgroups, while associa-
tions with blood pressure, if any, have not always been
consistent.
GLAUCOMA 707
FIGURE. Hydrostatic column effect of postural position on blood pressure and ocular perfusion pressure.
SYSTEMIC CARDIOVASCULAR
CONSIDERATIONS
DESPITE THE PROTECTION THAT HIGH BLOOD PRESSURE
may initially confer against glaucomatous damage, the
resultant microangiopathy of long-term hypertension can
produce harmful effects on the retina and optic nerve.
High blood pressure must be treated because it is one of the
most important risk factors for cardiovascular morbidity
and mortality. The risk of cardiovascular mortality doubles
with each 20 mm Hg rise in systolic blood pressure and
each 10 mm Hg rise in diastolic blood pressure. The
guidelines of the Joint National Committee on Preven-
tion, Detection, Evaluation, and Treatment of High Blood
Pressure32 define normal blood pressure as systolic blood
pressure ⬍120 mm Hg and diastolic blood pressure ⬍80
mm Hg. Pre-hypertension is defined as systolic blood
pressure of 120 to 139 mm Hg and a diastolic blood
pressure of 80 to 89 mm Hg. Stage I hypertension is defined
as systolic blood pressure of 140 to 159 mm Hg or diastolic
blood pressure of 90 to 99 mm Hg. Stage II hypertension is
defined as systolic blood pressure of 160 mm Hg or higher
or diastolic blood pressure of 100 mm Hg or higher. These
values are based on office measurements of blood pressure,
and 3 consecutive measurements over 3 or 4 weeks are
needed for diagnosis. The guidelines recommend blood pres-
sure goals based on risk factors and comorbidities. For a
patient with essential hypertension (no other risk factors) the
goal is ⬍140/90 mm Hg. For a patient with hypertension and
diabetes or renal disease, the goal is ⬍130/80 mm Hg. The
goal is even lower for patients with high-risk hyperten-
708 AMERICAN JOURNAL
sion (for example, patients with a history of heart
attacks or strokes, evidence of end-organ damage, or
aortic aneurysm).
Very low blood pressure, however, is not desirable. The
determination of a safe blood pressure must be determined
on an individual basis, and a systolic blood pressure of 100
mm Hg may be beneficial for one patient, but dangerous
for another. Some patients, such as the elderly and patients
with cardiovascular disease, are at risk for morbidity and
mortality from low blood pressure. For these patients, low
blood pressure may lead to strokes, heart attacks, renal
damage, and end-organ damage.
Office measurements of blood pressure can be problem-
atic both because of “white coat” syndrome, in which
patients exhibit elevated blood pressure readings in the
clinical setting but not elsewhere, or the converse phe-
nomenon of masked hypertension, in which office blood
pressure readings are lower than those in other settings.
Home monitoring of blood pressure has advantages, but
blood pressure has a 24-hour circadian rhythm including a
nocturnal dip (a 10% to 20% decrease in systolic and
diastolic blood pressure at night while the patient sleeps)
and an early morning rise. Not all these changes in blood
pressure can be captured with home monitoring. Ambula-
tory blood pressure monitoring is helpful because it is
reasonably accurate and the blood pressure can be mea-
sured every 15 to 30 minutes over 24 hours. Ambulatory
blood pressure monitoring can identify the white coat
phenomenon, masked hypertension, labile hypertension,
and the postural hypotension that can occur in elderly
individuals with autonomic dysfunction.
OF OPHTHALMOLOGY MAY 2010
 The nocturnal dip in blood pressure is caused by a
decrease in sympathetic nervous system activity during
sleep. Nocturnal dips occur in both normotensive and
hypertensive individuals. Approximately 10% of patients
have less than a 10% decrease in blood pressure or actually
have an increase in blood pressure during the night. These
patients are referred to as non-dippers. The lack of a
normal dipping pattern in these patients may result in part
from autonomic dysfunction, a high activity level during
the day, steroid use, renal disease, poor quality of sleep, or
a postmenopausal state in women. The non-dipping pat-
tern is a risk factor for cardiovascular mortality (death from
stroke, heart attack, or heart failure). Non-dippers have a
20% increased risk of cardiovascular mortality.33 The risk
is greatest in non-dippers with high blood pressure. In
contrast, extreme dippers (patients with a greater than
20% nocturnal dip in blood pressure) have a further
decreased cardiovascular risk compared with dippers.
The nocturnal dip in blood pressure has been well
established to be protective against cardiovascular mortal-
ity. Higher blood pressure at night increases the risk of
cardiovascular mortality, while extreme dippers are pro-
tected against end-organ damage. Non-dippers may have
comorbidities (eg, apnea) that cause cardiovascular mor-
tality, or the non-dipping pattern may itself cause problems
for unknown reasons.
Salt tablets may be given to patients with autonomic
dysfunction and extremely low blood pressure to increase
the blood pressure and prevent fainting. Patients must be
carefully chosen for this type of treatment, however.
Volume expander (eg, salt) treatment can be effective in
young healthy individuals with low blood pressure but can
be dangerous in patients with cardiovascular disease; in-
creasing the blood pressure in a normotensive patient
would increase the risk of cardiovascular mortality.
NOCTURNAL DIPS AND GLAUCOMA
PROGRESSION
THE PHYSIOLOGIC INCREASE IN OPP WHEN AN INDIVIDUAL
lies down has important implications regarding the extent
to which a nocturnal dip in blood pressure might affect
actual OPP and ocular blood flow (Figure). Since OPP
increases by about 15 mm Hg when an individual lies
down, blood pressure would have to decrease by more than
15 mm Hg before the resultant decrease of OPP could
cause an ischemic insult. In the normal dipping pattern
characterized by a 10% to 20% decrease in blood pressure
during the night, a nocturnal dip of blood pressure of 15
mm Hg is typical. This dip in blood pressure is also similar
to the dip in blood pressure that is seen when a patient
stands up, so it is physiologically normal.
The relationship between nocturnal dips in blood pres-
sure and glaucoma progression has been evaluated in
several studies. Most were retrospective and involved only
VOL. 149, NO. 5 PRESSURE AND
a small number of patients, and follow-up may have been
too short for reliable evaluation of progression. In some
studies, NTG and primary open-angle glaucoma patients
with visual field progression had lower nocturnal blood
pressure and greater nocturnal dips in blood pressure
compared with stable patients. For example, in one study,
5 years of progression data were retrospectively evaluated
in 70 glaucoma patients who then had blood pressure
measurements taken later at home with ambulatory mon-
itoring.34 The results suggested that the magnitude of the
nocturnal dip in glaucoma patients correlates with visual
field progression, as greater nocturnal dips were observed in
patients who presented with progressive visual field de-
fects. A recent prospective study found no significant
difference in nighttime blood pressures or nocturnal dips
between patients with NTG and age-matched controls,
but the NTG patients had greater variability of nighttime
blood pressure measurements compared with controls.35 A
study in 113 NTG patients showed that the variation in
circadian mean OPP (calculated with IOP and brachial blood
pressure measurements taken every 2 to 3 hours while sitting)
was related to the severity of visual field loss.36 Postural effects
on OPP were not evaluated in this study.
In two studies— a retrospective study in 70 patients,
and a prospective study in 38 patients— patients who
were non-dippers, as well as those who were extreme
dippers, were more likely to progress than those who had
a normal dipping pattern.37,38 This is consistent with
the findings of increased cardiovascular mortality and
end-organ damage in non-dippers. Large-scale studies of
longitudinal design are needed to further evaluate the
risk of glaucomatous progression in non-dippers, dip-
pers, and extreme dippers.
BLOOD PRESSURE MEASUREMENTS
IN GLAUCOMA
THE RECOGNITION OF LOW OPP AND LOW SYSTOLIC BLOOD
pressure as risk factors in glaucoma has led to a discussion
concerning the role of blood pressure monitoring in
glaucoma management. Is it necessary to take blood
pressures along with IOP measurements? Are office mea-
surements of blood pressure sufficient, or is home monitor-
ing or ambulatory monitoring required? These questions
have not been satisfactorily answered. Further, there is the
question of whether care must be taken to avoid excessive
lowering of blood pressure. Low blood pressure is not a
concern in most cases, but some individuals with systemic
hypotension may be at risk of damage to end organs including
the eye, and care of these individuals should be coordinated
with their internist. There have been anecdotal reports of
glaucoma patients with progression despite controlled IOP
who were asked to take salt tablets before bedtime in an effort
to prevent progression. It is unclear whether this practice is
appropriate, but it may be acceptable for carefully selected
GLAUCOMA 709
patients with systemic hypotension who are at low risk of
cardiovascular morbidity and mortality.
PROSPECTS FOR DRUG DEVELOPMENT
STUDIES WITH VARIOUS METHODS TO ASSESS OCULAR
blood flow have suggested that optic nerve perfusion may
be reduced in glaucoma,39 but all of the techniques used
clinically to evaluate blood flow have significant limita-
tions. The extent to which blood flow may be reduced, as
well as the accurate identification of the vascular beds
affected, remains to be determined. Even if ocular blood flow
in relevant vascular beds is reduced in glaucoma, the reduc-
tion may not be a cause of glaucomatous damage, but instead
may result from tissue loss, as blood supply could be reduced
to match metabolic supply with demand. Most importantly,
the fundamental question of whether increased ocular blood
flow would be beneficial for glaucoma patients has not been
answered, and there is no evidence at this time to support the
idea that increasing optic nerve perfusion would protect
retinal ganglion cells from damage. In the absence of new
relevant information, or evidence of beneficial effects, treat-
ment aimed specifically at increasing ocular blood flow does
not currently seem to be a promising strategy for glaucoma
management.
If we assume that it may someday be beneficial to
develop treatment aimed at increasing optic nerve perfu-
sion, a target for drug development (a receptor, enzyme, or
pathway) should be identified. The foremost priority would
be of course to do no harm with treatment. It must be
recognized that a drug that increases blood flow could be
detrimental if blood were diverted from vasculature sup-
plying other ocular circulatory beds. An example of this
may be Ca⫹⫹ channel blockers. These medications have
been reported to increase ocular blood flow,40 yet the
incidence of glaucoma was increased in patients on
Ca⫹⫹ channel blockers in the Rotterdam Eye Study.41
Thus, there is the possibility that improving optic nerve
perfusion by diverting blood from elsewhere (such as
retinal capillary beds) may have unforeseen adverse
effects.
CONCLUSIONS
THERE IS CURRENTLY LITTLE EVIDENCE THAT MEASURE-
ments of ocular circulation or blood flow are useful in
glaucoma management, or that vasoactive medications
have any benefit in glaucoma patients. Significant chal-
lenges remain in the measurement and interpretation of
ocular blood flow. The location of the microvascular beds
THE MEETING OF THE BLOOD FLOW IN GLAUCOMA DISCUSSION GROUP WAS SUPPORTED BY AN UNRESTRICTED GRANT
from Allergan, Inc, Irvine, California. Allergan, Inc had no control over the selection of participants or the selection of discussion topics, which were
710 AMERICAN JOURNAL
that are most relevant to glaucomatous damage continues
to be debated. The OPP estimated with current office
measurements is only a surrogate for the physiologic OPP,
and it may not be well correlated with the actual perfusion
of the optic nerve head. The estimated OPP should not be
assumed to reflect actual optic nerve blood flow or optic
nerve nutrition, let alone retinal ganglion cell nutrition.
Based on evidence that low OPP is a risk factor for
glaucoma progression, measurement of 24-hour systemic
blood pressure may be of value in patients with progressive
glaucoma despite “controlled” IOP, but there is currently
no evidence that manipulation of blood pressure or blood
flow improves outcomes in glaucoma. Although low OPP
is now an established risk factor in glaucoma, it is not clear
whether it is truly independent of the sum of 2 separate risk
factors— high IOP and low blood pressure. Low blood
pressure, rather than physiologic nocturnal dips in blood
pressure, may be the most important vascular risk factor for
glaucoma progression.
Glaucoma is a heterogeneous group of related diseases,
and there may be subgroups of patients in whom vascular
factors are important. Those patient subgroups have not
been well identified but may include patients with small
vessel disease and vasospasm, or elderly patients with a
history of vascular disease elsewhere.
It would be difficult to use a treatment strategy for
glaucoma that seeks to increase OPP by increasing blood
pressure, because high blood pressure greatly increases
morbidity and mortality, even at blood pressure levels
within the normal range. Eliminating the nocturnal dip in
blood pressure leads to an increased risk of cardiovascular
events. A treatment strategy aiming at increasing blood
flow could also be dangerous if it were not specifically
targeted at the “correct” capillary beds, which are yet to be
fully identified. For a small subgroup of patients who are
hypotensive, it may be beneficial to use a volume expander
(eg, salt) to produce a small increase in blood pressure, but
there is not yet any evidence to support this approach, and
this treatment would be contraindicated in many patients
because of systemic safety concerns.
In summary, given the paucity of current evidence of
ischemic damage in glaucoma, the lack of knowledge about
which vascular beds are important, the lack of methods to
accurately measure blood flow in relevant vascular beds,
safety concerns associated with treatments designed to
increase OPP and blood flow by increasing blood pressure,
and the lack of data on their effectiveness, we believe that
more research on the hemodynamics of glaucoma is needed
and that specific treatments for glaucoma based on altering
blood flow to the retina and optic nerve are not useful
options for most patients at this time.
OF OPHTHALMOLOGY MAY 2010
the sole responsibilities of the Chair, Dr Caprioli. Dr Kaufman is a consultant and has received honoraria from Inspire, Alcon, Santen, Allergan, Bausch
& Lomb, Cytokinetics, QLT, Danube Pharmaceuticals, and Cascade. He also acts as a consultant for Cara therapeutics. Dr Kaufman has received grants
from Inspire, Santen, Danube, Cara Therapeutics, Nu Lens, and Lens AR. Dr McKinnon is a consultant of Allergan, and has received grant support from
Pfizer and honoraria from Genentech. Dr Krupin is a consultant for and has received honoraria from Allergan, Merck & Co, and Pfizer Ophthalmics.
He is also a consultant for Ovation Pharmaceuticals and has received honoraria from Heidelberg Engineering. He has received grant support from Alcon,
Pfizer, and Allergan. Dr Alm has received an honorarium from and is a consultant for Pfizer and is a consultant for Novartis. Dr Wheeler is an employee
of Allergan. Dr Berliani has received honoraria from Novartis, Schering-Plough, Abbott Laboratories, and Sankyo Pharmaceuticals. Dr Chauhan is a
consultant for Allergan, and has received grant support from Heidelberg Engineering. Involved in design and conduct of the study (J.C., A.C., Discussion
Group); selection, analysis, and interpretation of data (J.C., A.C., Discussion Group); and preparation, review, and approval of the manuscript (J.C.,
A.C., Discussion Group). The authors had complete and sole control over the content of this perspective.
THE BLOOD FLOW IN GLAUCOMA DISCUSSION GROUP
Albert Alm, Arash Bereliani, Balwantray Chauhan, Paul Kaufman, Jeffrey Kiel, Theodore Krupin, Cristina Leske, Stuart McKinnon, and Larry
Wheeler participated in a Blood Flow in Glaucoma Discussion Group in Los Angeles, California on January 27, 2009. Allergan, Inc sponsored the
meeting.

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