MANAGING GLAUCOMA and INTRAOCULAR PRESSURE
Release Date: November 1, 2013
Expiration Date: October 31, 2014
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Principal faculty and their credentials
Glaucoma is among the most common causes of irreversible vision loss throughout the world, and the projected number of individuals with the disease in the year 2020 is 79.6 million. Of these, 74% will have open-angle glaucoma (OAG). In the United States alone, it is estimated that more than three million people will have OAG by 2020.
Reduction of intraocular pressure (IOP) has been shown to effectively reduce the risk of glaucoma progression across the spectrum of IOP, from low to high, and across the spectrum of disease severity, from ocular hypertension to advanced glaucoma. However, IOP reduction alone may be inadequate for preventing progression in some patients.
While IOP reduction is the only proven treatment for OAG, many patients experience progressive optic nerve degeneration and visual field loss despite significant IOP lowering. Normal-tension glaucoma (NTG) is a type of OAG resulting in damage to the optic nerve and abnormalities of the visual field, and IOP in this type of glaucoma is not higher than what is usually considered to be normal (<21 mmHg) for the eye. This form of glaucoma may account for as many as one-third of the cases of OAG in the United States.
This educational activity will explore several different facets of glaucoma management, including the role of IOP and related therapeutic strategies.
This educational activity is intended for comprehensive ophthalmologists interested in the care and management of patients with glaucoma.
Upon completion of this activity, participants should be able to:
- Distinguish when lowering IOP will not halt progression of glaucoma.
- Outline the diagnosis and management of normal-tension glaucoma.
- Identify therapeutic strategies for glaucoma that progresses despite very low IOP.
- Recall recent studies and trials, as well as their implications for glaucoma therapy beyond IOP reduction.
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I. DIAGNOSTICS IN CLINICAL PRACTICE
Patients with normal IOP are among the
Robert N. Weinreb, MD
The goal of glaucoma management is
to preserve visual function and visionrelated quality of life. To do this, we
must accurately diagnose glaucoma
and detect progression in the first place,
and then be able to offer treatments to
arrest the course of the disease.
Diagnosis and detection of progression remain challenging, despite
important technology developments in
our field. Many of us were taught that
both a visual field defect and optic disc
changes are necessary to diagnose
glaucoma. In fact, specific diagnosis can
be based on progressive change on either structural or functional measures.1 One can have very large changes in
structure without significant functional
loss early in the disease. However, late
in glaucoma, when there has already
been considerable loss of the retinal
nerve fiber layer (RNFL), small changes
in RNFL thickness are accompanied
by large changes in visual field. This
is a major reason why structure and
function don't seem to agree in so many
patients. In an ideal world, we don't
want to wait until this point to diagnose
glaucoma. A combined structure-function index, as Dr. Medeiros describes in
this supplement, may provide an opportunity to more reliably make a diagnosis
regardless of the stage of the disease.
Genetic testing, as Dr. Pasquale
describes in these pages, also holds
great promise for earlier identification
of those patients who are most likely
to develop glaucoma or to progress.
And better functional tests that actually
measure real-world visual performance
may also be helpful (sidebar).
Perhaps most challenging for clinicians are those patients who have
glaucomatous damage and perhaps
continue to progress despite normal
intraocular pressure. I do not generally use the term "normal-tension
glaucoma," and instead diagnose such
patients with open-angle glaucoma
(POAG). Nevertheless, having normal
intraocular pressure (IOP) does make
it more difficult to diagnose and follow
these patients, and to know whether
pressure-lowering medications will
Recent data suggest that patients
with normal IOP and glaucoma often
have a loss of spontaneous venous
pulsation. This may be due either to
mechanical venous factors as Morgan
suggests2 or to increased pressure in
the subarachnoid space, as Hanspeter
Killer, MD, believes.
- Medeiros FA, Lisboa R, Weinreb RN, et al. A
combined index of structure and function for
staging glaucomatous damage. Arch Ophthalmol.
- Morgan WH, Hazelton ML, Balaratnasingamm
C, et al. The association between retinal vein
ophthalmodynamometric force change and
optic disc excavation. Br J Ophthalmol. 2009;
DETECTING PROGRESSION IN
An index that combines structural and
functional estimates of retinal ganglion
cell counts may offer the most reliable
measure of progression.
Felipe A. Medeiros, MD, PhD
Clinicians often want to know whether
it is better to follow glaucoma patients
by measuring function (via standard
automated perimetry (SAP) visual field
testing) or structure, using any one of
a number of imaging devices. In fact,
neither method is sufficient on its own.
Experimental and clinical evidence
has shown that, in many patients,
significant retinal ganglion cell (RGC)
losses are required before a statistically
significant change in the visual field (VF) can be detected. Although the
amount of RGC loss associated with
early development of a field defect will
depend on the location and characteristics of the defect, on average one
would typically first detect VF loss at
a mean deviation of around –2 to –3
dB. That would correspond to an RGC
population of approximately 600, 000
to 700,000 cells, representing an approximately 30-percent loss from the
average RGC number in healthy eyes.
Visual field sensitivities and global
indices such as mean deviation are
reported in a logarithmic decibel scale.
Such scaling of perimetric data generates a curvilinear relationship between
structure and function (Figure 1).1 This relationship means that at early
stages of the disease, large structural
changes are associated with relatively
small functional changes. This would
explain the common clinical findings
of patients with extensive neuroretinal
rim thinning despite apparently statistically normal visual fields.
To progress from that very early
visual field defect of –3 dB to a
mean deviation of –10 dB, which
most would agree represents quite
severe visual field loss and potential
functional impairment, one need only
lose another 300,000 cells—fewer
than were lost to get to the point of a
detectable field loss in the first place.
Therefore, reliance on visual field testing alone will potentially result in late
diagnosis and underestimate the rate
of glaucoma progression, especially in
the early stages of the disease. There
are also challenges in using structural
measures to diagnose progression.
Optic nerve photos give us important
the current state
of the nerve, but
they don't offer a
sessment of the
loss over time.
Many studies have shown
such as confocal
laser polarimetry, and optical
coherence tomography (OCT) can
objectively quantify structural changes
in the neuroretinal rim and retinal
nerve fiber layer (RNFL). In advanced
disease, however, when the nerve
fiber layer has already thinned significantly, these tests reach a "floor";
relatively large changes in function
may be associated with only minor or
no detectable changes in structure.2
These observations about the
performance of SAP and OCT clearly
indicate the need for a combined approach to diagnose and monitor
glaucoma. They also indicate that
agreement between functional and
structural measures should not be
always expected. In fact, disagreements will be quite common in clinical
practice due to the different characteristics of these tests and their
relationship with the amount of neural
losses in the disease.
Combining Structure and
Identifying the extent of RGC loss
may be a better method for monitoring glaucoma progression. It is the
irreparable loss of these cells that
leads to both functional deficits and
changes in the RNFL. Although we
cannot precisely count RGCs in vivo,
Harwerth and associates showed that
the number of retinal ganglion cells
can be reliably estimated from either
visual field SAP sensitivity data or
from OCT RNFL analysis.3
We recently developed a single index
that combines structure and function
measures to provide an
age-corrected estimate of ganglion cell
loss.1 The two methods for estimating
RGC counts are weighted based on disease stage. Unlike visual field testing
alone, the combined structure-function
index (CSFI) performs well in detecting
pre-perimetric glaucoma. And, unlike
imaging alone, the CSFI is successful
at discriminating early vs. moderate
and moderate vs. advanced stages of
We have also shown that the CSFI
detects progression in a significantly
higher number of patients compared to
conventional indices.4 In this study, 288
eyes of glaucomatous subjects were
followed for an average of 3.8 years. The
combined index detected change in 22
percent of glaucomatous eyes compared
to 8.5 percent for visual fields and 14.6
percent for OCT average thickness, with
the same 95 percent specificity.
In conclusion, the ability of structural and functional methods to detect
change and accurately estimate the
rate of change depends on the stage
of the disease. An index that combines
both approaches can improve our
ability to diagnose, stage and detect
disease progression (Figure 2),
potentially resulting in more effective
management of our glaucoma patients.
- Medeiros FA, Zangwill LM, Anderson DR,
et al. Estimating the rate of retinal gan-
glion cell loss in glaucoma. Am J Ophthalmol.
- Medeiros FA, Lisboa R, Weinreb RN, et al. A
combined index of structure and function for
staging glaucomatous damage. Arch Ophthalmol. 2012;130(5):E1-10.
- Harwerth RS, Wheat JL, Fredette MJ, Anderson
DR. Linking structure and function in glaucoma.
Prog Retin Eye Res. 2010;29(4):249-71.
- Meira-Freitas D, Lisboa R, Tatham A, et al.
Predicting progression in glaucoma suspects
with longitudinal estimates of retinal gan-
glion cell counts. Invest Ophthalmol Vis Sci.
GENETIC TESTING FOR
Exciting developments make genetic
testing for glaucoma a possibility in
the not-too-distant future.
Louis Pasquale, MD, FARVO
The promise of genetic testing
for glaucoma is that it may help us
identify early-stage glaucoma patients before they have lost so many
retinal ganglion cells that their vision
As early as 1997, researchers had
identified a gene, myocilin (MYOC),
that causes primary open-angle
glaucoma (POAG).1 Yet 15 years later,
this discovery has had little impact
on clinical practice. The reason for
this translational lag is that we're just
beginning to understand the role of
these major genetic mutations, along
with many smaller but more common
For example, through mouse
models, we have recently learned
that a specific MYOC mutation, exon
3, causes a protein misfolding that
makes trabecular meshwork cells
become dysfunctional.2 When this
occurs, the intraocular pressure goes
up and the retinal ganglion cell counts
go down. More importantly, it has
recently been shown that if mice with
this specific mutation are given topical 4-phenylbutyrate eye drops, that
process can be reversed.3 This may
be a very important key to treat selected juvenile open angle glaucoma
Amassing More Clues
From the map of the human genome,
we know that at every 10 million
bases or so there is a common genetic
variation. Those common variants, also
known as single-nucleotide polymorphisms (SNPs), serve as risk factors
for complex diseases like primary
open angle glaucoma. There are several polymorphisms (each with a variety
of SNPs) that have been associated
with POAG. The most common of these
is CDKN2BAS, a non-coding variant
that, via epi-genetic mechanisms,
controls two nearby cell cycle genes.
The CDKN2BAS alleles are actually
associated with a reduced risk of glaucoma. These protective SNPs are much
more common in Caucasian populations compared to African population
(Figure 3), so part of the increased
risk for POAG among people of African
descent may be due to the fact that
they lack these protective variants.
Some genes implicated in POAG
may only be activated by environmental factors. For example, the nitric
oxide synthase 3 gene (NOS3) interacts with post-menopausal hormone
use and other factors. While NOS3
is not a gene that rises to the top
in a genome-wide scan for POAG, it
does appear to be a trigger in certain
environmental strata. Other potential
environmental factors that may modify
the association between NOS3 (or
other genetic variants) and POAG include aging, smoking, caffeine intake,
and antioxidant use.
We have a growing number of
genetic biomarkers that are susceptibility factors for glaucoma (Figure 4), but the important gains will come
when we are able to translate this
alphabet soup of allelic variants into
a genetic risk calculator that would
allow for early identification and intervention before an individual sustains
significant functional deficits from
glaucoma. This may be doable in the
next five to 10 years.
The Rotterdam Group is already
working on glaucoma prediction
models based on genetic information.4 Their models don't yet have the
high sensitivity and specificity that we
would like to see but with the discovery and incorporation into the models
of additional polymorphisms, that is
likely to change. This is already happening with conditions such as Crohn's
disease, for which there are close to
70 known polymorphisms.
At this point, it may be reasonable
to order genetic testing for some of
the rarer mutations for juvenile POAG
patients or for children in families
with a history of early-onset POAG.
But to the question of whether genetic
testing for the more common variants
implicated in the disease is appropriate, the answer today is unequivocally "no." There may be hundreds or
thousands of common variants that
collectively contribute to glaucoma.
Each of these on its own may have
very modest effects, with environmental factors creating additional uncertainty. We need more than the seven
biomarkers we have for POAG—or
the 19 we have for AMD, or even the
67 we have for Crohn's disease—to
figure out true risk.
The good news is that from modest beginnings, we are now entering
the second phase of the genomics
era in glaucoma. This next stage of
development will be characterized by
larger, more collaborative data sets
through the National Eye Institute's
NEIGHBORHOOD Consortium and the
International Glaucoma Genetics Consortium, so that we can identify more
biomarkers, not only for glaucoma
overall but for specific POAG-linked
traits such as central corneal thickness, intraocular pressure and cup/disc ratio. This ongoing development
will lead to improved diagnostic capability and, ultimately, new ways to
- Stone EM, Fingert JH, Alward WLM, et al.
Identification of a gene that causes primary
open-angle glaucoma. Science 1997;275:668.
- Zode GS, Kuehn MH, Nishimura DY, et al.
Reduction of ER stress via a chemical chaperone
prevents disease phenotypes in a mouse model
of primary open angle glaucoma. J Clin Invest
- Zode GS, Bugge KE, Mohan K, et al. Topi-
cal ocular sodium 4-phenylbutyrate rescues
glaucoma in a myocilin mouse model of primary
open-angle glaucoma. Invest Ophthalmol Vis Sci
- Ramdas WD, van Kookwijk LM, Cree AJ, et
al. Clinical implications of old and new genes
for open-angle glaucoma. Ophthalmology
WHAT DAMAGES THE
GLAUCOMA IS A NEURO-DEGENERATIVE DISEASE
Patients with normal IOL underscore
the importance of understanding how
optic nerve damage occurs—and
what factors other than IOP may be
Robert N. Weinreb, MD
A patient from several years ago
illustrates the conundrum we face in
dealing with glaucomatous progression in a patient with normal intraocular pressure (IOP). I monitored this
patient for years, initiated medical
therapy, performed a trabeculectomy,
and watched her experience expansion
of RNFL defect, loss of the neuroretinal
rim and substantial functional loss, despite peak pressures in the mid-teens
on medical therapy and ≤10 mmHg
following the trabeculectomy.
Clearly, my patient had glaucoma.
The question is, why did she continue
to progress? Did we not lower the
pressure enough? It's hard to imagine getting much below 8 mmHg,
which was typical for her. Perhaps
there was some other mechanism
at play and she needed something
beyond IOP lowering.
This case is a good example of how
patients can continue to lose visual
field despite lowering their pressure.
We do not yet have a definitive answer
for why retinal ganglion cells die in
glaucoma, or even whether that cell
death is primary or secondary to
some other process. The concept of
neuroprotection—of preventing retinal
ganglion cell death, independent of
lowering intraocular pressure—is an
Whether one calls this condition
"normal tension glaucoma" or, as I
prefer, simply "primary open angle
glaucoma" (POAG), the final common
pathway for all forms of glaucomatous visual impairment is neuronal
death. We recognize that glaucoma
is a progressive neurodegeneration
rather than merely a condition related
to intraocular pressure. In fact, I think
we're recognizing that glaucoma is not
just an eye disease.
Other neurodegenerative diseases,
such as Alzheimer's, Parkinson's,
stroke and Huntington's, involve the
entire central nervous system or
parts of the central nervous system.
But glaucoma, with 60 to 100 million
affected individuals worldwide, is
probably more prevalent than all of
There are some shared characteristics between these other neurodegenerative conditions and glaucoma,
particularly with regard to disease
progression. For example, in some
other neurodegenerative diseases it
is fairly well established that synap-
tic loss—a loss of the connections
between the neurons—occurs prior to
cell death. We have some indirect and
animal study evidence of synaptic loss
in glaucoma as well. Proteins implicated in Alzheimers may also play a role
in glaucoma. Beta amyloid, the protein
that forms plaques in the brains of Alzheimer's patients, may play a normal
physiologic role related to the maintenance of synapses between neurons
before it gets aggregated into plaques.
It is possible that the pathologic cleavage of beta amyloid that happens in
Alzheimer's disease may also be happening in the retina in glaucoma.
Retinal ganglion cells (RGCs) are the
optic nerve axons. Their target is the
lateral geniculate nucleus in the brain.
The lateral geniculate nucleus is made
up of several layers, each defined by
one of the three types of retinal ganglion cells targeting that layer. In addition
to these three major types of RGCs, we
have learned in recent years that there
are more than 20 different subtypes of
RGCs, but we don't yet know if there is
preferential loss of a particular type of
retinal ganglion cell in glaucoma.
An eye with glaucoma is not only
losing RGCs, but the optic nerve is
"shrinking." A healthy optic nerve is
like a thick, multi-strand rope going
from the eye to the lateral geniculate
nucleus. In glaucoma, as relay neurons
are lost, the thick rope becomes a
string, and the ability to transmit visual
signals travel to the brain is impaired.
And in fact, we actually see a loss of
neurons, not just in the optic nerve,
but in the lateral geniculate nucleus
itself in the brains of patients with
glaucoma. Glaucoma truly is a neurodegenerative disease that involves not
only the eye but also the brain.
THE ROLE OF IOP
We know IOP matters a great deal,
but deciding how high is too high
and how low is low enough remains
Yvonne Ou, MD
Since 1622, intraocular pressure
(IOP) has been very much linked with
glaucoma. The American Academy of
Ophthalmology's preferred practice
pattern for glaucoma currently defines
primary open-angle glaucoma (POAG)
as "a progressive chronic optic neuropathy in adults in which intraocular
pressure and other currently unknown
factors contribute to damage."
Major population-based studies
have shown that increasing IOP is
related to glaucoma prevalence.1,2 We
also know that the risk of developing
glaucomatous field loss increases with
increasing IOP, and that the greater
and more consistent the reduction in
IOP the greater the reduction in the
risk of subsequent optic nerve damage. But there is much that we still do
not understand about the role of IOP in
For example, what level of IOP results in glaucomatous optic neuropathy? Some would suggest IOP greater
than 21 mmHg. But according to population-based studies, the proportion
of patients with IOP > 21 mmHg who
have glaucomatous optic neuropathy
varies considerably, from a low of 13
percent in a study in Northern Italy
to as high as 71 percent in Barbados
(Figure 5). So, although higher IOP
is correlated with glaucomatous optic
neuropathy, high IOP alone is not sufficient for glaucoma diagnosis.
A number of important studies have
shown that lowering baseline IOP
prevents the onset of glaucoma3,4 and
that lowering IOP prevents glaucoma
progression (Figure 6). What these
studies have shown is that decreasing
IOP even by 1 mmHg reduces the risk
of progression and that reducing IOP
by 20 percent or more can significantly
decrease the risk of progression.
The Advanced Glaucoma Intervention Study (AGIS) showed that
patients with IOP below 18 mmHg at
100 percent of the study visits over
six years did appear to have more
stable disease compared to patients
in whom IOP may have fluctuated
above 18 mmHg over the course of
the study.5 Moreover, the mean IOP in
those patients who were consistently
below 18 mmHg at every visit was 12.3 mmHg. That has led some to
conclude that 18 mmHg is the magic
number—or that if we just keep
the pressure 12 mmHg or lower in
advanced glaucoma, we are going to
stop all progression.
Unfortunately, that is not the case.
While it is true that, on average, the
group with IOP consistently below
18 mmHg did not progress, within
the group there were certainly individuals who did progress, despite their
well-controlled IOP. The AGIS investigators acknowledge that maintaining
an IOP < 18 mmHg does not ensure
preservation of the visual field. Over
the seven years of the AGIS study,
in fact, 14 percent of the patients
in that well-controlled group had
There are many ways to measure
and think about IOP, and it is not at all
clear which way is most important. In
addition to baseline IOP and follow-up
IOP, for example, one might want to
look at nocturnal, diurnal or 24-hour
IOP. Peak IOP may predict visual field
progression better than mean IOP, or
it may be the degree of IOP fluctuation that matters most. And, if we
decide that fluctuation matters, it
is not clear whether the fluctuation
within a 24-hour period is more or
less important than longer-term, visitto-visit fluctuation.
A post hoc AGIS analysis tells us
that patients in whom the standard
deviation of IOP over the course
of follow-up visits was >3 mmHg
seemed to progress more than those patients where the IOP fluctua-
tion was <3 mmHg.6 However, this
analysis included post-intervention
IOPs. Almost by definition, those who
were progressing would be expected
to have more fluctuation because they
received an additional IOP-lowering
In another analysis that did not
include post-intervention IOPs, there
is a statistically significant difference
in progression between those who had
low IOP variation and high IOP variation, but only in the group in which
baseline mean IOP was low, suggesting that IOP fluctuation plays a greater
role in progression among that subset
According to a recent evidencebased review, the two prognostic
factors that are most strongly associated with glaucomatous visual field
progression are age (for all glaucoma)
and disc hemorrhages (for normaltension glaucoma).8 Baseline IOP and
baseline visual field loss, as one would
expect, are also strongly associated
with progression, although not as
strongly as age and disc hemorrhages.
In the future, glaucoma trials will
likely consider not only visual field or
functional progression but structural
progression as well. For example, the
United Kingdom Glaucoma Treatment
Study, the first trial of its kind to evaluate the benefit of medical IOP lowering
using prostaglandin analogs, will look
at baseline biomarkers and structural
imaging at all the follow-up visits, in
addition to the primary endpoint of
visual field deterioration.9
In conclusion, IOP is important but
cannot account for all glaucomatous
optic neuropathy. The large clinical trials have provided outstanding
evidence that lowering IOP will prevent
glaucoma onset and slow progression,
although treated patients do continue
While it is important to have a target
IOP in mind in treating this disease,
I would be wary of using any single
cutoff either for diagnosing or monitoring glaucoma. With each visit, as more structural and functional data are
gathered, one should re-assess the
ideal target. I would argue that in addition to lowering IOP we definitely need
other therapeutic targets. Researchers
continue to investigate IOP fluctuation and other parameters. Until we
have more information, consistently
lowering IOP is still the best treatment
we have for slowing the progression of
- Sommer AE, Tielsch JM, Katz J, et al.
Relationship between intraocular pressure
and primary open angle glaucoma among
white and black Americans. Arch Ophthalmol.
- Francis B, Varma R, Chopra V, et al, Los Angeles
Latino Eye Study Group. Intraocular pressure, central corneal thickness and prevalence of open-angle
glaucoma: the Los Angeles Latino Eye Study. Am J
- Kass MA, Heuer DK, Higginbotham EJ, e al.
The ocular hypertension treatment study: a
randomized trial determines that topical ocular
hypotensive medication delays or prevents the
onset of primary open-angle glaucoma. Arch
Ophthalmol. 2002; Jun;120(6):701-13; discussion 829-30.
- Miglior S, Zeyen T, Pfeiffer N, et al; European
Glaucoma Prevention Study Group. Results of the
European Glaucoma Prevention Study. Ophthalmology. 2005;112(3):366-75.
- The Advanced Glaucoma Intervention Study
(AGIS) 7. The relationship between control of
intraocular pressure and visual field deterioration. The AGIS Investigators. Am J Ophthalmol.
- Nouri-Madhavi K, Hoffman D, Coleman AL, et al;
Advanced Glaucoma Intervention Study. Predictive
factors for glaucomatous visual field progression
in the Advanced Glaucoma Intervention Study.
- Caprioli J, Coleman AL. Intraocular pressure
fluctuation a risk factor for visual field progression at low intraocular pressures in the advanced
glaucoma intervention study. Ophthalmology.
- Ernest PJ, Schouten JS, Beckers HJ, et al. An
evidence-based review of prognostic factors for
glaucomatous visual field progression. Ophthalmology. 2013;120(3):512-9.
- Garway-Heath DF, Lascaratos G, Bunce C,
et al; United Kingdom Glaucoma Treatment Study
Investigators. The United Kingdom Glaucoma
Treatment Study: A multicenter, randomized,
placebo-controlled clinical trial: design and methodology. Ophthalmology. 2013;120(1):68-76.
ROLE OF BLOOD FLOW
Ongoing research looks for ways to
better understand the role of ocular
perfusion pressure and retinal blood flow, particularly in patients with
Shan Lin, MD
Although insufficient evidence is
available regarding the role of blood
flow in glaucoma and how we can use
it in clinical treatment, researchers
continue to explore this topic, uncovering new information.
Most available clinical evidence
pertains to ocular perfusion pressure,
the gradient between intraocular pressure (IOP) and blood pressure.
Clinicians previously believed that
systemic hypertension was a factor
in increased IOP and glaucoma, but
the new paradigm is that low blood
pressure and low ocular perfusion
pressure (OPP) may be associated
with development or progression of
glaucoma. Any link with high blood
pressure is likely due to hypotension resulting from overtreatment of
hypertension. Substantial data support
the role of OPP in glaucoma, including
results from two recent investigations—the Barbados Eye Study and
the Early Manifest Glaucoma Trial
The Barbados Eye Study, a population-based investigation that found
125 patients with newly developed
glaucoma who were mostly of African
descent, identified risk factors that
included age, family history, higher
IOP, and thinner corneal thickness.1 When researchers examined systemic
factors, low systolic blood pressure
was of borderline significance and low
ocular diastolic and systolic perfusion
pressure and low ocular mean perfusion pressure were associated with a
significantly higher risk of glaucoma
in this population.
The Early Manifest Glaucoma Trial
(EMGT) identified age, higher IOP,
thinner corneal thickness, and low
ocular systolic perfusion pressure as
significant risk factors for progression
Although there is strong evidence
that low blood pressure may be a risk factor for glaucoma, we do not know
whether modifying it will affect development or progression of glaucoma.
Personally, I do not measure blood
pressure in all of my patients, but I do
measure it in study subjects and patients with low-tension glaucoma who
continue to progress despite treatment. I also check the blood pressure
of patients with low-tension glaucoma
who also have systemic hypertension to determine whether they have
overtreated high blood pressure.
Ocular blood flow can be examined
in a number of ways, such as through
retrobulbar flow with color Doppler
imaging.3,4 Cross-sectional studies
have shown blood flow to be reduced
in subjects with normal-tension glaucoma compared with controls.
Many studies also have examined
retinal blood flow, most often using the
Heidelberg retinal flowmeter. Research
has shown that peripapillary retinal
blood flow is also reduced in normaltension glaucoma.5
Frequency domain optical coherence tomography (FD-OCT) can be
used to examine retinal blood flow,
but research is ongoing to determine
whether these data are correlated
Examination of the optic nerve head
blood flow with a Heidelberg retinal
flowmeter has shown a potential correlation between reduced blood flow
and visual field defects.7-9 However,
this device is used in experimental
settings and not usually available to
those in clinical practice who are following patients.
Scanning laser ophthalmoscopy
angiography has indicated sluggish
blood flow in the choroid in normaltension glaucoma.10,11 Dynamic
contour tonometry also may be used
to indirectly look at choroidal blood
flow.12 Results are mixed on whether
these findings correlate with glaucomatous damage.
Ongoing efforts have not yet identified a proven modifiable risk factor
for glaucoma other than IOP. We
know that ocular perfusion pressure
and ocular blood flow are potential
vascular risk factors in glaucoma. I
am optimistic that we will someday
have proven information regarding
their role and—more importantly—
practical ways to affect the course
of the disease by modifying these
- Leske MC, Wu SY, Hennis A, et al; BES Study
Group. Risk factors for incident open-angle
glaucoma: the Barbados Eye Studies. Ophthalmology. 2008;115(1):85-93.
- Leske MC, Heijl A, Hyman L, et al. Predictors of long-term progression in the
Early Manifest Glaucoma Trial. Ophthalmology.
- Harris A, Sergott RC, Spaeth GL, et al. Color
Doppler analysis of ocular vessel blood velocity
in normal-tension glaucoma. Am J Ophthalmol.
- Siesky BA, Harris A, Amireskandari A,
Marek B. Glaucoma and ocular blood flow: an
anatomical perspective. Expert Rev Ophthalmol.
- Chung HS, Harris A, Kagemann L, Martin B. Peripapillary retinal blood flow in nor-
mal tension glaucoma. Br J Ophthalmol.
- Wang Y, Fawzi AA, Varma R, et al. Pilot study
of optical coherence tomography measurement of retinal blood flow in retinal and optic
nerve diseases. Invest Ophthalmol Vis Sci.
- Sato EA, Ohtake Y, Shinoda K, Mashima Y, Kimura I. Decreased blood flow at neuroreti-
nal rim of optic nerve head corresponds with
visual field deficit in eyes with normal tension
glaucoma. Graefes Arch Clin Exp Ophthalmol.
- Jonas JB, Harazny J, Budde WM, et al. Optic
disc morphometry correlated with confocal laser scanning Doppler flowmetry measurements
in normal-pressure glaucoma. J Glaucoma.
- Hosking SL, Embleton SJ, Cunliffe IA. Application of a local search strategy improves the
detection of blood flow deficits in the neuroretinal rim of glaucoma patients using scanning
laser Doppler flowmetry. Br J Ophthalmol.
- Yin ZQ, Vaegan Millar TJ, Beaumont P,
Sarks S. Widespread choroidal insufficiency
in primary open-angle glaucoma. J Glaucoma.
- Duijm HF, van den Berg TJ, Greve EL. A
comparison of retinal and choroidal hemodynamics in patients with primary open-angle
glaucoma and normal-pressure glaucoma. Am J
- Punjabi OS, Ho HK, Kniestedt C, et al.
Intraocular pressure and ocular pulse amplitude
comparisons in different types of glaucoma
using dynamic contour tonometry. Curr Eye Res.
III. THERAPEUTICS IN
WHEN AND HOW TO INITIATE
Although clinicians vary in their choice
of when to initiate glaucoma treatment, it is important to begin before
significant visual field loss occurs.
Shan Lin, MD
The decision as to whether to treat
suspected glaucoma—and when to begin treatment—is not always clear-cut.
Clinicians choose to begin treatment at
various points: When intraocular pressure (IOP) is high, visual field loss occurs, or glaucoma progresses? Ideally,
of course, one should begin treatment
prior to significant visual field loss.
Myopia and Glaucoma
Many studies have shown that high
myopia is an independent risk factor
for glaucoma. This is of great concern
particularly in Asian populations, who
have a much higher incidence of
myopia and high myopia than other
demographic groups. In a 1999 survey
of senior high school students in
Taiwan, for example, 84 percent were
myopic, with 16 percent being highly
myopic (-6D or greater).1
In the Blue Mountains Eye Study,
a cross-sectional population-based
study of 3,211 subjects from Australia, low myopes had a two-fold
increase in optic disc damage and
visual field defects compared to
those without myopia, and moderate
and high myopes had a three-fold
increased risk.2 The Beijing Eye Study,
a population-based, cross-sectional
study of 4,319 subjects, reported that
high myopes were five to six times
more likely to have optic disc or visual
In our recent study of 5,277
subjects in the United States using
frequency-doubling technology, we
found no association of myopia with
self-reported glaucoma or vertical
cup-to-disc ratio; however, visual
field defects were twice as likely in
mild myopes, three times as likely in
moderate myopes, and 14 times more
likely in severe myopes.4
When treating glaucoma, first-line
options include prostaglandins and
beta-blockers, depending on issues
such as cost, efficacy, diurnal benefit
and compliance. Research has shown
that prostaglandins more effectively
reduce intraocular pressure compared with beta-blockers. Zhang et
al. reported greater IOP efficacy with
latanoprost compared with timolol.5 Moreover, this meta-analysis found a
significant reduction in heart rate and
significant risk of hypotension and
bradycardia with timolol.
Additional adverse events also have
been associated with beta-blockers,
including breathing difficulties, depression, and erectile dysfunction, and
these drugs are contraindicated in patients with asthma. Furthermore, timolol does not reduce IOP very effectively
in patients taking higher systemic
doses of propranolol or metoprolol.
Although latanoprost use has not been
associated with these systemic issues,
there are cosmetic concerns. In addition, prostaglandins should not be used
in patients with cystoid macular edema,
uveitis or a history of ocular herpes.
It is worth considering efficacy
throughout the day and night. A comparison of latanoprost and timolol
showed that timolol has similar effects to baseline control at nighttime,
whereas prostaglandins significantly
reduce IOP during this time.6 For this
reason and others, I am more likely
to choose prostaglandins as first-line
therapy. Patients are also more likely
to be compliant with a once-daily
In a review of timolol and betaxolol
to assess the potential neuroprotective effects of betaxolol, timolol
almost always reduces IOP more effectively; however, betaxolol is usually
more effective than timolol in slowing
Although prostaglandins are usually
the drug of choice, beta-blockers may
be preferred as first-line therapy when
patients are concerned about drug
expense and/or cosmesis. Generics
also may be another option for costconscious patients.
When initiating treatment, patient
education is important to ensure efficacy. I instruct patients to close their
eyes for five minutes after administering the drops. I do not use one-eye
trials. Patients return for evaluation
four to six weeks later.
Laser trabeculoplasty often is not
considered as first-line therapy, but
given medication concerns, it may be
a good solution. It eliminates therapy
adherence issues and could be a less
expensive option for patients.8 Furthermore, selective laser trabeculoplasty
(SLT) potentially may be repeated and
cause less damage to the trabecular
In the Glaucoma Laser Trial, visual
field was better preserved and there
was less optic disc progression if
patients received laser treatment
rather than medication as first-line
therapy.9 This group also required less
medication overall compared with the
Clinicians need to be aware of the
need to diagnose and potentially treat
glaucoma early and understand the
benefits of available treatment options.
- Lin LL, Shih YF, Tsai CB, et al. Epidemiologic
study of ocular refraction among schoolchildren in Taiwan in 1995.Optom Vis Sci.
- Lim R, Mitchell P, Cumming RG. Refractive associations with cataract: the Blue Mountains Eye
Study. Ophthalmology. 1999;40(12):3021-36.
- Xu L, Wang Y, Wang S, Wang Y, Jonas JB. High
myopia and glaucoma susceptibility the Beijing
Eye Study. Ophthalmology. 2007;114(2):216-20.
- Qiu M, Wang SY, Singh K, Lin SC. Association
between myopia and glaucoma in the United
States population. Invest Ophthalmol Vis Sci.
- Zhang WY, Po AL, Dua HS, Azuara-Blanco A. Meta-analysis of randomised controlled
trials comparing latanoprost with timolol in the
treatment of patients with open angle glaucoma
or ocular hypertension. Br J Ophthalmol.
- Liu JH, Kripke DF, Weinreb RN. Comparison
of the nocturnal effects of once-daily timolol
and latanoprost on intraocular pressure. Am J
- Grieshaber MC, Flammer J. Is the medication
used to achieve the target intraocular pressure
in glaucoma therapy of relevance? An exemplary analysis on the basis of two beta-blockers.
Prog Retin Eye Res. 2010;29(1):79-93.
- Lee R, Hutnik CM. Projected cost comparison
of selective laser trabeculoplasty versus glaucoma medication in the Ontario Health Insurance
Plan. Can J Ophthalmol. 2006;41(4):449-56.
- The Glaucoma Laser Trial (GLT) and glaucoma
laser trial follow-up study: 7. Results. Glaucoma
Laser Trial Research Group. Am J Ophthalmol.
THREE RULES FOR ADVANCING
Decisions to advance treatment in
patients with glaucoma should depend
on each individual case, with treatment strategies tailored accordingly.
Felipe A. Medeiros, MD, PhD
In weighing whether to advance glaucoma treatment, clinicians must consider a range of factors based on each
individual patient. Essentially there are
three reasons to advance treatment:
- Intraocular pressure (IOP) higher
than one's established target IOP
- Structural or functional progression
despite IOP within the target range
- Detection of a new risk factor for
Establishing and Monitoring
It is essential to evaluate the patient's
target pressure, the range of intraocular
pressure (IOP) at which we believe progression is unlikely to affect a patient's
quality of life. This is established by
considering the risks and benefits of
treatment in the context of how a clinician believes glaucoma will progress
and whether it will cause disability.
In setting this target, clinicians must
consider the amount of glaucoma damage, IOP at which damage occurred,
and the patient's life expectancy, as
well as other factors such as the status
of the fellow eye and family history of
However, the target IOP is an estimate
and must be reevaluated periodically.
Treatment should be advanced if the
patient's first-line treatment fails to
achieve the target pressure.
Of course, IOP is only part of the
story. If progressive structural or
functional damage occurs over time
despite achieving the target pressure
with treatment, clinicians must reduce
the target pressure.
The Early Manifest Glaucoma Trial
(EMGT) demonstrated that betaxolol
and laser trabeculoplasty reduced IOP
by 25 percent in patients with newly
diagnosed glaucoma.1 They were treated
subsequently with prostaglandin analogs.
However, disease progression occurred in
59 percent of these patients during eight
years of follow-up.2 Therefore, it was
probably necessary to advance treatment
in most of these patients.
In contrast, the Advanced Glaucoma Intervention Study (AGIS) demonstrated that
little visual field change occurred when
IOP was less than 18 mmHg (average of
12 mmHg) during all visits.3 However, this
does not indicate that treatment should
be advanced for every patient to prevent
progression. Low pressures are preferred
to halt progression, but clinicians need to
consider the risks and benefits of advancing treatment and how it will affect each
patient's quality of life.
The most important factor in determining a patient's risk of impairment over time is the rate of damage
progression. EMGT data show that the
rates of change can vary greatly, with
disease progressing rapidly in some
patients and slowly in others. If disease progression is slow, higher levels
of IOP may be able to be tolerated.
It's important to treat the individual patient—not the average. With rapidly progressing disease and/or a younger patient,
disability is more likely to occur. Therefore,
advancing treatment is important in these
cases. The ultimate goal is to preserve
the patient's visual function during the
remaining years of his or her life.
Adapting Treatment to New Risks
Although the main risk factors used
to set the initial target pressure (e.g.,
age, central corneal thickness) may
not change, a new disc hemorrhage
will alter the patient's risk of progression. Evidence of disc hemorrhages
can nearly disappear in just a few
months, making them quite difficult to
detect if one isn't searching carefully.
We were interested to know whether
advancing treatment to further lower
IOP after a disc hemorrhage could alter
the course of the disease. In a longitudinal study, we evaluated more than 500
eyes for more than eight years.4 During
that time, 19 percent of the eyes had at
least one episode of disc hemorrhage.
The overall rate of change in the visual
field index was significantly faster in
eyes with hemorrhages than in those
without (–0.88 percent/year vs. –0.38
percent/year, respectively, p<0.001), but
there was considerable variability.
To examine whether IOP reduction
slows the rate of glaucoma progression
in patients with disc hemorrhage, we calculated the slopes of visual field changes
before and after disc hemorrhage. It
appears that advancing treatment and
reducing IOP in these patients results in
improved outcomes. Therefore, if disc
hemorrhages occur, clinicians must factor them in when considering whether to
There are no definitive rules dictating whether to advance treatment in
patients with glaucoma. Clinicians must
consider a range of factors in each individual patient, including rate of progression, life expectancy and potential risk
factors associated with treatment.
- Heijl A, Leske MC, Bengtsson B, et al.
Reduction of intraocular pressure and
glaucoma progression: results from the Early
Manifest Glaucoma Trial. Arch Ophthalmol.
- Leske MC, Heijl A, Hyman L, et al. Pre-
dictors of long-term progression in the
Early Manifest Glaucoma Trial. Ophthalmology.
- The Advanced Glaucoma Intervention Study
(AGIS): 7. The relationship between control of
intraocular pressure and visual field deterioration. The AGIS Investigators. Am J Ophthalmol.
- Medeiros FA, Alencar LM, Sample PA, Zangwill
LM, Susanna R Jr, Weinreb RN, et al. The relationship between intraocular pressure reduction
and rates of progressive visual field loss in eyes
with optic disc hemorrhage. Ophthalmology.
ADDRESSING THE NORMAL-TENSION
Improvement of retinal vascular
autoregulation may explain therapeutic agents' value in the treatment of
patients with normal IOP.
Louis R. Pasquale, MD, FARVO
Determining the ideal treatment
for patients with glaucomatous optic neuropathy whose intraocular pressure
is within the normal range remains a
major gap in clinical practice.
Fifteen years ago, the Collaborative Normal-Tension Glaucoma Study
(CNTGS) investigators reported that
aggressive intraocular pressure (IOP)
lowering significantly reduced progression at five years in patients with
normal-tension glaucoma (NTG).1 However, when they controlled for the
impact of cataract (which occurred at
higher rates in the treated group) on
visual field progression, the treatment
More recently, the Low-Pressure
Glaucoma Treatment Study (LoPGTS),
compared visual function in patients
with the normal-tension variant of
primary open-angle glaucoma (POAG)
treated with timolol 0.5% compared to
those treated with brimonidine 0.2%.
Brimonidine was found to be superior
to timolol in preserving visual field in
The rate of visual field progression in
the timolol arm of LoPGTS and the untreated arm of the CNTGS were similar
(33 percent to 39 percent) and considerably higher than the nine percent rate
in the brimonidine arm of LoPGTS (Figure 8). The pressure reduction in the
brimonidine group was not greater than
the timolol group in the LoPGTS, so the
preservation of visual field is unlikely
due to IOP lowering, which leads one to
question: what is happening?
It's important to find out. Progression
is often slow in NTG patients, but we
all have those very frustrating cases
like this one (Figure 9) who continued to progress to quite advanced
stages of glaucoma despite maximal
therapy that maintains very low IOP.
Role of Disc Hemorrhages
I suspect that disc hemorrhages play a
very important role. These are probably
more common than we think; the rate in a
cross-sectional study from Australia was
about two times higher in NTG patientsthan it was in open-angle glaucoma patients overall (25 percent vs. 13 percent).4
The reality is that patients with NTG
are getting frequent disc hemorrhages,
whether we see them or not. In a
number of well done studies using very
careful statistics, when researchers
control for intraocular pressure, disc
hemorrhage remains an independent
factor for either converting from no
disease to POAG or for progressing
from early disease to later forms of
the disease (Figure 10). So it is
possible that if we could stop the disc
hemorrhages in NTG, we could also
stop the progression. But how do disc
hemorrhages happen and how do they
contribute to optic neuropathy? Does
brimonidine affect hemorrhages in some
way that would explain its effects on NTG patients entered into the LoPGTS?
To answer these questions, we need
to look closely at retinal vascular
autoregulation, which is the ability to
maintain a stable retinal blood flow in
the face of changing ocular perfusion
pressure. This is an intuitive concept.
When you wake up in the morning and
get out of bed, gravity exerts downward pressure on the blood in your
head but you don't experience blurry
vision or lose consciousness because
there are compensatory changes occurring in the blood vessels that allow
the blood flow to all the organs above
the heart to remain constant. This
mechanism may be inherently faulty in
many NTG patients.
With my colleagues, I've conducted
a series of studies using a Cannon
Laser Bloodflow Meter that simultaneously measures retinal blood vessel
diameter and a Doppler signal that
allows us to directly calculate blood
flow. We measure the flow in a retinal
arteriole segment adjacent to the
optic nerve with the patient sitting up
(baseline), and then we measure the
same vessel with the patient lying
down. The supine retinal blood flow
measurements are repeated at 15 and
What we have found is that the results
for control subjects are very different
from those of patients with NTG. In normal controls, the retinal blood flow stays
relatively constant compared to the
baseline when the subject lies down.
But in an NTG patient, the blood flow
increases by as much as 60 percent
(Figure 11).5 Our hypothesis is that
the shear forces directed to the lamina
cribrosa capillaries by this hyperperfusion are so strong that the small blood
vessels hemorrhage. This may create a
kind of compartment syndrome in the
intrascleral portion of the optic nerve
with subsequent focal disc notching.
In a subsequent study, we showed
that in six of six subjects with NTG and
abnormal retinal vascular autoregulation, brimonidine 0.15% OU b.i.d. was
able to normalize autoregulation.6 Brimonidine is a vasomodulator; as such, it
causes larger retinal vessels (which do
not receive neurogenic input) to dilate
and smaller vessels to constrict. It may
be that this vasomodulation is able to
normalize the positional changes in
blood flow that would otherwise occur,
thereby reducing the rate of hemorrhages and helping to stabilize the disease.
Most recently, we have shown
that in patients with retinal vascular
dysfunction, combination therapy with
either dorzolamide/timolol or brimonidine/timolol improved autoregulation
over timolol alone.7 Basic science data
suggests that both brimonidine and
dorzolamide produce beneficial ocular
vasomodulatory effects via a mechanism that involves enhanced nitric
Additional research remains to be
done, but if these agents can improve
retinal vascular autoregulation and
reduce the rate of disc hemorrhages
and if there is a positive functional
consequence of that—which LoPGTS
suggests there is—than it is worth
considering them as an important
part of the management of NTG.
- Collaborative Normal-Tension Glaucoma
Study Group. Comparison of glaucomatous
progression between untreated patients with
normal-tension glaucoma and patients with
therapeutically reduced intraocular pressures.
Am J Ophthalmol. 1998;126(4):487-97.
- Collaborative Normal-Tension Glaucoma
Study Group. The effectiveness of intraocular pressure reduction in the treatment of normal-tension glaucoma. Am J Ophthalmol.
- Krupin T, Liebmann JM, Greenfield DS, et al; the
Low-pressure Glaucoma Study Group. A randomized trial of brimonidine versus timolol in preserving visual function: results from the Low-pressure
Glaucoma Treatment Study. Am J Ophthalmol.
- Healey PR, Mitchell P, Smith W, Wang JJ. Optic disc
hemorrhages in a population with and without signs of
glaucoma. Ophthalmology. 1998;105:216-23.
- Feke GT, Pasquale LR. Retinal blood flow
response to posture change in glaucoma patients
compared with healthy subjects. Ophthalmology.
- Feke GT, Hazin R, Grosskreutz CL, Pasquale
LR. Effect of brimonidine on retinal blood flow
autoregulation in primary open-angle glaucoma. J
Ocul Pharmacol Ther. 2011;27(4):347-52.
- Feke GT, Rhee DJ, Turalba AV, Pasquale LR.
Effects of dorzolamide-timolol and brimonidinetimolol on retinal vascular autoregulation and ocular perfusion pressure in primary open angle glaucoma. J Ocul Pharmacol Ther. 2013;29(7):639-45.
- Rosa RH, Hein TN, Yuan Z, et al. Brimonidine
evokes heterogenous vasomotor response of
retinal arterioles: diminished nitric oxide-mediated
vasodilation when size goes small. Am J Physiol
Heart Circ Physiol. 2006;291:231-8.
- Kringelholt S, Simonsen U, Bek T. Dorzolamide-induced relaxation of intraocular porcine
ciliary arteries in vitro depends on nitric oxide
and the vascular endothelium. Curr Eye Res.
Robert N. Weinreb, MD
There have been many exciting developments recently in our understanding
of glaucoma and in potential therapeutic
approaches to treating patients with glaucoma—especially those challenging
patients who progress despite having
low intraocular pressure.
Some important takeaways for clinical practice are that we should look
more closely for changes in structure,
rather than relying solely on standard
visual fields to detect progression. An
important takeaway is that one should
change or advance therapy if there
is a new risk factor, such as optic
disc hemorrhage. With the potential
for genetic testing, ongoing improvements in our understanding of the
role of blood flow and other vascular
risk factors, and new ideas about the
management of glaucoma, the future
for improved glaucoma treatments is