MANAGING GLAUCOMA: BEYOND INTRAOCULAR PRESSURE
Release Date: September 1, 2012
Expiration Date: August 31, 2013
Supported by an Independent Educational Grant from Allergan, Inc.
Jointly Sponsored by Institute for the Advancement of Human Behavior and Review of
Principal faculty and their credentials:
Claude F. Burgoyne,
MD, holds the Van
Buskirk Chair in Ophthalmic Research and is
Research Director of the
Optic Nerve Head Research Laboratory at the Devers Eye Institute in
Louis B. Cantor, MD, is the Jay C. and Lucile L. Kahn Professor of Glaucoma Research and Education and Chairman
of the Department of Ophthalmology
at the Indiana University School of
Medicine. He also serves as Director
of Indiana University's Eugene and
Marilyn Glick Eye Institute.
Robert Fechtner, MD, is Professor at the Institute of Ophthalmology and Visual Science and Director, of the Glaucoma Division, at the New Jersey
Christopher Leung, MD, MB, CHB, is Professor in the Department of Ophthalmology and Visual Sciences
at the Chinese University of Hong
Nils Loewen, MD, PhD, is an Assistant Professor of Ophthalmology at Yale University School of Medicine. He has
a special interest in low-pressure
Felipe Medeiros, MD, PhD, is Professor of Ophthalmology at the Hamilton Glaucoma Center at the University
of California, San Diego.
Robert N. Weinreb, MD, is Chairman and Distinguished Professor of Ophthalmology, the Morris Gleich Chair and Director of the Shiley Eye Center
at the University of California San
Glaucoma is a major cause of blindness and affects upwards of 60 million people worldwide. Normal-tension glaucoma (NTG) is a type of open-angle glaucoma (OAG) resulting in damage to the optic nerve and abnormalities of the visual field. IOP in this type of glaucoma is not higher than that 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.1
The typical treatment of glaucoma is directed at lowering eye pressure; however, traditional strategies of lowering IOP are not always effective at preventing glaucoma progression. The need to evaluate other therapies that augment the effect of lowering IOP is prevalent. In recent years, the focus of glaucoma research has shifted toward neuroprotection, which has been defined as the use of therapeutic agents to prevent, hinder and, in some instances, reverse neuronal cell death whatever the primary injury.2 Various neuroprotective drug-based approaches have been capable of reducing the death of retinal ganglion cells, which is the hallmark of glaucomatous optic neuropa-thy.3 Moreover, there is a growing trend toward using existing neuroprotective strategies in central nervous system diseases for the treatment of glaucoma.4 This continuing education activity will educate physicians on current theories for managing patients with normal-tension glaucoma, with particular focus on potential
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:
- Discuss the diagnosis and management of normal-tension glaucoma. recording the best answer to each question;
- Decipher when lowering IOP will not halt progression of the disease.
- Explain the biologic foundation and application of neuroprotection in glaucoma, as well as its value in the treatment of glaucoma.
- Describe the rationale for the use of glaucoma neuroprotection as a pressure-independent theory.
- Identify the goals and obstacles of neuroprotection in the treatment of normal-tension glaucoma.
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I. DIAGNOSTICS IN
UNDERSTANDING IOP IN CLINICAL PRACTICE
IOP remains a central feature in the diagnosis and management of glaucoma, but it must be
combined with measures of structure and function to determine progression.
NILS LOEWEN, MD, PHD
Intraocular pressure (IOP) is a central feature in the diagnosis and management of glaucoma—and yet it remains very diffi-cult to put a single IOP measurement during a clinic visit into context and determine, together with prior measurements, what the likelihood of progression is.
The father of evidence-based medicine, David M. Eddy, MD, PhD, challenged our field in 1983 when he said there is
no evidence that IOP is causatively linked to glaucoma. It took almost 16 years to develop strong evidence-based data to show that glaucoma is, in fact, caused by a pressure that is too high for the individual eye: the Ocular Hypertensive Treatment Study (OHTS) and the Early Manifest Glaucoma Trial (EMGT) demonstrated that lowering IOP prevents or delays progression.1,2 Animal models have also provided powerful evidence that surgical lowering
of elevated IOP prevents progression.3
There is an almost linear correlation of glaucoma incidence with increasing IOP.4 The prevalence of open-angle glaucoma also increases with age, albeit not in a linear fashion.5 Aging has profound effects on outflow pathology but is not correlated in linear fashion with the rise in IOP.
Which IOP to Treat
The first dilemma with IOP is that the standard of measurement to this day is Goldmann applanation, which is prone to various artifacts and influenced by many variables. There are better ways of measuring IOP that are often used in research (e.g., pneumatonometry), but they have not become as widely adopted.
When we treat elevated IOP, there is a wide range of options, including laser tra-beculoplasty, different classes of pressure-lowering topical medications, and surgery, including the ab interno trabeculotomy (Trabectome, NeoMedix), trabeculectomy, tube or suprachoroidal shunts.
We have to be aware of what exactly what we are treating with each option. Tra-beculoplasty and the Trabectome both treat the trabecular meshwork (TM) and enhance conventional outflow. Prostaglandin analogs and suprachoroidal shunts, on the other hand, enhance uveoscleral outflow. Brinzo-lamide and timolol affect outflow through the TM in a pressure-dependent fashion.
Because the surgical options mentioned utilize different routes of outflow, they have different effects on IOP throughout the diurnal cycle. For example, trabeculoplasty and latanoprost both reduce IOP throughout the day and night.6,7 Timolol, however, only lowers pressure during the day, not at night.7 Adding a second medication to latanoprost can achieve further lowering, but if the second medication is timolol, one will not achieve additional IOP reduction at night.8 Suprachoroidal drainage devices that shunt fluid into the suprachoroidal space lower IOP more in the morning than at night in our studies.
In following patients under treatment for elevated IOP, one can reach very different conclusions about the relative effectiveness of each of these interventions, depending on the time of day that IOP is measured. By consistently measuring IOP at 9:30 a.m., for example, one would always be understating the relative effect of trabeculoplasty and prostaglandin analogs and overstating the effects of timolol or a suprachoroidal shunt.
The answer to these challenges lies in continuous IOP monitoring, such as that recently reported by Weinreb and Mansouri using a telemetric contact lens sensor.9 Twenty-four-hour IOP measurements have the potential to completely change how we view IOP and, perhaps, how we view the efficacy of our pressure-lowering treatments (see sidebar below).
Upcoming Advances: 24-Hour IOP Monitoring
Robert N. Weinreb, MD
Intraocular pressure varies throughout the day. Both peak and mean IOP are important parameters to consider in evaluating the risk of glaucoma progression. For about two-thirds of individuals, however, peak IOP occurs during the night. Daytime measurements of IOP in the clinic, therefore, will often fail to capture peak IOP, which also skews one’s understanding of mean pressure.
Obtaining supine IOP can provide a crude estimate of the peak pressure. For a supine IOP measurement, tilt the patient back in the examining chair for two minutes, and use a pneumotonometer or a hand-held Perkins applanation tonometer (Haag-Streit). A Goldman tonometer cannot be used in the supine position; the Tono-Pen (Reichert Technologies) is less effective when IOP is above the mid-20s.
Another key consideration is that IOP doesn’t necessarily behave the same in an individual’s left and right eyes. This is one of the reasons why the monocular therapeutic trial has been invalidated. We simply cannot assume that a change in pressure in one eye will be accompanied by a similar change in the other. We have also shown that IOP is not conserved from day to day. So, while it is laudable to keep patients around for several hours for repeated pressure measurements (or even overnight for 24-hour pressure measurement), there is absolutely no guarantee that their IOP levels will be similar the next day, or the day after that.
This at fi rst seems discouraging, but I believe that recognition of the limitations of our current technology for measuring IOP is rapidly leading us toward continuous 24-hour IOP measurement. Disposable contact lenses that can accomplish this are already available in several countries outside the United States. Also on the horizon are implantable 24-hour pressure monitors that can be implanted at the time of cataract surgery or in conjunction with a glaucoma drainage device; these are under investigation in Europe. When these technologies become more widely available, they will revolutionize our understanding of IOP patterns and fl uctuations in our patients.
The good news is that even with single
IOP measures that offer just a snapshot
of one point in time we can still come to
the correct conclusions in clinical trials. In all the major epidemiological studies in
glaucoma—the Age-Related Glaucoma
Intervention Study (AGIS); Collaborative
Initial Glaucoma Treatment Study (CIGTS);
OHTS; EMGT; and Glaucoma Laser Trial
(GLT)—IOP was measured at one time
of the day only. Thanks to the power of
statistics, we know that, in the aggregate,
pressure-lowering actually prevents
progression or onset.
But how do we use that aggregate data
to determine whether an individual patient
is going to get worse? The answer is that
IOP alone is not enough. Multiple IOP
measures provide us with more security
but ideally we must combine IOP data with
multiple measures of structure and function over time so that we can understand
not just the magnitude of change, but the
rate of change.
For example, a mild visual field (VF) defect that is progressing rapidly is of more
concern, from a treatment perspective,
than a pronounced VF defect that has been
stabilized with IOP-lowering treatment and
is progressing slowly or not at all.
In summary, while a primary goal
in glaucoma management is to lower
IOP, there is no magic level for IOP that
will halt progression in every patient.
Diagnostic care that integrates IOP with
repeated measures of functional and
structural change is necessary to determine the urgency and impact of treatment. Additionally, treatment combinations that integrate both conventional and
uveoscleral outflow approaches may have
the highest rate of success.
- Kass MA, Heuer DK, Higginbotham EJ, et 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;120(6):701-13; discussion 829-30.
- Heijl A, Leske MC, Bengtsson B, et al; Early Manifest Glaucoma Trial Group. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol. 2002;120(10):1268-79.
- Nickells RW, Schlamp CL, Li Y, et al. Surgical lowering of elevated intraocular pressure in monkeys prevents progression of glaucomatous disease. Exp Eye Res. 2007;84(4):729-36.
- Leske MC, Connell AM, Wu SY, et al. Risk factors for open-angle glaucoma. The Barbados Eye Study. Arch Ophthalmol. 1995;113(7):918-24.
- Varma R, Ying-Lai M, Francis BA, et al; Los Angeles Latino Eye Study Group. Prevalence of open-angle glaucoma and ocular hypertension in Latinos: the Los Angeles Latino Eye Study. Ophthalmology. 2004;111(8):1439-48.
- Lee AC, Mosaed S, Weinreb RN, et al. Effect of laser trabeculoplasty on nocturnal intraocular pressure in medically treated glaucoma patients. Ophthalmology. 2007;114(4):666-70.
- Liu JH, Kripke DF, Weinreb RN. Comparison of the nocturnal effects of once-daily timolol and latano-prost on intraocular pressure. Am J Ophthalmol. 2004;138(3):389-95.
- Liu JH, Medeiros FA, Slight JR, Weinreb RN. Comparing diurnal and nocturnal effects of brinzolamide and timolol on intraocular pressure in patients receiving latanoprost monotherapy. Ophthalmology. 2009;116(3):449-54.
- Mansouri K, Weinreb RN. Meeting an unmet need in glaucoma: continuous 24-h monitoring of intraocular pressure. Expert Rev Med Devices. 2012;9(3):225-31.
STRUCTURAL AND FUNCTIONAL MEASURES IN GLAUCOMA
An index that combines both may offer the
most reliable estimate 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.
The Limitations of
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 dB to -3 dB.
That would correspond to an RGC population of approximately 600, 000 to 700,000
cells, according to a recent study (see Figure 1). Such number would represent
approximately 30 percent loss from the
average RGC number in healthy eyes.
Figure 1. Relationship between MD and RGC number. (Adapted from 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.)
VF 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 as shown in Figure 1. This relationship indicates 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 and exaction
despite apparently statistically
normal VFs (see Figure 2). In
contrast, at advanced stages
of the disease, relatively large
changes in function may be associated with only minor or no
detectable changes in structure.
Figure 2. At early stages of glaucoma, large structural changes can be associated with
statistically normal visual fields.
One could argue whether
treatment is necessary before
development of VF losses or
whether one could just wait
for the appearance of field
defects to initiate treatment
and then prevent the death of
the remaining RGCs.
Figure 1 can be used to illustrate the
importance of early detection of damage
and early treatment. To get from that
very early VF defect of -3 dB to a mean
deviation of -10 dB, which most would
agree would represent quite severe VF
loss and potential functional impairment,
one need only lose another 300,000
cells—far fewer than were lost to get
to the point of a detectable field loss in
the first place. Therefore, reliance on VF
testing alone will potentially result in late
diagnosis and underestimation the rate of
glaucoma progression, especially in the
early stages of the disease. It is important
to emphasize, however, that several factors need to be taken into account when
making treatment decisions, such as
life expectancy, potential side effects of
treatment, and patient's perceptions and
expectations about the treatment.
Structural Changes in
Many studies have shown
that imaging technologies
such as confocal scanning
laser ophthalmoscopy (CSLO),
scanning laser polarimetry, and
optical coherence tomography
(OCT) can objectively quantify
structural changes in the neu-roretinal rim and retinal nerve
fiber layer (RNFL).
Experimental studies have
shown that OCT-measured
RNFL thickness correlates well
with the RGC number until the
later stages of glaucoma, when
OCT measurements appear
to reach a plateau. Clinical
studies have also shown that OCT and
other devices actually perform poorly
in differentiating moderate from severe
glaucoma.1 These observations about
OCT performance and SAP performance
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.
A New Paradigm
We recently developed a single index
that combines structure and function
measures to provide an age-corrected
estimate of ganglion cell loss.2 This
is based on work showing
that the number of retinal
ganglion cells can be reliably
estimated from either VF SAP
sensitivity data or from OCT
RNFL analysis.3 Unlike VF
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
Figure 3. Patient with optic nerve progression over time. Note the essentially normal visual fields.
For example, the patient in Figure 3 showed optic nerve progression over time.
However, from the VF, one would not know
that this patient has glaucoma, as the results are essentially normal. However, the
combined index of structure and function
estimates that this patient has a loss of 39
percent of the nerve tissue. In another patient with more advanced glaucoma, OCT
imaging would seem to indicate a similar
rate of change in both eyes. The VFs tell a
different story, though. And, indeed, at
this stage of glaucoma, we should give
greater weight to the perimetry. The index
does this, giving us an estimate of a 74
percent loss of ganglion cells in the right
eye and 85 percent in the left eye, which
is the eye with the worse-looking VFs
(see Figure 4).
Figure 4. The Combined Structure Function Index (CSFI) estimates the loss of retinal ganglion cells based on both
structural and functional inputs.
We have also shown that the CSFI
detects progression in a significantly
higher number of patients compared to
conventional indices.4 In this study, 213
eyes of glaucomatous subjects were
followed for an average of 4.5 years. The
combined index detected change in 22
percent of glaucomatous eyes compared
to 8.5 percent for VFs and 14.6 percent for
OCT average thickness, with the same 95
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, potentially
resulting in more effective management of
our glaucoma patients.
- Sibota R, Sony P, Viney G, et al. Diagnostic capability of optical coherence tomography in evaluating the degree of glaucomatous retinal nerve fiber damage. Invest Ophthalmol Vis Sci 2006;47(5):2006-10.
- 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.
- Medeiros FA, Zangwill LM, Anderson DR, et al. Estimating the rate of retinal ganglion cell loss in glaucoma. Am J Ophthalmol. 2012; Jul 26. [Epub ahead of print].
II. WHAT DAMAGES
THE OPTIC NERVE IN GLAUCOMA?
GLAUCOMA IS A NEURODEGENERATIVE DISEASE
New information broadens our understanding of this common disease.
ROBERT N. WEINREB, MD
Glaucoma is more than a condition of
elevated intraocular pressure (IOP) and, in
fact, is more than a disease of the eye; it is
a progressive neurodegenerative disease.
Ophthalmologists are most interested in
what happens to the eye in glaucoma,
but the eye is part of the central visual
pathway. The optic nerve fibers target
the lateral geniculate nucleus—and, in
particular, it's relay neurons—in the brain
stem. From the lateral geniculate nucleus,
the optic nerve fibers then radiate to the
Working with University of Toronto
researchers Yeni Yucel, MD, PhD, and
Neeru Gupta, MD, PhD, we looked at the
lateral geniculate nucleus (LGN) in an
experimental monkey model of glaucoma. We found very apparent atrophy
and loss of the relay neurons in the LGN.1 So not only does glaucoma cause loss of
optic neurons—the retinal ganglion cells
in the eye—but it also causes neuronal
damage in the LGN. The damage we detected occurred in three major channels:
The magnocellular, the parvocellular, and
koniocellular.2 When we looked at other
areas of the central visual pathway, including the brain, it was readily apparent
to us that not only was there a change
in the brain stem but there were also
changes in the metabolic activity and cel-lularity of the visual cortex.3
Glaucoma is a disease of the entire
central visual pathway. It shares characteristics with other neurodegenera-tive diseases such as Alzheimer's and
Parkinson's disease. In fact, one can make
the case that glaucoma is more prevalent
than all other neurodegenerative diseases
With that, we can now pursue a deeper
understanding of what exactly causes
neuronal damage and degeneration in
primary open-angle glaucoma. Great
progress is being made on diagnostically
measuring and identifying the roles of IOP-related biomechanical stress, ocular perfusion, and cerebrospinal fluid pressure.
The results of this research, in addition to
new methods for identifying patterns of
cell damage, provide hope that we will be
able to identify successful strategies for
- Yucel YH, Zhang Q, Weinreb RN, et al. Atrophy of relay neurons in magno- and parvocel-lular layers in the lateral geniculate nucleus in experimental glaucoma. Invest Ophthalmol Vis Sci.
- Yucel YH, Zhang Q, Weinreb RN, et al. Effects of retinal ganglion cell loss on magno-, parvo-, konio-cellular pathways in the lateral geniculate nucleus and visual cortex in glaucoma. Prog Retin Eye Res.
- Gupta N, Yucel YH. Brain changes in glaucoma. Eur J Ophthalmol. 2003;13 Suppl 3:S32-5.
A BIOMECHANICAL APPROACH TO UNDERSTANDING THE OPTIC NERVE HEAD
The laminar and peripapillary sclera are subjected to IOP-related stress, systemic insults,
and cellular changes affecting nutrient delivery.
CLAUDE F. BURGOYNE, MD
In every experimental glaucoma model,
the primary site of damage to retinal
ganglion cell axons is within the optic
nerve head (ONH). To better understand
what happens to the ONH in glaucoma,
it may be helpful to think about the ONH
as a biomechanical engineer would—as
a load-bearing structure. Using techniques from other areas of medicine and
engineering, we can begin to make sense
of the physiologic dynamics at play in this
unusual structure, and arrive at a better
understanding of how connective tissues,
blood vessels, and astrocytic and glial cells
in the ONH all interact with one another
and with other factors in glaucoma.
Several etiological factors are implicated in glaucomatous ONH damage.
These include intraocular pressure (IOP)
and IOP-related connective tissue stress
and strain; retrobulbar determinants of
ONH blood flow, blood flow and nutrient
supply within the ONH (which may interact
with connective tissue stress and strain);
and systemic autoimmune or inflammatory insults that are likely to be completely
independent of IOP.
These etiological factors trigger two
major types of functional changes in the
ONH: ONH and peripapillary scleral connective tissue damage; and axonal damage within the lamina cribrosa. Both of
these pathophysiologies occur by multiple
mechanisms and they are connected to
one another via the astrocytes and glial
cells (see Figure 1).
Figure 1. Non-IOP-related effects such as autoimmune or inflammatory insults and retrobulbar determinants of ocular
blood flow can primarily damage the ONH connective tissues and/or axons, leaving them vulnerable to secondary damage by IOP-related mechanisms at normal or elevated levels of IOP. (Adapted from Burgoyne CF, Downs JC. Premise and
Prediction—How Optic Nerve Head Biomechanics Underlies the Susceptibility and Clinical Behavior of the Aged Optic
Nerve Head. J Glaucoma. 2008;17:318-28.)
IOP-Related Stress and Strain
IOP is a central determinant of ONH
physiology at all levels, including normal
pressure. Clinicians are interested in
a target IOP, below which the risk of
progression is close to zero. But the reality
is that there is no IOP level at which the
laminar and peripapillary sclera are not
under substantial stress and strain. In fact,
the connective tissues and vascular supply must be rather robust to avoid optic
neuropathy over a 70- or 80-year lifetime
of these strains.
At a given level of IOP, whether that
pressure is 6 mmHg or 30 mmHg, connective tissue stresses within the lamina
cribrosa and peripapillary sclera are
substantially higher than IOP, depending
upon the three-dimensional geometry
(anatomy or architecture) of these tissues.
Scleral stresses and strains are transferred to the lamina in a tensile manner,
adding to the lamina's ability to resist the
direct effects of IOP. The direct effects of
IOP on the lamina are not only resisted
by these scleral effects but also by retinal
laminar tissue pressure (RLTP), which is
related (but not identical) to cerebrospinal
fluid (CSF) pressure. The tissue behind the
laminar cribrosa is actually at a pressure
somewhat higher than the CSF pressure
itself. While the magnitude of the effects
of CSF pressure on the lamina are small
compared to those of the sclera, RLTP
may exert a very important effect on axon/
astrocyte physiology and transport through
its contributions to the translaminar pressure gradient.1
Blood Flow, Nutrient Supply
and Systemic Factors
The ONH is a rather unusual environment; it is the only place in the central
nervous system where astrocytes do not
have a direct connection to capillaries. In the brain and retina, astrocytes have
a direct connection to capillaries, but in
the ONH, nutrient transport from laminar
capillaries to the laminar astrocytes that
sit on the surface of the laminar beams
has not been studied. It is our working hypothesis that the connective tissues of the
laminar beam and the astrocyte basement
membranes may be barriers to nutrient
diffusion, and that aging and the disease
process itself likely alter these tissues
enough to diminish nutrient transport.
Ocular blood flow and perfusion pressure have become topics of great interest
in glaucoma research in recent years. We know that systemic factors such as
nocturnal hypotension and vasospasm can
influence blood flow within the eye.
Although we don't yet have the tools to
measure and confirm this, it makes sense that IOP-related stress and strain within
the scleral flange and laminar beams
should also influence blood flow. Cioffi and
others have shown that the principal blood
supply to the ONH passes through the
peripapillary sclera, on its way to supplying the peripapillary choroid, the lamina,
and the retro-laminar optic nerve.2 The
anatomy of the peripapillary scleral flange
is much thinner than the posterior sclera,
which creates concentrations of engineering stress and strain that should influence
the magnitude of blood flow.
Hayreh demonstrated the vulnerability
of peripapillary choroidal blood flow to
acute IOP elevation in non-human primate eyes using fluorescein angiograms
and hypothesized that the same thing
is likely to be true for blood flow within
human laminar capillaries.3
Systemic autoimmune or inflammatory insults have the potential to
influence the entire pathophysiology of
ONH damage, although the mechanism
and degree to which this happens is not
known at the present time.
There are multiple mechanisms for
axonal and connective tissue damage
within the ONH. Traditionally, we have
thought of axons as being compromised
by ischemic events or physical compression. These mechanisms feature
heavily in the glaucoma literature of the
past 20 years, and from an engineering standpoint, should be viewed as
compatible rather than controversial. It
is likely that ischemic events due to volume flow or nutrient alteration do cause
axonal damage. Physical compression
may also contribute to axonal damage,
particularly in certain regions of the
ONH. But most people who currently
study the mechanism of axonal injury in
glaucoma believe the final insult to the
axon is mediated by astrocyte and or
glial cell molecular biology.
The cells that govern the ONH connective tissues ought to be influenced
by the same phenomena as the axons.
However, an interesting point to consider
is that connective tissue insults could
actually be the primary mechanism of
damage, weakening the tissue and making the ONH thereafter more vulnerable
to normal levels of intraocular pressure.
This could partially explain why we
sometimes see glaucomatous damage at
normal IOP levels.
We know that connective tissues of
the ONH stiffen with age. Researchers
are beginning to explore alterations in
collagen and other extracellular matrix
components to assess their affect on
optic nerve susceptibility. It is somewhat
counterintuitive that stiffer tissues of the
aged eye contribute to ONH susceptibility,
because it would seem that more rigid
tissue would be less likely to deform.
It may be, however, that the increased
stiffness of the extracellular matrix and
thickness of the laminar beams alters
nutrient transport. If we can influence
that process to improve diffusion of nutrients and enhance blood flow, the impact
could be significant.
ONH cupping is an important clinical
sign of glaucoma, but it is also a complex structural process. Glaucomatous
cupping includes deformation and remodeling of the ONH connective tissues.
Axonal injury may occur prior to, during,
or after these connective tissue events.
In a series of publications on
deformation of the tissues in monkey
experimental glaucoma, my colleagues
and I have described this remodeling
as an outward migration or pialization
of the lamina cribrosa.4 At the transition
from ocular hypertension to detectable
glaucomatous damage by confocal
scanning laser tomography, the lamina
is not yet thinning; rather, it is profoundly thickened. As it is deforming, it also
migrates out of the sclera into the pial
sheath. This is a very consistent finding
in our model and it tells us that, in addition to physical deformation, there is
cellular activity involved in the process
of glaucomatous cupping.
This has some very important potential
implications. First, as this remodeling
occurs, it may alter the translaminar pressure gradient, particularly in the peripheral
regions of the nerve where axons are
already known to be most vulnerable.
There would have to be an accompanying
and equally profound remodeling of the
vascular supply to the lamina. If so, that
would occur exactly in the region underlying clinical nerve fiber layer hemorrhages.
Finally, the notion that connective
tissue remodeling may influence axonal
remodeling through myelin is emerging,
both in the mouse5 and monkey models of
glaucoma. In the monkey model, we are
seeing profound changes in myelin basic
protein signal by immunohistochemistry
within the retrolaminar optic nerve very
early in the disease.
IOP is always going to play a major
role in the management of glaucoma,
but the fact that the insult to the ONH
occurs even at normal levels of pressure
suggests there are factors independent of
or interacting with IOP that are also important. I believe that within our lifetimes
we'll be able to demonstrate clinically
important interactions between IOP and
blood flow. Gaining a better understanding of optic nerve head biomechanics will
be critical for the eventual development
of neuroprotective interventions aimed at
the ONH itself.
Note: These concepts have been described
in a series of recent publications.6,7
- Morgan WH, Yu D-Y, Cooper RL, et al. The influence of cerebrospinal fluid pressure on the lamina cribrosa tissue pressure gradient. Invest Ophthalmol Vis Sci.
- Cioffi GA, Van Buskirk EM, 1996. Vasculature of the Anterior Optic Nerve and Peripapillary Choroid,
second ed. Mosby, St. Louis.
- Hayreh SS, Revie IH, Edwards J. Vasogenic origin of visual field defects and optic nerve changes in
glaucoma. Br J Ophthalmol. 1970;54:461-472.
- Yang H, Williams G, Downs JC, et al. Posterior (outward) migration of the lamina cribrosa and early cupping in monkey experimental glaucoma. Invest
Ophthalmol Vis Sci. 2011;52(10):7109-21.
- Nguyen JV, Soto I, Kim KY, et al. Myelination transition zone astrocytes are constitutively phagocytic and have synuclein dependent reactivity in glaucoma.
Proc Natl Acad Sci. USA 2011;108(3):1176-81.
- Burgoyne CF. A biomechanical paradigm for axonal insult within the optic nerve head in aging and
glaucoma. Exp Eye Res. 2010;93:120-32.
- Downs JC, Roberts MD, Sigal IA. Glaucomatous cupping of the lamina cribrosa: a review of the evidence for active progressive remodeling as a mechanism. Exp Eye Res. 2011;93(2):133-40.
THE ROLE OF INTRACRANIAL CEREBRO-SPINAL FLUID PRESSURE IN POAG
A report on the Beijing Intracranial and
Intraocular Pressure (iCOP) Study.
ROBERT N. WEINREB, MD
Optic disc cupping and thinning of the
neuroretinal rim are the classic features
of primary open-angle glaucoma
(POAG), yet we still do not know why
these features develop. As early as the
1970s, animal studies showed that
cerebrospinal fluid pressure (CSF-P) or
intracranial pressure might contribute to
the pathogenesis of POAG,1,2 but there
was little follow-up at the time.
About 30 years later, Berdahl and
colleagues retrospectively analyzed a
large Mayo Clinic database of patients
undergoing lumbar puncture, some of
whom also happened to have glaucoma.
In that analysis, the cohort with glaucoma had lower CSF-P.3,4 Subsequent
retrospective and prospective studies
have shown that subjects with POAG
have lower intracranial pressure and
that glaucomatous visual field defects
are positively correlated with the trans-laminar pressure difference (TLPD) and
inversely correlated with CSF-P.5,6
The real essence of the problem may
be found in translaminar pressure difference (TLPD = IOP - CSFP). In normal
eyes, TLPD should be about 4 mmHg to
8 mmHg. When IOP is elevated and/or CSF-P is low, TLPD is significantly
higher and may lead to compression of
the laminar cribrosa.
In research performed at the Tongren
Eye Center by Ningli Wang, MD, PhD,
and colleagues, it was found that both
cup/disc ratio and neuroretinal rim area
are correlated with TLPD, and they are
better correlated than with IOP or CSF-P
only.7 However, the true TLPD is the
difference between IOP and orbital CSF
pressure, not the lumbar pressure that
was measured in all these studies.
To get a better grasp on the relationship between all these different
pressures, they used an experimental
dog model to continuously monitor
ventricle CSF-P, lumbar CSF-P, orbital
CSF-P and IOP. They found that ventricular pressure is higher than lumbar
pressure, which in turn is higher than
orbital CSF pressure. The true TLPD is
about 30 mmH2O (or 2 mmHg) larger
than our previously calculated TLPD.
So it appears that we have all been
underestimating translaminar pressure
difference by using lumbar instead of
orbital measures of CSF-P.
Role for MRI in Glaucoma
However, the assessment of the trans-laminar cribrosa pressure difference in
the clinical studies aforementioned was
based on lumbar CSF-P measurements,
but not on measurement of the orbital
CSF-P.3-7 Because a direct measurement
of the orbital CSF-P is invasive and not
acceptable in clinical practice, a noninvasive way to get an estimate of the
orbital CSF-P seems important.
As the orbital CSF-P provided a radial
stress to the optic nerve sheath, due
to Poisson's effect, higher intracra-nial pressure should lead to a wider
optic nerve subarachnoid space width
(ONSASW). It was hypothesized that in
patients with POAG the ONSASW may
narrow due to lower CSF pressure. The
ONSASW is calculated by measuring the
optic nerve sheath diameter (ONSD) and
optic nerve diameter (OND).
The best way to measure this tiny
space may be with magnetic resonance
imaging (MRI). MRI offers high resolution of the soft tissue, good imaging of
the CSF itself and of the whole length of
the optic nerve in the orbit, all without
radiation exposure.8,9 With patients
in a supine position, oblique coronal
optic images are obtained at different
distances (3 mm, 9 mm, and 15 mm)
posterior to the subarachnoid globe.
A comparison of these measurements
was made in 21 normal subjects, 21 POAG
subjects with IOP ≤ 21 mmHg, and 18
subjects with POAG and IOP >21 mmHg.10
The orbital optic nerve subarachnoid
space is significantly narrower in POAG
patients with normal IOP than in those
with high IOP or in healthy controls. This
is consistent with the idea that the optic
nerve subarachnoid fluid pressure is lower
in POAG patients, and very consistent with
research showing these patients have
As we think about how this research
might translate into clinical care, one
has to question whether it is possible to
estimate orbital CSF pressure through
lumbar puncture—and if so, whether the
risk/benefit ratio of lumbar puncture would
justify its use in glaucoma. It would be
ideal to find a less invasive technique for measuring or estimating orbital CSF-P.
With that in mind, a prospective observational study of patients who, for various
reasons, were undergoing a cranial MRI
and lumbar puncture in the neurological
department at Tongren Eye Center was
initiated over a one-year period. The same
scanning technique used in the previous
studies was used, with the patient again
in a supine position. In all, 30 subjects
with wide variations in age, body mass
index, mean arterial pressure, and CSF-P
were evaluated. A strong relationship was
found between CSF-P and the ONSASW
and a slightly less significant relationship
between CSF-P and optic nerve diameter.
This demonstrates that measuring the
optic nerve subarachnoid sheath width
with an MRI can provide a quantitative
estimate of CSF pressure and may be a
reliable predictor of the CSF pressure.
ONSASW measures are easily included
in routine cranial MRI scans and may be
useful in glaucoma and also in several
- Volkov VV. [Essential element of the glaucomatous process neglected in clinical practice]. Oftalmol Zh.
- Yablonski M, Ritch R, Pokorny KS. Effect of decreased intracranial pressure on optic disc. Invest
Ophthalmol Vis Sci. 1979;18[Suppl]:165.
- Berdahl JP, Allingham RR, Johnson DH. Cerebro-spinal fluid pressure is decreased in primary open-angle glaucoma. Ophthalmology. 2008;115:763-8.
- Berdahl JP, Fautsch MP, Stinnett SS, Allingham
RR. Intracranial pressure in primary open angle
glaucoma, normal tension glaucoma, and ocular
hypertension: a case-control study. Invest Ophthalmol
Vis Sci. 2008;49:5412-8.
- Jaggi GP, Harley M, Ziegler U, et al. Cerebrospinal fluid segregation optic neuropathy: an experimental model and a hypothesis. Br J Ophthalmol. 2010;94(8):1088-93.
- Ren R, Jonas JB, Tian G, et al., Cerebrospinal fluid pressure in glaucoma: a prospective study. Ophthalmology. 2010;117(2):259-66.
- Ren R, Wang N, Zhang X, et al. Trans-lamina cribrosa pressure difference correlated with neuro-retinal rim area in glaucoma. Graefes Arch Clin Exp Ophthalmol. 2011; 249(7):1057-63.
- Kimberly HH, Noble VE. Using MRI of the optic nerve sheath to detect elevated intracranial pressure. Crit Care. 2008;12(5):181.
- Jaggi GP, Miller NR, Flammer J, et al. Optic nerve sheath diameter in normal-tension glaucoma patients. Br J Ophthalmol. 2012;96(1):53-6.
- Wang NL, Xie XB, Yang DY, et al. Orbital cere-brospinal fluid space in glaucoma: The Beijing iCOP Study. Ophthalmology. 2012 Jun 28. [Epub ahead of print].
RETINAL GANGLION CELL IMAGING
New in vivo imaging techniques offer insight into patterns of retinal ganglion cell damage in
CHRISTOPHER K. S. LEUNG, MD, MB, CHB
The ability to follow changes in the
retinal ganglion cells (RGCs) is vital to understanding the mechanisms of glaucoma as well as other optic neuropathies.
Like any other neuronal cells, retinal
ganglion cells have a cell body or
soma, an axon, and dendrites. Although
we have not had the technology to
look at individual retinal ganglion cells
in humans, our team at the Chinese
University of Hong Kong, along with
Robert Weinreb, MD, at the University
of California, San Diego, has been
working to identify ways to assess the
retinal nerve fiber layer (RNFL) and all
aspects of the retinal ganglion cells
to better understand how and where
damage occurs in glaucoma.
In a number of studies, we have used
RNFL imaging with spectral-domain optical coherence tomography (OCT)
to observe axonal changes that occur
in glaucoma.1-6 There have been many
interesting findings from these studies.
For example, we have found that RNFL
progression is most frequently detected
inferotemporally at a distance approximately 2.00mm away from the disc
center and that tracking the topographic
changes of the RNFL using the RNFL
thickness map is informative to monitor
the continuum of glaucoma progression.7 Serial spectral domain OCT RNFL
imaging can help us monitor glaucoma
progression by following enlargement
and deepening of RNFL defects over
time (see Figure 1).
Figure 1. Serial retinal nerve fiber layer (RNFL) imaging with a spectral-domain optical coherence tomography showing
enlargement (A) and deepening (B) of RNFL defects in glaucoma. The RNFL thickness deviation maps and the RNFL
thickness maps are shown in the upper and lower panels, respectively. (Modified from Figures 3-4 in Leung CK, et al
Retinal nerve fiber layer imaging with spectral-domain optical coherence tomography: patterns of retinal nerve fiber
layer progression. Ophthalmology. 2012; In press.)
Beyond the Soma
Studies of neuroprotection and RGC
damage largely rely on counting the
number of retinal ganglion cell bodies.
However, there is mounting evidence
that RGC damage begins well before
For example, Weber and colleagues
found in an experimental glaucoma
model that RGC degeneration begins
with the dendritic arbor and ends with
shrinkage of the cell soma.8 Morgan
also provided evidence suggesting that
RGCs undergo dendritic shrinkage prior
to cell death in experimental glaucoma.9 In these studies, however, RGCs
were examined in histological sections.
We know there are different types of
RGCs, some of which are larger or
more complex than others. Ideally,
we want to be able to follow the cells
longitudinally in vivo to clearly identify
if there is loss of dendritic complexity
The first in vivo imaging of retinal ganglion cells was performed by Sabel and
colleagues.10 After injecting a neuronal
tracer into the superior colliculus to label
the RGCs in rats, they used a confocal
scanning laser ophthalmoscope to visualize individual RGCs. Only the cell body
was visible, not the axons or dendrites.
Cordeiro and colleagues used another
approach to label RGCs in rats. With
intravitreal injection of annexin V, which
is a marker for apoptosis, they imaged
apoptosing retinal cells after inducing
optic nerve injury.11,12
Notably, these labeling methods are invasive and may not be suitable for long-term repeated examination. Intracranial
and intravitreal injections may damage
Transgenic Mouse Models
In 2000, Feng and colleagues generated 25 strains of transgenic mice in
which red, green, yellow, or cyan fluorescent proteins (together termed XFPs) are
selectively expressed in neurons. In some
strains, <1 percent of RGCs are labeled,
providing the opportunity to examine not
only the cell body but also the dendritic
structures.13 These transgenic mice offer
an effective approach to visualize RGCs in vivo (see Figure 2).
Figure 2. A retinal montage showing retinal ganglion
cells (RGCs) imaged in vivo by a confocal scanning
laser ophthalmoscope in a Thy-1 YFP transgenic mouse.
The soma, axons and dendrites of individual RGCs can
be visualized and quantified (Adapted from Leung CK
et al. Long-term in vivo imaging and measurement
of dendritic shrinkage of retinal ganglion cells. Invest
Ophthalmol Vis Sci 2011;52:1539-47.).
We have used an optic nerve crush
model to study how the cells respond to
optic nerve injury. In the initial two weeks,
the first signs of damage are shrinkage
of the dendritic tree, followed by loss of
axons, and then the cell body (see Figure 3).14,15 The presence of the cell body,
therefore, is not indicative of a healthy cell.
This work demonstrates that loss of the
dendrites is actually a more sensitive bio-marker to examine the integrity of retinal
Figure 3. Long-term serial in vivo imaging of retinal ganglion cell degeneration after optic nerve crush. Progressive dendritic shrinkage precedes loss of the axons and the cell bodies.
Loss of dendritic branches and reduction in dendritic field were evident seven days after optic nerve crush. There was progressive dendritic shrinkage in the following week. The axon
became indistinct on day 13 with complete loss of dendrites and cell body on day 15. (Modified from Leung CK, et al. Long-term in vivo imaging and measurement of dendritic shrinkage of retinal ganglion cells. Invest Ophthalmol Vis Sci. 2011;52:1539-47.).
We are now using a similar experimental model to look at the retinal microglia. In this case, we use another type of
transgenic mouse (CX3CR1GFP/+), but the
same imaging techniques, to investigate
the change in morphology and density
of retinal microglia following optic nerve
injury. We are also working on a new
transgenic mouse model that will allow
us to examine the RGCs and microglia
together, which may help in understanding
their interaction in different forms of optic
These are exciting new techniques.
Imaging of protein expression in these
mice serves as a sensitive indicator
of the integrity of RGCs and provides
a non-invasive method for longitudinal study of the mechanism of RGC
degeneration. Measuring the rate of
dendritic shrinkage could become a
new paradigm for investigating neuronal degeneration and evaluating
the response of neuroprotective treatments in the future.
- Leung CK, Choi N, Weinreb RN, et al. Retinal nerve fiber layer imaging with spectral-domain optical coherence tomography: pattern of RNFL defects in
glaucoma. Ophthalmology. 2010;117:2337-44.
- Leung CK, Lam S, Weinreb RN, et al. Retinal nerve fiber layer imaging with spectral-domain optical coherence tomography: analysis of the retinal nerve
fiber layer map for glaucoma detection. Ophthalmology. 2010;117:1684-91.
- Leung CK, Ye C, Weinreb RN, et al. Retinal nerve fiber layer imaging with spectral-domain optical coherence tomography a study on diagnostic agreement with Heidelberg Retinal Tomograph.
- Leung CK, Choi N, Weinreb RN, et al. Evaluation of retinal nerve fiber layer progression in glaucoma a prospective analysis with neuroretinal rim and visual
field progression. Ophthalmology. 2011;118:1551-7.
- Leung CK, Chiu V, Weinreb RN, et al. Evaluation of retinal nerve fiber layer progression in glaucoma:
a comparison between spectral-domain and time-domain optical coherence tomography. Ophthalmology. 2011;118:1558-62.
- Leung CK, Cheung CY, Weinreb RN, et al.Evaluation of retinal nerve fiber layer progression in glaucoma: a comparison between the fast and the
regular retinal nerve fiber layer scans. Ophthalmology. 2011;118:763-7.
- Leung CK, Yu M, Weinreb RN, et al. Retinal nerve fiber layer imaging with spectral-domain optical coherence tomography: Patterns of retinal nerve fiber layer progression. Ophthalmology. 2012; Jun 5.
[Epub ahead of print].
- Weber AJ, Kaufman PL, Hubbard WC. Morphology of single ganglion cells in the glaucomatous primate
retina. Invest Ophthalmol Vis Sci. 1998;39:2304-20.
- Morgan JE. Retinal ganglion cell shrinkage in
glaucoma. J Glaucoma. 2002;11(4):365-70.
- Sabel BA, Engelmann R, Humphrey MF. In vivo confocal neuroimaging (ICON) of CNS neurons. Nat
Med. 1997;3:244 7.
- Cordeiro MF, Guo L, Luong V, et al. Real-time imaging of single nerve cell apoptosis in retinal neurodegeneration. Proc Natl Acad Sci USA.
- Guo L, Salt TE, Luong V, et al. Targeting amyloid-beta in glaucoma treatment. Proc Natl Acad Sci USA.
- Feng G, Mellor RH, Bernstein M, et al. Imaging neuronal subsets in transgenic mice expressing
multiple spectral variants of GFP. Neuron. 2000Oct;28(1):41-51.
- Leung CK, Weinreb RN, Li ZW, et al. Long-term in vivo imaging and measurement of dendritic shrinkage of retinal ganglion cells. Invest Ophthalmol Vis
- Li ZW, Liu S, Weinreb RN, et al. Tracking dendritic shrinkage of retinal ganglion cells after acute elevation of intraocular pressure. Invest Ophthalmol Vis Sci. 2011;52(10):7205-12.
III. THERAPEUTICS IN
CLINICAL PRACTICE AND BEYOND ADVANCING TREATMENT
Base decisions on a combination of pressure,
progression, and predicted risk.
ROBERT D. FECHTNER, MD, FACS
The decision of when to advance
treatment is one that glaucoma clinicians face daily. Regardless of your
personal choices for initial therapy, the
decision to add another medication or
otherwise advance treatment beyond
that initial choice must be based on
three factors: Pressure, progression, and
risk predictions for that patient.
Intraocular pressure (IOP) is the
simplest of these three considerations.
It is a prominent risk factor in glaucoma
and—at least in some patients—a
causative factor. Thus far, IOP is the
only approved modifiable factor; every
glaucoma treatment that we have has
received regulatory approval based on
its efficacy in reducing IOP.
We know from numerous studies
over the years that there is a direct
relationship between pressure and progression and that reducing IOP can
prevent or delay glaucomatous damage.
So, it makes sense to establish a target
pressure, with the first goal of therapy
being to maintain IOP at or below that
target. Treatment should be advanced
when initial monotherapy or laser fails
to achieve the target pressure, as it
eventually will for many patients.
In years past, clinicians have often
relied on a monocular drug trial for
advancing (or initiating) therapy. It has
been shown, however, that the monocular trial is an outdated model based on
flawed assumptions, and is no more informative than simply using the treated
eye's unadjusted IOP change.1
Undesirably high IOP is not the only
justification for advancing therapy. If the
disease is progressing despite what is
believed to be reasonable IOP control, it
may be necessary to move to the next
step in your treatment algorithm. It is
not always easy, however, to determine
what constitutes clinically significant
We have often relied on events alone
to identify progression. In other words,
when a patient moves from the "normal" into the "abnormal" range on a diagnostic test, that triggers the decision
to advance treatment (see Figure 1).
The problem with a purely event-driven
approach is that it ignores trends—not
detecting, for example, an eye that is
deteriorating rapidly but still within the
"normal" range. Events can be either
structural (e.g., cupping identified on an
optic nerve photographs) or functional
(e.g., the proliferation of black boxes on
the Humphrey Field Analyzer (Carl Zeiss
Meditec, Inc.) pattern deviation map). In either case, the event indicates that
something is statistically not normal.
Figure 1. Two photos of a patient's optic nerve, taken less than 12 months apart. The change from the image on the left
to the one on the right is an event that indicates significant progression and should trigger an advance in therapy.
Trend analysis is equally important
because it provides more detail about
the rate of change. If we knew our
patients' life expectancies and were
very good at predicting trends, we might
be able to make much better treatment
decisions. This is a difficult task, but I
believe that trend analysis will be increasingly important in glaucoma care.
We don't necessarily want to wait until
an eye crosses the threshold into identifiably statistically abnormal—it would
be far better to identify the deteriorating
trend prior to that point.
There are several strategies for
refining and improving upon our ability
to detect progression. Medeiros and
colleagues at the Hamilton Glaucoma
Center, University of California, San
Diego (UCSD) have recently published
a Bayesian hierarchical modeling
approach for integrating event- and
trend-based assessments of visual field
progression that appears to perform
better than either method alone.2 And
because both events and trends can
be measured on the same technology
platform, this is achievable for a non-academician.
The same group has shown that
combining structure and function in a
joint regression model results in more
accurate and precise estimates of the
slope of change.3 In clinical practice, it
can be challenging to combine structural and functional data because the
devices don't "talk" to one another, but
this approach has the potential to be
Another very promising paper from
Bowd and colleagues, also from the
Hamilton Glaucoma Center, UCSD,
shows that glaucomatous progression in suspect eyes can be predicted
from baseline confocal scanning laser
ophthalmoscope (CSLO) and standard
automated perimetry (SAP) measurements analyzed with relevance vector
machine (RVM) classifiers. The RVM
analyses predicted future progression
with a higher accuracy than either the
CSLO or SAP global indices.4
Despite the promise of newer diagnostic technologies, clinicians would be
remiss to abandon proven techniques
such as visual field testing and fundus
photography. Optic nerve photographs,
for example, have the advantage of
remaining accessible and useful over
time, regardless of changes in technology platforms.
Stein and colleagues at the University of Michigan recently analyzed
managed-care claims data for more
than 550,000 patients with open-angle
glaucoma or suspected glaucoma to
assess trends in visual field testing,
fundus photography, and other ocular
imaging between 2001 and 2009.5 Perhaps not surprisingly, the rate of fundus
photography was flat; photography
was the least common of the diagnostic tools analyzed. More disturbing
was the finding that over the decade,
both optometrists and ophthalmologists decreased their use of visual field
testing and dramatically increased their
use of newer ophthalmic imaging tests.
The authors concluded that increased
reliance on imaging technology, in lieu
of visual testing, may be detrimental to
We need both functional and structural testing. In addition to watching for
events that clearly demarcate progression, we also need to pay attention to
trends. If progression is highly suspected or confirmed, treatment should
In addition to predicting progression
based on real-time changes in diagnostic
testing, we can also use risk calculators
to predict how rapidly an individual eye is
likely to progress. Glaucoma is typically
a slow-moving disease and in many
patients may progress so slowly as not to
cause any significant visual impairment
during the patient's lifetime. But if we
could better identify those patients who
will progress rapidly, we would certainly
want to treat them more aggressively
from the start.
The Early Manifest Glaucoma Trial
(EMGT) was very helpful in identifying key risk factors for progression. In
that study, progression was more likely
with higher baseline IOP, exfoliation,
bilateral disease, worse mean deviation, and older age, as well as frequent
disc hemorrhages during follow-up (see Figure 2).6 These risk factors have since
been incorporated into a number of risk
calculation tools, but clinically we can
also look for these early indicators and
advance therapy accordingly.
Figure 2. At left: baseline factors for progression (Cox proportional hazard model); at right: follow-up factors for progression (Cox proportional hazard models). (Adapted from Leske
MC, Heijl A, Hussein M, et al.; Early Manifest Glaucoma Trial Group. Factor for glaucoma progression and the effect of treatment: the Early Manifest Glaucoma Trial. Arch Ophthalmol.
In conclusion, uncontrolled pressure
should trigger more advanced therapy,
as it always has, but IOP must not be
the only trigger. Evidence of progression,
using diagnostic tools both new and well-established, and risk prediction with risk
factor analysis and risk calculators should
also be considered for the most effective
management of glaucoma.
- Realini TD. A prospective, randomized, investigator-masked evaluation of the monocular trial in ocular hypertension or open-angle glaucoma.
- Medeiros FA, Weinreb RN, Moore G, et al. Integrating event- and trend-based analyses to improve detection of glaucomatous visual field progression.
- Medeiros FA, Zangwill LM, Girkin CA, et al. Combining structural and functional measurements to
improve estimates of rates of glaucomatous progression. Am J Ophthalmol. 2012;153(6):1197-205.
- Bowd C, Lee I, Goldbaum MH, et al. Predicting glaucomatous progression in glaucoma suspect eyes using relevance vector machine classifiers for combined structural and functional measurements.
Invest Ophthalmol Vis Sci. 2012;53(4):2382-9.
- Stein JD, Talwar N, Laverne AM, et al. Trends in use of ancillary glaucoma tests for patients with open-angle glaucoma from 2001 to 2009. Ophthalmology.
- Leske MC, Heijl A, Hussein M, et al; Early Manifest Glaucoma Trial Group. Factors for glaucoma progression and the effect of treatment: the early manifest glaucoma trial. Arch Ophthalmol. 2003;121(1):48-56.
LOGTS AND NEUROPROTECTION
Consider the effects of treatment regimens not
just on IOP but on the outcome of the disease
LOUIS B. CANTOR, MD
Glaucoma, like all of other optic
neuropathies, results in death of retinal
ganglion cells. Neuroprotection, which
can be defined as any strategy to prevent
retinal ganglion cell (RGC) damage, has long been of interest as a way to supplement intraocular pressure (IOP) lowering—particularly in those cases where
pressure management is insufficient to
manage the disease.
Although IOP is the primary risk factor
for glaucoma, we know there are many
other sources of stress or potential pathways for RGC damage, including mechanical, genetic, vascular, metabolic, and other
factors that are important in the maintenance of neuronal function. Neuroprotection offers the potential to rescue injured
retinal ganglion cells before they die or to
improve the eye's risk profile in the face of
elevated IOP or other stresses.
A number of neuroprotective strategies have been or are under investigation,
including neurotrophic factors, vasopro-tection with ocular blood flow enhancers,
calcium channel blockers, nitric oxide syn-thase (NOS) inhibitors, alpha-2 agonists,
N-methyl-D-asparate (NMDA) antagonists,
LOGTS Design and Results
The Low Pressure Glaucoma Treatment
Study (LOGTS), led by Theodore Krupin,
MD, was designed to evaluate brimonidine 0.2% vs. timolol 0.5% in preserving visual
function in patients with low-pressure
glaucoma. In this prospective trial, more
patients were randomized to brimoni-dine (n=99) than to timolol (n=79) due
to anticipated dropout from allergies.
Visual field progression was measured
using three different models: Progressor;
the glaucoma change probability maps
(GCPM); and 3-omitting method.
The theoretical background for a neu-roprotective benefit of brimonidine is solid.
The drug has been shown to penetrate the
eye in sufficient concentrations to have an
effect on the alpha-2 receptor.1 Alpha-2
receptors do exist in the retina and in the
retinal ganglion cell layer.2 And in several
experimental models, brimonidine has
been shown to promote RGC survival.2-4
The results of LOGTS add weight to
the theoretical underpinning. For the first
two years of the study there was very
little difference in progression. After 24
months, there was much better visual field
survival in the brimonidine-treated group
than those treated with timolol. And that
separation got wider with time throughout
the remaining two years of follow-up.5
These results were consistent across
all three methods of visual field analysis.
There were no IOP-related differences
between the groups—no matter how the
data were sliced—that would explain the
In managing our patients with glaucoma, it is important to consider the
effects of treatment regimens not just on
IOP but on the outcome of the disease
process itself. Treatment with brimonidine
in this study enhanced visual field survival
better than treatment with timolol in a
low-tension glaucoma population, but we
do not yet know the mechanism by which
this occurred. The similar IOP lowering in
the two groups suggests a non-IOP related
mechanism. Together with the pre-clinical
data, a neuroprotective mechanism seems
likely. However, the findings could be
related to differences in the mechanism
of action of the two drugs or to factors
not assessed in the study. Validation of
this possible neuroprotective mechanism
requires additional research.
- Acheampong AA, Shackleton M, Tang-Liu DD. Comparative ocular pharmacokinetics of brimoni-dine after a single dose application to the eyes of albino and pigmented rabbits. Drug Metab Dispos. 1995;23(7):708-12.
- Wheeler LA, Gil DW, WoldeMussie E. Role of alpha-2 adrenergic receptors in neuroprotection and glaucoma. Surv Ophthalmol. 2001;45 Suppl 3:S290-6.
- Wheeler LA, Lai R, Woldemussie E. Brimonidine protects retinal ganglion cells from the effects of optic nerve crush. Euro J Ophthalmol. 1999;9(suppl 1):S17-S21.
- Burke J, Chun T, Lee S, et al. Effect of topical brimonidine formulations or systemic administration on retinal ganglion cell survival vs. ERG preservation in a rat retinal ischemia/reperfusion model. Invest Ophthalmol Vis Sci. 2001;42(4):S23.
- Krupin T, Liebmann JM, Greenfield DS, et al, on behalf of 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. 2011;151:671-81.