New Insights in the Management of Glaucoma
Supported by an Allergan-funded medical educational grant.
Release Date: February 2010
Expiration Date: February 28, 2011
This activity has been designed to meet the educational needs of ophthalmologists with a basic knowledge of glaucoma.
A basic knowledge of ophthalmology is a prerequisite for this activity.
Statement of Need:
Glaucoma is a progressive optic neuropathy characterized by a loss of retinal ganglion cells and their axons beyond typical age-related baseline loss. It is the second leading cause of blindness worldwide. There are several known risk factors for glaucoma, but currently, the only manageable and proven risk factor is elevated intraocular pressure (IOP). Successful treatment for glaucoma has been to lower the IOP through therapies, laser and surgery. Ocular safety and tolerability of formulations of prescribed treatments play a key role in successful therapy. Therefore, a review of pharmacological properties and their effects on efficacy and tolerability in the management of primary open-angle glaucoma and ocular hypertension will be studied in this activity.
The concept of neuroprotection has been advanced to address the primary problem in glaucoma-neuronal death, a feature common to all optic neuropathies. This program will also evaluate the implications of new medical and surgical therapies and any emerging clinical data that are relevant to the prevention of neuronal death and also assess how measurement of visual function, optic disc and retinal nerve fiber layer helps to measure neuroprotection. Additionally, evaluating evidence that blood flow could factor into the neuroprotective tendencies will be studied.
Recently, there has been a plethora of papers as well as prospective and population-based studies regarding the relationship between perfusion pressure and vascular risk factors in glaucoma. This program will also cover prospective blood flow studies and look at clinical trials on blood pressure vs. eye pressure. The faculty will also review the current state of the clinical management of glaucoma; go over new findings on vascular risk factors, their association with the prevalence, progression and incidence of glaucoma; and point out new studies related to ischemia and glaucoma.
After completing this educational activity, participants should be better able to:
- Evaluate new data highlighting the importance of perfusion pressure for development, progression and incidence of glaucoma.
- Examine the relationship between ocular blood flow, visual function and optic nerve structure.
- Recognize the growing role of neuroprotection in ophthalmology.
- Delineate the relationship of medication tolerability and adherence with therapy.
- Identify the side effects of glaucoma medications.
Alon Harris, MS, PhD, is the Lois Letzter Endowed Professor of Ophthalmology and Professor of Cellular and Integrative Physiology at Indiana University. He also serves as Director of the Glaucoma Research and Diagnostic Center and Director of the Ocular Vascular Reading Center for the Department of Ophthalmology. He is co-chair of the World Glaucoma Congress Consensus on Ocular Blood Flow.
L. Jay Katz, MD, FACS, is Professor of Ophthalmology at Jefferson Medical College, Thomas Jefferson University, and Director of the Glaucoma Service at Wills Eye Institute in Philadelphia, Pa.
Nathan Radcliffe, MD, is Assistant Professor of Ophthalmology and Director of the Glaucoma Service at Weill Cornell Medical College and New York-Presbyterian Hospital in New York City.
This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of The National Retina Institute (NRI) and Jobson Medical Information LLC. NRI is accredited by the ACCME to provide continuing medical education for physicians.
The National Retina Institute designates this educational activity for a maximum of 2.0 AMA PRA Category 1 Credit(s). Physicians should only claim credit commensurate with the extent of their participation in the activity.
SCIENTIFIC INTEGRITY AND DISCLOSURE OF CONFLICTS OF INTEREST:
This activity was peer-reviewed for relevance, accuracy of content and balance of presentation by NRI. NRI requires that all continuing medical education (CME) information is based on the application of research findings and the implementation of evidence-based medicine. NRI promotes balance, objectivity and absence of bias in its content. All persons in position to control the content of this activity must disclose any relevant financial relationships. NRI has mechanisms in place to identify and resolve all conflicts of interest prior to an educational activity being delivered to the learners.
NRI is committed to providing its learners with high-quality CME activities and related materials that promote improvements or quality in health care and not a specific proprietary business interest of a commercial interest.
The faculty reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interest related to the content of this CME activity: Dr. Harris—Grant support: Allergan, Pfizer. Dr. Katz— Lecture fees and grant support: Alcon, Allergan, Pfizer, Lumenis. Consultant/advisor: Glaukos. Dr. Radcliffe—Consultant/advisor and lecture fees: Allergan.
The planners and managers reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interest related to the content of this CME activity: Jason Kaplan, MD, The National Retina Institute, has no relevant financial relationships. CarolAnn Love, The National Retina Institute, has no relevant financial relationships. Karen Rodemich, Review of Ophthalmology, has no relevant financial relationships. Alicia Cairns, Review of Ophthalmology, has no relevant financial relationships.
Method of Participation:
There are no fees for participating and receiving Continuing Medical Education credit for this activity. During the period of February 2010 and February 28, 2011, participants must:
- read the learning objectives and faculty disclosures;
- study the educational activity
- complete the post-test by recording the best answer to each question
A statement of credit will be issued only upon receipt of a completed activity evaluation form and a completed post-test with a score of 70% or better. Your statement of credit will be mailed to you within 4 weeks; online test takers will be issued a printer-friendly, real-time certificate. Any questions/problems with registration, CME certificate, etc. can be directed to email@example.com.
Estimated Time to Complete Activity:
DISCLOSURE OF OFF-LABELED USE:
This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. NRI and Review of Ophthalmology do not recommend the use of any agent outside of the labeled indications.
The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of NRI and Review of Ophthalmology. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings.
Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of the patient’s conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information and comparison with recommendations of other authorities.
Glaucoma Medical Therapy: Successes and Challenges
By L. Jay Katz, MD
Glaucoma is the leading cause of irreversible blindness in the world. In the United States
alone, there are an estimated four million people with glaucoma, including 200,000 who
are severely visually impaired. In addition to the human toll on patients and the costs of
medical care, glaucoma-related blindness costs society $2 billion dollars annually.
Treating this disease effectively remains a major public health challenge.
To prevent glaucoma-related blindness, it is important to expand access to early
intervention and ongoing care, improve patient compliance with medical therapy, and
take an aggressive approach to reducing intraocular pressure (IOP). There are also likely
non-IOP related components of the disease that might be pivotal for improving treatment
and preventing blindness in the future.
Over the past two decades, ophthalmology has sought to develop an evidence-guided
paradigm for glaucoma treatment. A series of large clinical trials has provided
significantly more information about glaucoma than we had in the past. The trials have
conclusively proven the benefits of lowering IOP for all risk categories, including ocular
hypertension, normal-tension glaucoma, and high-tension glaucoma.
We have several options for lowering IOP: medical therapy, laser, and surgery. Laser
may be the best choice for patients with a track record of non-compliance and is certainly
a reasonable option for initial therapy if the patient prefers it. However, one must
recognize the limits of laser trabeculoplasty in achieving target pressures. Most patients
will have to move on to medical therapy after laser.
The Collaborative Initial Glaucoma Treatment Study (CIGTS) recently compared
medical management to filtration surgery as initial therapy.1 Visual field preservation
over time is very similar between the two groups (Figure 1). However, the symptom
impact score favors medication (Figure 2). Because of the potential for complications
from filtration surgery, most clinicians rely on topical medications as initial therapy for
the vast majority of our patients.
In selecting an IOP-lowering medication, one must take into account four factors:
- safety and tolerability;
- patient compliance and, at least for some patients,
- the cost of chronic treatment.
The efficacy of the various topical glaucoma therapies has been well-documented.
Prostaglandin analogues are typically the best choice for initial therapy, due to their consistently good efficacy. When choosing among these drugs or considering adjunctive
therapies, side effect profiles become very important.
The beta-blocker class, of course, is effective and inexpensive, but also has some well-
known systemic side effects. Most other glaucoma drug classes cause only local side
effects, such as hyperemia, itching and changes in iris or periocular skin pigmentation.
Although clinicians may consider these ocular side effects to be relatively trivial, they
can affect compliance. In a recent survey by the San Francisco-based Glaucoma Research
Foundation, nearly 60 percent of glaucoma patients reported side effects from their
current glaucoma medications,2 with the most common being a burning/stinging
sensation (29 percent) or red eyes (18 percent). In a willingness-to-pay analysis, Jampel
found that drugs were most valued if they did not cause drowsiness, sexual dysfunction,
or blurring.3 Most patients (85 percent) are willing to pay more for a drop that does not
Compliance with glaucoma medications is known to be poor. Researchers at Wilmer
recently reported that 45 percent of patients given a free medication were compliant less
than 75 percent of the time.4 And electronic drop monitoring has shown that patients are
even less compliant than they report being.5 Although these are discouraging numbers, it
appears that easier dosing regimens can positively affect compliance. Claxton found, for
example, that compliance with both taking the medication and taking it at the proper
times is dramatically better with less frequent dosing (Table 1).6 Others have
reported better compliance with a single medication than with multiple medications.7 In any case, the chance of a third or fourth glaucoma medication being truly effective is
very low.8 To enhance compliance rates, the ideal drug therapy for glaucoma should
have simple dosing, good efficacy, minimal and tolerable side effects, and the fewest
Table 1: Compliance with Glaucoma Medical Therapy
IOP CONTROL NOT ENOUGH
Despite our success in documenting, understanding and improving pressure-lowering
therapy in glaucoma, we now know that pressure lowering alone is not enough to control
the disease in many patients. In every major trial, significant percentages of patients have
progressed, even with aggressive treatment.10-13
For example, it has been widely reported that patients in the Advanced Glaucoma
Intervention Study (AGIS) whose IOP was successfully kept at <18 mmHg at every study
visit had no mean change in visual field deficit. This has rightly been used to point to the
benefits of keeping IOP consistently low. However, it does not mean that none of the
patients in that group progressed. A closer look reveals that 24.8 percent of the patients in
the “stable” subgroup actually had worsening visual field deficits that were balanced out
by others whose visual field scores improved.13
Our current medications offer very good IOP lowering, but to prevent glaucoma
progression, it is likely that we will need to more directly address other factors, such as
ocular perfusion or neuro-injury, that may play a role in this disease. Identifying and
rigorously testing such therapies is the next crucial step in the medical management of
Innovations and Applications in the Field of Neuroprotection
By Nathan Radcliffe, MD
Optic nerve cupping and progressive visual field deterioration are the clinical
manifestations of glaucoma, a group of diseases more accurately characterized by
progressive retinal ganglion cell (RGC) apoptosis. We can see from the appearance of
retinal fiber layer defects that emanate from the optic nerve head that glaucomatous
damage occurs at the optic nerve (Figure 3).
Until recently, intraocular pressure (IOP) has been the only modifiable risk factor for
glaucoma. At least two studies have demonstrated that ocular perfusion pressure may also
be a modifiable risk factor.10,14 Until we have more evidence that perfusion pressure
can affect visual field progression, IOP reduction remains the only proven treatment for
Reducing IOP is one approach. Ideally we would also like to be able to treat or
therapeutically protect the optic nerve head (ONH), the site of injury in glaucoma. The
aim of neuroprotection in glaucoma is to slow progression by blocking the mechanisms
that lead to apoptosis and enhancing the survival of retinal ganglion cells and their axons,
independently of IOP reduction.15
RGC apoptosis, which has been demonstrated in animal models of elevated IOP,16 is a
non-inflammatory programmed process that is mediated by a variety of chemicals,
including extracellular glutamate concentration, intracellular calcium influx, expression
of pro-apoptotic genes, and generation of nitric oxide, free radicals, and other cytokines.
Both IOP-dependent and -independent mechanisms can push a cell down this final
common pathway toward apoptosis.17 The IOP-independent mechanisms may include
autoimmune phenomena, vascular factors, or mechanical stressors.
Neuroprotection has received a great deal of attention in the treatment of
neurodegenerative diseases other than glaucoma, including stroke, Alzheimer’s disease,
Lou Gehrig’s disease, multiple sclerosis and Parkinson’s disease. Methylprednisolone,
used off-label, has been shown to have some neuroprotective effects in patients with
acute spinal cord injury, reducing the rate of functional loss.18 There are two FDA-
approved neuroprotective therapies: Riluzol, a sodium channel blocker that prolongs
ventilator independence in Lou Gehrig’s disease and memantine, which slows cognitive
decline in Alzheimer’s disease.
There are very interesting similarities between glaucoma and Alzheimer’s disease that
warrant further investigation. In glaucoma we see a loss of retinal nerve fiber layer
(RNFL) that is far more accelerated than normal, age-related optic nerve degeneration. A
similar pattern of RNFL thinning is seen in Alzheimer’s disease, but it is still unclear
whether the RNFL thinning is caused by Alzheimer’s or due to an association between
POAG and Alzheimer’s. Amyloid-beta, a major constituent of Alzheimer’s plaques, co-
localizes with apoptotic retinal ganglion cells. In experimental animal models,
researchers have been able to inhibit the production of amyloid-beta and prevent retinal
ganglion cell apoptosis.19
NEUROPROTECTION CANDIDATES IN GLAUCOMA
Several classes of agents may have neuroprotective qualities. For effective use in the
treatment of glaucoma, a neuroprotective agent would need to be very well tolerated and
have a favorable side effect profile so that it can be taken for many years. Scientifically
rigorous studies including a human randomized clinical trial will be needed to prove the
value of any of these proposed agents in glaucoma therapy (Figure 4).
Statins. Long-term use of HMG-CoA reductase inhibitors has been associated with a
reduction in the incidence of Alzheimer’s, Parkinson’s and POAG.20 These statins have
multiple downstream anti-inflammatory and anti-apoptotic effects. A group of glaucoma
suspects who also happened to be taking statins for hypercholesterolemia demonstrated
less rim volume loss, as measured by HRT, than subjects in the same study who weren’t
taking statins.21 A potential confounding factor in this study, however, is that patients
with hypercholesterolemia may also have hypertension and potentially better ocular
perfusion, so the neuroprotective value of the statin is unclear.
Immunosuppressive agents. Tacrolimus (FK506) is a potent immunosuppressive agent
typically used to prevent organ rejection in liver transplant patients. It targets T-cells and
interleukin-2 and has also been shown to inhibit calcineurin cleavage, thereby interfering
with Bcl-2-mediated apoptosis.22 Although it was neuroprotective in an animal model,
tacrolimus also has high systemic toxicity. To be successful in a glaucoma treatment
setting, the compound would have to be modified or administered in such a way as to
greatly limit systemic absorption.
Erythropoietin. The glycoprotein hormone erythropoietin is the primary regulator of red
blood cell formation in humans, but also has a variety of downstream effects that result in
anti-apoptotic proteins (Bcl-XL) and inhibition of caspases.23 It has been shown to be
neuroprotective in a rat model of glaucoma, where it enhanced RGC survival.24 Erythropoietin levels are elevated in the vitreous humor of some diabetics and this
finding25 may partly explain the lower rate of POAG among diabetic patients in the
OHTS trial. While theoretical, this possible connection is worth investigating further.
However, there are also significant safety concerns with this compound. Erythropoietin
causes severe hypertension and may also exacerbate diabetic retinopathy issues that
would have to be overcome before using it as a treatment for glaucoma.
Glutamate antagonists. Memantine is an uncompetitive NMDA glutamate antagonist
that interferes with glutamate-mediated excitotoxicity. It has been shown to be
neuroprotective for both structure and function in monkey models of ocular
hypertension.26,27 In two Phase III, randomized clinical trials looking at the ability of
memantine to decrease visual field progression in patients, however, the drug did not
meet the primary efficacy endpoint. These trials, which included more than 2,000 patients
who were also being treated with ocular hypertensive agents, demonstrates the scale of
the research effort needed to test neuroprotective agents. We should expect to learn more
about neuroprotection?and glaucoma in general?when the results are published.
Alpha-2 agonists. A number of neuroprotective mechanisms have been proposed for the
ocular hypotensive agent brimonidine. These include the inhibition of glutamate release,
modulation of NMDA receptors, and up-regulation of brain-derived neurotrophic factors.
Brimonidine has been shown to be neuroprotective in experimental studies, both with
ocular hypertension as well as optic nerve crush models.28,29
We know already that topical dosing achieves therapeutic levels in the vitreous humor,30
an important step for effective neuroprotection. There are also several ongoing Phase II
clinical trials looking at brimonidine intravitreal implants for POAG, dry macular
degeneration and retinitis pigmentosa.
In animal studies comparing brimonidine to IOP-lowering medications that are not
thought to have neuroprotective effects, we have seen lower rates of RGC apoptosis in
the brimonidine-treated group.31 The potential neuroprotective effects of brimonidine
have similarly been tested recently in humans, in the Low-Pressure Glaucoma Treatment
Study (LoGTS). In LoGTS, 190 patients were randomized to receive either topical
brimonidine tartrate 0.2%, b.i.d. or topical timolol maleate 0.5%, b.i.d.32 One would
expect both treatment arms to have similar IOP reduction,33 but a reduction in the rate of
visual field progression in the brimonidine group, if supported by the study data, could be attributed to neuroprotection. This study has just been completed; results are expected
Collagen crosslinking. In corneal research, there has been a tremendous level of attention
in recent years to collagen cross-linking, a technique in which tissue is soaked with
riboflavin and treated with UVA light to cause stiffening of the tissue. Although typically
applied to keratoconus and post-LASIK ectasia, there may also be a role for crosslinking
in stiffening the optic nerve/lamina cribrosa complex. We know that elevated IOP causes
deformation of the optic nerve. In a recent experimental study in porcine eyes, collagen
crosslinking of the peripapillary scleral ring was able to reduce the biomechanical
sensitivity of the optic nerve/lamina cribrosa complex to elevated IOP.34 This is
fascinating research, albeit still in its infancy.
Natural compounds. Omega-3 fatty acids from fish oil, folic acid and curcumin are
natural compounds that are thought to be cardioprotective or cerebroprotective and may
also protect the optic nerve.35 Patients with POAG are deficient in fatty acids, so
replenishing them through diet, supplementation or some other therapeutic method may
have some benefit. Folic acid inhibits the overproduction of homocysteine, which is toxic
to RGCs. However, folic acid and homocysteine reduction have been studied in more
than 50,000 patients without conclusively demonstrating a cardioprotective effect.
Curcumin is an antioxidant, anti-inflammatory agent derived from the Indian spice
turmeric that is being investigated in a variety of diseases, including Alzheimer’s.
Gingko biloba extract has a variety of potentially beneficial effects on ocular blood flow.
It inhibits platelet aggregation and has antioxidant qualities. Intra-peritoneal injections of
gingko biloba extract in rat models of optic nerve crush have demonstrated a
neuroprotective effect.36 Unfortunately, we may not get beyond experimental data with
any of these natural compounds.
EVALUATING POTENTIAL NEUROPROTECTIVE AGENTS
Pioneers in this field have suggested that any potential new neuroprotective agents must
meet four criteria.37 The agent must:
- Target receptors in the retina or the optic nerve
- Reach adequate concentrations in target tissue
- Improve retinal ganglion cell survival in experimental testing
- Demonstration efficacy in humans in randomized clinical trials.
Passing the final test of efficacy in humans will be very challenging. Glaucoma is a very
slowly progressing disease, so one must follow large numbers of patients for a long time
in any therapeutic trial. Both control and treatment arms will have to get IOP-lowering
medications consistent with the current standard of care for glaucoma. To detect a
difference in the rate of progression between groups, thereby demonstrating an additive
benefit from the neuroprotective agent, the number of patients will need to be larger still.
Finally, the burden of proof for neuroprotective agents will likely be higher than for
glaucoma therapies currently in use. Regulatory agencies have already determined that
visual field or functional endpoints must be used to determine efficacy. Timolol, a very
well-studied glaucoma medication, has never been shown to decrease visual field
progression; it has only been shown to affect the surrogate endpoint of IOP.
Partly because of these difficulties, there has been a push to adopt structural measures of
glaucoma progression. We know that visual field scores can remain normal, even with
RGC loss of up to 30 percent,38 so the idea of measuring the RNFL directly, rather than
waiting for the corresponding—but potentially lagging—visual field deficit is very
appealing (Figure 5). But for reasons that remain unclear, there is very poor
agreement between structural and functional measures of glaucoma progression.11-12,39 Until we solve this riddle, I don’t think we will be able to successfully identify surrogate
structural endpoints, no matter how appealing the concept may be.
One potential approach to this problem, Detection of Apoptosing Retinal Cells (DARC),
has been tested in animal models.40,41 DARC allows direct, fluorescent visualization of
RGCs as they undergo apoptosis. If this could be validated against a functional endpoint
in humans, perhaps we could perform a baseline DARC measurement, then repeat after a
month to see if treatment has diminished the number of cells undergoing apoptosis.
Despite the challenges in evaluating neuroprotective agents, we must continue to pursue
careful study of the agents mentioned here and others not yet identified. There is a
growing body of experimental and clinical evidence validating at least the concept of neuroprotection. I am anxiously awaiting the results of the LoGTS study, as it may
provide us with the first strong evidence of a neuroprotective effect that would be
applicable to the treatment of glaucoma patients.
Ocular Blood Flow in Glaucoma
By Alon Harris, MS, PhD
Intraocular pressure (IOP) is the only approved treatable risk factor in glaucoma.
However, the blood supply is central to nearly every disease process that affects the
human body—and the eye is no exception. As early as 1879, Priestly Smith suggested the
glaucomatous optic disc cup is not purely a mechanical result but is at least in part “an
atrophic condition which, though primarily due to pressure, includes vascular changes
and impaired nutrition in the back of the disc and around its margin.”42 Research since
that time supports Smith’s intuition, and today we have some very compelling evidence
that blood flow is a factor in glaucoma pathology.
VASCULAR RISK FACTORS IN GLAUCOMA
Chief among the well-documented risk factors for glaucoma is elevated IOP. Several
large prospective clinical studies in the last decade have provided strong evidence
justifying IOP reduction in the treatment of glaucoma. Other risk factors, all non-
modifiable, include diurnal IOP fluctuations, age, race, family history, genetics, myopia,
central corneal thickness and female gender.
A growing body of literature suggests that there are also a number of vascular risk factors
for glaucoma incidence and progression, including low ocular perfusion pressure (the
most widely reported), diabetes, systemic hypertension, nocturnal systemic hypotension,
migraine and disc hemorrhage.
The Collaborative Normal Tension Glaucoma Trial (CNTGT) reported that optic disc
hemorrhages—clearly vascular events—are highly significantly associated with normal-
tension glaucoma progression.43 The hemorrhages tend to be larger in normal-pressure
glaucoma and without any cotton-wool spots.44 In the Beijing Eye Study, 80 percent of
eyes with a disc hemorrhage at baseline showed progression after five years.45 In Taiwan, analysis of a population database of more than one million subjects showed that
patients with POAG demonstrated a significantly increased risk of stroke development
over five years, compared to those without POAG.46
It is worth trying to understand, from a pathophysiological perspective, how blood flow
might affect glaucoma. Experimental animal studies have shown that ischemia can lead
to ganglion cell death and optic nerve head (ONH) atrophy.47,48 In his explanation of
IOP-related damage in POAG, Burgoyne shows that IOP-related stress and strain affects
blood flow and nutrient supply within the ONH, as do the retrobulbar determinants of the
ONH blood flow.49 All of these contribute to axonal damage within the lamina cribrosa
through a variety of mechanisms.
Whether a given optic nerve is more or less susceptible to vascular damage is very likely
affected by physiological age, either of the tissue itself or the vascular system. Age is a
profound risk factor for both prevalence and progression in glaucoma. IOP does not
correlate with age, so the association between age and glaucoma may be due to vascular
OCULAR PERFUSION PRESSURE
Ocular perfusion pressure, which is calculated as 2/3 mean arterial pressure minus IOP
(OPP = 2/3MAP - IOP), has been shown in several large studies to be an important risk
factor for glaucoma.
In the Egna-Neumarkt study, which enrolled 4,297 white subjects in Italy, the prevalence
of glaucoma increased as ocular perfusion pressure drops.50 Quigley and colleagues
made the same finding in Hispanic subjects in the ProyectoVER study conducted in the
United States.51 We have also recently learned that lower ocular systolic, diastolic, and
mean perfusion pressures were independent risk factors for glaucoma in the Barbados
Eye Studies.52 From these population-based studies, the optimum diastolic perfusion
pressure appears to be above 50 mmHg.
In addition to the prevalence risk factors reported by these population-based studies, we
now also have data indicating a vascular role in glaucoma progression. Two-thirds of
patients in the Early Manifest Glaucoma Trial progressed with long-term follow up (11
years). Lower systolic perfusion pressure, lower systolic blood pressure and
cardiovascular disease were predictive of progression among all subjects.53 In the subset
with higher baseline IOP, decreased central corneal thickness was a more significant risk
factor than in those with lower baseline IOP.
All of this evidence led the World Glaucoma Association to issue a consensus document
in 2009 that for the first time clearly identifies low ocular perfusion pressure as a risk
factor for POAG and recommends investigation of treatments to regulate OPP54 (sidebar). The “vascular theory” of glaucoma is no longer just a theory, but a scientific
World Glaucoma Congress Consensus Statements on Ocular Blood Flow
In 2009, the World Glaucoma Association recognized the importance of ocular blood
flow in a consensus publication (Consensus Series #6) edited by Alon Harris, MS, PhD,
and Robert Weinreb, MD.54 This paper summarizes the consensus of more than 200
glaucoma experts from more than 30 countries on the topic of ocular blood flow in
glaucoma. Key consensus statements from the group include:
- Low ocular perfusion is a risk factor for open-angle glaucoma.
- The hypothesis that treatment of OPP, rather than IOP alone, is beneficial in glaucoma
should be tested.
- Vascular dysregulation may contribute to the pathogenesis of glaucoma, more likely in
people with lower IOP.
- Longitudinal studies are necessary to confirm that blood flow abnormalities precede
visual field defects and correlate with their severity.
- At the present time, there is no single method for measuring all aspects of ocular blood
flow and its regulation in glaucoma.
- A comprehensive approach, ideally implemented in a single device, may be required to
assess the relevant pathophysiology of glaucoma.
An underappreciated fact is that two-thirds of individuals experience a drop in blood
pressure at night.55 IOP, on the other hand, tends to peak during the night and early
morning hours. For many people, then, simultaneous changes in blood pressure and IOP
lead to a period of low OPP during the early morning hours. The physiological link that
determines how individual patients actually respond to perfusion pressure changes is the
potential dysfunction of vascular autoregulation.
Much as we cannot rely on a single IOP measurement to give us the full picture of IOP,
single measurements of perfusion pressure are also not as meaningful. For example, in
patients with normal-tension glaucoma, low OPP itself is not associated with outcomes,
but age and mean OPP fluctuations are associated with functional and anatomical
outcomes.56 A 1.0-mmHg increase in mean OPP fluctuation is associated with a 0.23
increase in AGIS score and 0.53 decrease in the TSNIT (temporal, superior, nasal,
inferior and temporal) average score, linking perfusion fluctuations with clinical
Vascular dysregulation increases with age in the eye and other organ systems. In the
brain, which shares a common embryological source and similar control mechanisms
with the eye, the anterior, middle and posterior cerebral arteries all show increasing
resistance to blood flow with age.57 My colleagues and I have shown that between the
ages of 20 and 90, resistance to circulation in the retrobulbar arteries increases, especially
in women.58 Experimental studies also reveal significant age-related changes in the deep
plexus of retinal vasculature with age. Compared to the normal ocular vasculature of a
young rat, the deep plexus of an aged rat retina has loss of capillary patency, vessel
kinking and vascular looping59—all of which may provide an anatomical, morphological
explanation for the dysregulation of blood flow seen in older patients.
The combined effects of these vascular changes, along with IOP-related stress and strain,
may contribute to impaired regulation of blood flow during normal dips in perfusion
pressure. In other words, the effects of aging may reduce the eye’s ability to regulate and
cope with fluctuations in OPP, making it more susceptible to glaucomatous damage.
BLOOD FLOW, OPTIC NERVE STRUCTURE AND VISUAL FUNCTION
Structural damage of the optic nerve is correlated with low retinal blood flow.60 But the
relationship between glaucoma and blood flow is complex. Berisha suggests that thinner
retinal nerve fiber layer (RNFL) is actually associated with high retinal blood flow in
patients with early stage glaucoma.61 It is possible that early in the disease process, there
is some compensatory mechanism that increases blood flow. As RNFL tissue is lost,
however, one sees a decrease in blood flow.
The Thessaloniki Eye Study, a cross-sectional, population-based study, is providing some
answers to these puzzling questions. Low OPP secondary to the use of systemic
antihypertensive medications was associated in the study with increased cup area,
decreased rim area, and greater cup-to-disc ratio.62 The results cannot be attributed to
IOP, because the group taking antihypertensives had lower IOP than either the normal
blood pressure group or the group with high blood pressure not being treated with
antihypertensives. This suggests that blood pressure status is an independent factor
initiating optic disc changes and/or as a contributing factor to glaucoma damage.62 The
European Glaucoma Prevention Study (EGPS) also suggests that diuretics and other anti-
hypertensive medications are important intercurrent risk factors associated with the
development of POAG.63
There are two possible mechanisms of damage: ischemia to ocular tissues or translamina
cribrosa pressure differences—that is, differences between the IOP and the cerebral
spinal fluid pressure (CSFP) surrounding the optic nerve.64
Data coming from the Thessaloniki and EGPS studies produce, for the first time, a
potential for conflict between systemic and ocular health goals. In Europe, glaucoma
specialists are taking the approach of educating their cardiology colleagues about the
effects of systemic medications on the optic nerve. I believe we will see more discussion
on this topic among internists, cardiologists and ophthalmologists in the future.
Currently, we lack good longitudinal studies investigating the relationship between visual
function and ocular blood flow. Emerging evidence is supportive, however, as patients
with asymmetrical visual field loss exhibit corresponding asymmetric ocular blood
flow.65 In one longitudinal study of 44 newly diagnosed POAG patients followed for seven years, the odds of visual field deterioration were six times greater in patients with
higher resistance to flow.66 Additional studies are needed to confirm the relationship
between blood flow abnormalities and visual field defects described in these pilot studies.
MEASURING AND INFLUENCING BLOOD FLOW
While there have been reports that some medications may affect ocular blood flow, it is
important to keep in mind that blood pressure and perfusion pressure changes are only
detrimental to a glaucoma patient if that patient also has problems regulating blood flow.
In a patient who can regulate blood flow normally, changes in perfusion pressure may not
Another important question is whether ocular blood flow can be accurately measured in
humans. At this time, while we have many useful instruments for measuring particular
aspects of ocular hemodynamics, there is no single, comprehensive method for measuring
all vascular beds relevant to the optic nerve head.
I see great technological potential in retinal oximetry, the goal of which is to measure the
oxygen saturation in the back of the eye. That is because blood flow, which is so
challenging to measure, is actually only a surrogate for true metabolic changes. Some
researchers have recently found that normal tension glaucoma patients have decreased
arterial oxygen saturation compared to healthy controls.67,68 This suggests that in
patients with problems regulating blood flow, OPP fluctuations could potentially be
matched with changes in blood flow and further matched with problems related to
Recent developments with spectral domain Doppler optical coherence tomography
(OCT) are also very exciting. Specifically, advances in broadband low-coherence light
sources and high-speed array detectors have made it possible to produce blood flow
measurements within structural data.69 The high speed of SDOCT allows real-time
acquisition of measurement in three-dimensional volumes of living tissue. It measures
blood flow in branch retinal vessels in absolute units (µl/min), which is a significant
advantage over earlier forms of OCT.
Although it has great potential, we must acknowledge that SDOCT is a new technology
with limited information from clinical trials and with no normative database. The
measurement of blood flow in capillaries is not yet understood and demonstrated. It
requires repeated A-scans, and that increases scan time and eye motion, decreases
visualization, and usually requires some sacrifice in scan density.
Clinicians can expect to see reports on the potential of various topical or systemic agents
to influence ocular blood flow and OPP. These reports are likely to be confusing. I
would like to offer the reader some principal ways of thinking in assessing future claims.
First, all topical glaucoma medications that are currently available have been designed to
lower IOP by decreasing aqueous formation or increasing uveoscleral outflow. None of
them has really been designed to target the optic nerve or retinal vessels, although some
may indeed affect those structures. In assessing claims that a given agent (topical,
systemic or natural) does have structural effects, one should closely examine the
physiological rationale for such claims.
Secondly, to have such an effect, the agent must be able to penetrate to the back of the
eye in sufficient concentrations. Finally, we should all be very critical consumers of the
study design. Understand that lowering IOP will increase OPP. So in evaluating any
claims about effects on OPP, it is critical to ensure that the study compares drugs with
similar IOP effects or that it controls for those IOP effects. The study also needs to
continue long enough to tie blood flow changes to clinical endpoints.
Long-term prospective studies with standardized equipment and methods are necessary to
document the effects of individual therapies on specific vascular structures or
Ocular blood flow abnormalities play a key role in primary open angle glaucoma. This is
no longer just theory; it is reality. Unfortunately, there is no single device that is
sufficient for measuring these blood flow changes clinically because they have been
reported to occur in the optic nerve, in the retina, in the choroid and even systemically.
Perfusion pressure data is definitely compelling. There is evidence of relationships
between perfusion pressure and glaucoma prevalence, incidence, and progression. It is
too soon to make claims regarding specific drugs and their effects on visual function and
optic nerve structure secondary to their effect on ocular blood flow.
- Janz NK, Wren PA, Lichter PR, et al. The Collaborative Initial Glaucoma Treatment
Study: interim quality of life findings after initial medical or surgical treatment of
glaucoma. Ophthalmology 2001;108(11):1954-1965.
- Herndon LW, Brunner TM, Rollins JN. The Glaucoma Research Foundation patient
survey: Patient understanding of glaucoma and its treatment. Am J Ophthalmol
- Jampel HD, Schwartz GF, Robin AL, et al. Patient preferences for eye drop
characteristics: a willingness-to-pay analysis. Arch Ophthalmol 2003;121(4):540-546.
- Okeke CO, Quigley HA, Jampel HD, et al. Adherence with topical glaucoma
medication monitored electronically: the Travatan Dosing Aid study. Ophthalmology
- Kass MA, Meltzer DW, Gordon M, et al. Compliance with topical pilocarpine
treatment. Am J Ophthalmol 1986;101(5):515-523.
- Claxton AJ, Cramer J, Pierce C. A systematic review of the associations between dose
regimens and medication compliance. Clin Ther 2001;23:1296-1310.
- Patel SC, Spaeth GL. Compliance in patients prescribed eyedrops for glaucoma.
Ophthalmic Surg 1995;26:233-236.
- Neelakantan A, Vaishnav HD, Iyer SA, Sherwood MB. Is addition of a third or fourth
anti-glaucoma medication effective? J Glaucoma 2004;13(2):130-136.
- Robin AL, Covert D. Does adjunctive glaucoma therapy affect adherence to the initial
primary therapy? Ophthalmology 2005;112:863-868.
- Leske MC, Heijl A, Hyman L, et al. The EMGT Study Group. Predictors of long-
term progression in the early manifest glaucoma trial. Ophthalmology 2007;114:1965-
- 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;126:487-497.
- 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
- The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between
control of intraocular pressure and visual field deterioration.The AGIS Investigators. Am
J Ophthalmol 2000;130(4):429-440.
- Leske MC, Wu SY, Hennis A, et al and BESs Study Group. Risk factors for incident
open-angle glaucoma: The Barbados Eye Studies. Ophthalmology 2008;115(1):85-93.
- Weinreb RN. Glaucoma neuroprotection: What is it? Why is it needed? Can J
- Quigley HA, Nickells RW, Kerrigan LA, et al. Retinal ganglion cell death in
experimental glaucoma and after axotomy occurs by apoptosis. Invest Ophthalmol Vis
- Flammer J, Orgƒl S. Optic nerve blood flow abnormalities in glaucoma. Prog Retin
Eye Res 1998;17:267-289.
- Bracken MB, Shepard MJ, Holford TR, et al. Administration of methylprednisolone
for 24 or 48 hours or tirilazad mesylate for 48 hours in the treatment of acute spinal cord
injury. Results of the Third National Acute Spinal Cord Injury Randomized Controlled
Trial. National Acute Spinal Cord Injury Study. JAMA 1997;277:1597-1604.
- Guo L, Salt TE, Luong V, et al. Targeting amyloid-beta in glaucoma treatment. Proc
Natl Acad Sci USA 2007;104(33):13444-9.
- Schmeer C, Kretz A. Isenmann S. Therapeutic potential of 3-hydroxy-3-
methylglutaryl coenzyme a reductase inhibitors for the treatment of retinal and eye
diseases. CNS Neurol Disord Drug Targets 2007;6:282-287.
- De Castro DK, Punjabi OS, Bostrom AG, et al. Effect of statin drugs and aspirin on
progression in open-angle glaucoma suspects using confocal scanning laser
ophthalmoscopy. Clin Experiment Ophthalmol 2007;35:506-513.
- Huang W, Fileta JB, Dobberfuhl A, et al. Calcineurin cleavage is triggered by
elevated intraocular pressure and cacineurin inhibition blocks retinal ganglion cell death
in experimental glaucoma. Proc Natl Acad Sci USA 2005;102:12242-7.
- Tsai JC, Song BJ, Wu L, Forbes M. Erythropoietin: a candidate neuroprotective agent
in the treatment of glaucoma. J Glaucoma 2007;16:567-571.
- Tsai JC, Wu L, Worgul B, et al. Intravitreal administration of erythropoietin and
preservation of retinal ganglion cells in an experimental rat model of glaucoma. Curr Eye
- Watanabe D, Suzuma K, Matsui S, et al. Erythropoietin as a retinal angiogenic factor
in proliferative diabetic retinopathy. N Engl J Med 2005;353:782-792.
- Hare WA, WoldeMussie E, Lai RK, et al. Efficacy and safety of memantine treatment
for reduction of changes associated with experimental glaucoma in monkey, I: Functional
measures. Invest Ophthalmol Vis Sci 2004;45:2625-2639.
- Hare WA, WoldeMussie E, Weinreb RN, et al. Efficacy and safety of memantine
treatment for reduction of changes associated with experimental glaucoma in monkey, II:
Structural measures. Invest Ophthalmol Vis Sci 2004;45:2640-2651.
- Wheeler L, WoldeMussie E, Lai R. Role of alpha-2 agonists in neuroprotection. Surv
- Ma K, Xu L, Zhang H, et al. Effect of brimonidine on retinal ganglion cell survival in
an optic nerve crush model. Am J Ophthalmol 2009;147:326-331.
- Kent AR, Nussdorf JD, David R, et al. Vitreous concentration of topically applied
brimonidine tartrate 0.2%. Ophthalmology 2001;108:784-787.
- WoldeMusie E, Ruiz G, Wijono M, Wheeler LA. Neuroprotection of retinal ganglion
cells by brimonidine in rats with laser-induced chronic ocular hypertension. Invest
Ophthalmol Vis Sci 2001;42:2849-2855.
- Krupin T, Liebmann JM, Greenfield DS, et al. The Low-pressure Glaucoma
Treatment Study (LoGTS) study design and baseline characteristics of enrolled patients.
- Katz LJ. Brimonidine tartrate 0.2% twice daily vs timolol 0.5% twice daily: 1-year
results in glaucoma patients. Brimonidine Study Group. Am J Ophthalmol 1999;127:20-
- Thornton IL, Dupps WJ, Roy AS, Krueger RR. Biomechanical effects of intraocular
pressure elevation on optic nerve/lamina cribrosa before and after peripapillary scleral
collagen cross-linking. Invest Ophthalmol Vis Sci 2009;50(3):1227-1233.
- Ritch R. Natural compounds: Evidence for a protective role in eye disease. Can J
- Ma K, Xu L, Zhang H, et al. The effect of ginkgo biloba on the rat retinal ganglion
cell survival in the optic nerve crush model. Acta Ophthalmol 2009; epub ahead of print.
- Hare W, WoldeMussie E, Lai RK, et al. Efficacy and safety of memantine, an
NMDA-type open-channel blocker, for reduction of retinal injury associated with
experimental glaucoma in rat and monkey. Surv Ophthalmol 2001;45 Suppl 3:S284-289.
- Quigley HA, Nickells RW, Kerrigan LA, et al. Retinal ganglion cell death in
experimental glaucoma and after axotomy occurs by apoptosis. Invest Ophthalmol Vis
- Heijl A, Leske MC, Bengtsson B, et al and Early Manifest Glaucoma Trial Study
Group. Reduction of intraocular pressure and glaucoma progression: results from the
Early Manifest Glaucoma Trial. Arch Ophthalmol 2002;120(10):1268-79.
- Guo L, Cordeiro MF. Assessment of neuroprotection of the retina with DARC. Prog
Brain Res. 2008;173:437-450.
- Cordeiro MF, Guo L, Luong V, et al. Real-time imaging of single nerve cell apoptosis
in retinal neurodegeneration. Proc Natl Acad Sci USA 2004;101:13352-6.
- Kagemann L, et al. In : Fingeret M, Lewis TL, eds. Primary Care of the Glaucomas.
2nd ed. New York, NY: McGraw-Hill Professional; 2000:81-94.
- Drance S, Anderson DR, Schulzer M, Collaborative Normal-Tension Glaucoma
Study Group. Risk factors for progression of visual field abnormalities in normal-
tenstion glaucoma. Am J Ophthalmol 2001;131(6):699-708.
- Jonas JB, Xu L. Optic disk hemorrhages in glaucoma. Am J Ophthalmol
- Wang Y, Xu L, Hu L, et al. Frequency of optic disk hemorrhages in adult Chinese in
rural and urban china: the Beijing Eye Study. Am J Ophthalmol 2006;142(2):241-246.
- Ho JD, Hu CC, Lin HC. Open-angle glaucoma and the risk of stroke development: a
5-year population-based follow-up study. Stroke 2009;40(8):2685-2690.
- Cioffi GA, Sullivan P. The effect of chronic ischemia on the primate optic nerve. Eur
J Ophthalmol 1999;9 Suppl 1:S34-36.
- Cioffi GA, Wang L, Fortune B, et al. Chronic ischemia induces regional axonal
damage in experimental primate optic neuropathy. Arch Ophthalmol 2004;122(10):1517-
- Burgoyne CF, Downs JC, Bellezza AJ. The optic nerve head as a biomechanical
structure: a new paradigm for understanding the role of IOP-related stress and strain in
the pathophysiology of glaucomatous optic nerve head damage. Prog Retin Eye Res
- Bonomi L, Marchini G, Marraffa M, et al. Epidemiology of angle-closure glaucoma:
prevalence, clinical types, and association with peripheral anterior chamber depth in the
Egna-Neumarket Glaucoma Study. Ophthalmology 2000;107(5):998-1003.
- Quigley HA, West SK, Rodriguez J. The prevalence of glaucoma in a population-
based study of Hispanic subjects: Proyecto VER. Arch Ophthalmol 2001;119(12):1819-
- Leske MC, Wu SY, Hennis A, et al and BESs 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; and EMGT Group. Predictors of long-term
progression in the early manifest glaucoma trial. Ophthalmology 2007;114(11):1965-
- Weinreb RN, Harris A. Ocular Blood Flow in Glaucoma: Consensus Series 6. The
Netherlands: Kugler Publications; 2009.
- Verdecchia P, Schillaci G, Porcellati C: Dippers versus nondippers. J Hypertens
- Choi J, Kim KH, Jeong J, et al. Circadian fluctuation of mean ocular perfusion
pressure is a consistent risk factor for normal-tension glaucoma. Invest Ophthalmol Vis
- Krejza J, Mariak Z, Walecki J, et al. Transcranial color Doppler sonography of basal
cerebral arteries in 182 healthy subjects: age and sex variability and normal reference
values for blood flow parameters. AJR Am J Roentgenol 1999;172:213-218.
- Harris A, Harris M, Biller J, et al. Aging affects the retrobulbar circulation differently
in women and men. Arch Ophthalmol 2000;118(8):1076-1080.
- Hughes S, Gardiner T, Hu P, et al. Altered pericyte-endothelial relations in the rat
retina during aging: implications for vessel stability. Neurobiol Aging 2006;27(12):1838-
- Logan JF, Rankin SJ, Jackson AJ. Retinal blood flow measurements and neuroretinal
rim damage in glaucoma. Br J Ophthalmol 2004; 88(8):1049-1054.
- Berisha F, Feke GT, Hirose T, et al. Retinal blood flow and nerve fiber layer
measurements in early-stage open-angle glaucoma. Am J Ophthalmol 2008;146(3):466-
- Topouzis F, Coleman AL, Harris A, et al. Association of blood pressure status with
the optic disk structure in non-glaucoma subjects: the Thessaloniki eye study. Am J
- Miglior S, Torri V, Zeyen T, et al and EGPS Group. Intercurrent factors associated
with the development of open-angle glaucoma in the European glaucoma prevention
study. Am J Ophthalmol 2007;144(2):266-275.
- Jonas JB. Association of blood pressure status with the optic disk structure. Am J
- Plange N, Kaup M, Arend O, Remky A. Asymmetric visual field loss and retrobulbar
haemodynamics in primary open-angle glaucoma. Graefes Arch Clin Exp Ophthalmol
- Galassi F, Sodi A, Ucci F, et al. Ocular hemodynamics and glaucoma prognosis: a
color Doppler imaging study. Arch Ophthalmol 2003;121(12):1711-1715.
- Michelson G, Scibor M. Intravascular oxygen saturation in retinal vessels in normal
subjects and open-angle glaucoma subjects. Acta Ophthalmol Scand 2006;84(3):289-295.
- Olafsdottir OB, et al. Abstract presented at European Association of Vision and Eye
Research, Abstract, 2009.
- Bower BA, Zhao M, Zawadzki RJ, Izatt JA. Real-time spectral domain Doppler
optical coherence tomography and investigation of human retinal vessel autoregulation. J
Biomed Opt 2007;12(4):041214.