Managing Glaucoma: Beyond Intraocular Pressure. 2011
ESTIMATED TIME TO COMPLETE ACTIVITY:
This educational activity is intended for comprehensive ophthalmologists interested in the care and management of patients with glaucoma.
Educate physicians on current theories for managing patients with normal-tension glaucoma, with particular focus on potential neuroprotective strategies.
STATEMENT OF NEED:
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 what is usually considered normal. NTG accounts for many of the cases of OAG in the United States. The typical treatment of NTG is directed at lowering eyes pressure; however, traditional strategies of lowing IOP still do not prevent progressive vision loss in some glaucoma patients. 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. Various neuroprotective drug-based approaches have been shown to reduce the death of retinal ganglion cells, which is the hallmark of glaucomatous optic neuropathy. Moreover, there is a growing trend toward using existing neuroprotective strategies in central nervous system diseases for the treatment of glaucoma. This continuing education activity will educate physicians on current theories for managing patients with NTG, with particular focus on potential neuroprotective strategies.
After completing this educational activity, participants should be better able to:
- Discuss the diagnosis and management of normal-tension glaucoma.
- 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 therapy.
- Identify the goals and obstacles of neuroprotection in the treatment of NTG.
Physicians know and apply current strategies in the diagnosis and treatment of patients with normal-tension glaucoma to slow the progression and preserve the patient's quality of life.
Andrew Huberman, PhD, is an Assistant Professor in the Department of Neuroscience at the University of California-San Diego in La Jolla, Calif. Contact him at (858) 534-4740 or email@example.com.
Theodore Krupin, MD, is Professor of Ophthalmology at Northwestern University’s Feinberg School of Medicine in Chicago, Ill. Contact him at (312) 695-8150 or firstname.lastname@example.org.
Nils Loewen, MD, PhD is Assistant Professor of Ophthalmology, Director of Glaucoma Fellowship, and Director of the Academic Associate Program in the Department of Ophthalmology and Visual Science at Yale University School of Medicine in New Haven, Conn. Contact him at (203) 533-1004 or email@example.com.
Felipe A. Medeiros, MD, PhD, is Professor of Clinical Ophthalmology in the Department of Ophthalmology and Medical Director of the Hamilton Glaucoma Center at the University of California San Diego. Contact him at (858) 534-6290 or firstname.lastname@example.org.
Arthur J. Sit, SM, MD is a Consultant in the Department of Ophthalmology and Assistant Professor of Ophthalmology at the Mayo Clinic College of Medicine in Rochester, Minn. Contact him at (507) 284-2787 or email@example.com.
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 Diego. Contact him at (858) 534-8824 or firstname.lastname@example.org.
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 Bert M. Glaser National Retina Institute (NRI) and Review of Ophthalmology®/Jobson. NRI is accredited by the ACCME to provide continuing medical education for physicians.
CREDIT DESIGNATION STATEMENT:
NRI designates this educational activity for a maximum of 2.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
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 of heal care and not a specific proprietary business interest of a commercial interest.
This activity was peer-reviewed for relevance, accuracy of content and balance of presentation by NRI.
The following individuals have disclosed relevant financial relationships with commercial interests: Theodore Krupin, MD — (C) Allergan, Inc. Felipe A. Medeiros, MD — (C) Alcon, Allergan Inc.; (S) Merck, Pfizer, Carl Zeiss Meditec, Sensimed. Arthur J. Sit, SM, MD — (C) Allergan Inc., Alcon Laboratories Ltd., Glaukos Corp., AcuMEMS. Dr. Weinreb — (C) Allergan Inc., Alcon, Merck, Bausch + Lomb, Optovue, Carl Zeiss Meditec, Heidelberg Engineering, Topcon; (S) Optovue, Carl Zeiss Meditec, Heidelberg Engineering, Topcon.
The following individuals have disclosed that there are no relevant financial relationships with any commercial interests: Andrew D. Huberman, Ph.D., A. Tim Johnson, M.D., Nils A. Loewen, MD, Ph.D., Leticia Hall, Karen Rodemich.
(C) Consultant/Advisor Consultant fee, paid advisory boards or fees for attending a meeting (for the past year); (E) Employee Employed by a commercial entity; (L) Lecture Fees Lecture fees (honoraria), travel fees or reimbursements when speaking at the invitation of a commercial entity (for the past one year); (O) Equity Owner Equity ownership/stock options of publicly or privately traded firms (excluding mutual funds) with manufacturers of commercial ophthalmic products or services; (P) Patents/Royalty Patents and/or royalties that might be viewed as creating a potential conflict of interest; (S) Grant Support Grant support for the past one year (all sources).
METHOD OF PARTICIPATION:
There are no fees for participating and receiving CME credit for this activity. During the period of September 2011 and September 30, 2012, 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;
- complete the evaluation form
Monograph/Print Supplement and Internet
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.
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.
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.
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CHANGING PARADIGMS: DIAGNOSTICS IN CLINICAL PRACTICE
A New Understanding of Glaucoma
Glaucoma is the most common neurodegenerative disease. Our success in treating it depends on identifying strategies for monitoring and treatment that go well beyond IOP.
Robert N. Weinreb, MD
Our goal in treating glaucoma has always been to halt patients’ progress along the continuum that leads from undetectable disease to asymptomatic disease and, finally, to functional impairment. Our methods for detection and management of glaucoma have evolved significantly in recent decades, guided by the results of randomized clinical trials, the use of new diagnostic technology and improved therapeutic modalities.
Thirty years ago, intraocular pressure (IOP) was the primary measure in both diagnosis and treatment of glaucoma. Many clinicians commenced treatment when IOP exceeded 21 mmHg, with the goal of lowering it below that threshold. Our abilities to assess optic nerve structure and function were fairly crude and factored little into overall management of the disease.
By the late 1980s, automated perimetry was in widespread use and had become an essential component of the glaucoma evaluation. Clinical decision-making began to depend on both IOP measurements and functional changes in the visual field.
Standard automated perimetry remains the most widely used functional test, but there are several disadvantages to it, including the length of follow up required to confirm meaningful change. Furthermore, visual fields aren’t sensitive enough to detect early glaucomatous change. By the time a visual field defect is present, a majority of retinal ganglion cells (RGCs) may already be lost.
With the maturation and availability of imaging techniques during the past decade, evaluation of the structure of the optic disc and retinal nerve fiber layer has become a third key component for the diagnosis and management of glaucoma. In the Ocular Hypertension Treatment Study (OHTS), about half of the patients who progressed to glaucoma had detectable structural changes that preceded functional visual field los.1
Unfortunately, many clinicians still do not draw, actively evaluate or document the optic nerve at initial evaluation. These remain critical steps. Even as imaging tools such as spectral domain OCT and frequency-doubling perimetry continue to advance, they should be viewed as complementary to a good clinical examination with a handheld lens or a high quality optic disc photograph.
The New Paradigm
The most specific way to diagnose glaucoma is with a progressive structural or functional change in the disc, the retinal nerve fiber layer, or the visual field. However, without clear progression, one can detect presumed glaucoma with, for example, a disc abnormality with a corresponding RNFL defect or a disc or RNFL abnormality with a corresponding functional defect.2,3
Ultimately, we are moving toward a paradigm in which clinicians will rely purely on structural and functional tests to diagnose and manage glaucoma, and not the IOP. Our aim will be not just lowering IOP, but arresting changes in the optic nerve before there is functional vision loss.
Neurodegeneration and Neuroprotection
Today, many definitions of glaucoma do not even mention IOP. Elevated IOP is, of course, an important risk factor for the development of glaucomatous optic nerve damage and it may even be causal in many (if not most) patients, but it may be just one of several conditions that trigger the accelerated loss of retinal ganglion cells. Genetics, sub-optimal perfusion of the optic nerve, vascular dysregulation and oxidative and ischemic stressors are thought to be among the other potential triggers.
There is also a growing realization that glaucoma is not just an eye disease, but part of a broader neurodegenerative process that affects the entire central visual pathway, including the brain stem and the brain. Marked neuronal damage and cell death have been confirmed in the lateral geniculate nucleus regions of the brain in non-human primates and in postmortem human eyes with glaucoma. That makes glaucoma the most prevalent neurodegenerative disease in the world, affecting more people than Alzheimer’s, Huntington’s disease and Parkinson’s disease combined.
We have all seen clinically that neuronal death and glaucoma progression can continue even with very effective IOP lowering, so either the IOP is not being lowered sufficiently or there must be something going on that is independent of IOP. Many new treatments for glaucoma attempt to address this conundrum and prevent retinal ganglion cell death before it happens. This strategy, neuroprotection, refers to therapies other than IOP lowering, which are directed at protecting the structure and function of the retinal ganglion cells and the entire central visual pathway.
Neuroprotection is intended to tip the balance of cell protective and destructive factors in favor of RGC survival. One can envision many different ways to accomplish this: nerve growth factors might be able to enhance the survival mechanisms, while other interventions might inhibit cell death signals. I envision that successful neuroprotective strategies will complement rather than replace the very effective treatments we already have for lowering IOP.
- Gordon MO, Beiser JA, Brandt JD, et al. The Ocular Hypertension Treatment Study: baseline factors that predict the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120(6):714-20.
- Mansouri K, Leite MT, Medeiros FA, et al. Assessment of rates of structural change in glaucoma using imaging technologies. Eye (Lond). 2011;25(3):269-77.
- Weinreb RN, Medeiros FA. Is scanning laser polarimetry ready for clinical practice? Am J Ophthalmol. 2007;143(4):674-6.
Risk Analysis for Glaucoma Progression
To be meaningful, risk assessment should take into account the rate of change, life expectancy
and degree of functional impairment for activities of daily living.
by Felipe A. Medeiros, MD, PhD
The Ocular Hypertension Treatment Study (OHTS) identified several factors associated with a higher risk of developing glaucoma. These include older age, higher intraocular pressure (IOP), thinner corneas, a larger cup/disc ratio and greater pattern standard deviation.1
In 2005, we developed a predictive model that combined these factors into a calculator for determining an individual patient’s risk of developing glaucoma.2 Subsequently, another five- year risk estimator for patients with ocular hypertension was developed based on OHTS and the European Glaucoma Prevention Study (EGPS).2 It is available online at http://ohts.wustl.edu/risk/calculator.html. Both of these risk calculators rely on baseline information.
But risk calculation has continued to evolve. In another study, in which we followed 639 glaucoma suspect eyes over eight years, we found that progressive optic nerve damage over time is highly predictive of developing functional loss in glaucoma.3 Compared to baseline variables such as cup-to-disc ratio, optic disc progression over time had a much higher predictive value (see Figure 1).
All of the above-mentioned studies involve patients with ocular hypertension or other suspicion of glaucoma—in other words, they are looking at the risk of progression to glaucoma. What about the risk of progressive damage after a diagnosis of glaucoma? The Early Manifest Glaucoma Trial (EMGT) has actually found quite similar risk factors to those identified previously, including older age, higher IOP, thinner corneas, more severe disease, as well as the presence of disc hemorrhages.4 EMGT suggests that perfusion pressure is also a risk factor for progression.
Most patients with glaucoma in the EMGT actually progressed during follow up: 60 percent of the treatment group and 76 percent of the patients who were followed without treatment progressed.
Progression might not be a problem if it occurs very slowly. In a recently reported EMGT sub- analysis, researchers found a median rate of change (mean deviation of the visual field) of –0.4 dB per year.5 At that rate, it would take 75 years to progress from normal to end-stage visual fields, which sounds like an acceptable rate of change. However, upon closer examination of the data, one can see that a significant number of patients experienced much more rapid progression. We treat individuals, not averages, so we need to be concerned about those patients with more rapid progression who have a much higher chance of functional impairment from this disease.
There are a number of ways to measure the rate of change, including visual field (VF)
deterioration and structural changes in the nerve fiber layer. Scanning laser polarimetry (GDx)
shows that visual field changes correspond to a higher rate of change in the retinal nerve fiber
layer (RNFL). While non-progressors (as defined by visual field) have a loss of average RNFL
thickness of –0.34 µm, those with progressive VF loss also lose –1.24µm per year (or about 2
percent) of RNFL thickness, a statistically significant difference.6
The primary risk factor for glaucoma is high IOP, and it turns out that patients who have higher IOPs also have higher rates of RNFL thickness loss. At the highest levels of IOP, the RNFL loss can be as much as 10 percent per year (see Figure 2).6
Optic Disc Hemorrhages
Optic disc hemorrhages are another important risk factor for disease progression. In a recent study of 510 eyes of 348 patients with glaucoma who were followed for 8 years, 19 percent developed at least one episode of disc hemorrhage during the study.7 The rate of VF loss following optic disc hemorrhages was, again, quite variable, with some patients progressing very rapidly, despite a less worrisome mean rate. One patient who was being followed in this study was progressing at a rate of –0.8 percent visual field loss per year. After the disc hemorrhage, that patient had a substantial acceleration in the rate of change to –4 percent per year. At that rate, she would lose 40 percent of the visual field over 10 years.
Considering Functional Impairment
The disease severity of glaucoma ranges from asymptomatic normal vision in the early stages to blindness at the end stage of the disease. But long before reaching blindness, there is a “disability zone” of functional impairment, where the patient has a higher chance of falling, losing the ability to drive or not being able to read. At its most fundamental, the goal of glaucoma treatment is to prevent the patient from going into this disability zone before death.
From that perspective, life expectancy must be factored into our risk calculations. A younger patient or one with rapid progression may well cross over into functional disability while an elderly patient with severe disease may not (see Figure 3). Life expectancy calculators that take into account age, other diseases, diet, family history and other factors are available.
In conclusion, risk assessment tools have improved over time, and these can certainly help clinicians identify the patients who are at higher risk for progression. However, given the large amount of inter-subject variability, it is important to monitor the actual rate of progression of individual patients, using both structural and functional tests. Most importantly, perhaps, clinicians should take into account life expectancy along with rate of progression. Our standards for intervention must be different in those patients whose rate of progression is rapid or has increased significantly during the course of follow up, particularly if the patient is likely to experience significant decline of visual function during his lifetime.
- Gordon MO, Beiser JA, Brandt JD, et al, for the Ocular Hypertension Treatment Study Group. The Ouclar Hypertension Treatment Study: baseline factors that predict the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120:714-20.
- Medeiros FA, Weinreb RN, Sample PA, et al. Validation of a predictive model to estimate the risk of conversion from ocular hypertension to glaucoma. Arch Ophthalmol. 2005;123:1351-60.
- Medeiros FA, Alencar LM, Zangwill LM, et al. Prediction of functional loss in glaucoma from progressive optic disc damage. Arch Ophthalmol. 2009;127(10):1250-6.
- Leske MC, Heijl A, Hyman L, et al, and the EMGT Group. Predictors of long-term progression in the Early Manifest Glaucoma Trial. Ophthalmol. 2007;114(11):1965-72.
- Heijl A, Bengtsson B, Hyman L, Leske MC, for the EMGT Group. Natural history of open-angle glaucoma. Ophthalmology. 2009;116(12):2271-6.
- Medeiros FA, Zangwill LM, Alencar LM, et al. Rates of progressive retinal nerve fiber layer loss in glaucoma measured by scanning laser polarimetry. Am J Ophthalmol. 2010;149:908-15.
- Medeiros FA, Alencar LM, Sample PA, et al. The relationship between intraocular pressure reduction and rates of progressive visual field loss in eyes with optic disc hemorrhage. Ophthalmol. 2010;117:2061-6.
The Healthy Retinal Ganglion Cell
Understanding the biology of glaucoma helps researchers find clues to treating the disease.
by Andrew Huberman, PhD
The goal of my laboratory is to develop tools to label and visualize retinal ganglion cells, and to parse out the molecular and cellular mechanisms of ganglion cell function, both in healthy and diseased retinas.
We are very fortunate to now have ways to light up different cells in the nervous system using a genetic marker called green fluorescent protein (GFP). As I will discuss here in more detail, this wonderful gift from jellyfish can be expressed in mouse or primate retinal ganglion cells, which allows us to illuminate all the processes of that cell in the eye and brain (see Figure 1).
To understand a pathological process like the retinal ganglion cell (RGC) death associated with glaucoma, we first to have a solid grasp on the anatomy of a healthy, normal ganglion cell and the process by which this normal cell signals visual information to the brain. Then, we can compare the anatomy, physiology and genetic signatures of healthy and sick RGCs. Finally, we can turn our attention to ways to remedy deficiencies in that genomic signature in a sick ganglion cell.
In our laboratory, there are some essential questions we would like to answer: Which portions of the RGC are most vulnerable in glaucoma? Are some types RGCs more susceptible or resilient than others?
Most of our work in trying to answer these questions has been done in mouse models, because that is where the genetic tools are available to perform extensive testing and screening.
The more we learn about the mouse visual system and ganglion cells in particular, the more it astonishes me how similar it is to the primate and human visual system. However, we don’t know for certain that the RGC architecture and connectivity in a mouse is representative of the architecture in humans or that we can induce and repair similar types of damage to the glaucomatous damage in a human eye. Despite these potential problems, I believe there is a very high likelihood that discoveries in mice can be confirmed in primates and translated to the clinic in the future.
Retinal ganglion cells are actually a diverse population of neurons that include about 20 different types or what some people call ‘subtypes’. Mice have approximately the same number of subtypes (20) and connectivity parameters as have been observed in primate and human retinas. Not only does each RGC subtype look different from the next, but they also behave differently in terms of the kinds of visual information they signal to the brain. Despite what you might have heard, it is not the case that most of these subtypes project to arcane places in the visual system and that only a few of them project to regions of the brain that contribute to conscious visual processing or ‘sight’. In fact, virtually all RGCs project to the lateral geniculate nucleus—the principal relay for visual information reaching the cortex. This is true in mice and in primates.
Incredibly, there is still not a clear understanding of how exactly a ganglion cell dies in glaucoma. We don’t know, for example, whether the axon dies before the cell body or whether the dendrites die first or whether the entire cell dies in concert. Perhaps there is some sequence of events that would enable us to target a particular step in the sequence to prevent cell death.
In an endeavor to figure out which portions of the ganglion cell are most vulnerable (and why) we have screened many different mouse lines, each of which has a different constellation of cells expressing the glowing green fluorescent protein.
When GFP expression is controlled by a specific gene promoter, it provides a way of viewing a particular ganglion cell population and only that population (see Figure 2). That in turn allows a much more in-depth understanding than one could get with any conventional dye labeling. For instance, one way that RGCs are characterized is by their dendritic morphology, or the shape of their arbor that captures synaptic input. If I see a large cell body with a large, relatively sparse dendritic arbor in the “off” layer of the inner retina, I would suspect that it’s an off-cell. We can then target those specific off-cells, something that is impossible without a genetic marker, to determine their physiological signature and other properties.
The very diversity of RGCs, however, makes them challenging to study. If one cell has a dendritic arbor that is half the size of another cell’s dendritic arbor, it is hard to know whether the first cell is sick or simply a different kind of healthy cell. Following the expression of certain genes with GFP allows us to better characterize each type of cell and the range of normal for that subtype so that we can better detect small changes.
And once we have a genetic marker in a particular cell type, we can also assay the complete connectivity of that cell type with the brain. The connectivity of RGCs with the brain is remarkably specific. For the first time, we can appreciate how entire populations of one RGC subtype send their axons to particular targets and portions of those targets (see Figure 3). What this means is that each individual RGC subtype has highly specific circuitry. As that circuitry becomes better known for each cell type, we should be well positioned to detect very subtle changes in wiring specificity and physiology, as well as the consequences of those changes upon visual perception.
Much of this very comprehensive analysis of ganglion cell circuitry has been done in the mouse retina. We are searching for genetic markers of this sort in the primate retina that can be better applied to human retinas, and have now identified markers for 15 of about 20 different ganglion cell subtypes.
The goal of many biologists working on glaucoma is not just to slow the progression of glaucoma (although that would certainly be beneficial), but to actually regenerate RGCs with a functional connection to the brain. The problem with RGCs, of course, is that as CNS neurons, they do not regenerate the way cells in the peripheral nervous system do. One of the exciting things we have learned in the long process of screening genes in the mouse retina is that the regenerative capacity of different ganglion cells is likely to vary widely.
So as we move toward developing therapeutics based on genomic analysis, we need to be able to identify ways to enhance RGC survival and regeneration. Zhigang He at Children’s Hospital Harvard recently has done some very interesting work to enhance RGC regeneration. That work also points to the idea that some RGCs are better able to regenerate.1
Zhigang He and his colleagues found that a molecule that augments the mammalian target of rapamycin (mTOR) pathway causes an incredible and sustained regeneration of a subset of RGCs. In fact, Dr. He’s group showed this approach causes unprecedented levels of regeneration for mammalian CNS neurons.1 They also discovered that a subset of cells in the retina that have high baseline levels of mTOR regenerate better than other RGCs when given the proper stimulus. We’d love to harness this knowledge and eventually apply it toward treatments in humans.
One question that arises is whether regenerated RGCs can make functional connections with the appropriate targets in the brain to sustain vision. In the next few years, that will be a critical issue to resolve. We have to go back to our role as developmental neurobiologists and ask how the RGCs wire up with the lateral geniculate nucleus in the first place.
During development, ganglion cells manage to traverse out of the eye, down the nerve, and through the chiasm to find their very specific targets. We know there is a category of genes and proteins (e.g., cadherins) that allows RGCs to find and adhere to the appropriate targets in the brain. Making sure these cadherins and other proteins function with the new RGCs is critical if the regenerated neurons are to sustain vision.
Again, much of the work on this is being done in mice. The mouse model allows very high- throughput ways to look at how changes in ganglion cell number or health or connectivity relate to vision, hopefully positioning us to address whether or not particular therapeutics in animal models would be useful to push forward toward primate and eventually human models.
Mice, of course, can’t report back to us on what they see, the way your patients can say “yes” or “no, I did not see anything,” so we have to use a motor response to understand what they saw, if anything. We put the mice into operant chambers with a center trigger port and two adjacent ports are reward ports. When the mouse is thirsty, it pokes the middle port with its nose, causing two stimuli (in this case, one vertical, one horizontal) to pop up on an adjacent screen. To get a “reward” of a drop of water the mouse has to go toward the port on whichever side of the screen is displaying the vertical stimulus. This is essentially a two-forced choice discrimination task.
We can do this in healthy mice, mice with glaucoma, and mice where we think we’ve regenerated connections and see how each group of mice “reports” back to us what they saw.
Using this model, we can obtain psychometric functions about orientation, discrimination, or spatial frequency. Of course, there are limitations to the mouse model in terms of human comparisons. For one, the spatial frequency of mouse vision is very low compared to human visual acuity at the fovea—in fact, it is more similar to human peripheral vision.
The real power of these mouse psychophysics tests, in my opinion, is to be able to combine them with imaging approaches that visualize RGCs in the intact animal. We could then actually correlate the health and structure of an individual type of ganglion cell during the progression of the disease and see how that affects acuity in a quantitative way.
There is much work yet to be done, but this is a very exciting time for ganglion cell biology. As we move toward identifying biomarkers for primate and human retinal ganglion cells, I am optimistic that scientists can answer some of the critical questions that remain about glaucoma in humans in ways that will translate into vastly improved clinical outcomes.
- Park KK, Liu K, Hu Y, et al. Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway. Science. 2008 Nov 7;322(5903):963-6.
SOURCES OF OPTIC NERVE DAMAGE
Role of Ocular Perfusion Pressure
Low perfusion pressure associated with glaucoma progression points to clinical strategies to
reduce the impact of nighttime dips in blood pressure.
by Nils Loewen, MD, PhD
We must consider factors other than intraocular pressure if we are to gain a better understanding of glaucoma. One factor that may play a role in the development and/or progression of glaucoma is ocular perfusion pressure. Some may think perfusion pressure an odd factor to consider. After all, glaucoma is not generally thought of as an ischemic disease, and there is no direct evidence from randomized control trials that improving perfusion reduces the chance of progression.
There is only a weak epidemiological correlation between higher systemic blood pressure and higher intraocular pressure (IOP) that makes it not very likely that there is a direct causative link of blood pressure and high IOP in glaucoma.
In contrast, there is better evidence for a relationship between ocular perfusion pressure (OPP) and glaucoma. OPP is arterial blood pressure (aBP) minus IOP, with IOP serving as a surrogate for ocular venous pressure that counteracts perfusion in the perfusion formula. Low mean perfusion pressure is associated with a 2.6 times increased risk for primary open angle glaucoma (POAG).1 Low diastolic perfusion pressure increases POAG risk by 14-fold.2 And low systolic ocular perfusion pressure is associated with 1.5 times increased rate of progression.3
Perfusion pressure is well autoregulated. In healthy individuals, the ocular tissues are able to regulate blood flow locally, compensating for sudden increases or decreases in blood pressure or IOP to maintain a relatively constant perfusion pressure. In glaucomatous eyes, for some reason, autoregulation breaks down.
Uncontrolled or poorly controlled IOP will reduce perfusion pressure by the above formula. Low OPP may also be related to excessive nocturnal dips in blood pressure. We know that IOP typically increases at night, just when blood pressure naturally dips to about 15 percent below normal daytime blood pressure which may further decrease perfusion. Some individuals may experience excessive “dipping,” which is a further 10 percent decrease below the normal nocturnal blood pressure low.4 Dipping itself has been associated with progression in glaucoma.5-7
Dipping may overwhelm normal autoregulation, producing temporary ischemia. Ischemia alone is not necessarily doing the damage. Rather, it is likely that re-perfusion produces free radicals when the ischemia normalizes, which in return causes glutamate accumulation and excitotoxicity.8 This response is more consistent with neuronal toxicity than true ischemic damage, which might explain why it results in a pattern of glaucomatous change rather than the pale optic nerve that is typical for ocular ischemic diseases.
Certain medication classes, such as beta-blockers and calcium channel blockers, contribute to low perfusion pressure by decreasing blood pressure. We can help patients avoid dipping by dosing topical beta blockers only in the morning and working with their primary care physicians to reduce bedtime dosing of systemic beta-blockers and calcium channel blockers. This is particularly important in patients who are progressing despite aggressive IOP management. It may also be advisable to obtain nocturnal blood pressure measurements in patients one suspects of dipping.
Personally, I do not think there is a role for management of microperfusion. Although the idea that vasospasm might impair perfusion was fashionable for some time, trying to counteract it has not been proven to work in treatment. Rather the opposite may happen as we know from other specialties, such as neurology and cardiology, as e.g. vasodilators may induce steal syndrome. That is, healthy vessels dilate, essentially “stealing” perfusion from the diseased vessels, leaving them even less perfused than before. Microcapillaries in the eye have no or very limited ability to dilate anyway.
Posterior displacement of the laminar cribrosa and the resulting dis-insertion from the sclera likely impairs perfusion. It is easy to imagine how a significant posterior lamina cribrosa shift could disrupt perfusion along the optic nerve head. A physical stretch and rupture of capillaries as the lamina cribrosa moves back could explain why we see disc hemorrhages and visual field progression in these areas.
Our low pressure glaucoma research group is studying sleep position as a possible factor in perfusion. Low pressure glaucoma has been associated with significantly higher rates of visual field asymmetry that also correlates with asymmetric sleep behavior.9,10 In some patients, sleep position may induce a laminar displacement that causes circumscribed breakdown of perfusion.
In an ongoing study, we have equipped 28 lateral-sleeping glaucoma patients with sleep position monitors. So far we have found that the worse eye—the one that is progressing more rapidly—is not on the side on which the patient sleeps. That seems counterintuitive if one simply considers external pressure on the eye (e.g., by the pillow), but the superiorly positioned eye may have lower OPP contributing to more progression. This research is still in the early stages, but suggests promising insights for the future.
To improve ocular perfusion it is, above all, necessary to aggressively lower IOP. While increasing blood pressure might be helpful, such a course of action is not realistic or responsible given the systemic risks of high blood pressure. There is a correlation between low OPP and glaucoma progression but, as with IOP and central corneal thickness, an association does not necessarily imply causality.
Clinical Pearls for Improving Perfusion
- Leske MC, Wu SY, Hennis A, et al; BESs Study Group. Risk factors for incident open-angle glaucoma: the Barbados Eye Studies. Ophthalmology 2008;115(1):85-93.
- Bonomi L, Marchini G, Marraffa M, et al. Vascular risk factors for primary open angle glaucoma: the Egna-Neumarkt Study. Ophthalmology 2000;107(7):1287-93.
- Leske MC, Heijl A, Hyman L, et al; EMGT Group. Predictors of long-term progression in the early manifest glaucoma trial. Ophthalmology 2007;114(11):1965-72.
- Birkenhäger AM, van den Meiracker AH. Causes and consequences of a non-dipping blood pressure profile. Neth J Med 2007;65(4):127-31.
- Kaiser HJ, Flammer J, Graf T, Stümpfig D. Systemic blood pressure in glaucoma patients. Graefes Arch Clin Exp Ophthalmol 1993;231(12):677-80.
- Collignon N, Dewe W, Guillaume S, Collignon-Brach J. Ambulatory blood pressure monitoring in glaucoma patients. The nocturnal systolic dip and its relationship with disease progression. Int Ophthalmol 1998;22(1):19-25.
- Tokunaga T, Kashiwagi K, Tsumura T, et al. Association between nocturnal blood pressure reduction and progression of visual field defect in patients with primary open-angle glaucoma or normal-tension glaucoma. Jpn J Ophthalmol 2004;48(4):380-5.
- Flammer J, Orgül S, Costa VP, et al. The impact of ocular blood flow in glaucoma. Prog Retin Eye Res 2002;21(4):359-93.
- Thomas S, Hamill CE, Marcus IZ, et al. Visual field asymmetry and sleep position in low pressure glaucoma. Poster presentation, 2011 Association for Research and Vision in Ophthalmology (ARVO), Ft. Lauderdale, Fla.
- Thomas S, Hamill CE, Marcus IZ, Loewen NA. Primary open angle glaucoma asymmetry and sleep position. Poster presentation, 2011 American Academy of Ophthalmology, Orlando, Fla.
Role of Intracranial Pressure
A better understanding of translaminar pressure differences and pressure gradients may
elucidate glaucoma pathogenesis.
by Arthur J. Sit, SM, MD
Elevated intraocular pressure (IOP) is the greatest risk factor for glaucoma, but IOP alone is not sufficient to explain glaucoma pathogenesis. It is possible that intracranial pressure (ICP) may play some role.
The optic nerve is subject to a variety of forces, as described by Morgan and colleagues (see Figure 1).1 There is IOP from the anterior side of the optic nerve head; retrolaminar tissue pressure (RLTP) within the optic nerve, just behind the laminar cribrosa; orbital pressure from the sides; and finally, there is the fluid pressure of the optic nerve subarachnoid space (ONSAS) surrounding the optic nerve. The ONSAS is filled with cerebral spinal fluid (CSF), and is in communication with the intracranial cerebral spinal fluid, so presumably the ONSAS pressure is in some way related to ICP.
Given that the most obvious changes in glaucoma occur in the laminar cribrosa, we would ideally like to know what is happening to the RLTP. However, RLTP is obviously quite difficult to measure in humans—or in animals, for that matter.
However, research in dogs has correlated the RLTP with CSF pressure in the ventricles. That is, above a CSF pressure of 2.0 mmHg, RLTP is virtually identical to the CSF ventricular pressure.2 Below 2.0 mmHg, the tissue pressure is approximately constant, perhaps reflecting the orbital tissue pressing against the nerve when the CSF pressure drops very low.
This research is very useful because it allows us to simplify our analysis of the pressures that act on the laminar cribrosa. The translaminar pressure difference can simply be described as IOP minus ICP. In normal eyes, assuming an IOP of 16 mmHg and an ICP of 12 mmHg, the translaminar pressure difference is about 4 mmHg. This can be refined by taking into account the thickness of the laminar cribrosa to determine the pressure gradient. Normal eyes have a laminar cribrosa thickness of about 450 µm, for a pressure gradient of approximately 10 mmHg/mm. As the laminar cribrosa gets thinner, the translaminar pressure gradient increases.
Mechanisms of Damage
There are two potential mechanisms for glaucomatous damage related to translaminar pressure differences and gradients. The most direct mechanism would be deformation of the laminar cribrosa. In monkeys, acute elevation of intraocular pressure leads to posterior bowing of the optic nerve head (ONH), axial thinning and radial expansion of the posterior scleral portion of the neural canal, and laminar thinning, which increases the translaminar pressure gradient.3 Anterior or posterior deformation of the anterior laminar cribrosa surface may also occur.
In combination, these changes exert direct compression, expansion, and shear forces, which act on the axons, the astrocytes and the laminar and posterior ciliary blood supply to the optic nerve. Any of these forces could potentially contribute to glaucoma pathogenesis.
The second potential mechanism of action for ICP in glaucoma is that pressure forces may impair axonal transport. Normally, CSF pressure is lower than IOP, and retrograde transport from the lateral geniculate nucleus to the retinal ganglion cell bodies must cross a pressure barrier. However, an increase in IOP, a decrease in ICP, or a decrease in the laminar cribrosa thickness may increase the pressure barrier against which transport needs to occur (see Table 1).
Table 1: Potential mechanism for impairment of axonal transport. With acute changes in the IOP, ICP and/or laminar thickness, there can be a greater than four-fold increase in the pressure difference and pressure gradient compared with normal eyes.
These changes could cause a significant increase (more than four-fold, in the example in Table 1) in the pressure difference and pressure gradient compared to normal eyes. In theory, this would be sufficient to impair axonal transport, at least in the peripheral nerves, and presumably would have similar effects on central nervous system axons.4
The first clinical evidence that this might play a role in humans was described in a case- controlled study at the Mayo Clinic from Berdahl and colleagues involving 31,786 patients who underwent lumbar puncture over a 10-year period. Of that group, researchers were retrospectively able to identify 28 patients who had been diagnosed by glaucoma specialists as having characteristic optic nerve changes and visual field loss consistent with primary open- angle glaucoma (POAG).5 They also identified a control group of 49 subjects who had been seen by an ophthalmologist within a year of having a lumbar puncture, had documented cup/disc ratios, and no history of glaucoma, elevated IOP or optic nerve abnormality.
CSF pressure in the controls (13.0 ±4.2 mmHg) was significantly higher than in the POAG group (9.2 ±2.9 mmHg). Not surprisingly, IOP in the control group was lower than in the POAG group (16.4 ±2.8 mmHg vs. 24.3 ±6.1 mmHg).5 A subsequent study also included normal-tension glaucoma (NTG) and ocular hypertension (OHT) patients.6 There was a much larger translaminar pressure difference in the POAG patients than in the NTG patients who, in turn, had a higher translaminar pressure difference than in the controls. The OHT group also had a greater translaminar pressure difference than controls, whether one looked at the maximum IOP or the IOP closest to the date of the lumbar puncture.
More recently, Ren and colleagues prospectively compared CSF pressures in a cohort of patients with open-angle glaucoma to those of a control group slated for lumbar puncture for other reasons.7 Within the POAG group, patients were divided into normal-tension glaucoma (IOP ≤ 21 mmHg) and high pressure glaucoma (>21 mmHg). The results were very similar to those in the retrospective studies, with the control group having the highest CSF pressure and the smallest translaminar pressure difference (see Table 2).7
|Table 2: Translaminar pressure differences between controls and patients with primary open- angle glaucoma. Ren R, Jonas JB, Tian G, et al. Ophthalmology 2010;117:259–66.|
To answer the central question of whether patients with high translaminar cribrosa pressure barriers are more likely to develop glaucoma, we need longitudinal data in addition to the prospective, cross-sectional data available thus far. There are also a number of other issues that need to be explored in this emerging field. For example, what are the normal circadian variations in ICP? What effect does body position (e.g. supine vs. standing erect) have on ICP? As we move forward in trying to understand the role of ICP and glaucoma pathogenesis, is it possible to imagine a role for intracranial hypertensive agents?
Ultimately, ICP may serve primarily as an additional risk factor. Particularly in that subset of patients who continue to get worse despite significant IOP lowering, lumbar puncture to measure CSF pressure may provide another way to analyze risk. There are some patients who have abnormally low CSF pressures, related to CSF leaks in the skull base or other factors. Whether those patients are more susceptible to glaucoma is being investigated. If they are, treatment could safely raise the intracranial pressure. It is much less likely that clinicians would attempt to raise intracranial pressure in someone with normal ICP.
In conclusion, there is a clear theoretical basis for the importance of translaminar cribrosa pressure gradients in glaucoma. Early clinical evidence does suggest a relationship between intracranial or cerebrospinal fluid pressure and glaucoma, but further investigation is needed to understand the exact role of intracranial pressure, its diagnostic or therapeutic value in glaucoma, and the implications for clinical practice.
- Morgan WH, Yu DY, Balaratnasingam C. The role of cerebrospinal fluid pressure in glaucoma pathophysiology: the dark side of the optic disc. J Glaucoma 2008;17:408-13.
- Morgan WH, Yu DY, Alder VA, et al. The correlation between cerebrospinal fluid pressure and retrolaminar tissue pressure. Invest Ophthalmol Vis Sci 1998; 39:1419-28.
- Yang H, Downs JC, Sigal IA, et al. Deformation of the normal monkey optic nerve head connective tissue after acute IOP elevation within 3-D histomorphometric reconstructions. Invest Ophthalmol Vis Sci 2009;50(12):5785-99.
- Hahnenberger RW. Inhibition of fast anterograde axoplasmic transport by a pressure barrier. The effect of pressure gradient and maximal pressure. Acta Physiol Scand 1980;109(2):117-21.
- Berdahl JP, Allingham P, Johnson DH. Cerebrospinal fluid pressure is decreased in primary open-angle glaucoma. Ophthalmol 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(12):5412-8.
- Ren R, Jonas JB, Tian G, et al. Cerebrospinal fluid pressure in glaucoma. Ophthalmol 2010;117:259-66.
MANAGEMENT IN CLINICAL PRACTICE
Current and Future Approaches to Glaucoma Surgery
As new procedures become available, surgeons are moving away from trabeculectomy blebs and
toward less invasive procedures and future gene therapies.
by Nils Loewen, MD, PhD
Glaucoma surgery has evolved considerably in the past 10 years. In fact, there are so many new options that it can at times be challenging to determine which approach will best serve our patients. Ideally, glaucoma surgery should be fast, minimally invasive, and standardized, with predictable, long-lasting results and an uncomplicated postoperative course that doesn’t require additional procedures.
The surgical procedure that best meets this “ideal” definition for our glaucoma patients at present is actually cataract surgery. I find that eyes that have damaged outflow systems also tend to have prematurely aging crystalline lenses, so it is not difficult to reach a “medically necessary” threshold of 20/50 glare vision most glaucoma patients.
My current glaucoma treatment algorithm is fairly simple. I almost always start with selective laser trabeculoplasty (SLT) and will then advance by using medical therapy with prostaglandin analogs and carbonic anhydrase inhibitors for 24-hour pressure control. I will occasionally use brimonidine, which may have advantages in low-pressure glaucoma as reported by the Low Pressure Glaucoma Study Group. If surgery is indicated, either because IOP cannot be controlled or there is still progression, I perform cataract extraction with ab interno trabeculectomy with the Trabectome (Neomedix). I use trabeculectomy or Ahmed valve shunts (with mitomycin C and postoperative 5FU) as last-resort procedures for advanced glaucoma.
Considering all the Options
Classic surgical approaches for moderate to advanced glaucoma include laser trabeculoplasty, trabeculectomy, tube shunts and transscleral cyclophotocoagulation (CPC), but I think the field is gradually moving away from these more invasive or destructive procedures.
The challenge with all newer procedures is a lack of high quality scientific evidence. This makes it difficult to know which devices are worth investing one’s time and financial resources into— and which procedures will truly produce better results with fewer complications.
The procedure that has found a central place in my treatment algorithm is ab interno trabeculectomy with the Trabectome. The Trabectome handpiece is a single-use disposable device that incorporates bipolar electro-surgical pulse with simultaneous irrigation and aspiration to ablate a portion of the trabecular meshwork to unroof Schlemm’s canal (see Figure 1). When combined with cataract extraction (probably always advisable in order to maximally deepen the angle) this procedure fulfills the criteria for an “ideal surgery” as it is minimally invasive, vision- improving, fast and lasting.1 Published results are as good as those with a tube shunt or trabeculectomy, albeit in the hands of a single surgeon.2,3
Another new option is a trabecular bypass with the iStent (Glaukos). The iStent is a snorkel-like titanium micro-bypass implant for which a relatively small effect, comparable to that of cataract extraction alone, has been demonstrated.4 It is not yet approved in the United States, but is available in Canada and some European countries.
Canaloplasty (iScience Interventional), in the hands of surgeons who perform it often, has been reported to produce IOP control similar to that of trabeculectomy, with fewer complications.5 However, it is a lengthy procedure that is technically quite challenging.
According to informal polls at the recent meeting of the American Glaucoma Society, many
surgeons are performing trabeculectomy with the Ex-PRESS Glaucoma Filtration Device
(Alcon). This stainless steel shunt is purported to reduce the incidence of hypotony and choroidal
effusions. In the only randomized, controlled trial that has been published, it performed slightly
better than a simple trabeculectomy.6 I have some concerns about the long-term safety of such
shunts, which are made of metal and can be surprisingly mobile.
Endoscopic CPC (EndoOptiks) has been recommended as a good option in refractory glaucoma with poor corneal clarity.7 Transciliary filtration with a Fugo blade (MediSurg Ltd) also seems to have worked well in one very limited study.8
With any new procedure, the surgeon is unlikely to see superior results until he or she has learned the fine nuances of the procedure. Before acquiring and investing the time to learn to use the new technology, one must also consider the practice management aspects such as reimbursement (which can vary greatly from hospital to ASC setting), surgical time, postoperative management, device cost, and marketing advantages.
Remember the Goldman equation: IOP = F / C + Pv – U. That is, IOP is equal to the aqueous humor formation/facility, plus episcleral venous pressure, minus uveoscleral outflow. Our real problem in glaucoma is a genetic one—the outflow system is simply not equipped to last for the modern human life span. What is failing, both with normal aging and from glaucomatous damage, is the outflow through the trabecular meshwork and uveoscleral route. In the future, I anticipate that we’ll have new devices as well as biological solutions that address the underlying outflow problem more directly.
For example, we will be performing more deeply penetrating trabeculoplasty procedures for trabecular outflow enhancement with new lasers such as the titanium sapphire laser (SOLX). Mechanical trabecular meshwork ablation may be performed with present devices (Trabectome) and with newer ones such as the AquaLase (Alcon). This device, as many may remember, was relatively ineffective for cataract surgery, the application for which it was initially conceived. But when directed toward the trabecular meshwork, hydro-ablation may strip the trabecular meshwork of cellular resistance.
The suprachoroidal/uveoscleral outflow can also be enhanced using new devices and biological solutions. There are many suprachoroidal shunt devices in the pipeline, including one that we have tested, the GMS Plus Gold Shunt (SOLX, see Figure 2). It is surprisingly straightforward to implant. Using an inserter, the procedure is somewhat similar to implantation of an intraocular lens through a scleral tunnel, although it can be challenging for those who haven’t worked in the suprachoroidal space. International data suggest significant IOP lowering to 15 to 18 mmHg at 12 months in cases of refractory glaucoma. Hopefully, such devices will prove to provide better pressure reduction compared to earlier, more flow-restricted devices.
Vector tissue engineering may also be useful. For more than a decade, my colleagues and I at the Mayo Clinic have been working on gene therapy to specifically target the trabecular meshwork using lentiviral and other vectors.9-11 Genetically modifying the outflow tract does work in vivo. In 2008, we demonstrated the first lentiviral vector transduction of the non-human primate aqueous humor outflow pathway, supporting application of the system to humans.12 Biological trabecular ablation tract using cytoablative gene therapy vectors and stem cell engineering of the outflow tract are other modalities with potential that I am now pursuing at Yale University.
Most recently, my colleagues published the first report of gene therapy for uveoscleral flow enhancement.13 A lentiviral vector that mimics the prostaglandin pathway was injected into the left eyes of three cats. At 150 days following a single intracameral injection, a very solid pressure reduction was achieved. Much more work remains to be done to make gene therapy a reality, but it is a very promising area of research.
To summarize, I believe that we have found in the ab interno trabeculectomy with the Trabectome a first ideal surgical procedure that is minimally invasive, fast and long-lasting, but the quest for other such procedure continues. While there are a number of promising new options in glaucoma surgery, we have limited data on all of them, so surgeons must choose the procedure that works best in their hands and within their surgical environment and patient base. In the future, I believe some of these new devices, gene therapy approaches and biologicals that allow tissue engineering will allow us to have entirely bleb-free glaucoma surgery, without external drainage devices.
- Vold SD, Ab interno trabeculotomy with the trabectome system: what does the data tell us? Int Ophthalmol Clin. 2011;51(3):65-81.
- Francis BA, Winarko J. Combined trabectome and cataract surgery versus combined trabeculectomy and cataract surgery in open-angle glaucoma. Clin Surg Ophthalmol. 2011;29:2/3.
- Gedde SJ, Schiffman JC, Feuer WJ, et al; Tube Versus Trabeculectomy Study Group. Three-year follow-up of the tube versus trabeculectomy study. Am J Ophthalmol. 2009;148(5):670-84.
- Samuelson TW, Katz LJ, Wells JM, et al; US iStent Study Group. Randomized evaluation of the trabecular micro-bypass stent with phacoemulsification in patients with glaucoma and cataract. Ophthalmology. 2011;118(3):459-67.
- Grieshaber MC, Pienaar A, Olivier J, Stegmann R. Canaloplasty for primary open-angle glaucoma: long- term outcome. Br J Ophthalmol. 2010;94(11):1478-82.
- de Jong LA. The Ex-PRESS glaucoma shunt versus trabeculectomy in open-angle glaucoma: a prospective randomized study. Adv Ther. 2009;26(3):336-45.
Neuroprotection in Low-Pressure Glaucoma
Masked, prospective multi-center study shows significantly reduced rate of progression in eyes
treated with brimonidine vs. timolol.
by Theodore Krupin, MD
Although high intraocular pressure (IOP) is the leading risk factor for open-angle glaucoma (OAG), a substantial percentage of patients with this disease (20 percent to 39 percent) actually have IOP within the statistically normal range of <21 mmHg.1-3 These “low-pressure” or “normal-tension” glaucoma patients provide a means to investigate etiologic factors other than IOP for glaucomatous optic neuropathy.
Fundamentally, glaucoma is a neurodegenerative disease. Once we began to embrace this concept, many glaucoma researchers and clinicians began to focus on potentially neuroprotective strategies, aimed at keeping the retinal ganglion cell viability and preserve functionally connected to their targets in the brain. A neuroprotective strategy emphasizes pressure- independent factors over and above the IOP reduction that is the goal of typical glaucoma management.
Many people had high hopes that memantine, an NMDA receptor blocker, would be effective in optic nerve protection, as it has been in Alzheimer’s disease. Unfortunately, a massive prospective clinical study of the efficacy of memantine did not successfully meet its clinical endpoints.4
A number of laboratory studies have demonstrated that alpha2-adrenergic agonists such as brimonidine are neuroprotective. This has been shown in experimental optic nerve injury and models of glaucoma, ischemia-induced injury, and photoreceptor degeneration but, until recently, not in human clinical trials.5-7
The Low Pressure Glaucoma Treatment Study (LoGTS) was a robust study designed to test the effects of brimonidine compared to timolol in preserving visual function in patients with low- pressure glaucoma. I chaired the LoGTS Study Group, which included 23 investigators at 13 clinical sites around the U.S. The study was supported by grants from Allergan, the Chicago Center for Vision Research and Research to Prevent Blindness. Allergan also provided the study medications. None of the funding organizations played a role in the design, conduct of the study, interpretation of the data, or the preparation, review, or approval of the manuscript.
LoGTS was a four-year, masked, randomized, multi-center trial of monotherapy with brimonidine tartrate 0.2% versus timolol maleate 0.5%, two medications that have been reported to reduce IOP with similar effectiveness.
To be enrolled in the study, patients had to be age 30 or older, have a diagnosis of low-pressure glaucoma, IOP < 21 mmHg, and two or more reproducible visual fields with glaucomatous defects in one or both eyes. Patients were excluded if they had a history of IOP > 21 mmHg, acuity worse than 20/40 in either eye, or any history of incisional surgery, trauma, or ocular inflammatory disease. Patients who could not tolerate a beta–adrenergic antagonist were excluded, as well.
An independent pharmacy maintained the randomization list and provided the centers with medications in new 10-mL white bottles labeled only with the randomization number. This unique feature was very important in maintaining masking during the trial.
Discontinuation was required if the patient had IOP >21 mmHg that was repeated within one month. Only one patient was discontinued for this reason during the entire study. Symptomatic ocular allergic adverse events or safety concerns as judged by the physician were also grounds for discontinuation.
Subjects enrolled in the study underwent a four-week washout of IOP-lowering medications. Prior to randomization, the untreated (post-washout) baseline had to be <21 mmHg with < 5 mmHg difference between eyes on a diurnal curve (8:00 am, 10:00 am, 12:00 pm and 4:00 pm).
Visual field outcomes were measured at a single center, the Devers Eye Institute (see Table 1). The primary outcome was Progressor software with a significant negative slope at the same three or more test locations (not contiguous) that were confirmed on the next two examinations. Month 16 was the earliest that progression could be confirmed.
A secondary outcome was Humphrey glaucoma change probability maps based on pattern deviation. Again, change had to be seen at three or more noncontiguous test locations and confirmed on the next two examinations.
We also did a post-hoc analysis on the three-omitting method for point-wise linear regression. Progression was confirmed at two further visits when omitting from the series a field that caused progression to be suspected.
Recruitment started in April, 1999 and ended in June, 2000. Because of the known rate of allergy to brimonidine, three patients were assigned to timolol for every four assigned to brimonidine. Out of 190 patients randomized to treatment, 12 were withdrawn. Results were evaluated for the remaining 178 patients, with 99 in the brimonidine group and 79 in the timolol group.
Baseline demographics, ocular parameters, and systemic factors were the same in the two treatment groups.8 More subjects in the brimonidine group dropped out prior to year one, mainly due to allergy (20 cases in the brimonidine vs. three in the timolol group).
Study visits included full threshold Humphrey 24-2 visual fields at four-month intervals. Blood pressure, IOP, pulse rate, visual acuity, cup/disc ratio and the presence of disc hemorrhage were recorded at each examination. Mean overall follow-up was 30 months and for patients who completed year one (n=134), it was 35.6 months.
The progressor endpoint was reached in significantly fewer brimonidine (n=9, 10±4 percent) than timolol (n=31, 33±6 percent) patients (p<.001).9 In fact, more timolol patients vs. brimonidine patients progressed on each of the three outcome measures. Kappa analyses showed that five brimonidine vs. 18 timolol patients progressed by all three methods. There was good endpoint agreement between progressor and glaucoma change probability change maps and also between the progressor and the three-omitting method.
Patients in both arms of the study achieved similar IOP lowering of about 14 percent, and the rate of progression on timolol (31.0 percent at 3 years, 45.7 percent at 4 years) was similar to what has been reported in the literature for low-pressure glaucoma.10-11 There were no significant between-group differences in IOP when the data were stratified by study completion or time of dropout.
In conclusion, we found a significantly reduced rate of 4-year visual field progression in low- pressure glaucoma patients randomized to treatment with brimonidine vs. timolol.
The effectiveness of brimonidine has to be judged in the context of its adverse event profile, with relatively high rates of localized external ocular allergy. Additional validation of these study results is needed. However, at Northwestern, we are confident enough in the results that we now have all of our low-pressure glaucoma patients on brimonidine.
- Sommer S, Tielsch JM, Katz J. et al. Relationship between intraocular pressure and primary open angle glaucoma among white and black Americans. The Baltimore Eye Survey. Arch Ophthalmol 1991;109(8):1090-5.
- Klein BE, Klein R, Sponsel WE, et al. Prevalence of glaucoma. The Beaver Dam Eye Study. Ophthalmology 1992;99(10):1499-504.
- Heijl A, Leske MC, Bengtsson B, et al. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifeat Glaucoma Trial. Arch Ophthalmol 2002;120(10):1268-79.
- Danesh-Meyer HV. Neuroprotection in glaucoma: recent and future directions. Curr Opin Ophthalmol 2011;22(2):78-86.
- Sena DF, Ramchand K, Lindsley K. Neuroprotection for treatment of glaucoma in adults. Cochrane Database Syst Rev 2010;2:CD006539.
- 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(2):326-31.
- Lee KY, Nakayama M, Aihara M, et al. Brimonidine is neuroprotective against glutamate-induced neurotoxicity, oxidative stress, and hypoxia in purified rat retinal ganglion cells. Mol Vis 2010;16(2):246- 51.
- Krupin T, Liebmann JM, Greenfield DS, et al. The Low-pressure Glaucoma Treatment Study (LoGTS) study design and baseline characteristics of enrolled patients. Ophthalmology 2005;112(3):376-85.
- Krupin T, Liebmann JM, Greenfield DS, et al; 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(4):671-81.
- Werner EB. Normal-tension glaucoma. In: Ritch R, Shields MB, Krupin T, eds. The Glaucomas 2nd ed. St. Louis: Mosby Year Book, Inc; 1996:769-97.
- Noureddin BN, Poinoosawmy D, Fietzke FW, et al. Regression analysis of visual field progression in low tension glaucoma. Br J Ophthalmol 1991;75(8):493-95.