New Insights in the Management of Glaucoma

Supported by an Allergan-funded medical educational grant.

Hardware/Software Requirements:

This site is best viewed using Internet Explorer 7 and higher, or Firefox 3.0 and higher. An Internet connection with a minimum 56Kps modem is suggested. To view graphic images and references that appear in separate “pop-up” windows, you must have Javascript enabled on your computer. If you are having difficulty viewing pop-up windows, please disable Javascript.

Target Audience:

This activity has been designed to meet the educational needs of ophthalmologists with a basic knowledge of glaucoma.

PREREQUISITES:

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.

Learning Objectives:

After completing this educational activity, participants should be better able to:

1. Evaluate new data highlighting the importance of perfusion pressure for development, progression and incidence of glaucoma.
2. Examine the relationship between ocular blood flow, visual function and optic nerve structure.
3. Recognize the growing role of neuroprotection in ophthalmology.
4. Delineate the relationship of medication tolerability and adherence with therapy.
5. Identify the side effects of glaucoma medications.

Faculty/Editorial Board:

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.

Accreditation Statement:

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.

Credit Designation:

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:

1. read the learning objectives and faculty disclosures;
2. study the educational activity
3. 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 krodemich@jobson.com.

Media:

Monograph.

Estimated Time to Complete Activity:

2.0 hour(s)

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.

DISCLAIMER:

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.

TREATMENT OPTIONS

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:

1. efficacy;
2. safety and tolerability;
3. patient compliance and, at least for some patients,
4. 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 cause blurring.

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 bottles possible.⁹

Table 1: Compliance with Glaucoma Medical Therapy
Frequency of Dosing	Compliance with Dosing	Compliance with Timing
q.d. b.i.d. t.i.d. q.i.d.	79% 69% 65% 51%	74% 58% 46% 40%

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 glaucoma.

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 glaucoma.

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 soon.

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 risk factors.

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 reality.

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.

VASCULAR DYSREGULATION

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 outcomes.

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 be significant.

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 oxygen saturation.

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 functioning.

CONCLUSIONS

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.

References

1. 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.
2. Herndon LW, Brunner TM, Rollins JN. The Glaucoma Research Foundation patient survey: Patient understanding of glaucoma and its treatment. Am J Ophthalmol 2006;141(1 Suppl):S22-27.
3. 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.
4. Okeke CO, Quigley HA, Jampel HD, et al. Adherence with topical glaucoma medication monitored electronically: the Travatan Dosing Aid study. Ophthalmology 2009;116(2):191-199.
5. Kass MA, Meltzer DW, Gordon M, et al. Compliance with topical pilocarpine treatment. Am J Ophthalmol 1986;101(5):515-523.
6. Claxton AJ, Cramer J, Pierce C. A systematic review of the associations between dose regimens and medication compliance. Clin Ther 2001;23:1296-1310.
7. Patel SC, Spaeth GL. Compliance in patients prescribed eyedrops for glaucoma. Ophthalmic Surg 1995;26:233-236.
8. 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.
9. Robin AL, Covert D. Does adjunctive glaucoma therapy affect adherence to the initial primary therapy? Ophthalmology 2005;112:863-868.
10. 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- 1972.
11. 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.
12. Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular Hypertension Treatment Study: A randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol 2002;120(6):701-713.
13. 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.
14. 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.
15. Weinreb RN. Glaucoma neuroprotection: What is it? Why is it needed? Can J Ophthalmol 2007;42:396-398.
16. Quigley HA, Nickells RW, Kerrigan LA, et al. Retinal ganglion cell death in experimental glaucoma and after axotomy occurs by apoptosis. Invest Ophthalmol Vis Sci 1995;36(5):774-786.
17. Flammer J, Orgƒl S. Optic nerve blood flow abnormalities in glaucoma. Prog Retin Eye Res 1998;17:267-289.
18. 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.
19. Guo L, Salt TE, Luong V, et al. Targeting amyloid-beta in glaucoma treatment. Proc Natl Acad Sci USA 2007;104(33):13444-9.
20. 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.
21. 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.
22. 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.
23. Tsai JC, Song BJ, Wu L, Forbes M. Erythropoietin: a candidate neuroprotective agent in the treatment of glaucoma. J Glaucoma 2007;16:567-571.
24. 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 Res 2005;30:1025-1031.
25. 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.
26. 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.
27. 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.
28. Wheeler L, WoldeMussie E, Lai R. Role of alpha-2 agonists in neuroprotection. Surv Ophthalmol 2003;48(Suppl):547-551.
29. 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.
30. Kent AR, Nussdorf JD, David R, et al. Vitreous concentration of topically applied brimonidine tartrate 0.2%. Ophthalmology 2001;108:784-787.
31. 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.
32. 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;112:376-385.
33. 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- 26.
34. 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.
35. Ritch R. Natural compounds: Evidence for a protective role in eye disease. Can J Ophthlamol 2007;42(3):425-438.
36. 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.
37. 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.
38. Quigley HA, Nickells RW, Kerrigan LA, et al. Retinal ganglion cell death in experimental glaucoma and after axotomy occurs by apoptosis. Invest Ophthalmol Vis Sci 1995;36:774-786.
39. 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.
40. Guo L, Cordeiro MF. Assessment of neuroprotection of the retina with DARC. Prog Brain Res. 2008;173:437-450.
41. 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.
42. 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.
43. 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.
44. Jonas JB, Xu L. Optic disk hemorrhages in glaucoma. Am J Ophthalmol 1994;118(1):1-8.
45. 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.
46. 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.
47. Cioffi GA, Sullivan P. The effect of chronic ischemia on the primate optic nerve. Eur J Ophthalmol 1999;9 Suppl 1:S34-36.
48. 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- 1525.
49. 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 2005;24(1):39-73.
50. 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.
51. 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- 1826.
52. 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.
53. 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- 7192.
54. Weinreb RN, Harris A. Ocular Blood Flow in Glaucoma: Consensus Series 6. The Netherlands: Kugler Publications; 2009.
55. Verdecchia P, Schillaci G, Porcellati C: Dippers versus nondippers. J Hypertens 1991;9 (suppl):S42-44.
56. 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 Sci 2007;48(1):104-111.
57. 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.
58. 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.
59. 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- 1847.
60. Logan JF, Rankin SJ, Jackson AJ. Retinal blood flow measurements and neuroretinal rim damage in glaucoma. Br J Ophthalmol 2004; 88(8):1049-1054.
61. 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- 472.
62. 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 Ophthalmol 2006;142(1):60-67.
63. 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.
64. Jonas JB. Association of blood pressure status with the optic disk structure. Am J Ophthalmol 2006;142(1):144-145.
65. 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 2006;244(8):978-983.
66. 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.
67. 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.
68. Olafsdottir OB, et al. Abstract presented at European Association of Vision and Eye Research, Abstract, 2009.
69. 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.