Glaucoma Management: Beyond Intraocular Pressure

Supported by an Allergan-Funded Medical Educational Grant.

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Target Audience:

This educational activity is intended for comprehensive ophthalmologists interested in the care and management of patients with glaucoma.

ACTIVITY PURPOSE:

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 that usually considered to be normal (<21 mmHg) for the eye. This form of glaucoma may account for as many as one-third of the cases of OAG in the United States.

The typical treatment of NTG is directed at lowering eye pressure; however, traditional strategies of lowering 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 as been defined as the use of therapeutic agents to prevent, hinder and, in some instances, reverse neuronal cell death whatever the primary injury. Various neuroprotective drug-based approaches have been capable of reducing 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.

Learning Objectives and Desired Result:

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

1. Discuss the diagnosis and management of normal-tension glaucoma
2. Explain the biologic foundation and application of neuroprotection in glaucoma, as well as its value in the treatment of glaucoma
3. Describe the rationale for the use of glaucoma neuroprotection as a pressure-independent therapy
4. Identify the goals and obstacles of neuroprotection in the treatment of normal-tension glaucoma.

DESIRED RESULT/OUTCOME:

Physicians know and apply current strategies in the diagnosis and treatment of patients with normal-tension glaucoma to slow the progression of glaucoma and preserve the patient’s quality of life.

Faculty:

Jeffery L. Goldberg, MD, PhD, is Associate Professor of Ophthalmology at Bascom Palmer Eye Institute in Miami.  He holds secondary appointments to the graduate faculty in Cell Biology and Anatomy, the Program in Neuroscience, and Molecular and Cellular Pharmacology at the University of Miami Miller School of Medicine in Miami.

David S. Greenfield, MD, is Professor of Ophthalmology at the Bascom Palmer Eye Institute at the University of Miami Miller School of Medicine.

Neeru Gupta, MD, PhD, FRCSC, is the Dorothy Pitts Chair and Professor of Ophthalmology & Vision Sciences at the University of Toronto, where she also holds appointments in Laboratory Medicine and Pathobiology. She is Director of the Glaucoma Unit at the Keenan Research Center at the Li Ka Shing Knowledge Institute at St. Michael's Hospital, also at the University of Toronto.

Theodore Krupin, MD, is Professor of Ophthalmology at the Feinberg School of Medicine at Northwestern University in Chicago, Ill.

Tony Realini, MD, MPH, is Associate Professor of Ophthalmology at the West Virginia University Eye Institute in Morgantown, W.Va.

Peter J. Savino, MD, is Clinical Professor in the Department of Ophthalmology & Neurosciences at the Shiley Eye Center at the University of California, San Diego.

Rohit Varma, MD, is Professor of Ophthalmology & Preventive Medicine at the Doheny Eye Institute at the University of Southern California.

Robert N. Weinreb, MD, is Distinguished Professor of Ophthalmology and Director of the Hamilton Glaucoma Center at the University of California, San Diego.

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 STATEMENT:

NRI designates this Enduring Material 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:

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.

PEER REVIEW:

This activity was peer-reviewed for relevance, accuracy of content and balance of presentation by NRI.

DISCLOSURE:

The following individuals have disclosed relevant financial relationships with commercial interests:

Dr. Goldberg— Consultant/advisor: Quark Pharmaceuticals.
Dr. Greenfield—Consultant/advisor: Allergan, Pfizer, Topcon, Optovue, Alcon Laboratories; Lecture fees: Allergan, Pfizer, Alcon; Grant support: National Eye Institute, Allergan, Pfizer, Heidelberg, Carl Zeiss, Topcon, Optovue, Alcon.
Dr. Gupta—Consultant/advisor: Allergan, Merck, Pfizer; Lecture fees: Santen.
Dr. Krupin—Consultant/advisor: Allergan, GlaxoSmithKline; Lecture fees: Allergan; Grant support: Allergan.
Dr. Realini— has no relevant financial relationships.
Dr. Savino—Consultant/advisor: Newran, SpA, Merck-Serano.
Dr. Varma—Consultant/advisor: Alcon, Allergan, Aquesys, Bausch + Lomb, Genentech, Merck, Pfizer, Replenish; Lecture fees: Alcon; Equity owner: Aquesys, Replenish; Grant support: Allergan, Genentech, Optovue, Pfizer.
Dr. Weinreb—Consultant/advisor: Aciex, Alcon, Allergan, Bausch + Lomb, Carl Zeiss Meditec, Galxo, Merck, Mesotec, Novartis, Optovue, Othera, Pfizer, Sensimed, Topcon.  

The following individuals have disclosed that there are no relevant financial relationships with any commercial interests: T. Mark Johnson, NRI, CarolAnn Love, NRI, Jan Beting, Review of Ophthalmology, and Alicia Cairns, Review of Ophthalmology.

Method of Participation:

There are no fees for participating and receiving Continuing Medical Education credit for this activity. During the period of September 2010 and September 30, 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
4. complete the evaluation form

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/Print Supplement and Internet

Evaluation Method:

Post-Test

DISCLOSURE OF UNLABELED 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.

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. 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.

CONTACT INFORMATION:

Any questions/problems with registration, CME certificate, etc., can be directed to krodemich@jobson.com.
Copyright 2010, Review of Ophthalmology. All rights reserved.

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Changing Paradigms in the Understanding of Glaucoma
Robert N. Weinreb, MD

Our methods for detection and management of glaucoma have clearly been evolving in recent decades, guided by the results of randomized clinical trials and the introduction of advanced new diagnostic technology.

Thirty years ago, intraocular pressure (IOP) was the primary measure in both diagnosis and treatment of glaucoma. Many clinicians followed the “Rule of 21,” meaning that treatment commenced 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, the automated perimeter, which had been introduced 10 years earlier, was in widespread use.  Automated perimetry became an essential component of the glaucoma evaluation. Clinical decision-making depended on both IOP measurements and the visual field.

With the widespread dissemination of the results from The Ocular Hypertension Treatment Study (OHTS), many clinicians noted for the first time that detectable structural changes might in fact precede functional visual field loss¹. With the maturation and availability of imaging techniques during the past decade, the structure of the optic disc and retinal nerve fiber layer became a key component for the diagnosis and management of glaucoma.     

Today, many definitions of glaucoma do not even include the term IOP. Elevated IOP is, of course, an important risk factor for the development of glaucomatous optic nerve damage, 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.

We move today toward a paradigm that relies purely on structural and functional tests to diagnose and manage glaucoma. Our aim will be not just lowering IOP, but arresting changes in the optic nerve before there is functional vision loss. There is also a growing realization that glaucoma is not just an eye disease but part of a broader neuro-degenerative process that affects the entire central visual pathway, including the brain stem and the brain.

Here are the components of the new paradigm:

Structure. Progressive optic disc damage is an important risk factor for development of visual field loss.² Function and structure, as measured by retinal nerve fiber layer (RNFL) thickness and the topography of the optic disc, have a curvilinear relationship, meaning that, at least in the early stages of the disease, large structural changes correspond to relatively small changes in function.³ Drawings are insufficient for identifying structural change. Regular, systematic imaging and assessment of the “five Rs” (scleral ring, size of the neuroretinal rim, retinal nerve fiber layer, the region of parapapillary atrophy, and retinal and optic disc hemorrhages) should be an essential component of disease monitoring.⁴ 

Function. The concept that structural damage can precede functional loss is a logical one, but our methods for detecting and measuring structural loss are still limited. Both OHTS and the European Glaucoma Prevention Study showed that many patients still had functional progression without detectable structural progression. Functional measures will continue to be important in following glaucoma.

IOP. We know that lowering intraocular pressure is very important. Large clinical trials designed primarily to determine the effects of IOP have all shown that lowering IOP decreases the rate of disease progression. However, it still is not clear what IOP metrics are the most critical ones. There may be a non-linear relationship between IOP reduction and benefits: at higher levels of IOP, each millimeter of mercury reduction has more importance than in an eye that is already at lower intraocular pressure levels. Certainly, IOP is not the whole story, because we know that many people with elevated IOP never develop glaucoma and many people with glaucoma never have particularly elevated IOP. 

Treatment. As our understanding of and ability to measure and track the progression of glaucoma becomes more sophisticated so, too, will our range of therapeutic interventions. If we can better target those subjects at highest risk for progression of the disease or those who progress most rapidly, we may be able to deploy complementary approaches to IOP lowering. These include glaucoma neuroprotection in the form of medications, lifestyle modification, surgical and injectable interventions, vaccination, optic nerve regeneration and stem cell therapy.

Patient Reported Outcomes for Glaucoma Rohit Varma, MD To the typical measures of glaucoma—IOP, visual field loss, and structural changes—I would add a fourth area: Patient-reported outcomes. While rarely given much consideration, the patient’s daily functioning and perception of the success of treatment is quite relevant to compliance with drop schedules and follow-up visits.  Visual fields are an objective, surrogate measure for subjective functioning. But subjective assessments from the patient may be a valuable addition to monitoring. As glaucoma clinicians, it is important that we know what happens to our patients, not just to their optic nerves. How much change in IOP or visual field corresponds to a change in the ability of the patient to function? Most clinical trials have not addressed this question directly.  In the Los Angeles Latino Eye Study (LALES), we used the National Eye Institute Visual Function Questionnaire (NEI-VFQ-25), a well-validated, 25-item scale, to determine how the degree and location of field loss affected daily functioning.5 With even minimal field loss, we saw a decrement in patient perceptions of their ability to drive, as well as an increase in reported falls. As visual field loss worsened, there was a significant increase in driving difficulty. We found that people with central or para-central field loss were more likely to be negatively affected than people with just peripheral visual field loss. We also found that a 3- to 4-db change in visual field in the better eye is related to a patient perceived significant impact on their ability to function. Using the NEI VFQ routinely can help clinicians assess change in individual functioning over time, which is important in chronic disease management.

Glaucoma is a Neurodegenerative Disease
Neeru Gupta, MD, PhD

Neurodegenerative diseases are progressive, irreversible diseases involving the loss of specific neuron populations and accumulation of abnormal proteins. The spread of degeneration occurs transsynaptically, with a diseased neuron passing on disease to a connected neuron.   

Glaucoma is a neurodegenerative disease characterized by progressive, irreversible vision loss, loss of retinal ganglion cells, and transsynaptic degeneration that affects the retino-geniculo cortical pathway.⁶ Recognizing glaucoma as a neurodegenerative disease, with further research into central visual system injury, may stimulate the discovery of innovative intraocular pressure-independent strategies to help protect vision in glaucoma patients.

Most of the retinal ganglion cell axon lies outside of the eye to form the optic nerve, eventually terminating in the lateral geniculate nucleus (LGN) of the brain. LGN neurons convey visual information to the visual cortex. In primate glaucoma, significant degenerative changes such as cell shrinkage and cell loss occur in the LGN compared to the normal brain.^7,8  In primates with elevated eye pressure in the absence of significant optic nerve damage, significant changes were observed in LGN dendrites also, including reduced length and complexity.⁹ In the primate visual cortex, metabolic changes correlated with the degree of glaucomatous optic nerve damage.¹⁰

In a patient with advanced optic nerve damage and glaucoma, post-mortem neuropathological examination of the brain provided evidence of degenerative changes extending to the pre-chiasmal optic nerve, LGN, and the visual cortex, compared to age-matched controls.¹¹ A detailed prospective study of the lateral geniculate nucleus in patients with glaucoma using 1.5 Tesla MRI demonstrated significantly reduced LGN height compared to normal age-matched controls. These findings indicate that LGN atrophy may be a relevant biomarker of visual system injury and/or glaucoma progression.¹² 

The mechanisms underlying transsynaptic degeneration in glaucoma are not well understood, though oxidative stress, glutamate toxicity, and glial activation may be implicated. The abnormal protein Tau (serine 202) found in the neurofibrillary tangles of Alzheimer's disease has also been identified in human glaucomatous retinae.¹³ This suggests that glaucoma may share pathways of injury with other neurodegenerative diseases. It is likely that glaucoma, as we know it, is just the tip of the iceberg, and that it is the most common of the neurodegenerative diseases.

Retinal Ganglion Cell Protection
Jeffery L. Goldberg, MD, PhD

Glaucoma damages retinal ganglion cells and, importantly, decreases retinal ganglion cell (RGC) function. Lowering intraocular pressure prevents retinal ganglion loss, but even when IOP is significantly lowered, the rate of glaucoma progression is still quite high. 

In glaucoma, and in other neurodegenerative diseases such as Parkinson’s and Alzheimer’s, there is a significant loss of structure (or cell loss or atrophy) in relevant brain areas before our ability to detect physiologic loss of function occurs. This is likely due in part to our poor ability to detect early functional change and, in part, to built-in nervous system redundancies that allow us to function at full capacity without the full complement of functioning retinal ganglion cells.

Using a mouse model of glaucoma, Buckingham and colleagues have shown that there is injury, in the form of progressive degeneration of the axons, before the retinal ganglion cell dies.¹⁴ There is also evidence that acutely reducing intraocular pressure can improve objective retinal ganglion cell function.¹⁵ If the loss of RGC function precedes the loss of the retinal ganglion cells themselves, that tells us there is a window of opportunity to intervene and potentially save the RGCs by enhancing their function before their axons or cell bodies are irreversibly lost.

Currently, there is a great deal of exciting research into both neuroprotection, or increased RGC survival, and regeneration, or increased RGC axon growth. RGC axons, like those in the rest of the central nervous systems, typically do not regenerate. This is partly because glial cells in the optic nerve make proteins and other molecules that signal the RGC axons not to re-grow down the nerve. But there may be ways of modulating both the environment and the intrinsic capacity of retinal ganglion cells to regenerate their axons. For example:

• Intrinsic mechanisms. Suppression of transcription factor proteins in RGC nuclei called Kruppel-like factors (KLFs) may be able to re-tune the RGCs and allow more regenerative growth.¹⁶
  
  
• Neurotrophic factors. Although they have not yet been tested for glaucoma, I am very interested in peptide neurotrophic factors, brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF) and others. CNTF has been shown to protect RGCs from death in an animal hypertension model.¹⁷
  
  
• Stem cell therapy. Stem cells injected intravitreally have been shown to enhance retinal ganglion cell axon survival and presumably cell body survival in a rat model of glaucoma¹⁸. 
  
  
• Electrical stimulation. Research showing that electrical stimulation can save retinal ganglion cells after optic nerve crush¹⁹ holds great potential to be applied to human use.  We know that electrical activity improves the responsiveness of RGCs to neurotrophic factors like CNTF.

Studying any of these potential mechanisms of neuroprotection in humans is challenging, however. Glaucoma progression occurs very slowly and is hard to measure reliably over short intervals, requiring lengthy, expensive studies to translate theories into clinical therapies.

I think we can change that paradigm by focusing not on neuroprotection, which takes many years to confirm, but neuroenhancement, or improvement in RGC function. This concept, which has been much discussed in the Alzheimer’s literature, emphasizes early intervention during that window of opportunity when RGCs are dysfunctional but not yet dead. Neurotrophic factors such as BDNF and CNTF may be effective for neuroenhancement because they enhance RGC function and improve synaptic function in the retina as well as in the brain. Even if treated eyes continue to decline, we may, in a relatively short period of time, be able to measure an improvement in RGC function, structure, or both, (see Figure 1) and thus provide a mechanism to translate therapies from the laboratory to the clinic.

When to Consider Something Else Besides Glaucoma Peter J. Savino, MD There are a number of non-glaucomatous optic neuropathies that may be misdiagnosed as glaucoma. Here are five clues to aid in the differential diagnosis:   Glaucoma Non-Glaucomatous Optic Neuropathy Decreased visual acuity Rare until end stage disease Common early indicator Color vision anomalies None Alterations in red-green color vision one of the first functional abnormalities Visual field deficit Indicative of optic neuropathy Look for abnormal disc and disc-field association Indicative of optic neuropathy If disc looks normal, unlikely to be glaucoma Appearance of optic disc Cupping or excavation of the disc, thinning of the neurotretinal rim Pale and flat Pallor of the rim out of proportion to the cupping; May see some excavation, but different pattern from glaucomatous cupping Afferent pupillary defect Yes, if the visual field defect is unilateral or asymmetric Yes, if the visual field defect is unilateral or asymmetric

Progression: Prediction and Risk Assessment
David S. Greenfield, MD

The Ocular Hypertension Treatment Study (OHTS) and the European Glaucoma Prevention Study (EGPS) identified five major risk factors for the development of glaucoma among patients with ocular hypertension: increased age, elevated IOP, reduced central corneal thickness, increased pattern standard deviation, and increased cup-to-disc ratio.^1,20 Other studies have demonstrated that many of these variables (prognostic factors) are also important in predicting the risk of progression among patients with established glaucoma. It is widely believed that glaucoma risk factors and prognostic factors are identical and are useful in practice for predicting progression.

Prediction models generated from OHTS and EGPS have been incorporated into a widely-used 5-year risk calculator²¹ that incorporates these five clinical parameters (age, IOP, CCT, PSD, and CDR). Risk calculators can be helpful aids to clinical decision making, assuming patients resemble those who participated in these clinical trials. However, there are other risk factors that clinicians should consider that are not currently incorporated in this calculator.

Optic disc hemorrhage has been identified as a negative prognostic risk factor in multiple randomized clinical trials including the EGPS, Early Manifest Glaucoma Trial (EMGT), and Collaborative Normal Tension Glaucoma Study (CNTGS),^20,22-3 as well as OHTS.²⁴ According to OHTS, review of optic disc stereophotographs is more sensitive for detection of disc hemorrhage than clinical examination and is associated with a 6-fold increase in the risk of POAG.²⁴ A recent large retrospective study in New York City also identified disc hemorrhage as a major negative prognostic factor that was predictive of progression.²⁵

Progressive optic disc change over time has been demonstrated to be predictive of future visual field progression. Medeiros and colleagues found a 25-fold increase in risk of further functional loss if progressive structural change is identified using optic disc stereophotography.² Clearly, these studies underscore the importance of periodic optic disc photography and careful monitoring of the optic disc appearance over time.

Unfortunately, clinicians do not always have the luxury of long-term patient follow-up to help guide therapy. In the Medeiros study, an important finding was that baseline optic nerve abnormality judged using stereophotography was predictive of subsequent visual field loss, even without longitudinal follow up.² Thus, both baseline judgment of glaucomatous optic disc abnormality and progressive optic nerve damage represent important risk factors for progressive visual field loss.

Computerized optic disc and nerve fiber layer imaging can also provide useful information to assist the clinician in assessing the risk of progression.

Computerized Imaging for Risk Assessment
Baseline optic disc abnormalities are highly predictive of future glaucomatous change. Zangwill and colleagues showed that confocal scanning laser ophthalmoscopy using the Heidelberg Retina Tomograph (HRT) can detect optic disc topography abnormalities in glaucoma suspects before the development of standard automated perimetry abnormalities.²⁶ Abnormal baseline optic disc topography was also significantly associated with development of POAG in the OHTS within a five-year time period.²⁷ This indicates that even when the optic nerve is judged to be normal, a baseline abnormality is strongly predictive of the development of glaucoma.

Similar results have been generated using other computerized imaging technologies. Glaucoma suspects identified as having the lowest quartile baseline retinal nerve fiber layer thickness using scanning laser polarimetry (GDx) were found to be at significantly increased risk for development of open-angle glaucoma.²⁸ Thinner baseline RNFL thickness was an independent predictor of subsequent visual field loss, even when other risk factors such as age, IOP, CCT and vertical cup-to-disk ratio were considered in the statistical model. Using Stratus OCT, Lalezari and colleagues showed that baseline reduction in RNFL thickness was independently predictive of development of POAG.²⁹ 

In conclusion, established risk factors for the progression of ocular hypertension to glaucoma include increased age, intraocular pressure, cup-disc ratio, visual field pattern standard deviation, optic disc hemorrhage, and reduced central corneal thickness. Structural abnormalities detected in the optic nerve head and parapapillary retinal nerve fiber layer may predict the development of primary open-angle glaucoma in individuals at increased risk. Clinicians should use diagnostic imaging as an adjunct to supplement clinical examination. 

Diabetes and Glaucoma David S. Greenfield, MD When the original Ocular Hypertension Treatment Study reporting baseline risk factors was published in 2002, it appeared that diabetes was protective against developing POAG. This was surprising, as diabetes is a serious systemic disease and is associated with an increased risk for many other systemic illnesses. Importantly, however, diabetes was a self-reported factor; the OHTS investigators did not measure or monitor hemoglobin A1c levels or fasting blood sugar. Estimates of diabetes, like that of family history, are subject to considerable selection bias.30 In 2008, updated self-reported data was analyzed and clearly demonstrated that diabetes did not have a protective effect on glaucoma development.31 Diabetes should not be considered to reduce the risk of glaucomatous progression.

Ocular Perfusion Pressure
Tony Realini, MD, MPH

Ocular tissues are highly metabolically active. The retina’s continuous recycling of visual images requires a significant volume of blood to maintain a smooth stream of visual information. Ocular tissue perfusion is a balance between arterial inflow and venous outflow. The arterial flow—blood pressure—is easy to measure. Venous pressure is more challenging to measure so, in the case of ocular perfusion pressure (OPP), we use intraocular pressure as a surrogate for venous pressure.

Ocular perfusion pressure is blood pressure minus IOP (OPP = BP – IOP). It follows, then, that OPP would be reduced whenever the blood pressure drops or the IOP rises. However, we don’t suddenly get massive over-perfusion of the eye when IOP drops to zero during cataract surgery, nor do we have complete cessation of ocular perfusion when IOP spikes to 40 mmHg due to retained viscoelastic after cataract surgery. Auto-regulation is the reason that OPP doesn’t always react as the simple model would predict. In healthy individuals the ocular tissues can locally regulate blood flow. When blood pressure or IOP increases or decreases, local auto-regulatory compensation is able to keep OPP relatively constant.  

It is possible that glaucoma occurs when this auto-regulatory capacity is lost and the optic nerve becomes more vulnerable to fluctuations in blood pressure or IOP. Chronically high IOP in glaucoma would also be expected to reduce perfusion, further altering the ocular perfusion pressure equation. 

Across many studies, we have seen an association between higher systemic blood pressure and higher IOP, but the association between blood pressure and glaucoma prevalence is weak.^22,32 I do not routinely measure blood pressure in stable glaucoma patients. Much as central corneal thickness is of little relevance in patients who are well controlled and not progressing, blood pressure monitoring for glaucoma is probably not useful either, except in patients whose disease progression is not consistent with their apparent IOP control. Improving our understanding of the effects of OPP may help to put the role of systemic blood pressure in glaucoma into context.

There are a number of studies showing that low OPP is a risk factor for developing glaucoma.^30,32-3 The magnitude of the effect is fairly consistent from study to study, with a two- to four-fold increase in risk.

Low OPP is also a risk factor for glaucoma progression. In the Early Manifest Glaucoma Trial, low systolic perfusion pressure was a significant risk factor for the progression of glaucoma in high pressure glaucoma, but not in low pressure glaucoma, which makes sense because of the dual impact of low OPP and high IOP.²² 

Managing the Vasculopathic Patient
Given that low OPP is a significant risk factor for both developing glaucoma and glaucoma progression, it is worth asking whether we can identify vasculopathic patients in whom OPP may play a role in disease progression. 

In fact, there is a typical profile. The vasculopathic glaucoma patient is typically a middle-aged woman who suffers from migraine headaches and has the cold hands and feet that we associate with Raynaud’s phenomenon. These patients are active, slender, and often of above-average intelligence. They have a history of low blood pressure that may or may not manifest clinically in routine blood pressure monitoring, but will become apparent in 24-hour blood pressure assessments. These are the patients who seem to have well-controlled, low IOP, yet continue to progress. And they tend to have a characteristic pattern of optic nerve and visual field damage, with focal notches on the neuroretinal rim, disc hemorrhages, and dense paracentral scotomas. 

Keeping in mind the formula (OPP = BP – IOP), what can be done to help these patients? Clearly, lowering IOP is good, and the drug classes that lower IOP at night, such as prostaglandin analogues and carbonic anhydrase inhibitors, would be preferable. These drugs have the added benefit of increasing circadian ophthalmic perfusion pressure. It is wise to avoid IOP-lowering drug classes that also lower blood pressure, especially at night, such as the beta blockers and adrenergic agonists. Blood pressure is already lowest at night, during exactly the time period that IOP is highest and when we would expect autoregulation of OPP to be most challenged. 

The question of whether we should attempt to increase blood pressure in such patients is less straightforward. While it appears to be beneficial according to the OPP formula, we must also be cognizant that stroke is the third leading cause of death in the United States, so increasing blood pressure might involve unacceptable risks. A more moderate approach would be to work with the patient’s primary care physician to minimize over-treatment of systemic blood pressure, avoid systemic anti-hypertension agents such as calcium channel blockers that lower both blood pressure and IOP, and perhaps to encourage dosing medicines in the morning to avoid the nocturnal dip in blood pressure. 

Glaucoma Neuroprotection: From the Laboratory to the Clinic
Theodore Krupin, MD

Glaucoma is currently defined as a progressive, multi-factorial optic neuropathy involving the death of retinal ganglion cells, loss of their axons, optic nerve cupping, and visual field loss.  Elevated IOP is not part of this definition, although it remains the most important modifiable risk factor. As Dr. Gupta discussed, our current definition may not go far enough in taking into account the neurology of glaucoma—that is, the neurodegeneration happening in the lateral geniculate nucleus and visual cortex of the brain.

The concept of glaucoma as a neurodegenerative disease lends itself to the idea of therapeutic neuroprotection, aimed at keeping the retinal ganglion cells alive and 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.

Several investigations in animal models of optic nerve injury and elevated IOP have elucidated the mechanism for death of the retinal ganglion cell by apoptosis. These pre-clinical studies have shown that what happens on a cellular level in glaucoma does not at all match how we are treating our patients. 

Proving the clinical benefits of neuroprotection requires randomized clinical trials. Neuroprotection is of great interest in fields other than ophthalmology, such as stroke prevention, Alzheimer’s disease, ALS, and others, and there have been many attempts to conduct randomized clinical trials in these fields.  All of them, with the exception of memantine in Alzheimer’s and riluzole in ALS, have failed. 

Potential Neuroprotective Agents in Glaucoma
There has so far not been any human trial demonstrating neuroprotection in glaucoma.³⁴ But there are several agents with the potential for neuroprotection that continue to be investigated.

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 role of memantine did not successfully meet its clinical endpoints.  

There has also long been hope that the alpha-2 adrenergic agonist, brimonidine, might be neuroprotective. The alpha-2 agonist Precedex (dexmedetomidine HCI, Hopsira), used by anesthesiologists to delay anesthetics, was shown in 1993 to be neuroprotective in animal models. So when Allergan introduced brimonidine (Alphagan) in 1996 for IOP lowering, researchers soon began investigating its potential neuroprotective effects. Several laboratory studies have shown brimonidine to be neuroprotective in animal models^35,36 but that effect has not yet been able to be replicated in  human clinical trials. 

The Low-pressure Glaucoma Treatment Study (LoGTS) is a monotherapy trial comparing 2% brimonidine to 0.5% timolol in patients with low-pressure glaucoma.³⁷ Because of the high rate of allergy to brimonidine, 178 patients were randomized 4:3, brimonidine:timolol. Only one patient had to exit the study for a pressure greater than 21 mmHg, considerably lower than one might expect in a study population of this size. The LoGTS outcome manuscript is currently under journal review.

There are a number of neurotrophic factors that control nerve cell growth, division, and maturation. It has been theorized that nerve cell growth factor may be utilized as a neuroprotective agent. One study has been published showing good experimental and clinical results from nerve growth factor in the treatment of glaucoma.³⁸ We must be cautious in interpreting these results, as promising as they seem.

Taking any of these potential measures from animal testing in the laboratory to human clinical use is challenging. Unlike our best animal models, humans are on multiple medications, with various comorbidities and widely varying disease courses. But it is an important effort that must continue if we are to identify pressure-independent therapies to improve the effectiveness of our care of glaucoma patients.

REFERENCES

1. 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):714-720.
2. Medeiros FA, Alencar LM, Zangwill LM, et al. Prediction of functional loss in glaucoma from progressive optic disc damage. Arch Ophthalmol 2009;127(10):1250-1256.
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