3rd Annual

MANAGING GLAUCOMA: BEYOND INTRAOCULAR PRESSURE

Highlights from the Live Event

Sponsors/Support:

Supported by an Independent Educational Grant from Allergan, Inc.
Jointly Sponsored by Institute for the Advancement of Human Behavior and Review of Ophthalmology^®

Principal faculty and their credentials:

Claude F. Burgoyne, MD, holds the Van Buskirk Chair in Ophthalmic Research and is Research Director of the Optic Nerve Head Research Laboratory at the Devers Eye Institute in Portland, Ore.

Louis B. Cantor, MD, is the Jay C. and Lucile L. Kahn Professor of Glaucoma Research and Education and Chairman of the Department of Ophthalmology at the Indiana University School of Medicine. He also serves as Director of Indiana University's Eugene and Marilyn Glick Eye Institute.

Robert Fechtner, MD, is Professor at the Institute of Ophthalmology and Visual Science and Director, of the Glaucoma Division, at the New Jersey Medical School.

Christopher Leung, MD, MB, CHB, is Professor in the Department of Ophthalmology and Visual Sciences at the Chinese University of Hong Kong.

Nils Loewen, MD, PhD, is an Assistant Professor of Ophthalmology at Yale University School of Medicine. He has a special interest in low-pressure glaucoma.

Felipe Medeiros, MD, PhD, is Professor of Ophthalmology at the Hamilton Glaucoma Center at the University of California, San Diego.

Robert N. Weinreb, MD, is Chairman and Distinguished Professor of Ophthalmology, the Morris Gleich Chair and Director of the Shiley Eye Center at the University of California San Diego.

Description/Goal

Glaucoma is a major cause of blindness and affects upwards of 60 million people worldwide. Normal-tension glaucoma (NTG) is a type of open-angle glaucoma (OAG) resulting in damage to the optic nerve and abnormalities of the visual field. IOP in this type of glaucoma is not higher than that usually considered to be normal (<21 mmHg) for the eye. This form of glaucoma may account for as many as one-third of the cases of OAG in the United States.¹

The typical treatment of glaucoma is directed at lowering eye pressure; however, traditional strategies of lowering IOP are not always effective at preventing glaucoma progression. The need to evaluate other therapies that augment the effect of lowering IOP is prevalent. In recent years, the focus of glaucoma research has shifted toward neuroprotection, which has been defined as the use of therapeutic agents to prevent, hinder and, in some instances, reverse neuronal cell death whatever the primary injury.² Various neuroprotective drug-based approaches have been capable of reducing the death of retinal ganglion cells, which is the hallmark of glaucomatous optic neuropa-thy.³ Moreover, there is a growing trend toward using existing neuroprotective strategies in central nervous system diseases for the treatment of glaucoma.⁴ This continuing education activity will educate physicians on current theories for managing patients with normal-tension glaucoma, with particular focus on potential neuroprotective strategies.

Target Audience

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

Learning Objectives

Upon completion of this activity, participants should be able to:

1. Discuss the diagnosis and management of normal-tension glaucoma. recording the best answer to each question;
2. Decipher when lowering IOP will not halt progression of the disease.
3. Explain the biologic foundation and application of neuroprotection in glaucoma, as well as its value in the treatment of glaucoma.
4. Describe the rationale for the use of glaucoma neuroprotection as a pressure-independent theory.
5. Identify the goals and obstacles of neuroprotection in the treatment of normal-tension glaucoma.
   

Physicians 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 Institute for the Advancement of Human Behavior (IAHB) and Review of Ophthalmology^®/Jobson Medical Information LLC. The IAHB is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation Statement

The IAHB designates this enduring material for a maximum of 2.0 AMA PRA Category 1 Credit(s).^TM Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Statement of Disclosure

All faculty/speakers, planners, abstract reviewers, moderators, authors, co-authors and administrative staff participating in
the continuing medical education programs jointly sponsored by IAHB and Review of Ophthalmology are expected to disclose to the program audience any/all relevant financial relationships related to the content of their presentation(s). The list in the box below includes all individuals in control of content for this CME activity.

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How to Receive CME Credit

There are no fees for participating and receiving CME credit for this activity. During the period of September 1, 2012
through August 31, 2013, participants must: 1) read the learning objectives and faculty disclosures; 2) study the educational activity; 3) complete the post-test 4) complete the evaluation form; and 5) mail it with the answer key (not necessary for online format).

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 80 percent 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.

Contact Information

Any questions/problems with registration, CME certificate, etc., can be directed to rcombs@jhihealth.com.

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The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of IAHB and/or Review of Ophthalmology. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings.

Financial Relationship Key	Role	Last Name	First Name	Disclosure	Resolution
G-Grant/Research Support C-Consultant/Scientific Advisor S-Speaker’s Bureau E-Employee M-Major Stockholder O-Other N-Nothing to disclose Resolution Key R1- Restricted to Best Available    Evidence & ACCME content    validation statement R2- Removed/Altered Financial    Relationship R3-Altered Control R4- Peer Review with    2nd method of resolution N/A-Not Applicable	Speaker	Burgoyne	Claude	Heidelberg Engineering=G; Reichert Instruments=O	R1
	Speaker	Cantor	Lois	Abbott Medical Optics=C; AHRQ=G; Allergan=C, G; 3Glaukos=G; iScience=G	R1
				Merck=G; QLT, Inc.=C
	Speaker	Fechtner	Robert	N	N/A
	Speaker Speaker	Leung Loewen	Christopher Nils	Carl Zeiss Meditec=G; Alcon=C N	R1 N/A
	Speaker	Medeiros	Felipe	Alcon Laboratories=C, Allergan=C; Carl Zeiss Meditec=G, Heidelberg Engineering=G; Reichert Instruments=G; Sensimed=G	R1
	Planner	Rodemich	Karen	N	N/A
	CME Coordinator	Morgan	Sheryl	N	N/A
	Program Chair	Weinreb	Robert	Alcon Laboratories=C; Allergan=C; Altheos=C; Bausch + Lomb=C; Merck=C; Novartis=C

 

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I. DIAGNOSTICS IN CLINICAL PRACTICE
UNDERSTANDING IOP IN CLINICAL PRACTICE
IOP remains a central feature in the diagnosis and management of glaucoma, but it must be combined with measures of structure and function to determine progression.

NILS LOEWEN, MD, PHD

Intraocular pressure (IOP) is a central feature in the diagnosis and management of glaucoma—and yet it remains very diffi-cult to put a single IOP measurement during a clinic visit into context and determine, together with prior measurements, what the likelihood of progression is.

The father of evidence-based medicine, David M. Eddy, MD, PhD, challenged our field in 1983 when he said there is
no evidence that IOP is causatively linked to glaucoma. It took almost 16 years to develop strong evidence-based data to show that glaucoma is, in fact, caused by a pressure that is too high for the individual eye: the Ocular Hypertensive Treatment Study (OHTS) and the Early Manifest Glaucoma Trial (EMGT) demonstrated that lowering IOP prevents or delays progression.^1,2 Animal models have also provided powerful evidence that surgical lowering of elevated IOP prevents progression.³

There is an almost linear correlation of glaucoma incidence with increasing IOP.⁴ The prevalence of open-angle glaucoma also increases with age, albeit not in a linear fashion.⁵ Aging has profound effects on outflow pathology but is not correlated in linear fashion with the rise in IOP.

Which IOP to Treat

The first dilemma with IOP is that the standard of measurement to this day is Goldmann applanation, which is prone to various artifacts and influenced by many variables. There are better ways of measuring IOP that are often used in research (e.g., pneumatonometry), but they have not become as widely adopted.

When we treat elevated IOP, there is a wide range of options, including laser tra-beculoplasty, different classes of pressure-lowering topical medications, and surgery, including the ab interno trabeculotomy (Trabectome, NeoMedix), trabeculectomy, tube or suprachoroidal shunts.

We have to be aware of what exactly what we are treating with each option. Tra-beculoplasty and the Trabectome both treat the trabecular meshwork (TM) and enhance conventional outflow. Prostaglandin analogs and suprachoroidal shunts, on the other hand, enhance uveoscleral outflow. Brinzo-lamide and timolol affect outflow through the TM in a pressure-dependent fashion.

Because the surgical options mentioned utilize different routes of outflow, they have different effects on IOP throughout the diurnal cycle. For example, trabeculoplasty and latanoprost both reduce IOP throughout the day and night.^6,7 Timolol, however, only lowers pressure during the day, not at night.⁷ Adding a second medication to latanoprost can achieve further lowering, but if the second medication is timolol, one will not achieve additional IOP reduction at night.⁸ Suprachoroidal drainage devices that shunt fluid into the suprachoroidal space lower IOP more in the morning than at night in our studies.

In following patients under treatment for elevated IOP, one can reach very different conclusions about the relative effectiveness of each of these interventions, depending on the time of day that IOP is measured. By consistently measuring IOP at 9:30 a.m., for example, one would always be understating the relative effect of trabeculoplasty and prostaglandin analogs and overstating the effects of timolol or a suprachoroidal shunt.

The answer to these challenges lies in continuous IOP monitoring, such as that recently reported by Weinreb and Mansouri using a telemetric contact lens sensor.⁹ Twenty-four-hour IOP measurements have the potential to completely change how we view IOP and, perhaps, how we view the efficacy of our pressure-lowering treatments (see sidebar below).

Upcoming Advances: 24-Hour IOP Monitoring Robert N. Weinreb, MD

Intraocular pressure varies throughout the day. Both peak and mean IOP are important parameters to consider in evaluating the risk of glaucoma progression. For about two-thirds of individuals, however, peak IOP occurs during the night. Daytime measurements of IOP in the clinic, therefore, will often fail to capture peak IOP, which also skews one’s understanding of mean pressure. Obtaining supine IOP can provide a crude estimate of the peak pressure. For a supine IOP measurement, tilt the patient back in the examining chair for two minutes, and use a pneumotonometer or a hand-held Perkins applanation tonometer (Haag-Streit). A Goldman tonometer cannot be used in the supine position; the Tono-Pen (Reichert Technologies) is less effective when IOP is above the mid-20s. Another key consideration is that IOP doesn’t necessarily behave the same in an individual’s left and right eyes. This is one of the reasons why the monocular therapeutic trial has been invalidated. We simply cannot assume that a change in pressure in one eye will be accompanied by a similar change in the other. We have also shown that IOP is not conserved from day to day. So, while it is laudable to keep patients around for several hours for repeated pressure measurements (or even overnight for 24-hour pressure measurement), there is absolutely no guarantee that their IOP levels will be similar the next day, or the day after that. This at fi rst seems discouraging, but I believe that recognition of the limitations of our current technology for measuring IOP is rapidly leading us toward continuous 24-hour IOP measurement. Disposable contact lenses that can accomplish this are already available in several countries outside the United States. Also on the horizon are implantable 24-hour pressure monitors that can be implanted at the time of cataract surgery or in conjunction with a glaucoma drainage device; these are under investigation in Europe. When these technologies become more widely available, they will revolutionize our understanding of IOP patterns and fl uctuations in our patients.

Predicting Progression

The good news is that even with single IOP measures that offer just a snapshot of one point in time we can still come to the correct conclusions in clinical trials. In all the major epidemiological studies in glaucoma—the Age-Related Glaucoma Intervention Study (AGIS); Collaborative Initial Glaucoma Treatment Study (CIGTS); OHTS; EMGT; and Glaucoma Laser Trial (GLT)—IOP was measured at one time of the day only. Thanks to the power of statistics, we know that, in the aggregate, pressure-lowering actually prevents progression or onset.

But how do we use that aggregate data to determine whether an individual patient is going to get worse? The answer is that IOP alone is not enough. Multiple IOP measures provide us with more security but ideally we must combine IOP data with multiple measures of structure and function over time so that we can understand not just the magnitude of change, but the rate of change.

For example, a mild visual field (VF) defect that is progressing rapidly is of more concern, from a treatment perspective, than a pronounced VF defect that has been stabilized with IOP-lowering treatment and is progressing slowly or not at all.

In summary, while a primary goal in glaucoma management is to lower IOP, there is no magic level for IOP that will halt progression in every patient. Diagnostic care that integrates IOP with repeated measures of functional and structural change is necessary to determine the urgency and impact of treatment. Additionally, treatment combinations that integrate both conventional and uveoscleral outflow approaches may have the highest rate of success.

References

1. Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120(6):701-13; discussion 829-30.
2. Heijl A, Leske MC, Bengtsson B, et al; Early Manifest Glaucoma Trial Group. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol. 2002;120(10):1268-79.
3. Nickells RW, Schlamp CL, Li Y, et al. Surgical lowering of elevated intraocular pressure in monkeys prevents progression of glaucomatous disease. Exp Eye Res. 2007;84(4):729-36.
4. Leske MC, Connell AM, Wu SY, et al. Risk factors for open-angle glaucoma. The Barbados Eye Study. Arch Ophthalmol. 1995;113(7):918-24.
5. Varma R, Ying-Lai M, Francis BA, et al; Los Angeles Latino Eye Study Group. Prevalence of open-angle glaucoma and ocular hypertension in Latinos: the Los Angeles Latino Eye Study. Ophthalmology. 2004;111(8):1439-48.
6. Lee AC, Mosaed S, Weinreb RN, et al. Effect of laser trabeculoplasty on nocturnal intraocular pressure in medically treated glaucoma patients. Ophthalmology. 2007;114(4):666-70.
7. Liu JH, Kripke DF, Weinreb RN. Comparison of the nocturnal effects of once-daily timolol and latano-prost on intraocular pressure. Am J Ophthalmol. 2004;138(3):389-95.
8. Liu JH, Medeiros FA, Slight JR, Weinreb RN. Comparing diurnal and nocturnal effects of brinzolamide and timolol on intraocular pressure in patients receiving latanoprost monotherapy. Ophthalmology. 2009;116(3):449-54.
9. Mansouri K, Weinreb RN. Meeting an unmet need in glaucoma: continuous 24-h monitoring of intraocular pressure. Expert Rev Med Devices. 2012;9(3):225-31.

STRUCTURAL AND FUNCTIONAL MEASURES IN GLAUCOMA
An index that combines both may offer the most reliable estimate of progression.

FELIPE A. MEDEIROS, MD, PHD

Clinicians often want to know whether it is better to follow glaucoma patients by measuring function (via standard automated perimetry [SAP] visual field testing) or structure, using any one of a number of imaging devices. In fact, neither method is sufficient on its own.

The Limitations of Functional Testing

Experimental and clinical evidence has shown that, in many patients, significant retinal ganglion cell (RGC) losses are required before a statistically significant change in the visual field (VF) can be detected. Although the amount of RGC loss associated with early development of a field defect will depend on the location and characteristics of the defect, on average one would typically first detect VF loss at a mean deviation of around -2 dB to -3 dB. That would correspond to an RGC population of approximately 600, 000 to 700,000 cells, according to a recent study (see Figure 1). Such number would represent approximately 30 percent loss from the average RGC number in healthy eyes.

Figure 1. Relationship between MD and RGC number. (Adapted from Medeiros FA, Lisboa R, Weinreb RN, et al. A combined index of structure and function for staging glaucomatous damage. Arch Ophthalmol. 2012;130(5):E1-10.)

VF sensitivities and global indices such as mean deviation are reported in a logarithmic decibel scale. Such scaling of perimetric data generates a curvilinear relationship between structure and function as shown in Figure 1. This relationship indicates that at early stages of the disease, large structural changes are associated with relatively small functional changes. This would explain the common clinical findings of patients with extensive neuroretinal rim thinning and exaction despite apparently statistically
normal VFs (see Figure 2). In contrast, at advanced stages of the disease, relatively large changes in function may be associated with only minor or no detectable changes in structure.

Figure 2. At early stages of glaucoma, large structural changes can be associated with statistically normal visual fields.

 

One could argue whether treatment is necessary before development of VF losses or whether one could just wait for the appearance of field defects to initiate treatment and then prevent the death of the remaining RGCs.

Figure 1 can be used to illustrate the importance of early detection of damage and early treatment. To get from that very early VF defect of -3 dB to a mean deviation of -10 dB, which most would agree would represent quite severe VF loss and potential functional impairment, one need only lose another 300,000 cells—far fewer than were lost to get to the point of a detectable field loss in the first place. Therefore, reliance on VF testing alone will potentially result in late diagnosis and underestimation the rate of glaucoma progression, especially in the early stages of the disease. It is important to emphasize, however, that several factors need to be taken into account when making treatment decisions, such as life expectancy, potential side effects of treatment, and patient's perceptions and expectations about the treatment.

Structural Changes in Glaucoma

Many studies have shown that imaging technologies such as confocal scanning laser ophthalmoscopy (CSLO), scanning laser polarimetry, and optical coherence tomography (OCT) can objectively quantify structural changes in the neu-roretinal rim and retinal nerve fiber layer (RNFL).

Experimental studies have shown that OCT-measured RNFL thickness correlates well with the RGC number until the later stages of glaucoma, when OCT measurements appear to reach a plateau. Clinical studies have also shown that OCT and other devices actually perform poorly in differentiating moderate from severe glaucoma.¹ These observations about OCT performance and SAP performance clearly indicate the need for a combined approach to diagnose and monitor glaucoma. They also indicate that agreement between functional and structural measures should not be always expected. In fact, disagreements will be quite common in clinical practice due to the different characteristics of these tests and their relationship with the amount of neural losses in the disease.

A New Paradigm

We recently developed a single index that combines structure and function measures to provide an age-corrected estimate of ganglion cell loss.² This is based on work showing that the number of retinal ganglion cells can be reliably estimated from either VF SAP sensitivity data or from OCT RNFL analysis.³ Unlike VF testing alone, the combined structure-function index (CSFI) performs well in detecting pre-perimetric glaucoma. And unlike imaging alone, the CSFI is successful at discriminating early vs. moderate and moderate vs. advanced stages of glaucomatous damage.²

Figure 3. Patient with optic nerve progression over time. Note the essentially normal visual fields.

For example, the patient in Figure 3 showed optic nerve progression over time. However, from the VF, one would not know that this patient has glaucoma, as the results are essentially normal. However, the combined index of structure and function estimates that this patient has a loss of 39 percent of the nerve tissue. In another patient with more advanced glaucoma, OCT imaging would seem to indicate a similar rate of change in both eyes. The VFs tell a different story, though. And, indeed, at this stage of glaucoma, we should give greater weight to the perimetry. The index does this, giving us an estimate of a 74 percent loss of ganglion cells in the right eye and 85 percent in the left eye, which is the eye with the worse-looking VFs
(see Figure 4).

Figure 4. The Combined Structure Function Index (CSFI) estimates the loss of retinal ganglion cells based on both structural and functional inputs.

We have also shown that the CSFI detects progression in a significantly higher number of patients compared to conventional indices.⁴ In this study, 213 eyes of glaucomatous subjects were followed for an average of 4.5 years. The combined index detected change in 22 percent of glaucomatous eyes compared to 8.5 percent for VFs and 14.6 percent for OCT average thickness, with the same 95 percent specificity.

In conclusion, the ability of structural and functional methods to detect change and accurately estimate the rate of change depends on the stage of the disease. An index that combines both approaches can improve our ability to diagnose, stage and detect disease progression, potentially resulting in more effective management of our glaucoma patients.

References:

1. Sibota R, Sony P, Viney G, et al. Diagnostic capability of optical coherence tomography in evaluating the degree of glaucomatous retinal nerve fiber damage. Invest Ophthalmol Vis Sci 2006;47(5):2006-10.
2. Medeiros FA, Lisboa R, Weinreb RN, et al. A combined index of structure and function for staging glaucomatous damage. Arch Ophthalmol. 2012;130(5):E1-10.
3. Harwerth RS, Wheat JL, Fredette MJ, Anderson DR. Linking structure and function in glaucoma. Prog Retin Eye Res. 2010;29(4):249-71.
4. Medeiros FA, Zangwill LM, Anderson DR, et al. Estimating the rate of retinal ganglion cell loss in glaucoma. Am J Ophthalmol. 2012; Jul 26. [Epub ahead of print].

II. WHAT DAMAGES THE OPTIC NERVE IN GLAUCOMA?
GLAUCOMA IS A NEURODEGENERATIVE DISEASE
New information broadens our understanding of this common disease.

ROBERT N. WEINREB, MD

Glaucoma is more than a condition of elevated intraocular pressure (IOP) and, in fact, is more than a disease of the eye; it is a progressive neurodegenerative disease. Ophthalmologists are most interested in what happens to the eye in glaucoma,
but the eye is part of the central visual pathway. The optic nerve fibers target the lateral geniculate nucleus—and, in particular, it's relay neurons—in the brain stem. From the lateral geniculate nucleus, the optic nerve fibers then radiate to the visual cortex.

Working with University of Toronto researchers Yeni Yucel, MD, PhD, and Neeru Gupta, MD, PhD, we looked at the lateral geniculate nucleus (LGN) in an experimental monkey model of glaucoma. We found very apparent atrophy and loss of the relay neurons in the LGN.¹ So not only does glaucoma cause loss of optic neurons—the retinal ganglion cells in the eye—but it also causes neuronal damage in the LGN. The damage we detected occurred in three major channels: The magnocellular, the parvocellular, and koniocellular.² When we looked at other areas of the central visual pathway, including the brain, it was readily apparent to us that not only was there a change in the brain stem but there were also changes in the metabolic activity and cel-lularity of the visual cortex.³

Glaucoma is a disease of the entire central visual pathway. It shares characteristics with other neurodegenera-tive diseases such as Alzheimer's and Parkinson's disease. In fact, one can make the case that glaucoma is more prevalent than all other neurodegenerative diseases combined.

With that, we can now pursue a deeper understanding of what exactly causes neuronal damage and degeneration in primary open-angle glaucoma. Great progress is being made on diagnostically measuring and identifying the roles of IOP-related biomechanical stress, ocular perfusion, and cerebrospinal fluid pressure. The results of this research, in addition to new methods for identifying patterns of cell damage, provide hope that we will be able to identify successful strategies for neuroprotection.

References

1. Yucel YH, Zhang Q, Weinreb RN, et al. Atrophy of relay neurons in magno- and parvocel-lular layers in the lateral geniculate nucleus in experimental glaucoma. Invest Ophthalmol Vis Sci. 2001;42(13):3216-22.
2. Yucel YH, Zhang Q, Weinreb RN, et al. Effects of retinal ganglion cell loss on magno-, parvo-, konio-cellular pathways in the lateral geniculate nucleus and visual cortex in glaucoma. Prog Retin Eye Res. 2003;22(4):465-81.
3. Gupta N, Yucel YH. Brain changes in glaucoma. Eur J Ophthalmol. 2003;13 Suppl 3:S32-5.

A BIOMECHANICAL APPROACH TO UNDERSTANDING THE OPTIC NERVE HEAD
The laminar and peripapillary sclera are subjected to IOP-related stress, systemic insults, and cellular changes affecting nutrient delivery.

CLAUDE F. BURGOYNE, MD

In every experimental glaucoma model, the primary site of damage to retinal ganglion cell axons is within the optic nerve head (ONH). To better understand what happens to the ONH in glaucoma, it may be helpful to think about the ONH as a biomechanical engineer would—as a load-bearing structure. Using techniques from other areas of medicine and engineering, we can begin to make sense of the physiologic dynamics at play in this unusual structure, and arrive at a better understanding of how connective tissues, blood vessels, and astrocytic and glial cells in the ONH all interact with one another and with other factors in glaucoma.

Several etiological factors are implicated in glaucomatous ONH damage. These include intraocular pressure (IOP) and IOP-related connective tissue stress and strain; retrobulbar determinants of ONH blood flow, blood flow and nutrient supply within the ONH (which may interact with connective tissue stress and strain); and systemic autoimmune or inflammatory insults that are likely to be completely independent of IOP.

These etiological factors trigger two major types of functional changes in the ONH: ONH and peripapillary scleral connective tissue damage; and axonal damage within the lamina cribrosa. Both of these pathophysiologies occur by multiple mechanisms and they are connected to one another via the astrocytes and glial cells (see Figure 1).

Figure 1. Non-IOP-related effects such as autoimmune or inflammatory insults and retrobulbar determinants of ocular blood flow can primarily damage the ONH connective tissues and/or axons, leaving them vulnerable to secondary damage by IOP-related mechanisms at normal or elevated levels of IOP. (Adapted from Burgoyne CF, Downs JC. Premise and Prediction—How Optic Nerve Head Biomechanics Underlies the Susceptibility and Clinical Behavior of the Aged Optic Nerve Head. J Glaucoma. 2008;17:318-28.)

 

IOP-Related Stress and Strain

IOP is a central determinant of ONH physiology at all levels, including normal pressure. Clinicians are interested in a target IOP, below which the risk of progression is close to zero. But the reality is that there is no IOP level at which the laminar and peripapillary sclera are not under substantial stress and strain. In fact, the connective tissues and vascular supply must be rather robust to avoid optic neuropathy over a 70- or 80-year lifetime of these strains.

At a given level of IOP, whether that pressure is 6 mmHg or 30 mmHg, connective tissue stresses within the lamina cribrosa and peripapillary sclera are substantially higher than IOP, depending upon the three-dimensional geometry (anatomy or architecture) of these tissues. Scleral stresses and strains are transferred to the lamina in a tensile manner, adding to the lamina's ability to resist the direct effects of IOP. The direct effects of IOP on the lamina are not only resisted by these scleral effects but also by retinal laminar tissue pressure (RLTP), which is related (but not identical) to cerebrospinal fluid (CSF) pressure. The tissue behind the laminar cribrosa is actually at a pressure somewhat higher than the CSF pressure itself. While the magnitude of the effects
of CSF pressure on the lamina are small compared to those of the sclera, RLTP may exert a very important effect on axon/ astrocyte physiology and transport through its contributions to the translaminar pressure gradient.¹

Blood Flow, Nutrient Supply and Systemic Factors

The ONH is a rather unusual environment; it is the only place in the central nervous system where astrocytes do not have a direct connection to capillaries. In the brain and retina, astrocytes have a direct connection to capillaries, but in the ONH, nutrient transport from laminar capillaries to the laminar astrocytes that sit on the surface of the laminar beams has not been studied. It is our working hypothesis that the connective tissues of the laminar beam and the astrocyte basement membranes may be barriers to nutrient diffusion, and that aging and the disease process itself likely alter these tissues enough to diminish nutrient transport.

Ocular blood flow and perfusion pressure have become topics of great interest in glaucoma research in recent years. We know that systemic factors such as nocturnal hypotension and vasospasm can influence blood flow within the eye.

Although we don't yet have the tools to measure and confirm this, it makes sense that IOP-related stress and strain within the scleral flange and laminar beams should also influence blood flow. Cioffi and others have shown that the principal blood supply to the ONH passes through the peripapillary sclera, on its way to supplying the peripapillary choroid, the lamina, and the retro-laminar optic nerve.² The anatomy of the peripapillary scleral flange is much thinner than the posterior sclera, which creates concentrations of engineering stress and strain that should influence the magnitude of blood flow.

Hayreh demonstrated the vulnerability of peripapillary choroidal blood flow to acute IOP elevation in non-human primate eyes using fluorescein angiograms and hypothesized that the same thing is likely to be true for blood flow within human laminar capillaries.³

Systemic autoimmune or inflammatory insults have the potential to influence the entire pathophysiology of ONH damage, although the mechanism and degree to which this happens is not known at the present time.

Pathophysiology

There are multiple mechanisms for axonal and connective tissue damage within the ONH. Traditionally, we have thought of axons as being compromised by ischemic events or physical compression. These mechanisms feature heavily in the glaucoma literature of the past 20 years, and from an engineering standpoint, should be viewed as compatible rather than controversial. It is likely that ischemic events due to volume flow or nutrient alteration do cause axonal damage. Physical compression may also contribute to axonal damage, particularly in certain regions of the ONH. But most people who currently study the mechanism of axonal injury in glaucoma believe the final insult to the axon is mediated by astrocyte and or glial cell molecular biology.

The cells that govern the ONH connective tissues ought to be influenced by the same phenomena as the axons. However, an interesting point to consider is that connective tissue insults could actually be the primary mechanism of damage, weakening the tissue and making the ONH thereafter more vulnerable to normal levels of intraocular pressure. This could partially explain why we sometimes see glaucomatous damage at normal IOP levels.

We know that connective tissues of the ONH stiffen with age. Researchers are beginning to explore alterations in collagen and other extracellular matrix components to assess their affect on optic nerve susceptibility. It is somewhat counterintuitive that stiffer tissues of the aged eye contribute to ONH susceptibility, because it would seem that more rigid tissue would be less likely to deform.

It may be, however, that the increased stiffness of the extracellular matrix and thickness of the laminar beams alters nutrient transport. If we can influence that process to improve diffusion of nutrients and enhance blood flow, the impact could be significant.

ONH Remodeling

ONH cupping is an important clinical sign of glaucoma, but it is also a complex structural process. Glaucomatous cupping includes deformation and remodeling of the ONH connective tissues. Axonal injury may occur prior to, during, or after these connective tissue events.

In a series of publications on deformation of the tissues in monkey experimental glaucoma, my colleagues and I have described this remodeling as an outward migration or pialization of the lamina cribrosa.⁴ At the transition from ocular hypertension to detectable glaucomatous damage by confocal scanning laser tomography, the lamina is not yet thinning; rather, it is profoundly thickened. As it is deforming, it also migrates out of the sclera into the pial sheath. This is a very consistent finding in our model and it tells us that, in addition to physical deformation, there is cellular activity involved in the process of glaucomatous cupping.

This has some very important potential implications. First, as this remodeling occurs, it may alter the translaminar pressure gradient, particularly in the peripheral regions of the nerve where axons are already known to be most vulnerable. There would have to be an accompanying and equally profound remodeling of the vascular supply to the lamina. If so, that would occur exactly in the region underlying clinical nerve fiber layer hemorrhages.

Finally, the notion that connective tissue remodeling may influence axonal remodeling through myelin is emerging, both in the mouse⁵ and monkey models of glaucoma. In the monkey model, we are seeing profound changes in myelin basic protein signal by immunohistochemistry within the retrolaminar optic nerve very early in the disease.

Conclusions

IOP is always going to play a major role in the management of glaucoma, but the fact that the insult to the ONH occurs even at normal levels of pressure suggests there are factors independent of or interacting with IOP that are also important. I believe that within our lifetimes we'll be able to demonstrate clinically important interactions between IOP and blood flow. Gaining a better understanding of optic nerve head biomechanics will be critical for the eventual development of neuroprotective interventions aimed at the ONH itself.

Note: These concepts have been described in a series of recent publications.^6,7

References

1. Morgan WH, Yu D-Y, Cooper RL, et al. The influence of cerebrospinal fluid pressure on the lamina cribrosa tissue pressure gradient. Invest Ophthalmol Vis Sci. 1995;36(6):1163-72.
2. Cioffi GA, Van Buskirk EM, 1996. Vasculature of the Anterior Optic Nerve and Peripapillary Choroid, second ed. Mosby, St. Louis.
3. Hayreh SS, Revie IH, Edwards J. Vasogenic origin of visual field defects and optic nerve changes in glaucoma. Br J Ophthalmol. 1970;54:461-472.
4. Yang H, Williams G, Downs JC, et al. Posterior (outward) migration of the lamina cribrosa and early cupping in monkey experimental glaucoma. Invest Ophthalmol Vis Sci. 2011;52(10):7109-21.
5. Nguyen JV, Soto I, Kim KY, et al. Myelination transition zone astrocytes are constitutively phagocytic and have synuclein dependent reactivity in glaucoma. Proc Natl Acad Sci. USA 2011;108(3):1176-81.
6. Burgoyne CF. A biomechanical paradigm for axonal insult within the optic nerve head in aging and glaucoma. Exp Eye Res. 2010;93:120-32.
7. Downs JC, Roberts MD, Sigal IA. Glaucomatous cupping of the lamina cribrosa: a review of the evidence for active progressive remodeling as a mechanism. Exp Eye Res. 2011;93(2):133-40.

THE ROLE OF INTRACRANIAL CEREBRO-SPINAL FLUID PRESSURE IN POAG
A report on the Beijing Intracranial and Intraocular Pressure (iCOP) Study.

ROBERT N. WEINREB, MD

Optic disc cupping and thinning of the neuroretinal rim are the classic features of primary open-angle glaucoma (POAG), yet we still do not know why these features develop. As early as the 1970s, animal studies showed that cerebrospinal fluid pressure (CSF-P) or intracranial pressure might contribute to the pathogenesis of POAG,^1,2 but there was little follow-up at the time.

About 30 years later, Berdahl and colleagues retrospectively analyzed a large Mayo Clinic database of patients undergoing lumbar puncture, some of whom also happened to have glaucoma. In that analysis, the cohort with glaucoma had lower CSF-P.^3,4 Subsequent retrospective and prospective studies have shown that subjects with POAG have lower intracranial pressure and that glaucomatous visual field defects are positively correlated with the trans-laminar pressure difference (TLPD) and inversely correlated with CSF-P.^5,6

The real essence of the problem may be found in translaminar pressure difference (TLPD = IOP - CSFP). In normal eyes, TLPD should be about 4 mmHg to 8 mmHg. When IOP is elevated and/or CSF-P is low, TLPD is significantly higher and may lead to compression of the laminar cribrosa.

In research performed at the Tongren Eye Center by Ningli Wang, MD, PhD, and colleagues, it was found that both cup/disc ratio and neuroretinal rim area are correlated with TLPD, and they are better correlated than with IOP or CSF-P only.⁷ However, the true TLPD is the difference between IOP and orbital CSF pressure, not the lumbar pressure that was measured in all these studies.

To get a better grasp on the relationship between all these different pressures, they used an experimental dog model to continuously monitor ventricle CSF-P, lumbar CSF-P, orbital CSF-P and IOP. They found that ventricular pressure is higher than lumbar pressure, which in turn is higher than orbital CSF pressure. The true TLPD is about 30 mmH2O (or 2 mmHg) larger than our previously calculated TLPD. So it appears that we have all been underestimating translaminar pressure difference by using lumbar instead of orbital measures of CSF-P.

Role for MRI in Glaucoma Management

However, the assessment of the trans-laminar cribrosa pressure difference in the clinical studies aforementioned was based on lumbar CSF-P measurements, but not on measurement of the orbital CSF-P.^3-7 Because a direct measurement of the orbital CSF-P is invasive and not acceptable in clinical practice, a noninvasive way to get an estimate of the orbital CSF-P seems important.

As the orbital CSF-P provided a radial stress to the optic nerve sheath, due to Poisson's effect, higher intracra-nial pressure should lead to a wider optic nerve subarachnoid space width (ONSASW). It was hypothesized that in patients with POAG the ONSASW may narrow due to lower CSF pressure. The ONSASW is calculated by measuring the optic nerve sheath diameter (ONSD) and optic nerve diameter (OND).

The best way to measure this tiny space may be with magnetic resonance imaging (MRI). MRI offers high resolution of the soft tissue, good imaging of the CSF itself and of the whole length of the optic nerve in the orbit, all without radiation exposure.^8,9 With patients in a supine position, oblique coronal optic images are obtained at different distances (3 mm, 9 mm, and 15 mm) posterior to the subarachnoid globe.

A comparison of these measurements was made in 21 normal subjects, 21 POAG subjects with IOP ≤ 21 mmHg, and 18 subjects with POAG and IOP >21 mmHg.¹⁰

The orbital optic nerve subarachnoid space is significantly narrower in POAG patients with normal IOP than in those with high IOP or in healthy controls. This is consistent with the idea that the optic nerve subarachnoid fluid pressure is lower in POAG patients, and very consistent with research showing these patients have lower CSF-P.

As we think about how this research might translate into clinical care, one has to question whether it is possible to estimate orbital CSF pressure through lumbar puncture—and if so, whether the risk/benefit ratio of lumbar puncture would justify its use in glaucoma. It would be ideal to find a less invasive technique for measuring or estimating orbital CSF-P.

With that in mind, a prospective observational study of patients who, for various reasons, were undergoing a cranial MRI and lumbar puncture in the neurological department at Tongren Eye Center was initiated over a one-year period. The same scanning technique used in the previous studies was used, with the patient again in a supine position. In all, 30 subjects with wide variations in age, body mass index, mean arterial pressure, and CSF-P were evaluated. A strong relationship was found between CSF-P and the ONSASW and a slightly less significant relationship between CSF-P and optic nerve diameter.

This demonstrates that measuring the optic nerve subarachnoid sheath width with an MRI can provide a quantitative estimate of CSF pressure and may be a reliable predictor of the CSF pressure. ONSASW measures are easily included in routine cranial MRI scans and may be useful in glaucoma and also in several neurologic conditions.

References

1. Volkov VV. [Essential element of the glaucomatous process neglected in clinical practice]. Oftalmol Zh. 1976;31:500-4.
2. Yablonski M, Ritch R, Pokorny KS. Effect of decreased intracranial pressure on optic disc. Invest Ophthalmol Vis Sci. 1979;18[Suppl]:165.
3. Berdahl JP, Allingham RR, Johnson DH. Cerebro-spinal fluid pressure is decreased in primary open-angle glaucoma. Ophthalmology. 2008;115:763-8.
4. Berdahl JP, Fautsch MP, Stinnett SS, Allingham
   RR. Intracranial pressure in primary open angle glaucoma, normal tension glaucoma, and ocular hypertension: a case-control study. Invest Ophthalmol Vis Sci. 2008;49:5412-8.
5. Jaggi GP, Harley M, Ziegler U, et al. Cerebrospinal fluid segregation optic neuropathy: an experimental model and a hypothesis. Br J Ophthalmol. 2010;94(8):1088-93.
6. Ren R, Jonas JB, Tian G, et al., Cerebrospinal fluid pressure in glaucoma: a prospective study. Ophthalmology. 2010;117(2):259-66.
7. Ren R, Wang N, Zhang X, et al. Trans-lamina cribrosa pressure difference correlated with neuro-retinal rim area in glaucoma. Graefes Arch Clin Exp Ophthalmol. 2011; 249(7):1057-63.
8. Kimberly HH, Noble VE. Using MRI of the optic nerve sheath to detect elevated intracranial pressure. Crit Care. 2008;12(5):181.
9. Jaggi GP, Miller NR, Flammer J, et al. Optic nerve sheath diameter in normal-tension glaucoma patients. Br J Ophthalmol. 2012;96(1):53-6.
10. Wang NL, Xie XB, Yang DY, et al. Orbital cere-brospinal fluid space in glaucoma: The Beijing iCOP Study. Ophthalmology. 2012 Jun 28. [Epub ahead of print].

RETINAL GANGLION CELL IMAGING
New in vivo imaging techniques offer insight into patterns of retinal ganglion cell damage in glaucoma.

CHRISTOPHER K. S. LEUNG, MD, MB, CHB

The ability to follow changes in the retinal ganglion cells (RGCs) is vital to understanding the mechanisms of glaucoma as well as other optic neuropathies.

Like any other neuronal cells, retinal ganglion cells have a cell body or soma, an axon, and dendrites. Although we have not had the technology to look at individual retinal ganglion cells in humans, our team at the Chinese University of Hong Kong, along with Robert Weinreb, MD, at the University of California, San Diego, has been working to identify ways to assess the retinal nerve fiber layer (RNFL) and all aspects of the retinal ganglion cells to better understand how and where damage occurs in glaucoma.

In a number of studies, we have used RNFL imaging with spectral-domain optical coherence tomography (OCT) to observe axonal changes that occur in glaucoma.^1-6 There have been many interesting findings from these studies. For example, we have found that RNFL progression is most frequently detected inferotemporally at a distance approximately 2.00mm away from the disc center and that tracking the topographic changes of the RNFL using the RNFL thickness map is informative to monitor the continuum of glaucoma progression.⁷ Serial spectral domain OCT RNFL imaging can help us monitor glaucoma progression by following enlargement and deepening of RNFL defects over time (see Figure 1).

Figure 1. Serial retinal nerve fiber layer (RNFL) imaging with a spectral-domain optical coherence tomography showing enlargement (A) and deepening (B) of RNFL defects in glaucoma. The RNFL thickness deviation maps and the RNFL thickness maps are shown in the upper and lower panels, respectively. (Modified from Figures 3-4 in Leung CK, et al Retinal nerve fiber layer imaging with spectral-domain optical coherence tomography: patterns of retinal nerve fiber layer progression. Ophthalmology. 2012; In press.)

 

Beyond the Soma

Studies of neuroprotection and RGC damage largely rely on counting the number of retinal ganglion cell bodies. However, there is mounting evidence that RGC damage begins well before that point.

For example, Weber and colleagues found in an experimental glaucoma model that RGC degeneration begins with the dendritic arbor and ends with shrinkage of the cell soma.⁸ Morgan also provided evidence suggesting that RGCs undergo dendritic shrinkage prior to cell death in experimental glaucoma.⁹ In these studies, however, RGCs were examined in histological sections. We know there are different types of RGCs, some of which are larger or more complex than others. Ideally, we want to be able to follow the cells longitudinally in vivo to clearly identify if there is loss of dendritic complexity in glaucoma.

The first in vivo imaging of retinal ganglion cells was performed by Sabel and colleagues.¹⁰ After injecting a neuronal tracer into the superior colliculus to label the RGCs in rats, they used a confocal scanning laser ophthalmoscope to visualize individual RGCs. Only the cell body was visible, not the axons or dendrites.

Cordeiro and colleagues used another approach to label RGCs in rats. With intravitreal injection of annexin V, which is a marker for apoptosis, they imaged apoptosing retinal cells after inducing optic nerve injury.^11,12

Notably, these labeling methods are invasive and may not be suitable for long-term repeated examination. Intracranial and intravitreal injections may damage the RGCs.

Transgenic Mouse Models

In 2000, Feng and colleagues generated 25 strains of transgenic mice in which red, green, yellow, or cyan fluorescent proteins (together termed XFPs) are selectively expressed in neurons. In some strains, <1 percent of RGCs are labeled, providing the opportunity to examine not only the cell body but also the dendritic structures.¹³ These transgenic mice offer an effective approach to visualize RGCs in vivo (see Figure 2).

Figure 2. A retinal montage showing retinal ganglion cells (RGCs) imaged in vivo by a confocal scanning laser ophthalmoscope in a Thy-1 YFP transgenic mouse. The soma, axons and dendrites of individual RGCs can be visualized and quantified (Adapted from Leung CK et al. Long-term in vivo imaging and measurement of dendritic shrinkage of retinal ganglion cells. Invest Ophthalmol Vis Sci 2011;52:1539-47.).

We have used an optic nerve crush model to study how the cells respond to optic nerve injury. In the initial two weeks, the first signs of damage are shrinkage of the dendritic tree, followed by loss of axons, and then the cell body (see Figure 3).^14,15 The presence of the cell body, therefore, is not indicative of a healthy cell. This work demonstrates that loss of the dendrites is actually a more sensitive bio-marker to examine the integrity of retinal ganglion cells.

Figure 3. Long-term serial in vivo imaging of retinal ganglion cell degeneration after optic nerve crush. Progressive dendritic shrinkage precedes loss of the axons and the cell bodies. Loss of dendritic branches and reduction in dendritic field were evident seven days after optic nerve crush. There was progressive dendritic shrinkage in the following week. The axon became indistinct on day 13 with complete loss of dendrites and cell body on day 15. (Modified from Leung CK, et al. Long-term in vivo imaging and measurement of dendritic shrinkage of retinal ganglion cells. Invest Ophthalmol Vis Sci. 2011;52:1539-47.).

We are now using a similar experimental model to look at the retinal microglia. In this case, we use another type of transgenic mouse (CX3CR1^GFP/+), but the same imaging techniques, to investigate the change in morphology and density of retinal microglia following optic nerve injury. We are also working on a new transgenic mouse model that will allow us to examine the RGCs and microglia together, which may help in understanding their interaction in different forms of optic neuropathies.

These are exciting new techniques. Imaging of protein expression in these mice serves as a sensitive indicator of the integrity of RGCs and provides a non-invasive method for longitudinal study of the mechanism of RGC degeneration. Measuring the rate of dendritic shrinkage could become a new paradigm for investigating neuronal degeneration and evaluating the response of neuroprotective treatments in the future.

References

1. Leung CK, Choi N, Weinreb RN, et al. Retinal nerve fiber layer imaging with spectral-domain optical coherence tomography: pattern of RNFL defects in glaucoma. Ophthalmology. 2010;117:2337-44.
2. Leung CK, Lam S, Weinreb RN, et al. Retinal nerve fiber layer imaging with spectral-domain optical coherence tomography: analysis of the retinal nerve fiber layer map for glaucoma detection. Ophthalmology. 2010;117:1684-91.
3. Leung CK, Ye C, Weinreb RN, et al. Retinal nerve fiber layer imaging with spectral-domain optical coherence tomography a study on diagnostic agreement with Heidelberg Retinal Tomograph. Ophthalmology. 2010;117:267-74.
4. Leung CK, Choi N, Weinreb RN, et al. Evaluation of retinal nerve fiber layer progression in glaucoma a prospective analysis with neuroretinal rim and visual field progression. Ophthalmology. 2011;118:1551-7.
5. Leung CK, Chiu V, Weinreb RN, et al. Evaluation of retinal nerve fiber layer progression in glaucoma: a comparison between spectral-domain and time-domain optical coherence tomography. Ophthalmology. 2011;118:1558-62.
6. Leung CK, Cheung CY, Weinreb RN, et al.Evaluation of retinal nerve fiber layer progression in glaucoma: a comparison between the fast and the regular retinal nerve fiber layer scans. Ophthalmology. 2011;118:763-7.
7. Leung CK, Yu M, Weinreb RN, et al. Retinal nerve fiber layer imaging with spectral-domain optical coherence tomography: Patterns of retinal nerve fiber layer progression. Ophthalmology. 2012; Jun 5. [Epub ahead of print].
8. Weber AJ, Kaufman PL, Hubbard WC. Morphology of single ganglion cells in the glaucomatous primate retina. Invest Ophthalmol Vis Sci. 1998;39:2304-20.
9. Morgan JE. Retinal ganglion cell shrinkage in glaucoma. J Glaucoma. 2002;11(4):365-70.
10. Sabel BA, Engelmann R, Humphrey MF. In vivo confocal neuroimaging (ICON) of CNS neurons. Nat Med. 1997;3:244 7.
11. 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(36):13352-6.
12. Guo L, Salt TE, Luong V, et al. Targeting amyloid-beta in glaucoma treatment. Proc Natl Acad Sci USA. 2007;104(33):13444-9.
13. Feng G, Mellor RH, Bernstein M, et al. Imaging neuronal subsets in transgenic mice expressing multiple spectral variants of GFP. Neuron. 2000Oct;28(1):41-51.
14. Leung CK, Weinreb RN, Li ZW, et al. Long-term in vivo imaging and measurement of dendritic shrinkage of retinal ganglion cells. Invest Ophthalmol Vis Sci. 2011;52:1539-47.
15. Li ZW, Liu S, Weinreb RN, et al. Tracking dendritic shrinkage of retinal ganglion cells after acute elevation of intraocular pressure. Invest Ophthalmol Vis Sci. 2011;52(10):7205-12.

III. THERAPEUTICS IN CLINICAL PRACTICE AND BEYOND ADVANCING TREATMENT
Base decisions on a combination of pressure, progression, and predicted risk.

ROBERT D. FECHTNER, MD, FACS

The decision of when to advance treatment is one that glaucoma clinicians face daily. Regardless of your personal choices for initial therapy, the decision to add another medication or otherwise advance treatment beyond that initial choice must be based on three factors: Pressure, progression, and risk predictions for that patient.

Pressure

Intraocular pressure (IOP) is the simplest of these three considerations. It is a prominent risk factor in glaucoma and—at least in some patients—a causative factor. Thus far, IOP is the only approved modifiable factor; every glaucoma treatment that we have has received regulatory approval based on its efficacy in reducing IOP.

We know from numerous studies over the years that there is a direct relationship between pressure and progression and that reducing IOP can prevent or delay glaucomatous damage. So, it makes sense to establish a target pressure, with the first goal of therapy being to maintain IOP at or below that target. Treatment should be advanced when initial monotherapy or laser fails to achieve the target pressure, as it eventually will for many patients.

In years past, clinicians have often relied on a monocular drug trial for advancing (or initiating) therapy. It has been shown, however, that the monocular trial is an outdated model based on flawed assumptions, and is no more informative than simply using the treated eye's unadjusted IOP change.¹

Progression

Undesirably high IOP is not the only justification for advancing therapy. If the disease is progressing despite what is believed to be reasonable IOP control, it may be necessary to move to the next step in your treatment algorithm. It is not always easy, however, to determine what constitutes clinically significant progression.

We have often relied on events alone to identify progression. In other words, when a patient moves from the "normal" into the "abnormal" range on a diagnostic test, that triggers the decision to advance treatment (see Figure 1). The problem with a purely event-driven approach is that it ignores trends—not detecting, for example, an eye that is deteriorating rapidly but still within the "normal" range. Events can be either structural (e.g., cupping identified on an optic nerve photographs) or functional (e.g., the proliferation of black boxes on the Humphrey Field Analyzer (Carl Zeiss Meditec, Inc.) pattern deviation map). In either case, the event indicates that something is statistically not normal.

Figure 1. Two photos of a patient's optic nerve, taken less than 12 months apart. The change from the image on the left to the one on the right is an event that indicates significant progression and should trigger an advance in therapy.

Trend analysis is equally important because it provides more detail about the rate of change. If we knew our patients' life expectancies and were very good at predicting trends, we might be able to make much better treatment decisions. This is a difficult task, but I believe that trend analysis will be increasingly important in glaucoma care. We don't necessarily want to wait until an eye crosses the threshold into identifiably statistically abnormal—it would be far better to identify the deteriorating trend prior to that point.

There are several strategies for refining and improving upon our ability to detect progression. Medeiros and colleagues at the Hamilton Glaucoma Center, University of California, San Diego (UCSD) have recently published a Bayesian hierarchical modeling approach for integrating event- and trend-based assessments of visual field progression that appears to perform better than either method alone.² And because both events and trends can be measured on the same technology platform, this is achievable for a non-academician.

The same group has shown that combining structure and function in a joint regression model results in more accurate and precise estimates of the slope of change.³ In clinical practice, it can be challenging to combine structural and functional data because the devices don't "talk" to one another, but this approach has the potential to be very powerful.

Another very promising paper from Bowd and colleagues, also from the Hamilton Glaucoma Center, UCSD, shows that glaucomatous progression in suspect eyes can be predicted from baseline confocal scanning laser ophthalmoscope (CSLO) and standard automated perimetry (SAP) measurements analyzed with relevance vector machine (RVM) classifiers. The RVM analyses predicted future progression with a higher accuracy than either the CSLO or SAP global indices.⁴

Despite the promise of newer diagnostic technologies, clinicians would be remiss to abandon proven techniques such as visual field testing and fundus photography. Optic nerve photographs, for example, have the advantage of remaining accessible and useful over time, regardless of changes in technology platforms.

Stein and colleagues at the University of Michigan recently analyzed managed-care claims data for more than 550,000 patients with open-angle glaucoma or suspected glaucoma to assess trends in visual field testing, fundus photography, and other ocular imaging between 2001 and 2009.⁵ Perhaps not surprisingly, the rate of fundus photography was flat; photography was the least common of the diagnostic tools analyzed. More disturbing was the finding that over the decade, both optometrists and ophthalmologists decreased their use of visual field testing and dramatically increased their use of newer ophthalmic imaging tests. The authors concluded that increased reliance on imaging technology, in lieu of visual testing, may be detrimental to patient care.

We need both functional and structural testing. In addition to watching for events that clearly demarcate progression, we also need to pay attention to trends. If progression is highly suspected or confirmed, treatment should be advanced.

Risk Prediction

In addition to predicting progression based on real-time changes in diagnostic testing, we can also use risk calculators to predict how rapidly an individual eye is likely to progress. Glaucoma is typically a slow-moving disease and in many patients may progress so slowly as not to cause any significant visual impairment during the patient's lifetime. But if we could better identify those patients who will progress rapidly, we would certainly want to treat them more aggressively from the start.

The Early Manifest Glaucoma Trial (EMGT) was very helpful in identifying key risk factors for progression. In that study, progression was more likely with higher baseline IOP, exfoliation, bilateral disease, worse mean deviation, and older age, as well as frequent disc hemorrhages during follow-up (see Figure 2).⁶ These risk factors have since been incorporated into a number of risk calculation tools, but clinically we can also look for these early indicators and advance therapy accordingly.

Figure 2. At left: baseline factors for progression (Cox proportional hazard model); at right: follow-up factors for progression (Cox proportional hazard models). (Adapted from Leske MC, Heijl A, Hussein M, et al.; Early Manifest Glaucoma Trial Group. Factor for glaucoma progression and the effect of treatment: the Early Manifest Glaucoma Trial. Arch Ophthalmol. 2003;121(1):48-56.)

 

In conclusion, uncontrolled pressure should trigger more advanced therapy, as it always has, but IOP must not be the only trigger. Evidence of progression, using diagnostic tools both new and well-established, and risk prediction with risk factor analysis and risk calculators should also be considered for the most effective management of glaucoma.

References

1. Realini TD. A prospective, randomized, investigator-masked evaluation of the monocular trial in ocular hypertension or open-angle glaucoma. Ophthalmology. 2009;116(7):1237-42.
2. Medeiros FA, Weinreb RN, Moore G, et al. Integrating event- and trend-based analyses to improve detection of glaucomatous visual field progression. Ophthalmology. 2012;119(3):458-67.
3. Medeiros FA, Zangwill LM, Girkin CA, et al. Combining structural and functional measurements to improve estimates of rates of glaucomatous progression. Am J Ophthalmol. 2012;153(6):1197-205.
4. Bowd C, Lee I, Goldbaum MH, et al. Predicting glaucomatous progression in glaucoma suspect eyes using relevance vector machine classifiers for combined structural and functional measurements. Invest Ophthalmol Vis Sci. 2012;53(4):2382-9.
5. Stein JD, Talwar N, Laverne AM, et al. Trends in use of ancillary glaucoma tests for patients with open-angle glaucoma from 2001 to 2009. Ophthalmology. 2012;119:748-58.
6. Leske MC, Heijl A, Hussein M, et al; Early Manifest Glaucoma Trial Group. Factors for glaucoma progression and the effect of treatment: the early manifest glaucoma trial. Arch Ophthalmol. 2003;121(1):48-56.
   
   
   
   

LOGTS AND NEUROPROTECTION
Consider the effects of treatment regimens not just on IOP but on the outcome of the disease process itself

LOUIS B. CANTOR, MD

Glaucoma, like all of other optic neuropathies, results in death of retinal ganglion cells. Neuroprotection, which can be defined as any strategy to prevent retinal ganglion cell (RGC) damage, has long been of interest as a way to supplement intraocular pressure (IOP) lowering—particularly in those cases where pressure management is insufficient to manage the disease.

Although IOP is the primary risk factor for glaucoma, we know there are many other sources of stress or potential pathways for RGC damage, including mechanical, genetic, vascular, metabolic, and other factors that are important in the maintenance of neuronal function. Neuroprotection offers the potential to rescue injured retinal ganglion cells before they die or to improve the eye's risk profile in the face of elevated IOP or other stresses.

A number of neuroprotective strategies have been or are under investigation, including neurotrophic factors, vasopro-tection with ocular blood flow enhancers, calcium channel blockers, nitric oxide syn-thase (NOS) inhibitors, alpha-2 agonists, N-methyl-D-asparate (NMDA) antagonists, and others.

LOGTS Design and Results

The Low Pressure Glaucoma Treatment Study (LOGTS), led by Theodore Krupin, MD, was designed to evaluate brimonidine 0.2% vs. timolol 0.5% in preserving visual function in patients with low-pressure glaucoma. In this prospective trial, more patients were randomized to brimoni-dine (n=99) than to timolol (n=79) due to anticipated dropout from allergies. Visual field progression was measured using three different models: Progressor; the glaucoma change probability maps (GCPM); and 3-omitting method.

The theoretical background for a neu-roprotective benefit of brimonidine is solid. The drug has been shown to penetrate the eye in sufficient concentrations to have an effect on the alpha-2 receptor.¹ Alpha-2 receptors do exist in the retina and in the retinal ganglion cell layer.² And in several experimental models, brimonidine has been shown to promote RGC survival.^2-4

The results of LOGTS add weight to the theoretical underpinning. For the first two years of the study there was very little difference in progression. After 24 months, there was much better visual field survival in the brimonidine-treated group than those treated with timolol. And that separation got wider with time throughout the remaining two years of follow-up.⁵

These results were consistent across all three methods of visual field analysis. There were no IOP-related differences between the groups—no matter how the data were sliced—that would explain the study results.

In managing our patients with glaucoma, it is important to consider the effects of treatment regimens not just on IOP but on the outcome of the disease process itself. Treatment with brimonidine in this study enhanced visual field survival better than treatment with timolol in a low-tension glaucoma population, but we do not yet know the mechanism by which this occurred. The similar IOP lowering in the two groups suggests a non-IOP related mechanism. Together with the pre-clinical data, a neuroprotective mechanism seems likely. However, the findings could be related to differences in the mechanism of action of the two drugs or to factors not assessed in the study. Validation of this possible neuroprotective mechanism requires additional research.

References

1. Acheampong AA, Shackleton M, Tang-Liu DD. Comparative ocular pharmacokinetics of brimoni-dine after a single dose application to the eyes of albino and pigmented rabbits. Drug Metab Dispos. 1995;23(7):708-12.
2. Wheeler LA, Gil DW, WoldeMussie E. Role of alpha-2 adrenergic receptors in neuroprotection and glaucoma. Surv Ophthalmol. 2001;45 Suppl 3:S290-6.
3. Wheeler LA, Lai R, Woldemussie E. Brimonidine protects retinal ganglion cells from the effects of optic nerve crush. Euro J Ophthalmol. 1999;9(suppl 1):S17-S21.
4. Burke J, Chun T, Lee S, et al. Effect of topical brimonidine formulations or systemic administration on retinal ganglion cell survival vs. ERG preservation in a rat retinal ischemia/reperfusion model. Invest Ophthalmol Vis Sci. 2001;42(4):S23.
5. Krupin T, Liebmann JM, Greenfield DS, et al, on behalf of the Low-Pressure Glaucoma Study Group. A randomized trial of brimonidine versus timolol in preserving visual function: Results from the Low-pressure Glaucoma Treatment Study. Am J Ophthalmol. 2011;151:671-81.