MANAGING GLAUCOMA and INTRAOCULAR PRESSURE

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Release Date: November 1, 2013
Expiration Date: October 31, 2014

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Description/Goal

Glaucoma is among the most common causes of irreversible vision loss throughout the world, and the projected number of individuals with the disease in the year 2020 is 79.6 million. Of these, 74% will have open-angle glaucoma (OAG). In the United States alone, it is estimated that more than three million people will have OAG by 2020.

Reduction of intraocular pressure (IOP) has been shown to effectively reduce the risk of glaucoma progression across the spectrum of IOP, from low to high, and across the spectrum of disease severity, from ocular hypertension to advanced glaucoma. However, IOP reduction alone may be inadequate for preventing progression in some patients.

While IOP reduction is the only proven treatment for OAG, many patients experience progressive optic nerve degeneration and visual field loss despite significant IOP lowering. Normal-tension glaucoma (NTG) is a type of OAG resulting in damage to the optic nerve and abnormalities of the visual field, and IOP in this type of glaucoma is not higher than what is 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.

This educational activity will explore several different facets of glaucoma management, including the role of IOP and related therapeutic 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. Distinguish when lowering IOP will not halt progression of glaucoma.
  2. Outline the diagnosis and management of normal-tension glaucoma.
  3. Identify therapeutic strategies for glaucoma that progresses despite very low IOP.
  4. Recall recent studies and trials, as well as their implications for glaucoma therapy beyond IOP reduction.

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I. DIAGNOSTICS IN CLINICAL PRACTICE

DIAGNOSING GLAUCOMA

Patients with normal IOP are among the most challenging.
Robert N. Weinreb, MD

The goal of glaucoma management is to preserve visual function and visionrelated quality of life. To do this, we must accurately diagnose glaucoma and detect progression in the first place, and then be able to offer treatments to arrest the course of the disease.

Diagnosis and detection of progression remain challenging, despite important technology developments in our field. Many of us were taught that both a visual field defect and optic disc changes are necessary to diagnose glaucoma. In fact, specific diagnosis can be based on progressive change on either structural or functional measures.1 One can have very large changes in structure without significant functional loss early in the disease. However, late in glaucoma, when there has already been considerable loss of the retinal nerve fiber layer (RNFL), small changes in RNFL thickness are accompanied by large changes in visual field. This is a major reason why structure and function don't seem to agree in so many patients. In an ideal world, we don't want to wait until this point to diagnose glaucoma. A combined structure-function index, as Dr. Medeiros describes in this supplement, may provide an opportunity to more reliably make a diagnosis regardless of the stage of the disease.

Genetic testing, as Dr. Pasquale describes in these pages, also holds great promise for earlier identification of those patients who are most likely to develop glaucoma or to progress. And better functional tests that actually measure real-world visual performance may also be helpful (sidebar).


New Methods

 

Perhaps most challenging for clinicians are those patients who have glaucomatous damage and perhaps continue to progress despite normal intraocular pressure. I do not generally use the term "normal-tension glaucoma," and instead diagnose such patients with open-angle glaucoma (POAG). Nevertheless, having normal intraocular pressure (IOP) does make it more difficult to diagnose and follow these patients, and to know whether pressure-lowering medications will be beneficial.

Recent data suggest that patients with normal IOP and glaucoma often have a loss of spontaneous venous pulsation. This may be due either to mechanical venous factors as Morgan suggests2 or to increased pressure in the subarachnoid space, as Hanspeter Killer, MD, believes.

  1. 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.
  2. Morgan WH, Hazelton ML, Balaratnasingamm C, et al. The association between retinal vein ophthalmodynamometric force change and optic disc excavation. Br J Ophthalmol. 2009; May;93(5):594-6.



DETECTING PROGRESSION IN CLINICAL PRACTICE

An index that combines structural and functional estimates of retinal ganglion cell counts may offer the most reliable measure 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.

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 to –3 dB. That would correspond to an RGC population of approximately 600, 000 to 700,000 cells, representing an approximately 30-percent loss from the average RGC number in healthy eyes.

Visual field 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 (Figure 1).1 This relationship means 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 despite apparently statistically normal visual fields.


figure1

 

To progress from that very early visual field defect of –3 dB to a mean deviation of –10 dB, which most would agree represents quite severe visual field loss and potential functional impairment, one need only lose another 300,000 cells—fewer than were lost to get to the point of a detectable field loss in the first place. Therefore, reliance on visual field testing alone will potentially result in late diagnosis and underestimate the rate of glaucoma progression, especially in the early stages of the disease. There are also challenges in using structural measures to diagnose progression. Optic nerve photos give us important information about the current state of the nerve, but they don't offer a quantitative as- sessment of the loss over time.

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 neuroretinal rim and retinal nerve fiber layer (RNFL). In advanced disease, however, when the nerve fiber layer has already thinned significantly, these tests reach a "floor"; relatively large changes in function may be associated with only minor or no detectable changes in structure.2

These observations about the performance of SAP and OCT 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.

Combining Structure and Function

Identifying the extent of RGC loss may be a better method for monitoring glaucoma progression. It is the irreparable loss of these cells that leads to both functional deficits and changes in the RNFL. Although we cannot precisely count RGCs in vivo, Harwerth and associates showed that the number of retinal ganglion cells can be reliably estimated from either visual field SAP sensitivity data or from OCT RNFL analysis.3

We recently developed a single index that combines structure and function measures to provide an age-corrected estimate of ganglion cell loss.1 The two methods for estimating RGC counts are weighted based on disease stage. Unlike visual field 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.1

We have also shown that the CSFI detects progression in a significantly higher number of patients compared to conventional indices.4 In this study, 288 eyes of glaucomatous subjects were followed for an average of 3.8 years. The combined index detected change in 22 percent of glaucomatous eyes compared to 8.5 percent for visual fields 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 (Figure 2), potentially resulting in more effective management of our glaucoma patients.


figure2

 

  1. Medeiros FA, Zangwill LM, Anderson DR, et al. Estimating the rate of retinal gan- glion cell loss in glaucoma. Am J Ophthalmol. 2012;154(5):814-24.
  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. Meira-Freitas D, Lisboa R, Tatham A, et al. Predicting progression in glaucoma suspects with longitudinal estimates of retinal gan- glion cell counts. Invest Ophthalmol Vis Sci. 2013;54(6):4174-83.



GENETIC TESTING FOR GLAUCOMA

Exciting developments make genetic testing for glaucoma a possibility in the not-too-distant future.
Louis Pasquale, MD, FARVO

The promise of genetic testing for glaucoma is that it may help us identify early-stage glaucoma patients before they have lost so many retinal ganglion cells that their vision is impaired.

As early as 1997, researchers had identified a gene, myocilin (MYOC), that causes primary open-angle glaucoma (POAG).1 Yet 15 years later, this discovery has had little impact on clinical practice. The reason for this translational lag is that we're just beginning to understand the role of these major genetic mutations, along with many smaller but more common mutations.

For example, through mouse models, we have recently learned that a specific MYOC mutation, exon 3, causes a protein misfolding that makes trabecular meshwork cells become dysfunctional.2 When this occurs, the intraocular pressure goes up and the retinal ganglion cell counts go down. More importantly, it has recently been shown that if mice with this specific mutation are given topical 4-phenylbutyrate eye drops, that process can be reversed.3 This may be a very important key to treat selected juvenile open angle glaucoma patients.

Amassing More Clues

From the map of the human genome, we know that at every 10 million bases or so there is a common genetic variation. Those common variants, also known as single-nucleotide polymorphisms (SNPs), serve as risk factors for complex diseases like primary open angle glaucoma. There are several polymorphisms (each with a variety of SNPs) that have been associated with POAG. The most common of these is CDKN2BAS, a non-coding variant that, via epi-genetic mechanisms, controls two nearby cell cycle genes.

The CDKN2BAS alleles are actually associated with a reduced risk of glaucoma. These protective SNPs are much more common in Caucasian populations compared to African population (Figure 3), so part of the increased risk for POAG among people of African descent may be due to the fact that they lack these protective variants.


figure3

 

Some genes implicated in POAG may only be activated by environmental factors. For example, the nitric oxide synthase 3 gene (NOS3) interacts with post-menopausal hormone use and other factors. While NOS3 is not a gene that rises to the top in a genome-wide scan for POAG, it does appear to be a trigger in certain environmental strata. Other potential environmental factors that may modify the association between NOS3 (or other genetic variants) and POAG include aging, smoking, caffeine intake, and antioxidant use.

We have a growing number of genetic biomarkers that are susceptibility factors for glaucoma (Figure 4), but the important gains will come when we are able to translate this alphabet soup of allelic variants into a genetic risk calculator that would allow for early identification and intervention before an individual sustains significant functional deficits from glaucoma. This may be doable in the next five to 10 years.


figure4

 

The Rotterdam Group is already working on glaucoma prediction models based on genetic information.4 Their models don't yet have the high sensitivity and specificity that we would like to see but with the discovery and incorporation into the models of additional polymorphisms, that is likely to change. This is already happening with conditions such as Crohn's disease, for which there are close to 70 known polymorphisms.

At this point, it may be reasonable to order genetic testing for some of the rarer mutations for juvenile POAG patients or for children in families with a history of early-onset POAG. But to the question of whether genetic testing for the more common variants implicated in the disease is appropriate, the answer today is unequivocally "no." There may be hundreds or thousands of common variants that collectively contribute to glaucoma. Each of these on its own may have very modest effects, with environmental factors creating additional uncertainty. We need more than the seven biomarkers we have for POAG—or the 19 we have for AMD, or even the 67 we have for Crohn's disease—to figure out true risk.

The good news is that from modest beginnings, we are now entering the second phase of the genomics era in glaucoma. This next stage of development will be characterized by larger, more collaborative data sets through the National Eye Institute's NEIGHBORHOOD Consortium and the International Glaucoma Genetics Consortium, so that we can identify more biomarkers, not only for glaucoma overall but for specific POAG-linked traits such as central corneal thickness, intraocular pressure and cup/disc ratio. This ongoing development will lead to improved diagnostic capability and, ultimately, new ways to treat glaucoma.

  1. Stone EM, Fingert JH, Alward WLM, et al. Identification of a gene that causes primary open-angle glaucoma. Science 1997;275:668.
  2. Zode GS, Kuehn MH, Nishimura DY, et al. Reduction of ER stress via a chemical chaperone prevents disease phenotypes in a mouse model of primary open angle glaucoma. J Clin Invest 2011;121(9):3542-53.
  3. Zode GS, Bugge KE, Mohan K, et al. Topi- cal ocular sodium 4-phenylbutyrate rescues glaucoma in a myocilin mouse model of primary open-angle glaucoma. Invest Ophthalmol Vis Sci 2012;53(3):1557-65.
  4. Ramdas WD, van Kookwijk LM, Cree AJ, et al. Clinical implications of old and new genes for open-angle glaucoma. Ophthalmology 2011;118(12):2389-97.



II. UNDERSTANDING WHAT DAMAGES THE OPTIC NERVE

GLAUCOMA IS A NEURO-DEGENERATIVE DISEASE

Patients with normal IOL underscore the importance of understanding how optic nerve damage occurs—and what factors other than IOP may be implicated.
Robert N. Weinreb, MD

A patient from several years ago illustrates the conundrum we face in dealing with glaucomatous progression in a patient with normal intraocular pressure (IOP). I monitored this patient for years, initiated medical therapy, performed a trabeculectomy, and watched her experience expansion of RNFL defect, loss of the neuroretinal rim and substantial functional loss, despite peak pressures in the mid-teens on medical therapy and ≤10 mmHg following the trabeculectomy.

Clearly, my patient had glaucoma. The question is, why did she continue to progress? Did we not lower the pressure enough? It's hard to imagine getting much below 8 mmHg, which was typical for her. Perhaps there was some other mechanism at play and she needed something beyond IOP lowering.

This case is a good example of how patients can continue to lose visual field despite lowering their pressure. We do not yet have a definitive answer for why retinal ganglion cells die in glaucoma, or even whether that cell death is primary or secondary to some other process. The concept of neuroprotection—of preventing retinal ganglion cell death, independent of lowering intraocular pressure—is an appealing one.

Whether one calls this condition "normal tension glaucoma" or, as I prefer, simply "primary open angle glaucoma" (POAG), the final common pathway for all forms of glaucomatous visual impairment is neuronal death. We recognize that glaucoma is a progressive neurodegeneration rather than merely a condition related to intraocular pressure. In fact, I think we're recognizing that glaucoma is not just an eye disease.

Other neurodegenerative diseases, such as Alzheimer's, Parkinson's, stroke and Huntington's, involve the entire central nervous system or parts of the central nervous system. But glaucoma, with 60 to 100 million affected individuals worldwide, is probably more prevalent than all of these diseases.

There are some shared characteristics between these other neurodegenerative conditions and glaucoma, particularly with regard to disease progression. For example, in some other neurodegenerative diseases it is fairly well established that synap- tic loss—a loss of the connections between the neurons—occurs prior to cell death. We have some indirect and animal study evidence of synaptic loss in glaucoma as well. Proteins implicated in Alzheimers may also play a role in glaucoma. Beta amyloid, the protein that forms plaques in the brains of Alzheimer's patients, may play a normal physiologic role related to the maintenance of synapses between neurons before it gets aggregated into plaques. It is possible that the pathologic cleavage of beta amyloid that happens in Alzheimer's disease may also be happening in the retina in glaucoma.

Retinal ganglion cells (RGCs) are the optic nerve axons. Their target is the lateral geniculate nucleus in the brain. The lateral geniculate nucleus is made up of several layers, each defined by one of the three types of retinal ganglion cells targeting that layer. In addition to these three major types of RGCs, we have learned in recent years that there are more than 20 different subtypes of RGCs, but we don't yet know if there is preferential loss of a particular type of retinal ganglion cell in glaucoma.

An eye with glaucoma is not only losing RGCs, but the optic nerve is "shrinking." A healthy optic nerve is like a thick, multi-strand rope going from the eye to the lateral geniculate nucleus. In glaucoma, as relay neurons are lost, the thick rope becomes a string, and the ability to transmit visual signals travel to the brain is impaired. And in fact, we actually see a loss of neurons, not just in the optic nerve, but in the lateral geniculate nucleus itself in the brains of patients with glaucoma. Glaucoma truly is a neurodegenerative disease that involves not only the eye but also the brain.




THE ROLE OF IOP

We know IOP matters a great deal, but deciding how high is too high and how low is low enough remains challenging.
Yvonne Ou, MD

Since 1622, intraocular pressure (IOP) has been very much linked with glaucoma. The American Academy of Ophthalmology's preferred practice pattern for glaucoma currently defines primary open-angle glaucoma (POAG) as "a progressive chronic optic neuropathy in adults in which intraocular pressure and other currently unknown factors contribute to damage."

Major population-based studies have shown that increasing IOP is related to glaucoma prevalence.1,2 We also know that the risk of developing glaucomatous field loss increases with increasing IOP, and that the greater and more consistent the reduction in IOP the greater the reduction in the risk of subsequent optic nerve damage. But there is much that we still do not understand about the role of IOP in this disease.

For example, what level of IOP results in glaucomatous optic neuropathy? Some would suggest IOP greater than 21 mmHg. But according to population-based studies, the proportion of patients with IOP > 21 mmHg who have glaucomatous optic neuropathy varies considerably, from a low of 13 percent in a study in Northern Italy to as high as 71 percent in Barbados (Figure 5). So, although higher IOP is correlated with glaucomatous optic neuropathy, high IOP alone is not sufficient for glaucoma diagnosis.


figure5

 

A number of important studies have shown that lowering baseline IOP prevents the onset of glaucoma3,4 and that lowering IOP prevents glaucoma progression (Figure 6). What these studies have shown is that decreasing IOP even by 1 mmHg reduces the risk of progression and that reducing IOP by 20 percent or more can significantly decrease the risk of progression.


figure6

 

The Advanced Glaucoma Intervention Study (AGIS) showed that patients with IOP below 18 mmHg at 100 percent of the study visits over six years did appear to have more stable disease compared to patients in whom IOP may have fluctuated above 18 mmHg over the course of the study.5 Moreover, the mean IOP in those patients who were consistently below 18 mmHg at every visit was 12.3 mmHg. That has led some to conclude that 18 mmHg is the magic number—or that if we just keep the pressure 12 mmHg or lower in advanced glaucoma, we are going to stop all progression.

Unfortunately, that is not the case. While it is true that, on average, the group with IOP consistently below 18 mmHg did not progress, within the group there were certainly individuals who did progress, despite their well-controlled IOP. The AGIS investigators acknowledge that maintaining an IOP < 18 mmHg does not ensure preservation of the visual field. Over the seven years of the AGIS study, in fact, 14 percent of the patients in that well-controlled group had worsening disease.

Which IOP?

There are many ways to measure and think about IOP, and it is not at all clear which way is most important. In addition to baseline IOP and follow-up IOP, for example, one might want to look at nocturnal, diurnal or 24-hour IOP. Peak IOP may predict visual field progression better than mean IOP, or it may be the degree of IOP fluctuation that matters most. And, if we decide that fluctuation matters, it is not clear whether the fluctuation within a 24-hour period is more or less important than longer-term, visitto-visit fluctuation.

A post hoc AGIS analysis tells us that patients in whom the standard deviation of IOP over the course of follow-up visits was >3 mmHg seemed to progress more than those patients where the IOP fluctua- tion was <3 mmHg.6 However, this analysis included post-intervention IOPs. Almost by definition, those who were progressing would be expected to have more fluctuation because they received an additional IOP-lowering intervention.

In another analysis that did not include post-intervention IOPs, there is a statistically significant difference in progression between those who had low IOP variation and high IOP variation, but only in the group in which baseline mean IOP was low, suggesting that IOP fluctuation plays a greater role in progression among that subset of patients.7

Prognostic Factors

According to a recent evidencebased review, the two prognostic factors that are most strongly associated with glaucomatous visual field progression are age (for all glaucoma) and disc hemorrhages (for normaltension glaucoma).8 Baseline IOP and baseline visual field loss, as one would expect, are also strongly associated with progression, although not as strongly as age and disc hemorrhages.

In the future, glaucoma trials will likely consider not only visual field or functional progression but structural progression as well. For example, the United Kingdom Glaucoma Treatment Study, the first trial of its kind to evaluate the benefit of medical IOP lowering using prostaglandin analogs, will look at baseline biomarkers and structural imaging at all the follow-up visits, in addition to the primary endpoint of visual field deterioration.9

In conclusion, IOP is important but cannot account for all glaucomatous optic neuropathy. The large clinical trials have provided outstanding evidence that lowering IOP will prevent glaucoma onset and slow progression, although treated patients do continue to progress.

While it is important to have a target IOP in mind in treating this disease, I would be wary of using any single cutoff either for diagnosing or monitoring glaucoma. With each visit, as more structural and functional data are gathered, one should re-assess the ideal target. I would argue that in addition to lowering IOP we definitely need other therapeutic targets. Researchers continue to investigate IOP fluctuation and other parameters. Until we have more information, consistently lowering IOP is still the best treatment we have for slowing the progression of this disease.

  1. Sommer AE, Tielsch JM, Katz J, et al. Relationship between intraocular pressure and primary open angle glaucoma among white and black Americans. Arch Ophthalmol. 1991;109:1092.
  2. Francis B, Varma R, Chopra V, et al, Los Angeles Latino Eye Study Group. Intraocular pressure, central corneal thickness and prevalence of open-angle glaucoma: the Los Angeles Latino Eye Study. Am J Ophthalmol. 2008;146:743.
  3. Kass MA, Heuer DK, Higginbotham EJ, e 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; Jun;120(6):701-13; discussion 829-30.
  4. Miglior S, Zeyen T, Pfeiffer N, et al; European Glaucoma Prevention Study Group. Results of the European Glaucoma Prevention Study. Ophthalmology. 2005;112(3):366-75.
  5. The Advanced Glaucoma Intervention Study (AGIS) 7. The relationship between control of intraocular pressure and visual field deterioration. The AGIS Investigators. Am J Ophthalmol. 2000;130(4):429-40.
  6. Nouri-Madhavi K, Hoffman D, Coleman AL, et al; Advanced Glaucoma Intervention Study. Predictive factors for glaucomatous visual field progression in the Advanced Glaucoma Intervention Study. Ophthalmology. 2004;111(9):1627-35.
  7. Caprioli J, Coleman AL. Intraocular pressure fluctuation a risk factor for visual field progression at low intraocular pressures in the advanced glaucoma intervention study. Ophthalmology. 2008; 115(7):1123-9.
  8. Ernest PJ, Schouten JS, Beckers HJ, et al. An evidence-based review of prognostic factors for glaucomatous visual field progression. Ophthalmology. 2013;120(3):512-9.
  9. Garway-Heath DF, Lascaratos G, Bunce C, et al; United Kingdom Glaucoma Treatment Study Investigators. The United Kingdom Glaucoma Treatment Study: A multicenter, randomized, placebo-controlled clinical trial: design and methodology. Ophthalmology. 2013;120(1):68-76.



ROLE OF BLOOD FLOW

Ongoing research looks for ways to better understand the role of ocular perfusion pressure and retinal blood flow, particularly in patients with normal-tension glaucoma.
Shan Lin, MD

Although insufficient evidence is available regarding the role of blood flow in glaucoma and how we can use it in clinical treatment, researchers continue to explore this topic, uncovering new information.

Most available clinical evidence pertains to ocular perfusion pressure, the gradient between intraocular pressure (IOP) and blood pressure.

Clinicians previously believed that systemic hypertension was a factor in increased IOP and glaucoma, but the new paradigm is that low blood pressure and low ocular perfusion pressure (OPP) may be associated with development or progression of glaucoma. Any link with high blood pressure is likely due to hypotension resulting from overtreatment of hypertension. Substantial data support the role of OPP in glaucoma, including results from two recent investigations—the Barbados Eye Study and the Early Manifest Glaucoma Trial (Figure 7).


figure7

 

The Barbados Eye Study, a population-based investigation that found 125 patients with newly developed glaucoma who were mostly of African descent, identified risk factors that included age, family history, higher IOP, and thinner corneal thickness.1 When researchers examined systemic factors, low systolic blood pressure was of borderline significance and low ocular diastolic and systolic perfusion pressure and low ocular mean perfusion pressure were associated with a significantly higher risk of glaucoma in this population.

The Early Manifest Glaucoma Trial (EMGT) identified age, higher IOP, thinner corneal thickness, and low ocular systolic perfusion pressure as significant risk factors for progression of glaucoma.2

Normal-Tension Glaucoma

Although there is strong evidence that low blood pressure may be a risk factor for glaucoma, we do not know whether modifying it will affect development or progression of glaucoma. Personally, I do not measure blood pressure in all of my patients, but I do measure it in study subjects and patients with low-tension glaucoma who continue to progress despite treatment. I also check the blood pressure of patients with low-tension glaucoma who also have systemic hypertension to determine whether they have overtreated high blood pressure.

Ocular blood flow can be examined in a number of ways, such as through retrobulbar flow with color Doppler imaging.3,4 Cross-sectional studies have shown blood flow to be reduced in subjects with normal-tension glaucoma compared with controls.

Many studies also have examined retinal blood flow, most often using the Heidelberg retinal flowmeter. Research has shown that peripapillary retinal blood flow is also reduced in normaltension glaucoma.5

Diagnostic Technology

Frequency domain optical coherence tomography (FD-OCT) can be used to examine retinal blood flow, but research is ongoing to determine whether these data are correlated with glaucoma.6

Examination of the optic nerve head blood flow with a Heidelberg retinal flowmeter has shown a potential correlation between reduced blood flow and visual field defects.7-9 However, this device is used in experimental settings and not usually available to those in clinical practice who are following patients.

Scanning laser ophthalmoscopy angiography has indicated sluggish blood flow in the choroid in normaltension glaucoma.10,11 Dynamic contour tonometry also may be used to indirectly look at choroidal blood flow.12 Results are mixed on whether these findings correlate with glaucomatous damage.

Conclusion

Ongoing efforts have not yet identified a proven modifiable risk factor for glaucoma other than IOP. We know that ocular perfusion pressure and ocular blood flow are potential vascular risk factors in glaucoma. I am optimistic that we will someday have proven information regarding their role and—more importantly— practical ways to affect the course of the disease by modifying these risk factors.

  1. Leske MC, Wu SY, Hennis A, et al; BES Study Group. Risk factors for incident open-angle glaucoma: the Barbados Eye Studies. Ophthalmology. 2008;115(1):85-93.
  2. Leske MC, Heijl A, Hyman L, et al. Predictors of long-term progression in the Early Manifest Glaucoma Trial. Ophthalmology. 2007;114(11):1965-72.
  3. Harris A, Sergott RC, Spaeth GL, et al. Color Doppler analysis of ocular vessel blood velocity in normal-tension glaucoma. Am J Ophthalmol. 1994;118(5):642-9.
  4. Siesky BA, Harris A, Amireskandari A, Marek B. Glaucoma and ocular blood flow: an anatomical perspective. Expert Rev Ophthalmol. 2012;7(4):325-40.
  5. Chung HS, Harris A, Kagemann L, Martin B. Peripapillary retinal blood flow in nor- mal tension glaucoma. Br J Ophthalmol. 1999;83(4):466-9.
  6. Wang Y, Fawzi AA, Varma R, et al. Pilot study of optical coherence tomography measurement of retinal blood flow in retinal and optic nerve diseases. Invest Ophthalmol Vis Sci. 2011;52(2):840-5.
  7. Sato EA, Ohtake Y, Shinoda K, Mashima Y, Kimura I. Decreased blood flow at neuroreti- nal rim of optic nerve head corresponds with visual field deficit in eyes with normal tension glaucoma. Graefes Arch Clin Exp Ophthalmol. 2006;244(7):795-801.
  8. Jonas JB, Harazny J, Budde WM, et al. Optic disc morphometry correlated with confocal laser scanning Doppler flowmetry measurements in normal-pressure glaucoma. J Glaucoma. 2003;12(3):260-5.
  9. Hosking SL, Embleton SJ, Cunliffe IA. Application of a local search strategy improves the detection of blood flow deficits in the neuroretinal rim of glaucoma patients using scanning laser Doppler flowmetry. Br J Ophthalmol. 2001;85(11):1298-302.
  10. Yin ZQ, Vaegan Millar TJ, Beaumont P, Sarks S. Widespread choroidal insufficiency in primary open-angle glaucoma. J Glaucoma. 1997;6(1):23-32.
  11. Duijm HF, van den Berg TJ, Greve EL. A comparison of retinal and choroidal hemodynamics in patients with primary open-angle glaucoma and normal-pressure glaucoma. Am J Ophthalmol. 1997;123(5):644-56.
  12. Punjabi OS, Ho HK, Kniestedt C, et al. Intraocular pressure and ocular pulse amplitude comparisons in different types of glaucoma using dynamic contour tonometry. Curr Eye Res. 2006;31(10):851-62.



III. THERAPEUTICS IN CLINICAL PRACTICE

WHEN AND HOW TO INITIATE TREATMENT

Although clinicians vary in their choice of when to initiate glaucoma treatment, it is important to begin before significant visual field loss occurs.
Shan Lin, MD

The decision as to whether to treat suspected glaucoma—and when to begin treatment—is not always clear-cut. Clinicians choose to begin treatment at various points: When intraocular pressure (IOP) is high, visual field loss occurs, or glaucoma progresses? Ideally, of course, one should begin treatment prior to significant visual field loss.

Myopia and Glaucoma

Many studies have shown that high myopia is an independent risk factor for glaucoma. This is of great concern particularly in Asian populations, who have a much higher incidence of myopia and high myopia than other demographic groups. In a 1999 survey of senior high school students in Taiwan, for example, 84 percent were myopic, with 16 percent being highly myopic (-6D or greater).1

In the Blue Mountains Eye Study, a cross-sectional population-based study of 3,211 subjects from Australia, low myopes had a two-fold increase in optic disc damage and visual field defects compared to those without myopia, and moderate and high myopes had a three-fold increased risk.2 The Beijing Eye Study, a population-based, cross-sectional study of 4,319 subjects, reported that high myopes were five to six times more likely to have optic disc or visual field defects.3

In our recent study of 5,277 subjects in the United States using frequency-doubling technology, we found no association of myopia with self-reported glaucoma or vertical cup-to-disc ratio; however, visual field defects were twice as likely in mild myopes, three times as likely in moderate myopes, and 14 times more likely in severe myopes.4

Initiating Treatment

When treating glaucoma, first-line options include prostaglandins and beta-blockers, depending on issues such as cost, efficacy, diurnal benefit and compliance. Research has shown that prostaglandins more effectively reduce intraocular pressure compared with beta-blockers. Zhang et al. reported greater IOP efficacy with latanoprost compared with timolol.5 Moreover, this meta-analysis found a significant reduction in heart rate and significant risk of hypotension and bradycardia with timolol.

Additional adverse events also have been associated with beta-blockers, including breathing difficulties, depression, and erectile dysfunction, and these drugs are contraindicated in patients with asthma. Furthermore, timolol does not reduce IOP very effectively in patients taking higher systemic doses of propranolol or metoprolol.

Although latanoprost use has not been associated with these systemic issues, there are cosmetic concerns. In addition, prostaglandins should not be used in patients with cystoid macular edema, uveitis or a history of ocular herpes.

It is worth considering efficacy throughout the day and night. A comparison of latanoprost and timolol showed that timolol has similar effects to baseline control at nighttime, whereas prostaglandins significantly reduce IOP during this time.6 For this reason and others, I am more likely to choose prostaglandins as first-line therapy. Patients are also more likely to be compliant with a once-daily prostaglandin treatment.

In a review of timolol and betaxolol to assess the potential neuroprotective effects of betaxolol, timolol almost always reduces IOP more effectively; however, betaxolol is usually more effective than timolol in slowing progression.7

Although prostaglandins are usually the drug of choice, beta-blockers may be preferred as first-line therapy when patients are concerned about drug expense and/or cosmesis. Generics also may be another option for costconscious patients.

When initiating treatment, patient education is important to ensure efficacy. I instruct patients to close their eyes for five minutes after administering the drops. I do not use one-eye trials. Patients return for evaluation four to six weeks later.

Laser Trabeculoplasty

Laser trabeculoplasty often is not considered as first-line therapy, but given medication concerns, it may be a good solution. It eliminates therapy adherence issues and could be a less expensive option for patients.8 Furthermore, selective laser trabeculoplasty (SLT) potentially may be repeated and cause less damage to the trabecular meshwork.

In the Glaucoma Laser Trial, visual field was better preserved and there was less optic disc progression if patients received laser treatment rather than medication as first-line therapy.9 This group also required less medication overall compared with the medication-first group.

Clinicians need to be aware of the need to diagnose and potentially treat glaucoma early and understand the benefits of available treatment options.

  1. Lin LL, Shih YF, Tsai CB, et al. Epidemiologic study of ocular refraction among schoolchildren in Taiwan in 1995.Optom Vis Sci. 1999;76(5):275-81.
  2. Lim R, Mitchell P, Cumming RG. Refractive associations with cataract: the Blue Mountains Eye Study. Ophthalmology. 1999;40(12):3021-36.
  3. Xu L, Wang Y, Wang S, Wang Y, Jonas JB. High myopia and glaucoma susceptibility the Beijing Eye Study. Ophthalmology. 2007;114(2):216-20.
  4. Qiu M, Wang SY, Singh K, Lin SC. Association between myopia and glaucoma in the United States population. Invest Ophthalmol Vis Sci. 2013;54(1):830-5.
  5. Zhang WY, Po AL, Dua HS, Azuara-Blanco A. Meta-analysis of randomised controlled trials comparing latanoprost with timolol in the treatment of patients with open angle glaucoma or ocular hypertension. Br J Ophthalmol. 2001;85(8):983-990.
  6. Liu JH, Kripke DF, Weinreb RN. Comparison of the nocturnal effects of once-daily timolol and latanoprost on intraocular pressure. Am J Ophthalmol. 2004;138(3):389-95.
  7. Grieshaber MC, Flammer J. Is the medication used to achieve the target intraocular pressure in glaucoma therapy of relevance? An exemplary analysis on the basis of two beta-blockers. Prog Retin Eye Res. 2010;29(1):79-93.
  8. Lee R, Hutnik CM. Projected cost comparison of selective laser trabeculoplasty versus glaucoma medication in the Ontario Health Insurance Plan. Can J Ophthalmol. 2006;41(4):449-56.
  9. The Glaucoma Laser Trial (GLT) and glaucoma laser trial follow-up study: 7. Results. Glaucoma Laser Trial Research Group. Am J Ophthalmol. 1995;120(6):718-31.



THREE RULES FOR ADVANCING TREATMENT

Decisions to advance treatment in patients with glaucoma should depend on each individual case, with treatment strategies tailored accordingly.
Felipe A. Medeiros, MD, PhD

In weighing whether to advance glaucoma treatment, clinicians must consider a range of factors based on each individual patient. Essentially there are three reasons to advance treatment:

  1. Intraocular pressure (IOP) higher than one's established target IOP despite treatment
  2. Structural or functional progression despite IOP within the target range
  3. Detection of a new risk factor for progression.

Establishing and Monitoring Target IOP

It is essential to evaluate the patient's target pressure, the range of intraocular pressure (IOP) at which we believe progression is unlikely to affect a patient's quality of life. This is established by considering the risks and benefits of treatment in the context of how a clinician believes glaucoma will progress and whether it will cause disability.

In setting this target, clinicians must consider the amount of glaucoma damage, IOP at which damage occurred, and the patient's life expectancy, as well as other factors such as the status of the fellow eye and family history of severe glaucoma.

However, the target IOP is an estimate and must be reevaluated periodically. Treatment should be advanced if the patient's first-line treatment fails to achieve the target pressure.

Of course, IOP is only part of the story. If progressive structural or functional damage occurs over time despite achieving the target pressure with treatment, clinicians must reduce the target pressure.

The Early Manifest Glaucoma Trial (EMGT) demonstrated that betaxolol and laser trabeculoplasty reduced IOP by 25 percent in patients with newly diagnosed glaucoma.1 They were treated subsequently with prostaglandin analogs. However, disease progression occurred in 59 percent of these patients during eight years of follow-up.2 Therefore, it was probably necessary to advance treatment in most of these patients.

In contrast, the Advanced Glaucoma Intervention Study (AGIS) demonstrated that little visual field change occurred when IOP was less than 18 mmHg (average of 12 mmHg) during all visits.3 However, this does not indicate that treatment should be advanced for every patient to prevent progression. Low pressures are preferred to halt progression, but clinicians need to consider the risks and benefits of advancing treatment and how it will affect each patient's quality of life.

The most important factor in determining a patient's risk of impairment over time is the rate of damage progression. EMGT data show that the rates of change can vary greatly, with disease progressing rapidly in some patients and slowly in others. If disease progression is slow, higher levels of IOP may be able to be tolerated.

It's important to treat the individual patient—not the average. With rapidly progressing disease and/or a younger patient, disability is more likely to occur. Therefore, advancing treatment is important in these cases. The ultimate goal is to preserve the patient's visual function during the remaining years of his or her life.

Adapting Treatment to New Risks

Although the main risk factors used to set the initial target pressure (e.g., age, central corneal thickness) may not change, a new disc hemorrhage will alter the patient's risk of progression. Evidence of disc hemorrhages can nearly disappear in just a few months, making them quite difficult to detect if one isn't searching carefully.

We were interested to know whether advancing treatment to further lower IOP after a disc hemorrhage could alter the course of the disease. In a longitudinal study, we evaluated more than 500 eyes for more than eight years.4 During that time, 19 percent of the eyes had at least one episode of disc hemorrhage. The overall rate of change in the visual field index was significantly faster in eyes with hemorrhages than in those without (–0.88 percent/year vs. –0.38 percent/year, respectively, p<0.001), but there was considerable variability.

To examine whether IOP reduction slows the rate of glaucoma progression in patients with disc hemorrhage, we calculated the slopes of visual field changes before and after disc hemorrhage. It appears that advancing treatment and reducing IOP in these patients results in improved outcomes. Therefore, if disc hemorrhages occur, clinicians must factor them in when considering whether to advance treatment.

There are no definitive rules dictating whether to advance treatment in patients with glaucoma. Clinicians must consider a range of factors in each individual patient, including rate of progression, life expectancy and potential risk factors associated with treatment.

  1. Heijl A, Leske MC, Bengtsson B, et al. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol. 2002;120(10):1268-79.
  2. Leske MC, Heijl A, Hyman L, et al. Pre- dictors of long-term progression in the Early Manifest Glaucoma Trial. Ophthalmology. 2007;114(11):1965-72.
  3. The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration. The AGIS Investigators. Am J Ophthalmol. 2000;130(4):429–40.
  4. Medeiros FA, Alencar LM, Sample PA, Zangwill LM, Susanna R Jr, Weinreb RN, et al. The relationship between intraocular pressure reduction and rates of progressive visual field loss in eyes with optic disc hemorrhage. Ophthalmology. 2010;117(11):2061-6.



ADDRESSING THE NORMAL-TENSION GLAUCOMA PATIENT

Improvement of retinal vascular autoregulation may explain therapeutic agents' value in the treatment of patients with normal IOP.
Louis R. Pasquale, MD, FARVO

Determining the ideal treatment for patients with glaucomatous optic neuropathy whose intraocular pressure is within the normal range remains a major gap in clinical practice.

Fifteen years ago, the Collaborative Normal-Tension Glaucoma Study (CNTGS) investigators reported that aggressive intraocular pressure (IOP) lowering significantly reduced progression at five years in patients with normal-tension glaucoma (NTG).1 However, when they controlled for the impact of cataract (which occurred at higher rates in the treated group) on visual field progression, the treatment effect disappeared.2

More recently, the Low-Pressure Glaucoma Treatment Study (LoPGTS), compared visual function in patients with the normal-tension variant of primary open-angle glaucoma (POAG) treated with timolol 0.5% compared to those treated with brimonidine 0.2%. Brimonidine was found to be superior to timolol in preserving visual field in this study.3

The rate of visual field progression in the timolol arm of LoPGTS and the untreated arm of the CNTGS were similar (33 percent to 39 percent) and considerably higher than the nine percent rate in the brimonidine arm of LoPGTS (Figure 8). The pressure reduction in the brimonidine group was not greater than the timolol group in the LoPGTS, so the preservation of visual field is unlikely due to IOP lowering, which leads one to question: what is happening?


figure8

 

It's important to find out. Progression is often slow in NTG patients, but we all have those very frustrating cases like this one (Figure 9) who continued to progress to quite advanced stages of glaucoma despite maximal therapy that maintains very low IOP.


figure9

 

Role of Disc Hemorrhages

I suspect that disc hemorrhages play a very important role. These are probably more common than we think; the rate in a cross-sectional study from Australia was about two times higher in NTG patientsthan it was in open-angle glaucoma patients overall (25 percent vs. 13 percent).4

The reality is that patients with NTG are getting frequent disc hemorrhages, whether we see them or not. In a number of well done studies using very careful statistics, when researchers control for intraocular pressure, disc hemorrhage remains an independent factor for either converting from no disease to POAG or for progressing from early disease to later forms of the disease (Figure 10). So it is possible that if we could stop the disc hemorrhages in NTG, we could also stop the progression. But how do disc hemorrhages happen and how do they contribute to optic neuropathy? Does brimonidine affect hemorrhages in some way that would explain its effects on NTG patients entered into the LoPGTS?


figure10

 

To answer these questions, we need to look closely at retinal vascular autoregulation, which is the ability to maintain a stable retinal blood flow in the face of changing ocular perfusion pressure. This is an intuitive concept. When you wake up in the morning and get out of bed, gravity exerts downward pressure on the blood in your head but you don't experience blurry vision or lose consciousness because there are compensatory changes occurring in the blood vessels that allow the blood flow to all the organs above the heart to remain constant. This mechanism may be inherently faulty in many NTG patients.

With my colleagues, I've conducted a series of studies using a Cannon Laser Bloodflow Meter that simultaneously measures retinal blood vessel diameter and a Doppler signal that allows us to directly calculate blood flow. We measure the flow in a retinal arteriole segment adjacent to the optic nerve with the patient sitting up (baseline), and then we measure the same vessel with the patient lying down. The supine retinal blood flow measurements are repeated at 15 and 30 minutes.

What we have found is that the results for control subjects are very different from those of patients with NTG. In normal controls, the retinal blood flow stays relatively constant compared to the baseline when the subject lies down. But in an NTG patient, the blood flow increases by as much as 60 percent (Figure 11).5 Our hypothesis is that the shear forces directed to the lamina cribrosa capillaries by this hyperperfusion are so strong that the small blood vessels hemorrhage. This may create a kind of compartment syndrome in the intrascleral portion of the optic nerve with subsequent focal disc notching.


figure11

 

In a subsequent study, we showed that in six of six subjects with NTG and abnormal retinal vascular autoregulation, brimonidine 0.15% OU b.i.d. was able to normalize autoregulation.6 Brimonidine is a vasomodulator; as such, it causes larger retinal vessels (which do not receive neurogenic input) to dilate and smaller vessels to constrict. It may be that this vasomodulation is able to normalize the positional changes in blood flow that would otherwise occur, thereby reducing the rate of hemorrhages and helping to stabilize the disease.

Most recently, we have shown that in patients with retinal vascular dysfunction, combination therapy with either dorzolamide/timolol or brimonidine/timolol improved autoregulation over timolol alone.7 Basic science data suggests that both brimonidine and dorzolamide produce beneficial ocular vasomodulatory effects via a mechanism that involves enhanced nitric oxide signaling.8,9

Additional research remains to be done, but if these agents can improve retinal vascular autoregulation and reduce the rate of disc hemorrhages and if there is a positive functional consequence of that—which LoPGTS suggests there is—than it is worth considering them as an important part of the management of NTG.

  1. Collaborative Normal-Tension Glaucoma Study Group. Comparison of glaucomatous progression between untreated patients with normal-tension glaucoma and patients with therapeutically reduced intraocular pressures. Am J Ophthalmol. 1998;126(4):487-97.
  2. Collaborative Normal-Tension Glaucoma Study Group. The effectiveness of intraocular pressure reduction in the treatment of normal-tension glaucoma. Am J Ophthalmol. 1998;126(4):498-505.
  3. Krupin T, Liebmann JM, Greenfield DS, et al; 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(4):671-81.
  4. Healey PR, Mitchell P, Smith W, Wang JJ. Optic disc hemorrhages in a population with and without signs of glaucoma. Ophthalmology. 1998;105:216-23.
  5. Feke GT, Pasquale LR. Retinal blood flow response to posture change in glaucoma patients compared with healthy subjects. Ophthalmology. 2008;115(2):246-52.
  6. Feke GT, Hazin R, Grosskreutz CL, Pasquale LR. Effect of brimonidine on retinal blood flow autoregulation in primary open-angle glaucoma. J Ocul Pharmacol Ther. 2011;27(4):347-52.
  7. Feke GT, Rhee DJ, Turalba AV, Pasquale LR. Effects of dorzolamide-timolol and brimonidinetimolol on retinal vascular autoregulation and ocular perfusion pressure in primary open angle glaucoma. J Ocul Pharmacol Ther. 2013;29(7):639-45.
  8. Rosa RH, Hein TN, Yuan Z, et al. Brimonidine evokes heterogenous vasomotor response of retinal arterioles: diminished nitric oxide-mediated vasodilation when size goes small. Am J Physiol Heart Circ Physiol. 2006;291:231-8.
  9. Kringelholt S, Simonsen U, Bek T. Dorzolamide-induced relaxation of intraocular porcine ciliary arteries in vitro depends on nitric oxide and the vascular endothelium. Curr Eye Res. 2012;37:1107-13.



Conclusion

Robert N. Weinreb, MD

There have been many exciting developments recently in our understanding of glaucoma and in potential therapeutic approaches to treating patients with glaucoma—especially those challenging patients who progress despite having low intraocular pressure.

Some important takeaways for clinical practice are that we should look more closely for changes in structure, rather than relying solely on standard visual fields to detect progression. An important takeaway is that one should change or advance therapy if there is a new risk factor, such as optic disc hemorrhage. With the potential for genetic testing, ongoing improvements in our understanding of the role of blood flow and other vascular risk factors, and new ideas about the management of glaucoma, the future for improved glaucoma treatments is bright.