Glaucoma’s Time in the Spotlight Continues: Emerging Directions

Changing perspectives will influence the care and management of glaucoma in coming years.

By Richard J. Madonna, OD, MA

Glaucoma is the second leading cause of blindness worldwide, and the numbers of people with openangle and angle-closure glaucoma are predicted to continue rising.1 To deal with the increasing burden of glaucoma in the future, clinicians must be aware of recent developments that have aided in the understanding of this chronic, sight-threatening disease.

This article examines some of the ways in which our conceptions of glaucoma and glaucoma management are changing and are likely to continue changing in coming years. Awareness of these trends may help clinicians adapt to and adopt these new paradigms and to improve the care of their patients with glaucoma.

The discussion proceeds from a series of statements:

  • Genes and their environmental triggers will become important as we look to better understand how to manage or even prevent glaucoma.
  • The way we look at the optic nerve will change because of advances in imaging technology.
  • We will think about “pressure” and how it affects the optic nerve differently.
  • We will be better able to combine structural and functional data to stage glaucoma and to monitor progression.
  • Glaucoma surgery will play a different and increasing role in the management of patients with glaucoma.


Genes and their environmental triggers will become important as we look to better understand how to manage glaucoma.

During the past 10 to 15 years, numerous genes have been identified as associated with one or another of the many types of glaucoma. At the same time, it is increasingly recognized that, as with many diseases, just because an individual has one of these genes, this does not mean he or she necessarily will develop the disease, nor can the presence of the gene predict the severity of the disease. Studying the role of environmental triggers in the expression of these disease-associated genes may give researchers and clinicians opportunities to have an impact on the development or progression of certain forms of glaucoma.

An example of this can be seen in the condition called exfoliative glaucoma. Exfoliation syndrome is the most common identifiable cause of glaucoma. It is an age-related condition associated with a very aggressive open-angle form of glaucoma. Exfoliative syndrome and exfoliative glaucoma are found in high incidence in certain populations. It has been thought of as a Scandinavian disease, with high incidence in Norway and Finland, but it is also seen in other diverse populations including in Ireland and Turkey.

Investigators have linked exfoliative glaucoma with variants in a gene called lysyl oxidase-like 1, or LOXL1, and its protein. In two very diverse populations, one in Iceland and one in Australia, the gene variants in the LOXL1 gene are essentially identical.2,3 However, the prevalence of exfoliative syndrome in people over age 60 in those two populations differs greatly: the prevalence is about 20% in Iceland, compared with about 1% in Australia. It appears that something more than the genetic makeup of these individuals is determining their risk for exfoliative syndrome. But what is it?

Investigators have studied the geographic and climatic factors associated with exfoliative syndrome in the US population.4 In a retrospective study of 626,901 patients in a managed care network in 47 US states, there were 3,367 incident cases of exfoliation syndrome. When incidence of exfoliative syndrome was analyzed by geographic region, residence in the northern tier of states was associated with increased risk in comparison with the middle tier, and residence in the southern tier of states was associated with decreased risk. In addition, for every 1° increase in July high temperature, the risk decreased by 9%, and for every additional sunny day annually, the risk increased by 1.5%4.

The conclusion from this analysis was that ambient temperature and sun exposure may be important environmental triggers of exfoliative syndrome. This leads to the proposition that the discovery of environmental factors linked to exfoliative syndrome could lead to primary prevention measures for this condition, and therefore for exfoliative glaucoma.

So if you have this LOXL1 gene variant and a family history of exfoliation, do you move from New York to Florida? That might be extreme. But perhaps reducing one’s time in the sun, or reducing the time spent in cold temperatures, might reduce the risk of developing this very aggressive form of glaucoma.

As a result of this work and that of other researchers, The Glaucoma Foundation recently for the first time used the word cure in writing about the prospects for exfoliative glaucoma.5

We may see this type of thinking increasingly in the future, as our ability improves not only to identify genes, but further to understand and control their expression through the identification of environmental triggers, and thereby to reduce the risk of developing certain glaucomas.


The way we look at the optic nerve will change because of advances in imaging technology.

Histopathology indicates that the initial site of damage to the ganglion cell axons in glaucoma is in the lamina cribrosa, the structural area behind the optic nerve head through which the axon bundles must pass to exit the eye. Changes in the lamina cribrosa and in the optic nerve head are associated with development and progression of glaucoma.

Historically, examination of the optic nerve head has been performed with an ophthalmoscope, which offers only a surface or en face view. New imaging modalities are now providing a different, deeper view of the lamina and surrounding structures with higher image quality. With these devices, we will be able to image the lamina as our colleagues in retina are now able to image the choroid, sclera, and other posterior pole structures.

Enhanced depth imaging optical coherence tomography (EDI-OCT), first described by Margolis and Spaide as a way to image the choroid, 6 is now being applied to the study of the lamina cribrosa and other structures of interest to glaucoma specialists.7-10

As EDI-OCT technology achieves greater penetration of the market, clinicians will recognize that we can combine our traditional clinical examination and views of the nerve fiber layer and optic nerve head with new information. EDI-OCT and a related technology, swept-source OCT, will provide views of deeper structures including the lamina cribrosa, hopefully allowing us to identify patients with early disease and to more quickly detect disease progression.

With the technology currently available, investigators have been able to image the anterior and posterior surfaces of the lamina, to identify and evaluate the central retinal artery and vein, and to identify pores and defects in the lamina cribrosa.8 Additional laser wavelengths may allow these new OCT modalities to more easily image the lamina and optic nerve. This new information will have an impact on the way we envision glaucoma and will provide new insights into earlier diagnosis and treatment.


We will look at “pressure” on the disc differently.

Intraocular pressure (IOP) is the most important risk factor for glaucoma. It is also the only known modifiable risk factor, and, therefore, lowering IOP is the aim of all glaucoma therapies, whether medical or surgical. But although IOP has been widely studied, less attention has been paid to other pressures on the optic nerve. Lately, the question has been raised as to whether glaucoma is a dysregulation of pressures: IOP from inside the eye, cerebrospinal fluid (CSF) pressure from behind the lamina cribrosa, and blood pressure from the eye’s blood supply.

Behind the lamina cribrosa, the optic nerve becomes a central nervous system tract, and it is surrounded by and influenced by CSF pressure. Because there is a difference between IOP and CSF pressure, there has been recent interest in this trans-lamina cribrosa pressure gradient.

The normal pressure status, with IOP slightly higher than CSF pressure, maintains the optic nerve in its familiar shape. If CSF pressure becomes higher, as in a person with a brain tumor, papilledema can develop, and the nerve protrudes.

With that in mind, what happens if the pressure gradient goes too far in the opposite direction, if IOP exceeds some threshold in comparison with CSF pressure? Backbowing of the lamina and backbowing of the neuroretinal rim tissue might be expected, and this is exactly what is seen in glaucoma. Therefore, this pressure differential, influencing the lamina cribrosa, may be extremely important in the development of glaucomatous damage.

A number of studies have looked at the difference between IOP and CSF pressure in patients with primary open-angle glaucoma (POAG). In a case-control study, Berdahl and colleagues found that CSF pressure was significantly lower in patients with POAG (9.2 mm Hg) than in control patients without glaucoma (13.0 mm Hg).11

In a prospective study, Ren and coworkers looked at the differential in patients with normal-tension glaucoma (NTG) compared with patients without glaucoma.12 They found that CSF pressure was abnormally low in patients with NTG, leading to an abnormally high trans-lamina cribrosa pressure difference. The authors suggested that an abnormally low CSF pressure in patients with NTG may be pathogenetically similar to a high IOP in high-pressure glaucoma. That is, whether IOP is abnormally high or CSF pressure is abnormally low, the high pressure gradient that results is important in the ensuing nerve damage.

What are the clinical implications of this trans-lamina gradient? This is as yet unclear. There are many things we do not know. We do not know if CSF pressure as measured by lumbar puncture represents the CSF pressure in the subarachnoid space, and, even if it does, we cannot perform lumbar puncture in all of our glaucoma patients. Perhaps a noninvasive way to measure the orbital CSF pressure can be found, but currently none exists. And besides, we do not know if medical treatment of CSF pressure could be used to treat glaucoma. Based on these studies, however, this relationship of CSF pressure with glaucoma seems to be an important one.

The other factor in this pressure equation is the blood supply to the optic nerve. Ocular perfusion pressure is the difference between arterial blood pressure and IOP. Ocular perfusion is autoregulated to maintain constant blood flow to the optic nerve despite fluctuating blood pressure and IOP, within a certain range. Outside that range, the autoregulation does not work, and that puts the tissue at risk.

Low ocular perfusion pressure has been shown to be associated with the prevalence of glaucoma progression in multiple population-based studies.13-18

In the Los Angeles Latino Eye Study, a cross-sectional study of more than 6,000 Latinos greater than 40 years of age, individuals with low diastolic perfusion pressures had a higher risk of POAG.17 When diastolic perfusion pressure was less than 50 mm Hg, the prevalence of glaucoma rapidly increased linearly. (For example, if an individual’s blood pressure is 120/70 and IOP is 20 mm Hg, the diastolic perfusion pressure is 50 mm Hg.) The Barbados Eye Study found that low mean perfusion pressure was the biggest risk factor associated with glaucoma progression.18

These large studies provide strong evidence among different populations for the relationship between vascular deficits and the prevalence, incidence, and progression of glaucoma. However, we do not want to raise systemic blood pressure to improve ocular perfusion pressure; rather, lowering IOP remains the main goal.

The other concern raised by this relationship between IOP and blood pressure is its effect during the nocturnal period. The nighttime sleep period is when IOP is highest and blood pressure is lowest in their respective diurnal curves. Low blood pressure at night, coupled with high IOP in the supine position, compromises ocular perfusion pressure.

How do we use this information clinically? One suggestion is to ask patients to take blood pressure medications in the morning rather than at night to minimize nocturnal systemic hypotension. Another is to use glaucoma medications that work better at night; avoid using medications that appear to not lower IOP at night, such as beta-blockers and alpha-agonists. The prostaglandin analogues work well during the night, and the carbonic anhydrase inhibitors also appear to work well. In general, new strategies are needed to take advantage of the modifiable risk factor of ocular perfusion pressure.

It would be helpful to have a mechanism to measure IOP over the 24-hour period. A soft contact lens called the Triggerfish (Sensimed) that monitors IOP using a wireless technology is available in Europe, but it is not approved by the US Food and Drug Administration (FDA). The device senses changes in corneal curvature induced by variations in IOP.19 Implantable devices are in clinical trials as well.


In the future, we will be better able to combine structural and functional data to stage glaucoma and to monitor progression.

Structure and function in glaucoma are assessed by looking at different parameters. To measure structure, we examine the optic nerve head or OCT images, and for function, we look at visual field test results. The clinical dilemma is that patients with the same degree of neuroretinal rim loss can have different levels of visual field loss; patients with glaucomatous optic neuropathy may not have field loss, and occasionally patients have visual field loss that seems to have no structural correlate. What does that mean for patient care? When is measuring structural change more important, and when is functional change more important?

An algorithm that combines structural and functional information could help to detect and stage glaucomatous damage. Medeiros and colleagues have devised and evaluated one such algorithm, the combined structure and function index (CSFI).20 By combining data from automated perimetry and OCT data, the CSFI calculates percentage loss of retinal ganglion cells. In an observational study, the mean CSFI in 295 eyes with glaucoma detectable by perimetry was 41%, and the mean CSFI in 38 eyes with preperimetric glaucoma was 17% (P = .001), and both of these percentages were statistically significantly higher than the CSFI in a group of healthy eyes. The authors concluded that the CSFI performed better than isolated structural and functional measures for detection of perimetric and preperimetric glaucoma and for discriminating stages of the disease.


Glaucoma surgery will play a different and increasing role in the management of patients with glaucoma.

Glaucoma surgery is associated with numerous intraoperative and postoperative complications, and therefore, it is has historically been reserved for patients with more advanced disease. This paradigm is changing, however, now that we have entered the era of microinvasive glaucoma surgery (MIGS). MIGS procedures have a positive safety profile due to their ab interno approach and minimal damage to target tissues. The procedures effectively lower IOP, and patients’ recovery is rapid.

MIGS devices approved by the FDA include the iStent Trabecular Micro-Bypass Stent (Glaukos) and the Trabectome (NeoMedix). In clinical trials are the Cypass Micro-Stent (Transcend Medical), the AqueSys Implant (AqueSys), and the Hydrus Microstent (Ivantis).

Of these devices, the one I am most familiar with is the iStent, a heparin-coated titanium device inserted from the anterior chamber into the trabecular meshwork. It bypasses the trabeculum, the area with highest resistance to aqueous outflow, and carries aqueous fluid directly into Schlemm canal. The device is FDA approved for use in conjunction with cataract surgery for the reduction of IOP in adult patients with mild to moderate open-angle glaucoma currently treated with ocular hypotensive medication.

At the 2-year follow-up, patients receiving a single iStent at the time of cataract surgery had significantly better IOP control with no medications than patients who had cataract surgery alone. Both groups had a similarly favorable long-term safety profile.21

Another study found that use of multiple iStents with concurrent cataract surgery led to a greater degree of IOP lowering, allowing patients to achieve target IOP control with significantly fewer medications through 1 year.22 However, the FDA approval allows only implantation of one device at a time.

The downside—if it is a downside—of MIGS is that these procedures do not produce the large decreases in IOP seen with traditional incisional glaucoma surgery. Therefore, MIGS procedures are perhaps most appropriate for use in patients with mild to moderate glaucoma. These procedures are easily combined with cataract surgery, so in patients with concomitant cataract and moderate glaucoma, the surgeon can add a MIGS procedure to lower IOP at the time of cataract surgery.


New ways of looking at a multifactorial disease such as glaucoma can lead to development of new ways to follow and treat the disease. The issues enumerated in this article are among those that will help to advance the care of patients with glaucoma in the coming years and decades.

Richard J. Madonna, OD, MA, is professor and chair of the Department of Clinical Education and the director of continuing professional education at the SUNY College of Optometry in New York. He acknowledged no financial interest in the products or companies mentioned herein. Dr. Madonna may be reached at (212) 938-5818;

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