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Healio
September 29, 2011
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Ocular Surface Health in Glaucoma Management

The importance of ocular health in clinical practice has changed dramatically during the last few years. Although conditions such as dry eye syndrome were once poorly understood and of little interest to many clinicians, some important recent breakthroughs have helped to increase understanding of and interest in diseases of the ocular surface. More clinicians are beginning to appreciate the importance of ocular health and its impact on vision, quality of life, and the potential for interactions with other disorders such as glaucoma. Physicians must therefore be aware of how to manage and maintain the health of the ocular surface.

Ocular Surface Health

Terrence P. O’Brien, MD: What is meant by a “healthy ocular surface?”

Malik Y. Kahook, MD: One way to define a healthy ocular surface is as a state of balance between the tear film layers and the ocular surface epithelial cell layers. The tear film is a complex on top of the surface of the eye, and provides nutrients for the epithelial surface layers of both the cornea and the conjunctiva. A healthy ocular surface is present when the relationship between these components is in balance and able to overcome the multiple intrinsic and extrinsic stressors that are presented to the eye in the normal course of daily life (Sidebar below).

Sidebar
Figure 1. Classification of Dry Eye Syndrome
Figure 1. Classification of Dry Eye Syndrome The 2007 DEWS report classified dry eye syndrome as either aqueous-deficient or evaporative.
Source: Definition and Classification Subcommittee of the International Dry Eye WorkShop. Ocul Surf. 2007;5(2):75-92.


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Table 1. ICD-9-CM Codes Associated with Dry Eye
Figure 1. Classification of Dry Eye Syndrome Sources: Johnson MP, et al. Optometric Management. http://www.optometric.com/article.aspx?article=71025. Accessed July 2, 2011; Dean DC. Review of Optometry. http://www.revoptom.com/content/d/retina/c/15244/ Accessed July 2, 2011.


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Figure 2. Classification of Ocular Surface Disease
Figure 2. Classification of Ocular Surface Disease Ocular surface disease includes dry eye syndrome, lid-related diseases, and non-lid-related diseases such as allergic conjunctivitis and keratoconjunctivitis.
Key: MGD — meibomian gland dysfunction; OSD — ocular surface disease
Source: Diagnostic Methodology Subcommittee of the International Dry Eye WorkShop. Ocul Surf. 2007;5(2):108-152.


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Mark B. Sherwood, MD: I think we can look at it from 2 points of view. From the physician’s point of view, the important aspects are the signs and symptoms observed in various disease states. From the patient’s perspective, the discomfort in the eye caused by this imbalance in the tear film, and in general by an unhealthy ocular surface, can have significant effects on quality of life. So we can discuss a healthy ocular surface in terms of quality of life, and we can also talk about it in terms of the physiology of the tear film and the surface of the corneal epithelium and conjunctival epithelium (Sidebar below).

Sidebar
Figure 3. Pathology of Ocular Surface Disease
Figure 3. Pathology of Ocular Surface Disease There are a variety of pathological mechanisms of ocular surface disease.
Key: CL — contact lens; IL-1 — interleukin-1; MAPK — MAP kinase; MGD — meibomian gland dysfunction; MMP — matrix metalloproteinase; NFκB — nuclear factor κB; NSDE — non-Sjögren dry eye; SSDE — Sjögren syndrome dry eye; TNFα — tumor necrosis factor α
Source: Definition and Classification Subcommittee of the International Dry Eye Workshop. Ocul Surf. 2007;5(2):75-92.


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O’Brien: How does the health of the ocular surface affect the patient? What are the types of complaints heard from the patients, and what is observed on examination?

Kahook: In many cases, patients present with complaints of decreased vision, stinging, and foreign body sensation due to ocular surface disease. These patients have signs of abnormal tear film and ocular surface changes that are consistent with their complaints. However, although a significant number of patients come to my clinic in Denver, a city with a very dry environment, with a normal appearing tear film and epithelial surface, many have complaints that are consistent with ocular surface disease. This reminds us that quality of life, based on the patient’s perception, is just as important as what the physician finds during an examination.

Sherwood: In more severe cases, there can be diminished visual acuity. However, I think in the early phases the most common complaint is the actual discomfort that patients experience, which clearly affects quality of life. Patients say that their eyes feel “tired” — they cannot continue with activities like reading and computer work.

Kahook: Encountering patients with complaints of decreased vision or symptoms that equate to a decrease in contrast sensitivity is not uncommon. Patients may think that the problem is with their glasses or their contact lens, or the development of cataracts. But in fact, what they have is a compromised ocular surface, with diminished tear film health contributing to the complex of symptoms they are experiencing. Rehabilitating the ocular surface might improve their symptoms.

O’Brien: That has been my experience as well. As discussed, there is a mismatch between the patient-reported symptoms and the signs that are visible on examination. This discrepancy is one of the barriers to recognizing the early compromise of the ocular surface in patients who are symptomatic, but with minimal signs.

O’Brien: How prevalent is ocular surface disease? What data do we have that suggest the prevalence in terms of evaporative dry eye syndrome, meibomian gland dysfunction, and other conditions?

Kahook: There are studies that have defined ocular surface disease in various ways, showing that as much as 20% of the population have at least some symptoms of ocular surface disease.5 The question of prevalence of ocular surface disease must be viewed in terms of different patient populations. We know that the prevalence of dry eye syndrome increases with age and thus, signs and symptoms of ocular surface disease are becoming more of a burden as the patient population ages. Importantly, the prevalence of glaucoma also increases with age.5-8 Seeing the intersection of these 2 disease processes makes ocular surface disease a prominent part of my daily practice. In my glaucoma practice, we know that approximately 50% to 65% of patients who are being treated for glaucoma have symptoms of ocular surface disease affecting at least 1 eye, which is consistent with the prevalence reported in the literature.6,9

O’Brien: Describe the steps to diagnosing ocular surface disease.

Sherwood: One issue to consider is that there is often a tendency to combine all ocular surface diseases into a single disorder. In fact, there are a number of different disease entities, such as an aqueous deficiency in the tear film, meibomian gland dysfunction, and allergic problems. Not all ocular surface disease is the same (Sidebar).

O’Brien: A common mistake is missing the concomitant role of lid margin disease, specifically meibomian gland dysfunction and resultant accelerated evaporative tear loss that leads to a secondary aqueous tear layer insufficiency. Recent data suggest that this is present in at least 20% of cases of dry eye syndrome.10,11 Clinicians should have a heightened awareness of meibomian gland dysfunction, as well as the importance of examining tear film breakup time.

Sherwood: One problem is that we do not have a single test to describe the extent of ocular surface disease. There are multiple tests, and not all of them are reproducible.12

O’Brien: Furthermore, conditions that comprise ocular surface disease can overlap with other conditions, or comorbidities may be present that can confuse the specific diagnosis.

Kahook: This has also been a problem in research. In trying to design multicenter clinical trials, it has been challenging to choose metrics that are reproducible and consistent across the various centers. This also affects the definition of ocular surface disease. If you do not have a reproducible metric, it is difficult to quantify the disease in a way that is useful to physicians across different geographic areas and different clinical settings.

O’Brien: Are you using any validated questionnaires in clinical practice that have been useful to help uncover patients who are at higher risk within your populations?

Kahook: Studies have used different questionnaires, such as the ocular surface disease index (OSDI)13 and some of the National Institutes of Health-validated questionnaires such as the VFQ-25.14 Employing some of these questionnaires in a typical practice setting is difficult. However, in the study setting, they do provide reproducible information. Questionnaires that are short and adaptable for busy clinicians are in development. There are many other diagnostic tools, including measurement of tear breakup time, examination of meibomian gland secretions, and inspection of the tear film.11 Choosing a metric and using it in a consistent way is the most effective approach to obtaining reproducible data that can be used to diagnose the disease and follow the progression over time, regardless of whether another physician uses the metric differently. We typically use tear breakup time, and use it on every patient in a consistent manner.

O’Brien: The OSDI is a relatively short, easy to use, and clinically validated rating scale. The OSDI is designed to measure 3 domains of ocular functioning: ocular symptoms (eg, gritty sensation or sensitivity to light), vision-related function (eg, difficulties reading or driving), and environmental triggers (eg, sensitivity to windy conditions or dryness). Each of the 12 questions is answered on a rating scale of 0 to 4, and a final score is calculated on a range from 0 to 100, with a higher score indicating more severe impairment.13

I agree that it is possible to argue academically about the preferred method for conducting an individual test, but overall, there is a benefit to patient care from performing the same type of test. As long as the test is performed as consistently as possible, the information over time is valuable.

Kahook: If you are performing one of these tests, that means you are considering the ocular surface and possible disorders, which is the first step in managing it.

O’Brien: What steps can the busy clinician take to diagnose the vast majority of ocular surface disease? Which tests are the most useful to uncover a majority of patients having significant ocular surface disease?

Sherwood: Examination of tear breakup time and tear volume is quick and can be done relatively consistently in a busy clinic. Also, lissamine green staining can be helpful, but it is not always easy to obtain in the clinic, particularly in the preferred pre-made liquid form. Generally, the strip is used. Schirmer tests can be helpful and should be considered if an aqueous volume problem is suspected. Comparison of the patient’s pretreatment and post-treatment findings can be useful for many of these tests.

O’Brien: I think it is important first to have a heightened awareness, to listen to the patient, and to assess tear volume on direct examination as well as the tear film breakup time. For the patient who you think is truly aqueous-deficient, I think a Schirmer-1 test can be beneficial because if the score is less than 5 you know you have a significant aqueous tear deficiency.

Kahook: I evaluate tear breakup time and punctate epithelial erosions with fluorescein as my primary endpoints because we are using fluorescein anyway for IOP checks. As far as Schirmer testing, I know some of my cornea colleagues use it. I do not know how routinely they are performing it because it does take extra time and there are issues with false positive and false negative results. I do not perform this test often in my glaucoma practice.

O’Brien: We mainly reserve Schirmer testing for the study patients. Due to the variability in testing and other patient factors, it can sometimes give spurious results or lead to erroneous interpretation of results. Schirmer testing is therefore not as useful in the general clinic setting.

Sherwood: Actually, I think the Schirmer-1 is the more valuable test. Also, it is noteworthy to mention that because of the variability, we should not overdiagnose tear film or aqueous deficit because the diagnosis will follow the patient for many years. Patients may end up taking extra drops that they may not need.

Medications and the Eye

O’Brien: Other than naturally occurring conditions, what medications and preservatives can affect the ocular surface?

Kahook: In my practice, the most common extrinsic factor that leads to ocular surface disease is the treatments that we use for glaucoma therapy. Most patients are treated with a prostaglandin analog or another class of medication. Both the active ingredient and the preservative in these medications can lead to a breakdown of the healthy tear film.15 As stated earlier, the tear film is important in maintaining the health of the ocular surface. Once there is a breakdown in the tear film, it leads to a vicious cycle of further breakdown. In many cases, the cause of the disease can be traced to the initiation of the topical medication.

There are also many systemic medications that can contribute to ocular surface disease (Table 2).16,17 As ophthalmologists, we may not consider some of these medications as potential causes of ocular surface problems because we do not typically initiate many of them. They may have been prescribed by the primary care physician or another health care professional. When patients visit their ophthalmologists, they may recognize the disease but not take into consideration the various oral and systemic medications that are potential causes of the condition.

Table 2. Medications that Affect the Ocular Surface
Table 2. Medications that Affect the Ocular Surface
* Including but not limited to; Sources: Fraunfelder FW. Cornea. 2006;25(10):1133-1138; Wren V. J Behavioral Optom. 2000;11(6):149-157.


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O’Brien: I agree that it is important to query patients carefully about their medication use because they may either forget that it was prescribed by another health care professional or not think of the medication as something that could be affecting their eyes. In fact, an over-the-counter medicine can even contribute to ocular surface disease. We often have these very scattered health care arrangements and it is possible that the eye care provider has limited knowledge regarding medications the patient is taking or other medical conditions they are being treated for. We often must rely on the patient’s memory to understand their medical and medication history. This is where an electronic medical file carried by the patient may be useful.

In medications prescribed by the ophthalmologist, there are potential direct effects from the active ingredient, but also from the preservatives that may be present.

Sherwood: Twenty years ago we were using many medicines that we no longer use, particularly in glaucoma, such as epinephrine, guanethidine, or pilocarpine. There were preservative issues, but we were not paying much attention to the ocular surface. More recent work has prompted us to examine the effects of preservatives, particularly the commonly used benzalkonium chloride (BAK), as significant contributors to ocular surface issues. When we think about eye drops, we need to consider all the components of the formulation and not only the active ingredient. I think there has been increased recognition that the preservatives may be one of the more important factors when it comes to ocular surface disease in patients with glaucoma.

O’Brien: What do we know about the biology of the interaction between the preservative and the ocular surface? What is the specific nature of the toxicity?

O’Brien: In vitro investigations have examined the effects of preservatives on the surface cells of the eye. There is a well-defined concentration-dependent relationship between preservative use and the health of both the conjunctival and corneal cells (Figure 4).18-20

Figure 4. Effect of Glaucoma Medications on Cell Viability
Table 1. Dry Eye Syndrome Diagnosis and Treatment The preservative BAK was associated with a dose-dependent decrease in cell viability.
Key: BAK — benzalkonium chloride; PBS — phosphate-buffered saline; PF — preservative-free *P < .01 compared with PBS at the same time point; # P < .03 compared with 0.010% BAK at the same time point; $ P < .002 or P < .03 ($$) compared with 0.020% BAK at the same time point
Source: Reproduced from Liang H, et al. Br J Ophthalmol. 2011;95(6):869-875, with permission from BMJ publishing group LTD.


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Sherwood: There is a range of effects of these preservatives on the conjunctival and corneal cells. Cell death is generally caused by apoptosis at low doses and necrosis at high doses.21,22 We also have to keep in mind that for some patients, preservatives may be present in more than 1 medication. Particularly in the glaucoma population, many patients are taking multiple medications that may contain preservatives, and many of these patients are using glaucoma medications for years. Over time, with increased exposure, we can expect a higher risk for effects on the ocular surface.9

Kahook: Preservatives can be categorized into 2 groups: the detergent preservatives, such as BAK and chlorobutanol, and the oxidizing preservatives such as Purite and SofZia. Preservatives gained approval from regulatory agencies because they are effective in preserving the contents of multidose containers, which are typically used for medications such as eye drops. However, once they are on the ocular surface, they act in very different ways.

Detergent preservatives like BAK act by altering the permeability of the cell membrane and promoting cell lysis. These preservatives produce this effect on pathogens as well as the ocular surface cells, including both corneal and conjunctival epithelial cells. Thus, while BAK is effective at preserving the solution against pathogens, it also causes side effects when administered topically on the eye.

In contrast, oxidizing preservatives do not disrupt the cell membrane directly. They enter the cell and alter intracellular components of bacteria. These preservatives, which include sodium perborate and stabilized oxychloro complex (SOC), are thought to cause less ocular toxicity than detergent preservatives such as BAK and chlorobutanol. Human cells have oxidases that protect against this type of damage, whereas pathogens lack protective oxidases.

One weakness in our understanding, as I mentioned before, is the lack of in vivo metrics to help us comprehend subtle differences in the clinical setting. There can be a discrepancy between in vitro results observed in cell culture studies and clinical findings noted at the slit lamp. We may not be measuring the eye in exactly the same manner every time, or the metrics we are using may not be reproducible from day to day or from season to season. Further studies are required to correlate the in vitro effects of preservatives with what is observed in the clinic.

O’Brien: We have known for some time that BAK has indiscriminate effects on both eukaryotic and prokaryotic cells, contributing cytotoxicity and even death to both in a dose-dependent fashion. On the other hand, some of the newer preservative agents have a selective effect that may be less toxic to the ocular surface.

Sherwood: We must also remember that to some extent BAK was used initially to enhance the uptake of certain drugs through the ocular surface by interrupting the intracellular junction, which increases the absorption of the active agents. So there was a reason for its popularity in addition to its antimicrobial effects.

Kahook: Importantly, the newer medications are more lipophilic, and therefore do not need assistance in crossing the epithelial barrier. In contrast, some of the older medications required that assistance to increase the concentration within the anterior chamber. So by virtue of developing these new medications, we have to some extent obviated the need for disrupting the junctions in the epithelial layer.

Sherwood: I would also point out that time is an important factor. There is evidence that these preservatives, and in fact sometimes the drugs, can affect the inflammatory cell component of the conjunctiva. Studies have shown that interleukins and other inflammatory cytokines are present at increased levels in tears of patients treated with preserved eye drops.23 There is recruitment of inflammatory cells based upon chronic usage.24,25

O’Brien: How does the issue of preservatives affect your management of a patient with a compromised ocular surface and a comorbid condition such as glaucoma?

Sherwood: I think the issue of preservatives in glaucoma medications can affect the management of a patient like this in 1 of 2 situations. First, for a patient who is just beginning treatment, it may be preferable to use medications with preservatives that are less toxic, or to treat at low dosage levels, to reduce the risk of disruption of the ocular surface. Second, a more common situation is one in which we are seeing a patient who has already been on medications for some time, and we are trying to determine which medication or combination of medications is contributing to the patient’s discomfort or other signs of ocular surface disease.

O’Brien: Does the constellation of problems ever influence your decision to approach the patient with nonpharmacologic treatment to lower the pressure? That is, are there cases where we conclude that the patient’s eye is already so compromised that we are only going to make the problem worse by changing or adding a medication?

Sherwood: Absolutely. We often see patients in glaucoma practices who are using multiple medications and have significant eye irritation that is attributed to their treatment regimen. I think there has been an increasing trend toward earlier laser therapy, especially with the advent of selective laser therapy and the possibility of repeat laser therapy. There have been randomized studies that have compared primary surgery with medical therapy and/or laser therapy, and there is some evidence that early surgery is not detrimental.26-29

O’Brien: The situation is difficult. We know that a patient who has ocular surface disease has a proinflammatory state and that opting for a glaucoma surgical intervention without first addressing the ocular surface disease decreases the likelihood of success and increases the risk of a poor outcome.30,31

Sherwood: That is definitely a concern. We now have effective antifibrotic agents.32 There is some research suggesting that topical steroids before surgery may reverse some of the tissue changes.33

O’Brien: There may be an evolving preference to first control the ocular surface disease before proceeding with the nonpharmacologic surgical intervention, and this control could involve the use of anti-inflammatory agents and immunomodulatory drugs.

Sherwood: Yes, exactly. Topical NSAIDs have been attempted as well as topical steroids.34

Kahook: “Addition by subtraction” is a general concept that I try to apply when I see these patients in our clinic — sometimes more can be accomplished by removing medication from the patient’s regimen. For example, if someone is using 4 different glaucoma medications, I may recommend a break from all of the medications to get the ocular surface back to its state of health, and then reinitiate the medications one at a time to see which ones are necessary before proceeding with surgery. I have been surprised at how many times I can remove one or more medications from the regimen and attain control of IOP with 1 or 2 of the medications. Using fewer medications may also improve adherence, as decreased adherence to glaucoma medication may occur with an increased number of eye drops in the treatment regimen.

Impact of the Compromised Ocular Surface on Glaucoma

O’Brien: Adherence is a significant hurdle to overcome in managing patients with glaucoma because it is a chronic asymptomatic disease. How much more difficult is this when the patient has ocular surface disease?

Kahook: Often we add treatment with artificial tears or punctal plugs in this patient population, which can actually worsen the problem. Even if we prescribe an artificial tear that is preservative-free, the patient may go to the pharmacy and buy a generic formulation that contains BAK. Regarding punctal plugs, they trap the inflammatory cytokines in place within the tear film and may actually exacerbate patient symptoms. This worsening of symptoms often affects
treatment adherence.

O’Brien: The role of punctal plugs is controversial. At times they can help retain the tears that are being produced. However, if there is already an inflamed and unhealthy ocular surface, proinflammatory cytokines can be trapped, potentiating the inflammatory processes that affect the ocular surface. For patients with glaucoma, it is already difficult to maintain long-term treatment adherence. When the patient has both significant ocular surface disease and glaucoma, it is even more challenging.

Sherwood: I think we all see a number of patients who have glaucoma and tell us that they are intolerant of certain medications. I am unsure how much of this intolerance is due to ocular surface disease. We end up with a substantial number of patients for whom our prescribing options are fairly limited because of the medications they have tried in the past.

Kahook: Convincing a patient to start glaucoma medication when they are not really experiencing any symptoms is difficult enough. If they have a very early visual field impairment that they do not yet notice, it can take time to help the patient understand that we are trying to prevent them from becoming symptomatic in the future. What often happens is that they start taking the medication and they experience ocular surface side effects. Thus, on the next visit, we spend a significant amount of time convincing the patient that the ocular surface symptoms can be managed with different strategies, but that it is still important for them to adhere to their glaucoma medications so that they will not eventually become symptomatic from their glaucoma.

I think the idea of adherence to glaucoma therapy deserves more attention than it has been receiving because I think many treatment failures occur because of nonadherence, and the issue is worse when patients are experiencing ocular surface symptoms from the therapy that we are initiating.

O’Brien: Patients will be aware of their symptomatology and link some of these symptoms to a specific eye drop (particularly a preservative-containing drop), and will therefore be less compliant with their treatment regimen.

O’Brien: Who are the most vulnerable patients that clinicians need to think about? What risk factors should signal to the clinician that there should be a greater concern of the ocular surface?

O’Brien: I will begin by perhaps stating the obvious. Age and sex are both important risk factors for ocular surface disease, with older women being at especially high risk.35,36 Patients who are on multiple systemic medications that may affect tear film function are at increased risk. These medications include agents with antimuscarinic effects, oral antihistamines, and antidepressants.37 In ophthalmology, we often see patients with glaucoma who have a chronic disease for which they are typically taking more than 1 medication for an extended duration of time. Patients with prior ocular surgery may also be at increased risk. Previous LASIK surgery has received the most attention for exacerbating ocular surface disease. The corneal nerve supply is interrupted, and therefore, the tear film reflex arc is impacted. In patients with glaucoma, both filtering bleb surgery as well as filtering tube surgery increase the risk for ocular surface disease because of the effect of the devices and changes in the morphology of the conjunctiva. In patients with retinal surgery or strabismus surgery, there is the potential for extensive scarring. This changes the conjunctival fornices and goblet cell function, which also increases the risk for ocular surface disease.

O’Brien: How does the introduction of preservatives on a healthy eye differ from that of an eye with an already compromised ocular surface?

Sherwood: In many cases, the human body has reserves that allow it to continue to function even in the presence of significant pathology. For example, people can live without 1 kidney or 1 lung. I think that any situation where agents are added that may further disrupt the cells of the ocular surface, cause inflammatory effects, or decrease goblet cell function is more likely to affect the high-risk population than the young healthy population.

O’Brien: I agree, the healthy young ocular surface has a number of compensatory mechanisms that mitigate the impact of low-dose preservative-containing medications. For the most part, there will not be an accelerated or further deterioration of the ocular surface if used for the short-term. On the other hand, in a person who is showing signs of compromise, with the loss of this delicate balance of ocular surface function, the impact of medications on the natural compensatory mechanisms is more significant.

O’Brien: In addition to physiological effects, what other effects of preservative-containing eye drops might be observed specifically in the patients with glaucoma, and what impact might these effects have on treatment?

Sherwood: There is always some concern about the inflammatory changes in the conjunctival tissues in a patient with glaucoma, how it might affect the success rate if the patient needs surgery, and whether the risk of scarring is increased.

O’Brien: An aggressive approach to restore the delicate balance and to reduce the proinflammatory state of the unhealthy ocular surface would be advantageous before surgery.

Sherwood: That should certainly be considered. Unfortunately, by the time the surgery is being planned, the patient often has advanced disease and it is difficult to stop medication in enough time before surgery to restore the health of the surface tissue.

O’Brien: Is there any parallel to the patient with herpetic eye disease? There, toxicity is often observed in association with topical antivirals that contain preservatives, especially those with thimerosal. Many of those patients were treated with an oral antiviral after suspension of the topical antiviral. Do you ever consider short-term use of a systemic antiglaucoma agent while you are trying to control the inflammation on the ocular surface before surgery?

Sherwood: I do not usually do that. I think the risks of the medical comorbidities probably outweigh the ocular surface issues.

Kahook: This type of situation is rare, but I have done this a few times for patients who are on several different eye drops with an extremely inflamed conjunctiva. In this situation, I have used methazolamide more often than acetazolamide. Studies have shown that the surgical failure rate is much higher in patients who are using multiple topical glaucoma medications before surgery, which is attributed to greater conjunctival inflammation, fibrosis, and scarring with greater preservative exposure.32 The options would be to start a topical steroid while maintaining glaucoma medications, or stop the topical medication and initiate short-term methazolamide while treating them with topical steroids until surgery. Although the latter results in faster recovery of the ocular surface, I use this method rarely. More often I will add a steroid to the glaucoma medications for 3 to 4 weeks before surgery, which has been shown to reduce inflammation in the conjunctiva and improve the success rate of filtration surgery.33 This is an area where more research is needed to better quantify those effects, specifically with the newer medications that are being used. Many of the older studies were performed with medications that are no longer in use or not frequently used.

Improving Clinical Practice

O’Brien: How can we improve clinical practice? What steps should we as clinicians take to improve overall adherence among patients with glaucoma?

Kahook: I would primarily advocate for education. We often diagnose glaucoma, prescribe a topical medication, tell the patient to use it once or twice a day, and schedule an appointment for the patient to return in a few weeks for another IOP assessment. Even though it can be a struggle to find the time, I think we need to do more to educate the patient about glaucoma, what the disease is, what the treatments are, and how the treatments might affect other aspects of ocular health, specifically ocular surface disease. If we explain to the patient that some of our eye drops might cause effects such as redness, discomfort, or foreign body sensation, then that is something that the patient can understand after they leave the office, and it also gives them the opportunity to voice concerns when they return for their follow-up visit. They have heard about the possible side effects of treatment, and they are more comfortable discussing the issue with their physician. This facilitates the identification of patients experiencing side effects. Whether we are managing glaucoma, cataracts, AMD, or other disorders, this kind of patient education is not something we often do in ophthalmology. All of the diseases in ophthalmology practice would benefit from greater education and patient-physician interaction.

Sherwood: I agree completely. The problem is that it is difficult to find the time to have these conversations. Even if we explain to patients that their eye drops may cause some redness or burning or itching, patients may feel that this is something they have to tolerate as part of the disease. At first, patients may try to stay on their treatment because the symptoms are tolerable. Over the course of time, however, these problems often become more burdensome. Perhaps we need to create a better framework for discussion between the patient and the physician, and find better ways for patients to communicate with us about how intolerable treatment is at a particular point in time. Our patients differ in terms of what they are willing and able to tolerate.

Assessing how well patients are adhering to treatment is difficult. There is a lot of discussion about adherence, but there is sparse information about the scope of the problem because it is difficult to measure well.

O’Brien: Would you say that is true even in programs that have tried to use metered dosing?

Sherwood: Research has shown that metered dosing does not necessarily reveal proper administration of the medication. Even when the patient lifts the bottle up to the eye, the drops may not be correctly applied, as seen in many videos.38,39Some studies have examined how often patients fill prescriptions, but we do not always know from those data whether the patients obtained medications from other sources of supply.40,41 We do not know whether they are using their drops exactly as prescribed. We really do not know very much about individual adherence patterns in our own patients with glaucoma.42

Kahook: We performed a study that examined patient adherence to medication using a portable electronic dosing aid that recorded each time the medication was used, and the number of drops administered.43 Interestingly, most patients were very adherent the day before their next visit, but had more sporadic adherence in the weeks before their visit. This brings up another point: physicians are usually not very good at predicting which patients will remain adherent to therapy and which will not. So, in addition to the lack of effective metrics for evaluating ocular surface disease that we discussed earlier, we also do not have good metrics for evaluating adherence. Despite these obstacles, I think adherence is clearly a difficult problem that we should be considering and discussing with our patients who have glaucoma. The more it is discussed, the more patients might understand and internalize the need for adherence as a way to improve the effectiveness of therapy and, ultimately, of their disease outcomes.

Sherwood: There are data to suggest that other technological devices such as smartphone applications, phone call reminders, and device alarms may help to encourage patients to be more adherent to therapy.44 However, because we do not have effective metrics for adherence, this cannot be definitively concluded.

Kahook: This is not necessarily a new concept, but novel approaches are becoming available. We recently initiated a multicenter study that is examining patient education using glaucoma educators. We trained one of our technicians as a glaucoma educator to work closely with our patients and promote adherence using the technique of motivational interviewing. We are comparing treatment adherence for the education intervention cohort vs. a standard of care cohort, and we are monitoring adherence using personal electronic dose monitors. In a pilot study, we examined the feasibility of the motivational interviewing program, and we found that we were able to educate patients and those who received this extended glaucoma education were more likely to be adherent to medication.43

Of course, many devices have been developed to help patients become more adherent to treatment. For example, there are digital alarm systems that remind the patient when to administer eye drops, as well as various telephone and paging services. However, these devices overlook 2 key problems. First, patients might not understand why they need to be adherent. Second, even if they do, these methods do not overcome some of the physical limitations of treatment, such as the case where the patient is attempting to instill eye drops but misses the eye. We still have a great deal of work to do in order to improve adherence and our methods of drug delivery. Until then, we can utilize the pearls that have been discussed to improve adherence.

O’Brien: Glaucoma is especially challenging because it is a chronic yet often asymptomatic disease. Patient education is crucial, yet we have a limited amount of time in which to carry out this important educational process. We need to have tools that can be administered adjunctively with patient education to increase patient understanding of the chronic nature of glaucoma and the multifaceted approach that is required to manage their comorbid ocular surface disease and glaucoma.

O’Brien: Leaving aside any possible differences due to preservatives, the glaucoma medications themselves have different likelihoods of causing ocular surface symptoms. Are some medications fundamentally more likely to affect the ocular surface? If so, when should we consider stopping those medications in a patient who already has a compromised ocular surface?

Sherwood: One of the issues is the number of times per day a particular medicine must be taken to be effective. That affects not only the amount of drug or preservative that is being placed in the eye, but also compliance.

O’Brien: This is certainly one reason for the popularity of the prostaglandin analogs given the requirement for only once-daily administration.

Sherwood: Yes, a medication that is administered once a day has some potential benefit. Although I believe that there is some research suggesting that a twice-daily dosing may be associated with equally effective adherence as once-daily.45

Kahook: I think we should make the distinction between the direct effects of the active ingredient in a prostaglandin analog that can cause hyperemia secondary to dilation of the vessels on the ocular surface. That may be noticeable to the patient and to the patient’s family, even though it may not affect the actual health of the ocular surface. The hyperemia is a cosmetic issue. There is some irritation associated with it, but that is distinct from ocular surface disease that is caused directly by inflammation of the conjunctiva or of the ocular surface that results from either hypersensitivity to the active ingredient or to the preservative component. There is a high rate of adverse events or of ocular surface side effects that are caused by the alpha agonist class, typically with hypersensitivity to the active ingredient.46,47

In general, any medication that is placed on the ocular surface can cause hypersensitivity reactions or ocular surface disease, and it can be difficult to predict which patients are going to tolerate a specific class of medications. Following up with the patient after a new medication is initiated is important to see how each individual patient reacts to each specific medication class. If we have been closely monitoring the patient as we make changes to the treatment regimen, we are in a better position to address any problems that do arise.

O’Brien: Given the need for many patients to use several medications, avoiding preservatives completely is unlikely. What steps can patients take to minimize symptoms?

Kahook: I mentioned earlier the idea of “addition by subtraction” — that is, trying to understand exactly what is affecting the patient and removing medications that are causing problems. That might mean switching the patient to a medication with an alternative preservative, or to a preservative-free formulation to minimize some of the effects we have been talking about. Once the patient goes from 1 to 2 medications, I might start thinking about laser trabeculoplasty as a possibility to potentially decrease the likelihood of going to a third or fourth medication. Very few patients under my care are on 3 or 4 medications. Due to issues such as adherence and tolerability, I usually consider maximal medical therapy to be 2 eye drops. I think there is a significant decrease in adherence when a third eye drop is added to the treatment regimen, as well as a potential effect on the ocular surface. Physicians vary in terms of how they manage glaucoma. I try to be more aggressive about switching to alternatives to topical therapy once the patient either exhibits serious ocular surface issues or requires more than 2 medications.

Sherwood: We have research suggesting that adding a third or a fourth medication has a relatively low success rate for achieving significant additional pressure-lowering. One study retrospectively evaluated clinical safety and efficacy outcomes for 96 patients who had a third or fourth topical glaucoma medication added to an existing 2-drug (67 patients) or 3-drug (29 patients) regimen.48 Efficacy was defined as an improvement of IOP of at least 20% from baseline. Using Kaplan-Meier survival analysis, the cumulative probability of continued treatment success after 1 year was 23% for patients who went from 2 to 3 medications, and 18% for those who went from 3 to 4 medications. We also used a combined outcome measure that included both efficacy and several safety outcomes (drug-related adverse effects, need for further surgery, or a change in the patient’s medication regimen). Using this composite measure of overall clinical benefit, the likelihood of a successful outcome after 1 year was only 14% for both groups of patients. These observations suggest that most patients who are already using multiple glaucoma medications are not likely to derive significant clinical benefit from adding another agent, but they often do experience significant adverse events.

O’Brien: I have always worried that if the patient is encouraged to use lubricating drops at the time of initiation of the glaucoma medication, there will be potential for a significant dilutional effect on IOP control unless specific instructions are provided for a requisite interval between dosing.

O’Brien: Some people suggest that cooling the eye drops before instillation might improve tolerability. Are there concerns about the potential for chilling to reduce the enzymatic and other temperature-dependent activity of the medication?

Sherwood: I think one advantage of chilling is that it can help the patient to be sure that the drop definitely made it into the eye. Apart from that, I am not sure that there are any valid data showing that chilling medications is helpful.

Kahook: There is a potential concern of going below the temperature recommended on the label. Typically, the medications are approved for storage between 5°C and 25°C. If the temperature is below that, especially if the medication is frozen, there is potential to decrease the efficacy of the medication. Furthermore, there may be the potential to introduce contaminants from the bottle itself due to interactions between the fluid and the bottle when freezing or overheating occur. This may also be something to consider with some of the generic agents that are entering clinical practice. The susceptibility to chilling or heating often is not studied as vigorously with generic medications as with branded medications.

Summary and Conclusions

O’Brien: Ocular surface disease is a common condition with a significant overlap with glaucoma. Clinicians need to develop a heightened awareness to recognize patients who have significant ocular surface disease as well as glaucoma. A carefully planned, streamlined diagnostic routine is important, and may be simplified with the aid of validated questionnaires. A directed clinical exam is essential to identify the most common signs and symptoms. Treatment should begin with thorough patient education. Selection of medications and vehicles with minimal effects on the ocular surface, while simultaneously providing effective control of the glaucoma to prevent progression is also important. The challenge of treating ocular surface disease is the importance of developing a strategy to determine what is working best for an individual patient, and to monitor outcomes and modify the treatment approach accordingly.

Sherwood: Frequently in glaucoma, we follow a patient and track long-term changes in disease status. This is difficult to do for patients with ocular surface disease because of the challenges associated with developing a good baseline assessment to demonstrate long-term changes.

O’Brien: I think that there has been hope that some of the biomarkers we discussed such as the tear film osmolarity or tear lysozyme results would be able to provide that information. But unfortunately, we are still at a rather early adoptive stage of using these biomarkers to match patients to treatments. We do not have the type of objective information that is available in patients with glaucoma, where we have the ability to perform a longitudinal progression analysis. I think a key goal should be to choose a few tests and perform them as accurately and reproducibly as possible. For example, we can use tear film breakup time with the staining grids that have been used by National Eye Institute studies. However, we currently do not really have effective, objective criteria that would provide a longitudinal index of progression. With the recent increase in recognition and study of dysfunctional tear syndromes, it is indeed encouraging that there will be improved methods in the near future to simultaneously manage glaucoma and ocular surface diseases.

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