IOP Control and Quality of Life Improvement

FOCUS ON GLAUCOMA MANAGEMENT: CME MONOGRAPH

Jointly provided by New York Eye and Ear Infirmary of Mount Sinai and MedEdicus LLC.

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This continuing medical education activity is supported through an unrestricted educational grant from Santen Pharmaceutical Co, Ltd.

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FACULTY Norbert Pfeiffer, MD (Chair and Moderator)Gábor Holló, MDCindy M. L. Hutnik, MD, PhDTarek M. Shaarawy, MD, MSc, PD

Original Release: May 1, 2017

Last Review: April 14, 2017

Expiration: May 31, 2018

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LEARNING METHOD AND MEDIUMThis educational activity consists of a supplement and eight (8) study questions. The participant should, in order, read the learning objectives contained at the beginning of this supplement, read the supplement, answer all questions in the post test, and complete the Activity Evaluation/Credit Request form. To receive credit for this activity, please follow the instructions provided on the post test and Activity Evaluation/Credit Request form. This educational activity should take a maximum of 1.5 hours to complete.

CONTENT SOURCE This continuing medical education (CME) activity captures content from a roundtable discussion held on January 16, 2017.

ACTIVITY DESCRIPTIONControl of intraocular pressure (IOP) is the only therapeutic strategy for maintaining visual function in patients with glaucoma, and medical therapy remains the cornerstone of treatment. Although agent availability differs internationally, the regimen selected for any individual needs to take into account disease severity and risk of progression, along with medication cost and its effects on quality of life. The purpose of this activity is to update ophthalmologists on the medical management of glaucoma and the role that fixed-combination and preservative-free medications can have in achieving therapeutic goals.

TARGET AUDIENCEThis educational activity is intended for European, North American, and Asia-Pacific ophthalmologists caring for patients with glaucoma.

LEARNING OBJECTIVESUpon completion of this activity, ophthalmologists will be better able to:• Select appropriate ocular antihypertensive therapy to meet IOP goals throughout the day and night• Develop individualized regimens for IOP control with multitherapy or fixed- combination therapy in patients• Incorporate effective IOP-lowering strategies in patients with ocular surface disorders

ACCREDITATION STATEMENTThis activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of New York Eye and Ear Infirmary of Mount Sinai and MedEdicus LLC. The New York Eye and Ear Infirmary of Mount Sinai is accredited by the ACCME to provide continuing medical education for physicians.

AMA CREDIT DESIGNATION STATEMENTThe New York Eye and Ear Infirmary of Mount Sinai designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

GRANTOR STATEMENTThis continuing medical education activity is supported through an unrestrictededucational grant from Santen Pharmaceutical Co, Ltd.

DISCLOSURE POLICY STATEMENTIt is the policy of New York Eye and Ear Infirmary of Mount Sinai that the faculty and anyone in a position to control activity content disclose any real or apparent conflicts of interest relating to the topics of this educational activity, and also disclose discussions of unlabeled/unapproved uses of drugs or devices during their presentation(s). New York Eye and Ear Infirmary of Mount Sinai has established policies in place that will identify and resolve all conflicts of interest prior to this educational activity. Full disclosure of faculty/planners and their commercial relationships, if any, follows.

DISCLOSURESGábor Holló, MD, had a financial agreement or affiliation during the past year with the following commercial interest in the form of Consultant/Advisory Board: Alcon.

Cindy M. L. Hutnik, MD, PhD, had a financial agreement or affiliation during the past year with the following commercial interests in the form of Consultant/Advisory Board: Alcon; Allergan; and Bausch & Lomb Incorporated.

Norbert Pfeiffer, MD, had a financial agreement or affiliation during the past year with the following commercial interests in the form of Consultant/Advisory Board: Santen Pharmaceutical Co, Ltd; Contracted Research: Allergan; Honoraria from promotional, advertising or non-CME services received directly from commercial interests or their Agents (eg, Speakers Bureaus): Alcon; Allergan; and Santen Pharmaceutical Co, Ltd.

Tarek M. Shaarawy, MD, MSc, PD, has no relevant commercial relationships to disclose.

NEW YORK EYE AND EAR INFIRMARY OF MOUNT SINAIPEER REVIEW DISCLOSUREJoseph F. Panarelli, MD, had a financial agreement or affiliation during the past year with the following commercial interests in the form of Consultant/Advisory Board: Aerie Pharmaceuticals, Inc; and Allergan.

EDITORIAL SUPPORT DISCLOSURESCheryl Guttman Krader; Diane McArdle, PhD; Cynthia Tornallyay, RD, MBA, CHCP; Kimberly Corbin, CHCP; Barbara Aubel; and Michelle Ong have no relevant commercial relationships to disclose.

DISCLOSURE ATTESTATIONThe contributing physicians listed above have attested to the following:1) that the relationships/affiliations noted will not bias or otherwise influence their involvement in this activity;2) that practice recommendations given relevant to the companies with whom they have relationships/affiliations will be supported by the best available evidence or, absent evidence, will be consistent with generally accepted medical practice; and3) that all reasonable clinical alternatives will be discussed when making practice recommendations.

OFF-LABEL DISCUSSIONThis CME activity includes discussion of unlabeled and/or investigative uses of drugs. Please refer to the official prescribing information for each drug discussed in this activity for approved dosing, indications, and warnings.

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TO OBTAIN AMA PRA CATEGORY 1 CREDIT™To obtain AMA PRA Category 1 Credit™ for this activity, read the material in its entirety and consult referenced sources as necessary. Complete the evaluation form along with the post test answer box within this supplement. Remove the Activity Evaluation/Credit Request page from the printed supplement or print the Activity Evaluation/Credit Request page from the Digital Edition. Scan and return via email to cme@nyee.edu or fax to 212-353-5703. Your certificate will be sent to the email address you provide on the Activity Evaluation/Credit Request form. Please allow 3 weeks for Activity Evaluation/Credit Request forms to be processed. There are no fees for participating in and receiving CME credit for this activity.

Alternatively, we offer instant certificate processing and support Green CME. Please take this post test and evaluation online by going to http://tinyurl.com/IOPcontrol. Upon passing, you will receive your certificate immediately. You must score 70% or higher to receive credit for this activity, and may take the test up to 2 times. Upon registering and successfully completing the post test, your certificate will be made available online and you can print it or file it. DISCLAIMERThe views and opinions expressed in this educational activity are those of thefaculty and do not necessarily represent the views of New York Eye and Ear Infirmary of Mount Sinai; MedEdicus LLC; Santen Pharmaceutical Co, Ltd; or EuroTimes.

In July 2013, the Accreditation Council for Continuing Medical Education (ACCME) awarded New York Eye and Ear Infirmary of Mount Sinai “Accreditation with Commendation,” for six years as a provider of continuing medical education for physicians, the highest accreditation status awarded by the ACCME.

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INTRODUCTIONApproaches to management for patients with ocular hypertension (OHT) and glaucoma need to be individualized, but the goals for all patients remain the same: maintain visual function and quality of life. A panel of experts was convened to discuss strategies for achieving these goals, taking into account evidence-based guideline recommendations and opportunities for improving safety, effectiveness, and treatment adherence with preservative-free and fixed-combination medications.

RISK FACTORSDr Pfeiffer: What factors do you consider to determine a patient’s risk for glaucoma progression?

Dr Hutnik: Several large, prospective, randomized control trials identified risk factors for disease onset (Table 1)1-3 and progression (Table 2).4-6 The risk factors were specific to the types of individuals included in the studies, which represented different stages or types of disease (Table 1).1-3

I recently participated in a Canadian expert panel meeting organized to develop quality-based guidelines for glaucoma management. We reviewed risk factors and considered if these vary with the disease stage and/or type. The panel concluded that the risk factors for glaucoma progression are broad based and include characteristics that are identified in both the history and physical examination. Although risk factors are not indicative of disease certainty, they do allow a consideration of the likelihood of conversion to and/or progression of glaucoma.

Table 1. Risk Factors for Glaucoma Development From Randomized Controlled Trials

Table 2. Risk Factors for Glaucoma Progression From Randomized Controlled Trials

IOP Control and Quality of Life Improvement

FOCUS ON GLAUCOMA MANAGEMENT: CHAIR AND MODERATOR

Norbert Pfeiffer, MDMedical DirectorDepartment of OphthalmologyUniversity Medical CenterJohannes Gutenberg University MainzMainz, Germany

FACULTY

Gábor Holló, MDProfessor of OphthalmologyDirector, Glaucoma Service and Perimetry UnitDepartment of Ophthalmology Semmelweis UniversityBudapest, Hungary

Cindy M. L. Hutnik, MD, PhDProfessorIvey Eye InstituteLondon, Canada

Tarek M. Shaarawy, MD, MSc, PDChargé de cours Director, Glaucoma Sector Geneva University Hospital Geneva, Switzerland

CME REVIEWER FOR NEW YORK EYE AND EAR INFIRMARY OF MOUNT SINAI

Joseph F. Panarelli, MDAssistant Professor of OphthalmologyIcahn School of Medicine at Mount SinaiAssociate Residency Program DirectorNew York Eye and Ear Infirmary of Mount SinaiNew York, New York

This CME activity is copyrighted to MedEdicus LLC ©2017. All rights reserved.

Ocular Hypertension Treatment Study1,2

European Glaucoma Prevention Study3

• Older age• Higher intraocular pressure• Thinner central corneal thickness• Larger vertical and horizontal cup-to-disc ratios• Higher pattern standard deviation• Disc hemorrhages• Diabetes (protective)

• Older age• Higher intraocular pressure• Thinner central corneal thickness• Larger vertical cup-to-disc ratio • Larger vertical cup-to-disc ratio

asymmetry• Higher pattern standard deviation

Collaborative Normal-Tension

Glaucoma Study4

Early Manifest Glaucoma Trial5

Advanced Glaucoma Intervention Study6

• Disc hemorrhage• Migraine/

vasospasm• Female sex

• Older age• Higher intraocular pressure• Bilateral disease• Exfoliation syndrome• More baseline damage• Lower ocular systolic perfusion

pressure• Disc hemorrhages• Cardiovascular disease history

(in high-tension glaucoma)• Thinner central corneal thickness

(in high-tension glaucoma)• Low systolic blood pressure (in normal-tension glaucoma)

• Older age• Increasing number

of interventions• Intraocular pressure

fluctuations (normal-tension glaucoma only)

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Dr Pfeiffer: Dr Shaarawy, what are the risk factors for glaucoma progression that you consider?

Dr Shaarawy: I look at intraocular pressure (IOP), maximum IOP, IOP fluctuations and their amplitude, central corneal thickness (CCT), race, family history, and if there is a personal history for causes of secondary glaucoma. I also want to know how fast glaucomatous progression will occur, or is occurring.

I think that some physicians treat glaucoma as if it was a single disease, but it is really a multifaceted condition, and the role of different risk factors can vary in different patients. I do not define patients as having normal-tension glaucoma or high-pressure glaucoma according to whether their IOP is above or below 21 mm Hg. I do distinguish patients on the basis of whether I believe their risk for progression is related more to vascular issues or to IOP, and I manage for risk factors based on that assessment.

Dr Pfeiffer: We know that patients with pseudoexfoliation are at increased risk for developing glaucoma, and they have been reported to have high IOP fluctuations. Even though fluctuation as a risk factor for development and progression of pseudoexfoliation glaucoma is controversial, I think that it is important to follow these patients carefully because they can have rapid progression.

Dr Hutnik: I also believe patients with pseudoexfoliation glaucoma need to be monitored at more frequent intervals than those recommended by routine open-angle guidelines. Patients who have been stable for years can suddenly, over a matter of a few months, lose IOP control. In addition, patients with pseudoexfoliation can convert from having an open angle to becoming an angle-closure suspect or developing angle closure. I therefore repeat gonioscopy more frequently in these patients.

Dr Holló: Approximately 30% of patients with pseudoexfoliation develop glaucoma within 10 years,7 and the increased risk for glaucoma and its progression in these patients may be due, in part, to alterations in the elastin components of the lamina cribrosa.8 Pseudoexfoliation glaucoma is associated with a considerable increase in IOP fluctuation that plays an important role in the rapid progression of this glaucoma type in addition to the elevation of long-term average IOP.9 Patients with pseudoexfoliation not only require more frequent follow-up, but should have 24-hour IOP measurements.

MEDICAL TREATMENTEuropean Glaucoma Society GuidelinesDr Pfeiffer: Both Dr Holló and Dr Shaarawy were involved in developing the fourth edition of the European Glaucoma Society (EGS) Terminology and Guidelines for Glaucoma.10 What are the most important changes that the guidelines introduced for medical treatment recommendations?

Dr Holló: The EGS guidelines clearly state that treatment for open-angle glaucoma (OAG) should be initiated with monotherapy and that a second medication should be added if the first medication is well tolerated and effective in lowering IOP, but the target IOP has not been reached.10 The guidelines also recommend switching to a fixed combination, when available, when target IOP is reached using 2 separately instilled

medications. The preference for the fixed combination considers evidence that simplifying the treatment regimen can improve adherence, avoid medication washout, and reduce exposure to preservatives. The guidelines also address local toxicity caused by preservatives and state that preservative-free formulations should be considered in eyes with ocular surface disease (OSD).

Dr Shaarawy: I think the fourth edition of the EGS guidelines draws attention to the fact that we should never make the treatment of the disease more cumbersome than the disease itself. The mission statement says the goal of glaucoma treatment is to maintain visual function and related quality of life at a sustainable cost.10

I still see patients on referral who are using 3 drops in each eye, and they are not necessarily the same medications. We must not lose sight of the fact that we are first and foremost trying to preserve quality of life for our patients while at the same time treating the eye or lowering IOP.

Dr Pfeiffer: Dr Hutnik, what is the availability of fixed- combination IOP-lowering products in Canada?

Dr Hutnik: In Canada, we are fortunate to have access to a relatively large number of fixed combinations (Table 3). Many clinicians feel that they are the best option when adjunctive therapy is required and it is for this reason that they are used frequently. The products include medications from all pharmacologic classes. Unfortunately, the pilocarpine–β-blocker combination was discontinued in Canada; it was a very effective option for certain patients and needed only twice-daily dosing.

Table 3. Regional Availability of Fixed-Combination Intraocular Pressure–Lowering Medications

Treatment InitiationDr Pfeiffer: For a patient with primary open-angle glaucoma (POAG) who has early glaucomatous disc changes and an IOP of 27 mm Hg, what would be your first choice for treatment?

Product Europe Canada United States

Bimatoprost, 0.03%/Timolol, 0.5% X*

Brimonidine, 0.2%/Timolol, 0.5% X X X

Brinzolamide, 1%/Timolol, 0.5% X X

Dorzolamide, 2%/Timolol, 0.5% X* X* X*

Latanoprost, 0.005%/Timolol, 0.5% X X

Pilocarpine, 2%/Timolol, 0.5% X*

Pilocarpine, 4%/Timolol, 0.5% X*

Tafluprost, 0.0015%/Timolol, 0.5% X*

Travoprost, 0.0004%/Timolol, 0.5% X X

Pilocarpine, 2%/Metipranolol, 0.1%

Pilocarpine, 2%/Carteolol, 2% X X

Brimonidine, 0.2%/Brinzolamide, 1% X X X

* Available as preservative free

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Dr Hutnik: According to the Canadian guidelines, treatment for early-stage glaucoma should target at least a 25% reduction from baseline IOP.11,12 Assuming the patient does not appear to be in dire trouble with IOP > 30 mm Hg, I would start with prostaglandin analog monotherapy. Prostaglandin analogs have an excellent systemic safety profile, and their ocular side effects are usually well tolerated. If the IOP was 28 to 30 mm Hg and the person had severe optic disc damage or severely advanced visual field loss, I would consider starting with a fixed-combination product and would probably prescribe once-daily use of a prostaglandin/β-blocker combination.

Dr Pfeiffer: I always start with monotherapy, even if the IOP is exceedingly high, because treatment-naïve patients can sometimes achieve a tremendous IOP reduction using a prostaglandin analog or β-blocker alone.

Dr Shaarawy: I also initiate treatment with monotherapy, regardless of IOP.

Dr Holló: When initiating medication for the patient with an IOP of 27 mm Hg and early glaucoma, I also would start with prostaglandin analog monotherapy. If the patient is a responder to the prostaglandin analog, meaning IOP is reduced by at least 20%, but is not also ≤ 18 mm Hg, I would add a second medication, maybe a β-blocker. If the combination was effective, I would switch to a fixed-combination product.

Dr Pfeiffer: Some patients are reluctant to start medication when they are diagnosed with glaucoma, and I am seeing an increasing number of patients who have read or heard about minimally invasive glaucoma surgery (MIGS) and are interested in having a stent procedure for initial treatment. They may be familiar with the concept of stents because they know someone with a coronary artery stent and consider a stent procedure to be low risk. Is anyone else having the same experience?

Dr Shaarawy: The patients I see are often interested in having selective laser trabeculoplasty before starting medication or undergoing some other surgery. Patients needing cataract surgery are receptive to the idea of combining the cataract procedure with MIGS to reduce IOP.

Dr Hutnik: We are seeing a rapid evolution in the treatment algorithm in Canada. I think there is sufficient evidence to support using selective laser trabeculoplasty earlier in the treatment paradigm, before advancing to maximally tolerated medical therapy. There is, however, a relative paucity of information about the efficacy of stents for controlling IOP beyond 2 years. The number of patients interested in and demanding stents is rapidly escalating, especially now that so many patients access the Internet for information. In Canada, we are working with the government to figure out the most judicious pathway to offer cost-effective quality care to our patients in a way that is evidence based.

Dr Pfeiffer: Clinicians must be careful to always consider the scientific evidence and not let patient requests determine their management.

Preservative-Free MedicationsDr Pfeiffer: Benzalkonium chloride (BAK), which is commonly found as a preservative in ophthalmic medications, can cause or exacerbate OSD.13 As Dr Holló mentioned earlier, the EGS guidelines recommend considering a preservative-free formulation in eyes with OSD.10 Would anyone initiate IOP-lowering treatment using a preservative-free medication?

Dr Holló: Each patient represents a different situation, so my decision is individualized. In many cases, however, I initiate treatment using a preservative-free prostaglandin analog. When selecting treatment, I consider that, in addition to the preservative, the active ingredient can affect ocular comfort and ocular surface health.

Dr Hutnik: First, I want to mention that in Canada we are seeing a tremendous switch favoring use of generic medications over brand-name products. This is a cost-driven shift.

Uptake of preservative-free IOP-lowering medications seems to be lower in Canada than in Europe. There is no question in my mind, however, that a preservative-free agent should be used for a patient with OSD. There is a strong body of published evidence showing that use of a BAK-free medication will improve adherence among patients with OSD.14 A frequently cited study in 2002 demonstrated a significant reduction in ocular surface signs and symptoms when benzalkonium was removed from common glaucoma medications.15 I had the good fortune to be involved in a more recent study that showed no increase in discomfort after treatment-naïve patients were started on a preservative-free medication.16

Dr Pfeiffer: I am using a preservative-free medication more and more as my first-line treatment. Although many patients do well with a preservative-containing medication, many do not. I am aware, however, that higher cost may be a barrier for using a preservative-free formulation.

Dr Shaarawy: I always initiate treatment with a preservative-free product because there is no financial constraint in Switzerland to prohibit that choice. On the basis of the idea that less is better, patients appreciate an opportunity to minimize chemical exposure, and people who travel are happy to have single-dose containers that are convenient to carry. As an exception, I do not initiate a preservative-free product in patients who might have difficulty using the unit-dose containers, such as an elderly person with arthritic hands.

MEDICATION ADHERENCEDr Pfeiffer: Let us talk more about medication nonadherence, which I think has an important role in explaining visual function loss in patients with glaucoma. What are your strategies for finding out about adherence and, following that, improving adherence?

Dr Holló: Some patients are unwilling to use medication, and there is not much one can do in that situation, but there are several considerations for patients who wish to cooperate. First, all patients should be instructed on how to use the eye drops, and if they have some physical difficulties with administration, then it is important to involve a family member. Patient adherence also improves if patients see some benefit from treatment in

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He is diagnosed with brimonidine allergy, toxic ocular surface syndrome, POAG, and corticosteroid-induced secondary OAG. All topical treatment was stopped, and the patient was started on oral acetazolamide 250 mg twice a day with potassium supplementation.

After 1 week, IOP was 33/34 mm Hg OD/OS, and acetazolamide was decreased to 250 mg once daily. After 4 weeks, IOP was 25/24 mm Hg.

After 2.5 months, IOP was 19 mm Hg OU. The conjunctiva appeared normal (Figure 2), and it was expected that more time was needed for the corneal infiltrates to resolve. Three months after starting acetazolamide, IOP was 15/17 mm Hg, and the patient was started on a preservative-free dorzolamide/timolol fixed combination twice daily. Six weeks later, IOP was 18/17 mm Hg, and acetazolamide was stopped.

Approximately 1 year later, preservative-free tafluprost was added. During the next 3 years of treatment, the patient’s IOP, including at the last visit, was consistently around 15 mm Hg OU. He experienced no structural or functional worsening and was without any ocular surface problems.

Dr Holló: This case has several take-home messages. First, ophthalmologists need to know and be able to recognize the potential side effects of the medications they prescribe. Second, a topical corticosteroid should never be used as treatment for medication-induced allergic or inflammatory side effects while the eye remains on the therapy causing the problems because the corticosteroid may suppress the signs and symptoms, but it does not provide a long-term solution and poses the risk for corticosteroid-induced glaucoma. Third, when a medication needs to be changed because of poor tolerability, a preservative-free medication is preferred, but time should also be allowed for the side effects to resolve. Eliminating all topical treatment will hasten recovery.

Dr Pfeiffer: This is a very instructive case, and I would just like to add that ophthalmologists should not overlook that brimonidine may also cause anterior uveitis.17,18 The uveitis may resolve with termination of brimonidine, but a corticosteroid may be necessary to control the inflammation.

lowering IOP. To support adherence, it is also important to select medication that has good local comfort, so it is helpful if patients whose treatment has been switched see an improvement in subjective symptoms, such as burning, eye pain, or itching, which they experienced previously using other topical glaucoma drugs.

Dr Hutnik: It is important that we take the health literacy level of our patients into account when counseling them and that we use language they will understand to relay the message that glaucoma is a silent thief when it comes to vision loss. I think frequent repetition to reinforce the information is helpful. In Canada, an initiative known as the National Eye Strategy was announced in October 2016. It espouses a collaborative model among ophthalmologists, optometrists, opticians, and primary care physicians. By working as a team, we feel that the more often patients hear about the deleterious consequences of nonadherence, the more likely they are to use their medication as directed. Lastly, it is recognized that clinicians have to listen to their patients’ concerns about health-related quality of life and cost issues associated with medication. We have great treatments to offer, but we need to establish a bond with our patients and make sure that the treatments we prescribe are not making them miserable.

Dr Shaarawy: We started a program in Geneva approximately 2 years ago, which introduced therapeutic education to nurses for patient counseling. The nurses completed 6 months of training on glaucoma at the University of Geneva. Now every patient who is starting medication for IOP lowering or who we suspect is having a problem with adherence receives a 30-minute education session with a nurse. The patients are videotaped while they are using their drops to identify if they are having difficulty with administration, and the nurses explore potential quality of life issues related to medication use.

This program has improved patient satisfaction with care, and we believe that it is improving medication adherence. The program is very rewarding for the nurses, patients, and physicians, and I would recommend it to anyone who can mobilize the resources.

Dr Pfeiffer: Considering the time constraints that physicians face in providing patient counseling, involving nonphysician health care practitioners is a good way to cope with the need for patient education and discussions on medication adherence.

LESSONS FROM CLINICAL PRACTICEThe following real-life cases and ensuing discussions highlight management approaches for some challenging and more routine patient scenarios.

A Patient With Ocular Adverse Effects From Glaucoma MedicationFrom the Files of Gábor Holló, MD

A male being treated with fixed-combination brimonidine/timolol presents for evaluation for glaucoma surgery because of very high IOP (50/54 mm Hg OD/OS) and significant glaucomatous damage. On examination, he has hyperemia (Figure 1), corneal infiltrates, and open angles. Current medication includes a topical corticosteroid that was started 6 months earlier to treat eye redness and allergy.

Figure 1. Ocular allergy and toxic ocular surface disease at presentationImage courtesy of Gábor Holló, MD

Figure 2. Hyperemia is resolved 2.5 months after discontinuation of brimonidine/timololImage courtesy of Gábor Holló, MD

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Dr Holló: Still, the corticosteroid should be used short term and the patient needs to be taken off the brimonidine.

Dr Hutnik: I think there are 2 other important teaching points from this case. (1) Intraocular pressure control can be lost when there is significant ocular inflammation, whether it is provoked by medication or not. (2) Although the availability of MIGS may make earlier surgical intervention seem more appealing, one must be cautious about jumping to surgery too soon. With accurate diagnosis of the cause of red eye and modification of medical therapy, this patient avoided incisional surgery.

Dr Shaarawy: I think many ophthalmologists might forget that completely withdrawing topical therapy to eliminate potential causes of an ocular adverse event is an appropriate option for managing a case such as this. Topical treatment can be reintroduced after the reaction resolves. Once the new regimen is determined to be effective and well tolerated, the patient can be weaned off the oral acetazolamide.

A Patient With Fluctuating Intraocular Pressure and an Uncertain DiagnosisFrom the Files of Cindy M. L. Hutnik, MD, PhD

A 44-year-old female presents with a 5-year history of using levobunolol OU twice daily for treatment of POAG that was diagnosed by another ophthalmologist. Intraocular pressure at treatment initiation was 33/24 mm Hg OD/OS. Over the next few years, she had cataract surgery in both eyes, YAG (yttrium aluminum garnet) capsulotomy OD, and cryopexy for treatment of a retinal tear OS. Her medical history includes asthma, migraines, rosacea, and tubal ligation. Current medications include topical metronidazole gel, an oral contraceptive, and both oral and nasal-inhaled corticosteroids. She has no family history of glaucoma.

Currently, she has no visual complaints. Findings on examination are visual acuity 20/40 OU, IOP 12/15 mm Hg, and pachymetry 819/824 μm. Angles are open, corneas are clear, and her intraocular lenses are well centered.

On fundus examination, she has bilateral anomalous discs showing tilting that is typical for a myope, along with peripapillary atrophy, but cupping is questionable (Figure 3). Her visual fields show changes that are nonspecific (Figure 4).

The patient was seen at 7 visits over the next 40 months and was found to have tremendous fluctuation in both IOP (7-18 mm Hg OD; 12-20 mm Hg OS) and CCT (485-1017 μm OD; 466-1025 μm OS). These findings were noteworthy for being atypical.

Dr Hutnik: This patient is relatively young to have glaucoma, but she does have some risk factors, such as a history of multiple ocular surgeries and myopia. In addition to being a risk factor for glaucoma, myopia creates a challenge for clinical decision making because myopia makes it difficult to acquire and/or interpret the usual clinical information used to monitor glaucoma, including optic disc appearance, retinal nerve layer thickness, visual fields, IOPs, and CCTs.

When I first saw her, it was unclear from her visual fields and fundus photographs whether she truly had glaucoma and needed to be on medication. In a situation in which there is such uncertainty, physicians should consider discussing glaucoma risk with the patient as well as the risks and benefits of treatment. If the patient feels more comfortable being treated, then the chosen treatment should be one that offers the best safety and effectiveness. A patient such as this may benefit from a switch to monotherapy with a preservative-free prostaglandin analog if she wishes to remain on treatment.

Dr Pfeiffer: Glaucoma is not common in a 44-year-old female, but it can occur. Her visual field changes are not pathognomonic for glaucoma and may be explained by myopia. Thick corneas may be causing IOP overestimation, and her optic discs are more typical for high myopia than for glaucoma. The availability of earlier fundus photographs might allow a better determination of whether the optic disc appearance reflects myopia plus glaucoma. I think optic disc photographs are especially important to have in myopic eyes because of the potential for artifacts with optical coherence tomography or retinal tomography.

I would never tell a patient that he or she was misdiagnosed by a previous physician because that individual might have had access to other information supporting the diagnosis. A patient who has been on medication for several years may be reluctant to stop treatment.

Figure 3. Fundus photographs centered on the right and left optic discsImages courtesy of Cindy M. L. Hutnik, MD, PhD

Figure 4. Humphrey 24-2 SITA (Swedish interactive thresholding algorithm) visual field overview for the right and left eyeImages courtesy of Cindy M. L. Hutnik, MD, PhD

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I question, however, the use of a β-blocker in this patient because she has asthma. Even though levobunolol is cardioselective, I consider asthma an absolute contraindication for any β-blocker. I would discuss this information with the patient, say that it is difficult to develop a clear understanding of her case after seeing her just 1 time, and tell her that it will be important to follow up with her for the development of changes that will help pinpoint the diagnosis. I would also tell her that there are other medications that can be used for IOP control that I believe would be more appropriate for her while she is being followed.

Dr Shaarawy: Good patient-physician communication is essential in a situation like this. Patients can be told that glaucoma is not a disease that is likely to progress rapidly. Therefore, it can be reasonable to stop medication while initiating more frequent follow-up visits to watch for change or stability. The visits may be scheduled as often as every 2 or 3 months. Often, I can convince patients that is a good trade-off.

It is my observation that, compared with glaucoma specialists, general ophthalmologists in Switzerland have a tendency toward initiating treatment rather than recommending close surveillance and adding medication quickly if IOP increases. There are probably no right or wrong approaches in these situations, but glaucoma specialists have the benefit of greater experience, and I think it is helpful they share their ideas about more conservative management with general ophthalmologists.

Dr Holló: There is no reason to be in a hurry to treat in a case like this. Elevated IOP levels in a patient with fluctuating IOP and asthma may correspond to bronchospasm episodes. If several serial visual fields show no evidence of progression, the patient may become comfortable with stopping medication and simply being regularly monitored for visual field and disc changes.

Dr Hutnik: A take-home message from this case is that when it comes to diagnosis and treatment decisions, we are only as good as our data. In addition, use of preservative-free medication for IOP lowering does not have to be reserved only for patients with OSD or a tolerability issue. Rather, it may be an option to consider for first-line treatment, especially if the diagnosis of

glaucoma is uncertain and the goal is to minimize the potential risk of side effects.

Patients With High Untreated Intraocular PressureFrom the Files of Gábor Holló, MD

This is a series of consecutive patients presenting with very high untreated IOP who were diagnosed with pigmentary glaucoma, pigment dispersion with OHT, or OHT, which was possibly juvenile OAG (Table 4). None of the patients had confounding factors that could explain their high IOP.

Because of uncertainty about achieving IOP < 18 mm Hg with monotherapy, considering the high baseline level and diagnoses in these cases, treatment was initiated with a fixed-combination product. After approximately 10 days, a second medication was added to the regimen for some patients: either a single agent or a second fixed-combination product containing medications from different classes than the first 2 agents. In all cases, IOP was reduced by > 50% and to ≤ 18 mm Hg within 1 to 2 months.

Dr Holló: The message from this series is that early introduction of combined medication, preferably with a fixed-combination product because of its likelihood to optimize adherence, is justified when the untreated baseline IOP is so extremely high that monotherapy is not expected to achieve the target level.

Dr Pfeiffer: Cases such as these are unusual, but your point about the importance of fixed-combination treatment for such extremely high IOP is well taken. I do have a patient, however, who is similar to the first patient in your series. She presented with an IOP of 38 mm Hg, was diagnosed with OHT, did not want to start medication, and never developed glaucoma during almost 20 years of follow-up. I did counsel her that she was at risk for venous thrombosis.

Dr Hutnik: The decision to observe a patient with OHT is supported by the evidence. In the Ocular Hypertension Treatment Study, 90.5% of patients in the observation group did not convert to glaucoma during the 5 years of follow-up.19 Patients need to understand they have options. Further, it is important that

Abbreviations: IOP, intraocular pressure; L, left; OHT, ocular hypertension; R, right.Data courtesy of Gábor Holló, MD

Case Eye (R/L) Diagnosis Untreated IOP, mm Hg

Under Treatment IOP, mm Hg

Visual Field Mean Deviation, dB

Vertical Cup-to-Disc Ratio

1 R OHT 40 17 -0.6 0.3

2 L OHT 40 18 -0.7 0.3

3 R Pigmentary glaucoma 37 15 7.6 0.95

4 L Pigment dispersion with OHT 35 12 4.3 0.75

5 L Pigment dispersion with OHT 42 14 0.8 0.75

6 L Pigmentary glaucoma 36 17 6.3 0.3

Table 4. Consecutive Case Series: Management for High Untreated Intraocular Pressure With Fixed-Combination Medications

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patients understand the need to be adherent to regular follow-up appointments and monitoring if they choose not to start treatment.

Dr Shaarawy: As Dr Hutnik said, good communication with patients is essential in a case like this. To help patients with OHT understand the risk of glaucoma, I use high blood pressure and myocardial infarction as an analogy. I explain that high blood pressure needs to be managed, but there are millions of people who have high blood pressure and only a small fraction of them will have a heart attack. Similarly, not all patients with OHT develop glaucoma, and regular follow-up without treatment to reduce IOP may be appropriate management for OHT.

I ask many patients with OHT to give me the opportunity to follow them without treatment, but I am more likely to start treatment if I am concerned the patient will not return for follow-up visits. There is no guarantee the patient will use his or her medication, but at least the patient will probably understand that the situation is serious enough to merit therapy.

Dr. Pfeiffer: Let us consider Case 5 in the series (Table 4), who is a myope with an IOP of 42 mm Hg, an almost normal visual field, normal CCT, and enlarged vertical cup-to-disc ratio, but let us say the patient has POAG rather than pigmentary glaucoma. What would be your target IOP for such a patient?

Dr Holló: I would aim for a reduction of at least 30% with a target of ≤ 18 mm Hg, based on daytime phasing, for a patient such as this. For a patient with severe glaucomatous damage, I usually aim for a lower-target IOP while taking into account that it can take some time for medication to exert maximum efficacy. If the IOP is fluctuating between 14 and 18 mm Hg with tolerated medications, I would say the patient needs surgery to maintain an IOP below the targeted highest IOP, which is < 18 mm Hg.

Dr Shaarawy: I usually aim to reduce IOP as low as possible without severely affecting quality of life, and this means using the least number of medications without causing severe side effects. I am usually not satisfied with an IOP in the high teens. Today, we have effective surgeries that have a better safety profile than procedures used in the past. Because of this, I try to go to surgery as early as I can. I have learned in my career that it is not a good situation to operate on an eye with advanced glaucoma that has developed after many years of medical treatment. I believe we are doing a great service to operate earlier in the course of the disease rather than later.

Dr Hutnik: This particular scenario exemplifies the art of glaucoma management and how it has to be married to the science. My answer depends on whether I was meeting a patient for the first time, or if the patient was someone I was familiar with whose glaucoma was spiraling out of control. I would also consider the patient’s age, life expectancy, and if there is documentation of progression.

If it was a patient I was seeing for the first time, I would take all the guidelines into account and initially aim to reduce IOP by 30% incrementally while following the individual closely to get

an idea of whether the glaucoma was stable or progressing. If I had been following the patient for many years and saw that the glaucoma was progressing despite having reached the target IOP, I would be more aggressive about lowering it.

Now that MIGS procedures are available, I have heard colleagues in North America say, “12 is the new 21.” It is known that glaucoma tends to be more stable the closer IOP is to episcleral venous pressure. Still, we should be careful not to be dogmatic. For example, a patient with an IOP of 40 mm Hg that is reduced to approximately 28 mm Hg may have stable disease. Management decisions need to be based on close monitoring, believing the data from structural and functional tests, being up to date with the information from retinal nerve fiber imaging, and deciding if this information is identifying something that is not seen on the visual field.

Dr Pfeiffer: Dr Hutnik mentioned excellent points regarding the importance of considering disease progression, along with age and life expectancy, which we must try our best to estimate. Patients need to be seen at least twice and probably many more times than that to assess progression, and I think we have emphasized in our discussion that progression of open-angle glaucoma occurs over months or years, not days. Therefore, we have time to modify our treatment and do not need to rush to be aggressive. Once medication is started, it can be very difficult to convince patients that it can be stopped, and we should not recommend surgery until we are certain it is needed.

CONCLUSIONSDr Pfeiffer: Our discussion has covered the importance of considering risk factors for disease progression and rate of progression to guide management decisions and for monitoring patients, whether they have OHT or glaucoma. We noted that the EGS guidelines recommend monotherapy as first-line treatment.10 However, a fixed-combination product may be indicated initially or early in some cases and has several advantages. In addition, there are benefits for using preservative-free medications.

Dr Hutnik: The understanding of glaucoma and how to manage it continues to evolve. With that in mind, I encourage general ophthalmologists to stay current with ongoing developments. In addition, I believe it is important for glaucoma specialists to engage in discussions with colleagues and be receptive to the idea that there is always new information to learn.

Dr Holló: No physician knows everything or has the right answer for every patient, so I urge ophthalmologists to seek consultation when it seems appropriate or when they are unsure about the next step in management.

Dr Shaarawy: I would say that it is important to remember that we are treating human beings, not numbers or organs, and knowing that one is providing good patient care brings the greatest reward in the practice of medicine. We should also aim high and be demanding of ourselves, the technologies we use, and the industry. Looking ahead, we should not accept that glaucoma management might involve a lifetime of daily treatment with medications that may affect quality of life or new surgical procedures that are not cost effective for our patients.

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REFERENCES1. Gordon MO, Beiser JA, Brandt JD, et al. The Ocular Hypertension Treatment Study: baseline factors that predict the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120(6):714-720.

2. Budenz DL, Huecker JB, Gedde SJ, Gordon M, Kass M; Ocular Hypertension Treatment Study Group. Thirteen-year follow-up of optic disc hemorrhages in the Ocular Hypertension Treatment Study. Am J Ophthalmol. 2017;174:126-133.

3. European Glaucoma Prevention Study (EGPS) Group, Miglior S, Pfeiffer N, Torri V, Zeyen T, Cunha-Vaz J, Adamsons I. Predictive factors for open-angle glaucoma among patients with ocular hypertension in the European Glaucoma Prevention Study. Ophthalmology. 2007;114(1):3-9.

4. Drance S, Anderson DR, Schulzer M; Collaborative Normal-Tension Glaucoma Study Group. Risk factors for progression of visual field abnormalities in normal-tension glaucoma. Am J Ophthalmol. 2001;131(6):699-708.

5. Leske MC, Heijl A, Hyman L, Bengtsson B, Dong L, Yang Z; EMGT Group. Predictors of long-term progression in the Early Manifest Glaucoma Trial. Ophthalmology. 2007;114(11):1965-1972.

6. Nouri-Mahdavi 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):1627-1635.

7. Puska PM. Unilateral exfoliation syndrome: conversion to bilateral exfoliation and to glaucoma: a prospective 10-year follow-up study. J Glaucoma. 2002;11(6):517-524.

8. Kim S, Sung KR, Lee JR, Lee KS. Evaluation of lamina cribrosa in pseudoexfoliation syndrome using spectral- domain optical coherence tomography enhanced depth imaging. Ophthalmology. 2013;120(9):1798-1803.

9. Konstas AG, Hollo G, Astakhov YS, et al. Factors associated with long-term progression or stability in exfoliation glaucoma. Arch Ophthalmol. 2004;122(1):29-33.

10. European Glaucoma Society. Terminology and Guidelines for Glaucoma. 4th ed. Savona, Italy: PubliComm; 2014.

11. Harasymowycz P, Birt C, Gooi P, et al. Medical management of glaucoma in the 21st century from a Canadian perspective. J Ophthalmol. 2016;2016:6509809.

12. Canadian Ophthalmological Society Glaucoma Clinical Practice Guideline Expert Committee; Canadian Ophthalmological Society. Canadian Ophthalmological Society evidence-based clinical practice guidelines for the management of glaucoma in the adult eye. Can J Ophthalmol. 2009;44(suppl 1):S7-S93.

13. Baudouin C, Labbé A, Liang H, Pauly A, Brignole-Baudouin F. Preservatives in eyedrops: the good, the bad and the ugly. Prog Retin Eye Res. 2010;29(4):312-334.

14. Lopes JF, Hubatsch DA, Amaris P. Effect of benzalkonium chloride-free travoprost on intraocular pressure and ocular surface symptoms in patients with glaucoma previously on latanoprost: an open-label study. BMC Ophthalmol. 2015;15:166.

15. Pisella PJ, Pouliquen P, Baudouin C. Prevalence of ocular symptoms and signs with preserved and preservative free glaucoma medication. Br J Ophthalmol. 2002;86(4):418-423.

16. Hutnik C, Neima D, Ibrahim F, et al. Tolerability and effectiveness of preservative-free dorzolamide-timolol (preservative-free COSOPT) in patients with open-angle glaucoma or ocular hypertension. Clin Ophthalmol. 2010;4:581-590.

17. Nguyen EV, Azar D, Papalkar D, McCluskey P. Brimonidine-induced anterior uveitis and conjunctivitis: clinical and histologic features. J Glaucoma. 2008;17(1): 40-42.

18. Beltz J, Zamir E. Brimonidine induced anterior uveitis. Ocul Immunol Inflamm. 2016;24(2):128-133.

19. Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120(6):701-713.

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1. In randomized controlled trials, all the following were identified as a risk factor for glaucoma progression, EXCEPT:

A. Disc hemorrhage B. Exfoliation syndrome C. Female sex D. Higher ocular systolic perfusion pressure

2. According to the EGS Terminology and Guidelines for Glaucoma, treatment for OAG should be initiated with:

A. A fixed combination in eyes with high IOP and moderate- to-severe glaucoma damage B. Dual therapy with separately instilled medications in eyes with high IOP and moderate-to-severe glaucoma damage C. Monotherapy D. Preservative-free medications

3. In stating the goal of glaucoma treatment, the EGS guidelines mission statement addresses the importance of maintaining:

A. Diurnal IOP control B. IOP < 14 mm Hg for eyes with moderate-to-severe glaucoma C. IOP < 21 mm Hg for eyes with early glaucoma D. Quality of life

4. A patient presents with an IOP of 25 mm Hg and early glaucomatous disc changes. What is the recommended target IOP according to the Canadian clinical practice guidelines for the management of glaucoma in adults?

A. ≥ 25% reduction from baseline B. ≥ 25% reduction from baseline and IOP ≤ 18 mm Hg C. ≥ 30% reduction from baseline D. ≤ 18 mm Hg

5. The EGS guidelines recommend switching to a fixed combination, when available, when target IOP is reached using 2 separately instilled medications. The rationale for this recommendation considers all the following as potential benefits, EXCEPT:

A. Avoiding medication washout B. Likelihood for further lowering IOP C. Reducing exposure to preservatives D. Simplifying the treatment regimen

6. Preservative-free topical glaucoma medications:

A. Are recommended for first-line treatment of glaucoma, according to the EGS guidelines B. Eliminate the possibility of any generic substitution C. Have been shown to increase adherence to therapy D. Reduce treatment cost

7. Oral acetazolamide is a good option for controlling IOP when managing a patient with:

A. Concerns about treatment cost B. Local toxicity from topical medications C. OHT and low risk for progression to glaucoma D. OHT associated with pseudoexfoliation

8. A patient with glaucoma and chronic obstructive pulmonary disease is being treated with fixed-combination brimonidine/ brinzolamide and presents with red eye, elevated IOP, and cataract. How would you manage this patient?

A. Discontinue the topical medication and start oral acetazolamide B. Discontinue the topical medication and perform cataract surgery with a minimally invasive glaucoma procedure C. Switch to preservative-free fixed-combination dorzolamide/timolol D. Switch to preservative-free tafluprost

CME POST TEST QUESTIONSTo obtain AMA PRA Category 1 Credit™ for this activity, complete the CME Post Test by writing the best answer to each question in the Answer Box located on the Activity Evaluation/Credit Request form on the following page. Alternatively, you can complete the CME Post Test at http://tinyurl.com/IOPcontrol. See detailed instructions under To Obtain AMA PRA Category 1 Credit™ on page 2.

ACTIVITY EVALUATION/CREDIT REQUEST

FOCUS ON GLAUCOMA MANAGEMENT: IOP CONTROL AND QUALITY OF LIFE IMPROVEMENTTo receive AMA PRA Category 1 Credit™, you must complete this Evaluation form and the Post Test. Record your answers to the Post Test in the Answer Box located below. Scan this completed page and return via email to cme@nyee.edu or fax it to 212-353-5703. Your comments help us to determine the extent to which this educational activity has met its stated objectives, assess future educational needs, and create timely and pertinent future activities. Please provide all requested information below. This ensures that your certificate is emailed to the proper address. It also enables us to contact you about future CME activities. Please print clearly or type. Illegible submissions cannot be processed.

PARTICIPANT INFORMATION (Please Print) ☐ Home ☐ Office

Last Name ___________________________________________________________ First Name __________________________________________

Specialty ____________________Degree ☐ MD ☐ DO ☐ OD ☐ PharmD ☐ RPh ☐ NP ☐ RN ☐ PA ☐ Other __________________________

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E-mail _________________________________________ Phone ___________________________Fax_____________________________________

Please note: We do not sell or share e-mail addresses. They are used strictly for conducting post-activity follow-up surveys to assess the impact of this educational activity on your practice.Learner Disclosure: To ensure compliance with the US Centers for Medicare and Medicaid Services regarding gifts to physicians, New York Eye and Ear Infirmary of Mount Sinai Institute for CME requires that you disclose whether or not you have any financial, referral, and/or other relationship with our institution. CME certificates cannot be awarded unless you answer this question. For additional information, please email NYEE ICME at cme@nyee.edu. Thank you.☐ Yes ☐ No I and/or my family member have a financial relationship with New York Eye and Ear Infirmary of Mount Sinai and/or refer Medicare/Medicaid patients to it.☐ I certify that I have participated in the entire activity and claim 1.5 AMA PRA Category 1 Credits™.

Signature Required ____________________________________________________Date Completed ____________________________________OUTCOMES MEASUREMENT☐ Yes ☐ No Did you perceive any commercial bias in any part of this activity? IMPORTANT! If you answered “Yes,” we urge you to be specific about where the bias occurred so we can address the perceived bias with the contributor and/or in the subject matter in future activities.________________________________________________________________________________________________________________________Circle the number that best reflects your opinion on the degree to which the following learning objectives were met:5 = Strongly Agree 4 = Agree 3 = Neutral 2 = Disagree 1 = Strongly DisagreeUpon completion of this activity, I am better able to: • Select appropriate ocular antihypertensive therapy to meet IOP goals throughout the day and night 5 4 3 2 1• Develop individualized regimens for IOP control with multitherapy or fixed-combination therapy in patients 5 4 3 2 1• Incorporate effective IOP-lowering strategies in patients with ocular surface disorders 5 4 3 2 1

1. Please list one or more things, if any, you learned from participating in this educational activity that you did not already know. _________________________________________________________________________________________________________________________2. As a result of the knowledge gained in this educational activity, how likely are you to implement changes in your practice? 4 = definitely will implement changes 3 = likely will implement changes 2 = likely will not implement any changes 1 = definitely will not make any changes 4 3 2 1

Please describe the change(s) you plan to make: _________________________________________________________________________________

_________________________________________________________________________________________________________________________

3. Related to what you learned in this activity, what barriers to implementing these changes or achieving better patient outcomes do you face?

_______________________________________________________________________________________________________________________4. Please check the Core Competencies (as defined by the Accreditation Council for Graduate Medical Education) that were enhanced for you through participation in this activity. ☐ Patient Care ☐ Practice-Based Learning and Improvement ☐ Professionalism ☐ Medical Knowledge ☐ Interpersonal and Communication Skills ☐ Systems-Based Practice5. What other topics would you like to see covered in future CME programs? __________________________________________________________

ADDITIONAL COMMENTS ___________________________________________________________________________________________________________________________________________________________________________________________________________________________

POST TEST ANSWER BOX

ORIGINAL RELEASE: May 1, 2017LAST REVIEW: APRIL 14, 2017

EXPIRATION: May 31, 2018

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