The Impact on Glaucoma from the OUTSIDE IN - New York Eye and ...

<strong>The</strong> <strong>Impact</strong>
on Glaucoma
from the
OUTSIDE IN
Highlights From an
Experts Roundtable
Discussion
Sponsored by <strong>The</strong> New York Eye and Ear Infirmary
In joint sponsorship with
This continuing medical education activity is supported through
an unrestricted educational grant from Merck & Co, Inc.
Richard K. Parrish II, MD—Chair
Leon W. Herndon, MD
Richard A. Lewis, MD
Marlene R. Moster, MD
Stephen C. Pflugfelder, MD
Distributed with
Original Release: July 15, 2012 • Last Review: June 26, 2012 • Expiration: July 30, 2013

How OSD Affects IOP
<strong>The</strong> <strong>Impact</strong> on Glaucoma
OUTSIDE IN
FACULTY
from the
Richard K. Parrish II, MD—Chair
Associate Dean for Graduate Medical Education
Professor of Ophthalmology
University of Miami Miller School of Medicine
Bascom Palmer Eye Institute
Miami, Florida
Leon W. Herndon, MD
Associate Professor of Ophthalmology
Duke University School of Medicine
Durham, North Carolina
Richard A. Lewis, MD
Grutzmacher, Lewis & Sierra
Sacramento, California
Marlene R. Moster, MD
Professor of Ophthalmology
Thomas Jefferson University School of Medicine
Attending Surgeon
Glaucoma Service
Wills Eye Institute
Philadelphia, Pennsylvania
Stephen C. Pflugfelder, MD
Professor of Ophthalmology
<strong>The</strong> James and Margaret Elkins Chair
Baylor College of Medicine
Houston, Texas
LEARNING METHOD AND MEDIUM
This educational activity consists of a supplement and ten (10) study questions.
<strong>The</strong> participant should, in order, read the learning objectives contained at the
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CONTENT SOURCE
This continuing medical education (CME) activity captures content from an experts
roundtable discussion held on April 17, 2012.
ACTIVITY DESCRIPTION
This activity will address the prevalence and clinical significance of ocular surface
disease in patients with ocular hypertension/glaucoma, how to diagnose ocular
surface disease in these patients, the role of preservatives in ocular surface
disease, current treatment options and patient management.
LEARNING OBJECTIVES
Upon completion of this activity, you will have improved your ability to:
• State the prevalence of ocular surface disorders in patients with glaucoma or
ocular hypertension • Describe the effects of preservatives in glaucoma
medications on the ocular surface • Identify therapeutic approaches for patients
with glaucoma or ocular hypertension that maintain or improve ocular surface
health • Incorporate new strategies for improving therapeutic adherence in
patients with glaucoma or ocular hypertension
TARGET AUDIENCE
This educational activity is intended for comprehensive ophthalmologists and
glaucoma specialists in the United States.
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Areas and Policies of the Accreditation Council for Continuing Medical Education
through the joint sponsorship of <strong>The</strong> New York Eye and Ear Infirmary and
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to provide continuing medical education for physicians.
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This continuing medical education activity is supported through an unrestricted
educational grant from Merck & Co, Inc.
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FACULTY DISCLOSURES
Leon W. Herndon, MD, had a financial agreement or affiliation during the past year
with the following commercial interests in the form of Honoraria: Alcon, Inc; and
Reichert Technologies.
Richard A. Lewis, MD, had a financial agreement or affiliation during the past year
with the following commercial interests in the form of Honoraria: Alcon, Inc;
Allergan, Inc; and Merck & Co, Inc; Consultant/Advisory Board: Aerie
Pharmaceuticals, Inc; Alcon, Inc; Allergan, Inc; AqueSys Inc; iScience Interventional
Corporation; Ivantis; and Santen Pharmaceutical Co, Ltd.
Marlene R. Moster, MD, had a financial agreement or affiliation during the past
year with the following commercial interests in the form of Consultant/Advisory
Board: Alcon, Inc; Allergan, Inc; and Merck & Co, Inc; Honoraria for Lectures: Alcon,
Inc; Allergan, Inc; Bausch + Lomb Incorporated; ISTA Pharmaceuticals, Inc; and
Merck & Co, Inc; Contracted Research: Aeon Optical Inc; Aerie Pharmaceuticals,
Inc; Alcon, Inc; Allergan, Inc; Genentech, Inc; IOP Ophthalmics; and Solx, Inc.
Richard K. Parrish II, 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; Alimera Sciences; Allergan, Inc; AqueSys Inc;
Bausch + Lomb Incorporated; Glaukos Corporation; InnFocus, Inc; Innovia LLC; and
Merck & Co, Inc.
Stephen C. Pflugfelder, MD, had a financial agreement or affiliation during the past
year with the following commercial interests in the form of Consultant/Advisory
Board: Allergan, Inc; GlaxoSmithKline; Merck & Co, Inc; and Mimetogen
Pharmaceuticals; Contracted Research: Allergan, Inc; and GlaxoSmithKline.
PEER REVIEW DISCLOSURES
Ted M. Gerszberg, MD, has no relevant commercial relationships to disclose.
EDITORIAL SUPPORT DISCLOSURES
Derek Dore, PharmD; Cynthia Tornallyay, RD, MBA, CCMEP; Kimberly Corbin,
CCMEP; and Barbara Lyon have no relevant commercial relationships to disclose.
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<strong>The</strong> contributing physicians listed above have attested to the following:
1) that the relationships/affiliations noted will not bias or otherwise influence their
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accepted medical practice; and 3) that all reasonable clinical alternatives will be
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This CME activity is copyrighted to MedEdicus LLC ©2012. All rights reserved.
2

Recently, 4 glaucoma specialists and 1 cornea specialist
convened to discuss the evidence-based literature and their
insights relevant to the intersection of ocular surface health
and IOP management. This CME activity summarizes
highlights from the discussion and shares the faculty’s
expertise regarding the prevalence of OSD in patients with
glaucoma or ocular hypertension, the effects of preservatives
in ocular antihypertensives on the ocular surface, and
therapeutic approaches to improve patient outcomes.
INTRODUCTION
Historically, the health of the ocular surface in patients with
glaucoma or ocular hypertension has been overlooked and
underappreciated by both comprehensive ophthalmologists
and glaucoma specialists. Eye care clinicians have focused
on the reduction of intraocular pressure (IOP), and often
have not considered the consequences of patients’ red,
weepy, and uncomfortable eyes. Poor ocular surface health
has been considered the price to pay for control of IOP.
Recently, eye care clinicians have recognized the importance
of maintaining ocular surface health when managing IOP.
Studies show that approximately 50% of patients with
glaucoma or ocular hypertension treated with ocular
antihypertensives have symptoms consistent with ocular
surface disease (OSD). 1,2,3 Moreover, the evidence indicates
that there is a direct correlation between the number of
instilled drops and the severity of OSD symptoms. 1,2,3
Fortunately, the landscape of IOP-lowering medications has
changed to include products that are kinder to and gentler on
the ocular surface. Patients may no longer need to trade a
healthy ocular surface for control of IOP.
—Richard K. Parrish II, MD
EYE CARE CLINICIANS’ OBSERVATIONS
OF OCULAR SURFACE DISEASE
IN PATIENTS WITH GLAUCOMA
OR OCULAR HYPERTENSION
Dr Parrish: Dr Pflugfelder, as a cornea and external eye disease
specialist, what are typical findings of OSD in patients with
glaucoma or ocular hypertension?
Dr Pflugfelder: <strong>The</strong>re is no universal presentation; however,
patients often complain of ocular discomfort, particularly from
the administration of ocular medications. Signs of OSD include
redness of the eye, pathology of the corneal epithelium, and
severe posterior lid margin disease.
Dr Parrish: Dr. Moster, do you see OSD in a specific patient
population?
for cosmetic purposes and for successful treatment, including
medical therapy and surgical options.
Dr Parrish: Dr Lewis, with the patent expiration of branded
Xalatan ® , generic latanoprost is now available from many
different manufacturers. In your practice, have you noted
increased ocular surface complaints from patients who
switched from the branded Xalatan ® to generic latanoprost?
Dr Lewis: This is a bewildering issue. Each time a patient’s
generic latanoprost prescription is refilled, he or she may
receive the medication from a different manufacturer. In my
experience, this variation in manufacturers has been
associated with inconsistency in terms of both efficacy and
ocular redness.
Dr Moster: I agree with Dr Lewis. Although all formulations of
generic latanoprost should be equivalent, there may be slight
differences in the composition of the preservative or additional
ingredients that may cause increased ocular surface changes.
Dr Herndon: Generic medications provide an affordable
therapeutic option for my patients. In my practice, I have
observed only a few circumstances in which a generic alternative
has failed to uphold the efficacy of its brand-name equivalent.
IMPLICATIONS OF POOR OCULAR
SURFACE HEALTH IN PATIENTS WITH
GLAUCOMA OR OCULAR HYPERTENSION
Dr Parrish: Let us discuss the clinical implications of poor
ocular surface health in patients with glaucoma or ocular
hypertension. <strong>The</strong> first consideration relates to the practical
consequence of patient nonadherence to a medical regimen
that causes adverse effects. Our colleagues James C. Tsai,
MD, and Gail F. Schwartz, MD, have reported on the obstacles
to patient adherence to ocular medical therapy caused by
deleterious effects on the ocular surface. 5,6 Dr Pflugfelder, do
you see suboptimal adherence to therapy as a consequence of
the deteriorating health of the ocular surface in patients on
ocular antihypertensives?
Dr Pflugfelder: Yes, I receive complaints from patients who are
intolerant of their ocular antihypertensives, and poor adherence
is the outcome. Patients discontinue ocular agents because of
blurred and fluctuating vision due to unstable tear film and
corneal epitheliopathy.
Dr Moster: Patients also discontinue therapy because of the
unbearable symptoms they experience. We have all seen
patients who present with poorly controlled IOP, incredibly red
irritated eyes, with superficial punctate keratitis, and poor
corneal tear film. (Figure 1)
Dr Moster: <strong>The</strong> prevalence of symptomatic OSD appears to be
highest in adults aged 65 years and older. 4 Additionally, older
adults are commonly bothered by symptoms of OSD and often
complain of difficulty using their medications because of ocular
irritation.
Dr Parrish: Dr Herndon, you practice at a referral center and
see glaucoma patients who have OSD. What are your thoughts
with respect to ocular surface health in patients with
glaucoma?
Dr Herndon: I have become wiser to the importance of creating
a kinder and gentler environment for the ocular surface, both
Figure 1. Red and inflamed eye with a cornea that has almost confluent
superficial punctate staining. <strong>The</strong> patient presented with an IOP of
36 mm Hg and a failed bleb; she was put back on a topical ocular
antihypertensive.
Photo Courtesy of Marlene R. Moster, MD
3

Dr Pflugfelder’s Top 5 Ocular Surface
Assessments for the Comprehensive
Ophthalmologist
1. Lacrimal Puncta
Are there signs of ectropion or stenosis of the puncta?
Many older patients have either a subtle ectropion or
some stenosis of their puncta, which will interfere with
tear drainage.
2. Posterior Lids (Meibomian Glands)
Express the lids!
Has gland dropout occurred?
What is the quality of the meibum?
Is vascularization present?
Many older patients also have lid margin changes due to
posterior blepharitis/meibomian gland dysfunction.
Decreases in the quantity and/or quality of meibum lead to
lipid deficiency that can destabilize the tears and potentiate
the deleterious effects of ocular antihypertensives.
3. Tear Film Layer
What are the results of a fluorescein tear break-up time test?
Fluorescein tear break-up time may be the easiest test that
an eye care clinician performs. When I conduct the test,
I first moisten the fluorescein strip (any brand) with
preservative-free saline, touch the patient’s inferior tarsal
conjunctiva, and ask the patient to blink to disperse the
fluorescein. Viewing under cobalt blue illumination, I ask the
patient to blink and keep his or her eye open until I begin to
observe discontinuities in the tear film, which usually occur
in the center or the inferior cornea. I count in seconds to
determine the amount of time it takes for the tears to break
up. <strong>The</strong>re is some debate about what the normal tear breakup
time is. I consider 7 seconds or less to be abnormal. In
many older patients, tear break-up is instantaneous.
4. Cornea
Is erosion present?
Once fluorescein is instilled, I examine the cornea to
determine the presence of punctate fluorescein staining.
Staining in the center of the cornea indicates greater
severity of erosion, which has the potential to reduce vision.
5. Conjunctiva
Is redness present?
Is conjunctival chalasis present?
Redness and fluorescein staining in the conjunctiva indicate
epithelial disease. Conjunctival chalasis, or loosening of the
conjunctiva, can interfere with the spread of tears.
Conjunctival chalasis tends to compartmentalize the tears,
typically in the center of the lower lid, because the condition
blocks the flow of the tear meniscus both temporally and
sometimes nasally. Conjunctival chalasis also interferes with
tear clearance and increases the concentration of ocular
medications over the cornea.
Typically with ocular antihypertensive toxicity, most of the
redness occurs in the lower third of the eye, on the inferior
bulbar conjunctiva and the inferior tarsus, particularly
medially, where the tears are swept toward the lacrimal
drainage system. When I observe redness on the inferior
tarsus and the patient is using 1 or more ocular
antihypertensives, I suspect toxicity. (Figure 2)
Dr Parrish: It is hard to believe that anyone presenting with
these signs and symptoms would be willing to continue to use
the medications that we prescribe.
Dr Pflugfelder: Certainly, this presentation can negatively affect
patient quality of life (QOL). In fact, evidence suggests that dry
eye adversely affects QOL at a magnitude similar to that
caused by unstable angina. 7
Dr Moster: A patient’s ability to be productive in the workforce
also can be affected by symptoms of dry eye, which inhibit an
individual’s ability to keep visually focused for an extended
period of time. Given these critical financial times, people must
be able to work long hours. If they are uncomfortable doing their
job, the cause of the discomfort―ocular antihypertensives―will
most likely be the first thing to be eliminated by the patients in
an effort to reduce the discomfort. Such an action will likely
lead to worsening of existing glaucoma.
Dr Lewis: This is an important point, particularly with today’s
computer-related occupations. Most workers spend many
hours working in front of a video display terminal, which leads
to a decrease in blink rate and, consequently, a form of
occupational stress that exacerbates an already unstable tear
film brought on by the use of glaucoma medications.
Dr Moster: Older, retired glaucoma patients are spending
significant amounts of time at the computer as well, reading
e-mail messages and searching the Internet. <strong>The</strong> need to limit
this time because of OSD symptoms may negatively affect
their QOL.
ASSESSMENT OF THE OCULAR SURFACE
IN PATIENTS WITH GLAUCOMA OR
OCULAR HYPERTENSION
Dr Parrish: Dr Pflugfelder, what is your recommendation to a
comprehensive ophthalmologist without research tools and
advanced technologies for assessing the ocular surface?
Dr Pflugfelder: Assessment of the ocular surface and the lids
necessitates some effort on the part of the ophthalmologist;
the clinician, however, can quickly become efficient at the
evaluation. (see Sidebar)
Dr Parrish: Regarding OSD, many eye care clinicians report that
patient-reported symptoms and clinical signs do not always
correlate. What is the rationale for this disconnect?
Dr Pflugfelder: This is certainly a paradox in the world of
ophthalmology. It turns out that some patients with the most
severe corneal epithelial disease have the least troublesome
symptoms. Patients with long-standing OSD may develop nerve
Figure 2. Injection of
conjunctival blood vessels in
the inferior tarsal and bulbar
conjunctiva of a patient
chronically treated with
latanoprost.
Photo Courtesy of
Stephen C. Pflugfelder, MD
4

Typically with ocular antihypertensive toxicity, most of
the redness occurs in the lower third of the eye, on
the inferior bulbar conjunctiva and the inferior tarsus,
particularly medially, where the tears are swept
toward the lacrimal drainage system. When I observe
redness on the inferior tarsus and the patient is using
1 or more ocular antihypertensives, I suspect toxicity.
—Stephen C. Pflugfelder, MD
degeneration. Consequently, they develop relative corneal
anesthesia, and stop complaining of symptoms. Conversely,
some patients with early stages of OSD and minimal
epitheliopathy complain bitterly. In early-stage OSD, there may
be an inflammatory-mediated hyperesthesia of the nerve,
similar to that which occurs in a chronic pain syndrome.
CAUSES OF OCULAR SURFACE DISEASE
AND PATIENTS AT RISK
Dr Parrish: What are some of the extrinsic and intrinsic causes
of OSD?
Dr Lewis: In terms of extrinsic causes, geography can play a
part. In Sacramento, California, where I practice, the humidity
is low compared with many other regions of the United States.
Consequently, we note a dry eye problem, particularly in the
spring and summer. In addition, my practice is in a farming
valley, where there is exposure to many allergens. When
these environmental causes of OSD are combined with
blepharoconjunctivitis, contact lens wear, or the toxic effects
of preservatives in ocular medical therapy, patients experience
significant discomfort.
Dr Parrish: Meibomian gland dysfunction is an important
intrinsic cause of OSD, particularly subclinical evaporative dry
eye in older adults.
Dr Herndon: With older age, I certainly see eyelid issues as a
contributor. Thus, I pay close attention to the impact of
ectropion or entropion on the ocular surface.
Dr Lewis: Although Sjögren syndrome is cited as an associated
systemic finding with OSD, 8 I do not observe the syndrome as a
common concomitant condition. I do, however, see connective
tissue diseases as a common comorbidity. Interestingly, I find
that female patients complain more about red eye and irritation,
even though I see the problem more often in male patients.
Dr Pflugfelder: I agree with Dr Lewis: in my experience, male
patients complain less often than female patients, which is
counterintuitive, because women typically have a higher pain
threshold than men.
Dr Parrish: In my experience, male patients are more likely than
female patients to develop severe rosacea and concomitant
keratitis or lid margin disease.
Dr Pflugfelder: In addition to the autoimmune conditions, I often
see 2 diseases in the elderly that affect the ocular surface:
diabetes and Parkinson disease. When patients with diabetes
develop neuropathy that affects the corneal nerves, the result is
a decrease in blink rate, which diminishes the spread of tears.
Likewise, patients with moderate-to-severe Parkinson disease
do not blink often, which results in tear stagnation along the
lower lid and the development of blepharitis. Also, certain
antidepressants, urinary antispasmodics, and antihistamines
should be considered potential extrinsic causes of OSD.
<strong>The</strong> anticholinergic effects of these commonly prescribed
medications can reduce tear production. 9
THE EFFECTS OF PRESERVATIVES
ON OCULAR STRUCTURES
<strong>The</strong> Effects of Preservatives on
the Ocular Surface
Dr Parrish: Most commercially available ocular
antihypertensives contain preservatives, and the most
commonly employed preservative is benzalkonium chloride
(BAK). <strong>The</strong> deleterious effects of BAK on the ocular surface
have received a great deal of attention. Dr Pflugfelder, can you
provide an evidence-based summary of the safety of BAK as a
preservative in ocular preparations?
Dr Pflugfelder: <strong>The</strong> literature is replete with various toxic
effects of BAK in in vitro conjunctival and corneal epithelial cell
models, 10,11,12 in vivo animal models, 13,14,15 and clinical trials. 16
BAK is a detergent, and as such, the chemical compound can
have direct effects on the lipid layer in the cell membrane. BAK
has been found to disrupt the corneal epithelial tight junction
proteins, particularly occludin, which results in loss of the
barrier function in the apical epithelium and in rapid loss of
cells. This may account for the observed epitheliopathy with
BAK. 11 And, in the concentrations present in commercially
available ocular preparations, BAK can also cause programmed
cell death, apoptosis, and necrosis in epithelial cells. 10-12,15,17
BAK also has been found to incite various inflammatory
mediators, including cytokines, chemotactic factors, and
metalloproteinases that further cause loss of cells. 18-20
Dr Parrish: Additionally, a recent study by Sarkar and
colleagues showed that the application of BAK elicited corneal
neurotoxicity and reduced aqueous tear production in vivo and
in vitro in mouse eyes. 21 Although mouse eyes may not be
analogous to human eyes, the findings show the depth and
breadth of BAK’s deleterious effects. Clinical evidence has
demonstrated BAK’s dose-dependent relationship with OSD and
its negative effect on patient QOL. 1-3,22
Dr Moster: Patients using multiple topical agents are being
overexposed to BAK. <strong>The</strong> negative effect BAK has on the ocular
surface may be in part responsible for the symptomatology we
so often observe in clinical practice. 1-3
Dr Herndon: BAK’s detergent-like properties became clear to
me at, of all places, a local rib restaurant. Following my meal, I
proceeded to open a wet nap package. I noticed the active
ingredient of the cleanser was BAK. (Figure 3)
<strong>The</strong> Effects of Preservatives
on the Trabecular Meshwork
Figure 3. Example of a wet nap
product, with BAK as the cleanser,
commonly provided in restaurant
settings.
Photo Courtesy of
Leon W. Herndon, MD
Dr Parrish: It is difficult to accept the notion that as clinicians,
we may be harming the eye’s internal structures (ie, trabecular
meshwork) with the medicine that we prescribe. However, the
5

work of Ammar and Kahook 18,23 and that of Zhang and
colleagues 17 suggest that the toxic effects of BAK may not be
limited to the external surface of the eye, but that BAK may
actually penetrate through corneal skeletal limbal tissue and
thus both trabecular endothelial cells and non-pigmented ciliary
epithelial lines are also affected. What is your belief regarding
this evidence?
Dr Moster: A single drop of a BAK-containing ocular medication
can persist in ocular tissues for an extended period of time 24 ;
thus, I believe there is a strong possibility that BAK can enter
into and persist within internal tissues.
Dr Herndon: Before forming a definitive opinion on this issue, I
would like to see more evidence showing BAK’s toxicity on the
trabecular meshwork.
<strong>The</strong> Effects of Preservatives
on Surgical Outcomes
Dr Parrish: Some evidence suggests that the long-term use of
ocular antihypertensives is associated with failure of traditional
trabeculectomy limbal filtration surgery or with complications
with postoperative healing. 25,26 Do you see poor surgical
outcomes caused by ocular antihypertensives?
Dr Herndon: I believe that preservatives have a deleterious effect
on the conjunctival surface, leading to poor surgical outcomes.
This was demonstrated by the work of Broadway and colleagues
approximately 20 years ago. <strong>The</strong>y found that the long-term use of
multiple ocular antihypertensives induced preoperative subclinical
conjunctival inflammation, and that the long-term multidrug
regimens were associated with lower surgical success rates
compared with shorter-term monotherapy. Both exposure to
preservatives and duration of therapy were cited by the authors
as probable mechanisms that led to poor surgical outcomes. 25
Dr Moster: I recommend a drop holiday prior to surgery, even if
the patient’s IOP is high. Following a drop holiday, I often
observe decreased bleeding, less irritation, and improved
surgical outcomes. An oral agent can be employed to lower the
IOP until the time when the patient can be brought comfortably
to the operating room.
Dr Parrish: Do ocular antihypertensives negatively affect
outcomes of argon laser trabeculoplasty (ALT) or selective laser
trabeculoplasty (SLT)?
Dr Pflugfelder: It is a possibility. Ocular antihypertensive use,
specifically in terms of the inflammatory effects of BAK, has
been found to be a risk factor for failure or rejection of corneal
transplant, suggesting that the drops can gain access to the
anterior chamber. 27
Prostaglandin-Associated Periorbitopathy
Dr Parrish: Recently, prostaglandin-associated periorbitopathy
(PAP), or deepening of the superior lid sulcus, has received
increasing attention as a potential adverse effect of ocular
prostaglandin agonists. Do you observe this phenomenon in
your practice, and if so, what do you do about it?
Dr Herndon: I have clearly seen patients in my practice who
have presented with deeper orbits related to the use of ocular
prostaglandin analogs, particularly those who are treated in
only 1 eye. We should give credit to both Louis R. Pasquale,
MD, and Stanley J. Berke, MD, for bringing this adverse effect
to the attention of the ocular community. In this situation, the
eyelids become tighter and it can be difficult for the clinician to
lift up the patient’s eyelid.
Dr Moster: <strong>The</strong> condition is sometimes referred to as
pharmacologic blepharoplasty.
Dr Parrish: With limited literature on this subject, it is difficult
to ascertain if PAP is an effect of preservatives or of the
prostaglandin analog moiety. Could it be that BAK is enhancing
the penetration of the prostaglandin analog into the periorbital
tissue? Based on this hypothesis, perhaps a preservative-free
prostaglandin analog would have less extensive orbital
penetration? For the present, these scientific questions are
simply speculation.
MANAGING PATIENTS WITH GLAUCOMA
OR OCULAR HYPERTENSION AND
OCULAR SURFACE ISSUES
<strong>The</strong>rapeutic Strategies for Controlling IOP
and Maintaining Ocular Surface Health
Dr Parrish: What are the best practices for maintaining ocular
surface health while managing IOP? What do you do for the
patient who uses ocular antihypertensives and presents with a
myriad of ocular surface findings and complaints?
Dr Pflugfelder: <strong>The</strong> best method to determine if ocular
antihypertensive agents are the cause of ocular surface toxicity
is to initiate a drop holiday. Thus, in patients with ocular surface
toxicity, I discontinue all ocular antihypertensives and begin IOPlowering
therapy with an oral carbonic anhydrase inhibitor. In
severe cases, during the drop holiday, I will prescribe a low-dose,
preservative-free ocular steroid to reduce inflammation of the
ocular surface. <strong>The</strong> steroid typically accelerates improvement of
the ocular surface, and interestingly, usually does not increase
IOP. I typically use dexamethasone, 0.01%, which is compounded
by a specialty pharmacy. In close collaboration with the patient’s
glaucoma specialist, and with careful monitoring of IOP, I typically
continue the drop holiday for a few weeks. <strong>The</strong>n, if the patient’s
ocular surface improves, which it usually does, I resume ocular
antihypertensive therapy, but with non-BAK preserved or
preservative-free ocular antihypertensives. In some cases, I
prescribe the combination of a low-dose oral carbonic anhydrase
inhibitor and an ocular antihypertensive.
<strong>The</strong> best method to determine if ocular
antihypertensive agents are the cause of ocular
surface toxicity is to initiate a drop holiday. Thus, in
patients with ocular surface toxicity, I discontinue
all ocular antihypertensives and begin IOP-lowering
therapy with an oral carbonic anhydrase inhibitor.
—Stephen C. Pflugfelder, MD
Dr Moster: Because glaucoma is a lifelong disease, a drop
holiday makes sense. As does Dr Pflugfelder, I prescribe a lowdose,
preservative-free ocular steroid during the drop holiday,
followed by re-initiation of ocular antihypertensive therapy, but
with a preservative-free formulation.
Dr Parrish: Has anyone used the 1-eye trial to determine which
ocular antihypertensive in a regimen is causing ocular surface
distress? That is, has anyone discontinued 1 medication at a
time, in 1 eye, and followed the patient to observe for
improvement of ocular surface symptoms in the trial eye
compared with the eye that continues to be treated with the
original medical regimen.
6

Dr Herndon: Yes, for patients on multiple ocular antihypertensives,
I use the monocular approach to back down on the therapy,
1 medication at a time.
Medical <strong>The</strong>rapy
Non-BAK Preservatives
Dr Parrish: <strong>The</strong> only prostaglandin agonist with a non-BAK
preservative currently on the market is travoprost with SofZia.
Some studies suggest that SofZia is relatively nontoxic to
ocular structures. 20,28,29 What is your impression of the safety
and tolerability of travoprost with SofZia?
Dr Moster: I believe that replacing BAK with SofZia is a move in
the right direction. My patients complain less of ocular
symptoms with the use of travoprost with SofZia compared with
BAK-preserved ocular antihypertensives.
Dr Herndon: I have seen situations in which patients have
experienced red eye irritation with the use of BAK-preserved
ocular antihypertensives; when switched to travoprost with
SofZia, their ocular symptoms subsided.
Dr Moster: It is important to note that the prostaglandin
analog molecule itself causes hyperemia and some level of
discomfort. <strong>The</strong>refore, elimination of the BAK preservative may
not completely obliterate red eye in some patients. 30,31
Dr Parrish: I am curious about your thoughts on Purite as a
preservative. Although Purite may not be toxic, 19 I have noted
frequent toxic effects with the formulation of the alpha-2
adrenergic receptor agonist, brimonidine, preserved with Purite.
Dr Moster: <strong>The</strong> brimonidine moiety itself can be an allergen. 32
In my experience, the only factor that appears to limit
brimonidine’s ocular toxicity is when it is formulated in
combination with timolol.
Dr Pflugfelder: I believe that SofZia and Purite are gentler on
the ocular surface compared with BAK. Some studies suggest
that SofZia and Purite are less toxic to the epithelium 19,20,28,29 ;
these findings have not, however, been clearly or consistently
confirmed in clinical trials. 33-36
Dr Lewis: <strong>The</strong> early clinical trial comparing travoprost with
SofZia to travoprost with BAK showed no difference in terms
of efficacy and adverse events, 35 which was surprising.
Nonetheless, the more recent studies show that replacing
BAK with an alternative preservative is more protective to the
ocular surface. 20,29
Preservative-Free Formulations
Dr Parrish: Recently, the much anticipated first preservativefree
prostaglandin analog, preservative-free tafluprost, became
available in the United States. Results from peer-reviewed
clinical trials demonstrate preservative-free tafluprost’s 26% to
30% IOP-lowering effect (Figure 4) and the medication’s
equivalent IOP lowering when compared with latanoprost
preserved with BAK. 30,31,37,38 In addition, clinical studies show
that preservative-free tafluprost is better tolerated than
latanoprost with BAK―improving ocular comfort and quality of
life in patients who experience signs and symptoms of OSD
with latanoprost with BAK. 37,38 What is your perspective on and
clinical experience with preservative-free tafluprost?
Figure 4. Mean (± 95% confidence interval) IOP at baseline and at 2, 6,
and 12 weeks in patients with open-angle glaucoma or ocular hypertension
receiving preservative-free tafluprost or preservative-free timolol.
Reprinted with permission from Elsevier.
Dr Lewis: It is nice that we now have a preservative-free
prostaglandin analog option to complement the preservativefree
beta-blocker timolol.* In the past, we did not have
preservative-free ocular antihypertensive options and it was
difficult to control the cumulative effect of the preservatives on
the patient’s ocular surface, particularly when IOP control
required a multidrug regimen. <strong>The</strong> glaucoma community has
been struggling with the preservative-free effort for years,
searching for a safe and effective breakthrough. It is refreshing
that the preservative-free effort has not been abandoned by
glaucoma specialists.
Dr Moster: I have used preservative-free tafluprost in patients
who are sensitive to other prostaglandin analog preparations
and who have a history of dry eye. It is well tolerated and
efficacious in terms of lowering IOP and is a viable alternative,
particularly for patients who are plagued by BAK-induced ocular
adverse effects from other ocular antihypertensives. <strong>The</strong>re is a
commitment needed from patients to use the single-dose
containers, which are recommended to be stored refrigerated
when in unopened foil pouches. Once pouches are opened, the
single-use containers may be stored at room temperature for
up to 28 days. 39
Dr Lewis: Early clinical trials in Europe demonstrated that
preservative-free tafluprost is both safe and effective. 30,38
I believe preservative-free tafluprost is used in Europe because
Europeans have been very conscious of the problems with
BAK for many years now, largely because of the work of Dr
Christophe Baudouin. 40 Having preservative-free options
available to patients in the United States is important. In my
opinion, the future of drug delivery will lie in the preservativefree
formulations, and the issue of OSD caused by ocular
antihypertensives will become a moot point. In the future, we
will look back and find it hard to believe that, for decades, we
ophthalmologists applied BAK to our patients’ eyes.
Dr Parrish: As anticipated, clinical evidence has demonstrated
improvement of the ocular surface of patients when they are
* In addition, preservative-free dorzolamide-timolol has recently been approved in the United States.
7

switched from preserved ocular antihypertensives to
preservative-free formulations. Janulevičienė and colleagues
evaluated patients who were switched from BAK-preserved
latanoprost to preservative-free tafluprost. In the study,
patients who complained of ocular surface discomfort, who
also had abnormal tear film break-up and abnormal corneal
fluorescein staining with latanoprost with BAK, were switched
to preservative-free tafluprost, resulting in significant
improvements in these subjective and objective measures. 37
(Table) <strong>The</strong> other preservative-free ocular antihypertensive
available in the United States is timolol, supplied in a sterile
unit-dose dispenser. What is your experience with this
preservative-free option?
Dr Moster: I have a fair amount of patients on preservative-free
timolol; they are using the product twice daily as indicated. In
my experience, preservative-free timolol is very well tolerated
and is well suited for patients with dry eye who have been
unable to tolerate preserved ocular antihypertensives, but who
still require IOP-lowering therapy following ALT or SLT.
Dr Parrish: I have only a few patients on preservative-free
timolol. In my experience, I have not found preservative-free
timolol to make a long-term difference in the management of
many of these patients.
Dr Pflugfelder: I have been impressed with patient outcomes
when the ocular surface is no longer exposed to BAK. I
prescribe preservative-free timolol for all my severe dry eye
patients and for nearly every corneal transplant patient, and
consequently have hundreds of patients on this product.
Indeed, before the availability of preservative-free tafluprost,
preservative-free timolol was my go-to ocular antihypertensive
for re-initiating topical therapy following a drop holiday.
Dr Parrish: If equally effective, comparably priced products were
available, would you prescribe preservative-free ocular agents
for your patients with glaucoma or ocular hypertension?
Dr Pflugfelder: I certainly would choose a preservative-free
ocular antihypertensive in patients at risk of ocular surface
issues, in those with any corneal fluorescein staining, and in
any other eye condition in which ocular antihypertensives have
been implicated in making the condition worse, such as corneal
transplantation in a high-risk patient.
Dr Herndon: If efficacy is equivalent, prescribing preservativefree
ocular antihypertensives for patients makes perfect sense.
Dr Parrish: As an additional note, it is often thought that BAK
allows greater penentration of the active ingredients through
the cornea. If we compare bimatoprost, 0.3% with .05 mg/mL
of BAK to bimatoprost, 0.01% with a 4-fold higher amount of
BAK (0.2%) it may be that additional BAK was added to the
.01% solution for better penetration. 41 However, this is not
known. It is important to keep in mind that the other
prostaglandin analogs we just discussed, travoprost with SofZia
and preservative-free tafluprost, achieve 25% to 30% pressure
lowering, comparable to prostaglandin analogs with BAK.
Surgical Strategies for Controlling IOP and
Maintaining Ocular Surface Health
Dr Parrish: According to the American Academy of
Ophthalmology’s Glaucoma Preferred Practice Pattern ®
Guidelines on Primary Open-Angle Glaucoma, medical therapy,
laser trabeculoplasty, and standard limbal filtration surgery are
all viewed as acceptable modalities for the management of
open-angle glaucoma. 42 In my practice, most patients prefer
medical therapy as the first-line approach to manage IOP.
Generally, patients are not too eager to undergo surgery and
most patients are still concerned about laser procedures. Laser
trabeculoplasty is a viable first-line therapy, however, and
patients with poor ocular surface health or those who are
experiencing intolerable adverse events from ocular
antihypertensives occasionally opt for surgical management.
Dr Herndon: I offer laser trabeculoplasty as a first-line
treatment for some of my glaucoma patients. I counsel the
patients regarding the efficacy, safety, and cost-effectiveness of
laser options, particularly SLT. Approximately 8 out of 10 of my
patients choose SLT as the first-line therapy; in most cases,
after the procedure, medical therapy use is postponed.
Dr Moster: I discuss laser trabeculoplasty; however, most of my
patients expect to begin with medical therapy. <strong>The</strong>y will often
consider laser as an option if ocular antihypertensives are
causing symptoms or are not effectively controlling their IOP.
Dr Herndon: In patients with severe OSD, a trial of a preservativefree
ocular antihypertensive is a reasonable therapeutic approach
to potentially delay or avoid surgical options.
Table. Patients’ Dry Eye Complaints, Mean Tear Film Break-up Time (± SD), and Abnormal Corneal Fluorescein Staining at
Baseline (latanoprost with BAK), and at 2, 6, and 12 Weeks After Switching to Preservative-free Tafluprost 37
Baseline Week 2 Week 6 Week 12
P-value
(12 weeks
vs baseline)
Dry eye complaints
(n=30, patients)
Tear film break-up time
(seconds) (n=60, eyes)
Abnormal fluorescein
staining of the cornea
(n=60, eyes)
30 (100%) 19 (63.3%) 11 (36.7%) 11 (36.7%)

CASE VIGNETTES
Vignette 1
Dr Parrish: A 62-year-old white male is referred to the
ophthalmology clinic. <strong>The</strong> patient does not have a family history
of glaucoma. His IOP is 27 mm Hg. Examination shows an
open angle, moderate pigmentation, pseudoexfoliation following
dilation of the pupil, and obvious disc and field change that fit
with a diagnosis of early glaucoma with a paracentral scotoma.
Which additional assessments would you conduct, and what do
you consider best practice management for this patient, taking
into consideration the potential intersection of glaucoma and
ocular surface health?
Dr Moster: I would assess the patient’s visual field, nerve fiber
layer, and Tmax IOP. Additionally, I would examine the patient’s
ocular surface and anterior chamber, looking for signs of dry
eye, such as superficial punctate epitheliopathy and abnormal
tear break-up time. If the diagnosis is glaucoma with
concomitant ocular surface pathology, I would attempt to attain
a 30% decrease in IOP with an ocular prostaglandin analog
without BAK as a preservative.
Dr Herndon: I would determine the optimal IOP range for this
patient after evaluating the visual field and nerve fiber layer
studies. I would discuss treatment options (medical, laser,
surgical) with the patient, involving him in the decision. If he
chose to pursue topical therapeutic options, I would recommend
a prostaglandin analog without BAK as a preservative. SLT as a
first-line option would be reasonable as well.
Dr Parrish: Is Schirmer testing useful in this patient to evaluate
the presence of OSD?
Dr Pflugfelder: I believe that the Schirmer test is the least
valuable of the ocular surface evaluations because of the
variable ways in which the test can be done and the limited
amounted of information that the test provides.
Dr Parrish: I would evaluate the health of the patient’s
meibomian glands, assess the quality and quantity of meibum,
and look for signs of vascularization or loss of lashes.
Vignette 2
Dr Parrish: A 70-year-old African American female returns to the
ophthalmology clinic 6 months after starting generic latanoprost
with BAK for a newly diagnosed case of glaucoma. Her IOP is
well controlled; she is complaining, however, of ocular irritation
and foreign body sensation, and she is concerned about the
ocular redness she is experiencing. Ocular examination shows
signs of OSD, including increased tear osmolarity and corneal
fluorescein staining. What would you do?
Dr Herndon: I have had experience with similar cases. I would
switch the patient’s therapy to travoprost with SofZia. I am
encouraged by the clinical evidence demonstrating the
tolerability and efficacy of preservative-free tafluprost, and so
would consider prescribing that product for this patient.
Dr Moster: I would also switch the patient’s therapy to a BAKfree
preparation or to preservative-free tafluprost. Both patient
adherence and the patient-clinician relationship improve when
patients realize the clinician is making a change not only to
effectively manage IOP, but also to enhance patient comfort.
Dr Lewis: I would first investigate whether the irritation is from
the active ingredient, from the latanoprost, or from the
preservatives in the formulation. Perhaps the easiest way to
determine that is to switch to a nonprostaglandin agent, such
as timolol.
CONCLUSION
<strong>The</strong> deleterious effects caused by the preservative BAK in
ocular antihypertensive agents can lead to poor ocular surface
health in patients with glaucoma or ocular hypertension. 1-3 Poor
ocular surface health, in turn, can negatively affect patient
adherence to glaucoma therapy 5,6 and thus adversely affect
patient QOL. 7 It is therefore important for ophthalmologists to
assess the glaucoma patient’s ocular surface: effectively,
frequently, and efficiently. A drop holiday can be a safe and
effective strategy to reduce ocular surface distress without
adversely affecting IOP management. Fortunately, ocular health
researchers and clinicians have been working diligently to
develop glaucoma therapies that are both effective and gentler
on the ocular surface. Presently, ocular antihypertensives
without BAK—eg, travoprost with SofZia and brimonidine with
Purite—and ocular antihypertensives without preservatives—
among them, preservative-free timolol, preservative-free
dorzolamide-timolol, and preservative-free tafluprost—are
safely and effectively controlling IOP. 20,29,30-32,37,38,43 In some
patients, laser therapy is an option for IOP control. Today, eye
care clinicians no longer need to accept deterioration of ocular
surface health as the price to pay for the control of IOP: it is
encumbent upon them to be proactive in the management of
OSD in patients with glaucoma or ocular hypertension.
9

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15. Denoyer A, Ossant F, Arbeille B, et al. Very-high-frequency ultrasound
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16. Brandt JD, Wittpenn JR, Katz LJ, Steinmann WN, Spaeth GL.
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coding for dry eye and ocular infection in open-angle glaucoma and
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on tear film osmolarity, tolerability, and intraocular pressure in
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43. Shedden A, Adamsons IA, Getson AJ, et al. Comparison of the
efficacy and tolerability of preservative-free and preservativecontaining
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10

CME POST TEST
How OSD Affects IOP
<strong>The</strong> <strong>Impact</strong> on Glaucoma from the OUTSIDE IN
To obtain AMA PRA Category 1 Credit for this activity, you
must 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.
To take this post test/evaluation online, please see
"To Obtain AMA PRA Category 1 Credit" on page 2.
1. In what percentage of patients with glaucoma or ocular
hypertension treated with ocular antihypertensives are
symptoms of ocular surface disease (OSD) present?
a. 25
b. 50
c. 75
d. 100
2. Which of the following is directly correlated to the prevalence
of OSD?
a. Age 65 years or younger
b. <strong>The</strong> number of years in which eyeglasses are worn
c. <strong>The</strong> number of instilled ocular antihypertensive drops
d. A humid climate
3. Which of the following is/are a typical finding of OSD?
a. Patient-reported ocular discomfort
b. Redness of the eye
c. Pathology of the corneal epithelium
d. All the above are typical findings of OSD
4. A 67-year-old male patient presents to the ophthalmology clinic
for a follow-up appointment for glaucoma management. <strong>The</strong>
patient has been treated with latanoprost with benzalkonium
chloride (BAK) for 1 year. He complains of eye irritation, blurred
and fluctuating vision, and difficulty working on the computer for
an extended period of time. He has been using preservativefree
tear supplements for his symptoms. <strong>The</strong> patient’s
intraocular pressure (IOP) is 24 mm Hg (it was 16 mm Hg at
the 6-month follow-up appointment). On examination, the
patient has conjunctival redness, superficial punctate keratitis,
and poor corneal tear film. Which of the following is the most
likely cause of the patient’s poorly controlled IOP?
a. Patient tolerance to the pharmacological effects of
latanoprost with BAK therapy
b. Worsening of glaucoma
c. Drug interaction with preservative-free tear
supplements
d. Suboptimal adherence to latanoprost with BAK therapy
5. Dry eye affects patient quality of life in a similar magnitude
to that experienced in _____________.
a. Unstable angina
b. Diabetes mellitus
c. Osteoporosis
d. Hypertension
6. Which is NOT a deleterious effect of BAK?
a. Disruption of tight junction proteins
b. Programmed cell death, apoptosis, and necrosis in
epithelial cells
c. IOP elevation
d. Incitation of cytokines, chemotactic factors, and
metalloproteinases
7. A 68-year-old white female presents to the ophthalmology
clinic with complaints of red, irritated eyes. <strong>The</strong> patient is
treated with latanoprost with BAK for IOP lowering. On
examination, the patient has marked hyperemia of both
eyes. Which of the following therapeutic strategies would be
most likely to completely eliminate the patient’s red eyes?
a. Change therapy to preservative-free tafluprost
b. Add preservative-free dexamethasone, 0.01%
c. Change therapy to travoprost with SofZia
d. Initiate a drop holiday
8. Which statement regarding non-BAK preserved prostaglandin
analog ocular antihypertensives is true?
a. Preservative-free ocular antihypertensives are not as
effective as BAK-preserved ocular antihypertensives in
terms of lowering IOP
b. Travoprost with SofZia has been found to be ineffective
and not well tolerated
c. Preservative-free ocular antihypertensives are more
effective than BAK-preserved ocular antihypertensives
in terms of lowering IOP.
d. Preservative-free tafluprost has been found to have an
IOP-lowering effect of up to 30%
9. Which of the following treatment strategies is/are the most
reasonable option(s) for addressing therapeutic
nonadherence due to ocular surface complaints in a patient
currently on a prostaglandin analog with BAK?
a. Laser trabeculoplasty
b. Switch to a non-BAK preserved or preservative-free
ocular antihypertensive therapy
c. Add artificial tears to the current regimen
d. A and B are the most reasonable options
10. A 73-year-old African American female patient presents to
the ophthalmology clinic. <strong>The</strong> patient has been on an IOPlowering
regimen of brimonidine with Purite and latanoprost
with BAK. She is complaining of ocular irritation and foreign
body sensation. Ocular examination shows conjunctival
redness, rapid tear film break-up, and corneal fluorescein
staining. <strong>The</strong> patient’s IOP is 24 mm Hg and she reports
being adherent to her ocular antihypertensive therapy.
Which of the following is likely the most appropriate
therapeutic strategy for this patient?
a. Initiate a drop holiday and begin preservative-free
dexamethasone, 0.01%, followed by re-initiation of
ocular antihypertensive therapy with a preservative-free
formulation
b. Initiate a drop holiday and begin IOP-lowering therapy
with an oral carbonic anhydrase inhibitor, followed by
re-initiation of ocular antihypertensive therapy with a
preservative-free formulation
c. Initiate a drop holiday and begin preservative-free
dexamethasone, 0.01%, followed by re-initiation of
ocular antihypertensive therapy with brimonidine with
Purite and travoprost with SofZia
d. Initiate a drop holiday and begin preservative-free
dexamethasone, 0.01%; recommend laser
trabeculoplasty within 1 week
11

ACTIVITY EVALUATION/CREDIT REQUEST
How OSD Affects IOP
<strong>The</strong> <strong>Impact</strong> on Glaucoma from the OUTSIDE IN
Original Release: July 15, 2012
Last Review: June 26, 2012
Expiration: July 30, 2013
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