Download Medication-related Ocular Surface Disorders Among Glaucoma

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G ME
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A CONTINUING MEDICAL EDUCATION PUBLICATION
NOVEMBER 2016 • ISSUE 11
Medication-related Ocular Surface
Disorders Among Glaucoma Patients
Christophe Baudouin, MD, PhD
Eye drop preservatives prevent
microbial contamination of the
bottle but eventually affect the eye.
Eye care providers should know the
extent of the ocular surface risk of
chronic exposure to preservatives
and be prepared to modify therapy
for medication intolerance,
noncompliance, or in preparation for
surgery.
Ocular surface disorders, including
dry eye syndrome, are more prevalent
among age-matched glaucoma patients
(nearly 50%) compared with the general population (15%); and evidence
indicates that years or decades-long
exposure to topical ocular medication
may be the chief culprit.1,2 Greater
glaucoma severity, multitherapy, and
longer disease duration have all been
associated with increased rates of dry
eye among glaucoma patients.3
Notably, ocular surface signs and
symptoms are significantly more common among patients treated with
TARGET AUDIENCE This educational activity is intended
for ophthalmologists and ophthalmologists in residency or
fellowship training.
LEARNING OBJECTIVES Upon completion of this activity,
participants will be able to:
1. Identify factors that contribute to ocular surface disorders
among patients undergoing medical treatment for
glaucoma.
2. Modify management to counter ocular surface disease in
glaucoma patients.
3. Describe the main categories and clinical presentation
of secondary glaucomas outside of the exfoliative and
pigmentary types.
4. Describe treatment management strategies, and
anticipated complications that may be involved, for these
secondary glaucomas.
topical medications that contain preservative compared with those taking preservative-free formulations (Figure 1).
Many of these signs and symptoms
resolve or lessen when preservativefree formulations are substituted for
preserved formulations.4
WHY OSD MATTERS
Maintaining the health of the ocular
surface is of more than minor importance in the care of glaucoma patients.
First of all, regardless of cause, ocular
surface disorders are associated with
significant morbidity, often causing
stinging, burning, irritation, and dryness and taking a toll on quality of life.
The impact of dry eye on patients’
visual experience and comfort can go
underappreciated by clinicians who take
preservation of the optic nerve as their
sole aim and responsibility. Irritation,
foreign body sensation, photophobia,
and other symptoms can seem to us a
small price to pay for the chance to preserve eyesight. That may be true, but we
owe it to our patients to consider the full
range of their eye-related symptoms.
EDITORS
Paul L. Kaufman, MD, is a professor of ocular pharmacology and Department Chair Emeritus at the department of
ophthalmology & visual sciences at the School of Medicine &
Public Health in the University of Wisconsin-Madison.
Robert Noecker, MD, is an assistant clinical professor of
ophthalmology at the Yale University School of Medicine
and clinical professor of surgery at the Frank Netter School
of Medicine of Quinnipiac University, and he practices at
Ophthalmic Consultants of Connecticut.
Rohit Varma, MD, MPH, is director of the USC Eye Institute,
chair of the department of ophthalmology, and professor of
ophthalmology and preventive medicine at the Keck School
of Medicine at the University of Southern California.
To obtain CME credit for this activity, go to http://cme.ufl.edu/ed/self-study/tig/
FIGURE 1 Major inflammation of the ocular
surface in a patient receiving multiple antiglaucoma medications over the long term.
(Courtesy of Dr. Baudouin.)
Keep in mind that the substantial
benefit of IOP-lowering medication—
especially over the long-term—may
feel somewhat abstract, remote, or
intangible to patients. They often begin
treatment as a matter of faith, with no
outward signs of disease evident. Like
the disease, treatment is beleaguered
SEE INSIDE FOR:
Secondary Glaucoma: Beyond
Exfoliative and Pigmentary Glaucoma
by Leon W. Herndon, MD
Topics in Glaucoma is jointly sponsored by Candeo Clinical/
Science Communications, LLC, and the University of Florida
College of Medicine. This publication is administered by an
independent editorial board and supported by an unrestricted
educational grant from Bausch + Lomb, Inc.
Copyright 2016 Candeo Clinical/Science Communications,
LLC. All rights reserved. Neither the University of Florida nor
Candeo Clinical/Science Communications, LLC, assumes any
responsibility for injury or damage to persons or property
arising from the use of information or ideas contained in
this publication.
COURSE DIRECTOR
Matthew J. Gray, MD
University of Florida
Gainesville, FL, USA
Supported by an unrestricted educational grant
TOPICS
from Bausch
IN GLAUCOMA
+ Lomb, Inc.
1
by uncertainties: many patients will not
lose vision irrespective of treatment,
and a subset of less fortunate patients
will suffer visual loss despite treatment.
Compound these factors—the anxiety
of an uncertain fate and the baseline
gamble of lifelong treatment—with
real-time, treatment-induced suffering,
and standard of care becomes a considerably more complicated proposition.
Medication-related ocular surface
side effects can contribute to dissatisfaction with treatment and noncompliance, limiting patients’ prospects for
successful IOP control.5,6 Additionally
dry eye may influence quality of vision,
causing intermittent blurred or unstable vision that may interfere with visual
field performance and as a consequence
evaluation of glaucoma outcome. Side
effects are among the most common
reasons patients cite for discontinuing
therapy, second only to insufficient
understanding of the potential consequences of the disease.
The ocular surface also plays a role in
surgical outcomes.7 Long-term exposure
to antiglaucoma therapies has been associated with increased inflammatory
cells (eg, fibroblasts, lymphocyte, and
macrophages) and decreased goblet cells
in conjunctival tissue, both of which can
contribute to post-operative conjunctival fibrosis and compromise bleb functioning.3,8 Conversely, an uninflamed,
scar-free conjunctiva is more likely to
yield favorable outcomes.
TOXIC MECHANISMS
Chronic topical ocular antiglaucoma
medication use may initiate ocular surface inflammation or exacerbate underlying ocular surface disease such as dry
eye, meibomian gland dysfunction, or
chronic allergy (Figure 2).3 Most formulations contain a preservative, the most
common one being the quaternary ammonium benzalkonium chloride (BAK).
BAK is used for its high antimicrobial
potency, low antigenicity, and relative
safety compared with mercury and other
formerly favored preservative agents.3
Long-term exposure to BAK, however, is associated with cellular and
tissue damage precipitated by a variety
of mechanisms. In vitro studies show
that BAK damages conjunctival and trabecular meshwork cells in cell culture by
cytotoxic (eg, apoptosis and oxidative
stress) and proinflammatory mechanisms; animal studies reveal trabecular
meshwork damage due to BAK.3,9
As a detergent capable of permeating and disorganizing lipid membranes,
BAK disrupts the lipid layer of the human tear film leading to evaporative dry
eye. BAK has also been shown to reduce
the density of goblet cells, which has
the effect of reducing mucin produc-
TOPICS IN GLAUCOMA — ISSUE 11
STATEMENT OF NEED
Glaucoma, a group of ocular diseases characterized by progressive damage to the optic nerve, is the second leading cause of
blindness worldwide, affecting a significant and growing portion
of the US population.1,2
Much remains to be understood about the pathophysiology of
glaucoma, but high intraocular pressure (IOP) has been identified
as a key risk factor for progression. Medical and surgical therapies
for the disease are primarily directed at reducing IOP.
Recent years have seen significant innovation in the treatment
of glaucoma, including gentler and more effective topical
drugs, less invasive surgical techniques, and new molecules
and mechanisms of action. As pharmaceutical and surgical
treatments for glaucoma rapidly advance—and as research
continues to provide insights about the disease’s neurologic
underpinnings—comprehensive ophthalmologists are challenged to remain up-to-date.
To give their glaucoma patients the full benefit of treatment
advances, clinicians require clear, actionable insights from
subspecialists and researchers. Topics in Glaucoma will present
current research in the context of comprehensive care, providing
non-specialists with clearly presented, evidence-based clinical
judgments from experts in the field.
REFERENCES
1.Resnikoff S, Pascolini D, Etya’ale D, et al. Global data on visual
impairment in the year 2002. Bull World Health Organ. 2004
November;82(11):844-51.
2.Eye Diseases Prevalence Research Group. Prevalence of openangle glaucoma among adults in the United States. Arch
Ophthalmol. 2004;122:532-8.
OFF-LABEL USE STATEMENT
This work may discuss off-label uses of medications.
GENERAL INFORMATION
This CME activity is sponsored by the University of Florida College
of Medicine and is supported by an unrestricted educational
grant from Bausch + Lomb, Inc.
Directions: Select one answer to each question in the exam
(questions 1–10) and in the evaluation (questions 11–16).
The University of Florida College of Medicine designates this
enduring material for a maximum of 1 AMA PRA Category 1
Credit™. There is no fee to participate in this activity. In order
to receive CME credit, participants should read the report, and
then take the posttest. A score of 80% is required to qualify
for CME credit. Estimated time to complete the activity is 60
2 TOPICS IN GLAUCOMA
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DATE OF ORIGINAL RELEASE
November 2016. Approved for a period of 12 months.
ACCREDITATION STATEMENT
This activity has been planned and implemented in accordance
with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education through
the joint providership of the University of Florida College of
Medicine and Candeo Clinical/Science Communications, LLC.
The University of Florida College of Medicine is accredited by the
ACCME to provide continuing medical education for physicians.
CREDIT DESIGNATION STATEMENT
The University of Florida College of Medicine designates this
enduring material for a maximum of 1 AMA PRA Category 1
Credit™. Physicians should claim only the credit commensurate
with the extent of their participation in the activity.
FACULTY AND DISCLOSURE STATEMENTS
Paul L. Kaufman, MD (Faculty Advisor), is a professor of
ocular pharmacology and Department Chair Emeritus at the
department of ophthalmology & visual sciences at the School of
Medicine & Public Health in the University of Wisconsin-Madison.
He states that in the last 12 months, he has been a consultant
for Advanced Genetic Technology Corporation, Alcon, Allergan,
Bausch + Lomb, Amakem Therapeutics, Refocus Group, Sucampo
Pharmaceuticals, and Valeant Pharmaceuticals. Dr. Kaufman
also states that he has received grants from Lens AR, Inc./Frey
Research LLC, WARF, Vista Ocular, LLC, Regen Eye, and Z Lens LLC.
Dr. Kaufman also states that he has received royalties from WARF.
Robert Noecker, MD (Faculty Advisor), is an assistant clinical
professor of ophthalmology at the Yale University School of
Medicine and clinical professor of surgery at the Frank Netter
School of Medicine of Quinnipiac University, and he practices at
Ophthalmic Consultants of Connecticut. He states that in the last
12 months, he has received grant/research support for Glaukos,
InnFocus, Allergan, and Diopsys, and has been a consultant for
Alcon, Allergan, Ocular Therapeutix, IRIDEX, BVI, Katena, Diopsys, SOLX, Aerie Pharmaceuticals, Inotek Pharmaceuticals, and
Shire. Dr. Noecker also states that he has been on the speakers
bureau for Alcon, Allergan, IRIDEX, and Glaukos, and is a stock
shareholder for Ocular Therapeutix.
Rohit Varma, MD, MPH (Faculty Advisor), is director of the
USC Eye Institute, chair of the department of ophthalmology,
and professor of ophthalmology and preventive medicine at the
Keck School of Medicine at the University of Southern California.
He states that in the last 12 months, he has been a consultant
for Aerie Pharmaceuticals, Allergan, Bausch + Lomb, Genentech,
Isarna Therapeutics, and Merck.
Christophe Baudouin, MD, PhD, FARVO, is professor and
chairman, ophthalmology at Quinze-Vingts Hospital, University
of Paris, in Paris, France. Dr. Baudouin received grant/research
support from Horus Pharma, Santen Pharmaceutical Co., Ltd.,
and Thea Pharmaceuticals. He also serves as a consultant for
Alcon, Allergan, Dompé, Horus Pharma, Santen Pharmaceutical
Co., Ltd., and Thea Pharmaceuticals.
Leon W. Herndon, MD, is professor of ophthalmology and chief
of the glaucoma division at Duke Eye Center, Duke University,
Durham, NC. Dr. Herndon has received grant/research support
from Glaukos and is a consultant for Aerie Pharmaceuticals,
Inotek Pharmaceuticals, and Sight Sciences. He is also on the
speakers bureau for Alcon and Glaukos.
DISCLAIMER
Participants have an implied responsibility to use the newly
acquired information to enhance patient outcomes and
professional development. The information presented in this
activity is not meant to serve as a guideline for patient care.
Procedures, medications, and other courses of diagnosis and
treatment discussed or suggested in this activity should not be
used by clinicians without evaluation of their patients’ conditions
and possible contraindications or dangers in use, applicable
manufacturer’s product information, and comparison with
recommendations of other authorities.
COMMERCIAL SUPPORTERS
This activity is supported by an unrestricted educational grant
from Bausch + Lomb, Inc.
To obtain CME credit for this activity, go to http://cme.ufl.edu/ed/self-study/tig/
FIGURE 2 Toxic keratopathy characterized by
central corneal fluorescein staining. (Courtesy of Dr.
Baudouin.)
tion—necessary for even distribution of
tears across the ocular surface—which
further deteriorates tear film function.3
Clinical studies comparing exposure to
preserved vs preservative-free topical
beta-blocking agents revealed that
BAK exposure is indeed associated with
greater tear film instability and disruption of corneal barrier function.10
CUMULATIVE DAMAGE
Clinicians must be vigilant for
tolerability issues beyond the limited
parameters used in clinical trials, which
typically exclude patients with underlying ocular surface disease and are
performed over 6 to 12 months. Preservative-related ocular surface toxicity
is cumulative, taking months to years
to manifest, and it may be most severe
among patients with advanced disease
and those with ocular comorbidities.
All too commonly, eye care providers fail to consider medication effects
among patients whose therapeutic regimen has been well tolerated in the past
and remains unchanged, reasoning that
medication intolerance is an early event
and tolerance has been demonstrated.
This is true for many forms of drug
allergy, many cases of which present
shortly after initiation; however, when
taken over many years, medications
must still be on the differential diagnosis for late-presenting symptoms.
While the volume of preservative in
topical medication poses no clinically
meaningful threat to the ocular surface
in a single dose, repeated doses—particularly at frequent intervals—permit
insufficient time for ocular cells to natu-
rally regenerate between exposures. As
a consequence, histological and biochemical micro-insults will overwhelm
the restorative capacity of the eye over
time. Studies have shown that, among
glaucoma patients, risk for ocular surface toxicity and/or dry eye severity
increases with the following variables:
increased number of preserved medications used, greater number of drops per
day, duration of topical antiglaucoma
medication use, and severity of glaucoma.9,11-13 Advanced age and past drug
regimen change were also markers for
more severe ocular surface disease.9
REDUCING CYTOTOXIC
EXPOSURE
Minimizing exposure to inflammation-inciting agents—including
preservatives—is integral to the management of glaucoma, particularly
when ocular surface disease is evident.
It is a common mistake to fuel the fire
by adding another topical agent (eg,
antiinflammatory or artificial tear)
that contains BAK. A recent study of
glaucoma patients showed that among
the 40% who were also being treated for
ocular surface disorders, half of those
prescribed artificial tears were given a
preservative-containing product.6
For patients taking multiple anti­
glaucoma agents, the simplest way to
reduce exposure to preservatives is the
use of fixed combination drops, which
essentially cuts the preservative exposure
in half without compromising IOP-lowering potency. Fixed-dose combination antiglaucoma medications are more widely
available in Europe, where the collective
consciousness around the dangers of
preservatives (in medications, foods, etc)
is generally higher compared with the US.
Preservative-free medications dispensed
in single dose vials are available in Europe
for most classes of antiglaucoma agent;
studies have shown that switching patients to preservative-free antiglaucoma
agents improves signs and symptoms of
ocular surface disease.4,11,14
Preservative-free therapy may be
standard of care in 10 to 15 years6 with
increased awareness of BAK-induced
ocular toxicity and the importance of
ocular surface health. Demand, uptake,
To obtain CME credit for this activity, go to http://cme.ufl.edu/ed/self-study/tig/
CORE CONCEPTS
● The ocular surface is important
to the medical and surgical
management of glaucoma.
Ocular surface health affects
quality of life and treatment
compliance.
● Half of glaucoma patients
develop ocular surface disease
over years of exposure to
preservative-containing topical
medications.
● Avoid treating ocular surface
disease with additional
preservative-containing
(lubricants or antiinflammatory)
agents; they offer temporary
relief but ultimately exacerbate
the problem. The subtraction
strategy is preferred to the
additive one.
● Preservative toxicity is time- and
dose-dependent.
● Reduce toxic exposures in
glaucoma patients with ocular
surface disease by cutting the
number of medications when
possible or use combination
agents; choosing agents with
lower BAK concentrations,
dosing frequency, or less toxic
preservative; and seeking out
available preservative-free options.
and marketing of preservative-free
medications might follow a trajectory
similar to that of daily disposable contact lenses: first seen as an impractical
novelty reserved for select patients, daily
disposables quickly became preferred by
prescribers and patients for their safety
and gentleness on the ocular surface.
Some patients, however, find small
aliquots of medication in single-dose
vials cumbersome to handle and dispense; further, their currently low
market share keeps the costs high in
the US. As of today, two preservatives
have been developed as less toxic alternatives to BAK for use in ophthalmic
agents: Purite® and SofZia™.15 Purite®,
a stabilized oxychloro complex, is associated with fewer conjunctival and corneal toxic effects compared with BAK in
TOPICS IN GLAUCOMA 3
animal studies and fewer ocular surface
symptoms in clinical studies.16 Puritepreserved brimonidine ophthalmic
solution is formulated as Alphagan-P®
(Allergan, Parsippany-Troy Hills, NJ).
Travatan Z® (Alcon, Fort Worth, TX) is
the first prostaglandin analog preserved
with SofZia, a boric acid, propylene
glycol-based preservative that also
demonstrates reduced conjunctival and
corneal toxicity compared with BAK.17
ROLE OF SURGERY
Laser trabeculoplasty procedures
and minimally invasive glaucoma surgeries (MIGS) can reduce patients’ reliance on preservative-containing topical
ocular treatments. Reciprocally, preparing patients’ ocular surface for surgery is
important for optimal results and postsurgical IOP control. In my experience,
the process of preparing the ocular surface for surgery—reducing or stopping
toxic preserved medications and tackling
ocular surface inflammation—can have
the unexpected but welcome effect of
eliminating the need for surgery in
the first place; with the ocular surface
healed, patients sometimes tolerate and
respond better to medical therapy alone.
CONCLUSION
Preservatives protect the bottle but
do not protect the eye. BAK is known for
its cumulative ocular cytotoxicity via
multiple mechanisms; alternatives are
badly needed. Until that time, reducing exposure to BAK (and increasing
demand for combination agents and
affordable preservative-free options)
can delay and potentially prevent preservative-related ocular surface disease.
Christophe Baudouin, MD, PhD, FARVO, is professor and chairman, ophthalmology at Quinze-Vingts
Hospital, University of Paris, in Paris, France. Dr.
Baudouin received grant/research support from
Horus Pharma, Santen Pharmaceutical Co., Ltd.,
and Thea Pharmaceuticals. He also serves as a
consultant for Alcon, Allergan, Dompé, Horus
Pharma, Santen Pharmaceutical Co., Ltd., and
Thea Pharmaceuticals. Medical writer, Noelle Lake,
MD, assisted in the preparation of this manuscript.
REFERENCES
1.Fechtner RD, Godfrey DG, Budenz D, et al. Prevalence of ocular surface complaints in patients
with glaucoma using topical intraocular pressure
lowering medications. Cornea. 2010;29:618-21.
2. Baudouin C, Renard JP, Norman JP, et al. Prevalence
and risk factors for ocular surface disease among
patients treated over the long term for glaucoma or
ocular hypertension. Eur J Ophthalmol. 2012:1-12.
3.Baudouin C, Labbe A, Liang H. Preservatives in
eyedrops: the good, the bad and the ugly. Progress
Retinal Eye Res. 2010;1-23.
4.Jaenen N, Baudouin C, Pouliquen P, et al. Ocular
symptoms and signs with preserved and preservative-free glaucoma medications. Eur J Ophthalmol.
2007;17:341-9.
5.Nordmann JP, Auzanneau N, Ricard S, et al. Vision related quality of life and topical glaucoma
treatment side effects. Health Qual Life Outcomes.
2003;1:75.
6.Lemij HG, Hoevenaars JGMM, van der Windt C,
et al. Patient satisfaction with glaucoma therapy:
reality or myth? Clin Ophthalmol. 2015;9:785-93.
7.Boimer C, Birt CM. Preservative exposure and
surgical outcomes in glaucoma patients: the PESO
study. J Glaucoma. 2013;1-6.
8.Meziani L, Tahiri Joutei Hassani R, El Sanharawi
M, Brasnu E, Liang H, Hamard P, Baudouin C,
Labbe A. Evaluation of Blebs After Filtering
Surgery With En-Face Anterior-Segment Optical
Coherence Tomography: A Pilot Study. J Glaucoma. 2016 May;25(5):e550-8.
9. Baudouin C, Denoyer A, Descendit N, et al. In vitro
and in vivo experimental studies on trabecular
meshwork degeneration induced by benzalkonium
chloride. Trans Am Ophthalmol Soc. 2012;110:40-63.
10. Ishibashi, T, Yokoi, N, Kinoshita, S. Comparison of
the short-term effects on the human corneal surface
of topical timolol maleate with and without benzalkonium chloride. J Glaucoma. 2003;12:486-90.
11.Pisella, PJ, Pouliquen, P, Baudouin, C. Prevalence
of ocular symptoms and signs with preserved
and preservative free glaucoma medication. Br J
Ophthalmol. 2002;86:418-23.
12. Erb, C, Gast, U, Schremmer, D. German register for
glaucoma patients with dry eye. I. Basic outcome
with respect to dry eye. Graefes Arch Clin Exp
Ophthalmol. 2008;246:1593-1601.
13.Rossi, GC, Tinelli, C, Pasinetti, GM, et al. Dry
eye syndrome-related quality of life in glaucoma
patients. Eur J Ophthalmol. 2009;19:572-9.
14.Henry JC, Peace JH, Stewart JA, et al. Efficacy,
safety, and improved tolerability of travoprost
BAK-free ophthalmic solution compared with
prior prostaglandin therapy. Clin Ophthalmol.
2008;2:613-21.
15.Anwar Z, Wellik SR, Galor A. Glaucoma therapy
and ocular surface disease: current literature
and recommendations. Curr Opin Ophthalmol.
2013;24:136-43.
16.Noecker RJ, Herrygers LA, Anwaruddin R.
Corneal and conjunctival changes caused by
commonly used glaucoma medications. Cornea.
2004;23:490-6.
17.Kahook MY, Noecker RJ. Comparison of corneal
and conjunctival changes after dosing of travoprost preserved with sofZia, latanoprost with
0.02% benzalkonium chloride, and preservativefree artificial tears. Cornea. 2008;27:339-43.
Secondary Glaucoma: Beyond Exfoliative
and Pigmentary Glaucoma
Leon W. Herndon, MD
The less common forms of
secondary glaucoma can often
be the most difficult to treat, due
to the involvement of underlying
systemic disease, the complexity
of ocular tissues involved, and the
challenging differential diagnosis.
Secondary glaucomas include a
broad and clinically diverse group of
4 TOPICS IN GLAUCOMA
conditions that share an identifiable
cause of increased intraocular pressure
(IOP), which can ultimately result in
optic nerve damage and loss of vision.
The most common forms of secondary glaucoma are exfoliative and
pigmentary glaucoma, distinguished by
the deposition of fibrillary material (in
the former) and pigment granules (in the
latter) in the drainage angle of the eye.
In either case, these depositions cause
impaired aqueous fluid outflow and in-
creased IOP. The less common forms of
secondary glaucoma include neovascular,
uveitic, childhood, traumatic glaucoma,
and iridocorneal endothelial syndrome.
Improvements in techniques to evaluate the optic nerve and retinal nerve fiber
layer, such as optical coherence tomography (OCT), and improvements in techniques to evaluate the angle, such as ultrasound biomicroscopy and anterior segment OCT, are important for early diagnosis and treatment of these conditions.
To obtain CME credit for this activity, go to http://cme.ufl.edu/ed/self-study/tig/
NEOVASCULAR GLAUCOMA
Neovascular glaucoma is characterized by a hypoxic retina, which is commonly associated with an underlying
systemic disease such as diabetes mellitus or vascular occlusive disease. The
most common etiologies are diabetic
retinopathy and central retinal vein occlusion, but also include other retinal
venous obstructive diseases, carotid
artery obstructive disease, and, less
commonly, central retinal artery occlusion, rhegmatogenous retinal detachment, uveitis, radiation retinopathy,
and choroidal melanoma.
The retinal response to this localized
hypoxic and/or injured environment is
an upregulation of proangiogenic proteins including platelet-derived growth
factor, transforming growth factor-α,
β, tumor necrosis factor-α, hepatocyte
growth factor, matrix metalloproteinase
3, matrix metalloproteinase 9, erythroblast transformation specific gene encoded protein, and vascular endothelial
growth factor (VEGF).
The aberrant growth of new, poorly
patent vessels in the retina causes vitreous hemorrhage, macula edema, retinal
fibrosis, and, should they extend to the
anterior chamber of the eye, neovascularization of the iris or anterior chamber angle. This can result in peripheral anterior
synechiae, possible closure of the trabecular meshwork, prevention of normal aqueous fluid drainage from the anterior segment of the eye, elevated IOP and, if untreated, glaucomatous optic neuropathy.1
The eyes of patients presenting
with neovascular glaucoma are often
extremely red and painful, indicating
a requirement for immediate attention
since there is a high risk of significant vision loss. The management strategy for
this condition is at least two-fold. First,
it is necessary to provide immediate
attention to the localized pathology by
administration of IOP-lowering medications (such as prostaglandin analogues,
beta-blockers, cholinergic agonists or
carbonic anhydrase inhibitors) and
steroids to reduce local inflammation.
Second, collaboration with a retinal
specialist or an experienced general
ophthalmologist is often required to address the neovascular component of the
condition. Pan-retinal photocoagulation
is effective in decreasing the retinal
oxygen demand and associated ischemic
drive for angiogenic factor transcription, even in the early rubeosis (preglaucoma) stages of the disease, when
IOP levels may still be normal, through
to the open-angle and closed-angle stages of glaucoma, when IOP is elevated.2
A relatively recent advancement that
has revolutionized the management of
ocular neovascular pathologies is the use
of intraocular anti-VEGF therapy. The
most commonly used anti-VEGF used for
neovascular glaucoma is off-label bevacizumab (Avastin). Both ranibizumab (Lucentis) and aflibercept (Eylea) have yet to
be indicated for this condition, although
both drugs are indicated for treatment of
diabetic macular edema and retinal vein
occlusion, which often underlie neovascular glaucoma.1,3 The effectiveness of
anti-VEGF agents for the treatment of
neovascular glaucoma still requires investigation through randomized, controlled
trials to inform clinical practice decisions.4 The administration of anti-VEGF
injections prior to glaucoma surgery (traditionally trabeculectomy or insertion of
a drainage implant ) has the added benefit
of reducing the risk of bleeding during
surgery, which may further contribute
to blocking the drainage angle in the eye.
A third possible step in the management of neovascular glaucoma involves
collaboration with the patient’s general physician to address the underlying
systemic disease (such as diabetes or
hypertension) that may be implicated
in the etiology of certain neovascular
glaucoma pathologies.
UVEITIC GLAUCOMA
This range of inflammatory disorders, which occurs in up to 20% of patients with chronic uveitis,5 is one of the
most challenging to manage due to the
younger age of patients (thus requiring
lifetime management), high IOP with
acute elevations, and varied response to
treatment relative to other glaucomas.
Often resulting in more intense
optic nerve damage and visual impairment, uveitic glaucoma can be divided
into open- and closed-angle types: the
former is characterized by mechanical
To obtain CME credit for this activity, go to http://cme.ufl.edu/ed/self-study/tig/
CORE CONCEPTS
● Secondary glaucomas can
be complex to diagnose and
challenging to treat since
underlying systemic mechanisms
are often associated. An
interdisciplinary management
approach is advised involving
collaboration with other medical
specialties.
● Anti-VEGF therapies can be
effective in the management of
neovascular glaucoma to address
the angiogenic component of the
disease caused by retinal hypoxia
and associated upregulated
transcription factors.
● The conundrum of treating
inflammation-associated
secondary glaucomas is that
indicated antiinflammatory
medications, such as
corticosteroids, can exacerbate
the elevated IOP over time. Care
must be taken to monitor IOP in
these cases and switch to a less
potent steroid if necessary.
● Almost all antiglaucoma
medications are not licensed
for use in children. Measures
to reduce systemic absorption
should be taken in pediatric
cases to minimize the serious
side effects that can occur even
from topical drops.
obstruction of the trabecular meshwork
with inflammatory cells, proteins, debris, fibrin or inflammatory precipitates;
the latter is characterized by synechial
closure, neovascularization of the chamber angle, seclusion pupillae with subsequent appositional angle closure, or, less
commonly, ciliary body forward rotation
causing angle closure (such as observed
in Vogt-Koyanagi-Harada syndrome).6
In many of the uveitic glaucoma cases,
the observed ocular inflammation is associated with an underlying disease such
as sarcoidosis, spondyloarthropathies,
inflammatory bowel disease, Fuchs heterochromic iridocyclitis, herpes simplex,
zoster virus, Lyme disease, Vogt KoyanagiHarada disease, cancer, Behcet’s disease,
TOPICS IN GLAUCOMA 5
juvenile idiopathic arthritis, and syphilis.
However, there are cases in which the
underlying disease and the etiology of the
uveitis is not apparent in spite of detailed
laboratory investigations.
Some racial differences in the presentation and prevalence of uveitis,
which may ultimately predispose glaucoma, have been observed; for example;
sarcoidosis is more common in Blacks
than Whites in the United States, and
Blacks more commonly have anterior
segment involvement, while Whites
more commonly have posterior segment
involvement. Similarly, racial differences in response to treatment for uveitic
glaucoma (such as steroid implants and
trabeculectomy) have been postulated.7
One form of open-angle uveitic
glaucoma is Posner-Schlossman syndrome, or glaucomatocyclitic crisis. This
typically unilateral condition, which
presents mostly in younger patients
between the ages of 20 and 50, is characterized by recurrent episodes (ranging
from a few hours to a few weeks) of
self-limiting, mild, non-granulomatous
anterior uveitis. The observed inflammatory changes within the trabecular
meshwork that cause impaired aqueous
outflow and markedly elevated IOP are
postulated to be mediated by prostaglandins. The etiology of Posner-Schlossman
syndrome is not clear, but it is often
associated with cytomegalovirus and
herpes simplex virus; other proposed
etiologies include autonomic dysfunction, abnormal vascular response, and
developmental abnormalities.8
Diagnosis of Posner-Schlossman
syndrome can be difficult since the
subtle clinical features of the disease,
namely low-grade uveitis and the shortlived nature of each attack, can mimic a
variety of other ocular disorders. These
include acute angle-closure glaucoma,
chronic angle-closure glaucoma, Fuchs
heterochromic iridocyclitis, and primary open-angle glaucoma.
Posner-Schlossman syndrome responds well to a combined regimen of
an antiinflammatory and antiglaucoma
drug(s), although in rare cases the condition can be chronic, and recurrent
episodes of inflammation may lead
to long-term glaucomatous damage.
6 TOPICS IN GLAUCOMA
FIGURE 1 Uveitic Glaucoma Diagnosis Chart6 (Reprinted from Francisco J. Muñoz-Negrete, Javier
Moreno-Montañés, Paula Hernández-Martínez, and Gema Rebolleda, “Current Approach in the Diagnosis and
Management of Uveitic Glaucoma,” BioMed Research International, vol. 2015, Article ID 742792, 13 pages, 2015.
doi:10.1155/2015/742792. Copyright 2015 by Francisco J. Muñoz-Negrete et al.)
Potential IOP elevations caused by steroids in steroid-responsive patients may
complicate the treatment of PosnerSchlossman syndrome, in which case a
topical nonsteroidal antiinflammatory
drug helps to control the inflammation.
In rare cases where uncontrolled IOP
may result in progressive optic nerve
damage and visual field loss, glaucoma
filtration surgery may be required.8
Another form of open-angle uveitic glaucoma is Fuchs heterochromic
iridocyclitis. Presenting as a triad of
anterior uveitis, heterochromia, and
cataract, the condition is characterized
by chronic but mild inflammation that is
not associated with any scar tissue. Eyes
are often asymptomatic and respond
well to IOP-lowering medication and
corticosteroid drops, but filtering surgery may be needed to control the IOP.
The condition may be associated
with cytomegalovirus; in such cases, patients tend to be male, older at diagnosis,
and have nodular endothelial lesions.9
The uveitic glaucomas can be difficult
to differentially diagnose (Figure 1). Moreover, the very treatment that addresses
the inflammatory component of the disease (corticosteroids) can exacerbate the
elevated IOP over time, making it challenging to ascertain whether the observed
increase in IOP is related to the original
pathology or the steroidal treatment.
Regardless, the typical management
strategy for uveitic glaucoma is to treat
the inflammation component aggressively with corticosteroids and then
taper off once the inflammation and IOP
are controlled. In refractory cases, it is
important to take an interdisciplinary
approach that includes a uveitis specialist and a rheumatologist to address
not only the ocular inflammation and
elevated IOP but also the underlying
systemic inflammation. Often, these patients will require glaucoma surgery (eg,
trabeculectomy); however, care must be
taken to avoid the complication of hypotony, in which the IOP is lowered too
much, causing further ocular damage.
CHILDHOOD GLAUCOMA
These childhood pathologies, which
can be categorized as either primary childhood glaucoma (primary congenital glaucoma or juvenile open-angle glaucoma) or
secondary childhood glaucoma (associated with non-acquired ocular abnormalities or systemic diseases, acquired conditions, and post-cataract surgery) constitute some of the greatest clinical challenges for pediatric ophthalmologists and
glaucoma specialists. All conditions are
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traditionally characterized by raised IOP,
optic neuropathy, and visual field defects.
One of the main problems with treating childhood glaucoma with the variety
of typical IOP-lowering medications is that
none of these are licensed by regulatory
agencies for use in children. Thus, most
pharmacological treatments, such as topical beta-blockers, topical and systemic carbonic anhydrase inhibitors, prostaglandin
analogs, adrenergic agonists, parasympathomimetics, and combined preparations,
must be used off-label in the absence of
rigorous evidence collected from randomized, controlled trials. In the absence of
level 1, evidence-based guidelines, treatment should be customized based on
the age and general health of the child,
the type of glaucoma, and the known
efficacy and safety profiles of each drug.10
Certainly, increased systemic absorption due to a smaller blood volume
and reduced body mass compared with
adults and drug elimination half-life due
to their immature metabolic system may
make the risk of serious systemic adverse
effects more profound in children.11
TRAUMATIC GLAUCOMA
Typically related to accidents or
physical altercations, approximately
85% to 90% of traumatic glaucoma
cases present in males. Following the
traumatic event, risk factors for developing glaucoma are increased age, poor
visual acuity at presentation, perforating rather than penetrating injury, lens
dislocation, vitreous hemorrhage, presence of an intraocular foreign body, and
post-trauma cataract surgery. The condition develops secondary to the disturbance of the trabecular meshwork and
direct inflammatory scarring, or the accumulation of inflammatory debris, lens
particles, coagulated blood components,
and red blood cells from hyphema or
vitreous hemorrhage. Angle recession
or synechial angle closure may develop,
resulting in the impediment of aqueous fluid drainage and elevated IOP.12
Prevention of glaucoma development following open-globe injury is
critical. An important aspect of management is to appreciate that trabecular
meshwork scarring may develop some
significant period of time after the trau-
FIGURE 2 Clinical presentation of corneal
endothelial abnormalities in Cogan Reese
syndrome2 (Reprinted from Annadurai P, Vijay L.
Management of secondary angle closure glaucoma. J
Current Glau Prac. 2014; 8(1): 25­32. Copyright 2014 by
Jaypee Brothers Medical Publishers.)
matic event—in some cases only after
years—thus it is recommended that patients be followed up annually at a minimum, particularly for those patients
who have had significant eye trauma.
Where traumatic glaucoma develops,
IOP-lowering medications are the primary treatment, although many patients
will require surgery, such as trabeculectomy or insertion of a glaucoma drainage
device, to address the tissue damage.
Traumatic glaucoma can also be induced as a consequence of surgery, such
as cataract or retinal surgery; associated
bleeding can block the trabecular meshwork, causing elevated IOP. For this reason, it is very important to avoid bleeding during surgical procedures and, if
bleeding does occur, to ensure that all
blood is evacuated. Since antiinflammatory steroid medications are commonly prescribed for up to 3 to 4 weeks
after many surgical procedures, caution
should be taken to monitor the patient
for drug-related elevations in IOP;
switching to less potent antiinflammatory medications may be indicated.
IRIDOCORNEAL ENDOTHELIAL
SYNDROME
This spectrum of secondary angleclosure diseases includes corneal endothelial abnormalities, unilateral glaucoma, and iris stromal abnormalities. The
three main conditions that comprise
this group are essential iris atrophy,
Cogan Reese syndrome, and Chandler’s
syndrome (Figure 2). All share a common etiology of viral infection, typically
by herpes simplex or Epstein-Barr virus.
The condition is characterized by unabated growth of a corneal endothelium
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membrane over the anterior surface
of the iris and the angle structures
resulting in a distorted iris, peripheral
anterior synechiae and angle closure,
leading to elevated IOP and glaucoma.2
The management of iridocorneal
endothelial syndrome can be challenging
for ophthalmologists. The administration of IOP-lowering medication and
glaucoma surgery (such as mitomycin
C-augmented trabeculectomy) is usually
indicated. Glaucoma surgery, however,
may not be effective in the long-term, as
the membrane often regrows, requiring
multiple surgeries to achieve a successful
outcome. In refractory cases in which
trabeculectomy or shunt surgery have
repeatedly failed, cyclophotocoagulation
is indicated.2
CONCLUSION
In summary, secondary glaucomas
outside of the more common exfoliative
and pigmentary types comprise a clinically diverse and often complex group of
pathologies that, in many instances, are
associated with an underlying systemic
condition. Due to the complexity of
these conditions, an interdisciplinary
approach involving collaboration with
other medical specialists is often the
best strategy for effective treatment
management. The potential for patients
to develop glaucomatous optic neuropathy and severe or, at worst, irreversible
vision loss, makes it critical for ophthalmologists to diagnose and treat these
unusual pathologies in a timely manner.
Leon W. Herndon, MD, is professor of ophthalmology and chief of the glaucoma division at Duke Eye
Center, Duke University, Durham, NC. Dr. Herndon
has received grant/research support from Glaukos
and is a consultant for Aerie Pharmaceuticals,
Inotek Pharmaceuticals, and Sight Sciences. He
is also on the speakers bureau for Alcon and Glaukos. Medical Writer, Caroline M. Markey, PhD, of
Markey Medical Consulting Pty Ltd, assisted in the
preparation of this manuscript.
REFERENCES
1.Aref AA. Current management of glaucoma and
vascular occlusive disease. Curr Opin Ophthalmol.
2016;27:140-5.
HERNDON REFERENCES continue on page 9.
TOPICS IN GLAUCOMA 7
EXAMINATION ANSWER SHEET TOPICS IN GLAUCOMA — ISSUE 11
This CME program is sponsored by the University of Florida College of Medicine and supported by an unrestricted
educational grant from Bausch + Lomb, Inc. DIRECTIONS: Select the one best answer to each question in the exam
(Questions 1–10) and in the evaluation (Questions 11–16) below by circling one letter for each answer. Participants
must score at least 80% on the questions and complete the entire Evaluation section on the form below. The University
of Florida College of Medicine designates this enduring material for a maximum of 1 AMA PRA Category 1 Credit™.
There is no fee to participate in this activity. You can take the test online at http://cme.ufl.edu/self-study/tig/.
1. Which of the following is an
advisable option for patients
with long-standing glaucoma
and medication-related ocular
surface disease?
A. Switch to combination agent
B. Switch to preservative-free
treatment
C. A and B
D. None of the above are
advisable
2. Recommended strategies for
treating uveitic glaucoma
include:
A. Co-management of the
patient with a rheumatologist
in refractory cases
B. High potency antiinflammatory medications
for the majority of cases
C. Performing glaucoma
filtration surgery in almost
all patients presenting
with Posner-Schlossman
syndrome
D. Anti-VEGF therapy for
refractory cases
3. Which of the following factors
have NOT been demonstrated
to contribute to or correlate
with cumulative ocular surface
damage among glaucoma
patients?
A. Number of medications
B. Iris color
C. Glaucoma severity
D. Duration of treatment
4. Secondary glaucomas are always
characterized by:
A. The deposition of pigment
granules within the
trabecular meshwork which
impacts aqueous outflow
B. An underlying disease
etiology such as diabetes,
vascular occlusive disease,
uveitis and viral infection
C. Impediment of aqueous
outflow via the drainage
angle secondary to an
underlying disease,
congenital development or
an event
D. High intraocular levels of
VEGF
5. Childhood glaucomas:
A. Are always secondary to
congenital malformation of
the drainage angle
B. Are commonly treated
with licensed medications
in dosage formulations
that are pharmacologically
appropriate for the age
and body mass of juvenile
patients
C. Can be treated effectively
by trabeculotomy and
goniotomy in instances
where the disease is primary
congenital glaucoma
D. Are commonly associated
with the herpes simplex
virus in instances where
the disease is juvenile open
angle glaucoma
EXAMINATION ANSWER SHEET This CME activity is jointly sponsored by the University of Florida and Candeo Clinical/Science Communications, LLC, and supported by an unrestricted
educational grant from Bausch + Lomb, Inc. Mail
to: University of Florida CME Office, PO Box 100233,
Gainesville, FL 32610-0233. DIRECTIONS: Select the
one best answer for each question in the exam above
(Questions 1–10). Participants must score at least 80%
on the questions and complete the entire Evaluation
(Questions 11–16) to receive CME credit. CME exam
expires October 31, 2017.
ANSWERS:
6. Which type of conjunctival cell
is reduced by exposure to BAK?
A. Goblet cells
B. Lymphocytes
C. Fibroblasts
D. Macrophages
7. Neovascular glaucoma:
A. Develops most commonly
secondary to radiation
retinopathy and choroidal
melanoma
B. Is associated with the
upregulation of VEGF,
transforming growth
factor-α, β and PDGF
C. Is always associated with
increased HbA1c levels
D. Can be treated effectively
with on-label bevacizumab
and ranibizumab
8. Which of the following is
NOT a reason to prioritize the
ocular surface in glaucoma
management?
A. Compliance
B. Quality of life
C. Potential need for surgery
D. All are reasons to prioritize
the ocular surface
9. Which of the following is NOT
used in a currently available
antiglaucoma medication?
A. Purite
B. BAK
C. Mercury
D. SofZia
A. Comprises three conditions:
Cogan Reese syndrome,
Chandler’s syndrome
and Fuchs heterochromic
iridocyclitis
B. Is difficult to differential
diagnose as there is no
distinct clinical presentation
for the subgroup of
conditions
C. Is commonly associated
with viral infection, most
typically by herpes simplex
or Epstein-Barr virus
D. Commonly develops
secondary to open globe
injury
TOPICS IN GLAUCOMA — ISSUE 11
EVALUATION:
1=Poor 2=Fair 3=Satisfactory 4=Good 5=Outstanding
11. Extent to which the activity met the identified:
Objective 1: 1 2 3 4 5
Objective 2: 1 2 3 4 5
Objective 3: 1 2 3 4 5
Objective 4: 1 2 3 4 5
12. Rate the overall effectiveness of how the activity:
Related to my practice: 1 2 3 4 5
Will influence how I practice: 1 2 3 4 5
Will help me improve patient care: 1 2 3 4 5
Stimulated my intellectual curiosity: 1 2 3 4 5
Overall quality of material: 1 2 3 4 5
Overall met my expectations: 1 2 3 4 5
1.A B C D
6.A B C D
2.A B C D
7.A B C D
3.A B C D
8.A B C D
14. If yes, please describe: __________________________
4.A B C D
9.A B C D
________________________________________________
5.A B C D
10.A B C D
15. How committed are you to making these changes?
12345
8 TOPICS IN GLAUCOMA
10. The condition iridocorneal
endothelial syndrome:
Avoided commercial bias/influence: 12345
13. Will the information presented cause you to make any
changes in your practice? Yes No
If you wish to receive credit for this activity, please fill in the
following information. Retain a copy­for your records.
PLEASE PRINT CLEARLY
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16.Are future activities on this topic important to you?
To
obtain
CME credit for this activity, go to http://cme.ufl.edu/ed/self-study/tig/
Yes No
HERNDON REFERENCES continued from page 7
2.Annadurai P, Vijay L. Management of secondary
angle closure glaucoma. J Current Glau Prac. 2014;
8(1):25­32.
3.SooHoo JR, Seibold LK, Kahook MY. Recent
advances in the management of neovascular
glaucoma. Semin Ophthalmol. 2013;28(3):165-72.
4.Simha A, Braganza A, Abraham L, Samuel P,
Lindsley K. Anti-vascular endothelial growth factor for neovascular glaucoma. Cochrane Database
of Systematic Reviews 2013, Issue 10. Art. No.:
CD007920. DOI: 10.1002/14651858.CD007920.
pub2.
5.Sung VCT, Barton K. Management of inflammatory glaucomas. Curr Opin Ophthalmol.
2004;15(2):136-40.
6. Francisco J. Muñoz-Negrete, Javier Moreno-Montañés, Paula Hernández-Martínez, and Gema Rebolleda, “Current Approach in the Diagnosis and
Management of Uveitic Glaucoma,” BioMed Research International, vol. 2015, Article ID 742792,
13 pages, 2015. doi:10.1155/2015/742792.
7.Gregory II AC, Zhang MM, Rapoport Y, Ling
JD, Kuchtey RW. Racial influences of uveitic
glaucoma: consolidation of current knowledge
of diagnosis and treatment. Semin Ophthalmol.
2016;31(4):400-04.
8. Shazly TA, Aljajeh M, Latina MA. Posner–Schlossman glaucomatocyclitic crisis. Semin Ophthalmol.
To obtain CME credit for this activity, go to http://cme.ufl.edu/ed/self-study/tig/
2011;26(4-5):282-4.
9.Chee SP, Jap A. Presumed Fuchs heterochromic
iridocyclitis and Posner-Schlossman syndrome:
comparison of cytomegalovirus-positive and negative eyes. Am J Ophthalmol. 2008;146(6):883-9.
10.Samant M, Medsinge A, Nischal KK. Pediatric
glaucoma: pharmacotherapeutic options. Pediatr
Drugs. 2016;18:209-19.
11.Coppens G, Stalmans I, Zeyen T, Casteels I. The
safety and efficacy of glaucoma medication in
the pediatric population. J Pediatr Ophthalmol
Strabismus. 2009;46(1):12-18.
12.Osman EA. Glaucoma after open globe injury.
Saudi J Ophthalmol. 2015;29:222-4.
TOPICS IN GLAUCOMA 9