AYes - Review of Ophthalmology

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Review of Ophthalmology Vol. XIX, No. 8 • August 2012 • Treatment Options for Retinal Vein Occlusion • DME Trials Report • Endophthalmitis & the Role of Antibiotics • EHR in the Glaucoma Clinic
ENDOPHTHALMITIS: THE EVOLVING ROLE OF ANTIBIOTICS P. 56 • MASTERING INTACS P. 66
A CLOSER LOOK AT THE LENSX LASER P. 16 • GLAUCOMA AND EHR: A CLINIC CASE HISTORY P. 62
WILLS RESIDENT CASE SERIES P. 82 • CATARACT SURGERY AND THE PATIENT WITH UVEITIS P. 70
August 2012 • revophth.com
DME: What the Trials Tell Us About Treatment P. 30
Managing the Retina ‘Epidemic’ P. 26
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REVIEW
NEWS
Volume XIX • No. 8 • August 2012
Chemical Temporarily Reverses
Blindness in Mouse Model
A team of University of California, Berkeley, scientists in collaboration with researchers at the University of Munich
and University of Washington in Seattle has discovered a chemical that temporarily restores some vision to blind
mice, and is working on an improved
compound that may someday allow
people with degenerative blindness to
see again.
The approach could eventually help
those with retinitis pigmentosa, as well
as age-related macular degeneration.
In both diseases, rods and cones die,
leaving the eye without functional
photoreceptors.
The chemical, called AAQ, acts
by making the remaining, normally
“blind” cells in the retina sensitive to
light, said lead researcher Richard
Kramer, UC Berkeley professor of
molecular and cell biology. AAQ is a
photoswitch that binds to protein ion
channels on the surface of retinal cells.
When switched on by light, AAQ alters
the flow of ions through the channels
and activates these neurons much the
way rods and cones are activated by
light.
“This is similar to the way local anesthetics work: They embed themselves
in ion channels and stick around for a
long time, so that you stay numb for
a long time,” Kramer said. “Our molecule is different in that it’s light sensitive, so you can turn it on and off and
turn on or off neural activity.”
Because the chemical eventually
wears off, it may offer a safer alternative to other experimental approaches
for restoring sight, such as gene or
stem cell therapies, which permanently change the retina. It is also less
invasive than implanting light-sensitive
chips in the eye.
“The advantage of this approach
is that it is a simple chemical, which
means that you can change the dosage, you can use it in combination with
other therapies, or you can discontinue
the therapy if you don’t like the results.
As improved chemicals become available, you could offer them to patients.
You can’t do that when you surgically
implant a chip or after you genetically
modify somebody,” Prof. Kramer said.
“This is a major advance in the field
of vision restoration,” said co-author
Russell Van Gelder, MD, an ophthalmologist and chair of the Department
of Ophthalmology at the University of
Washington, Seattle.
The blind mice in the experiment
had genetic mutations that made their
rods and cones die within months of
birth and inactivated other photopigments in the eye. After injecting very
small amounts of AAQ into the eyes of
the blind mice, Prof. Kramer and his
colleagues confirmed that they had
restored light sensitivity because the
mice’s pupils contracted in bright light,
and the mice showed light avoidance,
a typical rodent behavior impossible
without the animals being able to see
some light. Kramer is hoping to conduct more sophisticated vision tests in
rodents injected with the next generation of the compound.
“The photoswitch approach offers real hope to patients with retinal
degeneration,” Dr. Van Gelder said.
“We still need to show that these compounds are safe and will work in people
the way they work in mice, but these
results demonstrate that this class of
compound restores light sensitivity to
retinas blind from genetic disease.”
The current technologies being
evaluated for restoring sight to people whose rods and cones have died
include injection of stem cells to regenerate the rods and cones; “optogenetics,” or gene therapy to insert a
photoreceptor gene into blind neurons
to make them sensitive to light; and
installation of electronic prosthetic
devices, such as a small light-sensitive
retinal chip with electrodes that stimulate blind neurons. Several dozen
people already have retinal implants
and have had rudimentary, low vision
restored, Dr. Kramer said.
Eight years ago, Prof. Kramer and
Prof. Dirk Trauner, a former UC
Berkeley chemist now at the University of Munich, and their colleagues
developed an optogenetic technique
to chemically alter potassium ion
channels in blind neurons so that a
photoswitch could latch on. Potassium
channels normally open to turn a cell
off, but with the attached photoswitch,
they were opened when hit by ultraviolet light and closed when hit by green
light, thereby activating and deactivating the neurons.
Subsequently, Prof. Trauner synthesized AAQ (acrylamide-azobenzene-quaternary ammonium), a photoswitch that attaches to potassium
channels without the need to genetically modify the channel. Tests of this
4 | Review of Ophthalmology | August 2012
004_rp0812_news.indd 4
7/27/12 1:22 PM
compound and the current study are
reported in the July 26 edition of the
journal Neuron.
New versions of AAQ now being
tested are better, Prof. Kramer said.
They activate neurons for days rather
than hours using blue-green light of
moderate intensity, and these photoswitches naturally deactivate in darkness, so that a second color of light is
not needed to switch them off.
“This is what we are really excited
about,” he said.
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REVIEW
News
The iStent device is implanted in conjunction with cataract surgery and
placed ab interno into Schlemm’s canal
using an inserter and intraoperative
gonioscopy.
The iStent is designed to create a bypass through the trabecular meshwork
to Schlemm’s canal to improve aqueous outflow through the natural, physiologic pathway.
The IDE pivotal study for iStent
conducted by Glaukos was the first
prospective, randomized U.S. IDE
trial for a glaucoma device. The trial,
conducted at 27 sites, enrolled 239
subjects with mild to moderate openangle glaucoma and clinically significant cataract. Subjects were randomized 1:1 to either iStent in conjunction
with cataract surgery, or cataract surgery alone. The results showed that 68
percent of subjects in the iStent treatment group (combined cataract and
iStent implantation) met the primary
endpoint of IOP ≤21 mmHg with no
medications at 12 months, compared
to 50 percent of subjects in the cataract surgery only group. The treatment
difference in favor of the iStent group
on the primary endpoint at 12 months
was statistically (p=.004) and clinically
significant. Similar results were obtained on the secondary endpoint of
a ≥20-percent IOP reduction versus
baseline at 12 months with 64 percent
of the iStent group achieving this endpoint compared to 47 percent in the
cataract only group (p=.01).
Because iStent is implanted ab interno, the procedure is conjunctivasparing and blebless and preserves
future therapeutic and surgical options for glaucoma patients. Glaukos
has enrolled more than 4,000 patients
worldwide in clinical studies evaluating
iStent devices in open-angle glaucoma.
The most common adverse events
included early postoperative corneal
edema (8 percent), BCVA loss of ≥one
line at or after the three-month visit (7
percent), posterior capsular opacification (6 percent), stent obstruction (4
percent) early postoperative anterior
chamber cells (3 percent), and early
postop corneal abrasion (3 percent).
A Micro Option for
Ocular Injection
Microneedles may soon provide a better
way to administer injections to treat
diseases such as macular degeneration.
For the first time, researchers from the
Georgia Institute of Technology and
Emory University have demonstrated
that microneedles less than a millimeter in length can deliver drug molecules and particles to the eye in an animal model. The injection targeted the
suprachoroidal space of the eye, which
provides a natural passageway for drug
injected across sclera to flow along the
eye’s inner surface and subsequently
into the back of the eye. The minimally
invasive technique could represent a
significant improvement over conventional methods that inject drugs into
the center of the eye, or use eyedrops,
which have limited effectiveness in
treating many diseases. The study was
reported in the July issue of Investigative Ophthalmology & Visual Science.
“This research could lead to a simple
and safe procedure that offers doctors
a better way to target drugs to specific
locations in the eye,” said Samirkumar Patel, the paper’s first author and
a postdoctoral researcher at Georgia
Tech when the research was conducted. “The design and simplicity of the
microneedle device may make it more
likely to be used in the clinic as a way to
administer drug formulations into the
suprachoroidal space that surrounds
the eye.”
Mr. Patel, now director of research
for Clearside Biomedical, a startup
company formed to commercialize the
technology, said the study also showed
that the suprachoroidal space could accommodate a variety of drugs and microparticles. That could open the door
for the use of timed-release drugs that
could reduce the need for frequent injections to treat chronic eye diseases.
The study showed that injections of
fluids containing molecules and particles into the suprachoroidal space not
only reach the targeted structures, but
remain there for extended time periods. And equally important, the molecules and particles do not significantly
reach the anterior chamber, where
side effects from drugs can occur.
“The study showed that if we inject
non-degradable particles into the suprachoroidal space and wait as long as
two months, the particles remain,” said
Mark Prausnitz, a Regents professor
in Georgia Tech’s School of Chemical
and Biomolecular Engineering. “That
means there is no natural mechanism
to remove the particles from the eye.
Knowing this, we can design biodegradable particles with drugs encapsulated in them that can slowly release
those drugs over a period of time that
we could control.”
Henry Edelhauser, MD, a professor
of ophthalmology at Emory School of
Medicine, said new compounds that
pharmaceutical companies are developing to treat eye diseases will be most
effective if they can be delivered directly to the portion of the eye that requires treatment, such as the choroid
and retina that this delivery method
targets. “With this technique, we are
keeping the drug right where it needs
to be for most therapies of interest in
the back of the eye,” he said.
The stainless steel microneedles
used in the technique are less than a
millimeter long. The researchers believe that they will cause less trauma
to the eye than larger hypodermic needles, and reduce the risk of infection.
The compounds used in this study
fluoresced inside the eye, showing that
they had reached their targets, but the
compounds were not drugs. The next
step, says Dr. Edelhauser, will be to
study how well the microneedle technique can get real drugs to the eye
structures of interest.
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Symptomatic VMA
Understanding the Disease
Symptomatic vitreomacular adhesion (VMA)
is an increasingly recognized sight-threatening
disease of the vitreoretinal interface
1
VMA:
› Can cause traction resulting in anatomical damage,2
leading to symptoms such as metamorphopsia,
decreased visual acuity, or central visual field defect1,3-6
» Persistent adhesion can induce severe ocular
consequences, including macular hole1,2,6
For more information, visit:
www.SymptomaticVMA.com/ROPH
REFERENCES
1. Schneider EW, Johnson MW. Emerging nonsurgical methods for the treatment of vitreomacular adhesion: a review. Clin Ophthalmol.
2011;5:1151-1165. 2. Akiba J, Quiroz MA, Trempe CL. Detachment in idiopathic macular holes. Ophthalmol. 1990;97:1610-1613. 3. Jaffe NS.
Vitreous traction at the posterior pole of the fundus due to alterations in the vitreous posterior. Trans Am Acad Ophthalmol Otolaryngol.
1967;71(4):642-652. 4. Hikichi T, Yoshida, A, Trempe, CL. Course of vitreomacular traction syndrome. Am J Ophthalmol. 1995;119(1):55-61.
5. Smiddy WE, Michels RG, Glaser BM, deBustros S. Vitrectomy for macular traction caused by incomplete vitreous separation. Arch Ophthalmol.
1988;106(5):624-628. 6. Reese AB, Jones IS, Cooper WC. Macular changes secondary to vitreous traction. Trans Am Ophth Soc. 1966;64:123-134.
ThromboGenics, Inc. 101 Wood Avenue South, 6th Floor, Iselin, NJ 08830 - U.S.A. ©2012 ThromboGenics, Inc. All rights reserved. THROMBOGENICS
and the THROMBOGENICS logo are trademarks or registered trademarks of ThromboGenics NV in the United States, European Union, Japan,
and other countries.
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August 2012 • Volume XIX No. 8 | revophth.com
Cover Focus
26 |
Managing the Retina ‘Epidemic’
By Michelle Stephenson
With the increased use of anti-VEGF injections,
retina practices are finding ways to squeeze in
more patient encounters.
30 |
DME: What Trials Tell Us About Treatment
By Walter Bethke
Even though anti-VEGF agents appear to be
effective, surgeons would like a long-term
solution.
35 |
Treating RVO: Which Options Work Best?
By Christopher Kent
Three experienced surgeons share their
experience using anti-VEGF drugs, steroids and
lasers to treat this condition.
Cover image: Eric Kegley, CRA, COA
August 2012 | Revophth.com | 11
011_rp0812_toc.indd 11
7/27/12 1:23 PM
Departments
4|
Review News
15 |
Editor’s Page
16 |
Technology Update
How to Succeed with the LenSx Laser
20 |
Medicare Q&A
New Decisions Bring Continuing Changes
22 |
Financial Focus
Home Purchasing & Financing Strategies
52 |
Therapeutic Topics
Vasoconstrictors: Myths and Realities
56
70
56 |
Retinal Insider
Endophthalmitis: The Evolving
Role of Antibiotics
62 |
Glaucoma Management
Glaucoma and EHR:
A Clinic Case History
66 |
Refractive Surgery
Overcoming Surgical Challenges with Intacs
70 |
Cornea/Anterior Segment
Cataract Surgery in the
Patient with Uveitis
73 |
Research Review
76 |
Classified Ads
81 |
Advertising Index
82 |
Wills Eye Resident Case Series
82
011_rp0812_toc.indd 12
7/27/12 1:23 PM
Proof positive
for more eyes
Proven therapeutic utility in a variety of superficial ocular
infections—including blepharitis, conjunctivitis, and others
O
Profound activity against common gram-positive
pathogens—Streptococci, Staphylococci,1 and MRSA2,3
OA sensitivity and resistance profile that’s remained virtually
unchanged over time4
O
Unsurpassed safety profile—allergenicity and side
reactions are practically non-existent1
O
Convenient dosing—1-3 times daily1
OTier 1 co pay vs. leading brands5
O
Important Safety Information
Bacitracin ophthalmic ointment should not be used in
deep-seated ocular infections or in those that are likely
to become systemic.
This product should not be used in patients with a
history of hypersensitivity to Bacitracin.
BACITRACIN OPHTHALMIC
OINTMENT USP
Please see adjacent page for full prescribing information
www.ferapharma.com
References: 1. Bacitracin Ophthalmic Ointment [Package Insert]. Locust Valley, NY; Fera Pharmaceuticals, LLC;2009.
2. Kowalski RP, Karenchak LM, Romanowski EG. Infectious disease: changing antibiotic susceptibility. Ophthalmol Clin N Am
2003;16:1-9. 3. Freidlin J, Acharya N, Lietman TM, Cevallos V, Whitcher JP, Margolis TP. Spectrum of eye disease caused by
methicillin-resistant Staphylococcus aureus. Am J Ophthalmol 2007;144:313-315. 4. Recchia FM, Busbee BG, Pearlman RB,
Carvalho-Recchia CA, Ho AC. Changing trends in the microbiologic aspects of postcataract endophthalmitis. Arch Ophthalmol
2005;123:341-346. 5. http://fingertipformulary.com/drugs/Bacitracinopthalmicointment/
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Some Good Tips at
The Tipping Point
In the early 2000s, a book came along
that spouted a lot of what I found to
be unsubstantiated bunk about Hush
Puppies and other things. It rewarded
its author with fame and fortune
beyond any I’ll ever sniff, and it
popularized a term that has resurfaced
this week with a government news
report about EHR.
It seems, says a Centers for Disease
Control and Prevention study, we have
reached the “tipping point” in physician adoption of electronic health records. In 2011, 55 percent of physicians
reported having adopted an EHR, and
of those, 85 percent said they were either somewhat or very satisfied with
the technology. Roughly three-quarters of physicians using EHRs said
the software enhanced overall patient
care. And an almost equal percentage
would buy their EHR program again.
Even among the laggards, nearly half
have begun or will soon begin the transition from paper records.
Out in the real world, many practices are still struggling with implementation, if not mastery, of their EHR
systems. We’re fortunate to have a
real-world report this month from
Dr. Michael Boland, who’s director
of IT at Wilmer Eye Institute, and his
colleague, Ravi R. Pandit. They were
wise enough to record the experience
of turning the EHR transition at their
glaucoma clinic into a formal study,
and generous enough to share some
of the lessons they learned with us.
You can find that enlightening report
on p. 62.
Another worthwhile resource,
though in the patient-care end rather
than the technical end of EHR implementation, appeared this month in
the American Medical Association’s
news publication. An article there
describes the Kaiser Permanentedesigned LEVEL system of doctorpatient interaction in the EHR setting. (See the link below for the full
report). To paraphrase LEVEL:
L: Let the patient look on; share
things on the computer screen with
the patient.
E: Eye contact. Maintain a normal
level and avoid a total focus on the
screen.
V: Value the computer. Take advantage of opportunities to point out
a benefit of the system to the patient.
And the reverse—avoid the temptation to vent frustration when things
aren’t going smoothly.
E: Explain what you’re doing. Talk
through each step.
L: Log off. Logging off while the
patient is still in the exam room enhances confidence about security.
For much of the past decade, the
only EHR-related tipping that most
physicians wanted to do involved tipping the computer over and getting
back to the business of treating patients. There’s still a ways to go, but
let’s hope the CDC is right.
http://www.ama-assn.org/amednews/2012/07/23/
bica0723.htm
015_rp0812_edit.indd 15
7/27/12 12:48 PM
REVIEW
Technology Update
Edited by Michael Colvard, MD, and Steven Charles, MD
How to Succeed with
The LenSx Laser
Though the femtosecond laser automates several steps of
surgery, it’s not foolproof. Here’s how to avoid complications.
Michael George, MD, and Ming Wang, MD, PhD, Nashville, Tenn.
he femtosecond laser offers many
possibilities for improving cataract
surgery. However, as with any new
technology, there is a learning curve.
Last year, our center became the first
in our state to purchase the LenSx laser for cataract surgery, and we now
perform most of our cases with it. In
this article, we’d like to share the pearls
that we’ve developed after working
with the device now that we have a
year’s worth of cases under our belt.
T
Preoperative Planning
As with conventional surgery, where
you end up depends a lot on where
you begin.
• Determine the astigmatism
treatment plan. Femtosecond laser
astigmatic keratotomy has shown more
precision in astigmatic correction than
manual limbal relaxing incisions and,
as a result, it’s more important to make
sure that surgically induced astigmatism is properly taken into account. We
use the LRI calculator and input the
corneal cylinder (composed of a summarized vector from measurements
made with IOLMaster, Atlas and Pentacam) and the surgically induced cyl-
inder, and arrive at the LAK treatment
plan which we put into the LenSx. In
cases where a secondary incision is
located in the same meridian as one
of the LAK cuts, we either rotate the
secondary incision to another position
or convert a two-cut LAK into a onecut by lengthening its arcuate length,
as long as the astigmatic treatment isn’t
very high.
• Capsulotomy and lens fragmentation pattern planning.
Though the laser produces more consistent capsulotomy sizes and locations
than a manual technique, laser capsulotomy presents some new challenges:
more difficulty in capsulotomy edge visualization; the occasional incomplete
capsulotomy cut and the risk of tags or
radial extension.
As surgeons trained in performing
manual capsulorhexes, we’re used to a
good light reflex and clear visualization
of capsulotomy edges. Such clear visualization may no longer be there with a
laser, due to multi-intralenticular cuts/
planes and the occasional stirred up
cortical material.
We make our capsulotomy diameter
at least 5.25 mm in order to achieve the
optimal width of overlap with most of
016_rp0812_tech update.indd 16
the intraocular lenses that we use (with
the exception of Crystalens, for which
we keep the size of capsulotomy at 4.8
mm). We intentionally keep the diameter of the cylindrical lens cut small at
3 mm, in order to avoid it being too
close to the capsulotomy edge, which
could interfere with visualization of
the edge and increase the risk of inappropriate pulling of tags and creating a
radial extension.
We also use a cross-hair lens fragmentation pattern and keep its length
at 5 mm, which is less than the size of
the capsulorhexis, just in case the lens
is tilted or the eye moves during the
cut and causes the cross-hair lens fragmentation cut to be too superficial and
cut the anterior lens capsule.
With the current generation of
femtosecond lasers built for cataract
surgery, in spite of the optimal laser
setting, tags on the edge of the capsulotomy are still present in about half of
the cases. We will discuss methods to
manage these tags in the section below
dealing with manual maneuvers.
LenSx Operation
Once the preparations have been
This article has no commercial sponsorship.
7/24/12 2:47 PM
made, we proceed with the LenSx
procedure. Here are tips for helping
it go smoothly.
• Docking. LenSx docking is a
more difficult process than docking
the Intralase. This is because there
are actually two separate mechanical
tasks that need to be accomplished in
docking: immobilization of the globe
and contact lens applanation to the
cornea. With Intralase for LASIK, a
suction ring is used to achieve the immobilization, while an applanation cylinder then goes inside of that ring to
achieve the second task, applanation
of the cornea. With LenSx, however,
a single docking device has to simultaneously achieve these two different
and independent mechanical tasks,
making docking somewhat more challenging. While the LenSx cone is being
docked, the globe underneath it can
torque (since there is nothing to fixate it apart from the docking device)
and the docking can fail. To combat
this, we have found the following techniques useful:
Having the cone sitting on top of the
edge of the eyelid is one of the more
common causes of docking failure with
the LenSx device. To help avoid this,
ask the patient to put his chin down.
This is a change from holding it up as
our patients are asked to do in other
eye surgeries. As the laser operator,
it’s usually easy to see if the cone hits
the edge of the upper lid, but it’s more
difficult to tell when it hits the edge of
the lower lid. Holding the chin down
helps with this. Next, gently proptose
the globe forward by pushing down on
the lid speculum. This is a maneuver
we picked up from Houston surgeon
Steve Slade.
Finally, since the applanation pressure is low and the patient can still
see for most of the docking process,
ask the patient to keep looking at the
center of the apparatus’ white circle.
You can also visualize the shadow of
the pupil long before contact, to help
continue to guide the patient’s gaze.
When planning the lens fragmentation, watch for tilt in the crystalline lens, which can
result in an uneven epinuclear layer of variable thickness. This unevenness increases the
risk of a posterior capsular rent and other complications.
The process of a good docking can be
monitored by looking at the right side
of the screen where one can see the
cornea rise up in height. Ideally, the
cornea should be horizontally flat with
a minimal amount of curve. Also, when
docking approaches the point at which
one needs to engage suction, the distance between corneal epithelium and
the top edge of the screen should be
uniformly reduced.
• The primary and secondary
incisions. The laser tends to cut a bit
more centrally than expected. Because
of this, we let the outer edge of the
incision override the limbus line rather
than fit inside of it whenever possible.
We’ve learned that if the incision is
too far inside the limbus, not only will
it create more regular and irregular
astigmatism, the angle of incision may
end up being too vertical to the corneal
plane, resulting in difficulty with the
wound self-sealing.
• Vertical height of the anterior
and posterior lens cut. We leave
about 500 µm (or more) in the thick-
ness of the anterior uncut layer to
minimize the number of gas bubbles
that escape from the lens into the anterior chamber during the process of
capsulotomy. These bubbles can block
subsequent laser shots and result in an
incomplete capsulotomy cut. For the
posterior lamellar cut, we also leave at
least 500 µm in order to reduce the risk
of perforating the posterior capsule.
Due to the order in which we cut the
lens, the gas bubbles are chased posteriorly and aggregate behind the lens
and in front of the posterior capsule.
It’s important to keep in mind that total
gas volume is proportional to the total
number of lens cuts, and too large of
a volume of gas accumulation behind
the lens can not only obscure the visualization of the anterior capsular edge
and increase the difficulty in completing the capsulotomy, it can also, in rare
cases, blow open the posterior capsule,
as has been reported by others.
• Gas bubbles in the anterior
chamber during capsulotomy.
Sometimes, despite perfect docking,
7/24/12 2:47 PM
REVIEW
Technology
Update
the initial laser pulses intended for the
capsulotomy end up in the anterior
chamber rather than on the anterior
capsule, creating bubbles in the chamber. If this occurs in the beginning of
capsulotomy, one should immediately
stop the machine, re-dock and start
again. If the vacuum is broken at any
point after the initial few seconds of the
capsulotomy process, one should never
re-attempt the capsulotomy, since the
cut won’t be in the same place as the
initial attempt and there’s a risk of multiple cut circles in the anterior lens
capsule that will increase the risk of
capsular break in the lens extraction
stage. If the vacuum breaks during
capsulotomy, there are two options:
abort the LenSx portion altogether or
restart the laser but bypass the capsulotomy program.
After the LenSx portion of the surgery, the patient can walk to the OR
without a problem as long as the next
part of the surgery begins immediately
(within five minutes). A longer break
will result in pupillary constriction
and iris floppiness due to the liberation of lens material in the anterior
chamber and the inflammatory reaction that this causes.
The Manual Aspects of Surgery
Though the size and location of the
capsulotomy are much more predictable and consistent than with a manual technique, the completion of a laser
capsulotomy is in fact more difficult
than a manual one, because the visualization of the capsulotomy edge is
poorer due to the visual interference
from cut lens planes, stirred up cortex
and the gas bubbles behind the lens.
We experimented with various
techniques of detaching and lifting
the capsulotomy circle from the edge
and found that the Sinskey hook is
best. The goal of this step is to indent the capsule centrally, to create
a radial line, gently detach the capsule circle from its circumference and
Early escape of gas in one quadrant can
block laser shots there, resulting in an
incomplete capsulorhexis in that area.
then drag the capsule centrally, under
Viscoat, without disturbing too much
cortex material. Instead of a Sinskey
hook, one can use a cannula filled with
Viscoat in a technique described by
Houston’s Dr. Slade.
In terms of where to start the centralization of the capsulotomy, starting
proximally is the best approach. This
is because cortex is stirred up as we go
along, and the proximal edge of capsulotomy is the most easily obscured and
the hardest area to reach with forceps
if it becomes necessary to do so later.
If pulling in centrally on the capsulotomy cap doesn’t work (as in the event
of a sizable uncut tag), we then use
Utrata forceps to perform a concentric
tear. As such, it’s critically important
to make sure the track of manual tear
stays as close to the laser track as possible. In cases where the laser-uncut
area is too long, direct indentation using a Sinskey hook has an increased
chance of causing a radial tear. In these
instances, we’ll use forceps to perform
a lift and peel.
After hydrodissection, an in-thebag technique such as that used by
Dr. Slade involves the aspiration of
the central cylinder core of the lens
with the phaco needle, followed by
chopping the lens into quadrants using the phaco tip and a chopper. For
this part of the procedure, we’ve de-
veloped a phaco-free technique that
involves first floating the lens into the
anterior chamber after the lens has
been pre-chopped by the laser (the
whole lens is still in one piece as it is
enveloped inside an eggshell of epinucleus) and then mechanically cracking
the laser-prechopped lens into small
pieces and vacuuming the pieces out
using a high vacuum setting and a
large-bore phaco tip, without the use
of any phaco energy.
It’s evident that femtosecond lasers such as the LenSx offer amazing new capabilities, including more
consistent capsulotomies, reduced
phaco energy (or in the case of our
phaco-free technique, no energy at
all) and hence less corneal edema
and less risk of breaking the capsular bag. They also create excellent
overlap of the capsulotomy with the
edge of the IOL for a more predictable effective lens position and final
refractive outcome.
Doing femtosecond cataract surgery
is similar to working with the first- or
second-generation phaco machines,
and though the early versions of the
phaco technology presented challenges, the later versions were much improved. Similarly, we feel that we are
just at the tip of iceberg of this technology’s potential. To us, femtosecond
cataract surgery is the digital upgrade
from manual—analog—surgery, and it
will prove superior to its predecessor in
every respect. The future of femtosecond cataract surgery is limited only by
our imagination.
Dr. George is a corneal specialist
in practice in Nashville and a former
cornea fellow of Wang Vision at the
University of Tennessee. Dr. Wang is a
clinical associate professor of ophthalmology at the University of Tennessee,
director of Wang Vision Cataract &
LASIK Center in Nashville and international president of Shanghai Aier
Eye Hospital. He can be reached at
[email protected].
7/24/12 2:48 PM
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RP0812_Keeler King.indd 1
7/17/12 2:41 PM
REVIEW
Medicare Q&A
Donna McCune, CCS-P, COE
New Decisions Bring
Continuing Changes
This mid-year update covers a variety of changes from DHHS
and CMS that may affect your billing and your practice.
Q
Were changes made to the
Medicare Physician Fee
Schedule after the president
signed the extension to the
Middle Class Tax Relief and
Job Creation Act of 2011,
postponing the planned cuts to
physician reimbursement?
A
Yes. Ophthalmologists
may find a reduction in their
reimbursement
on specific imaging services due
to the “imaging
cap.” The affected
imaging services
in ophthalmology are: indocyanine-green
angiography
(92240), fundus photos
(92250)
and endothelial cell
count photography
(92286). If the physician reimbursement
for the technical component of the service
calculates higher than the
outpatient facility rate, the
physician reimbursement is reduced
to the outpatient value. The interpretation reimbursement (modifier 26) is
not affected.
Q
Is Medicare reimbursing
bandage contact lenses
with the code 92071 for the
fitting of the lens and 99070 for
the supply?
A
No. Despite the direction in
the 2012 Current Procedural
Terminology manual to bill separately for the supply, Medicare
considers CPT code 99070 to be
a bundled code and not reimbursed in addition to the procedure code.
Q
Were changes made
to CPT code 92072
for fitting a contact lens for
keratoconus?
Yes; in April, the Centers
for Medicare & Medicaid
announced that the indicator
published in January was
incorrect and changed it
from a unilateral indicator
to a bilateral indictor. The
change was retroactive to January 1, 2012.
020_rp0812_mqa.indd 20
A
Q
Did the new drug
aflibercept (Eylea) receive
its own unique Healthcare
Common Procedure Coding
System code for physician
billing?
A
Yes, in a recent public notice,
CMS noted that a new HCPCS
code, Q2046, is in effect. In Transmittal 2450 to Medicare Administrative
Contractors (MACs), and MM7854 for
providers and other suppliers, Q2046
is described as “Injection, Aflibercept,
1 mg.” The new HCPCS code was effective on July 1, 2012. Q2046 is specifically described as “1 mg”; the usual
aflibercept dose per eye is 2 mg. Use “2
units” on your claims after July 1, 2012.
The old C9291 code and associated units remain in effect for dates
of service through June 30, 2012,
after which it will be deleted from
hospital outpatient department and
Ambulatory Surgical Center payment
systems. For physician claims, some
MACs may prefer that another code
for the supply of aflibercept be used
instead of Q2046; be sure to check
before filing claims.
Q
Are there any other new
codes of interest to
ophthalmologists?
7/24/12 2:59 PM
A
Yes, there are. HCPCS code
S0596, phakic intraocular lens
for correction of refractive error, was
introduced effective April 1, 2012.
No relative value units were assigned.
This is a refractive procedure, not
covered by Medicare and rarely covered by other third-party payers.
Q
A
Table 1. Surgical Procedures Per Category of Interest
Organ System
Procedure Category
Surgical Procedure Codes
Eye
Organ transplant (eye)
65756, V2785
Laser procedure of eye
65855, 66761, 66821
Glaucoma procedures
66170, 66180
Injection of eye
67028, J2778, J3300, J3396
Will ICD-10 be
implemented on
October 1, 2013?
No. In April 2012, the Department of Health and Human
Services announced a proposed rule
delaying compliance for ICD-10
to October 1, 2014. The proposed
rule was open for public comment
through mid-June with an expected
announcement of a delay to be published late this summer.
Q
Is the Recovery
Audit Contractor
program continuing to find
overpayments?
A
Yes. A recent report indicated
that in FY 2010 (October 2009
to September 2010), the RAC program collected $75.4 million in overpayments. In FY 2011, collections
were $797.4 million. The last quarter
of 2011 yielded $397.8 million; this
brings the program total to $1.27 billion as of December 31, 2011.
Q
Is CMS continuing to make
bonus payments under
the PQRS and eRx bonus
programs?
A
Yes. Payments for successful
participation in 2011 should be
made late summer or early fall.
Q
When will it be necessary
to meet the Stage 2
meaningful use requirements
for the Health Information
Technology bonus program?
Retina, macular and posterior segment 67041, 67042, 67210, 67228
procedures
Repair of surrounding eye structures
67900, 67904, 67917, 67924
Skin
Skin procedures
Repair of surrounding eye structures
A
In February 2012, the proposed
Stage 2 requirements were
released. CMS pushed back the
start date for Stage 2 compliance to
January 1, 2014.
Q
Did CMS finalize
the Quality Measure
specifications for ambulatory
surgery centers?
A
Yes. HCPCS Level II G codes
have been assigned to the five
quality measures that ASCs must
report. A detailed discussion of the
codes can be found in the CMS ASC
Quality Measures Specifications
Manual dated April 2012.
Q
A
When are ASCs required
to begin reporting these
measures?
ASCs must report these measures beginning October 1, 2012;
however, they may report them on
claims after April 1, 2012.
Q
Are there additional
quality measures for ASCs
beyond the five assigned Level
II G codes?
11042, 13132, 14040, 14060,
15260, Q4101, Q4102, Q4106
15823
A
Yes. Two additional measures exist. They are:
• ASC – 6: Safe surgery checklist
use 2012;
• ASC – 7: 2012 Volume of Certain
Procedures.
The safe surgery checklist use will
be reported through a Web-based
tool on the QualityNet website
(qualitynet.org). ASCs must report
the use of the safe surgery checklist as
a “yes” or “no” in 2012, following the
implementation schedule.
Q
What procedures should
be “counted” for reporting
quality measure number
seven?
A
ASCs will collect and report the
aggregate count of surgical procedures per category for January 1
to December 31, 2012. In ophthalmology, there are eight categories of
interest that will be reported through
a Web-based tool on the QualityNet
site. Please see Table 1 for the detailed list.
Ms. McCune is vice president of the
Corcoran Consulting Group. Contact
her at [email protected].
020_rp0812_mqa.indd 21
7/25/12 10:14 AM
REVIEW
Financial Focus
Edited by Jon C. Ylinen
Home Purchasing and
Financing Strategies
Our financial planning for physicians series continues with a look
at issues to consider when buying a home.
Jon C. Ylinen, Madison, Wis.
ypically the biggest purchase
any of us will make in our lives is
the home that we live in while we are
in the heart of our careers. Too often
though, I see people making some
critical errors in their home purchasing and financing strategies that can
damage their lifetime net worth.
T
Striking a Balance
There is a difference between how
much debt you can afford and how
much you should take on. I have
seen many folks make the mistake
of thinking they can afford to purchase a property for the amount
the bank approves them for. As
a physician, you must look at
home purchases as a piece of
your overall financial strategy. When you compile all of your
financial goals (retirement, kids’
college education, potential vehicles and recreational toys, saving
for a rainy day, etc.), you may find
that what size mortgage fits into
your overall strategy—after Uncle
Sam takes his cut—is not as large
as the bank may approve. We have
found that, from a comprehensive
financial preparation perspective,
most physicians can comfortably afford resident real estate purchases
that total two to three times their
gross income. If the home of your
dreams is more than this general
guideline, it may still be reasonable
to purchase as long as you accept the
fact that you may have to work a few
years into traditional retirement, may
not be able to fund as much college
for your children as you may have
022_rp0812_financialf.indd 22
hoped, or may not be able to have all
the extras in life that you might have
hoped for. On the flip side, if your
property is financed for less than two
times your gross wages, all the items
mentioned above may come more
quickly than anticipated.
Financing and Low Interest Rates
Considering that it is usually a longterm decision to settle into a sizeable
residence, it’s best to take a historical
and long-term perspective on home
financing. With depressed real estate
in most areas of the country and the
historically low interest rates that
are available to us at present, it is
a great time to be a buyer. Physicians need to realize that
locking into long-term fixed
rates below 4 percent is an
anomaly that we may never see
again in our lifetimes. Freddie Mac
rates topped off around 18.45 percent in October of 1981. More recently, 30-year fixed rates had been
locked in during the early 2000s at
above 8 percent. We must not lose
sight of the fact that we are all being
presented with an opportunity to fi-
7/25/12 3:41 PM
:64,:<9-(*,:(9,>69;/796;,*;05.
THE OCULAR SURFACE IS ONE.
© 2012 Novartis
2/12
SYS11179JAD
:\YMHJL7YV[LJ[PVUHUK4VYL
References
1. Christensen MT, Blackie CA, Korb DR, et al. An evaluation of the performance of a novel lubricant eye drop. Poster D692 presented at: The Association for Research in Vision and Ophthalmology Annual Meeting; May 2-6,
2010; Fort Lauderdale, FL. 2. Lane S, Paugh JR, Webb JR, Christensen MT. An evaluation of the in vivo retention time of a novel artificial tear as compared to a placebo control. Poster D923 presented at: The Association for
Research in Vision and Ophthalmology Annual Meeting; May 3-7, 2009; Fort Lauderdale, FL. 3. Davitt WF, Bloomenstein M, Christensen M, et al. Efficacy in patients with dry eye after treatment with a new lubricant eye drop
formulation. J Ocul Pharmacol Ther. 2010;26(4):347-353. 4. Alejandro A. Efficacy of a Novel Lubricant Eye Drops in Reducing Squamous Metaplasia in Dry Eye Subjects. Presented at the 29th Pan-American Congress of
Ophthalmology in Buenos Aires, Argentina, July 7-9, 2011. 5. Wojtowica JC., et al. Pilot, Prospective, Randomized, Double-masked, Placebo-controlled Clinical Trial of an Omega-3 Supplement for Dry Eye. Cornea 2011:30(3)
308-314. 6. Geerling G., et al. The International Workshop on Meibomian Gland Dysfunction: Report of the Subcommittee on Management and Treatment of Meibomian Gland Dysfunction. IOVS 2011:52(4).
RCCL0612_Alcon Systane.indd 1
5/24/12 2:08 PM
REVIEW
Financial
Focus
nance our homes (whether for the first
time or re-financing) at interest levels
close to the rate of inflation. (For more
informatiom on this, visit.)
Which Type of Mortgage
I am often asked at our educational lectures and by physicians in
our own client base which home
financing option is the right one. It
is important to point out that financial advisors do not provide specific
mortgage advice, and obviously you
need to consult a mortgage professional for advice pertaining to your
specific situation. Generally, however, the first determining factor is
how long you think you will be in
that home.
If you anticipate that you will be in
the house for a certain period (less
than 15 years) it may be a reasonable option to consider obtaining a
mortgage that is locked in for roughly two years beyond that time frame.
For example, if you know you will be
moving to start your own practice in
five years, you may want to consider
a 7/1 ARM. This a hybrid mortgage
that combines features from an adjustable rate mortgage and a fixed
mortgage; in this case, there’s a fixed
rate for the first seven years and a
rate that changes once each year for
the remaining life of the loan. Note
that an ARM will generally result
in lower monthly payments than
a fixed mortgage during the term
that is locked in; however, the loan
holder accepts the risk of changing
interest rates after that term. If rates
move upward significantly after the
term, your interest payments could
increase significantly.
However, if there is a reasonable
chance that you may not sell your
residence for 15 years or more, you
may consider locking into a longerterm, fixed solution.
A huge, often-overlooked variable
is that interest payments on a mort-
Doctor Mortgage Programs
... lenders recognize
that most new doctors
can easily afford to
pay their mortgage ...
but traditional loan
qualification programs
would prohibit them
due to high debt-toincome ratios.
gage are deductible on your taxes,
in many cases, until you hit the IRS
phase-out range (See an accountant
for specific advice on your situation).
So you need to plan based on the net
cost of borrowing. (For example, if
you are in a 25-percent tax bracket
and your fixed interest rate is at 4
percent, your true net cost of borrowing against your net worth is 3
percent, because at the end of the
year you are able to count all the
interest you paid when you itemize
your deductions, up to a mortgage of
$1 million—even if you are like many
physicians who are forced to pay under the Alternative Minimum Tax.)
There is no question that you will
pay far more interest on your home
financing when stretching it over a
30-year vs. a 15-year fixed period, but
this is a one-dimensional argument.
If you are able to out-invest the net
cost of your mortgage interest over
the term of your loan, you could potentially create a larger overall net
worth if you simply take any money
that you would have put towards accelerating the mortgage and put it
into an investment that may out grow
the cost of borrowing over the long
term. When analyzing this decision,
pay careful attention to your assumptions, which are not guaranteed. Investments will fluctuate.
There are a handful of mortgage
financing programs that are only
available to physicians. These programs originated because lenders
recognize the fact that most new
doctors can easily afford to pay their
mortgages after medical school (and
certainly when out of their residencies and fellowships) but traditional
loan qualification programs would
prohibit them due to high debt-toincome ratios.
One factor that makes these financing options so attractive is that
they waive private mortgage insurance, which I believe is one of the
largest wastes of money for a physician. These programs also allow
you to retain the mortgage with
sometimes as little as 0 to 5 percent
down. The waiver of PMI and the
opportunity to put little amounts
down usually come with the stipulation that you have a credit rating of
roughly 720 or higher. I would suggest that whatever loan you are looking into, it should be one that waives
PMI and offers the chance to put
low amounts down at closing.
Mr. Ylinen is a financial advisor
with North Star Resource Group. He
co-authored the book Real Life Financial Planning for Physicians. He
maintains a national comprehensive
financial planning practice that caters
almost exclusively to physicians. The
information provided in this article
is general in nature and is not intended to be specific recommendations.
Please consult a financial professional
for specific advice in relation to your
individual circumstances.
For information on this topic
or any other financial matter,
direct your inquiries to his website,
askjonylinen.com.
022_rp0812_financialf.indd 24
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7/12/12 3:14 PM
REVIEW
Cover Focus
Retinal Disease
Managing the
Retina ‘Epidemic’
Michelle Stephenson, Contributing Editor
With the increased
use of anti-VEGF
injections, retina
practices are
finding ways
to squeeze in
more patient
encounters.
T
hree factors are fueling what
some specialists are calling a
potential retina epidemic: the
increased use of anti-VEGF treatments, the aging population and the
increased incidence of obesity. With
all three expected to rise for the foreseeable future, the result is that retina
specialists need to see more patients
more often.
The Makings of an Epidemic
Anti-VEGF therapy is used for
several retinal conditions, and many
patients require frequent injections.
“One of the major prevalent diseases for retina-related evaluations
has been age-related macular degeneration,” says Timothy G. Murray,
MD, from the Bascom Palmer Eye
Institute in Miami. “Traditionally,
we’ve had very few treatment options
available for AMD, particularly for
patients with wet AMD. The introduction of anti-VEGF treatments has
pivotally changed our practices, because this whole group of patients
who existed but had no care options
now have moved into a treatable disease profile.”
Before the introduction of antiVEGF therapy, these patients may
have only been seen in the office once
a year. Now, they may be seen as often
026_rp0812_f1.indd 26
as monthly. “So, your practice volume in terms of the clinical impact
increased 12-fold,” Dr. Murray says.
That heralds what we are going to
potentially see going forward with
other diseases, such as proliferative
and nonproliferative diabetic retinopathy. For these conditions, we often
would treat once, and then we would
assess response to treatment in two to
four months. In many practices, that
response to treatment was assessed
in four months. When those diseases became amenable to anti-VEGF
therapy, where the clinical trials have
focused on a one-month interval to
treatment, patients whom you may
have been seeing twice a year or three
times a year are now seen 12 times a
year. As you rule conditions into treatment regimens that require active
intervention at short intervals, even
without changing the incidence or
prevalence of the disease, you greatly
change its impact on the retina practice.”
John Thompson, MD, a retina specialist practicing in Towson, Maryland, agrees. “Retina specialists have
become very busy during the past six
years with the availability of the antiVEGF drugs Lucentis and Avastin.
We thought we could give these treatments monthly for a while, and then
less often, and then stop, but it has
7/27/12 11:37 AM
John Thompson, MD
become increasingly apparhave appreciated in retina in
ent that these treatments for
particular is that we are able
macular degeneration have
to do that.”
to be given in most patients
In Dr. Murray’s practice, a
for a long time, often monthcertified ophthalmic technily or every other month.”
cian does the prescreening.
Central retinal vein ocThis technician tests vision,
clusion and branch retinal
refraction and intraocular
vein occlusion can also be
pressure and takes the inieffectively treated with antitial patient history. The
VEGF therapy. “All of these
technician also dilates the
conditions are incredibly
eye. Dr. Murray notes that
prevalent,” Dr. Murray says.
his practice provides ancilMany of these conditions
lary testing. “At most retina
are age-related, so the epipractices now, that includes
demic is just beginning. As
photographic and OCT
the baby boom generation Figure 1. Fluorescein angiogram of a subfoveal choroidal
documentation of the retibecomes older and life ex- neovascular membrane in a patient with macular degeneration.
na, which is performed by
pectancy is extended, more
a technician,” he says. “Adpatients will require treatment.
have to travel a long distance. There ditional testing like ultrasonography
Additionally, the population is hasn’t been a lot of interest on the part is performed by another technician
changing its environmental and life of general ophthalmologists for doing at most large practices. This allows
exposures. “As people become pro- these injections.”
retina specialists to be able to evaluate
gressively more obese, which we have
Some retina specialists have had patients thoroughly and rapidly.” For
seen over the past several decades, we to enlarge or reconfigure their office added efficiency, his practice has stanbecome at risk for diseases associated facilities. “They have had to increase dardized documentation for imaging.
with that, which includes obesity-re- the number of examination rooms to
The practice has also had to add
lated hypertension, diabetes, and car- allow them to handle more patients, space to accommodate the increasing
diovascular disease, all of which have and many practices have had to hire patient load. “This can be quite exa huge impact on a retinal practice,” additional staff to accommodate the pensive, because it requires that you
Dr. Murray explains.
patient flow,” Dr. Thompson adds.
have more lanes to practice in than
Dr. Murray agrees. “The volume you’ve had previously,” he explains.
of patients that each individual retina “In the past, some smaller offices may
Preparing Your Practice
specialist sees in a day has significantly not have had a technician, and the
To accommodate seeing more increased,” he says. “At an individual physician has done the entire exam.
patients more often, retina special- practitioner level, the way that you That was a wonderful interaction with
ists will need to become more effi- address this is to see more patients your patient but incredibly inefficient
cient and possibly add more space to during a day and to have more pa- for the physician. In my office, I have
their practices. “Doctors will need to tient-days per week. You can see more three technicians who have their own
streamline their operations to try to patients on a single day or you can add office lanes that are fully equipped for
make themselves more efficient and another patient day. When you add complete patient evaluation. The flow
to use technicians to do some of the patients to a day, how do you do that? goes from the technician to the phoother work that doesn’t require a phy- One way to do that is to add clinical tographer for imaging, to the echogsician,” Dr. Thompson says. “The ini- hours to the day. Another option is rapher and then comes back into a
tial response of most retinal specialists that the doctor works more efficiently separate room for me.”
He continuously goes from room
has been to use paraprofessionals in so that he is able to see more patients
our offices to help us to see patients per hour. The key for all of us is to to room seeing patients. “You have to
more efficiently. I am not aware of any understand that the thing we are most become very good at rapidly assimilatgeneral ophthalmologists doing anti- focused on is providing outstanding ing the complexity of data now availVEGF injections. However, this may clinical care. How do you provide care able to you, and you have to be very
be an option for patients in areas with- to a larger number of patients without good about establishing good rapport
out a retinal specialist so they wouldn’t compromising that care? What we with your patients very quickly,” says
026_rp0812_f1.indd 27
7/27/12 11:37 AM
REVIEW
Cover
Focus
Retinal Disease
Peter Westenskow, PhD, Martin Friedlander, MD, PhD
Dr. Murray. “You need to be able to
make a quick diagnosis and institute
a treatment plan. We are seeing 70
patients in a day. Because we do so
many intravitreal injections, 35 to 40
in a clinic day, I have two injection
rooms that are separate and staffed
by two nurses. So, we have three
rooms for techs, three rooms for
the doctor, two rooms for injections,
two rooms for photography and two
rooms for ultrasound. My singlephysician practice has now become
huge, and the costs of providing this
space, these services, personnel and
the equipment are high.”
Unfortunately, the revenues for
injections and imaging are not high.
Dr. Murray and his colleagues recently published an evaluation of
economic efficiencies in clinical
retina practice. 1 In this study, activity-based costing analyses were
performed at two different types of
retinal practices in the United States.
One practice was a small, single-specialty group practice, and the other
was Bascom Palmer Eye Institute, an
academic, hospital-based practice.
The study found that the small practice outperformed the larger practice
on almost all markers of efficiency.
At Bascom Palmer, only four service
lines were profitable: nonlaser surgery, laser surgery, non-OCT diagnostics and injections. Profit margins
ranged from 62 percent for nonlaser
surgery to 1 percent for intravitreal
injections. Office visits and OCT imaging were associated with the largest negative profit margins.
The financial burden can be huge.
“The cost of Lucentis for a year, given every four to six weeks, is substantial and runs in the tens of thousands
of dollars,” says Martin Friedlander,
MD, PhD, chief of the Retina Service in the Division of Ophthalmology at the Scripps Clinic in La Jolla,
Calif. “As the population ages and
the number of individuals with AMD
increases, that number will increase
Figure 2. Optical coherence tomography reveals that the injection of iPS-RPE (retinal
pigment epithelium derived from human induced pluripotent stem cells) in rats with
spontaneous RPE-mediated inherited photoreceptor degeneration prevents retinal
degeneration. A) Multiple b-scans across the region of the retina in which iPS-RPE were
injected in the subretinal space were combined to generate a 3D image. The arrow points
to the injected region. Note the increased thickness of the retina on the right side (iPS-RPE
injected) compared with the left side (uninjected region). B) The retinal thickness values
can be obtained from single b-scans. The blue lines mark the region measured (from the
RPE to the surface of the retina) and the thickness value in µm is displayed above the line.
by millions. We need to find alternative ways of delivering the drugs
that will decrease the frequency of
dosing or we need to find more costeffective treatments.”
The Future
Alternative treatments for these
conditions are currently under investigation. “Combination therapies
(which are more effective and last
longer), sustained-release drug delivery devices (like nanoparticles or
encapsulation cell-based therapies),
or treatments that target novel angiogenic/vascular permeability pathways would go a long way in helping
out,” Dr. Friedlander notes.
Dr. Thompson adds that Eylea,
which was recently approved by the
FDA, is also indicated for the treatment of wet AMD. “However, for
the next two years, there is nothing
new about to be approved for wet
macular degeneration, but there are
some trials looking at dry macular
degeneration,” he says. “Researchers are looking to find longer-acting
versions of anti-VEGF drugs or slowrelease versions that would need to
be implanted in the eye. If that were
to happen, then the actual number of
patient visits would decrease.”
Dr. Friedlander believes that future treatment will consist of combination therapy. “I’m talking about
targeting multiple angiogenic pathways that play a role in facilitating
abnormal blood vessel proliferation
of the type we see in macular degeneration,” he says. “Combination
therapies, cell-based therapies, and
maybe cell-based therapies in which
the cells are actually programmed
to deliver molecules that would enhance the anti-antigenic effect or
that would provide trophic support/
rescue for neurons and vasculature
may be the answer.”
For example, a recent study conducted at Bascom Palmer evaluated the efficacy of different dosing paradigms of PF-04523655 (an
RNAi therapeutic candidate that
has been in two Phase II trials for
diabetic macular edema and AMD)
compared with ranibizumab in pa-
026_rp0812_f1.indd 28
7/27/12 12:31 PM
tients with neovascular AMD. 2 In
this study, 151 patients were randomized to one of five treatment
groups. All groups received ranibizumab 0.5 mg at baseline. Then, one
group received 1 mg of PF every
four weeks from week four to week
12; one group received 3 mg of PF
every four weeks from week four to
week 12; one group received 3 mg
of PF every two weeks from week
four to week 12; one group received
1 mg of PF plus ranibizumab every
four weeks from baseline to week
12; and one group received ranibizumab every four weeks to week 12.
All treatments were given as intravitreal injections. At week 16, the combination treatment group achieved
greater improvement in mean bestcorrected visual acuity than the ranibizumab group (9.5 letters compared with 6.8 letters), and no safety
concerns were reported.
According to Dr. Murray, the
long-term fix is to train more retina
specialists in the future. “That is
an excellent strategy, but you need
to target the number of people in
training to the presumed need,” he
says. “A Rand Institute study published in 1995 signifi cantly underestimated the need for ophthalmologists. In fact, at a time when we
probably should have been training
more ophthalmologists in the United States, we elected to train fewer
ophthalmologists. By training fewer
ophthalmologists, we trained fewer
specialists in retina. Our long-term
goal is to match the training environment to the health-care needs of
the nation. It’s not a quick fix, however,” he adds.
1. Murray TG, Tornambe P, Dugel P, Tong KB. Evaluation of
economic efficiencies in clinical retina practice: Activity-based
cost analysis and modeling to determine impacts of changes in
patient management. Clin Ophthalmol 2011;5:913-925.
2. Nguyen QD, Schachar RA, Nduaka CI, et al; MONET Clinical
Study Group. Evaluation of the siRNA PF-04523655 versus
ranibizumab for the treatment of neovascular age-related
macular degeneration (MONET study). Ophthalmology 2012;
Jun 8. [E-pub ahead of print].
026_rp0812_f1.indd 29
7/27/12 11:37 AM
REVIEW
Cover Focus
Diabetic Macular Edema
DME: What Trials Tell
Us About Treatment
Walter Bethke, Managing Editor
Even though
anti-VEGF
agents appear
to be effective,
surgeons would
like a long-term
solution.
T
he treatment landscape for diabetic macular edema changed
drastically in just a few years
with the introduction of anti-vascular
endothelial growth factor drugs into
the mix. Instead of just getting by using laser to stabilize vision in some patients, with VEGF blockers physicians
could now actually improve it. However, keeping track of the recent landmark studies in DME treatment can
be challenging. Here, several retinal
specialists acquainted with the major
trials share insights into the studies’
results and discuss what they mean
for treatment in the clinic today and
in the future.
The Anti-VEGF Armamentarium
Several studies have taken a look at
anti-VEGF agents and where they fit
in terms of clinical use. Here’s a look
at the major agents and their trials.
First, the VEGF-blocker ranibizumab (Lucentis) has performed well
in several studies, particularly RISE
and RIDE and RESTORE. RISE and
RIDE will be used for Food and Drug
Administration approval for a DME
indication for Lucentis.
In the RISE study, 377 patients
were randomized to monthly injections of 0.3-mg ranibizumab, 0.5-mg
ranibizumab or sham. In the nearly
030_rp0812_f2.indd 30
Diabetic macular edema has responded
remarkably well to anti-VEGF treatment in
the major prospective trials.
identical RIDE study, 382 patients
were randomized to the same options.
Beginning at three months, macular
laser rescue treatment was available
to all patients, if necessary. Panretinal
laser was available as indicated. After
two years, patients in the sham group
were eligible to receive monthly injections of 0.5-mg ranibizumab.
At two years 18.1 percent of sham
patients gained at least 15 letters vs.
44.8 percent of 0.3-mg (p<0.0001)
and 39.2 percent of 0.5-mg ranibizumab patients (p<0.001). In RIDE,
significantly more ranibizumab-treated patients gained 15 letters or more:
12.3 percent of sham patients vs. 33.6
percent of 0.3-mg patients (p<0.0001)
and 45.7 percent of 0.5-mg ranibizumab patients (p<0.0001).1
7/25/12 10:12 AM
Surgeons familiar with the studies
say they were also pleased with the
safety profile of ranibizumab as demonstrated in RISE and RIDE. There
were four cases of endophthalmitis
in the treatment patients, and the total incidence of nonfatal myocardial
infarctions, nonfatal cerebrovascular
accidents, and deaths from vascular
or unknown causes was 4.9 percent to
5.5 percent of sham patients and 2.4
percent to 8.8 percent of ranibizumab
patients at two years.
In RESTORE, researchers compared 0.5-mg ranibizumab monotherapy or combined with laser to laser
alone in 345 patients randomized to
one of the three treatments. They administered ranibizumab or sham for
three months and then p.r.n., and they
performed laser or sham at baseline
and then p.r.n.
The study doctors found that ranibizumab alone and combined with laser
were superior to laser monotherapy in
improving the average change in bestcorrected letter score from baseline to
months one through 12 (+6.1 letters
for drug only and +5.9 for drug and laser vs. +0.8 for laser; both p<0.0001).
At one year, a significantly greater proportion of ranibizumab patients (22.6
percent) had a BCVA letter score of
15 or better, and 53 percent had a
BCVA letter score level greater than
73 (20/40 Snellen equivalent); for the
ranibizumab + laser group, it was
22.9 percent and 44.9 percent, respectively. For laser alone, 8.2 percent and 23.6 percent of patients
reached these endpoints.2
In RESTORE, the mean central
retinal thickness was significantly
reduced from baseline with ranibizumab (-118.7 µm) and ranibizumab
+ laser (-128.3 µm) vs. laser alone
(-61.3 µm; both p<0.001). Patients
received a mean of seven ranibizumab/sham injections over 12 months.
No endophthalmitis cases occurred in
RESTORE, but increased intraocular
pressure was reported for one patient
each in the ranibizumab arms. Neither ranibizumab monotherapy nor
the drug combined with laser was associated with an increased risk of cardiovascular or cerebrovascular events
in the study.
“In RISE/RIDE, anti-VEGF therapy proved to be a marked improvement over laser treatment for centerinvolved DME,” says Beverly Hills,
Calif., surgeon David Boyer, MD, who
participated in the study. “Also, this is
a vasculopathic group of patients, and
everyone in the study was concerned
that the patients would have a much
higher incidence of Antiplatelet Trialists’ Collaborative events [myocardial
infarction, stroke, etc.] but that wasn’t
borne out in the study. There was no
significant number of APTCs that
would cause alarm.”
Along with ranibizumab, another
drug being studied for possible approval for the treatment of DME
in the United States is Regeneron’s
VEGF Trap-Eye (Eylea, aflibercept).
Aflibercept was studied in the randomized, double-masked, Phase II
DAVINCI trial. In DAVINCI, 221
diabetic patients with center-involved
DME were randomized to one of five
treatments: aflibercept 0.5 mg every
four weeks (0.5q4); 2 mg every four
weeks (2q4); 2 mg every eight weeks
after three initial monthly doses (2q8);
or 2 mg dosing as needed after three
initial monthly doses (2p.r.n.); or macular laser photocoagulation.
The mean improvements in BCVA
in the aflibercept groups at six months
were 11 (0.5q4), 13.1 (2q4), 9.7 (2q8),
and 12 letters (2p.r.n.), vs. -1.3 letters
for the laser group (p≤0.0001). Proportions of eyes with gains in BCVA of
15 or more ETDRS letters at one year
in the aflibercept groups were 40.9
percent (0.5q4), 45.5 percent (2q4),
23.8 (2q8), and 42.2 percent (2p.r.n.)
vs. 11.4 percent for laser (p=0.0031,
p=0.0007, p=0.1608 and p=0.0016,
respectively, vs. laser).3
The mean reductions in central reti-
nal thickness in the aflibercept groups
at one year were -165.4 µm (0.5q4),
-227.4 µm (2q4), -187.8 µm (2q8),
and -180.3 µm (2p.r.n.) vs. -58.4 µm
for laser (p<0.0001). The researchers
say the most frequent ocular adverse
events with aflibercept were conjunctival hemorrhage, eye pain, ocular
hyperemia and increased intraocular
pressure, and common systemic adverse events included hypertension,
nausea and congestive heart failure.3
The next step for aflibercept is
VISTA, the three-year registration
study for FDA approval of the agent
for diabetic macular edema. “The recruitment is complete,” says Winter
Haven, Fla., retinal specialist Michael
Tolentino. “The study design is welldone, and it will answer such questions as aflibercept vs. laser.”
Rounding out the studies of the major anti-VEGF agents is the prospective, randomized BOLT study, which
analyzed the use of bevacizumab in
DME in 80 patients.4
In BOLT, at two years the average
BCVA was 20/50 in the bevacizumab
group vs. 20/80 in the macular laser
group (p=0.005). The bevacizumab
arm gained a median of nine ETDRS
letters vs. 2.5 for ML (p=0.005), with
a mean gain of 8.6 letters for bevacizumab vs. a mean loss of 0.5 letters
for ML. Forty-nine percent of bevacizumab patients gained 10 or more
letters (p=0.001) and 32 percent
gained at least 15 letters (p=0.004)
vs. 7 percent and 4 percent for MLT.
The percentage who lost fewer than
15 letters in the ML arm was 86 percent vs. 100 percent for bevacizumab
(p=0.03). The mean reduction in central macular thickness was 146 µm in
the bevacizumab arm vs. 118 µm in
the ML arm. The median number of
treatments over 24 months was 13 for
bevacizumab and four for MLT.
“It was reassuring that the treatment effect we saw at the end of 12
months was maintained out to 24
months,” says BOLT investigator
030_rp0812_f2.indd 31
7/25/12 10:12 AM
Michel Michaelides, MD, of Moorfield’s Eye Hospital in London. “We
didn’t see any significant adverse
events including those related to
macular perfusion.” Dr. Michaelides
cautions about applying the results
to all patients. “We were quite broad,
but even we excluded patients with
HBA1c of greater than 11 percent,”
he says.
Though the anti-VEGF drugs have
shown very good results, some physicians think differences in the agents’
molecular makeup will affect their
usability over the long term. “I have
patents on several molecules that I
designed,” says Dr. Tolentino, who
consults for Regeneron and Genentech. “In designing a molecule, you
can study it and give it properties that
are advantageous for your purposes.
Avastin, unfortunately, is a monoclonal
antibody, which is immunogenic, and
we know that DME in diabetes is an
inflammatory condition with antibodymediated inflammation.” He says it’s
possible long-term Avastin use could
feed the inflammation. “Lucentis is
a fab fragment, meaning it’s just one
of the arms of an antibody,” Dr. Tolentino continues. “Though it doesn’t
have the true inflammatory potential
of a full-length antibody like Avastin,
it still does things like form immune
complexes, so it is somewhat inflammatory. The thing about aflibercept
that’s special is that though it uses a
backbone of an antibody, it uses the
least inflammatory backbone.”
Dr. Michaelides, however, found
bevacizumab to be safe in the BOLT
trial. “There was nothing significantly
different between the drug and the
laser arms,” he says. “We found similar
side effects. If you remove adverse
events such as subconjunctival hemorrhage and ocular discomfort—which
we now know are predictable—there
really wasn’t a difference between the
groups.” Dr. Michaelides adds that he
also finds it encouraging that the number of required injections decreased in
intravitreal injections using a ProtocolI kind of approach [a protocol from
the Diabetic Retinopathy Clinical Research Network’s study of DME],”5
he says. “This would involve using an
intravitreal anti-VEGF agent followed
by laser coagulation, then treating
with anti-VEGF and reassessing for
the need for supplemental laser every
three to four months.”
Michel Michaelides, MD
REVIEW
Cover
Focus
Steroid Inserts
An eye treated with bevacizumab for
diabetic macular edema at baseline (top),
six months (middle) and a year shows a
persistent reduction in macular thickness.
the second year of the study.
There has also been a discussion
about how the molecules’ particular
designs might affect their ability to last
longer in the eye. “Because of aflibercept’s molecular makeup, it holds onto
VEGF for a long time,” says Dr. Boyer.
“It seems to have a higher affinity for
VEGF. Because of this, it appears its
effect may be longer. There have been
studies in AMD that show after three
loading doses you can give the drug
every two months and still get good
visual results. Of course, there will
be individual patients who require it
monthly anyway, but it may last longer
in general, so that’s why we’re going to
do studies to figure that out.”
The excellent efficacy anti-VEGF
agents have shown in their trials has
led physicians to change how they use
laser treatment for DME, and it’s no
longer the instant first-line treatment
it once was. “If you have a patient
with a focal area of leakage well away
from the foveal center, laser might be
a better option than a drug because
you have a high chance of curing that
leakage with laser therapy,” says Dr.
Michaelides. Andrew Antoszyk, MD,
of Charlotte, N.C., agrees. “A lot of
people will continue to use laser to
try to reduce the treatment burden of
Surgeons who had been hoping
for an implantable steroid for select
patients with DME had their hopes
dashed when the FDA denied approval of Alimera’s Iluvien fluocinolone insert in November of 2011, citing issues
with the risks of adverse reactions, including intraocular pressure increases
and cataract, that were manifest during the 36-month FAME study. The
insert, which is designed to deliver
drug for up to three years, is approved
in several European countries.
In FAME, at three years 33 percent
of patients receiving a 0.2-mg insert
and 31.9 percent of those receiving a
0.5-mg insert gained at least 15 letters
of vision, vs. 21.4 percent in a sham
group (p=0.030). However, patients
with DME with a duration of three
or more years had an even better result: 34 percent of low-dose patients
and 28.8 percent of high-dose patients
improved by 15 letters or more, vs.
just 13.4 percent of sham. In terms of
adverse events, 82 percent of low-dose
patients underwent cataract surgery, as
did 88 percent of the high-dose group.
Dr. Antoszyk, who took part in the
study, says 38 percent of the 0.2-mg
group and 47 percent of the 0.5-mg
group required glaucoma drops. Also,
4.8 percent of the low-dose group and
8.1 percent of the high-dose group
required incisional glaucoma surgery.
Many physicians, though, think the
benefits of Iluvien outweigh the side
effects. “I wish Iluvien were available,” says Szilard Kiss, MD, assistant
030_rp0812_f2.indd 32
7/25/12 10:12 AM
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1. Nilsson S, Lundqvist M, Lundgren B. Objective Scheimpflug evaluation of dispersive and viscoadaptive ophthalmic viscosurgical devices (ovds) at different clinically relevant
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2012.05.11-CT5257
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REVIEW
®
Important Safety Information–HEALON EndoCoat OVD
INDICATIONS: HEALON EndoCoat OVD is an ophthalmic viscoelastic containing
3% sodium hyaluronate indicated for use as a surgical aid in patients undergoing
ophthalmic anterior segment procedures including: cataract surgery with an
intraocular lens, cataract surgery without an intraocular lens, secondary intraocular
lens implantation. HEALON EndoCoat OVD maintains a deep chamber during
anterior segment surgery, aids in tissue manipulation during surgery, enhances
visualization during the surgical procedure and protects the corneal endothelium and
other ocular tissue. The viscoelasticity of the solution maintains the normal position
of the vitreous face and prevents formation of a flat chamber during surgery. It may
also be used to coat intraocular lenses and insertion instruments prior to intraocular
lens implantation.
CONTRAINDICATIONS: At present, there are no contraindications to the use of
HEALON EndoCoat OVD when used as recommended.
WARNINGS: The HEALON EndoCoat OVD Delivery system is not designed or
intended to be attached to instruments other than the one provided with the product.
Failure to follow the “Directions for Use” may result in cannula detachment. Mixing
of quaternary ammonium salts, such as benzalkonium chloride, with sodium
hyaluronate results in the formation of a precipitate. The eye should not be irrigated
with any solution containing benzalkonium chloride if HEALON EndoCoat OVD is to
be used during surgery.
PRECAUTIONS: CAUTION: Injection of viscoelastics creates pressure in the syringe.
To prevent expulsion of the cannula into the eye, ensure that the cannula is securely
attached to the fitting on the syringe. Use of the cannula guard is recommended.
CAUTION: The cannula should be fastened securely to the syringe; however, over
tightening may cause the hub to weaken and possibly detach from the syringe.
Extrusion of a test droplet is recommended prior to entering the eye, and excessive
force on the plunger should be avoided. CAUTION: Do not reuse the cannula. This
could release particulate matter. Product and cannula are for single use only. Re-use
may cause eye inflammation. CAUTION: The potential for early and short-term
postoperative intraocular pressure (IOP) spikes exists with dispersive OVDs, which
potentially require more time and care to remove from the eye. Therefore, it is
recommended that HEALON EndoCoat OVD be removed from the eye completely
by irrigating and aspirating with sterile irrigation solution to reduce the risk of early
postoperative IOP spikes. Observe the usual precautions taken during anterior
segment surgery. Pre-existing glaucoma, the surgery itself, or retained viscoelastic
(particularly in patients with compromised trabecular meshwork) can cause
increased intraocular pressure after the procedure (1).
The following precautions should be carefully considered:
s4HEINTRAOCULARPRESSUREOFPOSTOPERATIVEPATIENTSSHOULDBECAREFULLYMONITORED
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s$ONOTUSEEXCESSIVEAMOUNTSOFHEALON EndoCoat OVD.
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s3EEPRODUCTEXPIRATIONDATE
HEALON EndoCoat OVD does not require refrigeration. If refrigerated, HEALON
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have been isolated reports of diffuse particulates or haziness appearing after
injection of viscoelastics into the eye. While such reports are infrequent and seldom
associated with any effects on ocular tissue, the physician should be aware of
this occurrence. If observed, the viscoelastic should be removed by irrigation and/
or aspiration. HEALON EndoCoat OVD is derived from microbial fermentation by
a purified proprietary process. Although precautions have been taken to make this
device protein-free, it may contain trace amounts of protein. The physician should
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occur with injection of biological materials.
1. Miller D, Stegmann R. The use of Healon in intraocular lens implantation.
Int Ophthalmol Clin. 1982;22(2):177-181.
Cover
Focus
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2012.05.11-CT5257
professor of ophthalmology at Weill Cornell Medical College in Manhattan, “because there are certain patients I’d
like to use it on. Remember, in the Iluvien trials, patients
with macular edema longer than three years benefited
the most. In someone with longstanding edema, there
are other things going on of an inflammatory nature that
steroid would address that simple anti-VEGF treatment
would not. It’s one of those options where you know
there’s a side-effect profile that includes glaucoma and
cataract, but if the macular edema and vision improve
you’re willing to take such a risk—or at least I would be.”
When asked about the fate of the implant in the United
States, Alimera representatives said they couldn’t discuss
any possible plans.
U.S. ophthalmologists aren’t all out of implantable steroid
options, however, as Allergan’s Ozurdex dexamethasone
implant is making its way through the approval process for
a DME indication (it’s already approved for macular edema
due to retinal vein occlusion). The Ozurdex has a shorter
duration of action compared to the Iluvien, lasting two to
three months according to physicians.
Though the latest data from the trial hasn’t been made
available in the run-up to its application for FDA approval,
a study of Ozurdex in a subset of DME patients showed it
might fill a niche that anti-VEGF drugs can’t: vitrectomized
eyes. “Because of the vitrectomy, the pharmacokinetics of
all drugs is shortened dramatically, so even the anti-VEGF
drugs don’t work well in vitrectomized eyes,” says Dr.
Boyer. “So Ozurdex and Iluvien would both be welcomed
in those cases. In a small, Phase II trial, the Ozurdex implant was shown to be very effective in vitrectomized eyes.”
In the study of 55 patients with treatment-resistant DME,
at week eight, 30.4 percent of them had gained at least 10
letters in best-corrected visual acuity.6
Though anti-VEGF drugs currently yield the best results
with the fewest side effects, Dr. Tolentino says the idea
behind the sustained-release steroid is a good one, because
it cuts down on the number of injections. “Let’s say we start
a diabetic patient on anti-VEGF injections in his 40s, and
he lives to be 80,” he muses. “He’s going to be getting these
injections for almost 40 years. What’s the long-term consequence of this? You have to somehow reduce the number
of injections.”
1. Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for DME: Results from 2 phase III
randomized trials: RISE and RIDE. Ophthalmology 2012 Apr;119:4:789-801. Epub 2012 Feb 11.
2. Mitchell P, Bandello F, Schmidt-Erfurth U, et al. The RESTORE study: Ranibizumab monotherapy
or combined with laser versus laser monotherapy for DME. Ophthalmology 2011 Apr;118:4:615-25.
3. Do DV, Nguyen QD, Boyer D, et al. One-Year Outcomes of the DA VINCI Study of VEGF Trap-Eye in
Eyes with Diabetic Macular Edema. Ophthalmology 2012 Apr 24. [Epub ahead of print]
4. Michaelides M, Fraser-Bell S, Kaines A, et al. A 2-Year prospective randomized controlled trial of
intravitreal bevacizumab or laser therapy (BOLT) in the management of diabetic macular edema:
24-Month Data: Report 3. Arch Ophthalmol 2012 Apr 9. [Epub ahead of print]
5. Elman MJ, Aiello LP, Beck RW, et al. Randomized trial evaluating ranibizumab plus prompt or
deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology
2010;117:6:1064-1077.
6. Boyer DS, Faber D, Gupta S, et al. Dexamethasone intravitreal implant for treatment of diabetic
macular edema in vitrectomized patients. Retina 2011;31:5:915-23.
030_rp0812_f2.indd 34
7/25/12 10:12 AM
REVIEW
Cover Focus
Retinal Vein Occlusion
Treating RVO: Which
Options Work Best?
Christopher Kent, Senior Editor
Three experienced
surgeons share
their experience
using anti-VEGF
drugs, steroids
and lasers to treat
this condition.
F
or many years, ophthalmologists had few options for treating patients with retinal vein
occlusions other than laser and observation. But in recent years, the
advent of anti-VEGF drugs and the
use of steroids inside the eye have
changed that. Currently, anti-VEGF
drugs such as ranibizumab and bevacizumab appear to be the most frequently chosen treatment option, but
steroids are arguably a good choice in
many circumstances. Many surgeons
are using them both, either sequentially or simultaneously, and lasers are
still part of the equation—sometimes
in new ways.
Here, three retina specialists with
extensive experience treating central retinal vein occlusion and branch
retinal vein occlusion share their
thoughts on the pros and cons of steroids, anti-VEGF options and laser,
and how they apply these options in
the clinic.
The Pharma Approach
David M. Brown, MD, FACS, who
practices at Retina Consultants of
Houston, helped design most of the
major anti-VEGF retinal vein occlusion clinical trials, including BRAVO,
CRUISE and COPERNICUS; he
was also an investigator in the steThis article has no commercial sponsorship.
035_rp0812_f3.indd 35
roid trials SCORE and GENEVA.
“In the past five years we’ve had two
big breakthroughs,” he notes. “First,
doctors began using steroids in the
eye to treat vein occlusion, injecting
triamcinolone in the clinic. Then, we
began using the anti-VEGF drugs.
The latter were initially developed as
anti-cancer drugs; then it was discovered that their anti-edema effects in
the eye were remarkable. They’re actually much more effective for treating diabetic macular edema, branch
retinal vein occlusion and macular
degeneration than they are in the cancer realm. Oncologists still use antiVEGF as an adjuvant, but in our field
they caused a revolution.”
“Both classes of drugs have been
shown to be effective in large clinical
trials,” says Michael A. Singer, MD,
managing partner and director of
clinical trials at Medical Center Ophthalmology Associates in San Antonio,
Texas, and assistant clinical professor
at the University of Texas Health Science Center of San Antonio. “BRAVO, CRUISE, GALILEO and COPERNICUS have shown significant
improvements in both visual acuity
and macular edema with monthly
anti-VEGF injections. Similarly, the
SCORE and GENEVA studies demonstrated the value of treating with
steroids. In patients with central retiAugust 2012 | Revophth.com | 35
7/24/12 3:08 PM
REVIEW
Cover
Focus
How the Drugs Work
“Branch retinal vein occlusion and
central retinal vein occlusion both
cause a breakdown in vascular flow,
leading to bleeding and swelling,” explains Dr. Singer. “Because circulation is compromised, this results in
ischemia, inflammation and eventually macular edema. Each class of drug
attacks one of those problems. The
anti-VEGF drugs attack the ischemic
component; the steroids attack the
inflammatory component. Obviously,
there’s a certain amount of crossover,
because, for example, VEGF increases the capillary permeability that
causes vascular leakage and edema, so
decreasing VEGF will lead to some
amount of reduction in both edema
and inflammation.
“In a vein occlusion, you have a
blockage in either the central retinal
vein or a branch,” says Dr. Brown.
“The eye is a closed-loop vascular system, with arteries that bring in the
blood supply and veins that take it
back out. Initially we thought that
the edema in vein occlusion was at
least partly due to increased venous
pressure caused by the blockage, but
the data from the BRAVO, CRUISE,
Eric Kegley, CRA, COA
nal vein occlusion in the CRUISE
study, subjects had a 15-letter improvement over a six-month period of
time, which is pretty impressive. The
GALILEO and COPERNICUS studies had similar results. In the BRAVO
study, subjects had an 18-letter improvement over six months, which was
largely maintained during the second
six months with fewer injections. The
HORIZON study showed that this
improvement in swelling on OCT was
maintained in branch retinal vein occlusion with many fewer shots given
on a p.r.n. basis, although this wasn’t
the case in central retinal vein occlusion. I believe that’s because of the
higher VEGF load in CRVO, due to
peripheral ischemia.”
BRVO with ischemia (left), captured using Optos widefield imaging technology. Optos
pseudo-color image (right) reveals hemorrhaging.
COPERNICUS and GALILEO trials
showed that an anti-VEGF blockade
eliminates all the edema within a day
or two. That means that venous pressure probably has no role in causing
the edema. Instead, blocking venous
flow impedes arterial flow, causing
ischemia. The ischemic cells then release factors like VEGF and erythropoietin that drive the edematous
process.
“Anti-VEGF drugs block that process and make the edema go away,” he
continues. “So, if the individual’s poor
vision is just due to edema, his vision
gets better. In addition, the trial data
showed that anti-VEGF treatment
also seems to make hemorrhages go
away faster. We don’t know whether
this happens because the drugs restore the tight junctions of the retinal vessels, or whether macrophages
clear the intraretinal hemorrhages
faster in a retina that’s thinner and less
edematous.
“Ultimately, the anti-VEGF drugs
work like an antihistamine,” he adds.
“If there’s leakage, they stop the leakage. And when they wear off, the leakage starts again.”
Dr. Brown explains that the rationale for using steroids to treat vein
occlusion is somewhat different. “A
steroid also has anti-VEGF effects,
although not as strong as the effect of
a potent anti-VEGF blocker,” he says.
“Perhaps more to the point, steroids
help to stabilize retinal vessels’ tight
junctions, possibly treating inflamma-
tory activity that happens at the area
of the vein occlusion.
“The original histopathological descriptions of vein occlusion done in
1981 by Richard Green, MD, noted
that every patient who had a vein occlusion for more than a month had
lymphocytic infiltration within the
wall of the vein, or into the thrombus,” he adds. “An anti-VEGF drug
doesn’t address this. So it may be that
a steroid is addressing the root cause
of the occlusion in those patients, in
addition to its anti-VEGF effects.”
Like many retinal surgeons, Ravi D.
Patel, MD, who practices at Retinal
Vitreal Consultants in Chicago, says
he now relies on the Ozurdex implant
when a steroid is called for. “Ozurdex
is a bioerodable drug delivery device
loaded with dexamethasone,” he explains. “Dexamethasone by itself in
the vitreous cavity has a very short
life—only four to five hours. But delivered in this polymer implant, the
durability is about six months. Data
from the GENEVA study [of this
implant] showed about a 21-percent
gain in three lines in BRVO patients
at six months, and about a 17-percent
gain in three lines in CRVO patients
at six months. Admittedly, if someone
just saw those numbers by themselves
they wouldn’t be too impressed, but
in the past the recommended treatment for CRVO was observation. At
least we’re causing improvement.”
“The GENEVA studies show
that Ozurdex is a great sustained-
035_rp0812_f3.indd 36
7/24/12 3:08 PM
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Cover
Focus
CRVO at initial presentation (left) and after eight months of monthly anti-VEGF treatment.
delivery platform,” notes Dr. Singer.
“The Phase III data shows that at
six months vision is still better than
with placebo. However, in reality
most doctors use Ozurdex as a three
or four-month drug. The reason is
that the original Ozurdex data didn’t
include visits at months four or five,
so its performance during that time
period was extrapolated.”
Dr. Brown notes another relevant
point regarding Ozurdex: The steroid
dexamethasone is about five times
as potent as triamcinolone, the steroid favored in previous years. “Dexamethasone is 25 times as powerful as
cortisone,” he points out. “Triamcinolone is only about five times as powerful. Also, the therapy pulses on and
off over time; you get 40 to 45 days of
super high-dose steroids and then it
pulses off. The evidence suggests that
pulse therapy is probably safer for the
patient than sustained low-dose steroid. The Alimera implant provided
sustained low-dose fluocinolone, rather than pulsed therapy, and it resulted
in cataract formation almost 100 percent of the time.”
Anti-VEGF vs. Steroids
With the advent of anti-VEGF options, many retinal specialists have
switched from steroids to anti-VEGF.
“Most doctors treating retinal vein
occlusion today will initially use antiVEGF because they get a lot of bang
for their buck,” notes Dr. Brown. “You
get an eight-letter gain within a week,
according to the large clinical trials.
If you’re a truck driver and you’re
having trouble doing your job, you
want that anti-VEGF injection initially. Later, if you’re constantly getting monthly injections, you might be
inclined to take a little more risk and
go to steroids. Certainly there’s more
risk of pressure increase and cataract
with use of steroids, although that
hasn’t been tested in a standardized
fashion.”
“Today, the majority of doctors use
anti-VEGF as first-line therapy, primarily because the current studies
show anti-VEGF therapy producing
superior results compared to Ozurdex,” agrees Dr. Singer. “Some people
use Ozurdex as rescue therapy, or
when anti-VEGF therapy isn’t producing the desired results. However,
Ozurdex does have one significant
advantage over anti-VEGF: the convenience factor. You’re not locked into
monthly therapy to get those results.
In fact, the BRAVO and CRUISE
data show that if you only give people three anti-VEGF shots, you lose
20 percent of the improvement you
would have seen with all six shots.”
Dr. Brown also notes that the antiVEGF drugs are an easy sell to most
retinal physicians treating retinal vein
occlusion. “When you’re a physician,
you look at your chances of helping
somebody vs. hurting them with a
given therapy,” he says. “If you look at
the big studies of anti-VEGF therapy,
your likelihood of helping somebody
is over 99 percent. Your chance of
hurting somebody—the risk of endophthalmitis—is about one in 3,000.
With steroids, on the other hand, your
chance of helping someone may be
pretty high—though probably not as
high—but your chance of hurting the
patient by causing increased IOP or
cataract formation is probably one
in three. Given that risk-to-benefit
ratio, most physicians are going to
choose anti-VEGF therapy as firstline therapy. And they’re only going
to switch to steroids if they need a lot
of anti-VEGF effect to maintain the
repression of the edema.
“That being said,” he adds, “in a
long-standing vein occlusion, there
may be some theoretical benefit to
adding a steroid to address the inflammatory component at the actual site
of the blockade. In the closed space of
the optic nerve head in CRVO and the
common adventitial sheath in BRVO,
it makes sense that getting rid of the
inflammation there might give you a
little more flow. It’s worth noting that
Richard Green’s histological research
found that no one with retinal vein occlusion was totally blocked, so this is a
disease of decreased flow, not totally
blocked flow. And if there’s inflammation in the wall of the vessel, it’s likely
to cause further constriction and impede the flow—at least in theory.
“The main advantage of a steroid,
particularly Ozurdex, is that the antiVEGFs we have right now are 30- to
60-day drugs, whereas a lot of the steroids give you three or four months’
duration of action,” he continues.
“Even though the Ozurdex device
probably only gives you high steroid
levels for 40 or 45 days, it’s so strong
that it calms down the eye and it takes
longer for the edema to recur.”
Dr. Brown notes, however, that in
his experience Ozurdex doesn’t last six
months. “In the Ozurdex trial, most
of the patients lost the benefits by
six months,” he points out. “So if you
035_rp0812_f3.indd 38
7/24/12 3:09 PM
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Cover
Focus
Fluorescein angiography of CRVO at initial presentation at two timepoints (above, left and center). Right: Fluorescein angiogram of the
same eye four months after treatment with steroids. With edema reduced, the vessels are noticeably less tortuous.
compare the Ozurdex results with the
BRAVO or CRUISE results, the latter
have a 15-letter gain, while the former
has lost all of the benefit at six months.
Given that, why use Ozurdex? Because when it works—and it often
does—you only inject it every three to
four months. With anti-VEGF, many
patients need a monthly injection.”
Dr. Patel observes that it will be
helpful to have direct, head-to-head
clinical trial data comparing antiVEGF treatment to steroids. “They’re
now conducting the COMO study in
Europe and Israel,” he says. “They’ve
enrolled about 400 patients. They’re
going to treat with dexamethasone
implants at baseline, and again at
months five and 10, if needed, vs.
monthly ranibizumab injections for
six months, followed by as-needed
injections through month 12. The
primary endpoint will be the mean
change in baseline visual acuity at 12
months. I think this study will give
us more insight about which drug is
superior. Furthermore, sub-analysis may shed light on whether one
drug is better than the other for a
given population.”
Managing the Steroid Response
One factor that seems to be a primary concern when choosing between anti-VEGF and steroids is the
reality that steroids sometimes trigger
a belated rise in intraocular pressure,
putting some patients in danger of
developing glaucoma. ”Nobody wants
to talk about it, but it’s clear that the
reason most people don’t use steroids
is fear of causing glaucoma,” says Dr.
Singer. “In that respect, retina specialists aren’t really worried about pressures in the 20s; they’re worried about
pressures in the 30s and 40s.”
Dr. Patel notes, however, that in
many cases it’s not difficult to know
which patients are at risk of a steroid
response. “Patients with vein occlusion are often older and have been
followed by a comprehensive ophthalmologist for many years,” he points
out. “They generally have a good idea
of their IOP history. If they’ve had to
take steroid drops for a month after
cataract surgery, it’s pretty well documented whether or not they are steroid responders. And some patients
have a strong family history of glaucoma. In those situations you know
that you have to be very careful when
using Ozurdex, and I would shy away
from it. Ultimately, you have to decide
which disease process you primarily
want to treat.
“If we decide that Ozurdex is the
best treatment option for a patient
with a history of glaucoma or known
to be a steroid responder, we monitor their IOP very closely,” he says,
adding that he relies on his glaucoma-specialist colleagues to help him
manage these patients. “Before I start
Ozurdex, I send the patient to my colleague for a full glaucoma work-up,”
he explains. “I see the patient at six
weeks or two months, the period in
which the IOP spike typically occurs.
To date, when a spike has occurred
my glaucoma colleagues have started
the patient on an IOP-lowering agent
such as Combigan with great success.
We’ve never had a case where the
IOP was uncontrollable.”
Dr. Singer notes some new developments that may help to lessen
doctors’ concerns regarding pressure
spikes. “Right now, we’re working on
some technology that we presented at
the annual meeting of the Association
for Research and Vision in Ophthalmology and will be presenting at the
meeting of the American Society of
Retinal Specialists, showing that we
may be able to screen for what I call
super-responders—those individuals who will have pressure spikes in
response to steroid therapy—using
anterior segment optical coherence
tomography,” he says. “We may be
able to predict who is going to be most
vulnerable before any IOP spike occurs. Once you’ve identified them,
you can treat proactively with drops or
selective laser trabeculoplasty. We’re
very excited about this. We hope it
035_rp0812_f3.indd 40
7/24/12 3:09 PM
7 STUDIES
1,563 PATIENTS
1 POOLED RESULT
30%SUSTAINED
IOP lowering for up to a full day
1
FOR ALL YOUR PATIENTS NEEDING A PGA CONSIDER
BAK-FREE TRAVATAN Z SOLUTION
®
To learn more:
Visit www.travatanz.com/7studies1result
Scan the QR code using your smartphone,
or ask your local sales representative for a
free copy of the published study.
INDICATIONS AND USAGE:
TRAVATAN Z® Solution is a prostaglandin analog indicated for the reduction
of elevated intraocular pressure in patients with open-angle glaucoma or
ocular hypertension.
Dosage and Administration:
One drop in the affected eye(s) once daily in the evening.
IMPORTANT SAFETY INFORMATION
Warnings and Precautions:
Pigmentation: Pigmentation of the iris, periorbital tissue (eyelid) and eyelashes
can occur. Iris pigmentation likely to be permanent.
Eyelash Changes: Gradual change to eyelashes including increased length,
thickness and number of lashes. Usually reversible.
©2012 Novartis
053_rp0512_alcontrav.indd 1
4/12
Adverse Reactions:
Most common adverse reaction (30% to 50%) is conjunctival hyperemia.
Use In Specific Populations:
Use in pediatric patients below the age of 16 years is not recommended
because of potential safety concerns related to increased pigmentation
following long-term chronic use.
For additional information please refer to the accompanying brief
summary of prescribing information on adjacent page.
Reference:
1. Dubiner HB, Noecker R. Sustained intraocular pressure reduction throughout the day with travoprost ophthalmic
solution 0.004%. Clin Ophthalmol. 2012;6:525-531.
TRV12070JAD
4/19/12 5:06 PM
BRIEF SUMMARY OF PRESCRIBING INFORMATION
INDICATIONS AND USAGE
TRAVATAN Z® (travoprost ophthalmic solution) 0.004% is indicated for the reduction of elevated intraocular
pressure in patients with open-angle glaucoma or ocular hypertension.
DOSAGE AND ADMINISTRATION
The recommended dosage is one drop in the affected eye(s) once daily in the evening.
TRAVATAN Z® (travoprost ophthalmic solution) should not be administered more than once daily since it
has been shown that more frequent administration of prostaglandin analogs may decrease the intraocular
pressure lowering effect.
Reduction of the intraocular pressure starts approximately 2 hours after the first administration with
maximum effect reached after 12 hours.
TRAVATAN Z® Solution may be used concomitantly with other topical ophthalmic drug products to
lower intraocular pressure. If more than one topical ophthalmic drug is being used, the drugs should be
administered at least five (5) minutes apart.
CONTRAINDICATIONS
None
WARNINGS AND PRECAUTIONS
Pigmentation
Travoprost ophthalmic solution has been reported to cause changes to pigmented tissues. The most
frequently reported changes have been increased pigmentation of the iris, periorbital tissue (eyelid) and
eyelashes. Pigmentation is expected to increase as long as travoprost is administered. The pigmentation
change is due to increased melanin content in the melanocytes rather than to an increase in the number
of melanocytes. After discontinuation of travoprost, pigmentation of the iris is likely to be permanent, while
pigmentation of the periorbital tissue and eyelash changes have been reported to be reversible in some
patients. Patients who receive treatment should be informed of the possibility of increased pigmentation.
The long term effects of increased pigmentation are not known.
Iris color change may not be noticeable for several months to years. Typically, the brown pigmentation
around the pupil spreads concentrically towards the periphery of the iris and the entire iris or parts of the
iris become more brownish. Neither nevi nor freckles of the iris appear to be affected by treatment. While
treatment with TRAVATAN Z® (travoprost ophthalmic solution) 0.004% can be continued in patients who
develop noticeably increased iris pigmentation, these patients should be examined regularly.
Eyelash Changes
TRAVATAN Z® Solution may gradually change eyelashes and vellus hair in the treated eye. These changes
include increased length, thickness, and number of lashes. Eyelash changes are usually reversible upon
discontinuation of treatment.
Intraocular Inflammation
TRAVATAN Z® Solution should be used with caution in patients with active intraocular inflammation
(e.g., uveitis) because the inflammation may be exacerbated.
Macular Edema
Macular edema, including cystoid macular edema, has been reported during treatment with travoprost
ophthalmic solution. TRAVATAN Z® Solution should be used with caution in aphakic patients, in pseudophakic
patients with a torn posterior lens capsule, or in patients with known risk factors for macular edema.
Angle-closure, Inflammatory or Neovascular Glaucoma
TRAVATAN Z® Solution has not been evaluated for the treatment of angle-closure, inflammatory or
neovascular glaucoma.
Bacterial Keratitis
There have been reports of bacterial keratitis associated with the use of multiple-dose containers of
topical ophthalmic products. These containers had been inadvertently contaminated by patients who,
in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface.
Use with Contact Lenses
Contact lenses should be removed prior to instillation of TRAVATAN Z® Solution and may be reinserted
15 minutes following its administration.
ADVERSE REACTIONS
Clinical Studies Experience
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed
in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug
and may not reflect the rates observed in practice. The most common adverse reaction observed
in controlled clinical studies with TRAVATAN® (travoprost ophthalmic solution) 0.004% and
TRAVATAN Z® (travoprost ophthalmic solution) 0.004% was ocular hyperemia which was reported in 30 to
50% of patients. Up to 3% of patients discontinued therapy due to conjunctival hyperemia. Ocular adverse
reactions reported at an incidence of 5 to 10% in these clinical studies included decreased visual acuity, eye
discomfort, foreign body sensation, pain and pruritus. Ocular adverse reactions reported at an incidence of
1 to 4% in clinical studies with TRAVATAN® or TRAVATAN Z® Solutions included abnormal vision, blepharitis,
blurred vision, cataract, conjunctivitis, corneal staining, dry eye, iris discoloration, keratitis, lid margin
crusting, ocular inflammation, photophobia, subconjunctival hemorrhage and tearing.
Nonocular adverse reactions reported at an incidence of 1 to 5% in these clinical studies were allergy,
angina pectoris, anxiety, arthritis, back pain, bradycardia, bronchitis, chest pain, cold/flu syndrome,
depression, dyspepsia, gastrointestinal disorder, headache, hypercholesterolemia, hypertension,
hypotension, infection, pain, prostate disorder, sinusitis, urinary incontinence and urinary tract infections.
In postmarketing use with prostaglandin analogs, periorbital and lid changes including deepening of the
eyelid sulcus have been observed.
054_rp0512_alcontravpi.indd 1
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C
Teratogenic effects: Travoprost was teratogenic in rats, at an intravenous (IV) dose up to
10 mcg/kg/day (250 times the maximal recommended human ocular dose (MRHOD), evidenced by an
increase in the incidence of skeletal malformations as well as external and visceral malformations, such
as fused sternebrae, domed head and hydrocephaly. Travoprost was not teratogenic in rats at IV doses up
to 3 mcg/kg/day (75 times the MRHOD), or in mice at subcutaneous doses up to 1 mcg/kg/day (25 times
the MRHOD). Travoprost produced an increase in post-implantation losses and a decrease in fetal viability
in rats at IV doses > 3 mcg/kg/day (75 times the MRHOD) and in mice at subcutaneous doses
> 0.3 mcg/kg/day (7.5 times the MRHOD).
In the offspring of female rats that received travoprost subcutaneously from Day 7 of pregnancy to lactation Day
21 at doses of ≥ 0.12 mcg/kg/day (3 times the MRHOD), the incidence of postnatal mortality was increased, and
neonatal body weight gain was decreased. Neonatal development was also affected, evidenced by delayed eye
opening, pinna detachment and preputial separation, and by decreased motor activity.
There are no adequate and well-controlled studies of TRAVATAN Z® (travoprost ophthalmic solution) 0.004%
administration in pregnant women. Because animal reproductive studies are not always predictive of
human response, TRAVATAN Z® Solution should be administered during pregnancy only if the potential
benefit justifies the potential risk to the fetus.
Nursing Mothers
A study in lactating rats demonstrated that radiolabeled travoprost and/or its metabolites were excreted in
milk. It is not known whether this drug or its metabolites are excreted in human milk. Because many drugs
are excreted in human milk, caution should be exercised when TRAVATAN Z® Solution is administered to
a nursing woman.
Pediatric Use
Use in pediatric patients below the age of 16 years is not recommended because of potential safety
concerns related to increased pigmentation following long-term chronic use.
Geriatric Use
No overall clinical differences in safety or effectiveness have been observed between elderly and other
adult patients.
Hepatic and Renal Impairment
Travoprost ophthalmic solution 0.004% has been studied in patients with hepatic impairment and also in
patients with renal impairment. No clinically relevant changes in hematology, blood chemistry, or urinalysis
laboratory data were observed in these patients.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Two-year carcinogenicity studies in mice and rats at subcutaneous doses of 10, 30, or 100 mcg/kg/day
did not show any evidence of carcinogenic potential. However, at 100 mcg/kg/day, male rats were only
treated for 82 weeks, and the maximum tolerated dose (MTD) was not reached in the mouse study. The high
dose (100 mcg/kg) corresponds to exposure levels over 400 times the human exposure at the maximum
recommended human ocular dose (MRHOD) of 0.04 mcg/kg, based on plasma active drug levels. Travoprost
was not mutagenic in the Ames test, mouse micronucleus test or rat chromosome aberration assay.
A slight increase in the mutant frequency was observed in one of two mouse lymphoma assays in the
presence of rat S-9 activation enzymes.
Travoprost did not affect mating or fertility indices in male or female rats at subcutaneous doses up to
10 mcg/kg/day [250 times the maximum recommended human ocular dose of 0.04 mcg/kg/day on a mcg/kg
basis (MRHOD)]. At 10 mcg/kg/day, the mean number of corpora lutea was reduced, and the post-implantation
losses were increased. These effects were not observed at 3 mcg/kg/day (75 times the MRHOD).
PATIENT COUNSELING INFORMATION
Potential for Pigmentation
Patients should be advised about the potential for increased brown pigmentation of the iris, which may be
permanent. Patients should also be informed about the possibility of eyelid skin darkening, which may be
reversible after discontinuation of TRAVATAN Z® (travoprost ophthalmic solution) 0.004%.
Potential for Eyelash Changes
Patients should also be informed of the possibility of eyelash and vellus hair changes in the treated eye
during treatment with TRAVATAN Z® Solution. These changes may result in a disparity between eyes in
length, thickness, pigmentation, number of eyelashes or vellus hairs, and/or direction of eyelash growth.
Eyelash changes are usually reversible upon discontinuation of treatment.
Handling the Container
Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye,
surrounding structures, fingers, or any other surface in order to avoid contamination of the solution by
common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of
vision may result from using contaminated solutions.
When to Seek Physician Advice
Patients should also be advised that if they develop an intercurrent ocular condition (e.g., trauma or
infection), have ocular surgery, or develop any ocular reactions, particularly conjunctivitis and eyelid
reactions, they should immediately seek their physician’s advice concerning the continued use of
TRAVATAN Z® Solution.
Use with Contact Lenses
Contact lenses should be removed prior to instillation of TRAVATAN Z® Solution and may be reinserted
15 minutes following its administration.
Use with Other Ophthalmic Drugs
If more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5)
minutes between applications.
Rx Only
U.S. Patent Nos. 5,631,287; 5,889,052, 6,011,062; 6,235,781; 6,503,497; and 6,849,253
ALCON LABORATORIES, INC.
Fort Worth, Texas 76134 USA
© 2006, 2010, 2011, 2012 Novartis
4/12 TRV12070JAD
4/19/12 5:07 PM
REVIEW
Cover
Focus
Michael A. Singer, MD, and Angela Herro, MD
SLT can help to prevent intraocular pressure spikes when treating vein occlusions with steroids. Above: A 3-D view of the angle recess
before (left) and after SLT laser treatment (middle: postop day two; right: postop week four) reveals that mild damage is caused by the
laser (a new finding), although the tissue starts to remodel by week four. The result is an increase in the angle recess following treatment.
will take some of the fear out of using
steroids.”
Dr. Singer adds that he chooses
SLT to treat steroid super-responders
when he encounters them—and has
uncovered some new information
about how SLT works. “SLT does a
great job of preventing steroid-related
pressure spikes,” he says. “A study
by Ercument Bozkurt, MD, in the
American Journal of Ophthalmology
in December 2011, showed that by
pretreating patients with SLT prior
to triamcinolone injection you can
prevent an IOP rise.
“Meanwhile,” he continues, “our
work with in vivo 3-D imaging has
revealed some surprising information
about what SLT is doing inside the
eye. Everyone believes SLT does no
damage. In fact, it does cause some
mild damage, but the tissue remodels
itself within a month. [See images,
above.] By the time you look again,
you don’t see it. The end result is that
performing SLT causes an increase
in the angle recess size, lowering the
pressure significantly within a week.
We’re showing a 3-D movie of this at
the major meetings; we were the first
people to observe it.
“The bottom line is that if you want
to drop the pressure in steroid responders when treating retinal vein
occlusion, SLT is the way to go,” he
says. “It does it fast and effectively.”
Although fear of triggering a pressure spike is mostly associated with
the use of steroids, some recent evidence has indicated that a pressure
spike can also happen following antiVEGF treatment. “A few studies have
found that after repeated anti-VEGF
injections the trabecular meshwork
becomes inflamed on a microscopic
level, which prevents the drainage
system of the eye from working as effectively as it did before,” says Dr. Patel. “However, only a few small studies
have found this; it hasn’t been seen
in any large clinical trials. I’ve never
had a patient on anti-VEGF drugs
whose IOP has become uncontrollable or needed to use topical IOP
medications. In fact, I’ve had macular
degeneration patients whom I’ve injected with these drugs for the past 30
months who never had an IOP issue.
“Nevertheless, we should be cognizant of that possibility, because it is
in the literature,” he says. “However,
I’m sure the patients who had those
spikes had some predisposing issue
or factor or family history that made
them more prone to developing the
IOP abnormality.”
Perfect Together?
One possibility when considering
anti-VEGF and steroid options is to
use both. Many surgeons do, combining them in different ways, some
sequentially, some simultaneously.
Dr. Patel says he has sometimes
combined anti-VEGF and Ozurdex treatments in a single patient. “I
do think that’s promising,” he says.
“I’ve had a few patients on Ozurdex
who seemed to lose their response
over time or still had some refractory CME, so I’ve switched them to
Lucentis. Over a period of six months
I may give them three injections.
I’ve also switched to Ozurdex when
a patient wasn’t responding as well
after six months of Lucentis, or when
the patient was tiring of the monthly
injections. Either way, making the
switch does seem to be effective.
There seems to be a symbiotic relationship, where if one drug stops
working as effectively as it did initially,
the other drug brings back the treatment efficacy.”
“I think a lot of patients would
benefit from combination therapy,
although very few people do it,” says
Dr. Brown. “That’s mainly because
the anti-VEGF drugs appear so safe
and the patients quickly realize how
easy it is to get that 32-ga. injection.
In Great Britain where Ozurdex is
approved and anti-VEGF is not, there
are quite a few doctors using OzurAugust 2012 | Revophth.com | 43
035_rp0812_f3.indd 43
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REVIEW
Cover
Focus
dex. Next door in Ireland and Scotland, where Lucentis is approved, it’s
more like the United States—more
people are using anti-VEGF.”
Dr. Singer—who has developed a
protocol that uses both drugs simultaneously—notes that while getting
the best possible visual result is ideal,
the steps required to get that outcome
are sometimes not so feasible. “For
some patients, it’s hard to come in
every month,” he says. “So, I ask them
about their motivation. Do they need
the best possible vision, and are they
willing to put in the time to get that
vision? If they are, I’d start with antiVEGF therapy, at least for the first
six months. But if there’s a lifestyle or
convenience issue, then I would opt
for combination therapy, meaning the
concurrent use of both anti-VEGF
drugs and Ozurdex.
“We’ve run a number of clinical trials looking at this type of combination
therapy,” he continues. “What’s nice
about it, at least in our hands, is that
it gives us predictability. When I treat
with combination therapy, I can tell
you that the macular edema is going
to be controlled for about 108 days—
three and a half to four months. That’s
very consistent from cycle to cycle.
“Basically, I give one shot and two
weeks later I give the other shot, for
logistical reasons having to do with
reimbursement, convenience and so
forth,” he explains. “I know with a
high degree of certainty that these
patients will fall into one of two categories. About 20 percent of them
will improve and remain that way for
at least six months with just the one
treatment. The remainder will get
rebound edema three and a half to
four months later. What’s remarkable
about this is that we can’t make that
kind of timing prediction with any
other therapy for any other disease.
With monotherapy, we can’t be sure
how long the improvement will last.
But with this combination treatment,
we have statistically significant data
improvement respectively in central
retinal vein occlusion for VEGF-trap
at six months. Our data shows somewhere between 13 and 15 letters improvement with combination treatment. So the mean visual acuity gain
is slightly less with combination therapy, at least in our hands. However,
you do gain convenience. There’s no
free lunch—you’re getting one thing
in exchange for something else.”
An example of hemi-retinal vein occlusion.
Adding Laser to the Equation
showing that the timing of rebound
edema is predictable.”
Dr. Singer notes that this therapy
does require being proactive about
a potential steroid response. “In our
studies, about 18 to 20 percent of
patients have a steroid response to
Ozurdex,” he says. “Statistically, it
happens between six and 10 weeks,
regardless of the magnitude of the
pressure spike. So if you want to use
combination therapy, you can have
the patient seen by a general ophthalmologist or someone in your office to
check the pressure at a two-month
visit. If the patient happens to be a
responder, you can give him a drop
and send him on his way. Or, give the
patient a drop at the outset and don’t
worry about it—although some would
consider that overtreating.
“So, if the logistics of monthly injections are too hard for some patients, that’s the conversation I would
have with them,” he says. “I explain
that they’ll have three sets of combination therapy over the course of a
year, and we’ll make sure their pressure is checked at around two months
post-injection, just to be safe. Their
vision should improve. They may
need to use anti-glaucoma drops, but
I’ve decreased the number of visits
and shots they’ll need.
“Of course, the downside of the
combination approach is that patients
don’t do quite as well in terms of peak
improvement,” he adds. “The GALILEO study showed 17 and 18 letters
Laser treatment has been used to
treat retinal vein occlusion for some
time, although without the dramatic
results associated with anti-VEGF
therapy. Dr. Brown notes that when
treating branch retinal vein occlusion,
many surgeons add grid laser, particularly in those patients that need
continued therapy. “The Branch Vein
Occlusion Study data showed pretty
convincingly that if you can stop the
leakage, using the laser is better than
no laser,” he says. “Of course, now that
we have anti-VEGF drugs, we protect
the fovea by staying outside a 1,500µm circle. In any case, we haven’t yet
seen that tried in combination with
anti-VEGF in a clinical trial.”
Today, a number of surgeons are
trying a different laser protocol, using it only in the periphery. Early results are promising. “I’ve been giving
people anti-VEGF therapy or combination therapy for a number of years
now, and the reality is that the majority of people continue to get rebound
edema,” says Dr. Singer. “Patients get
tired of coming in for shots. The question is, how long will the edema continue to recur in a given patient?
“My experience—and the work of
several other researchers—has convinced me that peripheral ischemia is
what drives the edema,” he continues.
“Our group has recently done some
work with widefield angiography using the Optos machine. We’ve been
working with the University of Cali-
035_rp0812_f3.indd 44
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RP0812_Heidelberg.indd 1
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Cover
Focus
CRVO with neovascularization and edema, before peripheral laser treatment (left), immediately after laser (middle) and after post-laser
regression of neovascularization and edema. (These were taken with a Staurenghi contact lens, so the images are inverted and reversed.)
fornia reading center, using very precise algorithms to quantify peripheral
ischemia. We found that individuals
who have more edema have more peripheral ischemia. And, we’ve found
that giving anti-VEGF shots increases
circulation, causing a decrease in ischemia that’s accompanied by reduced
macular edema.”
Dr. Singer says that, with this finding in mind, they’ve been working to
use targeted laser photocoagulation
on the peripheral ischemia. “This is
not the same as using focal laser to
treat the areas of edema,” he points
out. “In the Central Vein Occlusion
Study, lasering the macula was not
significantly better than observation.”
Dr. Singer says the idea is to reduce
the production of VEGF in the ischemic part of the retina. “Think of it as
watering the grass, and you’ve got a
knot in the hose,” he says. “The water
runs out after a while, and because
the flowers don’t get any water they
scream for help, putting out VEGF.
That either builds more vessels, as
happens in diabetes or severe ischemic CRVO, or increases inflammation, which causes macular edema.
The idea is to stop the cycle by decreasing the amount of VEGF that’s
produced. We’re pulling the flowers
that are wilting out of the ground.
Hopefully, by using targeted laser you
won’t need to destroy much peripher-
al vision to stop the cycle of rebound
macular edema.”
Dr. Singer says he’s only at the first
stage of proving that this works. “The
next stage will be to laser individuals
for whom I already have wide-field
maps,” he explains. “Then I can get
quantitative data, hopefully showing
that the cycle length between injections is longer, or that they don’t need
any more shots.”
Dr. Brown is pursuing the same
kind of approach. “If we know that the
edema is triggered by VEGF, why not
try to shut down the VEGF drive?” he
asks. “Would peripheral laser to ischemic areas decrease the need for ongoing injections? That idea certainly
makes sense, although it’s never been
proven. Laser is inflammatory, after
all, so a panretinal photocoagulation
could trigger rebound edema.
“We’re currently doing two investigator-sponsored trials looking at
peripheral laser ablation combined
with anti-VEGF treatment,” he continues. “Half the patients are being
randomized to Lucentis and half to
Lucentis-plus-laser, using widefield
Optos imaging. Hopefully we’ll get
some preliminary data which will then
guide a larger trial.”
The Decision Tree
Drs. Brown, Singer and Patel ex-
plain how they choose the best approach to use when faced with a new
patient in the clinic. “When a patient
comes in, if he’s relatively asymptomatic and functioning fine, I say, ‘We
could treat you right away and maybe
make this better, but the problem may
fix itself,’ ” says Dr. Brown. “So, I give
those patients four to six weeks to
get better on their own. On the other
hand, if a patient comes in and says,
‘I can’t see, I can’t drive,’ I typically
inject anti-VEGF that day or within a
few days to get some rapid relief.
“I typically give anti-VEGF injections at least two or three times sequentially,” he continues. “If the eye is
bone dry and seeing better and doing
fine, I start to treat-and-extend pretty
early—maybe as early as the third
shot. But if the eye still has edema
at the end of the month, I bring the
patient back sooner to see if he may
be responding at a week but then rebounding. Some young patients have
such a high level of VEGF production that this is what happens. In that
situation, I’m much more likely to use
an option like Ozurdex. I also offer
Ozurdex as an option to patients who
constantly need monthly injections to
maintain their benefits.
“If a patient has a branch retinal
vein occlusion with microaneurysms
that are leaking, or areas of ischemia,
I’ll discuss the possibility of doing
035_rp0812_f3.indd 46
7/24/12 3:09 PM
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adjuvant grid laser at three or four
months,” he adds. “I’d typically do
the treatment a week or two after the
injection. If the patient has a central
retinal vein occlusion, we talk about
steroids vs. anti-VEGF, and how steroids may get you a little bit longer
time between treatments, as well as
the risk/benefit ratio. I also mention
the possibility of peripheral laser, although at this point, I’m mainly only
doing this in the confines of our randomized controlled trial.”
Dr. Patel notes that when dealing
with macular edema secondary to
retinal vein occlusion, every patient
presents as a different therapeutic
challenge. “Steroids and anti-VEGF
are not mutually exclusive in patients
with CRVO or BRVO, but choices
must be made based on relative benefit/risk ratios as to which option will
be the first-line treatment and which
will take an adjunctive role,” he says.
“That choice is always difficult.
“When patients come into the office with a retinal vein occlusion, the
first thing I consider is their age,” he
continues. “If they’re younger, I‘m
concerned about a systemic abnormality—whether they have an underlying cardiovascular or hematological abnormality that may make
them more prone to having retinal
vein occlusion. Oftentimes, younger
patients who present with retinal vein
occlusion are not aware of having any
systemic abnormality.
“This subset of patients must be diagnosed and treated aggressively, both
locally and systemically,” he notes. “In
atypical cases, such as younger patients and bilateral or recurrent retinal
vein occlusions, I collaborate closely
with my patient’s primary care physician. In the past, I’ve seen laboratory tests—such as a complete blood
count, fasting serum glucose, serum
protein electrophoresis, homocystein, serum viscosity or thrombophilic
screening (factor V Leiden mutation,
protein C or S deficiency, antithrom-
The Surgical Options
In the past, surgical options for treating retinal vein occlusion were more commonly
used than today, although reports of different techniques continue to appear in the literature. The current lack of enthusiasm for surgery is largely attributable to a paucity of
strong data supporting surgical options and a surplus of data showing the effectiveness
of alternatives such as anti-VEGF, steroids and laser.
“The surgical options for addressing retinal vein occlusion have not been shown to be
of benefit in the long term in randomized controlled clinical trials, at least so far,” notes
Michael A. Singer, MD, managing partner and director of clinical trials at Medical Center
Ophthalmology Associates in San Antonio, Texas. “Everyone who did surgery for vein occlusions many years ago saw patients who looked better but didn’t see any better. Today,
retina specialists have moved away from surgical options.”
David M. Brown, MD, FACS, who helped design most of the major anti-VEGF retinal
vein occlusion clinical trials, including BRAVO, CRUISE and COPERNICUS, agrees. “One
problem with vein occlusions is that about a third of the cases do pretty well, even if you
just watch them. That means if you do some surgical cases and you have a phenomenal
result, you don’t know whether you just got lucky and picked someone who would have
had a great outcome anyway. Furthermore, now that anti-VEGF works really well for
most people, you’re going to have to have a surgical complication rate of almost zero to
equal that safety profile.”
“There’s an old laser treatment that creates a chorioretinal venous anastomosis, in
which a shunt is created between a retinal vein and the choroids,” says Ravi D. Patel,
MD, who practices at Retinal Vitreal Consultants in Chicago. “This aims to bypass the
occluded vein, to improve retinal outflow and relieve the venous obstruction. However,
there are a lot of risk factors and side effects associated with that. For example, the
patient can develop a massive vitreous hemorrhage, requiring additional surgery.
“Surgical decompression of the central retinal vein with radial optic neurotomy is a
relatively new procedure in the management of CRVO,” he continues. “Some authors
describe it as a safe and effective way of protecting visual acuity, but others believe that
it’s far from being safe and does not serve its purpose of decompression of the scleral
outlet. In my opinion, there are so many safer options in our armamentarium today that I
think those approaches are mainly of historical interest.”
Dr. Brown thinks optic nerve fenestration probably has no scientific basis at this point.
“Choroidal anastomosis is interesting, especially if you can do it with a laser, so that
may have a role,” he says. “However, any surgical option that involves a vitrectomy is
problematic, because if you remove the vitreous you handicap yourself. You decrease the
effective half-life of every drug option except a sustained-release device like Ozurdex. So
you’ve given up your most effective agents if your surgical treatment doesn’t work.”
—CK
bin III deficiency or antiphospholipid
antibodies)—ordered with successful
screening outcomes.
“The second thing I consider is the
duration of the problem,” he continues. “Has the patient come in relatively soon after his vision has dropped,
or did he wait? Patients who present
right away respond well to either antiVEGF or steroid treatment.
“I had a patient about a year and a
half ago, just after Ozurdex was approved by the FDA, who came in with
extensive macular edema the day after
her CRVO,” he recalls. “Her vision in
the affected eye was 20/400. We had
a lengthy discussion about the pros
and cons of treating with Lucentis vs.
Ozurdex. She was in favor of Ozurdex
because of the decreased treatment
burden. It turned out that she only
required one Ozurdex treatment and
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one grid laser treatment two weeks
later. Her vision today is 20/25. Her
outcome was amazing—she was one
of those home-run patients.”
Regarding how long the problem has existed at first presentation,
Dr. Brown notes that the BRAVO,
CRUISE and COPERNICUS data
showed that even patients who have
six months or longer duration of blockage before they’re treated do benefit
from therapy. “They gain quite a bit
of vision, although they don’t seem
to gain quite as much as those who
start treatment early on,” he says. “In
fact, I’m just as aggressive in treating
someone who shows up with a sixmonth history as I am with somebody
that shows up with a two day history—maybe even more so. The natural
history studies suggest that about a
third of those who have just suffered
a blockage will improve on their own.
The ones who’ve had the problem for
six months are not going to improve
on their own. If you don’t intervene
with those patients, you’re only going
to lose more ground.”
Dr. Patel says that when using antiVEGF injections, his usual algorithm
is treating the patient for the first
six months with monthly injections.
“There are two reasons I do this,” he
explains. “First, it helps to clear the
macular edema very quickly; within
the first five days the patient notices a
significant improvement in his vision,
and the central macular thickness
from the macular edema is halved—
in some cases improved by as much
as 85 percent. So you get a dramatic
treatment effect. Second, it helps to
rapidly clear the retinal hemorrhages
that occur.”
Dr. Patel notes that these patients
usually like to be seen regularly, and
seeing them every month or every two
to three weeks makes the rapport between the physician and patient much
stronger. “These patients are usually
very keen on getting some treatment
and making sure that their vision is
improving,” he says. “Coming in every
month can be a burden for some patients and their families, but younger
patients are generally all for it.
“After six months it’s best to continue monthly follow-up visits, and
ranibizumab injections for recurrent
edema have been shown to maintain visual benefit,” he adds. “If I
find some minor residual edema in
a BRVO patient after six months of
anti-VEGF treatment, I’ll perform a
grid laser therapy in the area of the
macular edema. Combination therapy
with grid laser, in my experience, has
prolonged the therapeutic effect of
the previous six months of injections.”
Dr. Patel notes several circumstances in which he’d be inclined
to opt for Ozurdex rather than antiVEGF drugs:
• When the patient has had a
vitrectomy. “These patients do not
have the vitreous sink to hold onto the
anti-VEGF agent,” he says. “So if they
have no IOP or glaucoma issues, I
inject them with Ozurdex almost 100
percent of the time. Ozurdex provides
stable drug levels in vitrectomized
eyes, as opposed to the rapid clearance seen with Lucentis.”
• If the patient has an extensive
cardiovascular history. “In this situation, steroids may be safer than anti-VEGF,” he notes. “I try to avoid using monthly anti-VEGF treatments,
because these drugs do have a very
small risk of systemic side effects.”
• If the patient has significant
macular ischemia. “Suppose a patient has had diabetes before, and
on top of the diabetes he develops a
retinal vein occlusion,” says Dr. Patel.
“Repeated anti-VEGF injections have
been shown to increase macular ischemia. So in those patients you have to
be very careful about giving frequent
anti-VEGF injections.”
• If a treatment burden exists for
the patient. In this type of situation I
generally opt for treating with Ozurdex, which provides sustained release
for up to six months.” he says.
What’s Next?
Dr. Singer acknowledges that none
of these treatments really solves the
underlying problem—the occlusion.
“I believe that by giving all of these
interventions we’re actually prolonging the disease course,” he says.
“But hopefully we’re decreasing the
amount of scarring and fibrosis and
atrophy centrally that you’ll get compared to letting the body handle the
problem on its own.
“To me, the question is not whether
you can control the edema,” he adds.
“The question is, can you stop the
cycle? I’d like to see us reach a point
at which we can eliminate the edema,
leave the patient with good vision and
have that improved vision last, within
a year. I think this will come from a
combination of an anti-inflammatory,
an anti-VEGF and probably laser,
timed at intervals.”
Drs. Singer and Patel anticipate
eventually having the ability to deliver
multiple drugs through a sustaineddelivery platform. “In every other
field of medicine, people use combination therapy,” notes Dr. Singer.
“The way I see the future is, you find
a sustained-delivery method, you put
a number of different classes of drugs
in it, and you give the patient a shot
every six months. You mitigate the
side effects and actualize the potential
of the combination.”
Dr. Patel agrees. “Hopefully,” he
says, “the next advance will be combination therapy with multiple drugs
in an extended-release device, so the
patient’s treatment burden is significantly reduced.”
Drs. Singer and Brown have been
consultants to Genentech, Regeneron
and Allergan, and have received research funding from all three companies. Dr. Patel has no financial ties to
any company or product mentioned.
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REVIEW
Therapeutic Topics
Vasoconstrictors:
Myths and Realities
The facts about how vasoconstrictors work and thoughts about
mechanisms behind their purported negative side effects.
Mark B. Abelson, MD, CM, FRCS, FARVO and Lisa M. Smith, Andover, Mass.
or generations, we have used ophthalmic products to make our eyes
more attractive: There’s the alluring
gaze brought on by belladonna drops
and the bright contrast created by
the astonishing formulations containing methylene blue (now banned by
the Food and Drug Administration),
which are still popular in the French
product Collyre Bleu.1 There’s even
the recommended routine of selfurine eye drops promoted by Ayurvedic medicine, and you might be
surprised to hear that the purported
beneficial properties of urine have
trickled down to ophthalmic medicine in the original urea-containing
formulation of Murine, whose eardrop line still contains this urine
derivative.2
It’s during this quest for improved
appearance that vasoconstrictors
appeared. The easy entry of ocular
vasoconstrictors into medical practice, their utility and relative safety
and the thousands of patient-years
of experience we have with them are
all clear. However, critics allege that
these agents suffer from rebound
effects, tolerance issues and ocular
tachyphylaxis. This article takes a
F
closer look at vasoconstrictors’ various attributes, pros and cons.
safety concerns, and this labeling
has remained unchanged.
Vasoconstrictors Arrive
Mechanism of Action
Vasoconstrictors have been available for treating hyperemia for decades. When the cardiovascular activity of imidazoles was explored in
search of therapies, their introduction as nasal decongestants in the
mid-1940s was followed by ophthalmic preparations. To provide greater efficacy, ocular vasoconstrictors
were paired early on with topical
antihistamines to combat the itching
and redness associated with allergic
conjunctivitis. Legislation in 1962
mandated proof of efficacy for each
of these components, prompting inception of the conjunctival allergen
challenge model for evaluation of
antihistamine/decongestant combinations. 3 While studies of these
agents’ duration of action have
never been done, the FDA Overthe-Counter Code of Federal Regulations Title 21 Parts 349 and 369
recommend “up to four times daily
dosage” for these first-generation
vasoconstrictors due to theoretical
Vasoconstriction provides temporary relief from tissue congestion. The
mechanism by which vasoconstrictors
act is adrenergic receptor activation. All
ocular vasoconstrictors available today,
including naphazoline, tetrahydrozoline, phenylephrine and oxymetazoline,
act as adrenergic receptor agonists. ARs
mediate the physiological response to
catecholamines, norepinephrine and
epinephrine, and are central to cardiovascular and central nervous system activity. They are members of the superfamily of G-protein coupled receptors,
classified as α1-AR, α2-AR and β-AR,
each with multiple and mixed subtypes. Local sub-type concentrations,
distributions and ligand binding affinities all define a given tissue’s response
to adrenergic agonists. The ophthalmic
vasoconstrictors are α1- or mixed α1/
α2-adrenergic receptor agonists.4
ARs mediate stimulation of smooth
muscle contraction and, systemically,
play a role in control of blood pressure.
α1-ARs are excitatory post-synaptic
052_rp0812_ttops.indd 52
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receptors, constricting larger arterioles. α2-ARs often work in opposition
to α1 receptors, mediating nociception, blood pressure and spinal reflexes. α2-ARs mediate smooth muscle
contraction, and also inhibit release
of norepinephrine by sympathetic postganglionic fibers.
There are two classes of vasoconstrictors: sympathomimetic amines
and imidazoles. Sympathomimetic
amines mimic the actions of the sympathetic nervous system through the
pre-synaptic release of norepinephrine
in sympathetic nerves. Norepinephrine
then binds post-synaptically to α-ARs,
resulting in vasoconstriction. The imidazoles can be α2-AR agonists (e.g.,
brimonidine), or mixed α1-AR/α2-AR
agonists (e.g., naphazoline), and act
post-synaptically on sympathetic nerves
to cause vasoconstriction. They may
also lower production of norepinephrine, thus decreasing blood flow and
reducing congestion.
Vasoconstrictors and the Adrenergic Cascade
Ca2+ Ca2+
Ca2+ Ca2+
Ca2+
Ca2+
2+
Ca2+
Ca
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
Tachyphylaxis
G-protein-coupled adrenergic receptors activate phospholipase C, resulting in release of
intracellular calcium, ultimately leading to smooth muscle vasoconstriction.
Adrenergic-mediated vasoconstriction is associated with unwanted pharmacological and clinical phenomena,
such as tachyphylaxis, tolerance, rebound vasodilation, toxicity and the
potential for abuse. In contrast to tolerance, which occurs with chronic use of
a drug, tachyphylaxis is a rapidly decreasing response to a drug following
its initial administration. Tachyphylaxis
occurs in the presence of alpha-adrenergic agonists by reducing the availability of receptors in an effort to maintain
homeostasis within the affected cells.
Beta-blocker tachyphylaxis involves
binding and stabilizing receptors, as
well as inhibiting a cell’s ability to remove receptors from its surface.5
As early as 1946, there were reports
of the adverse rebound effects of nasal
vasoconstrictor use.6 In fact, most of
the studies describing rebound relate
to the use of nasal vasoconstrictors. The
picture is not as well-defined in the eye.
In 1984, we showed that use of tetrahydrozoline was clearly associated with
tachyphylaxis, but not rebound.7
Several studies suggest that tachyphylaxis and rebound nasal congestion
are due to changes in the α1-AR population.8-11 Receptor sequestration has
been proposed to be a rapid mechanism of desensitization to acute hyperstimulation, while down-regulation and
reduction in receptor number might
be an adaptive response to chronic
exposure to agonists. The complexities
of adrenergic-mediated vasoconstrictor tachyphylaxis and rebound will be
discussed in an upcoming column.
Tachyphylaxis leads to a rapid reduction in efficacy of nasal and ocular vasoconstrictors, prompting the patient
to overuse the medication and laying
the groundwork for a subsequent rebound effect in the nose, and a potential toxic reaction and medicamentosa
in the eye.
Rebound vs. Tachyphylaxis
Rebound is common in central nervous system pharmacology. It’s defined
as a return of symptoms, to a degree
stronger than present initially, upon
discontinuation of a drug. It is a known
risk of anxiolytics and nasal vasoconstrictors, and it’s assumed to occur with
ocular vasoconstrictor use. Our early
work didn’t demonstrate rebound with
ocular vasoconstrictors,7 but other reports of it can be found in the literature.12,13
It’s difficult to distinguish actual rebound, (i.e., greater redness and vasodilation resulting from abrupt drug
discontinuation), from tachyphylaxis
due to dampening of receptors, and
the resulting toxicity due to chronic
abuse. OTC labeling warns of a possible rebound effect with ocular vasoconstrictor use, though a distinction of
rebound vs. toxicity due to abuse hasn’t
7/27/12 12:59 PM
REVIEW
Therapeutic
Topics
Table 1. Ocular Vasoconstrictors Available Worldwide*
Commercial Name
Decongestant/Other Active
Commercial Name
Component(s)
naphazoline 0.12%/PEG as humectant Naphcon-A
Decongestant/Other Active
Component(s)
naphazoline 0.025%/pheniramine 0.3%
antihistamine
naphazoline 0.1%
Advanced Eye Relief
Redness Instant Relief
Advanced Eye Relief
Redness Maximum Relief
AK-Con
naphazoline 0.03%/hypromellose as
lubricant
naphazoline 0.1%
Nazil Ofteno
AK-Nefrin
phenylephrine 0.12%
Neofrin
phenylephrine 0.12%
Albalon
naphazoline 0.1%
Ocu-Phrin
phenylephrine 0.12%
All Clear
Ocu-Zoline
tetrahydrozoline 0.05%
Ocu-Clear
oxymetazoline 0.025%
All Clear AR
naphazoline 0.012%/PEG as
humectant
naphazoline 0.012%/zinc sulfate as
astringent
naphazoline 0.03%/lubricants
Opcon-A
Allerest
naphazoline 0.012%
Opti-Clear
naphazoline 0.2625%/pheniramine
0.315% antihistamine
Allersol
naphazoline 0.12%
Optigene 3
Altazine
Prefrin
phenylephrine 0.12%
Prefrin Liquifilm
phenylephrine 0.12%/lubricants
Refresh Redness Relief
phenylephrine 0.12%/lubricants
Tetrasine
Vasoclear
naphazoline 0.02%
Vasoclear-A
All Clear ACR
Clear Eyes ACR
Neo-Synephrine Ophthalmic phenylephrine 0.12%
astringent, glycerin as lubricant
Clear Eyes Complete
7 Symptom Relief
astringent, lubricants
Clear Eyes Cooling Itchy Eye naphazoline 0.012%/glycerin as
Relief
lubricant, zinc sulfate as astringent
Clear Eyes Maximum
naphazoline 0.3%/glycerin as
Redness Relief
lubricant
Clear Eyes Redness Relief
naphazoline 0.012%/glycerin as
lubricant
Collyrium Fresh
tetrahydrozoline 0.05%/glycerol as
lubricant
Comfort Eyedrops
naphazoline 0.03%
Vasocon
astringent
naphazoline 0.05%/antazoline 0.5%
antihistamine
naphazoline 0.1%
Degest 2
naphazoline 0.012%
Visine Original
Estivin 2
naphazoline 0.012%
tetrahydrozoline 0.05%/lubricants
Eyesine
Geneye
Visine Maximum
Redness Relief
Visine Advanced
Redness Relief
Visine-A.C.
Geneye Extra
tetrahydrozoline 0.05%/unknown
Visine Totality
Isopto Frin
phenylephrine 0.12%
Visine L.R.
Murine Tears Plus
Visine-A
Nafazair
tetrahydrozoline 0.05%/lubricant,
povidone
naphazoline 0.1%
Naphcon
naphazoline 0.012%
Naphcon Forte
naphazoline 0.1%
Vasocon-A
tetrahydrozoline 0.05%/lubricants
tetrahydrozoline 0.05%/zinc sulfate
as astringent
tetrahydrozoline 0.05%/zinc sulfate as
astringent, lubricants
oxymetazoline 0.025%
naphazoline 0.025%/pheniramine 0.3%
antihistamine
Zincfrin
phenylephrine 0.12%/zinc sulfate
as astringent
Zincfrin-A
astringent, antazoline 0.5% antihist.
* Trademarks are property of their respective owners.
7/27/12 12:59 PM
been established. Many cases of exaggerated redness are a combination of all
these events. One study identified 70
patients with vasoconstrictor-associated
conjunctivitis, though signs were present during therapy and appeared to be
related more to chronic vasoconstrictor
abuse due to tachyphylaxis rather than
rebound.12 Another study reported
five cases of eyes becoming redder after the suspension of a vasoconstrictor than they were before treatment.13
Medicamentosa,12 even with one case
resembling ocular pemphigoid,14 is
documented, as are reactions due to
vasoconstrictors in subjects with acute
angle-closure glaucoma.
Duration of Relief
With the exception of oxymetazoline, which is approved for dosing up
to every six hours, naphazoline, tetrahydrozoline and phenylephrine are
approved for dosing up to every four.
However, these recommendations are
based on historical usage patterns15
rather than pharmacokinetics, and are
now integrated by default into OTC
labeling. Consumer expectation is for a
duration of several hours, and a lack of
effect might lead to overuse and toxicity. Manufacturers have confounded
the duration issue by using modifiers
such as “maximum” and “advanced,”
which suggest a longer duration due to
lubricants meant to prolong comfort,
yet with unchanged active ingredients
and/or dose. Table 1 on p. 54 provides a
list of ocular vasoconstrictors.
Key to the issue of duration is the
indication for vasoconstrictors mandated by the FDA OTC Monograph,16
which provides the regulatory basis for
the wording of package inserts: “relief
of redness of the eye due to minor eye
irritations.” This certainly translates to
real-world use patterns: No one has yet
thought to preventively whiten their
eyes before heading out for a late night
of festivities. Consumers are undoubtedly self-medicating for treatment of
a self-limiting condition, and vasoconstrictors are used for relief of redness.
Remarkably, given this mandated indication and recognized use, there are no
published reports on relief of redness.
Thirty years ago, our original work on
vasoconstrictors in the histamine challenge model involved prevention of
redness, with duration of action demonstrated at one to two hours after dosing for naphazoline, tetrahydrozoline
and phenylephrine, but oxymetazoline
was not tested.17 Studies today are still
designed to establish the efficacy of
vasoconstrictors by their prevention of
redness induced by various challenges.
Ongoing efforts to establish a model
for relief of ocular redness induced by
irritation with a chlorine, salt-water,
allergen or histamine challenge might
substantiate efficacy and duration in a
more appropriate setting. Redness is
most often the short-lived result of one
discrete irritating or allergic stimulus
that the eye can suppress on its own,
rather than the result of continuous,
redness-inducing stimuli. This natural
decay makes it difficult to prove the efficacy of vasoconstrictors, and multiple
challenges might be necessary to maintain a baseline redness that can then be
modified pharmacologically.
We recently experienced this difficulty firsthand in a placebo- and active-controlled CAC evaluation (n: 17/
arm) of the 15-minute, four-, six- and
eight-hour efficacy and duration of action of 0.025% oxymetazoline, the goldstandard vasoconstrictor approved for
use every six hours. Surprisingly, for
the only vasoconstrictor with claims of
being long-acting, no significant effect
on prevention of redness was shown
at any time point. This lack of effect
prompted us to search without success
for published studies that showed the
efficacy and duration of oxymetazoline.
Unmet Need
Nine out of 10 subjects report selfmedicating for ocular redness, a condi-
tion associated with reduced quality of
life and negative social connotations
such as drinking and drug abuse, in
addition to general fatigue and cosmetic concerns. In the United States,
the OTC eye-care market represents
approximately $500 to $700 million annually on sales of 60 to 80 million units.
Redness relief products comprise ~ 37
percent of unit sales, and redness plus
allergy relief is close to 60 percent.
While all vasoconstrictor package
labeling contains the caveat to “stop
use and ask a doctor if condition worsens or lasts more than 72 hours,” most
eye-care specialists are confident that
vasoconstrictors are used for relief of
a temporary, self-limiting irritation and
will not mask a serious underlying condition. Thus, there is an unmet need
to develop a drug that provides clinically relevant relief of redness resulting from episodic irritation, without
the drawbacks of tachyphylaxis, abuse
and toxicity.
With emerging evidence that tachyphylaxis appears to be an α1-AR-related phenomenon, research efforts have
shifted to α2-AR agonists as potential
vasoconstrictors. Studies have shown
that nasal decongestion evoked by α2AR activation might have lower cardiovascular side effects than α1- or nonselective α-AR vasoconstrictors such as
phenylephrine and oxymetazoline.10,11
Brimonidine is a second generation
α2-AR agonist that was first approved
by the FDA in 1997 for treatment of
ocular hypertension with t.i.d. dosing.
It has greater selectivity for α2-ARs
(α2-AR/α1-AR binding affinity ratio ~
1000:1) and lower lipid solubility than
clonidine and apraclonidine, providing
a greater ocular hypotensive effect with
lower systemic side effects. The most
common side effects associated with
chronic ocular use of brimonidine for
elevated intraocular pressure are dry
mouth and ocular redness/conjunctivitis, the latter with a reported inci(Continued on page 69)
7/27/12 12:59 PM
REVIEW
Retinal Insider
Edited by Carl Regillo, MD and Emmett T. Cunningham Jr., MD, PhD, MPH
Infection: The Evolving
Role of Antibiotics
Endophthalmitis prevention continues to spur debate in
ophthalmology. A look at current policies and outcomes.
By Andrew M. Schimel, MD, and Harry W. Flynn Jr., MD, Miami
he appropriate use of antibiotics to prevent infection continues
to be a topic of great debate in ophthalmology. In our specialty, there is
increasing concern over reports of
significant bacterial resistance with
current antibiotics. At the same time,
there appears to be very little, if any,
major decrease in the rate of endophthalmitis after various procedures
T
when antibiotics are utilized.
Due to these issues and similar concerns in other specialties, the U.S.
Centers for Disease Control and Prevention announced it will be launching a new surveillance system to track
antibiotic use in hospitals.1 The CDC
has provided funding to four health
departments working with academic
institutions to establish the new track-
ing system in 70 hospitals. The new
system will automatically transfer
drug administration data and bar code
records into the tracking system. This
will allow providers to compare their
antibiotic use with that of other facilities and provide data to promote more
judicious use of antibiotics.
In this article, recent endophthalmitis publications will be reviewed
that play a significant role in the way
we address endophthalmitis, both in
terms of prophylaxis as well as current
policies and outcomes.
Peri-procedural Prophylaxis
Figure 1. Endophthalmitis after intravitreal injection is an infrequent complication that
carries potentially devastating visual consequences.
056_rp0812_rtinsider.indd 56
• Antisepsis with povidone-iodine. Intravitreal injections have become one of the most common medical procedures in the United States,
with well over 1 million intravitreal
injections performed in 2010 based
on Medicare data (Ross Brechner,
MD, MS, MPH, oral communication). Endophthalmitis after intravitreal injection (See Figure 1) is a rare
complication that carries potentially
devastating visual consequences with
an incidence of approximately one out
of 1,000 to 5,000 injections.2,3
7/25/12 3:27 PM
A panel of vitreoretinal medical and
surgical experts met in 2004 and established a set of guidelines for the
preparation, administration and postprocedural management of intravitreal injections based on the available
data and their collective experience.4
Of note, no consensus could be
reached regarding the value or the
need for topical antibiotics before,
during or after an intravitreal injection. Generally agreed upon recommendations included the application
of povidone-iodine (PI) to the eyelid
margin, eyelashes and conjunctival
ocular surface prior to injection, and
the use of a lid speculum. A number
of issues have come to light since the
publication of these guidelines. A recent editorial points out the important
distinction between topical antiseptic
agents compared to commonly used
topical antibiotics.5 The use or nonuse of face masks is another controversial issue.
PI is often used for peri-operative
ophthalmic antisepsis and provides
broad-spectrum microbicidal activity (See Figure 2). PI has been wellstudied in regards to antisepsis demonstrating bactericidal activity over a
wide range of concentrations (0.005%
to 10%). It has been shown to result
in a short kill time ranging from 15
to 120 seconds for concentrations of
0.1% to 10%6, with recent evidence
suggesting it may take longer in the
presence of higher bacterial loads.7
PI is also inexpensive, with the average cost of a 30-mL bottle of 5% ophthalmic preparation solution around
$12.00 (redbook.com).
• Topical antibiotics. The use
of prophylactic topical antibiotics as
a strategy to prevent endophthalmitis is controversial (See Figure 3).
Prospective studies have confirmed
that topical antibiotics administered
one hour before intravitreal injection significantly reduce conjunctival
bacteria flora, 8,9 and in vitro studies using fourth-generation fluoro-
Figure 2. Povidone-iodine is a uniformly recommended part of preparation for intravitreal
injection.
quinolones demonstrate eradication
of some endopthalmitis-causative
organisms in five to 15 minutes. 10
Therefore, topical antibiotics would
seem to have benefit given the presumed mechanisms of post-injection
endophthalmitis, which involve direct inoculation of ocular flora at the
time of injection or subsequent entry
through a wound track.11 However,
topical antibiotics have demonstrated
no additional effect on reducing conjunctival bacterial counts beyond the
effect of 5% PI alone.12,13
A recent randomized, controlled,
longitudinal study demonstrated that
repeated exposure of both ocular and
nasopharyngeal flora to ophthalmic
antibiotics as prophylaxis for intravitreal injections selects for resistant
strains of bacteria.14 The results of
this study showed macrolide- and
fluoroquinolone-resistant conjunctival coagulase-negative staphylococci emerging rapidly after exposure
to their respective antibiotic. Of
key significance, the resistance was
maintained or worsened by periodic
reexposure. This finding is thought
to have considerable implications
because conjunctival flora are presumed to be the predominant source
of post-injection endophthalmitis,
and because antibiotic-resistant S.
epidermidis is associated with greater
intraocular inflammation, virulence
and increased ocular infection rate
compared to antibiotic-susceptible
strains.15,16 A study we conducted further demonstrates the alarming increase in fluoroquinolone resistance
among coagulase-negative staphylococcus endophthalmitis isolates, with
rates of resistance of each of the fluoroquinolone antibiotics at more than
50 percent (in press, Archives of Ophthalmology).
The combination of longer kill time
for topical antibiotics,17 the inability
of topically applied antibiotics to attain sufficient therapeutic levels in
the vitreous cavity,18 the emergence
of antibiotic-resistant strains of bacteria and the high cost of these medicines suggests the use of peri-procedural topical antibiotics to prevent
7/25/12 3:28 PM
REVIEW
Retinal
Insider
Figure 3. The use of topical antibiotics before or after intravitreal injection remains a
controversial issue.
endophthalmitis needs to be reevaluated. At the Bascom Palmer Eye Institute, most retinal physicians do not
use peri-injection topical antibiotics.
• Intracameral antibiotic agents
for cataract surgery. A multicenter,
prospective, randomized study conducted by the European Society of
Cataract and Refractive Surgeons
provided positive data supporting
the use of a direct intracameral bolus of cefuroxime at the conclusion
of cataract surgery (See Figure 4).19
A recent update to this study demonstrates seven-year follow-up data
of the study and continued support
of this practice.20 The study initially
demonstrated rates of culture-proven infectious endophthalmitis at 0.07
percent in the groups receiving intracameral cefuroxime prophylaxis
compared with rates of 0.34 percent
in the control groups not receiving
intracameral prophylaxis. Despite
this significant difference, concerns
immediately surfaced because the
control group (operated on from January 1996 through December 2002)
had such an elevated rate of endophthalmitis compared to other studies
performed during the same time period (0.04 percent,21 0.128 percent22).
Rather than settling the debate, the
ESCRS fueled further controversy on
the choice of antibiotic and value of
this practice.
Cefuroxime is a second-generation
cephalosporin with antibacterial activity resulting from its ability to inhibit bacterial cell wall synthesis. It has
limited efficacy against gram-negative
bacteria and high rates of resistance
against methicillin-resistant Staphylococcus epidermidis and Staph. aureus,
two of the most common pathogens in
post-cataract surgery endophthalmitis
infections. Cefuroxime is not available
in a prepackaged form for intracameral
use and must be diluted from powder
form in the operating room, yielding
significant concerns for dilution errors
and contamination.23 Cases of dilutional errors with intracameral antibiotics,
including cefuroxime and vancomycin,
have reportedly resulted in macular
thickening, chronic cystoid macular
edema, serous retinal detachment
and macular infarction. Concerns of
intracameral antibiotics causing toxic
anterior segment syndrome (TASS),
an acute, severe, sterile postoperative
inflammation, have also limited the
regular use of intracameral antibiotics
in the United States.24 Their effectiveness is further questioned, as the safe
concentration of antibiotics in the irrigation fluid requires more than 140
minutes to exhibit a bactericidal effect,
and it is reported that the half-life of
antibiotics in the anterior chamber is
only 51 minutes.25,26
Since contemporary endophthalmitis rates after cataract surgery without intracameral antibiotics (0.03 percent27) are equivalent to or lower than
the ESCRS study rates with intracameral antibiotics (0.05 percent20), there
appears to be little support for their
use given the significant risks.
The Role of Face Masks
Two large studies have been recently released demonstrating a
significantly elevated percentage
of streptococcal species involved in
post-injection endophthalmitis isolates compared to postsurgical endophthalmitis isolates. The first study
was a large meta-analysis of endophthalmitis after intravitreal injection
of anti-VEGF agents including most
major U.S.-based studies from 2005 to
2010.2 In this evaluation, streptococcal isolates were approximately three
times more frequent after intravitreal
anti-vascular endothelial growth factor
injection than after intraocular surgery.
Another group conducted a study
over a similar six-year time period including 60,322 patients from a single
institution undergoing intravitreal injection and reported that five of seven culture-positive cases were due to
streptococcal species.3 The result of
these studies raised concerns regarding the possible oropharyngeal origin
of these streptococcal species. The au-
7/25/12 3:28 PM
thor of the first study proposed strategies to consider minimizing oropharyngeal moisture droplet transmission,
including avoiding talking, coughing
or sneezing, and wearing surgical face
masks during injection procedures. If
a true attempt to reduce aerosolized
moisture droplets is recommended,
then the physician, the nurse/assistant and the patient should all wear
face masks.
As a follow-up to these studies, a
simulation of injection conditions was
created to demonstrate the potential
oropharyngeal droplet contamination
of the field during intravitreal injection.28 The authors concluded that
significantly more colony-forming
bacteria are dispersed onto an agar
plate when speaking without a face
mask compared with when wearing a
face mask or remaining silent during a
simulated intravitreal injection procedure. However, when povidone-iodine
was utilized on the agar plates prior to
a similar in vitro procedure, the dispersed oral flora were effectively eliminated, suggesting that the use of face
masks is less necessary with adequate
antiseptic measures.29
A further review of the literature
reinforced the importance that the use
or nonuse of a face mask during intravitreal injections has yet to be studied as a modifiable risk factor for the
development of endophthalmitis. In
fact, there have been no known large
studies confirming that the use of face
masks decreases rate of infection during sterile procedures.30 We recommend that the use of appropriate aseptic technique, including a lid speculum
and povidone-iodine be used and that
an attempt be made to minimize talking by the nurse or technician, by the
physician, and by the patient during
intravitreal injection procedures.
Compounding Anti-VEGF Meds
In South Florida, a recent outbreak
of post-injection endophthalmitis in 12
Figure 4. Since contemporary endophthalmitis rates after cataract surgery without
intracameral antibiotics are equivalent to or lower than study rates with intracameral
antibiotics, there is little support for their use given the risks.
patients was reported after intravitreal
injection of bevacizumab (Avastin).31
All patients received topical antibiotics after the intravitreal injection. All
patients received intravitreal injections
of bevacizumab prepared by the same
compounding pharmacy in South Florida and 10 of 12 patients had positive
microbiologic cultures for Streptococcus mitis/oralis. Seven unused syringes
of bevacizumab prepared by the same
compounding pharmacy at the same
time also were also positive for S. mitis/
oralis. The visual outcomes were poor
in these cases, consistent with previous
studies reporting poor visual outcomes
in streptococcal endophthalmitis.32
While the majority of the literature
on reducing endophthalmitis rates after intravitreal injection has focused on
the peri-injection period, the importance of drug preparation has largely
been ignored. Bevacizumab is distributed in 4- or 16-mL, preservativefree, single-use vials, and is typically
aliquoted into smaller doses for intravitreal use. The report describes the
importance of compounding pharmacist compliance with the standards outlined in United States Pharmacopeia
chapter 797. These measures include
the use of trained and certified staff,
personal protective equipment and a
properly operated and certified ISO
class 5 environment. The study additionally calls into question whether
bevacizumab syringes prepared from
two different batches might be preferred in patients requiring bilateral
injections.
The use of peri-procedural topical
antibiotics when povidone-iodine is
utilized may not reduce endophthalmitis rates, imposes a large monetary
burden on our health-care system,
and is likely contributing to the rise
in bacterial resistance, particularly after repeated fluoroquinolone usage.
Physicians performing intravitreal
injection procedures are now aware
of the relatively increased frequency
of post-injection streptococcal endophthalmitis. Precautions include minimizing speech during the procedure
and adherence to an aseptic protocol.
Strict pharmacist compliance with
USP chapter 797 mandates is important in the preparation of bevacizumab
in order to reduce the chance of future
outbreaks of post-intravitreal injection
endophthalmitis. In general, cataract
7/25/12 3:28 PM
800.787.5426
haag-streit-usa.com
Imaging with Depth of Field. Just Dandy.
What if none of your slit images had blurry edges? You
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RP0412_Haag Imaging.indd 1
3/13/12 2:59 PM
REVIEW
Retinal
Insider
SPACE PLANNING
Dr. Schimel is a
fellow in vitreoretinal surgery and a
clinical instructor at
the Bascom Palmer
Eye Institute. Dr.
Flynn is the head of
the Retina Service
and the J. Donald M. Gass Distinguished Chair at the Bascom Palmer
Eye Institute at the University of Miami Miller School of
Medicine, Miami.
Contact Dr. Flynn
at: [email protected]. This work
was supported in
part by the National
Institute of Health
Center (grant P30EY014801) and an unrestricted grant
from Research to Prevent Blindness,
New York. The authors have no financial or proprietary interest in the
materials presented herein.
1. Kuehn B. Antibiotic Use Tracking. JAMA 2011;306(24):26612661.
2. McCannel CA. Meta-analysis of endophthalmitis after
intravitreal injection of anti-vascular endothelial growth factor
agents: Causative organisms and possible prevention strategies.
Retina 2011;31:654-661.
3. Moshfeghi AA, Rosenfeld PJ, Flynn HW Jr., et al. Endophthalmitis after intravitreal anti-vascular endothelial growth factor
antagonists: A six-year experience at a university referral center.
Retina 2011;31:662-668.
4. Aiello LP, Brucker AJ, Chang S, et al. Evolving guidelines for
intravitreous injections. Retina 2004;24(5 Suppl):S3-19.
5. Wykoff CC, Flynn HW, Jr., Rosenfeld PJ. Prophylaxis for endophthalmitis following intravitreal injection: Antisepsis and antibiotics. Am J Ophthalmol 2011;152:717-719 e712.
6. Berkelman RL, Holland BW, Anderson RL. Increased bactericidal
activity of dilute preparations of povidone-iodine solutions. J Clin
Microbiol 1982;15:635-639.
7. Hosseini H, Ashraf MJ, Saleh M, et al. Effect of povidoneiodine concentration and exposure time on bacteria isolated from
endophthalmitis cases. J Cataract Refract Surg 2012;38:92-96.
8. Ta CN, Egbert PR, Singh K, Shriver EM, et al. Prospective
randomized comparison of 3-day versus 1-hour preoperative
ofloxacin prophylaxis for cataract surgery. Ophthalmology
2002;109:2036-2040; discussion 2040-2031.
9. Moss JM, Nguyen D, Liu YI, et al. Comparison of one-day
versus one-hour application of topical gatifloxacin in eliminating
conjunctival bacterial flora. Ophthalmology 2008;115:20132016.
10. Callegan MC, Novosad BD, Ramadan RT, Wiskur B, Moyer AL.
Rate of bacterial eradication by ophthalmic solutions of fourthgeneration fluoroquinolones. Adv Ther 2009;26:447-454.
INTERIOR DESIGN
DISPLAY INNOVATION
MANUFACTURING
EYEDESIGNS.COM
800.346.8890
ED-011206
surgeons have not adopted the use of
intracameral antibiotics and yet the
rates of endophthalmitis remain very
low.
11. Kim SJ, Toma HS, Midha NK, Cherney EF, et al. Antibiotic
resistance of conjunctiva and nasopharynx evaluation study: A
prospective study of patients undergoing intravitreal injections.
Ophthalmology 2010;117:2372-2378.
12. Moss JM, Sanislo SR, Ta CN. A prospective randomized
evaluation of topical gatifloxacin on conjunctival flora in
patients undergoing intravitreal injections. Ophthalmology
2009;116:1498-1501.
13. Halachmi-Eyal O, Lang Y, Keness Y, Miron D. Preoperative
topical moxifloxacin 0.5% and povidone-iodine 5.0% versus
povidone-iodine 5.0% alone to reduce bacterial colonization in
the conjunctival sac. J Cataract Refract Surg 2009;35:21092114.
14. Kim SJ, Toma HS. Antimicrobial resistance and ophthalmic
antibiotics: 1-year results of a longitudinal controlled study of
patients undergoing intravitreal injections. Arch Ophthalmol
2011;129:1180-1188.
15. Mino De Kaspar H, Hoepfner AS, Engelbert M, et al. Antibiotic
resistance pattern and visual outcome in experimentally-induced
Staphylococcus epidermidis endophthalmitis in a rabbit model.
Ophthalmology 2001;108:470-478.
16. Miller D, Flynn PM, Scott IU, Alfonso EC, Flynn HW, Jr. In vitro
fluoroquinolone resistance in staphylococcal endophthalmitis
isolates. Arch Ophthalmol 2006;124:479-483.
17. Hyon JY, Eser I, O’Brien TP. Kill rates of preserved and
preservative-free topical 8-methoxy fluoroquinolones against
various strains of Staphylococcus. J Cataract Refract Surg
2009;35:1609-1613.
18. Costello P, Bakri SJ, Beer PM, et al. Vitreous penetration
of topical moxifloxacin and gatifloxacin in humans. Retina
2006;26:191-195.
19. Endophthalmitis Study Group, ESCRS. Prophylaxis of
postoperative endophthalmitis following cataract surgery: Results
of the ESCRS multicenter study and identification of risk factors. J
Cataract Refract Surg 2007;33:978-988.
20. Romero-Aroca P, Mendez-Marin I, Salvat-Serra M,
Fernandez-Ballart J, et al. Results at seven years after the use
of Intracamerular cefazolin as an endophthalmitis prophylaxis in
cataract surgery. BMC Ophthalmol 2012;12:2.
21. Eifrig CW, Flynn HW Jr., Scott IU, Newton J. Acute-onset
postoperative endophthalmitis: review of incidence and visual
outcomes (1995-2001). Ophthalmic Surg Lasers Sep-Oct
2002;33(5):373-378.
22. Taban M, Behrens A, Newcomb RL, et al. Acute endophthalmitis
following cataract surgery: A systematic review of the literature.
Arch Ophthalmol 2005;123:613-620.
23. Montan PG, Wejde G, Setterquist H, Rylander M, et al.
Prophylactic intracameral cefuroxime. Evaluation of safety
and kinetics in cataract surgery. J Cataract Refract Surg
2002;28:982-987.
24. Mamalis N, Edelhauser HF, Dawson DG, Chew J, et al.
Toxic anterior segment syndrome. J Cataract Refract Surg
2006;32:324-333.
25. Gritz DC, Cevallos AV, Smolin G, Whitcher JP, Jr. Antibiotic
supplementation of intraocular irrigating solutions. An in vitro
model of antibacterial action. Ophthalmology 1996;103:12041208; discussion 1208-1209.
26. Lehmann OJ, Thompson JP, White LO, Keys MF, Campbell MJ.
Half-life of intracameral gentamicin after phacoemulsification. J
Cataract Refract Surg 1997;23:883-888.
27. Wykoff CC, Parrott MB, Flynn HW, Jr., Shi W, Miller D, Alfonso
EC. Nosocomial acute-onset postoperative endophthalmitis at
a university teaching hospital (2002-2009). Am J Ophthalmol
2011;150:392-398 e392.
28. Wen JC, McCannel CA, Mochon AB, Garner OB. Bacterial
dispersal associated with speech in the setting of intravitreous
injections. Arch Ophthalmol 2011;129:1551-1554.
29. Doshi RR, Leng T, Fung AE. Reducing Oral Flora Contamination
of Intravitreal Injections with Face Mask or Silence. Retina
2012;32:473-6.
30. Schimel AM, Scott IU, Flynn HW, Jr. Endophthalmitis after
intravitreal injections: Should the use of face masks be the
standard of care? Arch Ophthalmol 2011;129:1607-1609.
31. Goldberg RA, Flynn HW Jr, Isom RF, Miller D, Gonzalez S. An
Outbreak of Streptococcus Endophthalmitis After Intravitreal
Injection of Bevacizumab. Am J Ophthalmol 2012;153:204-208.e1.
32. Miller JJ, Scott IU, Flynn HW Jr., Smiddy WE, et al. Endophthalmitis caused by Streptococcus pneumoniae. Am J Ophthalmol
2004;138:231-236.
7/25/12 3:28 PM
REVIEW
Glaucoma Management
Edited by Kuldev Singh, MD, and Peter A. Netland, MD, PhD
Glaucoma and EHR:
A Clinic Case History
In this instance, the switch to EHR went pretty smoothly—but
tracking the details did reveal a few surprises.
By Michael V. Boland, MD, PhD, and Ravi R. Pandit, MS-IV, Baltimore
ike most ophthalmologists,
those who treat glaucoma are
concerned about how switching to
electronic health records will affect
their practices. Will it compromise
their ability to see the same number
of patients they’re seeing now? Will
the expense and effort of making
the transition pay off by providing
significant benefits? Will the patientdoctor relationship suffer?
Our Wilmer Eye Institute glaucoma
clinic was the first in our department
to transition from a home-grown,
mixed computer and paper system to
an all-digital system. Because we were
concerned about the impact of making
the switch, we decided to conduct
a study during the transition to see
what actually occurred. By measuring
specific factors such as time spent on
different tasks and patient reactions,
we felt we could shed some light on
the concerns that ophthalmologists
have and provide some insights into
what strategies help to make the
transition go more smoothly.
L
Conducting the Study
For our study, we observed the
glaucoma clinic at three discrete
times. First, we measured the factors
we were interested in at baseline—
right before we switched to the new
system. Once the switch occurred,
we allowed two weeks for the clinic to
acclimate to the new system and then
measured the same factors again.
That allowed us to get a sense of what
happened in the short term. Finally,
about six months after the transition,
we repeated the observations.
At each time point we collected
three types of data. First, we measured
the timing of different activities during
the physician-patient interaction.
How long did the physician spend
talking to the patient? Examining the
patient? Looking at the computer?
Looking at paper charts? (Both the
physician and patient were masked as
to what we were measuring.)
Second, we monitored patient
movement through the clinic. We
recorded patients’ check-in times,
when they were called for testing,
when they left testing, when they saw
the physician and when they left the
exam room.
Finally, after the exam, we asked
patients to complete a 12-question
062_rp0812_gm.indd 62
survey about how they felt the visit
had gone. How efficient did the clinic
seem? How was the quality of care?
What the Data Showed
Overall, the results were positive—
although there were a few surprises.
One unexpected finding was that,
on average, there was an increase
in time dedicated to talking to and
examining the patient. That was not
what we had expected.
We’re still analyzing the timing
data, but anecdotally, our observations
indicate that the extra time came
from a change in the way physicians
documented the exams. Before the
switch to EHR, doctors would see
their patients without doing all of the
necessary documentation during the
visit; some was done after the patient
left. But after the switch to EHR,
most of the documentation happened
during the exam. As a result, as soon
as one patient left, another patient
was called in. So the extra time being
spent on the exams was subtracted
from the time between patients.
To confirm this hypothesis, we
calculated the yearly census for the
7/24/12 3:01 PM
All images: Michael V. Boland, MD, PhD
Although ophthalmologists agree that no current EHR system is perfect, an intelligently designed and customized system can prompt the
doctor to ask key questions that might be overlooked, provide a quick overview of a patient’s history, show data in graphic form, minimize
repetitive data entry and prevent data from being lost.
clinic. We found no significant change
in patient numbers between the year
prior to implementation and the year
after. So, the increase in time spent
doing the exam didn’t result in seeing
fewer patients.
We also noted that our physicians
were now spending more time talking
to their patients during the exam.
The most likely explanation appears
to be the nature of today’s EHR
systems. In the past, a computerized
documentation system was pretty
much a blank document into which
you typed your findings. The only
questions you asked during the exam
were those that occurred to you at the
time. In contrast, the new systems
have checklists and drop-down
boxes—mandatory fields that prompt
increased disclosure, because there
are questions on those forms that
many of us might not have asked. In
effect, the system is acting as a failsafe. This may explain the increased
time spent talking to the patient.
Is this a good thing? That depends
on how relevant the questions are.
(In general, we noted that when the
physician felt that questions were
clinically relevant they looked up and
engaged the patient in conversation;
if a question was considered not
clinically relevant, most never looked
away from the computer.) That’s
why the design of the EHR system
you choose is so important, and
why having a system customized for
ophthalmology is so valuable. You
want to elicit a lot of information,
but you want to be sure that the information is clinically useful.
How did patients feel about the
shift to EHR? The patient survey data
indicated that very little changed after
implementation; patients seemed
very neutral about what was going
on. The only thing that changed was
that patients were more likely to say
that the computer interfered with
their ability to talk to the physician.
We expected that, because the more
objective data showed that physicians
were spending more time just looking
at the computer or multitasking
(i.e., looking at the computer while
talking to the patient). But the surveys didn’t reveal any change in patient perception of quality of care,
relationship to the physician or
clinic efficiency.
One related thing that we noted—
not a statistically significant change—
was that our physicians were more
likely to mention to the patient that
the clinic was switching to a new
system. Some even apologized for any
inconvenience the switch might be
causing. Which raises the question:
If the doctors hadn’t called attention
to the change, would the patients
have noticed anything at all?
There’s no way to be sure, but it’s an
interesting question.
The last thing we found was that
the changes that did occur—i.e.,
increased time with the physician
talking to or examining the patient
and increased time on computerrelated tasks and multitasking—
happened within the first two weeks
062_rp0812_gm.indd 63
7/24/12 3:01 PM
REVIEW
Glaucoma
Management
and then stabilized. Many
themselves with the
people expected changes
system ahead of time were
to occur slowly over a long
undoubtedly those who felt
period of time, but at six
comfortable with computers.
months our data was very
So it may be valuable to
similar to what we found
determine which physicians
at two weeks. There was
in your group are less
a slight downward trend
comfortable with computers
(not statistically significant)
and perhaps provide them
in the amount of time
with some more rudimentary
physicians spent on the
training covering basic issues
computer between two A typical examination lane illustrates the challenges of interacting like keyboard shortcuts, the
weeks and six months. That with both the computer and patient simultaneously.
best ways to copy and paste,
makes sense, because the
and when to single-click vs.
doctors undoubtedly became more really change; the proportion of time when to double-click.
familiar with the system over time. patients spent in one station of the
• Be sure to get help with data
But the significant changes happened clinic vs. another didn’t really change. entry. The first three to six months
at the outset.
The changes that did occur were were a little bit painful as we adapted
The relative lack of change after subtle, and related to what happened to the new system, and a lot of that
the first two weeks is probably a good during the time the patient spent with had to do with some patient data not
thing; it implies that if you make the physician. Many of them could being in the system. Staring at mostly
the switch to EHR you can evaluate be considered beneficial, including blank screens when you’re with a
how well it’s working out fairly increased clinical exam time—the patient you’ve been seeing for years
quickly. (Furthermore, doing such time dedicated to examining and is a little bit frustrating. Fortunately,
an evaluation isn’t expensive; doing talking to the patient with eye contact. the screens weren’t completely blank,
our study cost the clinic less than $50,
• Expect the major changes to because we spent money to get
plus the time required to write some be accomplished fairly quickly. some of our prior data loaded into
simple software.)
Among other things, that means that the system for us. And, the painful
As a side note, we did ask the phy- if something isn’t working well for period tapered off pretty quickly as
sicians what they thought about the you, you won’t have to sit with it for six patients started coming back. Within
change, even though this question months before doing something about six months, almost every patient has
wasn’t part of the official study. Their it. You’ll be able to make adjustments been in the clinic at least once, so the
sentiments pretty much reflected and modifications pretty quickly.
data got filled in. Nevertheless, the
what you hear at conferences: EHR
• Provide training and encourage message was clear: If you make the
has a lot of potential, but there’s a individual experimentation. The switch to EHR without having any
long way to go. The challenge seems physicians who took a few moments existing data loaded ahead of time,
to be finding a balance between utility of their downtime to investigate the your productivity will take a much
and not overburdening the physician system and familiarize themselves bigger hit.
with checklists and other mandatory with it before implementation did
• Don’t worry too much about
documentation. Nevertheless, we better after the switch. They exper- patient reaction. As our survey
noted that no one seems interested in ienced fewer problems and issues found, patients scarcely noted the
returning to the old system.
during patient exams. As with any change—even with many physicians
EHR implementation, some invest- pointing it out to them.
ment in training on the part of the
• Don’t assume younger doctors
What We’ve Learned
practice is very important, whether it’s will pick it up faster. We expected
Based on our observations, here formal training or just something the our younger, newer doctors to have an
are a few bits of advice for those physician does on his own.
easier time with EHR, simply because
preparing to make the switch to EHR:
Along these same lines, it’s worth they grew up using computers. But
• Don’t expect a disaster. At least remembering that different people when we deployed the system in
in our clinic, we didn’t find the switch have different comfort levels when our resident clinic it wasn’t nearly as
to EHR to be particularly dramatic it comes to working with computers. successful as we expected. The reason
or catastrophic. The clinic flow didn’t The doctors who familiarized seems to be that the kind of computer
062_rp0812_gm.indd 64
7/24/12 3:01 PM
skills you need to be effective at
using EHR are not necessarily the
same skills honed by using Facebook
and Gmail and operating your
smartphone. Certainly many of the
skills you need to use EHR are not
intuitive, any more than performing
cataract surgery is intuitive. So
although it seemed like an obvious
assumption that our younger doctors
would do better, it turned out not to
be true.
• Don’t wait for an “ophthalmology-perfect” EHR system. So
far, no system is perfect. However,
there’s no point in waiting for
perfection; that may never happen.
The system we deployed was probably
a worst-case scenario; it had no ophthalmology content built into it at
all. We customized it from scratch,
yet we were still able to maintain
productivity. And the systems
available now are far better.
Regarding the kind of EHR features that help ophthalmologists to
do their jobs, the American Academy
of Ophthalmology has released
an official statement on the special
requirements for electronic health
records in ophthalmology, partly to
help doctors choosing an EHR system
and partly to inform the industry
about our needs. Many vendors are
now aiming to provide those kinds of
features in their systems. Information
on this was presented at last year’s
annual meeting of the academy, and
it’s available online for those just
beginning their search for an EHR
system. (Go to aao.org and search
for EHR Central.) You’ll find a guide
to implementing EHR, information
about proposals, technical details and
a list of features that are especially
useful for ophthalmologists.
deserve further study. For example,
it would be valuable to compare the
quality of documentation before and
after EHR. Certainly the current
systems prompt us to gather more
information; but it’s also very easy
to copy things forward and possibly
perpetuate errors. Also, it would also
be useful to see if there are changes to
efficiency over a longer time period.
As our survey found,
patients scarcely noted
the change.
Perhaps most important, it would be
worthwhile to determine how the use
of EHR affects the quality of patient
care we provide. Research has shown
that in many respects our testing of
glaucoma patients may be inadequate.
We’re not doing enough visual field
testing, and we’re not documenting
gonioscopy on everybody.
It would be interesting to see,
for example, how we’re doing with
EHR relative to the AAO Preferred
Practice Patterns for management
of glaucoma, compared to what we
were doing before. Our EHR patient screen has a little box labeled
“gonioscopy,” so if you forget to
think of it, it reminds you. And the
summary screen shows the results
of the previous gonioscopy; if that’s
blank you know there’s a problem.
These kinds of things could affect
our patient care for the better, but
someone will need to check insurance
claims data to find out whether that’s
actually the case.
Unanswered Questions
Outlook: Promising
Although our study provided some
interesting data, there are other issues
surrounding the switch to EHR that
At this point, we’re well into using
the new system and we’re starting to
appreciate its advantages. We’re able
to reuse relevant information that’s
already been entered, so we don’t
have to redo things multiple times.
And, we’re not losing data over time.
(In the past, if a technician forgot
to include somebody’s past medical
problem or surgical history on a piece
of paper, it sort of disappeared.)
Overall, we think we now have a
much more complete record for each
patient. Thanks to a clinical summary
page, we can now review all of the
patient’s problems, medications, eye
pressures over time, vision over time,
the last exam findings for gonioscopy
or corneal thickness, and other data
relevant to glaucoma at a glance.
Of course, as already noted, there’s
plenty of room for improvement. But
it’s clear that some of the shortcomings
of current EHR systems will disappear
as time passes. For example, we’re
still using desktop computers, and
with that equipment, no matter how
hard you try, at some point your back
will be toward the patient. But it’s easy
to imagine using handheld devices for
the same purpose in the near future,
simulating paper and clipboard. That
should make it possible to maintain the
benefits of computer documentation,
and still retain that old-school, facingthe-patient, clipboard-in-your-lap
kind of environment. Meanwhile, the
issue of insufficient ophthalmologyspecific content will improve slowly
but surely.
Overall, our experience making
the transition was good. Any change
of this magnitude is bound to be a
little scary, but it appears that with a
little forethought, a glaucoma practice
should be able to weather the storm
unscathed.
Dr. Boland is assistant professor
of ophthalmology and director of information technology at the Wilmer
Eye Institute in Baltimore. Mr. Pandit
is a fourth-year MD/MPH student at
Johns Hopkins University.
062_rp0812_gm.indd 65
7/24/12 3:01 PM
REVIEW
Refractive Surgery
Edited by Arturo Chayet, MD
Overcoming Intacs
Complications
There are several special maneuvers you can employ that will
enable you to deal with intraoperative challenges.
Walter Bethke, Managing Editor
ntracorneal ring segments such
as Intacs, originally proposed for
refractive procedures, have become a
popular option for stabilizing corneas
with keratoconus. Though the segments can be effective, surgeons say
there are some pitfalls that can occur
while working with them. Here’s a
look at ways you can avoid problems
with ICRS, and deal with them if they
occur.
ment may also be directed posteriorly
and cause a perforation.
“Because of these possible complications, many surgeons now choose to
use the Intralase to create the channels,” says Dr. Jacob. “The Intralase
allows you to precisely program the
depth you need, the inner and outer
channel diameter and the location of
the incision. It also allows the creation
of a complete 360-degree circumferential channel, unlike the manual method in which circumferential
channels are usually not possible.”
I
One of the problems that can occur with implanting ICRS is the false
channel, where the segment takes an
incorrect path through the cornea,
rather than following the one created
for it. This can happen even if one
uses a manual technique for channel creation if the blade follows the
wrong path. “The manual approach
can sometimes go too deep or too shallow,” says Soosan Jacob, MD, of Chennai, India. “Or, it might stay at the correct depth but go outside the path that
you intended; it might point too much
toward the limbus or too much toward
the pupil. In both cases, you might
have to abort the procedure.” The seg-
All images: Soosan Jacob, MD
Changing the Channel
Radial folds around the leading tip of the
segment (arrow) are a strong indicator that
the segment has entered a false channel.
066_rp0812_rs.indd 66
Even though Intralase-created
channels are more precisely made,
it’s still possible for a false channel to
occur. There are steps you can take to
avoid this, however. “The laser creates
the channel, as well as an entry incision that goes perpendicularly down to
the base of the circumferential channel,” explains Dr. Jacob. “The best way
to avoid creating a false channel when
introducing the Intacs is to hold the
Intacs segment perpendicular to the
eye when entering till it reaches the
base of the vertical entry cut and then
turn the segment so that it’s parallel to
the channel and can enter it.
“If you hold the segment at an angle
to the entry cut it will sometimes miss
the proper Intralase channel and start
dissecting a false one,” Dr. Jacob adds.
“You can also inadvertently angle it
posteriorly or anteriorly. Then, once
the false channel starts being dissected, it’s extremely difficult to reopen
the Intralase channel, as it will just
collapse. If you remove the segment
and reinsert it, it will enter the false
channel again. This is because there
is an internal lip composed of some of
the corneal collagen lamellae that is
separating the Intralase channel from
7/24/12 3:11 PM
the false channel.
straddling the entry
This lip acts as a
wound, this is a risk
barrier to the Infactor that can lead to
tralase channel
neovascularization and
and redirects the
infection.”
segment into the
false channel. This
Turn It Around
lip will be visible
if you look careThough a false
fully.” Dr. Jacob
channel prevents
says you can detect A: An internal lip that forms inside the Intralase channel acts as a gate to divert the
you from entering
the beginnings of segment into a false channel. B: Using the turnaround technique and entering from
through the blocked
a false channel by the opposite direction flattens the lip with the segment.
side of the Intralase
the resistance you
channel, Dr. Jacob
feel as you insert the segment. “Un- extrusion of the segment. Untreated, has developed a technique that alder normal circumstances, it should this can result in infectious keratitis lows you to complete the case.
go in smoothly with a series of small that’s very difficult to treat, since infec“In the turnaround technique, you
horizontal pushes,” she says. “But, if at tions in the setting of foreign bodies— first withdraw the segment that is cresome point you start to feel resistance in this case the Intacs segment—can ating a false channel,” she explains.
to the forward movement of the seg- be more difficult to manage. In the “Recall that the Intralase creates a
ment, that’s an indicator you might instance of an eroded segment, you 360-degree channel. So when you
have a false channel. The other sign must immediately remove the seg- then turn the segment around, you
is radiating or curved corneal folds ment to avoid infection.
can enter the channel from the oparound the advancing edge of the seg“A fourth scenario is one in which posite side. You push the segment in
ment.”
you implant the segment almost com- as far as it will go. Once it reaches as
False channels can lead to a few pletely but just before the end it en- far as it can be pushed in with a rod or
problems. First, you might have to ters a false channel,” continues Dr. other blunt instrument, you take the
abort the full procedure and just settle Jacob. “In this situation, the end of the second segment and use it as an intrafor having one segment implanted on segment may end up being implanted stromal instrument to keep pushing
the side without the false channel, says under the entry incision, rather than the first segment further forward. The
Dr. Jacob. “The second scenario is lying completely within the channel second segment is perfect for this, bethat you keep pushing the segment in and slightly separated from the entry cause it has the same arc as the chantoo much of a posteriorly angulated incision. In other words, there is no nel and its edge fits snugly with the
direction, rather than on a horizontal gap between the entry incision and edge of the other segment. As you do
plane,” she says. “This can lead to a the segment tip and you can’t push it this maneuver, the first segment will
perforation of the anterior chamber. in farther. If you leave the segment finally rotate all the way around and
meet the lip that obThird, you may uninstructed it in the first
tentionally push it so
place. Now however,
that it goes anterior
since you’re coming
and its tip is lying sufrom the other direcperficially in the cortion, the segment will
nea rather than in the
flatten the lip and it
horizontal plane of the
will thus reenter the
Intralase channel. In
channel from the
situations where the
opposite side.” This
segment is anteriorly
technique is effective
angled, the corneal
when the segments
lamellae overlying the
are symmetrical.
segment may not be
However, there
sufficiently thick, and In the turnaround technique, when you can’t push the first segment any farther
are patients with dethis can cause a corne- with an instrument, using the second segment as a kind of intrastromal
centered cones for
al melt in that area and instrument allows you to continue pushing the first segment the rest of the way.
066_rp0812_rs.indd 67
7/24/12 3:11 PM
REVIEW
Refractive
Surgery
whom symmetrical segments don’t
work, and the surgeon needs to use an
asymmetrical pair. In these cases, the
thicker segment is usually implanted
inferior to the cone, with a thinner
segment implanted superiorly. “With
asymmetrical segments, if you encounter a false channel while inserting the second segment and then perform the turnaround technique, you
might end up in a situation where the
thicker segment is superior and the
thinner is inferior,” explains Dr. Jacob.
“In this case you can do what I call a
double-pass turnaround technique.
In this maneuver, with the segments
in place but in opposite positions—in
other words the thin one on the bottom and the thicker one on the top—I
use a reverse Sinskey hook to engage
the positioning hole of the thicker
segment and pull it out through the
entry incision. I then reintroduce the
thicker segment again into the side
without a false channel and use it to
push the thinner segment forward
through the channel until the thinner
piece is in the superior position and
the thicker is inferior as planned.”
Other Complications
As mentioned earlier, a segment in
a false channel can result in complications such as extrusion and chamber
perforation. Here are ways to manage
these other adverse events.
“If you encounter an infection due
to a segment extruding, you have to
remove the segment immediately and
irrigate the channel with antibiotics,”
says Dr. Jacob. “The segment should
be sent for culture and sensitivity.
Start a course of hourly broad-spectrum fortified antibiotics and change
them according to the results of the
sensitivity reports. When the infection is under control, you can begin
tapering the drugs. If you can’t control
the infection with intensive medical
management, you sometimes have to
perform a penetrating keratoplasty.”
If a corneal perforation occurs, the
management strategy depends on the
size of the perforation, says Dr. Jacob.
“It will usually be small, and you’ll immediately feel the perforation occur
in the form of a lot of resistance; you’ll
know you’ve entered the anterior
chamber. If this happens, immediately withdraw and put an air bubble
in the anterior chamber, which will
tamponade the perforation from inside the eye. Remove the segment
and then suture the entry incision.
The prognosis is usually good, since
the perforations are usually small and
peripheral, lying outside of the visual
axis.”
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066_rp0812_rs.indd 68
7/24/12 2:56 PM
REVIEW
Therapeutic
Topics
(Continued from page 55)
dence of 10 to 30 percent.18 However,
a retrospective analysis of these data
showed that many original cases were
not of drug-induced allergy, but coexisting seasonal allergies and bacterial
infections. (Abelson MB, et al. IOVS
1999;40:ARVO Abstract 2718)
Exacerbation of redness by α2-agonists is thought to be dose-dependent;
the doses used for ocular hypertension are relatively high at 0.5% and
0.2%. Low-dose formulations (0.1%
or 0.15%) have since been introduced
with a different preservative, chlorine
dioxide (Purite, 0.005%), instead of
benzalkonium chloride, after studies
indicated that the latter contributed
to the incidence of side effects. We
are currently assisting in the development of low doses of brimonidine
(0.01 to 0.025%) in an improved
formulation with regard to comfort
and safety, and tailored for use as an
ocular vasoconstrictor/whitener. The
agent we’re working with, Luminesse
(0.025% brimonidine, Eye Therapies)
has provided greater microvessel constriction at mucosal surfaces and is
thought to retain more optimal blood
flow from larger feeder vessels. The
problems of tachyphylaxis, rebound
and toxicity due to abuse might be
resolved, and the eight-hour duration of action demonstrated for IOP
might be preserved, providing us with
a significantly longer-lasting vasoconstrictor. Results from initial studies of
this low-dose drug showed clinically
significant efficacy vs. placebo and
superiority to 0.025% oxymetazoline,
promising indications that it may be
breaking new ground in this often
problematic class of drugs.
Dr. Abelson is a clinical professor
of ophthalmology at Harvard Medical School and senior clinical scientist at the Schepens Eye Research Institute. Ms. Smith is a medical writer
at Ora Inc. The authors would like to
thank Wiley Chambers, MD, for his
assistance with the article.
1. http://thebeautybrains.com/2008/02/18/can-collyre-bleu-eyedrops-make-your-eyes-blue/. Accessed July 23, 2012.
2. Van der Kroon, C. The Golden Fountain: The Complete Guide to
Urine Therapy. Banbury, U.K.: Amethyst Books, 1996.
3. Abelson MB, Chambers WC, Smith LM. Conjunctival allergen
challenge: A clinical approach to studying allergic conjunctivitis.
Arch Ophthalmol 1990;108:84-88.
4. Cantor LB, WuDunn D, Gerber S, et al. Medical management
of glaucoma. Adrenergic agents. In: Albert DM, Jakobiec FA, eds.
Principles and Practices of Ophthalmology. Philadelphia: WB
Saunders, 2008:2788-2789.
5. Cao J, Chen M, Wang Q. Mechanisms of vascular desensitization
to agonists. Acta Academiae Medicinae Sinicae 1996;18:4:273-8.
6. Lake CF. Rhinitis medicamentosa. Proceedings Staff Meet
Mayo Clin 1946;21:367.
7. Abelson MB, Butrus SI, Weston JH, Rosner B. Tolerance
and absence of rebound vasodilation following topical ocular
decongestant usage. Ophthalmology 1984;91:1364-1367.
8. Fratelli, M, DeBlasi A. Agonist-induced alpha 1-adrenergic
receptor changes. FEBS Lett 1987;212:1:149-153.
9. Vaidyanathan S, Williamson P, et al. Fluticasone reverses
oxymetazoline induced tachyphylaxis of response and rebound
congestion. Am J Respir Crit Care Med 2010;182:1:19-24.
10. Corboz MR, Rivelli MA, Mingo GG, et al. Mechanism of
decongestant activity of a-2-adrenoreceptor agonists. Pulm
Pharmacol Ther 2008;21:449-54.
11. Corboz MR, Mutter JC, Rivelli MA, et al. α2-adrenoreceptor
agonists as nasal decongestants. Pulm Pharmacol Ther
2007;20:149-156.
12. Soparkar CN, Wilhelmus KR, Koch DD, Wallace GW, Jones
DB. Acute and chronic conjunctivitis due to over-the-counter
ophthalmic decongestants. Arch ophthalmol 1997;115:1:34-38.
13. Spector SL, Raizman MB. Conjunctivitis medicamentosa. J
Allergy Clini Immunol 1994;94:1:134-136.
14. Tappeiner C, Sarra GM, Abegg M. Abuse of vasoconstricting
eyedrops mimicking an ocular pemphigoid. Eur J Ophthalmol
2009;19:1:129-32.
15. Menger HC. New ophthalmic decongestant, tetrahydrozoline
hydrochloride; clinical use in 1,156 patients with conjunctival
irritation. JAMA 1959;170:2:178-09.
16. FDA OTC Monograph. Federal Register Vol. 53, No. 43: 7092.
17. Abelson MB, Yamamoto GK, Allansmith MR. Effects of ocular
decongestants. Arch Ophthalmol 1980;98:856-858.
18. Rahman, M. Q., K. Ramaesh, et al. Brimonidine for glaucoma.
Expert Opin Drug Saf 2010;9:3:483-491.
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7/27/12 12:59 PM
REVIEW
Cornea/Anterior Segment
Edited by Thomas John, MD
Cataract Surgery in the
Patient with Uveitis
These patients are at higher risk for postop complications. Here
are steps you can take to improve their prospects.
By Uday Devgan, MD, Los Angeles
history of prior uveitis can both
hasten the development of cataracts and make cataract surgery more
complicated. The cataractous changes
of the crystalline lens are due to intraocular inflammation as well as the topical steroids that are used to treat the
uveitis. Even with an anatomically successful cataract surgery, these patients
are at a higher risk of postoperative
complications, which could limit the
recovery of vision.
A
Preoperative Planning
While uveitis can affect any part of
the uveal tissue, from the front of the
eye to the back, the most commonly
encountered form is anterior uveitis,
which is the focus of this article. And
though there is a long list of potential causes of acute anterior uveitis,
most often, we are unable to pinpoint
the specific cause of the inflammation.
When planning phacoemulsification,
it is imperative that the uveitis is controlled and the eye is quiet prior to
surgery. This means that for at least
a few weeks, if not a few months, the
anterior chamber should be free from
cells. Often, it is nearly impossible to
have complete resolution of the flare,
so a minor degree of baseline flare is
permissible.
To lessen the postoperative inflammatory response, these patients are
started on topical steroids and nonsteroidal anti-inflammatory drugs days to
weeks prior to cataract surgery. These
uveitic eyes are prone to a pronounced
postoperative inflammatory response
as well as complications such as cystoid
macular edema. Subconjunctival, subTenon’s or even intravitreal injections
of steroids can be administered prior
to surgery, though this is not commonly
required. The use of systemic steroids
or other immune-suppressive drugs is
sometimes considered in particularly
aggressive forms of uveitis.
Intraoperative Technique
Many of these eyes with prior anterior uveitis have posterior synechiae
with the iris adherent to the anterior
lens capsule. The synechiae as well as
any pupillary membrane can limit pupil dilation and limit access to the cataract. The membrane and synechiae
can be dissected with forceps, a blunt
spatula or even with viscoelastic solu-
070_rp0812_cas.indd 70
tions. The pupil can then be expanded
mechanically and, if needed, held in
position with iris hooks or other expansion devices.
A sufficiently large capsulorhexis of
at least 5 mm in diameter should be
made because the iris tends to adhere
to the anterior lens capsule, which
would lead to further synechiae formation in the postoperative period. While
some surgeons advocate implanting a
three-piece IOL in the sulcus in order
to prevent the iris from contacting the
anterior lens capsule, this may lead to
iris chafe and further inflammatory issues. For most cases, traditional in-thebag placement of the IOL is preferred.
For IOL selection, a monofocal lens
design is recommended to maximize
image quality, because spectacle independence tends not to be a priority in
these eyes. The commonly used IOL
materials are hydrophobic acrylic or
silicone polymer, both of which have
been shown to be reasonable choices,
though some surgeons believe that
acrylic tends to be quieter in the eye.
While standard techniques are used
for the cataract surgery, additional
steps to help control postoperative
inflammation should be considered.
7/25/12 3:38 PM
30, endothelial cell denInjection of preservativesity was 195.52 cells/mm2
free triamcinolone into
the anterior chamber or
higher in the diflupredvitreous cavity can be a
nate-treated eyes, and at
powerful adjunct therapy.
day 15, retinal thickness
A subconjunctival or subwas 7.74 µm less in difluTenon’s injection of triamprednate-treated eyes.
cinolone or other steroids
When discontinucan further enhance the
ing steroids, a slow taper
anti-inflammatory effect.
should be used to prevent
A recent study found
rebound inflammation.
that intracameral injecBecause the long-term
tions of triamcinolone
use of a topical ketone steacetonide and gentamicin
roid, such as prednisolone
are a promising treatment
acetate 1%, is associated
option for controlling This eye has a history of prior uveitis, which has resulted in a pupillary
with complications such
postoperative inflamma- membrane, cataract formation and posterior synechiae.
as increased intraocular
tion after cataract surgery.1
pressure, switching to an
This study included 60 patients who as difluprednate 0.05% ophthalmic ester steroid like loteprednol 0.5%,
which has less of a propensity to do
underwent phacoemulsification. Post- emulsion may be a better choice.
operatively, patients were randomized
A recent study conducted in New so, may be advantageous.3 Continuto receive either single intracameral York found that a high-dose, pulsed- ing NSAIDs for at least six weeks may
injections of triamcinolone acetonide therapy regimen of difluprednate be helpful to prevent cystoid macular
and gentamicin followed by topical 0.05% reduced inflammation more edema, which tends to occur more
tobramycin eye drops four times a day effectively than prednisolone acetate commonly in uveitic eyes undergoing
for one week, or topical dexameth- 1%, which resulted in a more rapid re- cataract surgery. Serial optical coherasone-tobramycin combination eye turn of vision.2 Difluprednate was also ence tomography measurements of
drops four times daily until inflam- found to be better at protecting the the macula can be followed to watch
mation completely resolved. While no cornea and reducing macular thicken- for edema at the postoperative visits.
significant difference was observed ing after cataract surgery. This study
Once the eye has recovered from
between the treatment groups in an- included 104 eyes of 52 patients who cataract surgery and the eye is free
terior chamber cells at one day and underwent bilateral phacoemulsifica- from inflammation, the patient should
one week after surgery, there were tion. One eye of each patient received have a relatively routine postoperasignificantly fewer anterior chamber difluprednate, and the fellow eye re- tive course, though there is always the
cells in the intracameral triamcino- ceived prednisolone acetate. Eyes re- chance for a future recurrence of the
lone group than in the topical group ceived seven doses during a two-hour uveitis.
one month after surgery.
period before surgery and three doses
In some cases, systemic steroids after surgery. Corticosteroids were adDr. Devgan is in private practice at
are administered as an intravenous ministered every two hours for the rest Devgan Eye Surgery in Los Angeles
infusion during surgery and are then of the day, then four times daily for and Beverly Hills. He is also an associcontinued orally in the postoperative the next week, and then twice daily for ate clinical professor of ophthalmology
period.
another week.
at the University of California, Los
On day one, corneal thickness was Angeles, and chief of ophthalmology
33 µm less in difluprednate-treated at Olive View-UCLA Medical Center.
Postoperative Follow-up
eyes, and more eyes in the diflupredSimaroj P, Sinsawad P, Lekhanont K. Effects of intracameral
The use of topical steroids and nate group were without corneal 1.triamcinolone
and gentamicin injections following cataract surgery.
NSAIDs should be extended to ensure edema than eyes in the prednisolone J Med Assoc Thai 2011;94(7):819-825.
Donnenfeld ED, Holland EJ, Solomon KD, et al. A multicenter
that the inflammation is completely acetate group. Uncorrected and best- 2.randomized
controlled fellow eye trial of pulse-dosed difluprednate
controlled after surgery. While pred- corrected visual acuities were signif- 0.05% versus prednisolone acetate 1% in cataract surgery. Am J
2011;152:609-617.
nisolone acetate 1% ophthalmic sus- icantly better in the difluprednate- Ophthalmol
3. Controlled evaluation of loteprednol etabonate and prednisolone
pension is commonly used after cata- treated eyes than in the prednisolone acetate in the treatment of acute anterior uveitis. Loteprednol
US Uveitis Study Group. Am J Ophthalmol 1999;127:537ract surgery, stronger medications such acetate-treated eyes at day one. At day Etabonate
544.
070_rp0812_cas.indd 71
7/25/12 3:38 PM
SAVE THE DATE
2012
CALENDAR
CONTINUING PROFESSIONAL EDUCATION
FOR FELLOWS & THIRD-YEAR RESIDENTS
The Continuing Professional Education (CPE) Ophthalmology programs are CME activities designed to complement
a third-year ophthalmology residency medical education as well as fellows programs (Vitreoretinal, Cornea, and
Glaucoma). Please visit www.revophth.com/ResFellowEdu2012 for more information on the dates and curriculum. These
CME programs take place in a comfortable arena for residents and fellows to exchange ideas with their peers. Faculty for
these educational programs are comprised of physicians from both university programs and private practices. The format
of the programs consists of presentations of illustrative and unusual cases, panel discussions, and didactic lectures, as
well as a state-of-the-art, hands-on wet lab experience. It is our hope that you will encourage selected residents and
fellows to attend these educational programs, which are all accredited to ensure fair balance.
THIRD-YEAR RESIDENTS
September 14-15, 2012
Fort Worth, TX
VITREORETINAL FELLOWS
August 10-12, 2012
Chicago, IL
COURSE DIRECTOR
COURSE DIRECTOR
Anthony C. Arnold, M.D.
William F. Mieler, M.D.
Professor and Chief, Neuro-Ophthalmology
Division, Jules Stein Eye Institute, Department of
Ophthalmology University of California, Los Angeles
Professor of Ophthalmology, Vice Chairman
and Director of the Ocular Oncology Service,
University of Illinois Eye and Ear Infirmary
CORNEA FELLOWS
October 5-6, 2012
Fort Worth, TX
GLAUCOMA FELLOWS
October 19-20, 2012
Fort Worth, TX
COURSE DIRECTOR
COURSE DIRECTOR
Natalie Afshari, M.D.
Kuldev Singh, M.D.
Full-time faculty at Duke University Eye
Center, Durham, NC
Professor of Ophthalmology and Director,
Glaucoma Service at the Stanford University
School of Medicine in California
For more information and to register, go to:
www.revophth.com/ResFellowEdu2012
Email: [email protected] or Call: Denette Holmes 866–627–0714
There is no registration fee for these activities. Air, ground transportation in Fort Worth, hotel accommodations and modest meals will be provided through an educational scholarship for
qualified participants.
Credit Designation Statement:
These activities have been approved for AMA PRA Category1 Credit(s)TM.
Jointly Sponsored by:
072_rp0812CPEcal.indd 1
Supported by an independent
medical educational grant from:
7/19/12 10:25 AM
REVIEW
Research Review
Combination Therapy
For Patients with RVO
n a prospective, interventional case
series, researchers have shown that
the combination of bevacizumab and
dexamethasone in patients with retinal vein occlusion increases visual
acuity and prolongs the time between
injections compared with either of
these medications alone.
Patients diagnosed with RVO seen
between September 2009 and July
2010 were included in this study if they
had received previous anti-VEGF therapy. Patients were included in analysis
if the previous anti-VEGF therapy was
at least six weeks before, as long as their
optical coherence tomography showed
signs of edema defined as >300 on
spectral-domain OCT. Exclusion criteria included history of vitrectomy and/
or rubeotic or advanced glaucoma. All
patients were evaluated with Snellen
visual acuity and measured for macular
thickness and intraocular pressure. At
baseline, all patients were injected with
bevacizumab, followed by dexamethasone intravitreal implant two weeks
later. These patients were reexamined
on a monthly basis and treated when
edema occurred.
Thirty-four eyes of 33 patients, with a
mean age of 72.8 years, were identified.
Thirty-five percent were diagnosed
with central RVO, while the other 65
percent had branch RVO. Of treated
patients, 97 percent gained vision during the study. Macular thickness decreased with the combination treat-
I
ment; the effect continued an average
of 26 days from the initial bevacizumab
treatment. Retreatment was unnecessary in 18 percent of the population
during the six-month study period.
Retina 2012; 32:1289-1294
Singer M, Bell D, Woods P, Pollard J, et al.
Comparison of ACD Using
Four Devices
n a comparative case series, doctors
evaluated the congruity of anterior
chamber depth measurements in one
eye of 42 healthy participants using
three-dimensional corneal and anterior segment OCT, partial coherence
interferometry, Scheimpflug imaging
and ultrasound biomicroscopy. The
ACD measurements were significantly different between the devices and
not interchangeable, except for PCI
true and CAS-OCT auto, and CASOCT auto and CAS-OCT manual.
The differences between the measurements were evaluated by twoway analysis of variance and post hoc
analysis, and agreement between the
measurements was evaluated using
Bland-Altman analysis. To evaluate
true ACD using PCI, the automatically calculated ACD minus the central corneal thickness measured by
CAS-OCT was defined as PCI true.
Two ACD measurements were also
taken with CAS-OCT.
The mean ACD was 3.72 mm ±0.23
(PCI), 3.18 ±0.23 mm (PCI true),
I
073_rp0812_rr.indd 73
3.24 ±0.25 mm (Scheimpflug), 3.03
±0.25 mm (UBM), 3.14 ± 0.24 mm
(CAS-OCT auto) and 3.12 ±0.24 mm
(CAS-OCT manual). A significant difference was observed between PCI
biometry, Scheimpflug imaging and
the other methods. Post hoc analysis showed no significant differences
between PCI true and CAS-OCT
auto or between CAS-OCT auto and
CAS-OCT manual. Strong correlations were observed between all measurements; however, Bland-Altman
analysis showed good agreement only
between PCI true and Scheimpflug
imaging and between CAS-OCT auto
and CAS-OCT manual.
J Cataract Refract Surg 2012;
38:1207-1213
Nakakura S, Mori E, Nagatomi N, Tabuchi H, Kiuchi Y.
How Specialists Manage Chronic
Herpes Zoster Ophthalmicus
n November 2010, a survey of 15
questions was distributed to the
Cornea Society listserv. Questions
identified respondents’ treatment
practices for recurrent herpes zoster
ophthalmicus and opinions regarding
prolonged antiviral prophylaxis and
zoster vaccine. Responses indicate
many cornea specialists are managing
recurrent or chronic cases of HZO,
but there is variability in the use of
topical corticosteroids and antivirals.
Additionally, no consensus exists on
the efficacy of prolonged antiviral
I
7/24/12 2:58 PM
Save the Date
WESTIN RIVERWALK SAN ANTONIO, TEXAS
August 24 – 26, 2012
OPHTHALMOLOGIST
PROGRAM CHAIRS
OPTOMETRIST
PROGRAM CHAIR
ADMINISTRATOR
PROGRAM CHAIR
NURSE & TECHNICIAN
PROGRAM CHAIRS
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MD
Robert
b tP
Prouty,
t O
OD
Vonda
V
d Syler,
S l CO
COE
Eileen T
T. B
Beltramba,
lt
b R
RN, CRNO
PROGRAMS OFFERED
Resident/Fellow Wet Lab
Friday, August 24
Ophthalmologist Program
Mitchell
h ll P
P. W
Weikert,
ik t MD
Saturday and Sunday, August 25 and 26
Patricia A
A. L
Lamb,
b RN,
RN CRNO
Nurse, Technician & Office Staff Program
Provided by ASORN
Friday and Saturday, August 24 and 25
Administrator Program
Saturday, August 25
Optometrist Program
Saturday, August 25
FOR MORE INFORMATION AND TO REGISTER:
www.revophth.com/saos2012
Jointly sponsored by
Partially supported by educational grants from
Provided by
IAHB
Accreditation Statement
This activity has been planned and implemented in accordance with the Essential Areas and Policies
of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the
Institute for the Advancement of Human Behavior (IAHB) and Review of Ophthalmology®/Jobson
Medical Information LLC. The IAHB is accredited by the ACCME to provide continuing medical education
for physicians.
The Administrator’s Program is approved by the National Board for the
Certification of Ophthalmic Executives for 7 Category A Credits, Certified
Ophthalmic Executive Designation.
Credit Designation Statement
The IAHB designates this live activity for a maximum of 11.25 AMA PRA Category 1 Credit(s)™. Physicians
should claim only the credit commensurate with the extent of their participation in the activity.
ASORN is accredited as a provider of continuing nursing education
by the American Nurses Credentialing Center’s Commission on
Accreditation.
069_rp0812AlcSanAnt.indd 69
7/11/12 4:48 PM
REVIEW
Research
Review
therapy or the adult zoster vaccine to
reduce chronic or recurrent disease.
Of 100 respondents, the majority
were cornea specialists (83 of 98, 85
percent). Eighty-seven percent reported treating recurrent or chronic
cases of HZO in the last year. The
most common choice of treatment
in the posed recurrent HZO clinical
scenario was a combination of oral
antiviral and topical corticosteroid,
although significant variability existed
in the duration of oral antiviral administration. Fifty-four respondents
believed that prolonged acyclovir prophylaxis could reduce recurrent signs
of HZO; 28 percent believed that recurrences of HZO could be reduced
after the period of acyclovir administration. For patients with a history
of HZO, 64 percent of respondents
reported not recommending the adult
zoster vaccine, but 46 percent believed that the vaccine could reduce
recurrent signs or did not know.
Cornea 2012;21:786-790
Sy A, McLeod S, Cohen E, Margolis T, et al.
Posterior Corneal Surface
Altered Post-LASIK
esearchers from the Cole Eye
Institute evaluated the posterior
corneal surface response of 80 eyes at
a very early stage after myopic LASIK
with different ablation depths, observing posterior steepening and a
shift toward prolateness of the posterior surface, with a tendency to return toward the preoperative level
between one and three months. The
degree of change was related to the
amount of anterior tissue severed.
Healthy myopic eyes were divided
based on the achieved ablation depth
as follows: Group 1, more than 100
µm; Group 2, between 50 µm and 99
µm; Group 3, less than 50 µm. Posterior eccentricity and central (0 to
4 mm), paracentral (4 to 7 mm) and
peripheral (7 to 10 mm) posterior
corneal curvatures were measured
with the Galilei system preoperatively
R
and postoperatively after one day, one
week and one and three months.
Posterior surface steepening and
a shift toward prolateness occurred
in all groups, with a peak within the
first week before returning toward
the original level after one month.
The maximum change in the central
posterior cornea occurred after one
day in Group 1 and reached -0.106 D.
This change was statistically significant (p=0.03) and statistically greater
than the change in Group 2 (mean
-0.042 D; p=0.02) and Group 3 (mean
-0.026 D; p<0.01). This change was
not significant after three months.
J Cataract Refract Surg 2012;
38:1222-1231
Smadja D, Santhiago M, Mello G, Roberts C, et al.
Pilot Study for Detection of Wet
AMD with OCT
n this prospective, observational,
nonrandomized study, 79 patients
diagnosed with nonexudative macular
degeneration in one eye and exudative macular degeneration in its fellow underwent examination followed
by OCT in the study eye (nonexudative macular degeneration eye) every
three months for two years. Of the
15 patients who developed exudative
macular degeneration, 13 had disease
progression identified on OCT before
examination and/or fluorescein angiography showed changes.
Patient examination included visual
acuity, intraocular pressure, biomicroscopy and ophthalmoscopy followed by OCT. If the examination
did not show choroidal neovascularization, but OCT images raised suspicion, patients were re-examined in
four to six weeks and/or fluorescein
angiography was performed. Visual
acuity, OCT anomaly detection and
time between OCT and fluorescein
angiography detection were examined.
Fifteen patients (19 percent) developed exudative macular degeneration, as confirmed by fluorescein
angiography, in the study eye. Four
I
additional patients showed potential
exudative macular degeneration on
OCT only. Subretinal pigment epithelium fluid was the most common
OCT anomaly, with development of
sub-/intraretinal fluid also visible.
Retina 2012; 32:1045-1056
Padnick-Silver L, Weinberg A, LaFrano F, Macsai M.
Contact Lenses Affect Corneal
Biomechanical Parameters
esults from research out of Turkey suggest that ocular response
analyzer-generated parameters may
be different in subjects with and without contact lens usage. The study consisted of 56 myopic patients who used
contact lenses (study group) and 123
myopic patients who did not. Intraocular pressure was measured with
an ORA and a Goldmann applanation tonometer. Central corneal thickness was measured with an ultrasonic
pachymeter. Axial length and anterior
chamber depth measurements were
acquired with contact ultrasound Ascan biometry. The differences in ORA
parameters between study and control
group participants were analyzed.
The mean corneal hysteresis in
study and control groups was 10.1
±1.6 mmHg (6.5 to 15.9 mmHg) and
9.7 ±1.5 mmHg (6.3 to 14.2 mmHg)
(p=0.16). The mean corneal resistance factor was 10.4 ±1.9 mmHg (4.6
to 15.5 mmHg) in the study group
compared with 9.6 ±1.9 mmHg (5.1 to
15 mmHg) in the control group. The
difference in corneal resistance factor
was statistically significant (p=0.014).
There was no significant difference in
corneal-compensated IOP (p=0.24).
Mean Goldmann-correlated IOP was
significantly higher in the study group
than in control subjects (15.8 ±3.2 vs.
14.7 ±3.7 mmHg) (p=0.044). None
of the corneal biomechanical parameters was significantly correlated to
the duration of contact lens use in the
study group.
Cornea 2012;31:764-769
R
Cankaya A, Beyazyildiz E, Ileri D, Ozturk F.
073_rp0812_rr.indd 75
7/24/12 2:58 PM
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ROPH0812.indd 78
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RP0212_Allergan Lumigan PI.indd 1
1/11/12 10:36 AM
REVIEW
Resident Case Series
Before reading on, please see p. 82 for presenting complaint, history and examination.
Diagnosis, Workup and Treatment
The differential diagnosis in this
patient included acute retinal necrosis (ARN), progressive outer retinal
necrosis (PORN), cytomegalovirus
(CMV) retinitis, syphilis, tuberculosis,
toxoplasmosis, fungal infection, nocardia, sarcoid, lymphoma and other
metastatic disease. Given the presentation and severity of the fundus findings
and the patient’s socioeconomic issues,
he was admitted to the ophthalmology
inpatient service. An anterior chamber tap was done and sent for PCR
analysis and the patient was injected
Figure 2. Intravenous fluorescein
angiography of left eye. Note blocking
along inferior disc and mottled areas of
hypo- and hyperfluorescence.
with intravitreal
foscarnet 2.5 mg
and ganciclovir
2 mg, as well as
started on intravenous foscarnet,
ganciclovir and
valacyclovir. A
fluorescein angiography showed
mottled areas of
hypo- and hyperfluorescence Figure 3. OCT of left eye. Note the extensive subretinal fluid.
throughout, as
well as blocking at the disc inferiorly metabolic panel, ANA, ACE, RPR and
(See Figure 2). An optical coherence chest X-ray were all within normal limtomography was also performed, which its. ESR and liver function tests were
showed extensive subretinal fluid (See found to be elevated. On day three of
Figure 3).
admission, his HIV test was found to
A broad lab workup was initiated, be positive, with a CD4 count of 67
which included a complete blood and a viral load of 77,800 copies/mL. A
count (CBC), comprehensive metabol- clinical diagnosis of progressive outer
ic panel, anti-nuclear antibody (ANA), retinal necrosis was made. On day four,
angiotensin converting enzyme (ACE), a repeat anterior chamber tap and inRPR, ESR, Lyme antibody titer, chest travitreal injection was performed.
X-ray and HIV antibodies. MRI of the
The PCR results came back negative
brain was done and was normal. The for both herpes simplex virus (HSV)
initial CBC was remarkable for leu- and herpes zoster virus (HZV), but
kopenia with a decreased white blood positive in both cultures for CMV
cell count at 2,900 cell/µL and anemia PCR, with a viral load of 18,361 copwith a hemoglobin of 10.9 g/dL. Basic ies/mL.
Discussion
Progressive outer retinal necrosis
(PORN), first described in 1990, is
seen in patients who are immunocompromised (e.g., AIDS) who present with rapid outer retinal necrosis.1
Multifocal lesions with deep retinal
opacification are characteristic of
PORN. The lesions can be located
in the peripheral retina with or without macular involvement. About 30
percent of patients have deep outer
retinal lesions in the macula, which
become confluent to form a
cherry red spot. They classically have a “cracked mud”
appearance where there is
perivenular clearing of the
retinal opacification (See
Figure 4). There is minimal to no vasculitis. PORN
differs from acute retinal
necrosis syndrome in that
there is minimal intraocular Figure 4. Colored fundus photo of the left eye. Note the
inflammation in PORN. The areas of perivenular clearing.
080_rp0812_wills.indd 80
7/27/12 10:22 AM
REVIEW
majority of patients have a poor visual outcome.2,3
In this case, the patient was treated extremely aggressively with anti-viral therapy, given the poor visual outcome of the natural course of this disease. Due to the rare
nature of the disease and its quick progression, there are
no good randomized control trials regarding treatment. A
case series of patients with PORN who were treated with
both intravenous and intravitreal ganciclovir and foscarnet found that 45 percent of the patients achieved a VA
>20/80, and only 18 percent of patients evolved to no light
perception.4
CMV is a less common cause of progressive outer retinal necrosis, although there are a number of case reports
of CMV PORN in the ophthalmologic literature. A report
in 2002 described a 37-year-old Indian male with a clinical
diagnosis of PORN who had a CMV-positive PCR, with
negative PCR for HSV and VZV.5
While in the
hospital, our patient was started on HAART
therapy (emtricitabine/
tenofovir and
raltegravir) and
double strength
sulfamethoxazole and trimethoprim. He
was monitored
and on discharge, day 14,
Figure 5. Fundus photo of the left eye at
his final vision
discharge. Note increased retinal
was stable at
hemorrhages and resolution of the areas of
20/80 (See Figretinal whitening.
ure 5). Unfortunately, despite multiple attempts by both the Infectious
Disease Department and the Wills Eye Retina Service to
contact the patient, he did not return for further follow-up
visits.
The author would like to thank William E. Benson, MD,
FACS, of the Wills Eye Retina Service for his time and assistance in preparing this case.
1. Forster DJ, Dugel PU, Frangieh GT, et al. Rapidly progressive outer retinal necrosis in the
acquired immunodeficiency syndrome. Am J Ophthalmol 1990;110:341-8.
2. Margolis TP, Lowder CY, Holland GN, et al. Varicella-zoster virus retinitis in patients with acquired
immunodeficiency syndrome. Am J Ophthalmol 1991;112:119-31.
3. Holland, GN. The Progressive Outer Retinal Necrosis Syndrome. Int Ophthalmol 1994;18:163-5.
4. Scott I, Luu K, Davis J. Intravitreal Antivirals in the Management of Patients with Acquired Immunodeficiency Syndrome with Progressive Outer Retinal Necrosis. Arch Ophthalmol 2002;120:121922.
5. Biswas J, Choudhry S, Priya K, Gopal L. Detection of cytomegalovirus from vitreous humor in a
patient with progressive outer retinal necrosis. Indian J Ophthalmol 2002;50:319-21.
Advertising
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7/27/12 10:52 AM
REVIEW
Wills Eye Resident Case Series
Edited by Kristina Pao, MD
An apparently healthy young man experiences sudden
decreased vision and seeks treatment at the Wills ER.
David A. Salz, MD
Presentation
A 32-year-old Ecuadorian male with no significant past medical history presented to the Wills Eye Emergency
Room with four days of decreased vision in his left eye. He had no other complaints. He immigrated to the United
States seven years ago.
Medical History
The patient reported no medical problems. His family history and review of systems were non-contributory. He did
not smoke, drank occasionally, denied any intravenous drug use, and worked as a construction worker.
Examination
The patient’s ocular examination revealed an uncorrected visual acuity of 20/20 in the right eye and 20/40 in the left
eye. Color plates were 8/8 briskly in the right eye, and 8/8 slowly in the left eye. The patient was orthophoric with full
ductions and versions without diplopia or nystagmus. Visual fields were full in the right eye and decreased inferiorly in
the left eye. Pupils were notable for a relative afferent pupillary defect in the left eye. External exam showed no mass,
proptosis, lid lag or lid retraction. Slit lamp examination was notable for rare anterior chamber cell in the right eye and
two-plus anterior chamber cell in the left eye. Two-plus anterior vitreous cell was present in the right eye and three-plus
anterior vitreous cell was present in the left eye. Dilated fundus examination in the right eye showed areas of retinal pigment epithelial mottling along the arcades (See Figure 1). In the left eye, fundoscopic exam revealed multiple confluent
areas of retinal whitening with perivenular areas of sparing. There was also a disc hemorrhage inferiorly, and minimal
vitritis. There was no vascular sheathing.
Figure 1. Fundus photographs of right (left) and left eye (right). Note the retinal pigment epithelial mottling
along the arcades in the right eye and disc hemorrhages and multiple areas of retinal whitening in the left eye.
What is your differential diagnosis? What further workup would you pursue? Please turn to p. 80
7/27/12 10:37 AM
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