Dealing with - Review of Ophthalmology

Transcription

Review of Ophthalmology Vol. XX, No. 8 • August 2013 • Retina Issue • Diabetic Macular Edema • Plastics: The Aging Brow • Trabeculectomy: Postop Issues • Femto Flap Complications
TRABECULECTOMY: POSTOP ISSUES P. 64 • WILLS RESIDENT CASE SERIES P. 79
BIRDSHOT CHORIORETINOPATHY P. 42 • OCULOPLASTICS: THE AGING BROW P. 50
ACUPUNCTURE AS DRY-EYE THERAPY? P. 58 • FOILING FEMTO FLAP COMPLICATIONS P. 72
August 2013 • revophth.com
Dealing with
DME
Laser, Steroids or
Anti-VEGF? P. 22
Best Practices: Treating Exudative AMD P. 30
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ONE INJECTION,
EARLY INTERVENTION.
TAKE ACTION WITH JETREA®
(ocriplasmin) Intravitreal Injection, 2.5 mg/mL
The FIRST and ONLY pharmacologic treatment
for symptomatic Vitreomacular Adhesion (VMA).1
Indication
JETREA (ocriplasmin) Intravitreal Injection, 2.5 mg/mL,
is a proteolytic enzyme indicated for the treatment of
symptomatic vitreomacular adhesion.
Important Safety Information
Warnings and Precautions
• A decrease of ≥ 3 lines of best-corrected visual acuity (BCVA)
was experienced by 5.6% of patients treated with JETREA
and 3.2% of patients treated with vehicle in the controlled
trials. The majority of these decreases in vision were due
to progression of the condition with traction and many
required surgical intervention. Patients should be monitored
appropriately.
• Intravitreal injections are associated with intraocular
inflammation/infection, intraocular hemorrhage and
increased intraocular pressure (IOP). Patients should be
monitored and instructed to report any symptoms without
delay. In the controlled trials, intraocular inflammation
occurred in 7.1% of patients injected with JETREA vs 3.7%
of patients injected with vehicle. Most of the post-injection
intraocular inflammation events were mild and transient.
If the contralateral eye requires treatment with JETREA, it is
not recommended within 7 days of the initial injection in order
to monitor the post-injection course in the injected eye.
• Potential for lens subluxation.
• In the controlled trials, the incidence of retinal
detachment was 0.9% in the JETREA group and 1.6%
in the vehicle group, while the incidence of retinal tear
(without detachment) was 1.1% in the JETREA group and
2.7% in the vehicle group. Most of these events occurred
during or after vitrectomy in both groups.
• Dyschromatopsia (generally described as yellowish
vision) was reported in 2% of all patients injected with
JETREA. In approximately half of these dyschromatopsia
cases there were also electroretinographic (ERG) changes
reported (a- and b-wave amplitude decrease).
Adverse Reactions
• The most commonly reported reactions (≥ 5%) in
patients treated with JETREA were vitreous floaters,
conjunctival hemorrhage, eye pain, photopsia, blurred
vision, macular hole, reduced visual acuity, visual
impairment, and retinal edema.
VISIT US AT THE ASRS ANNUAL MEETING
TORONTO, ONTARIO, CANADA
AUGUST 24–28, 2013
Please see Brief Summary of full Prescribing
Information on adjacent page.
(ocriplasmin)
Intravitreal Injection, 2.5 mg/mL
Reference: 1. JETREA [package insert]. Iselin, NJ: ThromboGenics, Inc.; 2012.
©2013 ThromboGenics, Inc. All rights reserved. ThromboGenics, Inc., 101 Wood Avenue South, Suite 610, Iselin, NJ 08830 – USA. JETREA and the JETREA logo are trademarks or registered trademarks of ThromboGenics NV in
the United States, European Union, Japan, and other countries. THROMBOGENICS and the THROMBOGENICS logo are trademarks or registered trademarks of ThromboGenics NV in the United States, European Union,
Japan, and other countries.
JETREA.com
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BRIEF SUMMARY OF FULL PRESCRIBING
INFORMATION
Please see the JETREA® package insert for full
Prescribing Information.
1 INDICATIONS AND USAGE
JETREA is a proteolytic enzyme indicated for the treatment of
symptomatic vitreomacular adhesion.
2 DOSAGE AND ADMINISTRATION
2.1 General Dosing Information
Must be diluted before use. For single-use ophthalmic
intravitreal injection only. JETREA must only be administered
by a qualified physician.
2.2 Dosing
The recommended dose is 0.125 mg (0.1 mL of the diluted
solution) administered by intravitreal injection to the affected
eye once as a single dose.
2.3 Preparation for Administration
Remove the vial (2.5 mg/mL corresponding to 0.5 mg
ocriplasmin) from the freezer and allow to thaw at room
temperature (within a few minutes). Once completely
thawed, remove the protective polypropylene flip-off cap
from the vial. The top of the vial should be disinfected with
an alcohol wipe. Using aseptic technique, add 0.2 mL of
0.9% w/v Sodium Chloride Injection, USP (sterile,
preservative-free) into the JETREA vial and gently swirl the
vial until the solutions are mixed.
Visually inspect the vial for particulate matter. Only a clear,
colorless solution without visible particles should be used.
Using aseptic technique, withdraw all of the diluted solution
using a sterile #19 gauge needle (slightly tilt the vial to ease
withdrawal) and discard the needle after withdrawal of
the vial contents. Do not use this needle for the intravitreal
injection.
Replace the needle with a sterile #30 gauge needle, carefully
expel the air bubbles and excess drug from the syringe
and adjust the dose to the 0.1 mL mark on the syringe
(corresponding to 0.125 mg ocriplasmin). THE SOLUTION
SHOULD BE USED IMMEDIATELY AS IT CONTAINS NO
PRESERVATIVES. Discard the vial and any unused portion of
the diluted solution after single use.
2.4 Administration and Monitoring
The intravitreal injection procedure should be carried out
under controlled aseptic conditions, which include the use
of sterile gloves, a sterile drape and a sterile eyelid speculum
(or equivalent). Adequate anesthesia and a broad spectrum
microbiocide should be administered according to standard
medical practice.
The injection needle should be inserted 3.5 - 4.0 mm posterior
to the limbus aiming towards the center of the vitreous cavity,
avoiding the horizontal meridian. The injection volume of
0.1 mL is then delivered into the mid-vitreous.
Immediately following the intravitreal injection, patients
should be monitored for elevation in intraocular pressure.
Appropriate monitoring may consist of a check for perfusion
of the optic nerve head or tonometry. If required, a sterile
paracentesis needle should be available.
Following intravitreal injection, patients should be instructed
to report any symptoms suggestive of endophthalmitis
or retinal detachment (e.g., eye pain, redness of the eye,
photophobia, blurred or decreased vision) without delay [see
Patient Counseling Information].
Each vial should only be used to provide a single injection
for the treatment of a single eye. If the contralateral eye
requires treatment, a new vial should be used and the sterile
field, syringe, gloves, drapes, eyelid speculum, and injection
needles should be changed before JETREA is administered to
the other eye, however, treatment with JETREA in the other
eye is not recommended within 7 days of the initial injection
in order to monitor the post-injection course including the
potential for decreased vision in the injected eye.
Repeated administration of JETREA in the same eye is not
recommended [see Nonclinical Toxicology].
After injection, any unused product must be discarded.
No special dosage modification is required for any of the
populations that have been studied (e.g. gender, elderly).
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3 DOSAGE FORMS AND STRENGTHS
Single-use glass vial containing JETREA 0.5 mg in 0.2 mL
solution for intravitreal injection (2.5 mg/mL).
anterior chamber cell, photophobia, vitreous detachment,
ocular discomfort, iritis, cataract, dry eye, metamorphopsia,
conjunctival hyperemia, and retinal degeneration.
4 CONTRAINDICATIONS
None
Dyschromatopsia was reported in 2% of patients injected
with JETREA, with the majority of cases reported from two
uncontrolled clinical studies. In approximately half of these
dyschromatopsia cases there were also electroretinographic
(ERG) changes reported (a- and b-wave amplitude decrease).
5 WARNINGS AND PRECAUTIONS
5.1 Decreased Vision
A decrease of ≥ 3 line of best corrected visual acuity (BCVA)
was experienced by 5.6% of patients treated with JETREA and
3.2% of patients treated with vehicle in the controlled trials
[see Clinical Studies].
The majority of these decreases in vision were due to
progression of the condition with traction and many
required surgical intervention. Patients should be monitored
appropriately [see Dosage and Administration].
5.2 Intravitreal Injection Procedure Associated
Effects
Intravitreal injections are associated with intraocular
inflammation / infection, intraocular hemorrhage and increased
intraocular pressure (IOP). In the controlled trials, intraocular
inflammation occurred in 7.1% of patients injected with
JETREA vs. 3.7% of patients injected with vehicle. Most of the
post-injection intraocular inflammation events were mild and
transient. Intraocular hemorrhage occurred in 2.4% vs. 3.7%
of patients injected with JETREA vs. vehicle, respectively.
Increased intraocular pressure occurred in 4.1% vs. 5.3% of
patients injected with JETREA vs. vehicle, respectively.
5.3 Potential for Lens Subluxation
One case of lens subluxation was reported in a patient who
received an intravitreal injection of 0.175 mg (1.4 times
higher than the recommended dose). Lens subluxation was
observed in three animal species (monkey, rabbit, minipig)
following a single intravitreal injection that achieved vitreous
concentrations of ocriplasmin 1.4 times higher than achieved
with the recommended treatment dose. Administration of a
second intravitreal dose in monkeys, 28 days apart, produced
lens subluxation in 100% of the treated eyes [see Nonclinical
Toxicology].
5.4 Retinal Breaks
In the controlled trials, the incidence of retinal detachment
was 0.9% in the JETREA group and 1.6% in the vehicle group,
while the incidence of retinal tear (without detachment) was
1.1% in the JETREA group and 2.7% in the vehicle group. Most
of these events occurred during or after vitrectomy in both
groups. The incidence of retinal detachment that occurred
pre-vitrectomy was 0.4% in the JETREA group and none in
the vehicle group, while the incidence of retinal tear (without
detachment) that occurred pre-vitrectomy was none in the
JETREA group and 0.5% in the vehicle group.
5.5 Dyschromatopsia
Dyschromatopsia (generally described as yellowish vision)
was reported in 2% of all patients injected with JETREA. In
approximately half of these dyschromatopsia cases there were
also electroretinographic (ERG) changes reported (a- and
b-wave amplitude decrease).
6 ADVERSE REACTIONS
The following adverse reactions are described below and
elsewhere in the labeling:
• Decreased Vision [see Warnings and Precautions]
• Intravitreal Injection Procedure Associated Effects
[see Warnings and Precautions and Dosage and
Administration]
• Potential for Lens Subluxation [see Warnings
and Precautions]
• Retinal Breaks [see Warnings and Precautions and
Dosage and Administration]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying
conditions, adverse reaction rates in one clinical trial of a drug
cannot be directly compared with rates in the clinical trials
of the same or another drug and may not reflect the rates
observed in practice.
Approximately 800 patients have been treated with an
intravitreal injection of JETREA. Of these, 465 patients
received an intravitreal injection of ocriplasmin 0.125 mg
(187 patients received vehicle) in the 2 vehicle-controlled
studies (Study 1 and Study 2).
The most common adverse reactions (incidence 5% - 20%
listed in descending order of frequency) in the vehiclecontrolled clinical studies were: vitreous floaters, conjunctival
hemorrhage, eye pain, photopsia, blurred vision, macular
hole, reduced visual acuity, visual impairment, and retinal
edema.
Less common adverse reactions observed in the studies at
a frequency of 2% - < 5% in patients treated with JETREA
included macular edema, increased intraocular pressure,
6.2 Immunogenicity
As with all therapeutic proteins, there is potential for
immunogenicity. Immunogenicity for this product has not
been evaluated.
The number of patients with at least 3 lines increase in visual
acuity was numerically higher in the ocriplasmin group
compared to vehicle in both trials, however, the number of
patients with at least a 3 lines decrease in visual acuity was
also higher in the ocriplasmin group in one of the studies
(Table 1 and Figure 1).
Table 1: Categorical Change from Baseline in BCVA
at Month 6, Irrespective of Vitrectomy (Study 1
and Study 2)
Study 1
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not
been conducted with ocriplasmin. There are no adequate and
well-controlled studies of ocriplasmin in pregnant women. It
is not known whether ocriplasmin can cause fetal harm when
administered to a pregnant woman or can affect reproduction
capacity. The systemic exposure to ocriplasmin is expected to
be low after intravitreal injection of a single 0.125 mg dose.
Assuming 100% systemic absorption (and a plasma volume
of 2700 mL), the estimated plasma concentration is 46 ng/mL.
JETREA should be given to a pregnant woman only if clearly
needed.
8.5 Geriatric Use
In the clinical studies, 384 and 145 patients were ≥ 65 years
and of these 192 and 73 patients were ≥ 75 years in the
JETREA and vehicle groups respectively. No significant
differences in efficacy or safety were seen with increasing age
in these studies.
10 OVERDOSAGE
The clinical data on the effects of JETREA overdose are limited.
One case of accidental overdose of 0.250 mg ocriplasmin
(twice the recommended dose) was reported to be associated
with inflammation and a decrease in visual acuity.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment
of Fertility
No carcinogenicity, mutagenicity or reproductive and
developmental toxicity studies were conducted with
ocriplasmin.
13.2 Animal Toxicology and/or Pharmacology
The ocular toxicity of ocriplasmin after a single intravitreal
dose has been evaluated in rabbits, monkeys and minipigs.
Ocriplasmin induced an inflammatory response and transient
ERG changes in rabbits and monkeys, which tended to resolve
over time. Lens subluxation was observed in the 3 species
at ocriplasmin concentrations in the vitreous at or above
41 mcg/mL, a concentration 1.4-fold above the intended
clinical concentration in the vitreous of 29 mcg/mL. Intraocular
hemorrhage was observed in rabbits and monkeys.
A second intravitreal administration of ocriplasmin
(28 days apart) in monkeys at doses of 75 mcg/eye (41 mcg/
mL vitreous) or 125 mcg/eye (68 mcg/mL vitreous) was
associated with lens subluxation in all ocriplasmin treated eyes.
Sustained increases in IOP occurred in two animals with lens
subluxation. Microscopic findings in the eye included vitreous
liquefaction, degeneration/disruption of the hyaloideocapsular ligament (with loss of ciliary zonular fibers), lens
degeneration, mononuclear cell infiltration of the vitreous,
and vacuolation of the retinal inner nuclear cell layer.
These doses are 1.4-fold and 2.3-fold the intended clinical
concentration in the vitreous of 29 mcg/mL, respectively.
14 CLINICAL STUDIES
The efficacy and safety of JETREA was demonstrated in two
multicenter, randomized, double masked, vehicle-controlled,
6 month studies in patients with symptomatic vitreomacular
adhesion (VMA). A total of 652 patients (JETREA 464,
vehicle 188) were randomized in these 2 studies.
Randomization was 2:1 (JETREA:vehicle) in Study 1 and 3:1
in Study 2.
Patients were treated with a single injection of JETREA or
vehicle. In both of the studies, the proportion of patients who
achieved VMA resolution at Day 28 (i.e., achieved success
on the primary endpoint) was significantly higher in the
ocriplasmin group compared with the vehicle group through
Month 6.
Vehicle
Difference
N=219
N=107
(95% CI)
≥ 3 line Improvement in BCVA
Month 6
28 (12.8%)
9 (8.4%)
4.4 (-2.5, 11.2)
> 3 line Worsening in BCVA
Month 6
16 (7.3%)
2 (1.9%)
5.4 (1.1, 9.7)
Study 2
8.3 Nursing Mothers
It is not known whether ocriplasmin is excreted in human
milk. Because many drugs are excreted in human milk, and
because the potential for absorption and harm to infant
growth and development exists, caution should be exercised
when JETREA is administered to a nursing woman.
8.4 Pediatric Use
Safety and effectiveness in pediatric patients have not been
established.
JETREA
JETREA
Vehicle
Difference
N=245
N=81
(95% CI)
≥ 3 line Improvement in BCVA
Month 6
29 (11.8%)
3 (3.8%)
8.1 (2.3, 13.9)
> 3 line Worsening in BCVA
Month 6
10 (4.1%)
4 (5.0%)
-0.9 (-6.3, 4.5)
Figure 1: Percentage of Patients with Gain or Loss
of ≥ 3 Lines of BCVA at Protocol-Specified Visits
15%
10%
5%
0%
-5%
-10%
-15%
7
14
28
90
180
Days
Study 1
JETREA
Study 1
Vehicle
Study 2
JETREA
Study 2
Vehicle
16 HOW SUPPLIED/STORAGE AND HANDLING
Each vial of JETREA contains 0.5 mg ocriplasmin in 0.2 mL
citric-buffered solution (2.5 mg/mL). JETREA is supplied in a
2 mL glass vial with a latex free rubber stopper. Vials are for
single use only.
Storage
Store frozen at or below -4˚F ( -20˚C). Protect the vials from
light by storing in the original package until time of use.
17 PATIENT COUNSELING INFORMATION
In the days following JETREA administration, patients are at
risk of developing intraocular inflammation/infection. Advise
patients to seek immediate care from an ophthalmologist if
the eye becomes red, sensitive to light, painful, or develops a
change in vision [see Warnings and Precautions].
Patients may experience temporary visual impairment after
receiving an intravitreal injection of JETREA [see Warnings
and Precautions]. Advise patients to not drive or operate heavy
machinery until this visual impairment has resolved. If visual
impairment persists or decreases further, advise patients to
seek care from an ophthalmologist.
Manufactured for:
ThromboGenics, Inc.
101 Wood Avenue South, 6th Floor
Iselin, NJ 08830
U.S. License Number: 1866
©2013, ThromboGenics, Inc. All rights reserved.
Version 1.0
Initial U.S. Approval: 2012
ThromboGenics U.S. patents: 7,445,775; 7,547,435; 7,914,783
and other pending patents.
JETREA and the JETREA logo are trademarks or registered
trademarks of ThromboGenics NV in the United States,
European Union, Japan, and other countries.
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NEWS
Volume XX • No. 8 • August 2013
Two-Year IVAN Results: Avastin,
Lucentis Equally Effective
The two-year results of IVAN published
July 19 in The Lancet show that Lucentis and Avastin are equally effective
in treating neovascular or wet age-related macular degeneration.
The study estimates that the National Health Service could save £84.5 million ($130 million) annually by switching from Lucentis to Avastin. Avastin
is already used to treat wet AMD in
some parts of the UK and extensively
elsewhere in the world and also for
other eye conditions.
Six hundred ten people with wet
AMD were included in IVAN, which
is one of the largest ever carried out in
the field of eye disease in the UK. Patients received injections of the drug
into the affected eye every month for
the first three months. Patients were
then subdivided to receive the injections at every visit (monthly group) or
only if the specialist decided there was
persistent disease activity (as-needed
group).
The two-year results show that sight
was equally well-preserved with either
of the two drugs. Giving the treatment regularly every month resulted
in slightly better levels of sight, which
was detected through testing of near
visual acuity and contrast sensitivity.
The as-needed group received on average 13 injections over the two year
period compared to 23 for the monthly
treatment group. However, continuous treatment caused a higher proportion of eyes to develop a condition
known as geographic atrophy, a thinning of the retina and its blood supply.
Abbott to Acquire OptiMedica Corp.
Abbott announced it has entered into an agreement to purchase OptiMedica Corp.,
maker of the Catalys Precision Laser System. The acquisition will enable Abbott to expand
its vision-care business into the femtosecond laser-assisted cataract surgery market.
Under the terms of the agreement, Abbott will acquire OptiMedica for $250 million, plus
additional payments totaling up to $150 million upon completion of certain development,
regulatory or sales milestones.
The Catalys laser system has both CE Mark in Europe and clearance from the U.S. Food and
Drug Administration. “The acquisition of OptiMedica will provide Abbott with an entry point
into the rapidly developing laser cataract surgery market,” said Murthy Simhambhatla, senior
vice president, Medical Optics, Abbott. “The Catalys laser system provides physicians with a
state-of-the-art, computer-guided alternative in treating patients suffering from cataracts.”
The global demand for vision care is on the rise, as the worldwide population ages and the
emerging middle class grows in developing nations. Nearly 22 million cataract surgeries
will be performed globally in 2013. The average age of a cataract patient is between 65
and 70, and approximately 12 percent of the global population is age 60 or older. Abbott
also features the Tecnis line of monofocal, multifocal and toric intraocular lenses. Cataractrelated sales represent approximately 60 percent of Abbott’s vision-care sales. The
transaction is expected to close by the end of the year and is subject to customary closing
conditions, including antitrust clearances.
Professor Usha Chakravarthy of
Queen’s University Belfast’s Centre
for Vision and Vascular Science, who
led the research study team said:
“The IVAN results at the end of year
two show that Lucentis and Avastin
have similar functional effectiveness
regardless of the drug received. With
respect to monthly versus as-needed
treatment, while there was marginally better eyesight in the former, the
development of atrophy is a matter of
concern in the longer term.”
Serious adverse events, which included death, heart attacks, strokes,
and any other event that was life
threatening, disabling or resulted in
hospitalization, were similar for the
two drugs. However, deaths occurred
less frequently in the group that received monthly treatment, although
there were fewer deaths overall among
people taking part in the trial than
were expected based on their age and
gender and national death rates. When
these safety results were combined
with those of a similar study called the
CATT trial in the United States, the
findings continued to indicate fewer
deaths when treatment was given
monthly.
Photoreceptors
Successfully
Produced in Lab
For the first time, light-sensing photo-
receptor cells have been grown from
scratch in the lab, and then success-
4 | Review of Ophthalmology | August 2013
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7/26/13 11:17 AM
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www.RheinMedical.com
Meibum Expression Is Recommended As A Subsequent Procedure To
Meibomian Gland Probing, Insuring The Patency Of Meibomian Glands.
Call 800-637-4346 For More Information.
3360 Scherer Drive, Suite B, St. Petersburg, FL 33716
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fully transplanted into the eyes of blind
mice.
The transplanted cells successfully
matured and connected with nerves
that transmit visual signals to the brain.
The researchers say that if the procedure can be repeated with human
stem cells, they believe they can cure
most forms of blindness that result
from degeneration of these photoreceptor cells, due to either the effects of
aging or diseases.
“We can treat a really broad range of
patients,” says Robin Ali of University
College London, head of the team that
performed the transplant.
Another experimental stem-cell
treatment, one involving a transplant
of cells that support and nourish photoreceptors in the eye, has restored
the sight of a man blinded by the degeneration of his retinal cells. But Ali
says that this treatment will only work
in people with some surviving photoreceptor cells, whereas the new therapy
would work even where these cells
have completely degenerated.
Dr. Ali and his colleagues made the
photoreceptors using a relatively new
procedure that allows embryonic stem
cells to self-organize into retina-like
structures within a three-dimensional
glob of jelly.
Crucially for developing human
treatments, they also identified the optimal stage in the cells’ development –
at around 24 days – to transplant them
into the eyes of mice. At that point, the
photoreceptor cells are still relatively
immature, but when implanted they
find their own way to the correct sites
in the eye where they mature fully. If
the cells had already started to become
fully mature photoreceptor structures
called outer segments, they would not
have been able to do this when transplanted, says Dr. Ali.
“We now have a route map for doing this with human embryonic stem
cells,” he says. The team has already
grown the precursors to human retinal
photoreceptor cells. “The challenge is
2HEIN-EDICAL3TYLIZED%YE
BABB
7/26/13 11:17 AM
REVIEW
News
to get [the procedure] efficient enough
for transplants,” he says.
In the meantime, the team wants to
carry out more transplants and show
that the treated mice can see. They say
that although the transplanted cells
developed and connected up successfully in their first attempt, not enough
of the cells were implanted to restore
the mouse’s vision. “It’s a numbers
game,” says Dr. Ali.
“Until recently, photoreceptor loss
was thought to be irreversible, but
with this paper, there’s now enough
evidence to think we might be able to
reverse blindness in the future,” says
Robert Lanza, medical director of Advanced Cell Technology, a company in
Marlborough, Mass., that is evaluating
whether implanting retinal pigment
epithelial cells that nourish other types
of retinal cells can prevent age-related
blindness. “But it needs to be repeated
using human cells, and there are lots
of technical issues that need to be addressed, such as scaling up the threedimensional culture system.”
The work was reported in Nature
Biotechnology.
Evidence Lacking
For General
Glaucoma Screens
care setting,” said task force co-vice
chairman Albert Siu, MD, MSPH.
The task force’s evidence review focused on primary open-angle glaucoma, which is the most common form
of the disease.
It is important to note that this recommendation applies specifically to
screening adults without vision problems in primary-care settings. While
there are many new treatments for
glaucoma, the USPSTF found that
there is not enough evidence to determine how best to screen for and diagnose glaucoma in adults with no signs
or symptoms of vision problems. Also,
there is a lack of evidence showing
that screening reduces the likelihood
of vision loss and blindness. “We call
on the health-care community to conduct critically needed research on effective screening tests and treatments
for glaucoma,” Dr. Siu says. “Findings
from new research may be able to improve the lives of many Americans and
help the task force update its recommendation in the future.” The final
recommendation statement is published online in the Annals of Internal
Medicine and is available at uspreven
tiveservicestaskforce.org.
Retinal Genes
Catalogued
The U.S. Preventive Services Task Force
Investigators at Massachusetts Eye and
released its final recommendation
statement on screening for glaucoma,
finding that there was not enough evidence to determine the accuracy and
effectiveness of glaucoma screening in
primary-care settings for adults who
do not have vision problems. Based
on this lack of clear evidence, the task
force could not make a recommendation for or against screening adults for
glaucoma.
“Unfortunately, we don’t have
enough evidence to know how best to
screen for the disease and who would
benefit from screening in the primary
Ear and Harvard Medical School have
published the most thorough description of gene expression in the human
retina reported to date. In a study
published in BMC Genomics, Michael
Farkas, PhD, Eric Pierce, MD, PhD,
and colleagues in the Ocular Genomics Institute at Mass Eye and Ear reported a complete catalog of the genes
expressed in the retina.
The investigators used a technique
called RNA sequencing to identify
all of the messenger RNAs (mRNAs)
produced in the human retina. The resulting catalog of expressed genes, or
transcriptome, demonstrates that the
majority of the 20,000-plus genes in
the human body are expressed in the
retina. This in itself is not surprising,
because the retina is a complex tissue
comprising 60 cell types.
In a more surprising result, Dr. Farkas and colleagues identified almost
30,000 novel exons and more than 100
potential novel genes that had not been
identified previously. Exons are the
portions of the genome that are used
to encode proteins or other genetic
elements. The investigators validated
almost 15,000 of these novel transcript
features and found that more than 99
percent of them could be reproducibly detected. Several thousand of the
novel exons appear to be used specifically in the retina. In total, the newly
detected mRNA sequence increased
the number of exons identified in the
human genome by 3 percent.
“While this may not sound like a lot,
it shows that there is more to discover
about the human genome, and that
each tissue may use distinct parts of
the genome,” said Dr. Pierce, director of the OGI and the Solman and
Libe Friedman associate professor of
ophthalmology at Harvard Medical
School.
Identifying the genetic cause of
patients’ retinal degeneration has
become especially important with
the recent success of clinical trials
of gene therapy for RPE65 Leber
congenital amaurosis. As a followup to these initial proof-of-concept
trials, clinical trials of gene therapy
for four other genetic forms of inherited retinal degeneration are
currently in progress. Further, studies in animal models have reported
successful gene therapy for multiple
additional genetic types of inherited
retinal degeneration. There is thus an
unprecedented opportunity to translate research progress into providing
sight-preserving and/or -restoring
treatment to patients with retinal degenerative disorders.
7/26/13 11:17 AM
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1
The Scientific Journal of the Royal College of Ophthalmology
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7/17/13 2:05 PM
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7/26/13 11:17 AM
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LET’S TALK
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August 2013 • Volume XX No. 8 | revophth.com
Cover Focus
22 |
Treating DME: Laser,
Anti-VEGF or Steroids?
By Christopher Kent, Senior Editor
Surgeons are debating which option—or
combination of options—makes the most sense.
30 |
Best Practices:
Treating Exudative AMD
By Walter Bethke, Managing Editor
How treatment approaches are evolving to
combat this dreaded disease.
36 |
Settling on an Anti-VEGF
Dosing Regimen
By Michelle Stephenson, Contributing Editor
Current options include continuous treatment
at a fixed interval, as-needed treatment, and the
“treat-and-extend” strategy.
Cover image:
Mark Erickson,
jirehdesign.com
August 2013 | Revophth.com | 11
011_rp0813_toc.indd 11
7/26/13 11:18 AM
Departments
4|
Review News
15 |
Editor’s Page
16 |
Technology Update
A First Look at the Trulign IOL
20 |
Medicare Q&A
Essentials of Diagnostics Documentation
42 |
Retinal Insider
Diagnosis and Treatment of
Birdshot Retinochoroidopathy
BSRC requires early therapy to limit damage,
preserve vision and induce long-term remission.
50 |
42
50
Plastic Pointers
The Surgical Treatment of the Aging Brow
This powerful rejuvenative technique beautifully
complements other facial cosmetic procedures.
58 |
Therapeutic Topics
Acupuncture: A Dry-Eye Therapy?
Patients seeking alternative ways to treat their
disease may turn to this ancient medical art.
64 |
Glaucoma Management
Trabeculectomy Postop:
Staying on Track
With this procedure, the toughest challenges for
the surgeon often occur after the surgery.
72 |
Refractive Surgery
How to Dodge Femto Flap Complications
74 |
Research Review
Bevacizumab for ROP
76 |
Classified Ads
78 |
Advertising Index
79 |
Wills Eye Resident Case Series
64
011_rp0813_toc.indd 12
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REVIEW
®
Editor’s Page
Christopher Glenn, Editor in Chief
E D I T O R I A L S TA F F
Editor in Chief
Christopher Glenn
(610) 492-1008
[email protected]
Managing Editor
Walter C. Bethke
(610) 492-1024
[email protected]
Senior Editor
Christopher Kent
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Chief Medical Editor
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Senior Director, Art/Production
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(610) 492-1027
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When a Person Turns
Into People, We All Pay
“A person is smart. People are dumb,
panicky dangerous animals and you
know it.”—Agent K, Men in Black.
The difference between a person
and people figures prominently and
from different perspectives in two
studies released this month, one that
received a lot of mainstream coverage,
the other not so much.
A widely publicized JAMA survey
article laid out physicians’ views about
their role in controlling health-care
costs.1 A number of noteworthy but
not-so-surprising findings emerged,
and I trust that you’ve seen them already or can track them down; they’re
worth finding.
One of the survey questions proposed that physicians “should sometimes deny beneficial but costly
services to certain patients because
resources should go to other patients
that need them more.” Predictably,
85 percent of respondents strongly
or moderately disagreed. Physicians
are not in the rationing business, and
besides—a person needs a test; people
get too many tests.
For many physicians, though, familiarty with the patient plays a role. To
be sure, the majority disagreed, but
nearly half of respondents moderately
or strong agreed that they “generally
order more tests when I don’t know
the patient well.”
Receiving less attention but touching on a related theme, a study from
the NIH and several other institutions
shed some interesting light on the
patient perspective on the issue of financing.2
Through focus groups and question-
naires, researchers looked at patients’
willingness to discuss cost of treatment
alternatives with their physicians. Participants in the study “felt that discussions of out-of-pocket costs, with some
caveats, could be appropriate in the
clinical encounter,” the researchers
say. “ ... a trusted physician with whom
they have a strong relationship seemed
to make some participants more positively disposed to discussing costs and
taking costs into account when making
choices among competing interventions in the clinical encounter.”
There are a host of factors that go
into building a relationship between
doctors and patients, some of them beyond your control. And no one is holding out for the return of Marcus Welby,
MD. (You youngsters go google that.)
But everyone seems to intuitively get
that a person is better than people; my
patient is not just a health-care consumer; and my doctor cares a lot more
about me than physicians. There’s now
even reason to believe that those relationships are more cost-effective.
As we undertake the greatest change
to our health-care system in decades, it
might be wise to put a little more effort
into understanding and building those
relationships.
1. JAMA 2013;310(4):380-388. doi:10.1001/
jama.2013.8278.
2. J Gen Intern Med 2013 Jul 24. doi:10.1007/
s11606-013-2543-9.
015_rp0813_edit.indd 15
7/26/13 2:53 PM
REVIEW
Technology Update
Edited by Michael Colvard, MD, and Steven Charles, MD
A First Look at
The Trulign IOL
Tips and techniques for working with the first toric presbyopic
intraocular lens approved in the United States.
Walter Bethke, Managing Editor
or years, U.S. surgeons have been
able to correct either astigmatism
or presbyopia with intraocular lenses,
but not both. With the recent Food
and Drug Administration approval
of the toric Crystalens, the Trulign
(Bausch + Lomb), surgeons are now
able to expand the application of presbyopia-correcting technology to meet
the needs of many of their patients
with corneal astigmatism. In this article, surgeons who’ve worked with the
Trulign lens share their experiences
and tips for getting the best outcomes
while avoiding complications.
correction,” says Encino, Calif., surgeon and Trulign investigator Michael
Colvard. “Eyes with higher cylinders
are far less common. Patients with
higher levels of astigmatism who are
without corneal pathology such as
keratoconus, in my experience, can
have their correction augmented with
peripheral corneal incisions.”
In the Trulign FDA study of 210
subjects, 79.9 percent of the 1.25-D
toric cohort achieved the intended
reduction in cylinder vs. 46.5 percent
of non-toric controls (p<0.001). The
mean percentage reduction of cylinder for the 2-D toric cohort was 88
percent, for the 2.75-D cohort it was
97 percent and for all torics it was 85
percent.
Ninety-six percent of implants
F
The Trulign, like the standard Crystalens, is a silicone lens with a 5-mm
optic and flexible, rectangular hinged
haptics with polyamide loops. It’s available in +4 to +10 D spherical equivalent powers (in 1-D increments)
and +10.5 to +33 D powers (in 0.5D increments). It was approved for
three cylinder powers: 1.25; 2.00 and
2.75 D, measured at the IOL plane.
“This range of astigmatic correction
covers roughly 90 percent of patients
who can benefit from astigmatism
John Jarstad, MD
Trulign by the Numbers
Surgeons say the Trulign’s haptics allow it
to rotate easily as they dial it into position.
016_rp0813_tech update.indd 16
rotated 5 degrees or less between
the day of surgery and three to six
months postop.1 “I think the key to
that is the polyamide loops,” explains
Jay Pepose, MD, medical monitor for
the Trulign FDA study. “They seem
integral to the rotational stability of
the lens.”
In terms of acuity, 97.8 percent of
the patients could see 20/40 or better
at distance and intermediate postop,
and 70 percent had 20/40 uncorrected
near vision. “The predictability was
high,” says Dr. Pepose. “Eighty percent were within 0.5 D of target. We
tell patients they may need low-power
reading glasses in some settings, especially if the light is low.”
In 147 patients studied for safety at
three to six months in the FDA study,
one patient had macular edema (0.7
percent) and one needed a secondary
surgery to reposition the IOL, but this
repositioning wasn’t related to axis
misalignment or rotation. One patient
experienced a significant visual disturbance, while 99 percent had none.
Dr. Pepose says this is a boon for older
patients. “I explain to them that one
advantage to the lens is they’re not
going to be at increased risk for glare,
This article has no commercial sponsorship.
7/25/13 4:02 PM
NEW
For the treatment of elevated IOP
UNLOCK NEW TREATMENT POSSIBILITIES
SIMBRINZA™ Suspension provided additional
1-3 mm Hg IOP lowering compared to
the individual components1
■ IOP measured at 8 AM, 10 AM, 3 PM, and 5 PM
was reduced by 21-35% at Month 32-4
■ Efficacy proven in two pivotal Phase 3 randomized,
multicenter, double-masked, parallel-group, 3-month,
3-arm, contribution-of-elements studies2,3
■ The most frequently reported adverse reactions (3-5%)
were blurred vision, eye irritation, dysgeusia (bad taste),
dry mouth, and eye allergy1
■ Only available beta-blocker-free fixed combination2,3
INDICATIONS AND USAGE
SIMBRINZA™ (brinzolamide/brimonidine tartrate ophthalmic suspension)
1%/0.2% is a fixed combination indicated in the reduction of elevated
intraocular pressure (IOP) in patients with open-angle glaucoma or
ocular hypertension.
Dosage and Administration
The recommended dose is one drop of SIMBRINZA™ Suspension
in the affected eye(s) three times daily. Shake well before use.
SIMBRINZA™ Suspension 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.
IMPORTANT SAFETY INFORMATION
Contraindications
SIMBRINZA™ Suspension is contraindicated in patients who are
hypersensitive to any component of this product and neonates and
infants under the age of 2 years.
Sulfonamide Hypersensitivity Reactions—Brinzolamide is a sulfonamide,
and although administered topically, is absorbed systemically. Sulfonamide
attributable adverse reactions may occur. Fatalities have occurred due
to severe reactions to sulfonamides. Sensitization may recur when a
sulfonamide is readministered irrespective of the route of administration.
If signs of serious reactions or hypersensitivity occur, discontinue the use
of this preparation.
Corneal Endothelium—There is an increased potential for developing
corneal edema in patients with low endothelial cell counts.
Severe Hepatic or Renal Impairment (CrCl <30 mL/min)—SIMBRINZA™
Suspension has not been specifically studied in these patients and
is not recommended.
Adverse Reactions
In two clinical trials of 3 months’ duration with SIMBRINZA™ Suspension,
the most frequent reactions associated with its use occurring in
approximately 3-5% of patients in descending order of incidence included:
blurred vision, eye irritation, dysgeusia (bad taste), dry mouth, and eye allergy.
Adverse reaction rates with SIMBRINZA™ Suspension were comparable to
those of the individual components. Treatment discontinuation, mainly due to
adverse reactions, was reported in 11% of SIMBRINZA™ Suspension patients.
Drug Interactions—Consider the following when prescribing
SIMBRINZA™ Suspension:
Concomitant administration with oral carbonic anhydrase inhibitors is not
recommended due to the potential additive effect. Use with high-dose
salicylate may result in acid-base and electrolyte alterations. Use with
CNS depressants may result in an additive or potentiating effect. Use with
antihypertensives/cardiac glycosides may result in additive or potentiating
effect on lowering blood pressure. Use with tricyclic antidepressants may
blunt the hypotensive effect of systemic clonidine and it is unknown if use
with this class of drugs interferes with IOP lowering. Use with monoamine
oxidase inhibitors may result in increased hypotension.
For additional information about SIMBRINZA™ Suspension,
please see Brief Summary of full Prescribing Information on
adjacent page.
References: 1. SIMBRINZA™ Suspension Package Insert. 2. Katz G, DuBiner H,
Samples J, et al. Three-month randomized trial of fixed-combination brinzolamide, 1%,
and brimonidine, 0.2% [published online ahead of print April 11, 2013]. JAMA Ophthalmol.
doi:10.1001/jamaophthalmol.2013.188. 3. Nguyen QH, McMenemy MG, Realini T,
et al. Phase 3 randomized 3-month trial with an ongoing 3-month safety extension
of fixed-combination brinzolamide 1%/brimonidine 0.2%. J Ocul Pharmacol Ther.
2013;29(3): 290-297. 4. Data on file, 2013.
© 2013 Novartis 4/13
RP0613_Alcon Simbrinza.indd 1
MG13003JAD
5/20/13 10:07 AM
BRIEF SUMMARY OF PRESCRIBING INFORMATION
SIMBRINZA™ (brinzolamide/brimonidine tartrate ophthalmic
suspension) 1%/0.2% is a fixed combination of a carbonic anhydrase
inhibitor and an alpha 2 adrenergic receptor agonist indicated for
the reduction of elevated intraocular pressure (IOP) in patients with
open-angle glaucoma or ocular hypertension.
DOSAGE AND ADMINISTRATION
The recommended dose is one drop of SIMBRINZA™ Suspension
in the affected eye(s) three times daily. Shake well before use. SIMBRINZA™ Suspension 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.
DOSAGE FORMS AND STRENGTHS
Suspension containing 10 mg/mL brinzolamide and 2 mg/mL
brimonidine tartrate.
CONTRAINDICATIONS
Hypersensitivity - SIMBRINZA™ Suspension is contraindicated in
patients who are hypersensitive to any component of this product.
Neonates and Infants (under the age of 2 years) - SIMBRINZA™
Suspension is contraindicated in neonates and infants (under the age
of 2 years) see Use in Specific Populations
WARNINGS AND PRECAUTIONS
Sulfonamide Hypersensitivity Reactions - SIMBRINZA™
Suspension contains brinzolamide, a sulfonamide, and although
administered topically is absorbed systemically. Therefore, the same
types of adverse reactions that are attributable to sulfonamides
may occur with topical administration of SIMBRINZA™ Suspension.
Fatalities have occurred due to severe reactions to sulfonamides
including Stevens-Johnson syndrome, toxic epidermal necrolysis,
fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and
other blood dyscrasias. Sensitization may recur when a sulfonamide
is re-administered irrespective of the route of administration. If signs
of serious reactions or hypersensitivity occur, discontinue the use of
this preparation [see Patient Counseling Information]
Corneal Endothelium - Carbonic anhydrase activity has been
observed in both the cytoplasm and around the plasma membranes
of the corneal endothelium. There is an increased potential for developing corneal edema in patients with low endothelial cell counts.
Caution should be used when prescribing SIMBRINZA™ Suspension
to this group of patients.
Severe Renal Impairment - SIMBRINZA™ Suspension has not been
specifically studied in patients with severe renal impairment (CrCl
< 30 mL/min). Since brinzolamide and its metabolite are excreted
predominantly by the kidney, SIMBRINZA™ Suspension is not recommended in such patients.
Acute Angle-Closure Glaucoma - The management of patients with
acute angle-closure glaucoma requires therapeutic interventions in
addition to ocular hypotensive agents. SIMBRINZA™ Suspension has
not been studied in patients with acute angle-closure glaucoma.
Contact Lens Wear - The preservative in SIMBRINZA™, benzalkonium chloride, may be absorbed by soft contact lenses. Contact lenses
should be removed during instillation of SIMBRINZA™ Suspension
but may be reinserted 15 minutes after instillation [see Patient
Counseling Information].
Severe Cardiovascular Disease - Brimonidine tartrate, a component
of SIMBRINZATM Suspension, has a less than 5% mean decrease in
blood pressure 2 hours after dosing in clinical studies; caution should
be exercised in treating patients with severe cardiovascular disease.
Severe Hepatic Impairment - Because brimonidine tartrate, a
component of SIMBRINZA™ Suspension, has not been studied in
patients with hepatic impairment, caution should be exercised in
such patients.
Potentiation of Vascular Insufficiency - Brimonidine tartrate, a
component of SIMBRINZATM Suspension, may potentiate syndromes
associated with vascular insufficiency. SIMBRINZA™ Suspension
should be used with caution in patients with depression, cerebral or
coronary insufficiency, Raynaud’s phenomenon, orthostatic hypotension, or thromboangitis obliterans.
Contamination of Topical Ophthalmic Products After Use - There
have been reports of bacterial keratitis associated with the use
of multiple-dose containers of topical ophthalmic products. These
containers have been inadvertently contaminated by patients who, in
most cases, had a concurrent corneal disease or a disruption of the
ocular epithelial surface [see Patient Counseling Information].
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 the
rates in the clinical studies of another drug and may not reflect the
rates observed in practice.
SIMBRINZA™ Suspension - In two clinical trials of 3 months
duration 435 patients were treated with SIMBRINZA™ Suspension,
and 915 were treated with the two individual components. The most
frequently reported adverse reactions in patients treated with SIMBRINZA™ Suspension occurring in approximately 3 to 5% of patients
in descending order of incidence were blurred vision, eye irritation,
dysgeusia (bad taste), dry mouth, and eye allergy. Rates of adverse
reactions reported with the individual components were comparable.
Treatment discontinuation, mainly due to adverse reactions, was
reported in 11% of SIMBRINZA™ Suspension patients.
Other adverse reactions that have been reported with the individual
components during clinical trials are listed below.
RP0613_Alcon Simbrinza PI.indd 1
Brinzolamide 1% - In clinical studies of brinzolamide ophthalmic
suspension 1%, the most frequently reported adverse reactions
reported in 5 to 10% of patients were blurred vision and bitter,
sour or unusual taste. Adverse reactions occurring in 1 to 5% of
patients were blepharitis, dermatitis, dry eye, foreign body sensation,
headache, hyperemia, ocular discharge, ocular discomfort, ocular
keratitis, ocular pain, ocular pruritus and rhinitis.
The following adverse reactions were reported at an incidence
below 1%: allergic reactions, alopecia, chest pain, conjunctivitis,
diarrhea, diplopia, dizziness, dry mouth, dyspnea, dyspepsia, eye
fatigue, hypertonia, keratoconjunctivitis, keratopathy, kidney pain,
lid margin crusting or sticky sensation, nausea, pharyngitis, tearing
and urticaria.
Brimonidine Tartrate 0.2% - In clinical studies of brimonidine
tartrate 0.2%, adverse reactions occurring in approximately 10 to
30% of the subjects, in descending order of incidence, included oral
dryness, ocular hyperemia, burning and stinging, headache, blurring,
foreign body sensation, fatigue/drowsiness, conjunctival follicles,
ocular allergic reactions, and ocular pruritus.
Reactions occurring in approximately 3 to 9% of the subjects, in
descending order included corneal staining/erosion, photophobia,
eyelid erythema, ocular ache/pain, ocular dryness, tearing, upper
respiratory symptoms, eyelid edema, conjunctival edema, dizziness,
blepharitis, ocular irritation, gastrointestinal symptoms, asthenia,
conjunctival blanching, abnormal vision and muscular pain.
The following adverse reactions were reported in less than 3% of
the patients: lid crusting, conjunctival hemorrhage, abnormal taste,
insomnia, conjunctival discharge, depression, hypertension, anxiety,
palpitations/arrhythmias, nasal dryness and syncope.
Postmarketing Experience - The following reactions have
been identified during postmarketing use of brimonidine tartrate
ophthalmic solutions in clinical practice. Because they are reported
voluntarily from a population of unknown size, estimates of frequency
cannot be made. The reactions, which have been chosen for
inclusion due to either their seriousness, frequency of reporting,
possible causal connection to brimonidine tartrate ophthalmic
solutions, or a combination of these factors, include: bradycardia,
hypersensitivity, iritis, keratoconjunctivitis sicca, miosis, nausea, skin
reactions (including erythema, eyelid pruritus, rash, and vasodilation),
and tachycardia.
Apnea, bradycardia, coma, hypotension, hypothermia, hypotonia,
lethargy, pallor, respiratory depression, and somnolence have
been reported in infants receiving brimonidine tartrate ophthalmic
solutions [see Contraindications].
DRUG INTERACTIONS
Oral Carbonic Anhydrase Inhibitors - There is a potential for an
additive effect on the known systemic effects of carbonic anhydrase
inhibition in patients receiving an oral carbonic anhydrase inhibitor
and brinzolamide ophthalmic suspension 1%, a component of
SIMBRINZA™ Suspension. The concomitant administration of
SIMBRINZA™ Suspension and oral carbonic anhydrase inhibitors is
not recommended.
High-Dose Salicylate Therapy - Carbonic anhydrase inhibitors
may produce acid-base and electrolyte alterations. These alterations
were not reported in the clinical trials with brinzolamide ophthalmic
suspension 1%. However, in patients treated with oral carbonic
anhydrase inhibitors, rare instances of acid-base alterations have
occurred with high-dose salicylate therapy. Therefore, the potential
for such drug interactions should be considered in patients receiving
SIMBRINZA™ Suspension.
CNS Depressants - Although specific drug interaction studies have
not been conducted with SIMBRINZA™, the possibility of an additive
or potentiating effect with CNS depressants (alcohol, opiates, barbiturates, sedatives, or anesthetics) should be considered.
Antihypertensives/Cardiac Glycosides - Because brimonidine tartrate, a component of SIMBRINZA™ Suspension, may reduce blood
pressure, caution in using drugs such as antihypertensives and/or
cardiac glycosides with SIMBRINZA™ Suspension is advised.
Tricyclic Antidepressants - Tricyclic antidepressants have been
reported to blunt the hypotensive effect of systemic clonidine. It is not
known whether the concurrent use of these agents with SIMBRINZA™
Suspension in humans can lead to resulting interference with the
IOP lowering effect. Caution is advised in patients taking tricyclic
antidepressants which can affect the metabolism and uptake of
circulating amines.
Monoamine Oxidase Inhibitors - Monoamine oxidase (MAO) inhibitors may theoretically interfere with the metabolism of brimonidine
tartrate and potentially result in an increased systemic side-effect
such as hypotension. Caution is advised in patients taking MAO
inhibitors which can affect the metabolism and uptake of circulating
amines.
USE IN SPECIFIC POPULATIONS
Pregnancy - Pregnancy Category C: Developmental toxicity
studies with brinzolamide in rabbits at oral doses of 1, 3, and 6 mg/
kg/day (20, 60, and 120 times the recommended human ophthalmic
dose) produced maternal toxicity at 6 mg/kg/day and a significant
increase in the number of fetal variations, such as accessory skull
bones, which was only slightly higher than the historic value at 1 and
6 mg/kg. In rats, statistically decreased body weights of fetuses from
dams receiving oral doses of 18 mg/kg/day (180 times the recommended human ophthalmic dose) during gestation were proportional
to the reduced maternal weight gain, with no statistically significant
effects on organ or tissue development. Increases in unossified
sternebrae, reduced ossification of the skull, and unossified hyoid
that occurred at 6 and 18 mg/kg were not statistically significant. No
treatment-related malformations were seen. Following oral adminis-
tration of 14C-brinzolamide to pregnant rats, radioactivity was found
to cross the placenta and was present in the fetal tissues and blood.
Developmental toxicity studies performed in rats with oral doses of
0.66 mg brimonidine base/kg revealed no evidence of harm to the
fetus. Dosing at this level resulted in a plasma drug concentration
approximately 100 times higher than that seen in humans at the
recommended human ophthalmic dose. In animal studies, brimonidine crossed the placenta and entered into the fetal circulation to a
limited extent.
There are no adequate and well-controlled studies in pregnant women. SIMBRINZA™ Suspension should be used during pregnancy
only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers - In a study of brinzolamide in lactating rats,
decreases in body weight gain in offspring at an oral dose of 15 mg/
kg/day (150 times the recommended human ophthalmic dose) were
observed during lactation. No other effects were observed. However,
following oral administration of 14C-brinzolamide to lactating rats,
radioactivity was found in milk at concentrations below those in the
blood and plasma. In animal studies, brimonidine was excreted in
breast milk.
It is not known whether brinzolamide and brimonidine tartrate are
excreted in human milk following topical ocular administration.
Because many drugs are excreted in human milk and because of the
potential for serious adverse reactions in nursing infants from SIMBRINZA™ (brinzolamide/brimonidine tartrate ophthalmic suspension)
1%/0.2%, a decision should be made whether to discontinue nursing
or to discontinue the drug, taking into account the importance of the
drug to the mother.
Pediatric Use - The individual component, brinzolamide, has been
studied in pediatric glaucoma patients 4 weeks to 5 years of age. The
individual component, brimonidine tartrate, has been studied in pediatric patients 2 to 7 years old. Somnolence (50-83%) and decreased
alertness was seen in patients 2 to 6 years old. SIMBRINZA™
Suspension is contraindicated in children under the age of 2 years
[see Contraindications].
Geriatric Use - No overall differences in safety or effectiveness have
been observed between elderly and adult patients.
OVERDOSAGE
Although no human data are available, electrolyte imbalance,
development of an acidotic state, and possible nervous system
effects may occur following an oral overdose of brinzolamide. Serum
electrolyte levels (particularly potassium) and blood pH levels should
be monitored.
Very limited information exists on accidental ingestion of brimonidine
in adults; the only adverse event reported to date has been hypotension. Symptoms of brimonidine overdose have been reported in
neonates, infants, and children receiving brimonidine as part of medical treatment of congenital glaucoma or by accidental oral ingestion.
Treatment of an oral overdose includes supportive and symptomatic
therapy; a patent airway should be maintained.
PATIENT COUNSELING INFORMATION
Sulfonamide Reactions - Advise patients that if serious or unusual
ocular or systemic reactions or signs of hypersensitivity occur, they
should discontinue the use of the product and consult their physician.
Temporary Blurred Vision - Vision may be temporarily blurred
following dosing with SIMBRINZA™ Suspension. Care should be
exercised in operating machinery or driving a motor vehicle.
Effect on Ability to Drive and Use Machinery - As with other drugs
in this class, SIMBRINZA™ Suspension may cause fatigue and/or
drowsiness in some patients. Caution patients who engage in hazardous activities of the potential for a decrease in mental alertness.
Avoiding Contamination of the Product - Instruct patients that
ocular solutions, if handled improperly or if the tip of the dispensing
container contacts the eye or surrounding structures, can become
contaminated by common bacteria known to cause ocular infections.
Serious damage to the eye and subsequent loss of vision may result
from using contaminated solutions [see Warnings and Precautions ]. Always replace the cap after using. If solution changes color
or becomes cloudy, do not use. Do not use the product after the
expiration date marked on the bottle.
Intercurrent Ocular Conditions - Advise patients that if they have
ocular surgery or develop an intercurrent ocular condition (e.g., trauma or infection), they should immediately seek their physician’s advice concerning the continued use of the present multidose container.
Concomitant Topical Ocular Therapy - If more than one topical
ophthalmic drug is being used, the drugs should be administered at
least five minutes apart.
Contact Lens Wear - The preservative in SIMBRINZA™, benzalkonium chloride, may be absorbed by soft contact lenses. Contact lenses
should be removed during instillation of SIMBRINZA™ Suspension,
but may be reinserted 15 minutes after instillation.
©2013 Novartis
U.S. Patent No:
6,316,441
ALCON LABORATORIES, INC.
Fort Worth, Texas 76134 USA
1-800-757-9195
[email protected]
© 2013 Novartis 4/13
MG13003JAD
5/20/13 10:09 AM
halo or reduced contrast sensitivity,”
he says. “Patients are living longer and
longer—it’s not uncommon for us to
have patients in their 90s coming in to
see us—and we don’t know what’s going to happen to those 75-year-olds as
they age. Are they going to get macular degeneration? Epiretinal membrane? Something else that will decrease contrast sensitivity? If I put in
a multifocal lens that decreases their
contrast and then they live that long,
maybe I didn’t do these patients a
favor. The accommodative lens might
not produce as much near vision as a
multifocal, though, so it’s a trade-off.”
Nicholas Batra, MD
REVIEW
Technology
Update
Using ORA’s Verifye system, the surgeon
was able to rotate this Trulign until the
astigmatism was less than 0.5 D.
an ideal rhexis size to maximize intermediate near vision,” he says. “We
found that 5.5 mm seemed to be a
good size, just slightly larger than the
optic of the lens.”
• Use ORA carefully. If you use
Wavetech’s ORA for intraoperative
aberrometry with the Trulign, Auburn, Wash., surgeon John Jarstad
advises to check and re-check your
measurements. “We’ve done about
10 Trulign implantations so far, and
they’ve all done really well,” he says.
“The one thing we’re still trying to
work out though is, in patients with
high amounts of astigmatism, we’re
not getting complete accuracy in the
lens power measurement from the
ORA system. As a result, we’re relying
more on the IOLMaster-predicted
lens power than the ORA in patients
with high astigmatism. Hopefully, the
new ORA software will work well and
we’ll be able to nail down these lens
power measurements.”
• Cortical cleanup and lens posi-
Trulign users say they’ve learned
some things about implanting the lens
that can help get the best outcomes.
• Preop planning. “Surgeons use
the Trulign toric calculator [https://
trulign.toriccalculator.com] to plan
the case,” says Dr. Colvard. “There,
you enter the customary info for toric
IOL calculations, including keratometric data with steep and flat corneal
axis, the IOL power and the location
of your planned incision. I like to work
on the steep axis but I think it’s important to realize that if you place your
incision on a vertical axis the surgically
induced astigmatism will be slightly
greater than if you work horizontally.”
• Size the capsulotomy properly. Dr. Colvard says that, like the
standard Crystalens, capsulotomy size
plays a role in the proper positioning
of the lens. “The capsulotomy size is
important with the Crystalens,” he
says. “You want it to be in the 5- to
6-mm range. It’s my clinical impression that this size gives you more stable refractive outcomes. I believe that
a larger capsulorhexis allows the lens
to move forward more and produce
more of a myopic shift postop.”
Dr. Pepose says a 5.5-mm capsulorhexis seems like a good fit. “We did
regression analysis to see if there was
Michael Colvard, MD
Tips and Techniques
The Trulign has markings on the toric axis
to allow surgeons to line it up in the bag.
tion. Oakland surgeon Nicholas Batra
says this phase of the procedure is
important. “Similar to other premium
lens surgeries, make sure to do a good
job with the cataract aspiration and
cortical cleanup,” he says. “Also, make
sure there’s no tilt evident with the
lens or the haptics. If the lens isn’t
at the equator of the capsular bag, if
three of the four haptic loops are at
the equator and one isn’t, the lens can
be tilted. I’ll spin the lens in the bag
before putting it on-axis to ensure that
the haptics are at the equator.”
• Close the wound tightly. Surgeons agree that, part and parcel with
making sure the lens is seated properly is ensuring that the wound is sealed
and watertight. “It’s very important to
make sure the incision is absolutely
secure,” says Dr. Colvard. “If there
is any loss of chamber volume postop
the lens will tend to vault forward
inducing an unplanned myopic shift.
With unsutured clear corneal incisions used in conjunction with standard intraocular lenses, a small, transient loss of anterior chamber volume
may occur postoperatively but go unnoticed because it doesn’t have much
of an effect on the refractive outcome.
But if this occurs with Crystalens or
Trulign, a loss of chamber volume,
even a temporary one, will cause the
lens to vault forward and stay there.”
Dr. Pepose concurs, saying, “You want
the optic in a posterior position with
the haptics seated way out in the fornix of the capsular bag, and you want
a nice, watertight seal with no leakage,
Seidel-negative.”
Going forward, Dr. Pepose says he
feels the lens fills a niche that surgeons will appreciate. “In the past, we
had monofocal, non-accommodative
toric lenses, but this combines the
two platforms,” he says. “It’s nice not
to have to have patients undergo multiple procedures.”
1. FDA Summary of Safety and Effectiveness Data: Trulign. http://
www.accessdata.fda.gov/cdrh_docs/pdf3/P030002S027b.pdf.
Accessed 24 June 2013.
016_rp0813_tech update.indd 19
7/25/13 4:02 PM
REVIEW
Medicare Q&A
Donna McCune, CCS-P, COE
Essentials of Diagnostic
Test Documentation
Diagnostic tests beyond eye exams: what constitutes an order;
the difference between interpretation and report; and more.
Q
Are the ophthalmic
diagnostic tests
listed in the 2013
Current Procedural
Terminology
manual treated
discretely
and separately
reimbursed?
A
Yes. The CPT manual
contains a section,
“Special Ophthalmological Services,” that
describes diagnostic
tests that go beyond
eye exams: “Special
ophthalmological
services may be
reported in addition to the
general ophthalmological services or evaluation and
management services.”
These tests are usually reimbursed separately by most
payers.
Q
Does the Center for
Medicare Services
monitor a physician’s or
group’s practice patterns for
billable diagnostic tests?
020_rp0813_mqa.indd 20
A
CMS does track the
frequency of claims
paid for all CPT codes
for each provider, as
well as for provider
groups.
Q
Will an
abnormal
frequency of
a particular
test(s)
be a red
flag for an
audit?
A
P o s s i b l y.
CMS data
is gathered for the
specialty of ophthalmology (18).
A subspecialist is
compared to all
ophthalmologists. Therefore, a
glaucoma
specialist or a
retina
s p e cialist is
likely to have a
higher utilization of
certain diagnostic tests than a general
ophthalmologist. An abnormal utilization does not necessarily indicate that
a physician has done something incorrect, but it can be a red flag.
Q
A
Who can order a
diagnostic test, and what
constitutes an order?
Physicians order diagnostic tests.
It may be a notation as simple as
“VF today,” “FA – OD next visit” or as
complex as ordering extensive blood
chemistry tests at the hospital. It is
usually noted as part of the plan in
the medical record. The order should
include the medical rationale for the
test, especially if it is not immediately
obvious to a reviewer.
Q
What is meant by the
phrase “interpretation and
report” contained in many of
the CPT code descriptions for
tests?
A
The Medicare guidelines for
interpretation of diagnostic
tests are discussed in the Medicare
Claims Processing Manual, Chapter
13, §100: Interpretation of Diagnostic Tests. CMS makes a distinction
between a review of a test and an
7/25/13 4:16 PM
“interpretation and report.”
“Carriers generally distinguish between an ‘interpretation and report’
of an X-ray or an EKG procedure and
a ‘review’ of the procedure. A professional component billing based on a
review of the findings of these procedures, without a complete, written
report similar to that which would
be prepared by a specialist in the
field, does not meet the conditions
for separate payment of the service.
This is because the review is already
included in the ... E/M payment.”
Simple, brief notations such as
“normal” or “abnormal” are construed
as a review of the test rather than as
an interpretation and report.
Q
What documentation
essentials would
constitute an “interpretation”
and not just a “review” of a
diagnostic test?
A
The value of an “interpretation
and report” derives from the answers to important questions about
the diagnostic test:
• Physician’s order – Why is the
test desired?
• Date performed – When was it
performed?
• Technician’s initials – Who did
it?
• Reliability of the test – Was the
test of any value?
• Patient cooperation – Was the
patient at fault?
• Test findings – What are the results of the test?
• Assessment, diagnosis – What do
the results mean?
• Impact on treatment, prognosis
– What’s next?
• Physician’s signature – Who is
the physician?
The documentation of the answers
would constitute an interpretation.
In ophthalmology, tests such as perimetry are much more valuable for
making decisions about treatment
when there is a series. Does the series demonstrate disease progression? If so, this would also be included in the interpretation.
Q
Where should the
interpretation be
documented in the patient’s
medical record?
A
If the interpretation is written
as part of the office visit note, it
might appear to be an element of the
evaluation and management service.
Because of this, it’s better to keep it
separate, or differentiate it from the
rest of the eye exam by surrounding
the notations with a box and a title like
“perimetry report.”
Within an electronic medical record, we often find a designated spot
to record the physician’s interpretation of a test as a report.
Q
A
When does the
interpretation and report
need to be completed?
Ideally, the interpretation of a
test follows immediately after
the technical component is finished.
In practice, there may be a delay;
however, the delay should not be
lengthy or affect patient care. Since
many ophthalmic tests require only
general supervision, and the physician need not be present during the
performance of the test, the interpretation might take place the next
day. If a weekend intervenes, there
may be two days’ delay.
As a practical alternative, bill the
entire test upon completion, after
the interpretation is documented in
the medical record, since it is not
clear what diagnosis would be used
for the technical component alone.
Q
Are screening tests
covered by third-party
payers?
A
As a general rule, diagnostic tests
performed as baseline documentation of a healthy eye, or as preventive medicine to screen for potential disease, are not covered by most
medical insurance plans, including
Medicare. Screening is differentiated
from other diagnostic testing by several features:
• Screening is part of a wellness
program to check for disease that may
otherwise go undetected.
• Screening is not required by
medical necessity; it’s optional.
Do not to file claims for screening
tests; collect your fee from the patient. Use an Advanced Beneficiary
Notice of Noncoverage (CMS-R-131)
to notify the beneficiary in advance
that the test is being performed as a
screening service and that Medicare
will not pay for it. For other thirdparty payers, a Notice of Exclusion
from Health Benefits form serves the
same purpose.
Q
A
Are tests reimbursed when
performed in the postop
period?
Yes. Certain services associated
with a major procedure are not
considered part of the global surgical package and are separately reimbursed. They include medically necessary diagnostic tests.
Q
Are coverage guidelines,
e.g., approved diagnosis
codes, consistent among
Medicare contractors?
A
No. Some contractors publish
more policies than others for diagnostic tests and each contractor may
publish different coverage guidelines.
Check your local Medicare contractor
for specifics in your area.
Ms. McCune is vice president of the
Corcoran Consulting Group. Contact
her at [email protected].
020_rp0813_mqa.indd 21
7/25/13 4:16 PM
REVIEW
Cover Focus
Retina Issue
Treating DME: Laser,
Anti-VEGF or Steroids?
Christopher Kent, Senior Editor
Surgeons are
still debating
which option—or
combination of
options—makes
the most sense.
W
hen it comes to treating diabetic macular edema, this
is arguably both the best of
times and the worst of times. “We’ve
never had more treatment options,”
notes Allen C. Ho, MD, FACS, director of retina research at Wills Eye
Hospital and professor of ophthalmology at Thomas Jefferson University
School of Medicine in Philadelphia.
“At the same time, we’re witnessing
more patients with the problem than
ever, because as much as 10 percent
of the U.S. population may have diabetes mellitus. Over time, particularly
if your blood sugar remains uncontrolled, you’ll develop problems such
as diabetic retinopathy, and more
specifically, diabetic macular edema.
That’s the number one mechanism
of vision loss in patients with diabetic
retinopathy.”
The positive side of the equation—
the availability of multiple treatment
options, including anti-vascular endothelial growth factor drugs, steroids
and laser—raises some important
questions regarding which of the alternatives are most effective and how
they might best be used.
Working With Anti-VEGF
Currently, drugs that treat an overabundance of VEGF inside the eye
022_rp0813_f1.indd 22
are the most popular approach to
managing DME. However, their use
requires a number of decisions involving which drug to choose, how to use
it, and whether to combine it with
other treatment options such as steroids or laser.
Steve Charles, MD, FACS, FIC,
founder of the Charles Retina Institute in Memphis, Tenn., is particularly
concerned with dispelling one popular
myth regarding the choice between
ranibizumab and bevacizumab. “Doctors often have the impression that the
two anti-VEGF drugs are equivalent
because of the results of the Comparison of AMD Treatments Trial, which
showed that the two drugs were almost equivalent when treating macular degeneration,” he says. “What they
may not realize is that eyes with DME
have 5,000 times as much VEGF as
eyes with macular degeneration. This
is also true for central retinal vein occlusion, as was shown by Lloyd Paul
Aiello, MD, in one of the most important retina articles ever published,
back in 1994.1
“At the same time,” he continues,
“the molecular affinity of ranibizumab
for VEGF is 25 times higher than that
of bevacizumab. With 5,000 times as
much VEGF to manage in DME, this
increased molecular affinity makes a
huge difference. So when surgeons
7/25/13 3:47 PM
tell me they use steroids
There’s also the Allergan
because they tried bedexamethasone implant,
vacizumab and were not
Ozurdex, which can
impressed by the results,
work for diabetic macuI tell them they tried the
lar edema, although it’s
wrong drug.” Dr. Charles
approved because of its
adds that aflibercept also
results with retinal vein
appears to be 25 times as
occlusion. Our other
effective as bevacizumab,
tools include laser treatalthough it isn’t approved
ment, and of course the
for treating DME at this
general medical guidejuncture.
lines that address diabeDr. Ho agrees that when
tes by optimizing blood
it comes to DME, the two Anti-VEGF drugs are often the first-choice treatment for DME. This eye
pressure and blood suganti-VEGF options are not received ranibizumab monthly (baseline, left; 24 months, right). ETDRS
ar levels.
equal. “In my clinical ex- letters improved from 64 to 71; Snellen acuity improved from 20/50 to
“Beyond that,” he
perience, Lucentis is supe- 20/40. (Images courtesy of Genentech.)
adds, “many retina sperior to Avastin for diabetic
cialists, including mymacular edema,” he says. “So, that’s Boyer notes that the jury is still out self, were surprised that the FDA did
my first choice for treating a patient, on whether this is true in a clinical not approve the Alimera fluocinolone
as long as the patient has no issues setting. “Our feeling is that it dries the implant that’s approved in Europe for
with insurance coverage or copays. retina better, and patients do a little the treatment of DME. I believe the
I think it’s a better drug. But which better,” he says. “The big question we lack of that option, particularly for
one I use becomes a reimbursement have is, in a year or two, will that make pseudophakic eyes, is detrimental to
issue, because most patients can’t af- a difference in vision? That’s why our patients.”
ford Lucentis at $1,800 to $2,000 per they’re doing the Protocol T trial at
However, not all surgeons see steinjection, per eye.”
DRCR.net, working with the National roids as an acceptable treatment opDavid S. Boyer, MD, in private Eye Institute. Protocol T is compar- tion. Dr. Charles says he may be the
practice with the Retina-Vitreous As- ing treatment of DME using bevaci- only vitreoretinal surgeon in the world
sociates Medical Group in Los An- zumab, ranibizumab and aflibercept. who never uses steroids to treat DME.
geles and part of the clinical faculty After the initial treatment, subjects are “This is true for two reasons,” he says.
at the Doheny Eye Institute, USC treated as needed, whenever fluid is “First, although steroids have posiSchool of Medicine, says he has also present. We’ll see how all three drugs tive effects—they do make the edema
found ranibizumab to be a little more do. Recruitment is going well and will regress—nobody has found a way to
efficacious, but agrees that insurance probably be done sooner than expect- decouple them from their negative
coverage is an issue. “A lot of these ed, because everybody really wants to side effects, which are steroid glaupatients have commercial insurance,” know the answer to this question.”
coma and cataract formation. Those
he says. “Until we can sort out the inside effects are built into the mechasurance issues, I’d rather go with beva- Steroid Pros and Cons
nism of the drug. Second, I believe the
cizumab just to make sure the patients
reasoning behind choosing steroids
In addition to the anti-VEGF op- over anti-VEGF treatment is based on
don’t have to pay out of pocket. You
don’t want people who have private tions, a number of steroids are some- faulty assumptions.”
Regarding the first point, Dr.
insurance with large deductibles to times used to address DME. “We have
end up in a bad situation. However, if several products available off-label for Charles notes that people often unthe eye has a large amount of leakage the treatment of diabetic macular ede- derestimate the likelihood that side
that doesn’t respond to treatment, I ma, including triamcinolone, available effects will occur in any given patient.
might add a steroid or change from from Alcon as Triesence,” says Dr. Ho. “Steroids provide immediate gratificabevacizumab to ranibizumab. Hope- “That’s not approved for diabetic mac- tion,” he says. “You inject them and
fully, aflibercept will also be an option ular edema, but it works. I like that the edema goes away and the patient’s
product because it’s not compound- happy. But if the patient is phakic, the
in the future.”
Despite the general agreement that ed; it’s made specifically for the eye, odds of creating a cataract are about
ranibizumab is more effective, Dr. and we know its benefits and risks. 90 percent if you use triamcinolone,
022_rp0813_f1.indd 23
7/25/13 3:47 PM
REVIEW
Cover
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Retina Issue
David S. Boyer, MD
and a significant percentage if
ple, the doctor may ask the
you use Ozurdex.
scheduler to give a patient
“Then, there’s steroid glaua one-month appointment.
coma,” he continues. “There’s
How many days does that
an idea left over from the
turn out to be? In many of1970s that only 6 percent of
fices, it ends up being six or
the population are steroid reseven weeks, because at the
sponders. That’s simply false.
one-month mark the docThat’s based on the notion of
tor’s out of the office going
using topical 1% prednisolone
to a meeting or the patient
drops—Pred Forte and the
is busy. The next thing you
like. With intravitreal steroids,
know, the one-month apthe incidence of steroid glaupointment happens eight
coma is much higher, and it’s A patient treated with Kenalog before treatment (left) and at five
weeks later, and the patient
dose-related. For example, weeks (right). Corticosteroids can reduce edema, but frequently
has had good vision for four
with fluocinolone steroid injec- produce serious side effects such as glaucoma and cataract.
weeks and four weeks of nottions, the incidence of glaucoma
so-good vision. Some doctors
is greater than 90 percent, and about good results with anti-VEGF com- then conclude that the anti-VEGF
35 percent of patients receiving this pounds,” he explains. “Inevitably, drug isn’t working and switch to stedrug need glaucoma filtering proce- when I ask which one they tried, it was roids instead. The reality is that ranibidures. That’s completely unacceptable. bevacizumab. Usually, the rationale zumab works for almost every patient
It might be less so if glaucoma filtering for choosing bevacizumab is that the if you get the interval right.”
procedures had an enormous success surgeon doesn’t want to burden MediIn fact, Dr. Charles feels strongly
rate and no complications, but that’s not care with enormous fees, but the fact that ranibizumab should be the firstthe case; they have a significant failure is that bevacizumab simply isn’t very line treatment. “This isn’t rescue therrate and often lead to hypotony, choroi- effective when treating DME, while apy, where first you do grid laser and
dals, infected blebs and other problems. ranibizumab is.”
then you see the patient in 91 days, the
This is an operation you want your paDr. Charles adds that insufficient global period for reimbursement, and
tient to avoid at all costs.
frequency of injection is also a com- if that doesn’t work you use steroids,
“The other issue with steroid glau- mon reason for inadequate results. and if that causes steroid glaucoma,
coma is that we were taught, based on “There is no six-week rule or eight- then you see the patient in 91 days,”
the use of 1% topical prenisolone ac- week rule, or every-three-months he says. “Then you finally try bevacietate, that the side effects are revers- rule,” he says. “Patients have differ- zumab and the edema goes away but
ible; stop the drops and the problem ent levels of VEGF, and when you the patient’s vision doesn’t improve
goes away,” he says. “But that’s not true inject the drug into the vitreous cavity enough. Big mistake. You should have
with intravitreal steroids. After a few it dissipates at different rates. Some started with ranibizumab.
months the drug will lose its effect, but surgeons inject every six weeks, and
“Does the data support this apsteroid glaucoma may become perma- when the patient complains that vision proach?” he adds. “Yes. The DRCR.net
nent. So if you’re relying on steroids deteriorates after three weeks the sur- study published two years ago did a
to manage the DME, you’re going to geon concludes that anti-VEGF drugs head-to-head comparison of triamcinhave to inject again and again, and in don’t work as well as steroids. In fact, olone, laser and ranibizumab. Ranibitime the patient will develop a cataract the doctor just needs to shorten the zumab won big-time. Given that fact,
and glaucoma. That’s why I never use interval for that patient. Some patients it’s amazing to me that some of the
steroids.”
produce more VEGF than others, and steroid options are still so popular.”
they need more frequent injections.
Surgeons treating macular degenera- Still in the Running
Steroids vs. Anti-VEGF
tion encounter the same phenomenon
Dr. Charles also sees problems with all the time.
Despite the downsides of treating
the reasoning that leads many sur“Another problem with injection with steroids, many surgeons still see
geons to choose steroids over anti- frequency is that practical realities them as a valuable second-line option.
VEGF treatment. “I’m well aware that often cause the interval to become Dr. Ho says he generally only resorts
some surgeons say they’ve never had lengthened,” he notes. “For exam- to steroids if anti-VEGF injections and
022_rp0813_f1.indd 24
7/25/13 3:47 PM
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INDICATION AND DOSING
PATADAY® Solution is a mast cell stabilizer indicated for
the treatment of ocular itching associated with allergic
conjunctivitis. The recommended dose is one drop in each
affected eye once a day.
PATADAY® Solution is for topical ocular use only. It is not for
injection or oral use.
To prevent contaminating the dropper tip and solution, care
should be taken not to touch the eyelids or surrounding areas
with the dropper tip of the bottle. Keep the bottle tightly closed
when not in use.
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References: 1. IMS Health, IMS National Prescription Audit , August 2010 to December 2012, USC 61500
OPHTH ANTI-ALLERGY. 2. PATADAY® Solution package insert. 3. Formulary data provided by Pinsonault
Associates, LLC, PathfinderRx, April 2013.
©2013 Novartis 5/13 PAT13131JAD
RP0813_Alcon Pataday.indd 1
Patients should be advised not to wear contact lenses
if their eyes are red.
PATADAY® Solution should not be used to treat contact
lens-related irritation. The preservative in PATADAY® Solution,
benzalkonium chloride, may be absorbed by soft contact
lenses. Patients who wear soft contact lenses and whose
eyes are not red should be instructed to wait at least ten
minutes after instilling PATADAY® Solution before they insert
their contact lenses.
Symptoms similar to cold syndrome and pharyngitis were
reported at an incidence of approximately 10%.
For additional information about PATADAY® Solution,
please refer to the brief summary of prescribing
information on adjacent page.
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7/17/13 11:12 AM
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PATADAY® solution is indicated for the treatment of ocular itching associated with allergic conjunctivitis.
CONTRAINDICATIONS
None.
WARNINGS
For topical ocular use only. Not for injection or oral use.
PRECAUTIONS
Information for Patients
As with any eye drop, to prevent contaminating the dropper tip and solution, care should be taken not to
touch the eyelids or surrounding areas with the dropper tip of the bottle. Keep bottle tightly closed when
not in use. Patients should be advised not to wear a contact lens if their eye is red.
PATADAY® (olopatadine hydrochloride ophthalmic solution) 0.2% should not be used to treat contact
lens related irritation. The preservative in PATADAY® solution, benzalkonium chloride, may be absorbed
by soft contact lenses. Patients who wear soft contact lenses and whose eyes are not red, should be
instructed to wait at least ten minutes after instilling PATADAY® (olopatadine hydrochloride ophthalmic
solution) 0.2% before they insert their contact lenses.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Olopatadine administered orally was not carcinogenic in mice and rats in doses up to 500 mg/kg/day and
200 mg/kg/day, respectively. Based on a 40 μL drop size and a 50 kg person, these doses were
approximately150,000and50,000timeshigherthanthemaximumrecommendedocularhumandose(MROHD).
No mutagenic potential was observed when olopatadine was tested in an in vivo bacterial reverse
mutation (Ames) test, an in vivo mammalian chromosome aberration assay or an in vivo mouse
micronucleustest.Olopatadineadministeredtomaleandfemaleratsatoraldosesofapproximately100,000
times MROHD level resulted in a slight decrease in the fertility index and reduced implantation rate; no
effects on reproductive function were observed at doses of approximately 15,000 times the MROHD level.
Pregnancy
Teratogenic effects: Pregnancy Category C
Olopatadine was found not to be teratogenic in rats and rabbits. However, rats treated at 600 mg/kg/day, or
150,000 times the MROHD and rabbits treated at 400 mg/kg/day, or approximately 100,000 times
the MROHD, during organogenesis showed a decrease in live fetuses. In addition, rats treated with
600 mg/kg/day of olopatadine during organogenesis showed a decrease in fetal weight. Further, rats treated
with 600 mg/kg/day of olopatadine during late gestation through the lactation period showed a decrease in
neonatal survival and body weight.
There are, however, no adequate and well-controlled studies in pregnant women. Because animal studies
are not always predictive of human responses, this drug should be used in pregnant women only if the
potential benefit to the mother justifies the potential risk to the embryo or fetus.
Nursing Mothers
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known whether topical ocular administration could result in sufficient systemic absorption to produce
detectable quantities in the human breast milk. Nevertheless, caution should be exercised when
PATADAY® (olopatadine hydrochloride ophthalmic solution) 0.2% is administered to a nursing mother.
Pediatric Use
Safety and effectiveness in pediatric patients below the age of 2 years have not been established.
Geriatric Use
No overall differences in safety and effectiveness have been observed between elderly and younger
patients.
ADVERSE REACTIONS
Symptoms similar to cold syndrome and pharyngitis were reported at an incidence of approximately 10%.
The following adverse experiences have been reported in 5% or less of patients:
Ocular: blurred vision, burning or stinging, conjunctivitis, dry eye, foreign body sensation, hyperemia,
hypersensitivity, keratitis, lid edema, pain and ocular pruritus.
Non-ocular: asthenia, back pain, flu syndrome, headache, increased cough, infection, nausea, rhinitis,
sinusitis and taste perversion.
Some of these events were similar to the underlying disease being studied.
The recommended dose is one drop in each affected eye once a day.
HOW SUPPLIED
PATADAY® (olopatadine hydrochloride ophthalmic solution) 0.2% is supplied in a white, oval, low
density polyethylene DROP-TAINER® dispenser with a natural low density polyethylene dispensing plug
and a white polypropylene cap. Tamper evidence is provided with a shrink band around the closure and
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Store at 2°C to 25°C (36°F to 77°F)
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laser are not working. “I tend not to use steroids primarily because of their side effects: elevating the pressure in
the eye and causing cataracts,” he says. “However, there’s
definitely a role for steroids. Some patients don’t respond
to anti-VEGF, but respond very well to steroids.”
Dr. Boyer says that in his experience steroids still have
a place in the treatment of DME. “I think steroids are a
second-line drug, not a primary drug, mainly because of
the side-effect profile,” he says. “Nothing dries as effectively as anti-VEGF, but if there’s a lot of fluid and vision is
down, steroids do a very good job. I’ve had pseudophakic
patients in whom I used a steroid and then continued antiVEGF afterwards, periodically giving the steroid. They’ve
done very well. As long as patients can get followed for the
glaucoma aspect of it, I think it’s a reasonable way to treat.
“Some studies have shown that patients with poor vision
and a lot of fluid do better with steroids,” he continues.
“And if you look at patients who are aphakic, where cataract formation is not an issue, steroids can be very comparable to anti-VEGF as far as drying and visual outcomes.
In addition, one of the steroid implants that isn’t yet FDA
approved has shown significant benefit in patients with
longstanding macular edema. An implant could turn out to
be a valuable tool to add to other treatments in appropriate patients, hopefully reducing the number of treatments
required and improving vision.
“Of course, you have to pick your patients,” he adds.
“You’re not going to use a steroid in a young patient who
is phakic, because he’ll develop a cataract. But if you pick
your patients properly, I think there’s a place for steroids.
They’re just not a primary treatment.”
Treating With Laser
Laser was one of the earliest DME management options, and although it’s largely been eclipsed by the drugbased alternatives, most surgeons still see it as a valuable
part of their armamentarium. For example, Dr. Charles
says he still uses laser to treat DME, but only certain types
of laser, and only under certain conditions. “Treating microaneurysms using focal laser with short-duration pulses,
like those produced by the OptiMedica Pascal laser, is still
an appropriate therapy,” he says. “Of course, you can’t use
the laser if the microaneurysms are parafoveal.”
Dr. Boyer agrees that a key factor when deciding on
treatment is whether the edema is center-involving. “If the
patient has clinically significant macular edema that’s not
center-involving, we may decide to do laser treatment,”
he explains. “If you have a lesion outside the fovea, laser
is usually a very effective treatment. If we find center
involvement, and the leaks are near the fovea, we’re going
to start with an anti-VEGF drug. The problem has been
© 2013 Novartis 5/13 PAT13131JAD
022_rp0813_f1.indd 26
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Mark S. Blumenkranz, MD
An eye previously treated with long-duration laser (nasal) and short-duration laser (temporal) at different times. Conventional laser burns
with a duration of 100 to 1,220 ms (close-up view, center) can cause heat diffusion, inducing collateral cell death (sometimes called “RPE
creep”). This can cause a 100-µm spot to grow to 300 µm in two to three years. In contrast, PASCAL-type laser burns (close-up view, right)
are 2 to 30 ms in duration; these eliminate heat diffusion and lesion growth post-treatment, remaining smaller and more regular in shape.
that in all of the studies up to now that
have center-involving macular edema,
the addition of laser has never been
shown to be that helpful. I rarely use
it in center-involving because the antiVEGF drugs do such a good job. But
I think if the edema is non-centerinvolving there’s a place for it.”
However, the way the laser is used
makes a difference. “I’ve never used,
nor do I recommend, grid-style laser,”
says Dr. Charles. “I’ve never understood the rationale for grid laser—ablating areas of the retina that are not
involved, hoping somehow to affect
the macular edema. Some people say
that it’s similar to selective laser trabeculoplasty, upregulating cytokines,
which somehow reduces the edema.
There are some studies showing that
it does have an effect, but it still seems
like a questionable approach. Others
use micropulse laser and claim that it
works.
“One of the main problems with
these approaches is that if you don’t
use Pascal-style laser, thermal diffusion can cause the damage from the
laser spots to grow to triple the size
two years after you treat the patient,”
he says. “There can be sub-lethal damage that ultimately kills cells surrounding what you thought was a 50-micron
spot. Once those cells die, it becomes a
150-micron spot. Because of this phenomenon, surgeons who treat fairly
close to the fovea can leave the patient
with visual field loss. In our practice
we’ve seen many grid laser treatments
done by other surgeons where the patients’ current chief complaint was
simply, ‘I can’t see,’ even though their
vision was 20/25 or 20/20. The reason
they couldn’t see was that the visual
field surrounding their foveal visual
field had been ablated. For all of these
reasons I never use grid laser. I think
it’s a bad idea.”
Nevertheless, Dr. Boyer believes
that in some cases there may be an
argument for using panretinal photocoagulation. “When you see large
areas of capillary dropout, at least in
diabetics, there may be a place for
panretinal photocoagulation, targeted
just to the area of nonperfusion,” he
says. “That’s something I think should
be investigated to determine whether
it really is helpful.”
Dr. Boyer adds that he’s been using the Navilas laser (OD-OS, Teltow,
Germany), an advanced, computerguided system. “I’m extremely impressed with its accuracy,” he says.
“When the accuracy is this high it may
be possible to get a better result with
less energy and less damage than we
can get with conventional lasers. The
problem is, there aren’t a lot of these
lasers out there. For that reason, we
don’t yet know when to use it and
when it will give us better results.”
Ultimately, Dr. Boyer admits that
knowing when to use the laser is an
imperfect science at present. “We
don’t have a paradigm that tells us
when to apply it,” he says. “We all
think we know, and we try to do the
best for our patients. If a patient has
a lot of leaks outside the fovea I apply
it, but in the long run, we don’t really
know if it makes a difference. So I’m
using it judiciously.”
Clinical Protocol
In terms of treatment protocol, Dr.
Ho says he usually starts with injections of Avastin or Lucentis. “We see
how the patient responds,” he explains. “We do that monthly for a while
to dry out the macula, sometimes in
combination with laser treatments.
Corticosteroids are my next option;
surgery with peeling of the internal
limiting membrane is my last option.
Often, our primary therapy will shift
to less-frequent-than-monthly injections, with laser used secondarily.
Sometimes when the macular edema
is discrete and outside the center of
the macula I’ll just use laser therapy
and not even resort to the injection.
“The secret becomes, how do you
figure out the right cadence for the
injections?” he continues. “Let’s say a
patient responds to a series of three
or four injections of Lucentis and is
stable. We’ll gradually extend the interval between the injections because
patients often don’t need them on a
022_rp0813_f1.indd 27
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REVIEW
Cover
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Retina Issue
monthly basis. Some will only need an
injection every six, eight or 10 weeks.
It’s the treat-and-extend approach.”
Dr. Ho notes that surgeons don’t
have to be quite as aggressive about
treating diabetic macular edema as
they tend to be with wet macular
degeneration. “The macula is more
tolerant in diabetic macular edema,
so I’m not as aggressive in terms of
looking at an OCT scan with macular
edema and reflexively injecting,” he
says. “When the problem is due to
diabetic retinopathy you don’t have
to dry every little cyst in the macula.
I’m more aggressive with wet macular
degeneration, based on how the OCT
looks. However, I do treat DME if
I find significant edema in both the
OCT and the clinical exam, including
areas of leakage in the macula.”
Although he doesn’t use steroids,
Dr. Charles has no problem combining laser with anti-VEGF treatment.
“I say, if it’s bad neovascularization,
knock it down with ranibizumab and
keep it down with laser,” he says. “I
often combine them. And the same
argument applies with DME.”
Dr. Boyer agrees that combining
options may be advantageous in some
patients. “This is not a case of one or
the other,” he says. “In my experience,
combination therapies can work very
well. I tend to use combination therapy if I think it’s really a bad case, but
it’s a paradigm that’s still being finetuned at this point.
“The bottom line is, every patient is
different,” he adds. “The blood pressure is different, the hemoglobin is
different, and every patient has a different level of capillary dropout. So
every patient may respond to treatment differently.”
Helpful Clinical Strategies
The following additional strategies
can also help maximize the effectiveness of DME treatment:
• Don’t skip the fluorescein an-
giogram when there’s a disconnect
between visual acuity and clinical exam and OCT information.
“A fluorescein angiogram still plays a
role in evaluation of diabetic macular
edema, particularly when you treat
and the edema goes away, but vision
is not better,” says Dr. Ho. “That may
be because there’s macular ischemia.
Even without adequate macular capillary perfusion the macula can become
edematous due to a breakdown of the
outer blood retinal barrier at the level
of the retinal pigment epithelial tight
junctions. The fluorescein angiogram
can help you determine that.” Dr. Ho
notes that he would try anti-VEGF
and steroids to treat the macular edema in the setting of macular ischemia,
but would avoid using the laser.
• Be persistent with your treatment. “One good thing about DME is
that it’s inner-retinal, not outer-retinal,
so if the patient does miss a treatment
and leakage increases, usually they
can get back the vision they’ve lost,”
says Dr. Boyer. “Nevertheless, you
have to be persistent. Whether you do
treat-and-extend or some other protocol, you can’t treat three times and
give up. And the patients have to realize they’re going to receive a number
of injections so they can get the best
possible results.”
• Remember that steroids have
fewer downsides when the patient
is pseudophakic. “You can resort to
steroids more quickly when the patient is pseudophakic,” Dr. Ho points
out. “A pseudophakic patient obviously can’t develop a cataract.”
• Get the patient involved in
treatment. “The patient has to take
part in the treatment, by coming in,
and by controlling the disease,” says
Dr. Boyer. “I try to emphasize to patients that they can control their blood
sugar and blood pressure and lipids,
and doing so will give them a much
better chance of stopping or reducing the progression of their macular
edema.”
Dr. Boyer says he uses images of the
retina to help motivate patients. “I’ll
do photographs and fluorescein and
show patients what’s going on in their
eye,” he says. “I explain that if that
edema doesn’t settle they’re going to
lose vision and not be able to function.
That’s usually a big wake-up call. A lot
of noncompliant patients become very
compliant after that.”
Getting Treatment to the Patient
Of course, none of the current treatments can prevent or reverse the disease itself, but that simply increases
the urgency of getting treatment to
the individuals who need it.
Dr. Ho notes that when diabetic
patients come in for an exam, it often looks like a bomb exploded inside
their eye—yet they claim they haven’t
been having any problems and didn’t
think they needed to be seen. “This
is not acceptable,” he says. “We need
to get to these patients sooner. They
need to know that their eyes should
be examined regularly and completely, including a dilated retinal exam.
“Every day I come into the clinic
and see patients who are legally blind
from advanced diabetes who haven’t
received any care,” he adds. “It may
be their own fault, but we’ve got to do
a better job of educating them. They
need complete eye exams, whether
or not they’re complaining of vision
problems.”
Dr. Ho is a consultant for, or on the
scientific advisory boards of, Alcon,
Allergan, Janssen / J&J, Genentech,
Merck, ONL, Ophthotech, Regeneron
and Thrombogenics. Dr. Charles is a
consultant for Topcon Medical Lasers.
Dr. Boyer is a consultant for Alcon,
Allergan, Genentech, Regeneron and
Novartis.
1. Aiello LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD, Shah ST,
Pasquale LR, Thieme H, Iwamoto MA, Park JE, et al. Vascular
endothelial growth factor in ocular fluid of patients with
diabetic retinopathy and other retinal disorders. N Engl J Med
1994;331:22:1480-7.
022_rp0813_f1.indd 28
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Retina Issue
Best Practices:
Treating Wet AMD
How treatment
approaches
are evolving
to combat this
dreaded disease.
I
nhibitors of vascular endothelial
growth factor have taken the ophthalmology world by storm, proving themselves against a number of
diseases that have historically resisted
effective treatments, especially wet
age-related macular degeneration.
Now that ophthalmologists have three
anti-VEGF agents to choose from,
surgeons are beginning to settle on
treatment protocols for their patients,
and are getting a feel for the pros and
cons of these powerful drugs. Here is a
look at the results and safety profiles of
the VEGF inhibitors, how physicians
are using them and the issues involved
with choosing a particular agent.
The First-Line Agent
Surgeons say that bevacizumab
(Avastin, Genentech/Roche), though
not officially approved for ocular use, is
historically the most-used anti-VEGF
agent in the United States. However
they add that in some instances they,
or their wet AMD patients, feel more
comfortable using a Food and Drug
Administration-approved agent, either
ranibizumab (Lucentis, Genentech/
Roche) or aflibercept (Eylea, Regeneron).
“All of us agree that an anti-VEGF
agent is the way to go when treating
exudative AMD,” says Julia Haller,
030_rp0813_f2.indd 30
MD, ophthalmologist-in-chief of the
Wills Eye Institute. “So, that’s how
we start out. But then the question is:
Which agent do you choose? What I’ve
found recently, particularly with all the
controversy of compounding pharmacies [with bevacizumab] and the like,
at least some patients are more interested in going with the FDA-approved
drugs, ranibizumab or aflibercept,
rather than bevacizumab. It just might
be my patient population, but we’re
seeing some savvy patients come in
and request that they receive a drug
that was formulated and packaged specifically for the eye. Now, if there’s a
financial issue such as a copay or the
like, then, of course there’s no hesitation about using the bevacizumab.”
Philip Rosenfeld, MD, professor of
ophthalmology at Bascom Palmer Eye
Institute, chooses aflibercept for wet
AMD patients that he treats in his hospital-based practice. “When Eylea first
came out, I only used it on patients
who weren’t responding optimally to
Avastin or Lucentis,” Dr. Rosenfeld
says. “So my initial experience with
it was in that group of patients. But
when I saw how well the drug did with
them, that’s when I made the decision to use it as initial therapy for my
hospital-based patients.”
As to why anti-VEGF agents are
the only choice for wet AMD patients,
7/25/13 4:19 PM
Carl Regillo, MD
physicians point to high-quality data
that has emerged over the past several
years on all of the drugs. The National
Eye Institute-sponsored Comparison
of Age-related macular degeneration
Treatments Trials, which were multicenter, prospective, randomized
studies, compared ranibizumab to bevacizumab in two different dosing approaches, monthly or p.r.n. The CATT
enrolled 1,185 patients.
At two years, the mean increase
in letters of visual acuity was 8.8 for
monthly ranibizumab, 7.8 for monthly bevacizumab, 6.7 for ranibizumab
p.r.n. and five letters for bevacizumab
p.r.n. The CATT researchers noted
that after adjusting for baseline predictors of visual acuity in a multivariable longitudinal regression model,
the estimated change in acuity was
0.7 letters better for ranibizumab in
terms of drug (p=0.41) and 1.7 letters
better for patients treated monthly in
terms of dosage regimen, though the
mean visual acuity at two years was
similar for all treatment groups at approximately 20/40 (drug p=0.17, dose
regimen p=0.41).1
Aflibercept was investigated in the
Regeneron-sponsored VIEW and
VIEW2 studies, which enrolled about
2,400 patients to compare the drug to
a monthly dosage regimen of ranibizumab. When the two studies’ results
were combined, researchers found
that aflibercept and ranibizumab patients’ mean visual acuity scores were
within one letter of each other at week
52, and that aflibercept given at twomonth intervals (after three straight
monthly injections) achieved a visual
acuity result that was within 0.3 letters of monthly ranibizumab.2 The
results with bi-monthly aflibercept
helped drive interest in the drug, as
clinicians are constantly seeking ways
to decrease the frequency of injections while maintaining efficacy. The
VIEW researchers also point out that,
in the CATT, none of the other treatment regimens could match the retinal
The treat-and-extend injection protocol, shown above, is gaining favor with physicians. In
it, the patient receives an injection at each visit and, if the macula is dry at that visit, the
visit schedule is extended. If disease recurs, the schedule is shortened for a while.
thickness and fluid benefits of monthly
doses of ranibizumab, but all three aflibercept regimens—bi-monthly (with
three initial monthly injections), 0.5
mg monthly and 2 mg monthly—yielded similar anatomic results to monthly
ranibizumab.2
In terms of adverse events from the
drugs, surgeons say the large-scale
studies noted some safety signals, but
nothing that would stop anyone from
using the agents. In the CATT after
two years, the rates of death, heart attack and stroke didn’t differ between
bevacizumab and ranibizumab,1 and
the VIEW studies didn’t find a difference between aflibercept and ranibizumab in terms of adverse events.2
“People have tried like the dickens to
demonstrate an increased risk of heart
attack, stroke, thromboembolic phenomena and/or vascular death from
Avastin, but they really haven’t found
it,” says Dr. Rosenfeld. “I’d argue that
if these risks were real, then Eylea,
which acts like an antibody and has a
much higher affinity for VEGF than
Avastin, and which caused adverse
events when given systemically in cancer trials, should have demonstrated
adverse events when used ocularly—
but it hasn’t.”
After reviewing all the data, Wills
Eye Institute’s Carl Regillo, MD,
doesn’t think there’s an inherent safety issue with the drugs. “I don’t think
there’s any difference in safety,” he
says. “Unless there’s a compounding
pharmacy issue with Avastin, I think all
of them are safe, and no real definitive
difference between them has come
up in clinical studies,” he says. “I think
everyone is very comfortable with the
safety and efficacy profile of Avastin,
and it’s definitely comparable to Lucentis and Eylea. Whether it’s exactly
the same, we can’t say for sure. Some
may look at the CATT results and say
that they see some trends that maybe
Lucentis works a little bit better or is a
little bit safer, but that’s only a ‘maybe.’
Maybe means that nothing emerged
as being statistically significant, though
people still like to look at some trends,
anyway.”
When considering aflibercept, however, surgeons say the dosing schedule
may vary when the drug is used in everyday practice. “Eylea costs slightly
less than Lucentis,” says Dr. Regillo,
who begins patients on either Eylea or
Lucentis as first-line therapy. “Because
it costs a little less, if it lasts longer then
it would be an even greater value. But
whether it lasts longer or not is up in
the air. Theoretically, based on some
030_rp0813_f2.indd 31
7/25/13 4:19 PM
REVIEW
Cover
Focus
Retina Issue
Philip Rosenfeld, MD
Avastin: The Low-Cost Leader
Some surgeons say that switching recalcitrant AMD cases to aflibercept can help. Above,
a patient who didn’t respond optimally to more than a year of ranibizumab treatment (top
images) was switched to aflibercept, to which he responded well (bottom images).
of its chemical properties, it should last
longer, but there’s no proof yet that it
does, though many believe it might last
a little longer than Lucentis. If it does
last longer, it’s probably by a little bit,
but we just don’t have firm evidence
that it lasts significantly longer yet.”
Eylea, by way of relatively smallscale studies, is also gaining a reputation as an effective alternative for
patients who don’t respond well to
Lucentis or Avastin. In one Phase
IV controlled clinical trial, for example, 45 patients with recalcitrant wet
AMD despite treatment received the
VIEW bi-monthly dosing regimen. In
the patients available for six-month
visits, the optical coherence tomography improvement from baseline was
-33 µm, and they gained an average of
0.8 letters. (Maldonado ME, et al;IOVS
2013;54;ARVO E-abstract 3800)
Integral to the efficacy of these
drugs, and surgeons’ approach to
treating AMD, is the schedule with
which they’re injected. Though surgeons may differ on the agent they
use first, the one thing most of them
agree on, at least according to the
2012 survey of the American Society
of Retinal Specialists, is that a treatand-extend approach is preferable to
either monthly dosing or p.r.n. “Last
year’s survey shows that only 9 per-
cent of ASRS members use a monthly or bi-monthly approach,” says Dr.
Regillo. “Though most of us were
using p.r.n. treatment for years, it’s
falling out of favor, and only 24 percent use it on the survey. Data such
as the two-year results from CATT
and IVAN are showing us that, in the
long run, p.r.n. doesn’t really stack up
well against monthly therapy. It looks
good after one year, but after two
you can see the results aren’t quite
as good. As a result, in comes what
most think is the best of both worlds:
treat-and-extend, which is used by 67
percent of ASRS members.
“In treat-and-extend, my patients
all start the same way: Monthly therapy until the macula is dry,” Dr. Regillo
continues. “I treat at the visit at which
the macula is finally dry, then extend
the patient’s follow-up to six weeks—
it’s usually two-week intervals of extension. If he comes back at six weeks
and the macula still looks good, I treat
and extend him to eight weeks. I keep
extending until the disease recurs, at
which point I back off on the interval
by two weeks and keep him at that
resulting interval for a while to minimize recurrences. I might then try to
re-extend him later. So, if there’s no
activity, you tend to extend. If there is
activity, you cut back.”
Surgeons say financial considerations have always been a fact of practicing medicine, and have become
even more significant recently. It’s
against this backdrop that Avastin, a
dose of which costs about $50 vs. a
$2,000 dose of Lucentis—and a fraction of Eylea, which costs slightly less
than Lucentis—looms large due to its
combination of low cost and good efficacy, despite being unapproved for
ocular use.1
“The drug that I use depends on
where I am,” says Dr. Rosenfeld. “I
have two kinds of practices. One is a
hospital-based practice and the other is
a provider-based practice. In the hospital-based practice, right now I start
with Eylea because, based on analyses we’ve done and papers that have
been published, it seems to be a better
drug. In my provider-based practice,
though, I start them with Avastin. This
is because, in a hospital-based practice,
Medicare doesn’t reimburse sufficiently for Avastin. This is the result of a ruling back in September of 2009, when
Medicare was influenced to stop reimbursement for all Avastin. We were
able to get that decision reversed, but
only for non-hospital based practices.
As a result, CMS only reimburses a
hospital-based practice about $7 for
the use of Avastin.”
Dr. Rosenfeld says that very few patients in his provider-based practice
pay their 20-percent share of the 80/20
split with Medicare due to secondary
insurance or HMO Medicare Advantage plans. He’s quick to add, however,
that this appears to be changing, and
patients are feeling more of a financial
squeeze that can be alleviated by a
low-cost option like Avastin. “Some insurance programs are getting fussy,” he
says. “Now, some patients have to pay
either a high deductible or their insurance makes them pay a percentage of
that 20 percent. So, what we’re finding is that a lot of HMOs’ Medicare
Advantage plans and PPO insurance
030_rp0813_f2.indd 32
7/25/13 4:20 PM
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Retina Issue
plans are putting pressure on patients
to use Avastin. I’ve also got patients
from the Caribbean and Central and
South America who don’t have insurance. Those patients all get Avastin.”
Dr. Rosenfeld also makes use of the
Chronic Disease Fund, a charity that
will provide free drugs to patients who
can’t afford them. “In the hospitalbased practice, whenever we start using Lucentis or Eylea, we sign patients
up with the CDF,” Dr. Rosenfeld explains. “Regeneron and Genentech
have an arrangement with the CDF in
which the CDF reviews the insurance
of the patient, contacts the insurer and
determines if the patient qualifies for
free drug. I’ll also sign a patient up in
the provider-based practice, because if
I can’t get him past six weeks without
drying the fluid, I’ll try Eylea.”
Though Avastin provides a low-cost
option for patients, some physicians
are gun-shy of the drug because in
order to be used it needs to first be
put into single-use syringes by a compounding pharmacy, and this process
has resulted in serious infections and
vision loss in some patients.3 “The compounding pharmacy issue does factor
into Avastin’s safety,” says Dr. Regillo.
“You have to realize the product is in
someone else’s hands, and there’s the
possibility of contamination. So, I use
Avastin as second-line.”
Dr. Rosenfeld, though, hasn’t had
any problems with Avastin contamination, but says there’s a reason for that.
“We’re lucky since we compound our
own Avastin, so I haven’t been affected
by what’s happened,” he says. “But, if
you’re in private practice, you’d better
pick a really good compounding pharmacy that you can personally inspect
and ensure that it follows Chapter 797
guidelines.” Chapter 797 refers to the
chapter on compounding pharmacies
in the U.S. Pharmacopeia National
Formulary.
Dr. Rosenfeld co-authored a paper
on the subject of compounding pharmacies that offered advice on how to
choose one:
• Verify the licenses of the pharmacy, the pharmacy manager and its
pharmacists via resources on the Web;
• request the last two to three years’
worth of health-department inspections of the facility;
• ensure the preparation area itself
is sterile;
• ensure the pharmacists take 10
percent of the batch of drug and incubate it microbiologically, and don’t
release the samples for two weeks until
they can prove they’re sterile;
• ensure they use a laminar airflow
hood in the preparation area; and
• find out if the facility is accredited
by the Pharmacy Compounding Accreditation Board, a distinction that
shows it’s gone above and beyond the
normal certifications.4
“Having a good compounding pharmacy is more expensive,” says Dr.
Rosenfeld. “You can’t get a $10 syringe
of Avastin; it’s more like $35 if you do
it correctly. However, that’s how you
have to do it.”
AREDS2 and Good Nutrition
Along with anti-VEGF treatment,
physicians say it’s also important to
counsel patients with intermediate
AMD about the benefits of good nutrition in staving off worse disease.
The latest report from the Age-related Eye Disease Study, AREDS2, was
designed to test the effect of the carotenoids lutein + zeaxanthin, the omega-3 fatty acids eicosapentaenoic acid +
docosahexaenoic acid or a combination
of them on the rate of progression to
advanced AMD. They compared the
three new formulations to a placebo
that consisted of the existing AREDS
formula. The study spanned 82 clinics
and included 4,203 patients.
The researchers found that when
they looked at the entire group and
compared approaches that contained
lutein + zeaxanthin vs. those without the two carotenoids, there was a
10-percent additional reduction in the
risk of progression to advanced disease. This group also had an 11-percent greater reduction in the risk of
progression to neovascular AMD in
patients who didn’t have choroidal
neovascularization at baseline. The
researchers didn’t find a beneficial
effect with DHA/EPA supplementation. When the investigators looked
at the effects of lutein + zeaxanthin
vs. beta-carotene supplementation,
they found that the former was better,
yielding an 18-percent greater reduction in risk of progression to advanced
AMD, and a 22-percent greater reduction in the risk of progressing to
neovascular disease. In terms of the
risk of severe vision loss, the lutein +
zeaxanthin formulations produced a
16 percent greater reduction in the
risk of losing 30 or more letters, and
an 18-percent greater reduction in the
risk of becoming legally blind, than the
beta-carotene formulation.5
Dr. Haller says AREDS2 has made
it easy to discuss nutrition. “I tell my
patients that, through AREDS2, we
discovered that you can swap out the
vitamin A, the beta carotene, which
had some risk for cancer in patients
who were smokers or previous smokers—and that amounts to a lot of patients,” she says. “We swap in the other
carotenoids: lutein and zeaxanthin. I
also make sure to note that the omega-3s didn’t show any benefit. I have
everyone on the AREDS2 formula,
both my wet AMD patients and all my
stage-3 dry AMD patients, too.”
1. Martin DF, Maguire MG, Fine SL, et al. Ranibizumab and
bevacizumab for treatment of neovascular age-related macular
degeneration: 2-year results: Comparison of age-related macular
degeneration treatments trials. Ophthalmology 2012;119:7:1388.
2. Heier JS, Brown DM, Chong V, et al. Intravitreal aflibercept (VEGF
trap-eye) in wet age-related macular degeneration. Ophthalmology
2012;119:12:2537-48.
3. Goldberg RA, Flynn HW, Isom RF, et al. An outbreak of
streptococcus endophthalmitis after intravitreal injection of
bevacizumab. Am J Ophthalmol 2012;153:2:204-208.
4. Gonzalez S, Rosenfeld PJ, Stewart MW, et al. Avastin doesn’t
blind people, people blind people. Am J Ophthalmol 2012;153:196203.
5. Age-Related Eye Disease Study 2 Research Group. Lutein +
zeaxanthin and omega-3 fatty acids for age-related macular
degeneration: The age-related eye disease study 2 (AREDS2)
randomized clinical trial. JAMA 2013;309:19:2005-15.
030_rp0813_f2.indd 34
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ETL Approved
035_rp0813_Varitronics.indd 1
7/15/13 11:19 AM
REVIEW
Cover Focus
Retina Issue
Settling on an AntiVEGF Dosing Regimen
Michelle Stephenson, Contributing Editor
Current options
include continuous
treatment at a
fixed interval, p.r.n.
treatment, and the
“treat and extend”
strategy.
D
rugs that block the effects of
vascular endothelial growth
factor have become a mainstay in treating retinal diseases. The
process of selecting the best treatment
regimen continues to evolve, however,
and depends on a number of factors.
Retina specialists are generally using on of three approaches to treat wet
age-related macular degeneration with
intravitreal anti-VEGF agents.
“You can do a continuous treatment
at a fixed interval, where you treat every month or every two months,” says
Carl Regillo, MD. “That’s the least
popular approach. Very few people
do that because it may represent overtreatment in some people. The next is
p.r.n. treatment, which is an approach
to individualize therapy and minimize
overtreatment. You treat monthly until
the macula is dry and then you monitor
closely and treat recurrences. The third
approach is the treat-and-extend strategy, which some believe may represent the best of both worlds in disease
control and treatment burden.” Dr.
Regillo is director of the Retina Service
of Wills Eye Institute, and a professor
of ophthalmology at Thomas Jefferson
University School of Medicine.
Continuous Treatment
Treating every month or two is ef36 | Review of Ophthalmology | August 2013
036_rp0813_f3.indd 36
fective, but it is not ideal. As mentioned, it may be overtreating some
patients. Additionally, it can be costly
and inconvenient for patients, especially if they are treated monthly.
PRN Treatment
According to Dr. Regillo, some of
the big clinical studies that have put
p.r.n. regimens to the test have shown
that the results are pretty good on average for about a year or so. “However,
into year two, as shown in the CATT
and IVAN studies,1,2 the approach
doesn’t quite hold up with disease control and visual acuity improvement on
average compared to monthly, fixed
therapy. It is probably adequate for
some people but not ideal for others,”
he says.
The downside is that this approach
allows for recurrences before retreating, and multiple recurrences over
time may lead to significant disease
progression from which some patients
may not be able to completely recover.
CATT and IVAN
Two recent studies have evaluated
anti-VEGF injections for the treatment of neovascular AMD.1,2 In the
IVAN study, the efficacy and safety of
ranibizumab and bevacizumab intra-
7/26/13 2:26 PM
ILEVRO™ Suspension
Designed to put potency
precisely where you need it 1,2
ONCE-DAILY
POST-OP
One drop should be applied once daily beginning
1 day prior to surgery through 14 days post-surgery,
with an additional drop administered 30 to 120 minutes
prior to surgery 3
Use of ILEVRO™ Suspension more than 1 day prior to
surgery or use beyond 14 days post-surgery may increase
patient risk and severity of corneal adverse events3
ILEVRO™ Suspension is a nonsteroidal, anti-inflammatory prodrug indicated
for the treatment of pain and inflammation associated with cataract surgery.
Dosage and Administration
One drop of ILEVRO™ Suspension should be applied to the affected eye
one-time-daily beginning 1 day prior to cataract surgery, continued on the
day of surgery and through the first 2 weeks of the postoperative period. An
additional drop should be administered 30 to 120 minutes prior to surgery.
Contraindications
ILEVRO™ Suspension is contraindicated in patients with previously
demonstrated hypersensitivity to any of the ingredients in the formula
or to other NSAIDs.
1
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epithelial defects, diabetes mellitus, ocular surface diseases (e.g., dry eye
syndrome), rheumatoid arthritis, or repeat ocular surgeries within a short
period of time may be at increased risk for corneal adverse events which
NBZCFDPNFTJHIUUISFBUFOJOH5PQJDBM/4"*%TTIPVMECFVTFEXJUI
caution in these patients.
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may increase patient risk and severity of corneal adverse events.
t$POUBDU-FOT8FBSo*-&730™ Suspension should not be administered
while using contact lenses.
Adverse Reactions
5IFNPTUGSFRVFOUMZSFQPSUFEPDVMBSBEWFSTFSFBDUJPOTGPMMPXJOHDBUBSBDU
surgery occurring in approximately 5 to 10% of patients were capsular
opacity, decreased visual acuity, foreign body sensation, increased
intraocular pressure, and sticky sensation.
t*ODSFBTFE#MFFEJOH5JNFo8JUITPNFOPOTUFSPJEBMBOUJJOýBNNBUPSZ
For additional information about ILEVRO™ Suspension, please refer to the
drugs including ILEVRO™ Suspension there exists the potential for
brief summary of prescribing information on adjacent page.
increased bleeding time. Ocularly applied nonsteroidal anti-inflammatory
drugs may cause increased bleeding of ocular tissues (including hyphema)
References: 1. Ke T-L, Graff G, Spellman JM, Yanni JM. Nepafenac, a unique nonsteroidal prodrug
in conjunction with ocular surgery.
with potential utility in the treatment of trauma-induced ocular inflammation, II: In vitro bioactivation and permeation of external ocular barriers. Inflammation. 2000;24(4):371-384. 2. Data on file.
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3. ILEVRO™ Suspension package insert.
including ILEVRO™ Suspension may slow or delay healing. Concomitant
use of topical NSAIDs and topical steroids may increase the potential
for healing problems.
t$PSOFBM&GGFDUTo6TFPGUPQJDBM/4"*%TNBZSFTVMUJOLFSBUJUJT*O
some patients, continued use of topical NSAIDs may result in epithelial
breakdown, corneal thinning, corneal erosion, corneal ulceration or corneal
QFSGPSBUJPO5IFTFFWFOUTNBZCFTJHIUUISFBUFOJOH1BUJFOUTXJUIFWJEFODFPG
corneal epithelial breakdown should immediately discontinue use.
©2013 Novartis
RP0513_Alcon Ilevro.indd 1
2/13 ILV13030JAD
4/3/13 3:15 PM
Non‐Ocular Adverse Reactions
Non‐ocular adverse reactions reported at an incidence of 1 to 4% included
headache, hypertension, nausea/vomiting, and sinusitis.
BRIEF SUMMARY OF PRESCRIBING INFORMATION
ILEVRO™ Suspension is indicated for the treatment of pain and inflammation
associated with cataract surgery.
Recommended Dosing
One drop of ILEVRO™ Suspension should be applied to the affected eye onetime-daily beginning 1 day prior to cataract surgery, continued on the day
of surgery and through the first 2 weeks of the postoperative period. An
additional drop should be administered 30 to 120 minutes prior to surgery.
Use with Other Topical Ophthalmic Medications
ILEVRO™ Suspension may be administered in conjunction with other topical
ophthalmic medications such as beta-blockers, carbonic anhydrase inhibitors, alpha-agonists, cycloplegics, and mydriatics. If more than one topical
ophthalmic medication is being used, the medicines must be administered
at least 5 minutes apart.
CONTRAINDICATIONS
ILEVRO™ Suspension is contraindicated in patients with previously demonstrated hypersensitivity to any of the ingredients in the formula or to other
NSAIDs.
Increased Bleeding Time
With some nonsteroidal anti-inflammatory drugs including ILEVRO™ Suspension, there exists the potential for increased bleeding time due to interference with thrombocyte aggregation. There have been reports that ocularly
applied nonsteroidal anti-inflammatory drugs may cause increased bleeding
of ocular tissues (including hyphemas) in conjunction with ocular surgery. It
is recommended that ILEVRO™ Suspension be used with caution in patients
with known bleeding tendencies or who are receiving other medications
which may prolong bleeding time.
Delayed Healing
Topical nonsteroidal anti-inflammatory drugs (NSAIDs) including ILEVRO™
Suspension, may slow or delay healing. Topical corticosteroids are also
known to slow or delay healing. Concomitant use of topical NSAIDs and
topical steroids may increase the potential for healing problems.
Corneal Effects
Use of topical NSAIDs may result in keratitis. In some susceptible patients,
continued use of topical NSAIDs may result in epithelial breakdown, corneal
thinning, corneal erosion, corneal ulceration or corneal perforation. These
events may be sight threatening. Patients with evidence of corneal epithelial
breakdown should immediately discontinue use of topical NSAIDs including
ILEVRO™ Suspension and should be closely monitored for corneal health.
Postmarketing experience with topical NSAIDs suggests that patients
with complicated ocular surgeries, corneal denervation, corneal epithelial
defects, diabetes mellitus, ocular surface diseases (e.g., dry eye syndrome),
rheumatoid arthritis, or repeat ocular surgeries within a short period of time
may be at increased risk for corneal adverse events which may become
sight threatening. Topical NSAIDs should be used with caution in these
patients.
Postmarketing experience with topical NSAIDs also suggests that use
more than 1 day prior to surgery or use beyond 14 days post surgery may
increase patient risk and severity of corneal adverse events.
Contact Lens Wear
ILEVRO™ Suspension should not be administered while using contact lenses.
ADVERSE REACTIONS
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 the rates in the clinical studies of another drug and
may not reflect the rates observed in practice.
Ocular Adverse Reactions
The most frequently reported ocular adverse reactions following cataract
surgery were capsular opacity, decreased visual acuity, foreign body sensation, increased intraocular pressure, and sticky sensation. These events
occurred in approximately 5 to 10% of patients.
Pregnancy
Teratogenic Effects.
Pregnancy Category C: Reproduction studies performed with nepafenac
in rabbits and rats at oral doses up to 10 mg/kg/day have revealed no
evidence of teratogenicity due to nepafenac, despite the induction of maternal toxicity. At this dose, the animal plasma exposure to nepafenac and
amfenac was approximately 70 and 630 times human plasma exposure at
the recommended human topical ophthalmic dose for rats and 20 and 180
times human plasma exposure for rabbits, respectively. In rats, maternally
toxic doses ≥10 mg/kg were associated with dystocia, increased postimplantation loss, reduced fetal weights and growth, and reduced fetal
survival.
Nepafenac has been shown to cross the placental barrier in rats. There
are no adequate and well‐controlled studies in pregnant women. Because
animal reproduction studies are not always predictive of human response,
ILEVRO™ Suspension should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus.
Non‐teratogenic Effects.
Because of the known effects of prostaglandin biosynthesis inhibiting drugs
on the fetal cardiovascular system (closure of the ductus arteriosus), the
use of ILEVRO™ Suspension during late pregnancy should be avoided.
Nursing Mothers
ILEVRO™ Suspension is excreted in the milk of lactating rats. It is not
known whether this drug is excreted in human milk. Because many drugs
are excreted in human milk, caution should be exercised when ILEVRO™
Suspension is administered to a nursing woman.
Pediatric Use
The safety and effectiveness of ILEVRO™ Suspension in pediatric patients
below the age of 10 years have not been established.
Geriatric Use
No overall differences in safety and effectiveness have been observed
between elderly and younger patients.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Nepafenac has not been evaluated in long‐term carcinogenicity studies.
Increased chromosomal aberrations were observed in Chinese hamster
ovary cells exposed in vitro to nepafenac suspension. Nepafenac was not
mutagenic in the Ames assay or in the mouse lymphoma forward mutation
assay. Oral doses up to 5,000 mg/kg did not result in an increase in the formation of micronucleated polychromatic erythrocytes in vivo in the mouse
micronucleus assay in the bone marrow of mice. Nepafenac did not impair
fertility when administered orally to male and female rats at 3 mg/kg.
Slow or Delayed Healing
Patients should be informed of the possibility that slow or delayed healing
may occur while using nonsteroidal anti‐inflammatory drugs (NSAIDs).
Avoiding Contamination of the Product
Patients should be instructed to avoid allowing the tip of the dispensing
container to contact the eye or surrounding structures because this could
cause the tip to become contaminated by common bacteria known to cause
ocular infections. Serious damage to the eye and subsequent loss of vision
may result from using contaminated solutions.
Use of the same bottle for both eyes is not recommended with topical eye
drops that are used in association with surgery.
Contact Lens Wear
ILEVRO™ Suspension should not be administered while wearing contact
lenses.
Intercurrent Ocular Conditions
Patients should be advised that if they develop an intercurrent ocular
condition (e.g., trauma, or infection) or have ocular surgery, they should
immediately seek their physician’s advice concerning the continued use of
the multi‐dose container.
Concomitant Topical Ocular Therapy
If more than one topical ophthalmic medication is being used, the medicines must be administered at least 5 minutes apart.
Shake Well Before Use
Patients should be instructed to shake well before each use. U.S. Patent
Nos. 5,475,034; 6,403,609; and 7,169,767.
Other ocular adverse reactions occurring at an incidence of approximately
1 to 5% included conjunctival edema, corneal edema, dry eye, lid margin
crusting, ocular discomfort, ocular hyperemia, ocular pain, ocular pruritus,
photophobia, tearing and vitreous detachment.
Some of these events may be the consequence of the cataract surgical
procedure.
RP0513_Alcon Ilevro PI.indd 1
ALCON LABORATORIES, INC.
Fort Worth, Texas 76134 USA
© 2013 Novartis 2/13 ILV13030JAD
4/3/13 3:20 PM
REVIEW
Cover
Focus
Retina Issue
2013
vitreal injections
were compared.
Patients were randomized to one
of four groups:
ranibizumab or
bevacizumab
given either every
month (continuous) or as needed
(p.r.n.). Six-hundred ten patients
were randomized
and treated. The
comparison of visual acuity at one
year between the
two drugs was inconclusive, and visual acuities with
continuous and
PRN treatment
were equivalent.
Fewer patients
receiving bevacizumab had an
arteriothrombotic
event or heart failure. There was also
no difference between the drugs in the
proportion of patients experiencing a
serious systemic adverse event. Serum
VEGF was lower with bevacizumab
and higher with as-needed treatment.
The CATT study was conducted to
describe the effects of ranibizumab
and bevacizumab when administered
monthly or as needed for two years
and to describe the impact of switching to as-needed treatment after one
year of monthly study. At enrollment,
patients were assigned to one of four
treatment groups: ranibizumab or bevacizumab either monthly or as needed.
At one year, patients initially assigned
to monthly treatment were reassigned
randomly to monthly or as-needed
treatment, but the drug assignment
did not change. Among patients who
were given the same treatment regimen for two years, the mean gain in
visual acuity was similar for both drugs.
The mean gain was greater for month-
ly than for as-needed treatment. The
proportion of eyes without fluid ranged
from 13.9 percent in the bevacizumab
as-needed group to 45.5 percent in the
ranibizumab monthly group. Eyes that
switched from monthly to as-needed
treatment experienced a greater mean
decrease in vision during year two and
a lower proportion of eyes without
fluid. Both drugs had similar rates of
death and arteriothrombotic events.
The proportion of patients with one or
more systemic serious adverse events
was higher with bevacizumab than ranibizumab (39.9 percent compared
with 31.7 percent).
Treat and Extend
Treat and extend is a more customized approach to treatment. “My impression that customized or individualized dosing is the best approach to
manage patients led me to originate a
regimen called ‘treat and extend,’ ” says
K. Bailey Freund, MD, of Vitreous Ret-
ina Macula Consultants
of New York,
New York City. “This
dosing schedule and
technique has become very popular
with retina specialists
in the United States.
Although I treat most
of my patients with
treat and extend, I
also frequently use
OCT-guided therapy
in specific situations.”
Dr. Freund believes that treat and
extend balances
some of the benefits
of both continuous
monthly dosing and
discontinuous OCTguided treatment;
however, there is
currently no randomized clinical trial
data showing that this strategy gives
results as good as strict monthly dosing or OCT-guided dosing. “While it is
unproven that visual results with treat
and extend are equivalent to the alternatives, it is clear that the monthly
visits required with the alternative
regimens are onerous for patients
to continue year after year,” says Dr.
Freund. “I found that when I previously extended the interval between
visits and injections to more than seven
or eight weeks, there were more recurrent sight-threatening hemorrhages.
These longer intervals may also occur
because a patient forgets an appointment or needs to reschedule due to
an illness. I think it’s best to factor in a
little bit of a safety net even if you think
a patient might be able to be extended
longer.”
Because of the risks of longer intervals without continued examinations
and injections, treat and extend is more
of a “real-world” dosing strategy. “ObAugust 2013 | Revophth.com | 39
036_rp0813_f3.indd 39
7/26/13 2:26 PM
REVIEW
Cover
Focus
Retina Issue
viously, there are some patients who
cannot be extended beyond monthly
therapy without developing recurrent fluid, so treat and extend helps us
identify those patients who truly need
monthly dosing,” Dr. Freund says.
According to Dr. Regillo, this strategy starts with treating monthly until
the macula is dry. Once it is dry, the
time to retreatment is extended out
a little bit each time, such as by twoweek intervals. The interval between
treatments is extended until the patient recurs.
“You may be treating every four
weeks at first,” he says. “If the patient
is doing well, you extend it to every
six weeks. If she is doing well, you
extend it to eight weeks. If there is
a recurrence at eight weeks, you go
back to six weeks, or the longest, previously demonstrated disease-free
interval. Over time, you often can
figure out a given patient’s optimal
treatment interval and maintain her
in a steady fashion over long time
frames.”
An added benefit of the treat and
extend strategy is cost savings for the
patient. Most patients have a co-pay,
so cost is also a consideration.
Karl Csaky, MD, PhD, of the Retina Foundation of the Southwest in
Dallas, says the challenge is that the
three agents typically used all have
very similar pharmacokinetics and
durability plus or minus a week or so.
“One confounding problem is that
there appears to be an individualized
durability interval that each patient
demonstrates,” he says. “It becomes
a question of what strategy you use to
dial in that sweet spot between injections and find out whether they are,
for example, a five-weeker or a sixweeker. It is unclear how to predict
that upfront, although there will be
strategies in the future for us to more
quickly dial that interval in.”
He also notes that choosing a treatment strategy also depends somewhat on the status of the eye: “So, if
it is the only good seeing eye, then
you might want to be a little bit more
aggressive with the interval. At the
interval after which such an eye demonstrates recurrent fluid, we might
want to have the patient come back
even every four weeks just to be absolutely sure that we don’t put him
at risk for a bleed. That is the major
catastrophic event that we want to
avoid.”
“Right now, we don’t
have any reliable
anatomic marker that
says how long we can
go between injections;
it is basically all trial
and error.”
-Karl Csaky, MD, PhD
Catastrophic bleeds are even more
concerning in a one-eyed patient who
has good vision. “In someone with a
poor seeing first eye that has not responded to injections, we tend to be
a little bit more liberal about the injection regimen, says Dr. Csaky. “We
will still try to keep the eye stable,
but if there is little hope for vision
improvement and the vision is bad,
say worse than 20/200, and the fellow
eye is seeing well, then we may not
want to be as aggressive. The individual interval will be moderated by the
status of the eye and the visual acuity
of that eye. Right now, we don’t have
any reliable anatomic marker that
says how long we can go between injections; it is basically all trial and error. This is one of the areas of future
research because it is clear that there
is a spectrum of patients in terms of
how long of an interval can be used
between anti-VEGF injections.”
Dr. Freund believes it is also
theoretically possible that treat and
extend may lead to a lower risk of
geographic atrophy than is observed
with continuous monthly treatment.
At two years, both the IVAN and
CATT trials showed that eyes receiving monthly treatment were more
likely to develop geographic atrophy
than eyes receiving fewer injections
in the discontinuous or p.r.n. cohorts.
“We may eventually see these
small short-term visual benefits of
monthly dosing over less frequent
treatment will be offset by a greater
long-term risk of vision loss due to
GA,” he says. “While I think treat
and extend represents a favorable
compromise in terms of trying to
reduce the dosing frequency while
maintaining a ‘dry’ macula, given my
concern that continuous treatment
may increase the risk of GA, I am beginning to use OCT-guided therapy
more commonly in my practice. I
believe I’ve identified certain eyes in
which OCT-guided therapy is more
appropriate than treat and extend.”
For example, eyes developing foveal-threatening GA without vascularized pigment epithelial detachments
or subretinal fibrosis may be suitable
to consider switching to OCT-guided
therapy as they are less likely to develop hemorrhage when they develop
recurrent neovascular activity.
“I believe that combining what we
learn from clinical trials and realworld experience allows retinal specialists to optimize their dosing regimen for each individual patient. Treat
and extend is the most appropriate
treatment strategy for most patients,
and a subset of patients are better
followed using OCT-guided therapy,”
Dr. Freund says.
1. IVAN Study Investigators, Chakravarthy U, Harding SP, Rogers
CA, et al. Ranibizumab versus bevacizumab to treat neovascular
age-related macular degeneration: one-year findings from the
IVAN randomized trial. Ophthalmology 2012;119:1399-1411.
2. CATT Research Group, Martin DF, Maguire MG, Fine SL, et al.
Ranibizumab and bevacizumab for treatment of neovascular agerelated macular degeneration: two-year results. Ophthalmology
2012;119:1388-1398.
036_rp0813_f3.indd 40
7/26/13 2:27 PM
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RP0813_Keeler Indirects.indd 1
7/10/13 2:15 PM
REVIEW
Retinal Insider
Edited by Carl Regillo, MD and Emmett T. Cunningham Jr., MD, PhD, MPH
Diagnosis and
Treatment of BSRC
Birdshot retinochoroidopathy requires early therapy to limit
damage, preserve vision and induce long-term remission.
By Akbar Shakoor, MD, and Albert T. Vitale MD, Salt Lake City
irdshot retinochoroidopathy is an
uncommon chronic bilateral posterior uveitis affecting predominantly
middle-aged, Caucasian females who
present with blurred vision, floaters,
photopsias, paracentral scotomas and
nyctalopia. Presenting visual acuity is
a notoriously poor surrogate marker
for disease severity.
B
Epidemiology
BSRC is a disease seen almost exclusively in the Caucasian population with a mean age of onset of 53
years. A slight female preponderance
is present, ranging from a reported
51.7 percent to 72.7 percent in various studies. Given its rarity, little data
exists on the true national or global
prevalence of the disease although
it accounts for between 0.6 and 1.5
percent of cases referred to specialty
uveitis centers, or 6 to 7 percent of
those with posterior uveitis.1
Pathogenesis
Retinal autoimmunity is thought to
play an important role in the pathogenesis of BSRC, possibly by en-
hanced expression self-peptides to
T-lymphocytes through the A29 molecule or through molecular mimicry
with microbial antigen. The HLAA29 haplotype, which is found in 85
to 98 percent of patients with BSRC,
confers significantly increased risk
for the development of this disease.2,3
However, it should be noted that it is
present in 7 percent of the general
Caucasian population.4
Clinical Findings
Patients often present in the subacute phase of the disease with floaters, photopsias, scotomata, nyctalopia, and poor color and contrast
sensitivity.5 Not infrequently, they
may complain of blurry vision despite fairly good Snellen visual acuity.
This may be attributable to metamorphopsia and poor contrast sensitivity.1
Photophobia and pain are infrequent
findings as are clinical signs and structural complications of anterior segment inflammation such as posterior
synechiae; however, mild vitritis is
almost universally present.1 Macular
edema as seen clinically, angiographically or by optical coherence tomog-
042_rp0813_rtinsider.indd 42
raphy is the most common cause of
central vision loss in patients with
BSRC.1 Retinal vasculitis manifests
predominantly as a periphlebitis, is
best delineated by fluorescein angiography and is an important sign of disease activity.6,7 Funduscopic findings
include ovoid cream-colored lesions
at the level of the choroid and retinal
pigment epithelium, which are typically post-equatorial in location, have
a nasal and radial distribution, and
are best visualized by indirect ophthalmoscopy8,9 (See Figure 1). Funduscopic findings later in the disease
include vascular attenuation,6 nerve
pallor and diffuse retinal atrophy with
pigmentary changes6,10,11 progressing
ultimately to extinguished amplitudes
on electroretinography.
Imaging
FA yields inconsistent findings and
typically fails to highlight the birdshot
lesions themselves. It may, however,
highlight important components of
active disease including retinal vasculitis, macular edema and optic
nerve head leakage (See Figure 2).
Late findings include retinal vascular
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REVIEW
Retinal
Insider
Figure 1. Fundus photograph of a patient with birdshot retinochoroidopathy. The lesions, typically at the level of the choroid or retinal
pigment epithelium, are ovoid and cream-colored with indistinct borders. They are between 50 and 1,500 µm in size with a characteristic
nasal, radial distribution in the post-equatorial fundus.
attenuation, optic atrophy, epiretinal membrane formation6,7 and the
uncommon occurrence of choroidal
neovascularization.12,13
Indocyanine green angiography
(See Figure 3) on the other hand
discloses multiple hypofluorescent
spots, which correspond to funduscopic lesions and are typically more
numerous than those appreciated on
clinical examination or on FA. They
are typically larger than those seen
with multiple evanescent white dot
syndrome (MEWDS) or multifocal
choroiditis and panuveitis (MCP),
and smaller than those seen with
acute posterior multifocal placoid
pigment epitheliopathy (APMPPE)
or Vogt-Koyanagi-Harada disease
(VKH) with a distribution around the
choroidal vessels and not clustered on
the optic nerve.
Fundus autofluorescence and OCT
are newer, non-invasive and now
readily available imaging techniques
that can provide information on both
disease activity and progression in
BSRC. FAF findings in BSRC include diffuse RPE atrophy as well as
discrete areas of RPE loss without
reliable spatial correspondence to lesions seen on fundoscopy and color
photography. 14,15 Areas of placoid
macular hypoautofluorescence were
significantly correlated with VA of
20/50 or worse as well with decreased
mean foveal thickness.14
As with other posterior uveitides,
OCT is invaluable in the detection
and quantification of macular edema, intraretinal and subretinal fluid
associated with choroidal neovascularization.16 High-resolution OCT is
particularly useful in the evaluation
of reversible and irreversible macular
changes in BSRC. Macular thinning
and loss of the inner segment—outer
segment (IS/OS) demarcation has
been noted using both time domain
and spectral domain OCT but are
more accurately visualized with the
latter modality. The degree of measurable macular thinning was associated with a loss of thickness of the
segment subtending the proximal
border of the outer plexiform layer
and the Bruch’s membrane/choroid
interface suggesting that macular
atrophy in BSRC occurs largely in
the outer retina.17,18 Restoration of
macular outer retinal architecture has
been described with the institution of
systemic immunomodulatory therapy
(IMT).19
Psychophysical Testing
Electroretinography and perimetry
are invaluable in the longitudinal follow-up of patients with BSRC. Visual
field abnormalities are common and
include generalized constriction of
the peripheral visual field, central and
paracentral scotomata, and enlargement of the blind spot.6,8,9,20,21 While
reports of visual field testing in the
literature are fraught with inconsistency, these defects have been shown
to both progress over time in association with disease activity8,9,20,22,23 and
to improve under systemic IMT,5,24-26
suggesting that standardized evaluations may provide data that is useful
in the longitudinal management of
these patients.1
A characteristic electroretinographic abnormality in BSRC is a
prolongation of 30 Hz flicker implicit time.27,28 In addition to cone
B wave implicit times, dim rod scotopic amplitudes are also severely
attenuated with both indices declining with progression of the disease.29
Institution of IMT has been shown
to stabilize or even partially reverse
the decline of electroretinographic
changes, which can occur even in
7/25/13 3:56 PM
the absence of overt signs of
inflammation.30
period of clinically silent,
insidious global photoreceptor loss punctuated by waxNoninfectious
ing and waning inflammatory
Sarcoidosis
Differential Diagnoses
episodes. While some invesAcute posterior multifocal placoid pigment epitheliopathy
The diagnosis of BSRC is a
tigators have suggested that
Multifocal choroiditis and panuveitis
clinical one, and while highly
as many as 20 percent of paVogt-Koyanagi-Harada syndrome
associated with the disease,
tients with birdshot may have
Sympathetic ophthalmia
HLA-A29 positivity in and of
self-limited disease, 8 in the
Punctate inner choroidopathy
itself is not diagnostic of the
majority of patients, long-term
Multiple evanescent white dot syndrome
disease, as HLA-A29-negative
follow-up suggests a course
cases exist. Conversely, the ab- Infectious
marked by multiple inflamSyphilis
sence of the typical clinical feamatory exacerbations and proTuberculosis
tures of BSRC in the presence
gressive visual loss replete with
Diffuse unilateral subacute neuroretinitis
of the HLA-A29 positivity
structural complications and
should prompt consideration
global retinal dysfunction over
of an alternative diagnosis, as Masquerade syndromes
the long term, independent
Primary intraocular lymphoma
7 percent of the general popuof previous oral corticosteroid
lation carries this haplotype.
therapy.2,6,7,9,10,23,24
A thorough medical and ophthalmic distinguished from BSRC includes
Indeed, few patients maintain good
history, review of systems, directed MCP, which typically exhibits small- visual acuity without treatment, with
laboratory investigations, and imag- er, discrete, punched out hyper- and a 20 percent, five-year cumulative
ing studies serve to differentiate the hypo-pigmented lesions that block incidence of visual acuity of less than
various inflammatory, infectious and early, stain late, and are typically clus- 20/200.26 Visual acuity may be limited
neoplastic entities that may mimic tered around the optic nerve.37
by vitritis, cataract and cystoid macuBSRC (See Table 1). Infectious entiBilateral choroidal lesions appear- lar edema, but the later phases of
ties that may produce white dots in ing in the acute uveitic phase of VKH the disease are marked by significant
the retina and choroid, such as syphi- disease may be distinguished from photoreceptor loss and attenuation of
lis and tuberculosis, must be consid- those of BSRC by the presence of ex- electroretinographic amplitudes.
ered in the differential diagnosis, as udative retinal detachment with pinthese require specific antimicrobial point areas of hyperfluorescence at Treatment
therapy.
the level of the RPE with subneuroIn the absence of anterior segment sensory pooling on FA versus retinal
While periocular, ocular, intravitreal
stigmata of granulomatous inflamma- vascular inflammation. In addition, and systemic corticosteroids may be
tion, posterior involvement by sar- VKH is a systemic disease with char- effective in the short-term managecoidosis may closely resemble that acteristic extraocular differentiating ment of vitritis and macular edema,
of BSRC both morphologically and features.38
they are of inconsistent efficacy in the
angiographically,31-34 particularly in
Finally, patients with primary intra- long run. Unacceptably high mainthe presence of anterior segment stig- ocular lymphoma may present with tenance doses of prednisone are remata of granulomatous inflammation. multiple bilateral yellowish lesions quired, resulting in frequent developIn contrast to birdshot, the cream- and vitritis; however, their subretinal, ment of serious adverse effects when
colored lesions of APMPPE have a sub-RPE location in the clinical con- used as chronic monotherapy.
plaque-like morphology, are locat- text usually distinguishes them from
Given the guarded visual prognoed predominantly in the posterior those seen in BSRC.39-42
sis, the early introduction of steroidpole, and exhibit characteristic ansparing IMT at the outset, has been
giographic features of early block- Clinical Course
advocated in the treatment of birdage and late staining. Moreover, the
shot retinochoroidopathy, as extendacute lesions of AMPPE typically reBSRC is often described as hav- ed treatment is anticipated in most
solve with retinal pigment epithelial ing two distinct phases with an acute patients.43 Indeed, numerous studies
hyperpigmentation, whereas those phase, dominated by significant vit- have demonstrated that both preswith BSRC do not.35,36
ritis, cystoid macular edema and vi- ervation of visual function with a reAnother white dot syndrome to be sion loss followed by a subsequent duction of inflammation and macular
Table 1. Differential Diagnoses
7/25/13 3:56 PM
REVIEW
Retinal
Insider
Figure 2. Fluorescein angiography findings in birdshot are inconsistent and depend on the
age of the lesions and the phase of the study. Early birdshot lesions display early
hypoflourescence with subtle late staining. Leakage at the optic nerve is typically seen, as
is segmental phlebitis. Cystoid macular edema and choroidal neovascularization may also
be evident.
edema, and preservation of global
retinal integrity as well as the induction of long-term remission are possible in patients with birdshot managed
with steroid-sparing IMT. 8,23,24,26,30,44-46
Systemic immunomodulatory options include anti-metabolites, T-cell
transduction/calcineurin inhibitors,
Figure 3. Indocyanine green angiography in birdshot chorioretinopathy reveals
hypofluorescent spots that are more numerous than on fluorescein angiography. The spots
are distributed along choroidal vessels and not clustered around the optic nerve. The
hypofluorescence is sustained into the later phases of the angiogram.
biologics, intravenous immunoglobulin (IVIg) 47 and emerging use of
other biologic therapies alone or in
combination. For patients unable to
tolerate systemic corticosteroids or
IMT, the sustained-release fluocinolone acetonide implant (Retisert)
may be a viable alternative.48,49 The
efficacy of this implant and the decision to use it as initial therapy should
be tempered by the almost universal
development of cataract and high
incidence of ocular hypertension
and glaucoma, requiring incisional
surgery in more than a third of patients.44
Symptomatic patients with BSRC
who present with or develop vitritis,
retinal vasculitis, macular edema or
evidence of peripheral retinal dysfunction should be treated. In an initial retrospective study of 19 patients
with BSRC and in the subsequent
study of 28 in patients from the same
institution treated with very low initial doses of cyclosporine (2.5 mg/
kg/day) alone or in combination with
antimetabolites (methotrexate, azathioprine, mycophenolate mofetil)
or daclizumab, a favorable visual
outcome, inflammatory control, stabilization of electroretinographic parameters and the absence of demonstrable nephrotoxic side effects were
achieved.24,30
Similarly, a recent retrospective
analysis of 76 HLA-A 29-positive
birdshot patients, 46 of whom were
followed for five years and 18 for more
than 10 years, demonstrated that visual outcomes were better for those
treated with methotrexate as compared to untreated individuals and
corticosteroid-based regiments.11,30
While the use of methotrexate or
cyclosporine alone may be superior
to the long-term use of systemic corticosteroids in the treatment of BSRC,
monotherapy with cyclosporine, in
our experience, has been associated
with need for exceedingly prolonged
therapy with the recurrences of
7/25/13 3:56 PM
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Nashville, TN
Additional Chicago-area
Vitreoretinal Specialists
George A. Williams, MD
Jennifer J. Kang-Mieler, PhD
Royal Oak, MI
Swissôtel
323 EAST WACKER DRIVE, CHICAGO, IL 60601 • RESERVATIONS: 888-737-9477
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048_rp0613AlcAVTT.indd 57
7/19/13 10:53 AM
inflammation with tapering of this
medication.
In an effort to achieve durable remission of inflammation within two
years, the combination of cyclosporine
or mycophenolate has been exploited
in 49 patients (98 eyes), over a mean
follow up time of 52 months. At that
one-year time point, vitreous inflammatory scores, the presence of angiographic leakage, but not the presence
of cystoid macular edema, were significantly reduced from baseline, with
67 percent of patients achieving inflammatory control with no deterioration of electroretinographic indices.46
The use of monoclonal antibodies
to tumor necrosis factor α (TNF-α)
is an emerging treatment alternative
to conventional IMT, either alone or
in combination. In a recent retrospective report of 22 patients with
BSRC refractory to conventional
IMT treated with infliximab, inflammatory control was achieved in 88.9
percent of patients at the one year
follow-up.51 Over the course of the
study, six patients discontinued infliximab due to adverse effects.
In summary, birdshot retinochoroidopathy is a chronic, progressive
sight-threatening disease, which requires the early introduction of immunomodulatory therapy in an effort
to limit ocular structural damage, preserve global visual function and induce long-term remission. Markers of
active and progressive disease, which
may influence treatment decisions,
include not only clinical indices of intraocular inflammation, but also those
seen on imaging studies, particularly
fluorescein angiography, perimetry
and electroretinography.
Dr. Vitale is a professor of ophthalmology and visual sciences. chief of
the Uveitis Division and a member
of the Vitreoretinal Division at John
A Moran Eye Center, University of
Utah. Contact him at (801) 581-2352
or e-mail: [email protected].
edu. Dr. Shakoor is a retina fellow at
the Moran Eye Center.
1. Shah KH, Levinson RD, Yu F, et al. Birdshot chorioretinopathy.
Surv Ophthalmol 2005;50:519-41.
2. Nussenblatt RB, Mittal KK, Ryan S, Green WR, Maumenee
AE. Birdshot retinochoroidopathy associated with HLA-A29
antigen and immune responsiveness to retinal S-antigen. Am J
Ophthalmol 1982;94:147-58.
3. Baarsma GS, Priem HA, Kijlstra A. Association of birdshot
retinochoroidopathy and HLA-A29 antigen. Curr Eye Res 1990;9
Suppl:63-8.
4. Brezin AP, Monnet D, Cohen JH, Levinson RD. HLA-A29 and
birdshot chorioretinopathy. Ocul Immunol Inflamm 2011;19:397400.
5. Ladas JG, Arnold AC, Holland GN. Control of visual symptoms in
two men with birdshot retinochoroidopathy using low-dose oral
corticosteroid therapy. Am J Ophthalmol 1999;128:116-8.
6. Gass JD. Vitiliginous chorioretinitis. Arch Ophthalmol
1981;99:1778-87.
7. Ryan SJ, Maumenee AE. Birdshot retinochoroidopathy. Am J
Ophthalmol 1980;89:31-45.
8. Gasch AT, Smith JA, Whitcup SM. Birdshot retinochoroidopathy.
Br J Ophthalmol 1999;83:241-9.
9. Priem HA, Oosterhuis JA. Birdshot chorioretinopathy: Clinical
characteristics and evolution. Br J Ophthalmol 1988;72:646-59.
10. Rothova A, Berendschot TT, Probst K, van Kooij B, Baarsma
GS. Birdshot chorioretinopathy: Long-term manifestations and
visual prognosis. Ophthalmology 2004;111:954-9.
11. Rothova A, Norel AO, Los LI, Berendschot TT. Efficacy of LowDose Methotrexate Treatment in Birdshot Chorioretinopathy.
Retina 2011.
12. Brucker AJ, Deglin EA, Bene C, Hoffman ME. Subretinal
choroidal neovascularization in birdshot retinochoroidopathy. Am
J Ophthalmol 1985;99:40-4.
13. Godel V, Baruch E, Lazar M. Late development of chorioretinal
lesions in birdshot retinochoroidopathy. Ann Ophthalmol
1989;21:49-52.
14. Koizumi H, Pozzoni MC, Spaide RF. Fundus autofluorescence
in birdshot chorioretinopathy. Ophthalmology 2008;115:e15-20.
15. Giuliari G, Hinkle DM, Foster CS. The spectrum of fundus
autofluorescence findings in birdshot chorioretinopathy. J
Ophthalmol 2009;2009:567693.
16. Gallagher MJ, Yilmaz T, Cervantes-Castaneda RA, Foster CS.
The characteristic features of optical coherence tomography in
posterior uveitis. Br J Ophthalmol 2007;91:1680-5.
17. Birch D, Williams P, Callanan D, Wang R, et al. Macular
atrophy in birdshot retinochoroidopathy: An optical coherence
tomography and multifocal electroretinography analysis. Retina
2010;30:930-7.
18. Forooghian F, Yeh S, Faia L, Nussenblatt R. Uveitic foveal
atrophy: Clinical features and associations. Arch Ophthalmol
2009;127:179-86.
19. Forooghian F, Gulati N, Jabs DA. Restoration of retinal
architecture following systemic immunosuppression in birdshot
chorioretinopathy. Ocul Immunol Inflamm 2010;18:470-1.
20. Fuerst DJ, Tessler HH, Fishman GA, Yokoyama MM, Wyhinny
GJ, Vygantas CM. Birdshot retinochoroidopathy. Arch Ophthalmol
1984;102:214-9.
21. Priem HA, De Rouck A, De Laey JJ, Bird AC. Electrophysiologic
studies in birdshot chorioretinopathy. Am J Ophthalmol
1988;106:430-6.
22. de Courten C, Herbort CP. Potential role of computerized
visual field testing for the appraisal and follow-up of birdshot
chorioretinopathy. Arch Ophthalmol 1998;116:1389-91.
23. Oh KT, Christmas NJ, Folk JC. Birdshot retinochoroiditis:
long term follow-up of a chronically progressive disease. Am J
Ophthalmol 2002;133:622-9.
24. Vitale AT, Rodriguez A, Foster CS. Low-dose cyclosporine
therapy in the treatment of birdshot retinochoroidopathy.
Ophthalmology 1994;101:822-31.
25. Le Hoang P, Girard B, Deray G, et al. Cyclosporine in the
treatment of birdshot retinochoroidopathy. Transplant Proc
1988;20:128-30.
26. Thorne JE, Jabs DA, Peters GB, Hair D, Dunn JP, Kempen JH.
Birdshot retinochoroidopathy: Ocular complications and visual
impairment. Am J Ophthalmol 2005;140:45-51.
27. Holder GE, Robson AG, Pavesio C, Graham EM.
Electrophysiological characterisation and monitoring in the
management of birdshot chorioretinopathy. Br J Ophthalmol
2005;89:709-18.
28. Zacks DN, Samson CM, Loewenstein J, Foster CS.
Electroretinograms as an indicator of disease activity in
birdshot retinochoroidopathy. Graefes Arch Clin Exp Ophthalmol
2002;240:601-7.
29. Sobrin L, Lam BL, Liu M, Feuer WJ, Davis JL.
Electroretinographic monitoring in birdshot chorioretinopathy. Am
J Ophthalmol 2005;140:52-64.
30. Kiss S, Ahmed M, Letko E, Foster CS. Long-term followup of patients with birdshot retinochoroidopathy treated with
corticosteroid-sparing systemic immunomodulatory therapy.
31. Brinkman CJ, Rothova A. Fundus pathology in
neurosarcoidosis. Int Ophthalmol 1993;17:23-6.
32. Brod RD. Presumed sarcoid choroidopathy mimicking
birdshot retinochoroidopathy. Am J Ophthalmol 1990;109:357-8.
33. Yoshioka T, Yoshioka H, Tanaka F. [Birdshot retinochoroidopathy
as a new ocular sign of the sarcoidosis]. Nippon Ganka Gakkai
Zasshi 1983;87:283-8.
34. Read RW, Rao NA, Sharma OP. Sarcoid choroiditis initially
diagnosed as birdshot choroidopathy. Sarcoidosis Vasc Diffuse
Lung Dis 2000;17:85-6.
35. Ryan SJ, Maumenee AE. Acute posterior multifocal placoid
pigment epitheliopathy. Am J Ophthalmol 1972;74:1066-74.
36. Gass JD. Acute posterior multifocal placoid pigment
epitheliopathy. Arch Ophthalmol 1968;80:177-85.
37. Dreyer RF, Gass DJ. Multifocal choroiditis and panuveitis. A
syndrome that mimics ocular histoplasmosis. Arch Ophthalmol
1984;102:1776-84.
38. Moorthy RS, Inomata H, Rao NA. Vogt-Koyanagi-Harada
syndrome. Surv Ophthalmol 1995;39:265-92.
39. Chatzistefanou K, Markomichelakis NN, Christen W, Soheilian
M, Foster CS. Characteristics of uveitis presenting for the first
time in the elderly. Ophthalmology 1998;105:347-52.
40. Gupta R, Murray PI. Chronic non-infectious uveitis in the
elderly: Epidemiology, pathophysiology and management. Drugs
Aging 2006;23:535-58.
41. Kirsch O, Lautier-Frau M, Labetoulle M, Offret H, Frau E.
[Characteristics of uveitis presenting de novo in the elderly]. J Fr
Ophtalmol 2003;26:720-4.
42. Sen HN, Bodaghi B, Hoang PL, Nussenblatt R. Primary
intraocular lymphoma: diagnosis and differential diagnosis. Ocul
Immunol Inflamm 2009;17:133-41.
43. Jabs DA, Rosenbaum JT, Foster CS, et al. Guidelines for
the use of immunosuppressive drugs in patients with ocular
inflammatory disorders: recommendations of an expert panel.
Am J Ophthalmol 2000;130:492-513.
44. Kempen JH, Altaweel MM, Holbrook JT, et al. Randomized
comparison of systemic anti-inflammatory therapy versus
fluocinolone acetonide implant for intermediate, posterior,
and panuveitis: The multicenter uveitis steroid treatment trial.
45. Becker MD, Wertheim MS, Smith JR, Rosenbaum JT. Longterm follow-up of patients with birdshot retinochoroidopathy
treated with systemic immunosuppression. Ocul Immunol
Inflamm 2005;13:289-93.
46. Cervantes-Castaneda RA, Gonzalez-Gonzalez LA, CorderoComa M, Yilmaz T, Foster CS. Combined therapy of cyclosporine
A and mycophenolate mofetil for the treatment of birdshot
retinochoroidopathy: A 12-month follow-up. Br J Ophthalmol
2013.
47. LeHoang P, Cassoux N, George F, Kullmann N, Kazatchkine
MD. Intravenous immunoglobulin (IVIg) for the treatment of
birdshot retinochoroidopathy. Ocul Immunol Inflamm 2000;8:4957.
48. Srivastava SK, Nguyen QD, Callanan D, Goldstein DA, Albini
TA. The Use Of The Fluocinolone Acetonide (Retisert) Implant In
Patients With Birdshot Choroidopathy. Invest Ophthalmol Vis Sci
2011;52:2751.
49. Rush RB, Davis J, Goldstein D, Tessler H, Lin P, Meghpara
B. Birdshot Chorioretinopathy and Fluocinolone Acetonide
Intravitreal Sustained Release Devices: An Analysis of Efficacy
and Complications. Invest Ophthalmol Vis Sci 2009;50:6044.
50. Cervantes-Castaneda RA, Bhat P, Fortuna E, Acevedo S,
Foster CS. Induction of durable remission in ocular inflammatory
diseases. Eur J Ophthalmol 2009;19:118-23.
51. Artornsombudh P, Gevorgyan O, Payal A, Siddique SS, Foster
CS. Infliximab Treatment of Patients with Birdshot Retinochoroidopathy. Ophthalmology 2012.
7/25/13 3:56 PM
REVIEW
Plastic Pointers
Edited by Ann P. Murchison, MD, MPH
The Surgical Treatment
Of the Aging Brow
Surgical browlift remains a powerful rejuvenative technique and
can beautifully complement other facial cosmetic procedures.
Ryan N. Heffelfinger, MD and Jill N. D’Souza, MD, Philadelphia
he term browlift describes a procedure that repositions sagging
tissue of the forehead and eyebrows.
Even at relatively young ages, patients may see a change in the location of their eyebrows and the
emergence of forehead and periorbital rhytids. The aging brow is
often interpreted as tired or angry.
There are a wide variety of surgical
techniques that address the upper
T
third of the face, including forehead
lifts, browlifts and blepharoplasties.
All should be considered and tailored to each patient’s specific cosmetic need. This review will provide
a brief overview of brow and forehead lifting techniques.
Evaluation
The evaluation of the cosmetic
brow patient should include thorough questioning to elicit the patient’s subjective aesthetic complaints, a history of previous facial
surgery and any ocular abnormalities. This is followed by a complete
head and neck and ophthalmologic
exam. Preoperative facial photography should be obtained to assist in
performing a comprehensive facial
analysis to include an assessment of
brow position. The brow should lie
roughly 1 cm above the medial canthus along an imaginary line perpendicular to the nasal ala, and end laterally at an oblique line extending from
the alar ridge through the lateral canthus. Although debated, the highest
point of the brow should generally be
near the lateral limbus, and the arc is
more pronounced in the female (See
Figure 1). The female brow should
lay 0.5 to 1 cm above the supraorbital
ridge, while the male brow should be
located at the level of the supraorbital ridge.
Anatomy & Surgical Technique
Figure 1. The accepted “normal” position for the brow is different in females and males. In
females, a higher arched brow is considered normal, whereas the male brow is flat and at
the supraorbital rim.
050_rp0813_plastics.indd 50
Browlifting addresses brow ptosis primarily, but some techniques
7/25/13 3:41 PM
Figure 2. These are the five incisions commonly used in performing the endoscopic browlift.
may impact forehead and periorbital rhytids. Structures at risk during
brow and forehead lifts include the
neurovascular bundles emanating
from the supraorbital region, as well
as the temporal (or frontal) branch
of the facial nerve. It is imperative to
understand the neurovascular anatomy of the forehead to avoid damage
to these structures intraoperatively.
The layers of the scalp include the
skin, connective tissue, galea aponeurotica, loose areolar tissue and
the periosteal layer. The superficial
temporal artery supplies the lateral
forehead, while the medial forehead
receives its vascular supply from the
supraorbital and supratrochlear arteries, both branches of the ophthalmic artery (which itself arises from
the internal carotid artery). The
medial forehead receives its sensory supply via the supraorbital and
supratrochlear nerves from the V1
branch of the trigeminal nerve, while
the lacrimal (V1), zygomaticofacial
(V2) and the auriculotemporal (V3)
address the lateral forehead sensation.
The temporal branch of the facial nerve courses superomedially
through the area between the brow
and hairline within the temporoparietal fascia (TPF). Anatomic studies revealed that the sentinel vein,
a structure encountered in the subtemporoparietal fascial plane in the
temple, is a reliable predictor of the
nerve’s course, and runs inferior to
the nerve within 2 mm2. Forehead
and periorbital rhytids are caused
by contraction of the upper facial
musculature, including the corrugator, frontalis and procerus muscles.
The corrugator muscles are small,
fan-shaped muscles that underlie the
eyebrows and cause vertical glabellar
wrinkling. The frontalis muscle is a
broad, bi-lobed muscle that raises
the eyebrows. The procerus extends
from the dorsal nose to the lower
forehead, and is responsible for upper nose wrinkling.
Here are the different surgical options for treating the brow and fore-
head, in order of popularity in our
practice.
Endoscopic Browlift
In our opinion, the endoscopic
browlift is the procedure of choice
for rejuvenating the brow. The advantages of the endoscopic browlift
include its minimally invasive nature
and the absence of long incisions; the
inherent ability to provide a natural result and avoid overly-elevated
brows; the ability to directly visualize
the procerus and corrugator muscles
Figure 3. Six month postoperative results after an endoscopic browlift and upper blepharoplasty.
7/25/13 3:41 PM
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REVIEW
Plastic
Pointers
for resection;
the endoscopand the low
ic approach.
incidence of
An incision is
scalp paresmade 8 to 10
thesia. Dismm posterior
advantages
to hairline
include the
over the temneed for anporal suture
esthesia; costs
line. Dissecassociated
tion is carried
with fixation;
down to the
and a postesuperficial
rior hairline
layer of the
shift.
deep tempoA full disral fascia, uncussion of
der the temsurgical detail
poroparietal
is not possible Figure 4. This patient had a temporal browlift in conjuction with a facelift and laser resurfacing.
fascia. Using
in this review,
sharp elevabut we will provide a brief review of and depressor supercilli muscles are tors, care is taken to stay in this plane
our technique. We most often com- performed if necessary. However, it as dissection proceeds towards the
bine the endoscopic browlift with the is commonly thought that myecto- lateral orbital rim. The sentinel vein
temporal browlift described here- mies are not a permanent solution should be identified and preserved
after. Five scalp incisions are made to forehead rhytids, and patients are if possible. If it is necessary to ligate
posterior to the hairline; one mid- routinely counseled that they will the sentinel vein, this should be done
line, two in the paramedian position need botulinum toxin indefinitely to as close to the temporalis muscle as
over the brow arch, and two that are treat these.
possible to avoid injury to the facial
parallel to the hairline in the temple
Once the tissue is released from nerve. Ligation may increase post(See Figure 2).
periosteum, it is redraped and fixed operative edema. The periosteal atPeriosteal elevators are used to dis- posteriorly after adequate flap ad- tachments to the lateral supraorbital
sect in the subperiosteal plane to the vancement. There are several flap ridge/lateral orbital rim are released.
supraorbital ridge, avoiding the su- fixation techniques, generally using The precanthal tendon, or lateral
praorbital and supratrochlear nerves. screws or other bioabsorbable soft orbital thickening, is elevated. The
The temporal browlift is completed tissue fixation devices. We prefer fix- temporal scalp flap is retracted upas described below in the sub-TPF ation screws, which are removed 10 wards and excess skin excised. To
plane. The temporal dissection is to 14 days postoperatively. Periosteal fixate the lateral brow, the TPF is
connected to the frontal dissection reattachment is stable within six to sutured superolaterally to the tempoby dividing the conjoint fascia, or eight weeks (See Figure 3).
ralis fascia (See Figure 4).
temporal line. This is done through
the temporal pocket in a lateral to Temporal Browlift
Direct Browlift
medial fashion, which protects the
The temporal browlift can be perThe direct browlift is most usefacial nerve. Around the glabellar
and superior orbital rim areas the formed in conjunction with the en- ful in the comprehensive manageperiosteum is divided transversely doscopic browlift or as a separate ment of facial paralysis and in male
with reverse elevators or endoscopic procedure to address lateral brow patients with prominent rhytids. It
scissors. It should be noted that fron- and periorbital rhytids. There are is rarely used for cosmetic patients
tal paresis occurs more commonly many different ways to perform a in our practice. Separate incisions
on the left because on this side the temporal browlift, from endoscopic are made over each brow; the infeendoscope is positioned directly un- (most commonly in conjunction with rior edge of each incision is placed
der the frontal branch. Following ad- a full browlift) to subcutaneous (most within the superior most aspect of
equate periosteal release, partial my- commonly an office procedure under the eyebrows, and carried to the
ectomies of the procerus, corrugator local anesthesia). We will describe lateral aspect of the eyebrow and
7/25/13 3:42 PM
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7/24/13 3:08 PM
extended horizontally in a gentle
disadvantages include hairline elarc. It should not extend more
evation and paresthesia posterior
medially than the medial aspect
to the incision.
of the eyebrow as this may result
An incision is placed posterior
in glabellar scarring. The superior
to the hairline in an arcuate design
incision should be placed a maxitowards the helical root. Dissecmum of 10 to 12 mm above the
tion is carried out in the subgainferior incision, with its highest
leal plane to the superior orbital
point at the lateral limbus. The
rim, with attention to the course
superior incision determines the
of the superficial temporal branch
new brow positioning, and the deof the facial nerve. The corrugagree of femininity or masculinity
tor muscles are dissected out and
of the rejuvenated face depends
removed with sharp scissor dissecon the angle of the eyebrow at the
tion, avoiding the supratrochlear
lateral limbus. This is a powerful
nerve. The procerus muscle can
technique and care the surgeon
be similarly addressed if desired.
should err on the conservative
Replacing the flap is carried out
side to avoid an over-elevated
with relaxing incisions and carbrow (See Figure 5). The advandinal sutures placed in areas retages of a direct browlift include
quiring the greatest amount of lift.
its short operative duration, the
After satisfactory replacement of
ability to perform under local anthe brow, redundant areas of scalp
esthesia, and its precise control
skin are excised. Galeal sutures
over the design of brow contour Figure 5. A direct browlift was done to correct brow
are placed in several areas along
and shape. It does not change the ptosis in this patient with a right-sided facial paralysis. the incision, with emphasis along
appearance of forehead or glabel- The right brow is over-elevated.
the dome of the head to avoid
lar rhytids, and does leave a vispostoperative scar spread.
ible eyebrow scar.
but avoids transection of the sensory
branches of the forehead. The fore- Pretrichial Browlift
head incision should be meticulously
Midforehead Lift
closed with vertical mattress suture
The pretrichial browlift is indicatThis technique utilizes deep fore- ensuring eversion of the skin edges, ed in women with high hairlines or
head furrows via a transverse mid- and often requires meticulous post- for long vertical forehead heights. It
forehead incision. As with the direct operative management that often in- is a modification of the coronal lift,
lift, this technique is rarely indicated cludes laser resurfacing and/or derm- and does not lift the anterior hairline
in the female cosmetic patient. It is abrasion (See Figure 6).
further. The incision is placed apindicated almost exclusively for men
proximately 2 mm posterior to the
and for patients that may benefit from Coronal Forehead Lift
hairline in a beveled fashion that
forward advancement of the hairline.
transects the hair follicles, which enIt does not address forehead rhytids,
The coronal lift is useful for situa- courages postoperative hair growth
but rather uses them to hide the in- tions in which endoscopic procedures through the resultant scar. Alternacisional scar. Ideally, adjacent trans- have failed or are not indicated or for tively, a W-plasty technique has been
verse rhytids are incised, and the in- patients who do not require a pret- described with limbs 5 to 6 mm in
tervening skin removed. Dissection richial incision. In our practice, this length that interdigitate at 35-degree
may be carried out in subgaleal or situation is exceedingly rare. The ad- angles. The remainder of the procesubcutaneous fashion. The subgaleal vantages of the coronal lift include the dure is carried out the same as the
flap is easier to elevate and a more ability to address the corrugator, pro- coronal forehead technique.
cosmetically appealing scar, however cerus and frontalis muscles to theoretit transects sensory nerves and causes ically eliminate dynamic rhytids; the Browpexy
postoperative forehead numbness. wide surgical exposure for teaching
The subcutaneous flap in contrast, re- purposes; and the possibility to powA browpexy may be used in comquires more tension on the skin edge erfully elevate the brow. Two major bination with the upper blepharoAugust 2013 | Revophth.com | 55
7/25/13 3:42 PM
REVIEW
Plastic
Pointers
plasty and may negate the need for
a forehead procedure. It cannot address forehead rhytids or other aesthetic concerns of the upper third of
the face. It is performed through an
upper blepharoplasty incision after
identification of the supraorbital vessels and nerves surrounding the supraorbital notch. The blepharoplasty
incision is extended superiorly to 1.5
cm above the superior and lateral
orbital rim deep to the orbicularis oculi muscle. Blepharoplasty is carried
out first, then browpexy is carried
out to elevate and suspend the brow.
Sutures are placed at the infrabrow
hairs and passed in the periosteal
plane to 1 cm above the supraorbital
ridge. Tying down these sutures will
elevate the eyebrow, and therefore
placement and tension of the suture
guides repositioning of the brow.
Complications
Main complications of the browlift
procedures include bleeding, injury
to sensory or motor nerves, lagophthalmos and alopecia. Bleeding can
occur from the superficial temporal
artery and zygomaticotemporal artery, as well as the supratrochlear
and supraorbital arteries. Given the
close proximity to nerves throughout
the lateral forehead, cautery with the
bipolar is recommended. The development of postoperative hematoma
could compromise flap vascularity and survival, and is an indication
for urgent exploration and cautery.
Stretching of the supratrochlear and/
or supraorbital nerve can result in
temporary hypesthesia over the supraorbital rim. In the direct browlift,
permanent hypesthesia generally results surrounding the incision. The
browpexy is also associated with hypesthesia, generally of several months’
duration, over the lateral eyebrow
margin.
Damage to the temporal branch
of facial nerve can result both from
Figure 6. A midforehead browlift was performed to correct brow ptosis in this patient.
Preoperative (A); three months (B); and one year postoperative (C) views are shown.
injection of the local anesthetic and
from damage during surgical dissection in the temporal region. Care
to observe anatomic landmarks and
caution with retraction are essential
to preserve this branch. Temporary
lagophthalmos is common postoperatively, for which judicious use of eye
drops and ointment is imperative. A
corneal ulceration can occur, especially when the browlift is associated
with a blepharoplasty, and should be
recognized early to avoid permanent
ocular damage. Alopecia can result
from trauma to hair follicles during
surgery, or dissection in a superficial
Figure 7. This patient underwent an endoscopic browlift, four-lid blepharoplasty, facelift, laser
resurfacing and rhinoplasty. Pre- (top) and postoperative views (bottom) are shown.
7/25/13 3:42 PM
plane that transects hair follicles.
Although the surgical browlift
seems less popular in favor of volume replacement techniques recently, it remains a powerful rejuvenative
technique in the plastic surgeon’s arsenal. It can beautifully complement
other facial cosmetic procedures (See
Figure 7). There are several procedures to address the aesthetic aspects
of the upper third of the face. Each
should be tailored to the specific
needs of the patient undergoing the
procedure. Choice of technique will
depend on the position of the patient’s hairline, the amount of lift that
is necessary, and the need to concurrently address forehead rhytids or
brow asymmetries. Only browlifts
were discussed in this review, however, a thorough consideration of all
aspects of the individual patient and
the aging forehead, brow and eyelids
should be undertaken in order to
optimize facial rejuvenation.
Dr. Heffelfinger is the director of
the Division of Facial Plastic and Reconstructive Surgery and co-director
of the Herbert Kean Center for Facial
Aesthetics at Thomas Jefferson University Hospital. He also the director of Head and Neck Microvascular
Surgery at Jefferson. Contact him at
925 Chestnut St. 6th fl. Philadelphia,
PA 19107. E-mail: ryan.heffelfinger@
jefferson.edu. Dr. D’Souza is a thirdyear resident in Jefferson’s otolaryngology residency program. Contact
her at [email protected].
1. Codner MA, Kikkawa DO, Korn BS, Pacella SJ. Blepharoplasty
and Brow Lift Plast Reconstr Surg 2010;126(1):1-17.
2. Sabini P, Wayne I, Quatela V. (2003) Anatomical Guides to
Precisely Localize the Frontal Branch of the Facial Nerve. Arch
Facial Plast Surg 2003;5(2):150-152.
3. Adamson P, Dahiya R. The Aging Forehead. In: Bailey B, Johnson
J. eds. Head and Neck Surgery—Otolaryngology. Philadelphia:
Lippincott Williams & Wilkins 4th Ed, 2006;2663-2683.
4. Paul M. The Evolution of the Brow Lift in Aesthetic Plastic
Surgery. Plast Reconstr Surg 2001;108:1409-1424.
5. Graham DW, Heller J, Kurkjian TJ, Schaub TS, Rohrich RJ.
Brow Lift in Facial Rejuvenation: A Systematic Literature Review
of Open versus Endoscopic Techniques. Plast Reconstr Surg
2011;128(4):335-341.
6. Vinas JC, Caviglia C, Cortinas JL. Forehead Rhytidoplasty and
Brow Lifting. Plast Reconstr Surg 1976;57:445.
7. Knize DM (2009) Anatomic Concepts for Brow Lift Procedures.
Plast Reconstr Surg 124(6):2118-2126.
8. Agarwal CA, Mendenhall SD 3rd, Foreman KB, Owsley JQ.
The Course of the Frontal Branch of the Facial Nerve in Relation
to Fascial Planes: An Anatomic Study. Plast Reconstr Surg
2010;125(2):532-7.
9. McKinney P, Mossie RD, Zukowski ML. (1991) Criteria for the
Forehead Lift. Aesthetic Plast Surg 15:141-147.
10. Vasconez IO, de la Torre JI. (2002) Fine Tuning the Endoscopic
Brow Lift. Aesthet Surg J 2002;22:69-71.
11. Nassif PS. Kokoska MS, Homan S. (1998) Comparison of
subperiosteal vs subgaleal elevation techniques used in forehead
lifts. Arch Otolaryngol Head Neck Surg 1998;124(11):1209-1215.
12. Mackay GJ, Nahai F. (1995) The Endoscopic Forehead Lift.
Operative techniques in plastic and reconstructive surgery. Plast
Reconstr Surg 1995; 2(2):137-144.
13. Matarasso A, Hutchinson O. Evaluating Rejuvenation of the
Forehead and Brow—an Algorithm for Selecting the Appropriate
Technique. Plast Reconstr Surg 2000;106: 687-689.
14. Elkwood A, Matarasso A, Rankin M. (2001) National Plastic
Surgery Survey: Brow Lifting Techniques and Complications. Plast
Reconstr Surg 2001;108:2143-2150.
15. Byun S, Mukovozov I, Farrokhyar F, Thoma A. Complications in
Brow Lift Techniques: A Systematic Review. Plast Reconstr Surg
2012;130:90.
16. Swanson E. Objective Assessment of Change in Apparent Age
after Facial Rejuvenation Surgery. J Plast Reconstr Aesthet Surg
2011; 64(9):1124-1131.
17. Angelos PC, Stallworth CL, Wang TD. 2011 Forehead Lifting:
State of the Art. Facial Plast Surg 2011;27(1):50-57.
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7/25/13 3:40 PM
REVIEW
Therapeutic Topics
Acupuncture:
A Dry-Eye Therapy?
This ancient medical art may have some usefulness for patients
seeking alternative ways to treat their disease.
Mark B. Abelson, MD, CM, FRCSC, FARVO, and James McLaughlin, PhD, Andover, Mass.
u m a n s a r e a visual species.
When daily activities are disrupted by impaired vision, patients are
confronted with the reality of how
important their eyes are to them, and
how often they take good visual function for granted. This fundamental
importance of visual health in everyday life distinguishes ophthalmology
from other medical specialties. Many
of our patients may come to us with
the apprehension that stems from a
disruption of something that is central to their day-to-day living: their
eyesight.
Dry eye is one disease that can have
a significant impact on visual function. The burning, the blurring of vision and the inability to sustain simple
activities like reading or driving can
be the cause of great frustration for
patients with dry eye. Without truly
efficacious treatments, we are left to
provide a combination of eye drops,
plugs, humidifiers and an assortment
of palliative approaches that often
only mitigate the symptoms of the
disease. Due to the constant impact
of the disease on their lives, patients
with dry eye, particularly those suffering with the most severe forms,
H
are motivated to try any and all remedies, treatments or procedures that
promise substantial relief. One such
non-traditional approach is acupuncture, the ancient Chinese method of
physiologic manipulation using fine
needles targeting specific points on
the body.1,2 Now, more than 40 years
after its “introduction” to Western
medicine, acupuncture is generally
accepted as an alternative anti-nociceptive and anti-emetic therapy. Despite this, its use for treating other
conditions, such as dry eye, is generally considered more speculative.
As alternative medical techniques
such as acupuncture move into the
mainstream, there is a growing need
for evidence-based studies that allow
us to assess them relative to other
therapeutic interventions. In recent
years randomized clinical trials of
acupuncture for a number of ocular
indications including dry eye have
been conducted, and several are currently under way. In our June column,
we discussed the importance of applying principles of evidence-based
medicine to herbal and other nontraditional therapies; this month, we’ll
examine the data from clinical studies
058_rp0813_ttops.indd 58
of acupuncture, with a particular focus on its use as a treatment modality
for dry eye.
Acupuncture’s Origins
The exact history of acupuncture
isn’t known, but there is evidence of
wooden and bone needles suitable
for acupuncture in Chinese ruins dating back to before 1000 B.C.1-3 The
most often-cited early written reference to acupuncture as an established
therapy is the Nei Jing, a manual of
Chinese medicine that dates to the
first century B.C., and describes the
bodily paths of energy flow (sometimes referred to as a wind), or Qi
(pronounced “chee”), that are a primary target of acupuncture. It’s likely
that the method is much older than
this ancient text, as various forms of
the technique were well-established
in both Japan and Korea around the
time of the Nei Jing. In addition,
there is evidence that a frozen Neolithic man found in the Swiss Alps
may have been part of a Stone-Age society that practiced a well-developed
form of acupuncture.4 That finding
pushes the origins of the technique
7/25/13 3:58 PM
back by several thousand years, and
also brings into question the dogma of
a Chinese origin. It’s not likely that a
man from central Europe circa 3000
B.C. made weekend trips to Beijing to
see his acupuncturist.
From the earliest records, the goal
of acupuncture treatments has been
described as a means to restore balance, and therefore health, by manipulation of the flow of Qi through invisible tracts running from head to toe.
These pathways, commonly referred
to as meridians, are distinct from anatomical networks such as nerves or
blood vessels. The rationale for acupuncture rests heavily on concepts of
duality, of the yin and yang, central to
eastern philosophies; in the body, the
duality is represented by blood and
Qi. Earliest records referred to bloodletting and acupuncture as parallel
means of balance restoration. Treatments often include needle manipulation at a dozen or more acupoints,
the precisely mapped points used for
needle insertion.
There are several hundred acupoints in most manuals of acupuncture, and treatments often involve
a combination of sites surrounding
the symptomatic areas together with
more distant acupoints. For example,
trials of acupuncture therapy for dry
eye typically employ 13 to 19 needle
sites, and include those near the orbits as well as sites in the hand and in
the foot.5 Despite skepticism about
a technique based upon an invisible
network of wind energy, it’s clear from
both history and recent scientific
studies that there is more to this than
smoke, mirrors or needles.
In recent years there has been a
significant research effort focused on
identifying the physiological basis of
acupuncture, and much of this work
has yielded clear mechanistic details
for some of the effects of the method.
The earliest of these studies showed
a link between the anti-nociceptive
action of acupuncture and the release
Acupuncture maps areas of therapy as meridians (appearing as lines on the model above)
and acupoints (the alphanumerically labeled points).
of endogenous endorphins. 6 A key
part of this work was the demonstration that pain relief provided by acupuncture could be prevented by the
narcotic antagonist naloxine. Other
studies in animals and in humans have
linked acupuncture-mediated pain
relief with needle-evoked release of
adenosine and adenosine triphosphate.7,8 Local accumulations of these
transmitters can lead to adenosine
receptor activation on nearby afferent
nerves, and this is likely to be responsible for acupuncture-elicited local
analgesia. These effects can be replicated with direct adenosine injections,
and do not occur in mice lacking the
adenosine A1 receptor. Another finding of this work, replicated in many
other studies, is the importance of
needle manipulation. While descriptions of acupuncture tend to focus on
the specific locations of the acupoints,
it’s also equally important to note that
duration of treatment and the amount
of needle manipulation are also integral parts of the method.
In addition to the traditional meth-
ods that rely on needle manipulation,
other variations combine use of acupuncture with heat application (moxibustion), or focus on specific body
regions (e.g., auricular acupuncture).1
However, there are few controlled
studies examining the efficacy of these
methods, and even fewer focusing on
potential ocular indications.
Part of the interest and demand
for alternative treatments such as
acupuncture comes from a growing
patient population that seeks alternatives to mainstream pharmacotherapies that they view as inherently dangerous. In contrast, it is common to
find descriptions of acupuncture as
a therapy “without adverse effects.”2
Fortunately, even some of the most
vocal proponents of the technique are
quick to point out that although it is
an exceptionally safe treatment modality, it is not without risk: For example, inappropriate use of acupuncture
needles can result in the puncturing
of vital organs. A consideration of the
potential risks of acupuncture treatment has to be part of the therapeutic
7/25/13 3:58 PM
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REVIEW
Therapeutic
Topics
decision-making process for both patient and practitioner.9
Acupuncture in the Clinic
Since its re-introduction into western medicine in the 1970s, there has
been a sustained effort to assess the
clinical efficacy of acupuncture in a
controlled, empirical fashion. By the
late 1990s, acupuncture had become
more accepted as a viable treatment
for alleviation of pain and/or nausea,
and since then has been generally acknowledged as an effective therapeutic option for these indications. In
addition, acupuncture has been used
for a number of ophthalmic disorders,
including ocular allergy, glaucoma
and dry eye. While there is no consensus as to the effectiveness of acupuncture for these indications, there
is a growing body of evidence-based
data that clinicians can use to make an
informed appraisal.
Clinical trials involving acupuncture-based treatments face the same
difficulties that other procedural
therapies, such as surgery, encounter,
including the need for valid placebo
groups and for appropriate treatment masking. Many studies have
used sham needles placed at positions
other than the acupoints designated
in study protocols. This approach has
revealed a significant placebo effect
in many acupuncture trials, while at
the same time providing an appropriate comparator with which to judge
acupuncture efficacy.10,11 Some of the
best data has come from studies using both sham needle placebos and
active comparators (drug) that allow
for both a direct assessment of the
relative efficacy of acupuncture, and
a measure of the technique’s utility as
adjunct therapy.
Use of acupuncture for allergic and
inflammatory diseases including asthma, rhinitis and allergic conjunctivitis
is common among traditional practitioners. Several small-scale (n=24
Acupuncture orbital acupoints (sites designated as BL2, GB14 and TE23). Among those
points used for dry-eye therapy are points surrounding the orbit.
to 30) randomized trials compared
standard and sham acupuncture effects on either signs and symptoms of
seasonal allergic disease12 or on circulating IgE levels in allergic patients13
and were unable to demonstrate a significant clinical effect. More recently,
a larger trial (n=422) was able to show
a statistically significant improvement
in Rhinitis Quality of Life Questionnaire scores in the acupuncture-treated group compared with either sham
acupuncture or oral cetirizine alone
(all patients were provided medication).14 In addition, those receiving
acupuncture treatments (but not
sham treatments) reduced their cetirizine intake by between 10 to 15 mg
per day. These improvements were
transient, however, and did not reach
a clinically significant level.
There are also studies of acupuncture treatments for primary openangle glaucoma patients, including
a recent study that examined the effect of acupuncture on intraocular
pressure and ocular hemodynamics.15
This study had a small sample size
(20 eyes) and no true placebo group,
but it was able to show a decrease in
IOP following acupuncture, and also
reported Doppler imaging-based increases in ocular blood flow following
treatment. The value of acupuncture,
as with any other treatment approaches for the disease, will be measured in
future studies that evaluate the ability
of the technique to slow or reverse
the retinal damage associated with
POAG.
Acupuncture for Dry Eye
In contrast to glaucoma, dry eye is a
condition with significant unmet therapeutic need, and so would seem to
be an appropriate condition for acupuncture therapy. The chronic nature
of dry eye further supports an examination of acupuncture treatment efficacy. A number of early studies were
designed to test mechanistic actions of
acupuncture on tear-film physiology;
in one study, periorbital acupuncture
was shown to cause a 0.44 C decrease
in ocular surface temperature, an efAugust 2013 | Revophth.com | 61
7/25/13 3:59 PM
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REVIEW
Therapeutic
Topics
fect that would be expected to reduce
evaporative tear loss.16 A small-scale
trial of acupuncture showed positive
effects on subjective, patient-reported symptoms, but this early study
lacked randomization and control
groups necessary for objective assessment.17 Another, more recent pilot
study compared acupuncture and
sham acupuncture treatments, (Shaw
KS, IOVS 2011;52:ARVO E-abstract
3839) but found no significant differences between the two groups. In
general, early trials of acupuncture,
both for dry eye and for other conditions, suffered from a lack of rigorous controls, masking and other study
features necessary for evidence-based
assessments.
Studies conducted in the past three
to five years have addressed these issues and so provide a growing dataset
from which to draw clear conclusions.
Two studies conducted in Korea have
employed a specific set of acupoints
together with more clearly defined
treatment and control criteria, including parallel sham acupoints.5,18
Acupuncture efficacy was measured
using score reduction in questionnaires including the Ocular Surface
Disease Index, the Visual Acuity Scale
and quality-of-life scales of subjective
symptomology. Both groups also examined endpoints including tear-film
breakup time and Schirmer’s scores
with anesthesia. One study involved
a four-week course of acupuncture
treatments, and although researchers found no significant differences
between groups at the end of the
treatment period, re-examination at
eight weeks showed statistically significant improvements in both subjective scores and in TFBUT for the
acupuncture treatment group.18 The
study’s use of artificial tears for the
control group further strengthens
these findings.
Sham-needle controls provide the
best means to assess the placebo effect of needle treatments in order to
clearly define the therapeutic benefit of acupuncture. In one study,
three weeks of nine different treatments were compared with the same
number of sham treatments.5 Both
groups demonstrated significant improvements in OSDI and VAS scores,
and TFBUT scores were improved.
However, sham treatments also improved signs and symptoms, again
suggesting a significant placebo effect. The one exception to this was the
TFBUT measures, for which only the
acupuncture group showed significant improvement (3.29 ±1.01 to 4.24
±1.26 sec.). While not an overwhelming endorsement for acupuncture as
a treatment approach, it does suggest that additional studies, including
those with objective endpoints such
as corneal staining or reduced use of
artificial tears, may be warranted.
Sham-needle controls
provide the best
means to assess the
placebo effect of needle
treatments in order
to clearly define the
therapeutic benefit of
acupuncture.
The verdict is still out on acupuncture’s use as a treatment for dry eye;
while we are not ready to adopt a policy of referring dry-eye sufferers for
acupuncture treatments just yet, the
whiff of possible effectiveness is intriguing nonetheless. As long as drugs
with proven efficacy are unavailable,
people suffering with symptoms that
disturb their everyday visual function
will undoubtedly fill the void with alternative therapies. It is essential that
we continue to seek evidence regard-
ing whether any possible treatments,
including those such as acupuncture,
have a potential place in the armamentarium available to treat patients
with dry eye.
Dr. Abelson is a clinical professor
of ophthalmology at Harvard Medical
School. Dr. McLaughlin is a medical
writer at Ora Inc.
1. Kaptchuk TJ. Acupuncture: Theory, efficacy, and practice. Ann
Intern Med 2002;136:374-383.
2. Yang ES, Li P-W, Nilius B, Li G. Ancient chinese medicine and
mechanistic evidence of acupuncture physiology. Pflugers Arch Eur J Physiol 2011;462:645–653.
3. Zhao ZQ. Neural mechanism underlying acupuncture analgesia.
Prog Neurobiol 2008;85:355-75.
4. Dorfer L, Moser M, Bahr F, Spindler K, Egarter-Vigl E,
Giulleń S, et al. A medical report from the stone age? Lancet
1999;354:1023-5.
5. Shin MS, Kim JI, Lee MS, et al. Acupuncture for treating dry
eye: A randomized, placebo-controlled trial. Acta Ophthalmol
2010;88:8.
6. Mayer DJ Price DD Raffii A. Antagonism of acupuncture
analgesia in man by the narcotic antagonist naloxine. Brain Res
1977;121:368-372.
7. Goldman N, Chen M, Fujita T, et al. Adenosine A1 receptors
mediate local anti-nociceptive effects of acupuncture. Nature
Neurosci 2010;13:883-888.
8. Takano T, Chen X, Luo F, et al. Traditional acupuncture
triggers a local increase in adenosine in human subjects. J Pain
2012;13:1215-23.
9. Ernst E. Acupuncture—a treatment to die for? J R Soc Med
2010;103:384-385.
10. Vickers AJ, Cronin AM, Maschino AC, et al. Acupuncture for
chronic pain: Individual patient data meta-analysis. Arch Intern
Med 2012;172:1444-53.
11. Coeytaux RR, Park JJ. Acupuncture research in the era
of comparative effectiveness research. Ann Intern Med
2013;158:4:287-8.
12. Xue CC, English R, Zhang JJ, Da Costa C, Li CG. Effect of
acupuncture in the treatment of seasonal allergic rhinitis: A
randomized controlled clinical trial. Am J Chin Med 2002;30:1-11.
13. Magnuson A, Svensson RE, Leirvik C, Gunnarsson RK. The
effect of acupuncture on allergic rhinitis: A randomized controlled
clinical trial. Amer J Chinese Med 2004;32:105-115.
14. Brinkhaus B, Ortiz M, Witt CM, Roll S, Linde K, Pfab F,
Niggemann B, Hummelsberger J, Treszl A, Ring J, Zuberbier
T, Wegscheider K, Willich SN. Acupuncture in patients with
seasonal allergic rhinitis: A randomized trial. Ann Intern Med
2013;158:4:225-34.
15. Takayama S, Seki T, Nakazawa T, et al. Short-term effects
of acupuncture on open-angle glaucoma in retrobulbar
circulation: Additional therapy to standard medication. Evid Based
Complement Alternat Med 2011;2011:157090.
16. Nepp J, Tsubota K, Goto E, Schauersberger J, Schild G,
Jandrasits K, Abela C, Wedrich A. The effect of acupuncture on
the temperature of the ocular surface in conjunctivitis sicca
measured by non-contact thermography: Preliminary results. Adv
Exp Med Biol 2002;506(Pt A):723-6.
17. Grönlund MA, Stenevi U, Lundeberg T. Acupuncture treatment
in patients with keratoconjunctivitis sicca: A pilot study. Acta
Ophthalmol Scand 2004;82:283-90.
18. Kim T-H, Kang JW, Kim KH, Kang K-W, Shin M-S, et al.
Acupuncture for the treatment of dry eye: A multicenter,
randomised, controlled trial with active comparison intervention
(artificial teardrops). PLoS ONE 2012;7:5:e36638.
7/25/13 3:59 PM
REVIEW
Glaucoma Management
Edited by Kuldev Singh, MD, and Peter A. Netland, MD, PhD
Trabeculectomy Postop:
Staying on Track
With this procedure, the toughest challenges for the surgeon
often occur after the surgery.
By Marlene R. Moster, MD, Philadelphia
rabeculectomies have been
a gold standard glaucoma management tool for many years. So far,
they are still our best way of achieving
a very low intraocular pressure in
a glaucomatous eye. However, the
surgery is associated with numerous
potential complications. That’s why,
when it comes to trabeculectomy, the
follow-up is the hard part.
With that in mind, I’d like to share
some of my post-surgery experience
with thousands of these patients over
the years, in hopes that some of what
I’ve learned may help other surgeons
and patients achieve the best possible
outcomes.
T
Follow-up (When All Is Well)
Once the trabeculectomy itself is
complete, I usually see the patient the
following day and then a week later
to adjust the releasable sutures. After
that, depending on the IOP, I’ll see
the patient either one or two weeks
later, because by three weeks—except
in a hypotonous situation—all the
conjunctival and releasable sutures
are usually out.
I aim to keep the IOP at around
15 to 20 mmHg on postop day one;
this allows vision to return to normal
(or close to normal), so the patient
can resume daily activities. In most
cases pressure is slightly elevated
relative to the goal, which is ideal at
that point because we want to avoid
hypotony. Depending on my pressure
goal, a releasable suture can be cut
as early as the first day or within the
first three weeks. (My goal is usually a
50-percent drop in IOP.)
Suture removal is done at the slit
lamp with a needle or a blade, and
jeweler’s forceps. Occasionally, if the
pressure is elevated, I’ll use a laser
with either a Blumenthal or Hoskins
lens to cut the internal sutures.
However, I usually reserve the laser
for later in the postoperative period,
because in most cases the pressure
can be controlled by removing a
single releasable suture; the flow is
increased immediately and the IOP
comes down.
I generally keep the patient on
antibiotic drops for a week, with
steroids q.i.d. for two weeks, t.i.d.
for two weeks, b.i.d. for two weeks,
and once a day for two weeks before
stopping. I also prescribe an NSAID
064_rp0813_gm.indd 64
once a day for at least six weeks.
(Note: I don’t prescribe an NSAID
with the steroid if the eye has a lot of
corneal epithelial irregularity.)
One reason I continue NSAIDs for
this length of time is that I believe
that low levels of inflammation, leading to scarring, are a significant cause
of trabeculectomy failure. This is
something that might not be easily
noted at the slit lamp, but the NSAID
will help to prevent or alleviate it.
We also encourage the patient to use
tears, to keep the eye comfortable.
If all is well at three weeks, I’ll see
the patient again in a month, or he’ll
return to the referring doctor. If all
is not well, then I see the patient as
often as is needed.
Postop Examination
When you see the patient on the
first day postop, it’s crucial to be a
careful observer, because there’s
no other way to be sure everything
is as it should be. For example, if
the patient’s vision is perfect on
postoperative day one, that usually
means the pressure is not low enough.
On the other hand, blurry vision could
7/25/13 4:27 PM
All images: Marlene R. Moster, MD
Left: Excellent low, diffuse bleb with a healthy display of blood vessels; IOP is 9 mmHg. Center: A choroidal detachment following
trabeculectomy. Right: A grade III flat anterior chamber. This is an emergency and must be re-formed, as there is corneal involvement with
decompensation.
mean a number of different things.
Perhaps the pressure is too low, or
at the expected level, or perhaps
even too high with corneal edema
or with blood blocking the osteum,
causing the pressure to rise. That’s
why it’s critical to carefully check the
cornea, the anterior chamber depth,
the amount of inflammation and
subconjunctival hemorrhage and how
much blood is near the superior flap.
It’s also important to know which
signs are relatively insignificant. For
example, a dense inferior subconjunctival hemorrhage may look awful,
but it won’t have any negative consequences as long as the superior
trabeculectomy is not affected. The
blood will resorb within 10 days.
Signs you want to look for on the
first day postop include corneal
edema, indicating that the pressure’s
too high, and endothelial folds, which
indicate that the pressure’s too low.
The latter is usually associated with
shallowing of the anterior chamber.
Managing a Shallow Chamber
Shallowing of the anterior chamber
often occurs when the IOP goes
from high to low. Simultaneously,
you may see the development of a
choroidal detachment, fluid in the
suprachoroidal space that pushes
the lens-iris diaphragm forward and
further flattens the chamber. It’s a
vicious cycle, because one feeds into
the other.
A shallow anterior chamber calls
for different levels of response,
depending on the severity. The
severity is graded at four levels: Grade
0 means the chamber is shallow but
the endothelium isn’t touching any
other tissues, even at the periphery;
grade 1 suggests that there’s peripheral touching, but the chamber is
still formed everywhere else. If the
chamber is between grades 0 and 1,
we just follow the patient carefully,
seeing him at one week and every
week thereafter.
Grade 2 implies that the endothelium is touching the mid-iris but
not the pupil; grade 3 means the
endothelium, lens and iris are all
touching. Grade 2 is very serious because it can get worse and become
grade 3. To restore the anatomy and
remove the threat of a grade 3 chamber, we usually re-form the chamber
at the slit lamp, with informed consent from the patient. We insert a
speculum, apply antibiotics and betadine, and then inject viscoelastic
through the paracentesis using a
30-ga. needle. Grade 3 is a medical
emergency; you need to reform the
anterior chamber immediately. If the
chamber is grade 2 or 3, we see the
patient every day, or every couple
of days, to make sure the chamber
doesn’t become even more shallow.
Whenever there’s a shallow chamber, you should dilate the pupil to
move the lens-iris diaphragm back.
Moving the lens-iris diaphragm
backwards may jump-start the
ciliary body to make more aqueous,
thereby deepening the chamber
and raising the pressure. About 80
percent of the time this will cause the
choroidal detachment to disappear.
To accomplish this, we usually use
atropine 1%, two to three times a
day. (However, we avoid atropine in
patients who have prostate issues.)
We always check to see if there are
choroidals when the pressure is low;
if there are, we explain to the patient
that 80 percent of the time this will
heal by itself. We monitor the patient
every week or every two weeks, if the
chamber is not excessively shallow.
About 20 percent of the time we
need to intervene and drain the
choroidal detachment in the OR.
Doing so usually encourages the
ciliary body to produce more aqueous, reestablishing the anterior chamber depth and improving vision. In
addition, we usually increase the
steroids and make sure there’s no
leak causing the hypotony. Then,
we always instruct the patient not
to rub the eye and to use a shield at
night. All these preventive measures
should encourage the eye to become
pressurized once again. Because
this is often a long, drawn-out affair,
we want to prevent this whole cycle
by keeping the pressure between
15 and 20 mmHg early on in the
postoperative period.
Most of the time, we can tell
which patients are in danger of
064_rp0813_gm.indd 65
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063_rp0711Reviews_Platter.indd 1
6/14/11 9:35 AM
REVIEW
Glaucoma
Management
developing a shallow chamber
any question of vitreoretinal
by the amount of flow coming
adhesions, our retinal colleagues
through the trabeculectomy flap.
take over.
If after pressuring the eye with
BSS through the paracentesis
Managing a Bleb Leak
we notice that there’s too much
egress of aqueous or BSS through
Ultimately, you want a low,
the flap, that’s a warning sign
diffuse, minimally vascular bleb
to either put more permanent
without any leaks. In reality, of
sutures in, tie the flap tighter, or
course, bleb leaks can occur
put in a few releasable sutures to
early or late in the postoperative
restrict the egress.
period, and there are a number
A Seidel-positive leaking bleb. The hole is on the dome
On the other hand, sometimes of the bleb; the tissue is thin and friable. Conjunctival
of different ways to deal with
a shallow chamber catches us by advancement was used to repair the leak.
them. In recent years there’s
surprise; there doesn’t seem to be
been a move toward fornixa lot of flow when we check the bleb, 1% lidocaine and subconjunctival based surgery, since it provides a
but in the postoperative period the lidocaine. That strategy allows us to more diffuse bleb; as a result, conpressure is lower than we expected. stop any bleeding because we can see junctival sutures at the limbus are
In fact, sometimes the eye shuts down it if it happens.
now part of the picture. These sualtogether when the pressure starts
Sometimes when the IOP goes from tures occasionally leak, which can
very high and drops after surgery. The high to low a patient will develop a lead to a shallow anterior chamber,
eye may simply stop making aqueous, suprachoroidal hemorrhage instead of a hypotonous situation and failure of
causing the pressure to drop very low just a choroidal detachment, which is the bleb.
despite all of our efforts.
Any bleb leak requires intervention;
very serious. In fact, a suprachoroidal
Fortunately, most of the time we do hemorrhage can often be diagnosed the rate of endophthalmitis is 1 perhave a good idea which patients are at over the phone. The patient will be cent per year in the presence of a
risk of hypotony, and we make every sitting in the kitchen glancing up at leaking bleb. For this reason, one of
effort to avoid that outcome during the clock, and exactly at 10:02, she’ll the steps glaucoma surgeons need to
the surgery. In general, I’d say we experience extreme pain in the eye. go through every time they examine
encounter hypotony about 5 percent The patient can often tell you exactly patients post-trabeculectomy is checkof the time.
what she was doing when it occurred. ing for bleb leaks, usually using the
When we hear a story like that, we Seidel test.
If a bleb leak is noted in the early
have a good idea what the diagnosis
Managing Hemorrhages
is. We see the patient the next postoperative period, caused by a gap
Hemorrhages are a part of life morning and sure enough, the eye between the sutures or a retraction
when performing trabeculectomy. has had a significant bleed. If we’re of the conjunctiva, the most common
That’s partly because most of these lucky, it wasn’t so significant that it treatment is a bandage contact lens or
patients are older individuals who broke through the retina into the monitoring, to give the leak a chance
are on blood thinners such as Plavix, vitreous cavity, and it’s contained in to heal. Sometimes if mitomycin gets
to the edge of the conjunctiva it will
Coumadin or just aspirin—sometimes the suprachoroidal space.
When this occurs, I usually be slower to heal—or simply will not
a combination—for various systemic
reasons, most of which are pretty have a retina colleague check out heal—and the flap may require an
serious. In my practice, I don’t the patient as well, to make sure additional suture. This is pretty rare
have patients stop taking their there’s no vitreoretinal adhesions in our practice because we check the
blood thinners. But I also don’t use if the choroidals are kissing, which wound carefully at the end of the
peribulbar blocks, so there’s a bit of might lead to further retinal issues. trabeculectomy. Even if it does occur,
a safety factor there, in that we’re Often, these hemorrhages need to it’s not the end of the world because a
not giving any needles in locations be drained, but we usually wait 10 contact lens will often heal it. I usually
where we can’t see what’s happening. days for the blood to liquefy. If the choose a plano bandage lens and
Instead, we use a blitz anesthesia choroidals are not kissing, then the leave it in place for about two weeks,
technique combining topical lidocaine glaucoma doctor usually drains them checking the patient at one week and
2% jelly, intracameral nonpreserved and reforms the chamber. If there’s maintaining antibiotic use whenever
064_rp0813_gm.indd 67
7/25/13 4:28 PM
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3/7/12 1:27 PM
REVIEW
Glaucoma
Management
Overfiltration of a bleb causing tearing and
decreased vision. Compression sutures can
help with bleb dysesthesia.
the contact lens is on.
If a bleb leak occurs later in the
postoperative period, it’s a very
different matter. The seriousness of
that type of leak depends on where
the leak is, and how easy it is to fix.
Sometimes autologous blood injected into the dome of the bleb
will help to close the hole. About
50 to 60 percent of the time a very
large bandage contact lens such as
the Kontur lens (Hercules, Calif.),
can cover the hole. Occasionally,
we initiate aqueous suppressants to
decrease the flow and encourage
the hole to heal. If the patient has
to be brought back to the OR, conjunctival advancement will often
help; compression sutures might also
encourage it to heal.
During the healing process we
have patients use antibiotic drops.
However, I don’t recommend using
them for a long time because over
time they’ll self-select for bacteria
that are resistant to the antibiotic.
possibility of blebitis. If a patient
presents with irritation or redness,
that’s definitely a warning sign. When
any of these signs are present, we
look very carefully for a leak, and/
or a purulent discharge in or around
the bleb. (The most common bacteria responsible for blebitis are
Staphylococcus and Streptococcus,
which are gram-positive.)
A hypopyon tells us that there
may be endophthalmitis, probably
originating from the bleb. When
there are cells in the vitreous as well
as the anterior chamber, the diagnosis
is very clear. This is an emergency,
because endophthalmitis can lead
to a rapid downward spiral toward
blindness.
When we observe these signs,
an alarm goes out. In this situation
the patient is treated with fortified
antibiotics or fluoroquinolone every
hour. If possible, the aqueous is
cultured. A retina specialist usually
sees the patient, and may perform a
tap-and-inject treatment. The patient
will have an ultrasound to determine
the level of cells in the vitreous cavity.
Once it’s clear that the infection is
under control, we begin steroids to
quiet the eye down and hopefully save
the bleb.
Post-surgery Patient Advice
Our advice to patients following
trabeculectomy is routine: no eye
rubbing, and they need to wear the
shield for at least one week post-
A vascularized bleb in a noncompliant
patient who did not use postoperative
steroids as directed.
surgery. If there’s blood in the eye, I
discourage any bending; the patient
should sleep with extra pillows so
the blood can settle inferiorly and
then dissipate. We don’t encourage
swimming during the first week or so
while the stitches are still in place, or
any weight-lifting or yoga during this
period, although aerobic exercise is
OK. Patients can resume showering,
shaving and shampooing almost immediately after surgery.
Perhaps most important, we tell
patients that if their vision changes,
they should call us immediately. Since
we’re worried about spontaneous
bleeding, we’re worried about infection. Luckily, it’s rare that we get a
call like this; more commonly we get
a call reporting discomfort, tearing
or scratching. But among those calls
there are occasionally some very serious ones, so we always encourage our
patients to call us immediately if they
notice any significant change.
When a Bleb Is Failing
Managing Infection
That brings us to a complication all
surgeons dread: infection. Infection
is always a serious matter, whether
the bleb alone is infected (blebitis)
or the chamber has become involved
(endophthalmitis). When a patient
complains of itching in the operated
eye, that tells me that there may be
a small leak somewhere, raising the
A case of blebitis that has evolved into
endophthalmitis.
Unfortunately, bleb failure is not
uncommon, no matter how perfectly
the surgery is done. Usually we allow
two to three months before deciding
whether a bleb is a success or has
failed. Obviously, if the pressure goes
up at three to four weeks, we have to
be on the lookout for continued rise
in pressure, but this is often just a
Tenon’s cyst that needs to soften, in
064_rp0813_gm.indd 69
7/25/13 4:28 PM
SAVE THE DATE
2013
CALENDAR
CONTINUING PROFESSIONAL EDUCATION
The Continuing Professional Education (CPE) Ophthalmology programs are CME activities designed to complement
third-year ophthalmology residency medical education as well as Glaucoma fellows programs. 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-ofthe-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.
GLAUCOMA FELLOWS
September 27-28, 2013
Fort Worth, TX
Course Director:
October 18-19, 2013
Fort Worth, TX
Course Director:
Anthony C. Arnold, MD
Kuldev Singh, MD
Professor & Chief, Neuro-Ophthalmology
Division, Jules Stein Eye Institute,
Department of Ophthalmology
University of California, Los Angeles
Professor of Ophthalmology and
Director ofGlaucoma Service at
the Stanford University
School of Medicine, California
For more information and to register
Online: www.revophth.com/ResFellowEdu2013
Email: [email protected] 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.
These activities have been approved for AMA PRA Category 1 Credit(s)TM.
Jointly sponsored by:
070_rp0613CPEcal_new.indd 86
Supported by an independent
medical educational grant from:
7/19/13 10:47 AM
REVIEW
Glaucoma
Management
A thin-walled cystic bleb surrounded by a
“ring of steel” or fibrosis with increased
intraocular pressure.
which case we place the patient back
on glaucoma medication and wait.
A bleb that’s failing can often
be revived by needling it with
mitomycin C. However, the best
success with needling is usually
long after the trabeculectomy has
been established—usually a year
or more. At that point, we have a
64-percent success rate of bringing
a trabeculectomy back to life. If a
trabeculectomy fails early, needling
the bleb generally will not yield a
successful result. In the meantime,
if I notice that the eye is excessively
red and there are blood vessels in the
conjunctiva, and I’m fearful that the
bleb will fail, I will sometimes give
an Avastin injection into the bleb. (Of
course, this is off-label.)
Occasionally the trabeculectomy
will start to fail as early as six weeks.
If that happens, depending on the
health of the optic nerve and the
visual field, we may need to move on
to another management approach. In
that situation, we usually wait until
the eye totally quiets down, within
about two months. Then we reassess
the situation. If the trabeculectomy
has definitely failed, I would consider
an ExPress shunt on either side of the
eye, if possible, or move on to a tube
shunt if necessary.
Helpful Points to Remember
A few things to keep in mind when
managing trabeculectomy patients:
• Make patients aware of
potential complications beforehand. Patients who are going into
the surgery with very high IOPs,
for example, should be warned that
they are at a greater risk of having
the eye shut down and stop making
aqueous postop. (You should also
make it clear that you’re going to do
everything possible to prevent this
from happening.)
• Make sure the patient has
realistic expectations regarding
cataract. The patient needs to understand that a minimal cataract may
progress following the trabeculectomy.
• Consider removing an existing cataract during the trabeculectomy. We often do this as a way
to improve vision in addition to
controlling the IOP, since cataract
surgery in this select subpopulation
is inevitable and is often best treated
with a single trip to the OR.
• If the patient’s vision is perfect
on postop day one, don’t assume all
is well. As noted earlier, this probably
indicates that the IOP is higher than it
should be and needs to be addressed.
• Keep the focus on visual rehabilitation. It’s very important
to get people back to their normal
activities as quickly as possible, and
not just focus on the IOP. Sometimes
the patient’s refraction changes after
the surgery, so you should discuss this
with the patient beforehand.
Postop, we remove the releasable
and conjunctival sutures by three
weeks and encourage a re-refraction,
if needed, as long as everything
is stable. I like to make sure that
patients are refracted and back to
daily activities quickly, and engaging
in all work activities by six to eight
weeks at the latest.
• Be on the lookout for subtle
bleb leaks. Not every leak is obvious,
but the consequences can still be
serious. So, always check for a leak,
even if all seems well.
A scarred but still functioning bleb. The IOP
was acceptable at 17 mmHg with the
addition of a beta blocker.
• Consider pre-placing the
scleral sutures before the sclerostomy. Trabeculectomies can
sometimes trigger the development
of against-the-rule astigmatism.
One way we prevent that in the OR
is by pre-placing the scleral sutures
before taking out the block. That
way, when the eye softens the sutures
are in place, so we don’t induce any
additional astigmatism.
• Consider not using an anesthetic block. This will avoid the
possibility of unseen hemorrhages
that might be caused by the injection.
Better Options: Coming Soon?
I’m tremendously encouraged by
all of the research into ways to lower
IOP by maximizing outflow without
making a bleb. The problem is that
so far there’s no one procedure
that will lower IOP sufficiently in
patients who need a very low, singledigit pressure—at least none reliable
enough to become the new gold
standard. So for now, trabeculectomy
is still the go-to surgery for these
patients. It’s imperfect, but when
compared to blindness, the risks are
definitely worth taking.
Dr. Moster is a professor of ophthalmology at Thomas Jefferson
University School of Medicine and
an attending surgeon at Wills Eye
Institute’s Department of Glaucoma.
064_rp0813_gm.indd 71
7/25/13 4:28 PM
REVIEW
Refractive Surgery
Edited by Arturo Chayet, MD
How to Dodge Femto
Flap Complications
Though these lasers have an excellent track record, surgeons
need to be ready when something unwanted rears its head.
urgeons who use a femtosecond laser to create their LASIK
flaps are used to pristine dissections,
but they acknowledge that they can
occasionally run into complications,
even when using the most high-tech
laser flap makers. Suction can be lost,
patients can have a pre-existing scar
or their epithelium can slough, resulting in problems. Here, several surgeons tell how you can avoid common
femtosecond flap complications, and
manage them if they occur.
S
Suction Breaks
Surgeons say suction loss can result from a number of factors, but it
doesn’t have to bring an end to the
case.
“There are three main causes for
suction loss,” says Chicago surgeon
Surendra Basti, user of the IntraLase.
“The most common reason is that you
didn’t place the suction ring properly
the first time, so making an adjustment
can be useful in certain patients. In patients with narrow palpebral fissures,
sometimes space is limited. If you turn
the patient’s head away from the eye
that’s having surgery, that causes the
eyeball to rotate away from the nose,
and creates a little extra space to place
the suction ring.
“The second reason suction is lost is
if a patient is a lid-squeezer,” Dr. Basti
continues. “Sometimes, as soon as you
separate the lids to put the suction
ring in, he starts to squeeze. If you
prompt the patient not to do that and
add an anesthetic drop, that can help
keep the eye anesthetized and help
keep him from squeezing the lid shut.
Also, putting a little anesthetic in the
fellow eye and prompting the patient
to keep it open can actually facilitate
keeping the surgical eye open.
“The third common cause of suction loss is something that the surgeon
can’t do much about, unfortunately,”
says Dr. Basti. “Sometimes patients
just have loose, boggy conjunctiva. In
these cases, the conjunctiva closes the
suction port rather than the eyeball itself, giving pseudo-suction. When this
happens it’s challenging, and it’s not
always possible to work around it. If
you’re not able to do the case in such
a patient, you can instead perform a
surface ablation.”
Rochester surgeon Scott MacRae
uses the Ziemer femtosecond laser,
072_rp0813_rs.indd 72
which uses a handpiece on an articulated arm to deliver the energy to the
cornea. “Getting the handpiece onto
the cornea and getting it centered take
a bit of moving and angulation of the
patient’s head,” Dr. MacRae says. “Often, I’ll have my assistant push down
slightly on the lid speculum to get
more clearance if it’s a small orbit.”
Dr. MacRae notes that a special lid
speculum, the ASICO AE1016 speculum, has been “fabulous” for helping
to get the eye open to achieve suction.
“It has 10-mm blades to open the lids
wider, and a hexagonal shape to better
fit the Ziemer’s suction ring,” he says.
Vancouver, Wash., surgeon Brian
Will says that, though he doesn’t usually use a speculum, he may use an
open-wire lid speculum if there’s a lot
of redundant conjunctiva. The speculum’s design “tends to shove the conjunctiva back to the fornix, and gives
you better exposure to get the vacuum
ring into the eye,” he explains. “Another thing that really helps is using some
downward compression, particularly if
you’ve lost vacuum. Retropulsing the
globe, so to speak, sort of forces the
eye back into the orbit. In these cases,
I’ll release the snapper that clips the
7/25/13 4:00 PM
pincers open and leave the pincers
closed. That way, I can bring the cone
down and use it to push the globe back
a bit. I then gently crack the pincers
open a little just to get the cone to start
moving down into the docking port.”
Managing the result of a suction
break varies depending on when it
occurs during the case, say surgeons.
“If a suction break occurs early, such
as with a squeezer, you don’t have
to change anything,” says Dr. Basti.
“Redo the placement of the suction
ring and restart the laser. But if it occurs once the laser is working on the
eye, especially if it’s gone past the first
few millimeters, it’s more challenging.
If the laser hasn’t gone well into the
cornea, and you’re just starting the
procedure, changing the suction ring,
but not the cone, is a good strategy.
Sometimes these rings are defective.
“If the break occurs when half the flap
has been created, you can’t complete
the case,” Dr. Basti adds. “Your choices are to abort and do surface ablation
or redo the flap creation. If you choose
to make a new flap, you have to start
deeper than the original one, at least
40 to 50 µm deeper, as long as there’s
adequate corneal thickness. However,
when you then try to lift the new flap,
be careful. You want to be in the plane
of the new flap, not the partial one. I
find it’s useful to enter the interface
of the new flap distal to the aborted
flap’s edge.”
Surgeons say if the suction break
occurs during the creation of the
side cut, you can place the ring again
and program the laser to do only the
side cut. To help ensure the cut isn’t
made outside the diameter of the flap,
surgeons recommend programming
the laser to make the side cut 0.2 to
0.3 mm smaller than the flap.
A String of Pearls
In addition to methods for dealing
Surgeons say getting the Ziemer’s
handpiece centered on the eye may take
some movement of the patient’s head.
with suction loss, surgeons also have
several techniques they use to avoid
complications in other phases of flap
creation.
• Chilled, neutral proparacaine.
Dr. Will says that using chilled proparacaine that’s pH-neutral is helpful
in avoiding epithelial sloughing. “Proparacaine ships from its maker with a
4.5 pH—very acidic,” he says. “This is
to keep it active for as long a period
as possible, but it’s not helpful for the
eye. We instill 15 drops of 0.1 mmol
sodium hydroxide per bottle, which
will bring most proparacaine solutions
to a pH of 7. This markedly changes
the negative effect of the proparacaine
on the epithelium. Also, we have our
proparacaine shipped to us on ice and
then we freeze it solid—the maker
doesn’t condone this but it doesn’t say
you can’t do it, either. Then, the day
before surgery, I thaw the bottles I
want to use. Chilling the proparacaine
and titrating its pH to neutral keeps
the epithelium a lot healthier postop,
and it minimizes the inflammatory
mediators being released by the epithelium. Also, if you get some loose
epithelium during the case, this preparation means you will almost never see
that turn into a basement membrane
issue or recurrent erosion.”
• Lifting the flap. Dr. MacRae
says occasionally he’ll encounter ar-
eas of the flap that are difficult to
lift. “Rather than ripping across that
area, take the instrument you’re using
for separation and come at the area
from multiple directions,” he advises.
“Come from the right, the left, above
and below. That will slowly weaken the
area that’s bound down.”
For retreatments where you’re relifting the flap, Dr. MacRae developed
the MacRae flap flipper (ASICO), in
which he has no financial interest. He
adds that the Storz E9103 instrument
is similar and works well, also. “The
flipper is like a dandelion digger, with
sharp inner blades,” he explains. “You
sort of ski along the edge of the flap
with it, and it cuts the edge where the
epithelium is and separates the flap
from the bed. However, one of the
problems with this approach is you
get some scrolling of the epithelium,
which causes an epithelial defect. So,
when I do a relift, rather than using
the cutting edge of the flap flipper, I
get into the interface with it and then
lift it slightly, doing what I call ‘localized lifts’ that gradually lift the flap
from the bed. This method avoids
scrolling and the possible epithelial
ingrowth that can occur in the area of
the epithelial defect.”
• Corneal scars. If a patient has
a pre-existing scar, the LASIK can
still be successful, say surgeons. “The
key is understanding what caused the
scar,” says Dr. Will. “If it’s herpetic,
don’t operate. If it’s from trauma, get
a sense of how deep and opaque it
is at the slit lamp. If you can’t determine that at the slit lamp, the OCT
or Pentacam might help. During the
surgery, I usually want to cut the flap
below the scar if I can, depending on
the corneal thickness and the amount
of treatment. However, if it’s a mild to
moderate scar, a new laser like the iFS
or the 60 kHz IntraLase can cut right
through it. If it’s denser, though, try to
go deeper if possible.”
072_rp0813_rs.indd 73
7/25/13 4:01 PM
REVIEW
Research Review
Bevacizumab for ROP:
Refractive Error Results
n interventional comparative
study of refractive error in infants
who underwent a single intravitreal
bevacizumab injection for treatment
of threshold retinopathy of prematurity suggests that, compared to conventional retinal laser coagulation, bevacizumab is helpful therapy leading to
less myopization and less astigmatism.
The study group included 12 infants
(23 eyes; mean birth weight: 622 ±153
g; gestational age: 25.2 ±1.6 weeks)
who received a single injection of intravitreal bevacizumab (0.375 mg or
0.625 mg) for threshold ROP in fundus zone one or zone two. The control
group included 13 infants (26 eyes;
birth weight: 717 ±197 g; gestational
age: 25.3 ±1.8 weeks) who had previously undergone retinal argon laser
therapy of ROP. The groups did not
differ significantly in birth age, weight
or follow-up. The follow-up examination included refractometry under
cycloplegic conditions.
At the end of follow-up at 11.4 ±2.3
months after birth, refractive error
was less myopic in the study group
than the control group (-1.04 ±4.24
vs. -4.41 ±5.50; p=0.03). Prevalence
of moderate myopia (17 percent ±8
percent vs. 54 percent ±10 percent;
p=0.02) and high myopia (9 percent
±6 percent vs. 42 percent ±10 percent; p=0.01) was significantly lower
in the bevacizumab group. Refractive
astigmatism was also significantly low-
A
er in the study group (-1.0 ±1.04 D vs.
1.84 ±1.41 D; p=0.03). In multivariate analysis, myopic refractive errors
were significantly associated with laser
therapy vs. bevacizumab therapy.
Am J Ophthalmol 2013;155:11191124.
Harder B, Schlichtenbrede F, Von Baltz S, Jendritza W, et al.
Glaucomatous Progression in
Patients with Ocular Hypertension
esearchers at the Devers Eye
Institute longitudinally followed
168 individuals (336 eyes) with ocular hypertension or early glaucoma to
determine clinical features of optic
disc progression. Their results indicate that eye-care providers should
pay particular attention to increased
excavation and neuroretinal rim thinning in these patients–especially in
the inferotemporal quadrant.
Two glaucoma specialists independently graded the baseline and most
recent optic disc photographs for optic disc progression, as well as location
of changes. Optic disc progression
was defined as: new or increased neuroretinal rim thinning (two or more
clock hours); notching (one clock hour
or less of thinning of the neuroretinal
rim); excavation (undermining of the
neuroretinal rim or disc margin); and
nerve fiber layer defect(s).
Of the 336 eyes, 92 (27.4 percent)
showed optic disc progression after
a median of 6.1 years. Of those with
R
074_rp0813_rr.indd 74
progression, excavation occurred in
89 percent of eyes; rim thinning occurred in 54 percent of eyes; and
notching occurred in 16 percent of
eyes. In the cohort, 56 percent had
two or more features of progression.
The inferotemporal quadrant was the
most common location for progression, but more than one location of
progression occurred in at least 30
percent of eyes.
J Glaucoma 2013;22:343-348.
Lloyf M, Mansberger S, Fortune B, Nguyen, Torres R.
Safety Testing Results for
Epimacular Brachytherapy
pimacular brachytherapy did not
produce deleterious effects on
macular function or choroidal perfusion, tested using microperimetry and
indocyanine green angiography. Wet
AMD areas receiving higher doses
of radiation showed greater improvement in retinal sensitivity. The presence of a dose-response suggests the
positive effect of epimacular brachytherapy related more to beta irradiation than vitrectomy.
A prospective intervention case series of 12 participants with neovascular AMD requiring frequent ranibizumab underwent vitrectomy and
epimacular brachytherapy. The Strontium 90/Yttrium 90 source delivered
a single 24-Gy dose at the center of
the treatment zone. The dose attenuated with increasing distance from
E
7/25/13 4:12 PM
the source. Microperimetry and indocyanine green angiography were performed at baseline and at 12 months.
The main outcome measures were
mean sensitivity and choroidal nonperfusion. A linear mixed model was
used to assess the association between
the dose of radiation and the change
in mean sensitivity.
Mean visual acuity remained within
one letter of baseline at 12 months
(-0.33 ±13.2 letters). There was no
statistically significant change in
mean sensitivity within the neovascular AMD lesion area (gain of 0.95,
±3.25 dB; p=0.0339) or in neighboring unaffected retina (0.66 ±4.14 dB;
p=0.594), defined using fluorescein
angiography. Within the lesion area,
mean sensitivity improved by an average of 0.23 ±0.16 dB (p=0.006) for
every additional gray of radiation received. Indocyanine green angiography failed to demonstrate any choroi-
074_rp0813_rr.indd 75
dal nonperfusion or radiation damage
at 12 months after the treatment.
Retina 2013;33:1232-1240.
Petrarca R, Richardson M, Douri A, Nau J, et al.
Kamra Corneal Inlay Implant to
Treat Presbyopia After LASIK
ix-month results evaluating visual outcomes after the implantation
of a Kamra small-aperture corneal
inlay into a femtosecond-created corneal pocket to treat presbyopia in patients who had previous LASIK suggest that the implant improves near
vision with minimal effect on distance
vision. This results in high patient
satisfaction and less dependence on
reading glasses, researchers say.
The study enrolled 223 eyes of 223
post-LASIK presbyopic patients with
a mean age of 53.6 years (r: 44 to 65
years) and a mean manifest spherical
equivalent of -0.18 D (r: -1.0 to
+0.5 D). The inlay was implanted
S
into a corneal pocket created by a
femtosecond laser at a depth of 200
µm, a minimum of 80 µm below the
previous LASIK flap interface, in the
nondominant eye. Uncorrected and
corrected distance visual acuities,
near visual acuity, and a patient
questionnaire on satisfaction, the
use of reading glasses and visual
symptoms were evaluated.
The mean uncorrected distance
visual acuity in the operated eye decreased one line from 20/16 preop to
20/20 six months postop (p<0.001).
The mean uncorrected near visual
acuity improved four lines from Jaeger 8 to J2 (p<0.001). At six months,
significant improvements were observed in patient dependence on
reading glasses and patient satisfaction of vision without reading glasses.
J Cataract Refract Surg 2013;39:
898-905.
Tomita M, Kanamori T, Waring G, Nakamura T, et al.
7/26/13 11:06 AM
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REVIEW
Wills Eye Resident Case Series
Edited by Matthew Dykhuizen, MD
After initial success with treatment for bacterial keratitis, a young
man’s condition dertiorates, prompting a visit to the Cornea Service.
Nina Ni, MD
Presentation
A 35-year-old man presented to the Wills Eye Institute’s Cornea Service complaining of two weeks of pain, light sensitivity and decreased vision in the left eye. Prior to his referral he was treated for bacterial keratitis for two weeks with initial
improvement. After tapering off antibiotic drops, he returned 10 days later complaining of redness and decreased vision. At
this point, he was started on gatifloxacin drops every hour, prednisolone four times daily, and referred to Wills Eye Institute
for further management.
Medical History
Past ocular history was significant for keratoconus in both eyes. He wears daily wear soft contact lenses in the right eye and
a hybrid contact lens in the left eye. He denied any history of trauma, swimming, hot tub use or showering with his contact
lenses. He had no past medical history, prior medication use or allergies.
Examination
Christopher J. Rapuano, MD
Ocular examination revealed corrected visual acuity of 20/25 in the right eye, uncorrected visual acuity of 20/400 in the
left eye. Pupils were equal and reactive to light. Intraocular pressure was 18 mmHg in the right eye and 19 mmHg in the
left eye. Visual fields were full to confrontation and extraocular movements were full in both eyes.
On slit lamp exam, the right cornea showed keratoconus with a Fleisher ring and inferior pannus. Examination of the left
cornea revealed a triangular infiltrate measuring 0.8 x 1.0 mm, with fine satellite infiltrates superiorly, inferior stromal edema
and large white keratic precipitates. The anterior chamber had 3+ white blood cells but no hypopyon (See Figure 1). The
posterior exam was unremarkable.
Figure 1. Slit-lamp photos demonstrate 0.8 x 1.0 mm infiltrate, with fine satellite infiltrates
superiorly, stromal edema and large white keratic precipitates. No hypopyon was noted.
What is your differential diagnosis? What further workup would you pursue? Please turn to p. 80
079_rp0813_wills.indd 79
7/25/13 3:52 PM
REVIEW
Resident Case Series
Before reading on, please see p. 79 for presenting complaint, history and examination.
Diagnosis, Workup and Treatment
Christopher J. Rapuano, MD
the infiltrate remained. His intraocular pressure increased to 24 mmHg.
At this time, additional treatment
for fungal keratitis was initiated with
oral voriconazole, and IOP-lowering
agents were started. Despite this aggressive therapy he failed to improve.
Given the lack of improvement
he underwent intrastromal injection
of voriconazole. Five small aliquots
of voriconazole (50 micrograms in
0.1 ml) were injected into the midstroma using a 27-ga. needle to surround the infiltrate. The total dose
was approximately 0.10 to 0.15 ml.
Amphotericin drops once every two
hours around the clock were added.
Several days later, examination revealed an area of corneal thinning
and cystic bulging at the center of the
infiltrate, signaling impending perforation (See Figure 2). The following
day, the patient underwent an urgent
penetrating keratoplasty, with half
Ralph C. Eagle Jr., MD
The differential diagnosis included
inadequate treatment of bacterial
keratitis, fungal keratitis, acanthamoeba keratitis and atypical mycobacteria keratitis. The patient opted to
undergo corneal culture, while starting fortified tobramycin and cefazolin every hour around the clock, and
scopolamine twice daily. On followup three days later, the vision in the
left eye decreased to count fingers
at 1 foot, and the anterior examination revealed a new, 1.4 x 1.4 mm
epithelial defect, with the infiltrate
increasing to 2.0 x 3.1 mm, and a new
hypopyon of 0.5 mm.
The corneal culture did not demonstrate any growth. However, given
the suspicion for fungal infection,
topical voriconazole 1% was started.
Four days later, his vision further
decreased to hand motion. His epithelial defect had resolved, but the
hypopyon increased to 1 mm and
Figure 3. Gomori methenamine silver stain
of corneal button and anterior chamber
contents after penetrating keratoplasty,
demonstrating septate fungal hyphae
among inflammatory debris.
the corneal button sent to pathology
and half the corneal button sent to
microbiology. He continued the topical and oral voriconazale and topical
amphoteracin.
Pathology revealed fungal elements in the cornea and in the anterior chamber hypopyon (See Figure 3). The culture was negative. By
postoperative week two
there was no evidence
of residual or recurrent infection so steroids were started and
antifungals tapered. He
continued to improve
without episodes of infection or rejection, and
by postoperative month
seven, his refraction was
-4.75+1.00x155 with a
best corrected visual
Figure 2. Slit-lamp photos demonstrate larger infiltrate with anterior chamber hypopyon, as well as a
central area of corneal thinning and cystic bulging, signaling impending perforation.
acuity of 20/40.
Discussion
Fungal keratitis is more commonly
seen in developing nations and tropical
climates. Annual incidence in North
America is approximately 1,500 cases
per year.1 Common fungal organisms
can be divided into filamentous and
non-filamentous. The most common
filamentous fungi include Fusarium
and Aspergillus species. In North
America, the most common cause of
fungal keratitis is the yeast Candida.
Risk factors for filamentous fungal in-
7/25/13 3:52 PM
fection include trauma, especially if
plant matter is involved. Non-filamentous organisms are more commonly
seen in patient with diabetes and other
immunocompromised states. Signs of
fungal infection which may differentiate it from bacterial infection include
feathery borders with satellite lesions,
and deep stromal and anterior chamber invasion. Progressive corneal thinning or perforation may occur in the
setting of unrecognized and thus improperly treated ulcers.
The diagnosis of fungal keratitis is
often delayed, as it may be difficult to
recognize and is often initially treated
as a bacterial infection. For patients
with the above risk factors who do not
improve on topical antibiotics, especially fortified agents, fungal etiologies
should be suspected. Corneal scraping for smears and cultures, including for fungus, should be obtained.
Corneal biopsy can also be considered
if scrapings fail to help determine the
causative agent. Biopsy can be up to
83 percent sensitive in identifying the
pathogen.2
The antifungal agents most commonly used to treat fungal keratitis include polyenes, azoles and pyrimidine
analogues. Polyenes such as amphotericin and natamycin bind ergosterol,
leading to interference with fungal cell
membrane synthesis. Azoles interfere
with cell membrane formation through
a different method of action by inhibition of cytochrome P450. Azoles include voriconazole, itraconazole, fluconazole and miconazole. Flucytosine
is an antimetabolite pyrimidine analogue, which is less commonly used.
Various randomized controlled studies have been conducted to compare
the efficacy of different antifungals,
and all have enrolled patients in developing countries. According to a recent Cochrane review of the literature,
there is no conclusive evidence in favor of any one agent.3 Multiple agents
as well as methods of administration
have been compared with each other,
generally without any observed difference in outcome.4-9 However, the
recent Mycotic Ulcer Treatment Trial
(MUTT) did demonstrate results in
favor of topical natamycin over voriconazole for one organism. For cases of
Fusarium keratitis, natamycin use resulted in a significantly decreased rate
of perforation compared with voriconazole use (odds ratio of 0.06).10 While
the MUTT study is the only large scale,
randomized control trial for fungal
keratitis that showed statistical significance for commonly used agents, it
must be emphasized that all patients
were enrolled in South India, and no
contact lens wearers were included.
In developed countries such as the
United States, a large proportion of
fungal infection is contact lens-related
or found in patients severely immunocompromised. Therefore, generalizations must be made cautiously.
First-line antifungal agent selection in
the absence of culture data should be
made considering the mechanism of
infection as well as the suspected organism. Subconjunctival, intrastromal,
as well as intracameral agents have also
been used with variable success, and
without large head-to-head comparison trials. In particular, intrastromal
voriconazole has been shown to be
beneficial as an adjunctive therapy to
topical natamycin.9 In patients with
systemic fungemia, infectious disease
consultation should be obtained. For
patients who are candidates for topical monotherapy, natamycin 5% is the
only commercially available agent
while other agents must be mixed at
compounding pharmacies or in the
clinic.
For patients who fail medical therapy and progress to impending or frank
perforation, as in our patient, an urgent
penetrating keratoplasty is often the
next step. Two studies from China have
examined outcomes following penetrating keratoplasty in this setting.11,12
Recurrence rates ranged from 6 to 7
percent, while the cure rate was over
80 percent. However, there was a high
rate of rejection of approximately 30
percent, likely secondary to the avoidance of topical steroids in the immediate postoperative setting. In these
studies, steroids were only considered
starting at two weeks if the eye was
healing well and exhibited no significant inflammation. Risk factors for
recurrence include hypopyon, perforation or limbal and lens involvement.
In summary, fungal keratitis is a
vision-threatening problem that is important to diagnose early. While natamycin is the only commercially available topical agent, many agents and
methods of administration are available to the cornea specialist. For ulcers that are resistant to initial medical
therapy, early referral may be necessary for further intervention, and possible surgical treatment.
The author would like to thank
Christopher J. Rapuano, MD, and
Dr. Ralph C. Eagle Jr., MD, for their
help in preparing this case.
1. Thomas PA, Kaliamurthy J. Mycotic keratitis: Epidemiology, diagnosis and management. Clin Microbiol Infect
2013;19(3):210-20.
2. Alexandrakis G, Haimovici R, Miller D, Alfonso EC. Corneal
biopsy in the management of progressive microbial keratitis. Am
J Ophthalmol 2000;129(5):571-6.
3. FlorCruz NV, Peczon IV, Evans JR. Medical interventions for
fungal keratitis. Cochrane Database Syst Rev 2012;2:CD004241.
4. Agarwal PK, Roy P, Das A, Banerjee A, Maity PK, Banerjee AR.
Efficacy of topical and systemic itraconazole as a broad-spectrum antifungal agent in mycotic corneal ulcer. A preliminary
study. Indian J Ophthalmol 2001;49(3):173-6.
5. Prajna NV, John RK, Nirmalan PK, Lalitha P, Srinivasan M. A
randomised clinical trial comparing 2 percent econazole and
5 percent natamycin for the treatment of fungal keratitis. Br J
Ophthalmol 2003;87(10):1235-7.
6. Mahdy RA, Nada WM, Wageh MM. Topical amphotericin B and
subconjunctival injection of fluconazole (combination therapy)
versus topical amphotericin B (monotherapy) in treatment of
keratomycosis. J Ocul Pharmacol Ther 2010;26:281-5.
7. Prajna NV, Mascarenhas J, Krishnan T, et al. Comparison of
natamycin and voriconazole for the treatment of fungal keratitis.
Arch Ophthalmol 2010;128:672-8.
8. Arora R, Gupta D, Goyal J, Kaur R. Voriconazole versus
natamycin as primary treatment in fungal corneal ulcers. Clin
Experiment Ophthalmol 2011;39(5):434-40.
9. Sharma N, Chacko J, Velpandian T, et al. Comparative evaluation of topical versus intrastromal voriconazole as an adjunct
to natamycin in recalcitrant fungal keratitis. Ophthalmology
2013;120:677-81.
10. Prajna NV, Krishnan T, Mascarenhas J, et al. The mycotic
ulcer treatment trial: A randomized trial comparing natamycin vs
voriconazole. JAMA Ophthalmol 2013;131:422-9.
11. Shi W, Wang T, Xie L, et al. Risk factors, clinical features, and
outcomes of recurrent fungal keratitis after corneal transplantation. Ophthalmology 2010;117:890-6.
12. Xie L, Dong X, Shi W. Treatment of fungal keratitis by penetrating keratoplasty. Br J Ophthalmol 2001;85(9):1070-4.
7/25/13 3:52 PM
LUMIGAN 0.01% AND 0.03%
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LUMIGAN® 0.01% and 0.03% (bimatoprost ophthalmic solution) is indicated for the
reduction of elevated intraocular pressure in patients with open angle glaucoma or
ocular hypertension.
CONTRAINDICATIONS
None
Pigmentation: Bimatoprost 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 bimatoprost 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 bimatoprost,
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
LUMIGAN® 0.01% and 0.03% (bimatoprost ophthalmic solution) can be continued in
patients who develop noticeably increased iris pigmentation, these patients should
be examined regularly.
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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 bimatoprost ophthalmic solution. LUMIGAN® 0.01%
and 0.03% 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: LUMIGAN® 0.01% and
0.03% 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 LUMIGAN® 0.01% and 0.03% 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.
In clinical studies with bimatoprost ophthalmic solutions (0.01% or 0.03%) the
most common adverse reaction was conjunctival hyperemia (range 25%–45%).
Approximately 0.5% to 3% of patients discontinued therapy due to conjunctival
hyperemia with 0.01% or 0.03% bimatoprost ophthalmic solutions. Other common
reactions (>10%) included growth of eyelashes, and ocular pruritus.
Additional ocular adverse reactions (reported in 1 to 10% of patients) with
bimatoprost ophthalmic solutions included ocular dryness, visual disturbance,
ocular burning, foreign body sensation, eye pain, pigmentation of the periocular
skin, blepharitis, cataract, superficial punctate keratitis, periorbital erythema,
ocular irritation, eyelash darkening, eye discharge, tearing, photophobia, allergic
conjunctivitis, asthenopia, increases in iris pigmentation, conjunctival edema,
conjunctival hemorrhage, and abnormal hair growth. Intraocular inflammation,
reported as iritis, was reported in less than 1% of patients.
Systemic adverse reactions reported in approximately 10% of patients with
bimatoprost ophthalmic solutions were infections (primarily colds and upper
respiratory tract infections). Other systemic adverse reactions (reported in 1 to 5% of
patients) included headaches, abnormal liver function tests, and asthenia.
Postmarketing Experience: The following reactions have been identified during
postmarketing use of LUMIGAN® 0.01% and 0.03% in clinical practice. Because they
are reported voluntarily from a population of unknown size, estimates of frequency
cannot be made. The reactions, which have been chosen for inclusion due to either
their seriousness, frequency of reporting, possible causal connection to LUMIGAN®, or
a combination of these factors, include: dizziness, eyelid edema, hypertension, nausea,
and periorbital and lid changes associated with a deepening of the eyelid sulcus.
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Pregnancy: Pregnancy Category C
Teratogenic effects: In embryo/fetal developmental studies in pregnant mice and
rats, abortion was observed at oral doses of bimatoprost which achieved at least 33
or 97 times, respectively, the maximum intended human exposure based on blood
AUC levels.
At doses at least 41 times the maximum intended human exposure based on blood
AUC levels, the gestation length was reduced in the dams, the incidence of dead
fetuses, late resorptions, peri- and postnatal pup mortality was increased, and pup
body weights were reduced.
There are no adequate and well-controlled studies of LUMIGAN® 0.01% and 0.03%
(bimatoprost ophthalmic solution) administration in pregnant women. Because
animal reproductive studies are not always predictive of human response LUMIGAN®
should be administered during pregnancy only if the potential benefit justifies the
potential risk to the fetus.
Nursing Mothers: It is not known whether LUMIGAN® 0.01% and 0.03% is excreted
in human milk, although in animal studies, bimatoprost has been shown to be
excreted in breast milk. Because many drugs are excreted in human milk, caution
should be exercised when LUMIGAN® 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 Impairment: In patients with a history of liver disease or abnormal ALT,
AST and/or bilirubin at baseline, bimatoprost 0.03% had no adverse effect on liver
function over 48 months.
OVERDOSAGE
No information is available on overdosage in humans. If overdose with LUMIGAN®
0.01% and 0.03% (bimatoprost ophthalmic solution) occurs, treatment should
be symptomatic.
In oral (by gavage) mouse and rat studies, doses up to 100 mg/kg/day did not
produce any toxicity. This dose expressed as mg/m2 is at least 70 times higher
than the accidental dose of one bottle of LUMIGAN® 0.03% for a 10 kg child.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility: Bimatoprost was not
carcinogenic in either mice or rats when administered by oral gavage at doses
of up to 2 mg/kg/day and 1 mg/kg/day respectively (at least 192 and 291 times
the recommended human exposure based on blood AUC levels respectively) for
104 weeks.
Bimatoprost was not mutagenic or clastogenic in the Ames test, in the mouse
lymphoma test, or in the in vivo mouse micronucleus tests.
Bimatoprost did not impair fertility in male or female rats up to doses of 0.6 mg/kg/day
(at least 103 times the recommended human exposure based on blood AUC levels).
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 LUMIGAN® 0.01% and 0.03% (bimatoprost
ophthalmic solution).
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
LUMIGAN® 0.01% and 0.03%. 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 LUMIGAN® 0.01% and 0.03%.
Use with Contact Lenses: Patients should be advised that LUMIGAN® 0.01% and
0.03% contains benzalkonium chloride, which may be absorbed by soft contact
lenses. Contact lenses should be removed prior to instillation of LUMIGAN® and may
be reinserted 15 minutes following its administration.
Use with Other Ophthalmic Drugs: Patients should be advised that if more than one
topical ophthalmic drug is being used, the drugs should be administered at least five
(5) minutes between applications.
© 2012 Allergan, Inc., Irvine, CA 92612
marks owned by Allergan, Inc
Patented. See: www.allergan.com/products/patent_notices
Made in the U.S.A.
Rx only
APC70EN12 based on 71807US13.
®
12/10/12 1:37 PM
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