Topography-guided Ablation: Pros and Cons P. 20 Refractive

Transcription

Review of Ophthalmology Vol. XIX, No. 7 • July 2012 • Topography-guided Ablation • Intrastromal Refractive Surgery • Presbyopia Surgery Options • Genetic Testing for AMD
CATCHING DIABETIC MACULAR EDEMA EARLY P. 16 • A CLOSER LOOK AT A NEW EXCIMER LASER P. 61
GENETIC TESTING FOR AMD P. 56 • A LOOK BACK AT ARVO HIGHLIGHTS P. 44
WILLS RESIDENT CASE SERIES P. 74 • NOT YOUR FATHER’S TRABECULECTOMY P. 51
Part 1 of 2
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Topography-guided Ablation: Pros and Cons P. 20
Refractive Surgery Goes Intrastromal P. 32
Presbyopia Surgery: Beyond Multifocal IOLs P. 38
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Get there at the speed of WaveLight.
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11/11
WaveLight® FS200
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ALL11498JAD
*Treatment times are approximate.
For Important Safety Information and Full Directions for Use, Please Reference the WaveLight® ALLEGRETTO WAVE® Laser System Full Directions for Use on Adjacent Pages.
RP0212_Alcon Wavelight.indd 1
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Health Care Professional Information Sheet-All
WaveLight® Allegretto Wave® System Indications
The WaveLight® ALLEGRETTO WAVE® / ALLEGRETTO
WAVE® Eye-Q Excimer Laser System
CAUTION: Federal (USA) law restricts this device to
sale by, or on the order of a physician.
Statements regarding the potential benefits of
wavefront-guided and Wavefront Optimized® laserassisted in-situ keratomileusis (LASIK) are based upon
the results of clinical trials. These results are indicative
of not ony the WaveLight® ALLEGRETTO WAVE® /
ALLEGRETTO WAVE® Eye-Q Excimer Laser System
treatment but also the care of the clinical physicians, the
control of the surgical environment by those physicians,
the clinical trials’ treatment parameters and the clinical
trials’ patient inclusion and exclusion criteria. Although
many clinical trial patients after the wavefront-guided
and Wavefront Optimized® procedure saw 20/20 or
better and/or had or reported having better vision
during the day and at night, compared to their vision
with glasses or contact lenses before the procedure,
individual results may vary. You can find information
about the clinical trials below and in the Procudure
Manuals for the WaveLight® ALLEGRETTO WAVE® /
ALLEGRETTO WAVE® Eye-Q Excimer Laser System.
As with any surgical procedure, there are risks
associated with the wavefront-guided and Wavefront
Optimized® treatment. Before treating patients with
these procedures, you should carefully review the
Procedure Manuals, complete the Physician WaveLight®
System Certification Course, provide your patients with
the Patient Information Booklet, and discuss the risks
associated with this procedure and questions about the
procedure with your patients.
INDICATIONS: The WaveLight® ALLEGRETTO WAVE® /
ALLEGRETTO WAVE® Eye-Q Excimer Laser System is
indicated to perform LASIK treatments in patients with
documented evidence of a stable manifest refraction
defined as less than or equal to 0.50 diopters (D) of
preoperative spherical equivalent shift over one year
prior to surgery, exclusive of changes due to unmasking
latent hyperopia in patients 18 years of age or older: for
the reduction or elimination of myopic refractive errors
up to -12.0 D of sphere with and without astigmatic
refractive errors up to
-6.0 D; for the reduction or elimination of hyperopic
refractive errors up to +6.0 D of sphere with and without
astigmatic refractive errors up to 5.0 D at the spectacle
plane, with a maximum manifest refraction spherical
equivalent (MRSE) of +6.0 D; and in patients 21 years of
age or older for the reduction or elimination of naturally
occurring mixed astigmatism of up to 6.0 D at the
spectacle plane.
LASIK is an elective procedure with the alternatives
including but not limited to eyeglasses, contact lenses,
photorefractive keratectomy (PRK), and other refractive
surgeries. Only practitioners who are experienced in
the medical management and surgical treatment of
the cornea, who have been trained in laser refractive
surgery including laser system calibration and operation,
may use the device as approved. Prospective patients,
as soon as they express an interest in an indicated
LASIK procedure and prior to undergoing surgery, must
be given the WaveLight® System Patient Information
Booklet and must be informed of the alternatives for
refractive correction including eyeglasses, contact
lenses, PRK, and other refractive surgeries.
RP0212_Alcon Wavelight PI.indd 1
Clinical Data Myopia: The WaveLight® ALLEGRETTO
WAVE® / ALLEGRETTO WAVE® Eye-Q Excimer Laser
System for LASIK treatments of myopic refractive errors
up to -12.0 D of sphere with and without astigmatic
refractive errors up to -6.0 D at the spectacle plane was
studied in clinical trials in the United States with 901
eyes treated, of which 813 of 866 eligible eyes were
followed for 12 months. Accountability at 3 months was
93.8%, at 6 months was 91.9%, and at 12 months was
93.9%.
The studies found that of the 844 eyes eligible for
the uncorrected visual acuity (UCVA) analysis of
effectiveness at the 3-month stability time point, 98.0%
were corrected to 20/40 or better, and 84.4% were
corrected to 20/20 or better without spectacles or
contact lenses.
The clinical trials showed that the following subjective
patient adverse events were reported as moderate to
severe at a level at least 1% higher than baseline of the
subjects at 3 months post-treatment: visual fluctuations
(12.8% at baseline versus 28.6% at 3 months). Long
term risks of LASIK for myopia with and without
astigmatism beyond 12 months have not been studied.
Clinical Data Hyperopia: The WaveLight® ALLEGRETTO
WAVE® / ALLEGRETTO WAVE® Eye-Q Excimer Laser
System for LASIK treatments of hyperopic refractive
errors up to +6.0 D of sphere with and without
astigmatic refractive errors up to 5.0 D with a maximum
MRSE of +6.0 D has been studied in clinical trials in
the United States with 290 eyes treated, of which 100
of 290 eligible eyes were followed for 12 months.
Accountability at 3 months was 95.2%, at 6 months was
93.9%, and at 12 months was 69.9%.
The studies found that of the 212 eyes eligible for the
UCVA analysis of effectiveness at the 6-month stability
time point, 95.3% were corrected to 20/40 or better,
and 67.5% were corrected to 20/20 or better without
spectacles or contact lenses.
The study showed that the following subjective patient
adverse events were reported as much worse by at least
1% of the subjects (in order of increasing frequency)
at 6 months post final treatment: glare from bright
lights (3.0%); night driving glare (4.2%); light sensitivity
(4.9%); visual fluctuations (6.1%); and halos (6.4%).
Long term risks of LASIK for hyperopia with and without
Clinical Data Mixed Astigmatism: The WaveLight®
ALLEGRETTO WAVE®/ ALLEGRETTO WAVE® Eye-Q
Excimer Laser System for LASIK treatments of naturally
occurring mixed astigmatism of up to 6.0 D at the
spectacle plane has been studied in clinical trials in the
United States with 162 eyes treated, of which 111 were
eligible to be followed at 6 months. Accountability at 1
month was 99.4%, at 3 months was 96.0%, and at 6
months was 100.0%.
time point, 95.8% achieved acuity of 20/40 or better,
and 67.6% achieved acuity of 20/20 or better without
severe at a level at least 1% higher than baseline of
the subjects at 3 months post-treatment: sensitivity to
light (43.3% at baseline versus 52.9% at 3 months);
visual fluctuations (32.1% at baseline versus 43.0%
at 3 months); and halos (37.0% at baseline versus
42.3% at 3 months). Long term risks of LASIK for mixed
Clinical Data Wavefront-guided Treatment of Myopia:
The WaveLight® ALLEGRETTO WAVE® / ALLEGRETTO
WAVE® Eye-Q Excimer Laser System used in conjunction
with the WaveLight® ALLEGRO Analyzer® device. The
device uses a 6.5 mm optical zone, a 9.0 mm ablation/
treatment zone, and is indicated for wavefront-guided
LASIK: 1) for the reduction or elimination of up to
-7.0 D of spherical equivalent myopia or myopia with
astigmatism, with up to -7.0 D of spherical component
and up to 3.0 D of astigmatic component at the
spectacle plane; 2) in patients who are 18 years of
age or older; and 3) in patients with documentation
of a stable manifest refraction defined as ≤0.50 D of
preoperative spherical equivalent shift over one year
prior to surgery was studied in a randomized clinical
trial in the United States with 374 eyes treated; 188
with wavefront-guided LASIK (Study Cohort) and 186
with Wavefront Optimized® LASIK (Control Cohort). 178
of the Study Cohort and 180 of the Control Cohort were
eligible to be followed at 6 months. In the Study Cohort,
accountability at 1 month was 96.8%, at 3 months was
96.8%, and at 6 months was 93.3%. In the Control
Cohort, accountability at 1 month was 94.6%, at 3
months was 94.6%, and at 6 months was 92.2%.
time point in the Study Cohort, 99.4% were corrected
to 20/40 or better, and 93.4% were corrected to 20/20
or better without spectacles or contact lenses. In the
Control Cohort, of the 176 eyes eligible for the UCVA
analysis of effectiveness at the 6-month stability time
point, 99.4% were corrected to 20/40 or better, and
92.8% were corrected to 20/20 or better without
severe at a level at least 1% higher than baseline of
the subjects at 3 months post-treatment in the Study
Cohort: light sensitivity (37.2% at baseline versus 47.8%
at 3 months); and visual fluctuations (13.8% at baseline
versus 20.0% at 3 months). In the Control Cohort: halos
(36.6% at baseline versus 45.4% at 3 months); and
visual fluctuations (18.3% at baseline versus 21.9% at 3
months). Long term risks of wavefront-guided LASIK for
myopia with and without astigmatism beyond 6 months
have not been studied.
CONTRAINDICATIONS: LASIK treatments using the
WaveLight® ALLEGRETTO WAVE® / ALLEGRETTO WAVE®
Eye-Q Excimer Laser System are contraindicated
if any of the following conditions exist. Potential
contraindications are not limited to those included
in this list: pregnant or nursing women; patients
with a diagnosed collagen vascular, autoimmune or
immunodeficiency disease; patients with diagnosed
keratoconus or any clinical pictures suggestive of
keratoconus; and patients who are taking one or both
of the following medications: isotretinoin (Accutane®1),
amiodarone hydrochloride (Cordarone®2).
WARNINGS: Any LASIK treatment with the WaveLight®
ALLEGRETTO WAVE® / ALLEGRETTO WAVE® Eye-Q
Excimer Laser System is not recommended in patients
who have: systemic diseases likely to affect wound
healing, such as connective tissue disease, insulin
dependent diabetes, severe atopic disease or an
immunocompromised status; a history of Herpes
simplex or Herpes zoster keratitis; significant dry eye
that is unresponsive to treatment; severe allergies; and
unreliable preoperative wavefront examination that
precludes wavefront-guided treatment. The wavefrontguided LASIK procedure requires accurate and reliable
data from the wavefront examination. Every step of
every wavefront measurement that may be used as the
basis for a wavefront-guided LASIK procedure must be
validated by the user. Inaccurate or unreliable data from
1/12/12 2:30 PM
the wavefront examination will lead to an inaccurate
treatment.
PRECAUTIONS: Safety and effectiveness of the
WaveLight® ALLEGRETTO WAVE® / ALLEGRETTO
WAVE® Eye-Q Excimer Laser System have not been
established for patients with: progressive myopia,
hyperopia, astigmatism and/or mixed astigmatism;
ocular disease; previous corneal or intraocular
surgery, or trauma in the ablation zone; corneal
abnormalities including, but not limited to, scars,
irregular astigmatism and corneal warpage; residual
corneal thickness after ablation of less than 250
microns increasing the risk for corneal ectasia;
pupil size below 7.0 mm after mydriatics where
applied for wavefront-guided ablation planning;
history of glaucoma or ocular hypertension of > 23
mmHg; taking the medication sumatriptan succinate
(Imitrex®3); under 18 years (21 years for mixed
astigmatism) of age; over the long term (more
than 12 months after surgery); corneal, lens and/
or vitreous opacities including, but not limited to,
cataract; iris problems including, but not limited to,
coloboma and previous iris surgery compromising
proper eyetracking; taking medications likely to
affect wound healing including, but not limited to,
antimetabolites; treatments with an optical zone
below 6.0 mm or above 6.5 mm in diameter;
treatment targets different from emmetropia (plano)
in which the wavefront-calculated defocus (spherical
term) has been adjusted; myopia greater than –
12.0 D or astigmatism greater than 6 D; hyperopia
greater than + 6.0 D or astigmatism greater than
5.0 D; mixed astigmatism greater than + 6.0 D; and
in cylinder amounts > 4.0 to < 6.0 D.
Due to the lack of large numbers of patients in the
general population, there are few subjects with
cylinder amounts in this range to be studied. Not
all complications, adverse events, and levels of
effectiveness may have been determined.
Pupil sizes should be evaluated under mesopic
illumination conditions. Effects of treatment on vision
under poor illumination cannot be predicted prior to
surgery. Some patients may find it more difficult to
see in such conditions as very dim light, rain, fog,
snow and glare from bright lights. This has been
shown to occur more frequently in the presence of
residual refractive error and perhaps in patients with
pupil sizes larger than the optical zone size.
The refraction is determined in the spectacle
plane, but treated in the corneal plane. In order
to determine the right treatment program to
achieve the right correction, assessment of
the vertex distance during refraction testing is
recommended. Preoperative evaluation for dry eyes
should be performed. Patients should be advised
of the potential for dry eyes post LASIK and post
wavefront-guided LASIK surgery. This treatment
can only be provided by a licensed healthcare
professional.
Adverse Events and Complications for Myopia:
Certain adverse events and complications occurred
after the LASIK surgery. Two adverse events
occurred during the postoperative period of the
clinical study: 0.2% (2/876) had a lost, misplaced,
or misaligned flap reported at the 1 month
examination.
The following adverse events did NOT occur:
corneal infiltrate or ulcer requiring treatment,
RP0212_Alcon Wavelight PI r.indd 1
corneal edema at 1 month or later visible in the slit
lamp exam; any complication leading to intraocular
surgery; melting of the flap of >1 mm2; epithelium
of >1 mm2 in the interface with loss of 2 lines or
more of BSCVA; uncontrolled IOP rise with increase
of >5 mmHg or any reading above 25 mmHg;
retinal detachment or retinal vascular accident;
and decrease in BSCVA of >10 letters not due to
irregular astigmatism as shown by hard contact lens
refraction.
The following complications occurred 3 months after
LASIK during this clinical trial: 0.8% (7/844) of eyes
had a corneal epithelial defect; 0.1% (1/844) had
any epithelium in the interface; 0.1% (1/844) had
foreign body sensation; 0.2% (2/844) had pain; and
0.7% (6/844) had ghosting or double images in the
operative eye.
The following complications did NOT occur 3 months
following LASIK in this clinical trial: corneal edema
and need for lifting and/or reseating the flap/cap.
Adverse Events and Complications for Hyperopia:
Certain adverse events and complications occurred
after the LASIK surgery. Only one adverse event
occurred during the clinical study: one eye (0.4%)
had a retinal detachment or retinal vascular accident
reported at the 3 month examination.
The following adverse events did NOT occur:
corneal infiltrate or ulcer requiring treatment; lost,
misplaced, or misaligned flap, or any flap/cap
problems requiring surgical intervention beyond
1 month; corneal edema at 1 month or later visible
in the slit lamp exam; any complication leading to
intraocular surgery; melting of the flap of > 1 mm2;
epithelium of > 1 mm2 in the interface with loss
of 2 lines or more of BSCVA; uncontrolled IOP rise
with increase of > 5 mmHg or any reading above
25 mmHg and decrease in BSCVA of > 10 letters
not due to irregular astigmatism as shown by hard
contact lens refraction.
The following complications occurred 6 months after
LASIK during this clinical trial: 0.8% (2/262) of eyes
had a corneal epithelial defect and 0.8% (2/262) had
any epithelium in the interface.
following LASIK in this clinical trial: corneal edema;
foreign body sensation; pain, ghosting or double
images; and need for lifting and/or reseating of the
flap/cap.
Adverse Events and Complications for Mixed
Astigmatism: Certain adverse events and
complications occurred after the LASIK surgery. No
protocol defined adverse events occurred during the
clinical study. However, two events occurred which
were reported to the FDA as Adverse Events.
The first event involved a patient who
postoperatively was subject to blunt trauma to the
treatment eye 6 days after surgery. The patient
was found to have an intact globe with no rupture,
inflammation or any dislodgement of the flap. The
second event involved the treatment of an incorrect
axis of astigmatism which required retreatment.
The following adverse events did NOT occur: corneal
infiltrate or ulcer requiring treatment; corneal
epithelial defect involving the keratectomy at
1 month or later; corneal edema at 1 month or later
visible in the slit lamp exam; epithelium of > 1 mm2
in the interface with loss of 2 lines or more of
BSCVA; lost, misplaced, or misaligned flap, or any
flap/cap problems requiring surgical intervention
beyond 1 month; decrease in BSCVA of > 10 letters
not due to irregular astigmatism as shown by hard
contact lens refraction; any complication leading to
intraocular surgery; melting of the flap of > 1 mm2;
uncontrolled IOP rise and retinal detachment or
retinal vascular accident.
None of the following complications occurred
at 3 months after LASIK during this clinical trial:
corneal edema; corneal epithelial defect; any
epithelium in the interface; foreign body sensation,
pain, ghosting or double images; and need for lifting
and/or reseating of the flap/cap.
Subjects were asked to complete a patient
questionnaire preoperatively and at 3-months,
6-months, and 1-year postoperatively.
Adverse Events and Complications for Wavefront
- guided Myopia: Certain adverse events and
complications occurred after the wavefront-guided
LASIK surgery. No adverse event occurred during
wavefront-guided treatments during this clinical
study.
The following adverse events did NOT occur: corneal
infiltrate or ulcer requiring treatment; lost, misplaced
or misaligned flap or any flap/cap problems
requiring surgical intervention beyond 1 month;
corneal edema at 1 month or later visible in the slit
lamp exam; any complication leading to intraocular
surgery; melting of the flap of > 1 mm2; epithelium
of > 1 mm² in the interface with loss of 2 lines or
more of BSCVA; uncontrolled IOP rise with increase
of > 5 mmHg or any reading above 25 mmHg;
and decrease in BSCVA of > 10 letters not due to
irregular astigmatism as shown by hard contact lens
refraction.
The following complications occurred 3 months
after wavefront-guided LASIK during this clinical
trial: corneal epithelial defect (0.6%); foreign body
sensation (0.6%); and pain (0.6%).
following wavefront-guided LASIK in this clinical
trial: corneal edema; any epithelium in the interface;
ghosting or double images; and need for lifting and/
or reseating of the flap/cap.
ATTENTION: The safety and effectiveness of LASIK
surgery has ONLY been established with an optical
zone of 6.0 – 6.5 mm and an ablation zone of 9.0
mm.
Reference the Directions for Use labeling for a
complete listing of indications, warnings and
precautions.
1. Accutane® is a registered trademark of
Hoffmann-La Roche Inc.
2. Cordarone® is a registered trademark of
Sanofi S.A.
3. Imitrex® is a registered trademark of
Glaxo Group Limited
© 2011 Novartis 11/11 ALL11498JAD-PI
1/12/12 2:32 PM
REVIEW
NEWS
Volume XIX • No. 7 • July 2012
Ocular Pulse Testing May Offer a
Method of Detecting Stroke Risk
A simple eye test may someday offer
an effective way to identify patients
who are at high risk for stroke, say
researchers at the University of Zurich. They showed that a test called
ocular pulse amplitude (OPA) can
reliably detect carotid artery stenosis
(CAS), a known risk factor for stroke.
The OPA test could be performed
by ophthalmologists during routine
exams. The study, published in the
June Ophthalmology, confirmed that
patients who had the lowest OPA
scores also had the most seriously
blocked arteries.
Each year, approximately 795,000
Americans suffer a new or recurrent
stroke, and more than 137,000 of
these people die as a result. People
with severe CAS are much more
likely to suffer stroke. Physicians
would like to catch and treat CAS
before that can happen, but because
CAS has no symptoms and an efficient test is not currently available,
the disease often goes undetected.
The Swiss research team used a
device called the dynamic contour
tonometer to check the OPA of 67
patients who were assumed to have
CAS. The OPA score is calculated by
finding the difference between the
intraocular pressure levels during
the systolic and diastolic phases of
the heartbeat. The tonometer measures the two pressure levels, then
instantly computes the patient’s OPA
score. When blood flow to the eye is
blocked by CAS, there is not much
difference between the two pressure
levels, so the OPA score is low. The
study confirmed that patients with
the lowest OPA scores also had the
most seriously blocked arteries. The
researchers used ultrasound exams
to corroborate that each study participant had CAS and to detail the
severity of the blockage.
“Our results show that ocular pulse
amplitude is a reliable, safe screening test for carotid artery stenosis,”
said lead researcher Pascal Bruno
Knecht, MD. “We recommend further study to confirm the value of
using OPA to detect and assess the
severity of CAS and to define its use
in stroke prevention.”
A research review performed for
the U.S Preventive Services Task
Force indicated that if an efficient
screening test for CAS were available, the incidence of stroke and
fatalities due to stroke could be substantially reduced. The review stated
that the test should be able to detect
clinically significant CAS, defined as
60 percent to 99 percent blockage
of the carotid arteries. Some hightech tests, such as magnetic resonance angiography and color duplex
ultrasound, already meet this standard, but they are expensive and not
widely available. Their primary use
is in diagnosing patients who already
have symptoms of stroke.
It could be efficient to perform
the OPA test during a standard eye
exam, if the ophthalmologist is already using the dynamic contour
tonometer to screen for glaucoma.
This type of tonometer is not widely
used in the United States, although
it is in Europe.
The researchers say that other
than CAS, very few diseases could
cause low OPA scores, and that an
ophthalmologist could easily rule
out these other diseases during an
eye exam.
Lenses May Slow
Myopia Progress in
Children
Research at the University of Houston
College of Optometry suggests that
optical treatments warrant further
study for their potential to slow the
progression of nearsightedness in
children.
Conducted by UH assistant professor David Berntsen, OD, PhD, and his
colleagues from Ohio State University, the study compared the effects of
wearing and then not wearing progressive addition lenses in children who
are nearsighted. The study examined
85 children from 6 to 11 years old over
the course of two years. The results
were published in Investigative Ophthalmology and Visual Science.
Selected according to their eye
alignment and accuracy of focusing
on near objects, the myopic children
were fitted with either normal singlevision lenses or no-line bifocals to
correct their nearsightedness. In addition to observing and testing the
children, the doctors obtained feedback from parents and guardians of
both the children’s outdoor activities
July 2012 | Revophth.com | 5
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REVIEW
News
and near-work tasks, such as reading
and computer use.
Previous research suggested that
nearsighted children who do not focus
accurately when reading books or doing other near work may benefit more
from wearing no-line bifocal glasses
than nearsighted children who focus
more accurately. Dr. Berntsen’s study
found a small, yet statistically significant, slowing of myopia progression
in children wearing the bifocals compared to those who simply wore singlevision lenses. Dr. Berntsen asserts,
however, that the results do not suggest that children be fitted with no-line
bifocal lenses solely for the purpose of
slowing the progression of myopia.
“While the small effect found in
the group of children wearing bifocal
spectacles does not warrant a change
in clinical practice, we found the beneficial effect was still present for at least
one year after children stopped wearing no-line bifocal lenses,” Dr. Berntsen said. “This is promising if other
optical lens designs can be developed
that do an even better job of slowing
how fast myopia increases in children.”
By understanding why different
types of lenses result in the slowing of
myopia progression, Dr. Berntsen says
researchers will be better able to design lenses that may be more effective
in slowing the increase of nearsightedness in children.
“Single-vision lenses are normally
prescribed when a child gets a pair
of glasses, but glasses with progressive addition lenses were shown to
slightly reduce myopic progression in
our study,” he said. “For any treatment
that reduces myopia progression in
children to be useful, the effect of the
spectacles or contact lenses must persist after children stop wearing them.
The fact that the small treatment effect from our study was still present
one year after discontinuing the treatment is promising. The results suggest
that if newer optical designs currently
being investigated do a better job of
slowing myopia progression, the effects may be expected to persist and
decrease how nearsighted the child
ultimately becomes.”
Dr. Berntsen says the study results
and evidence from other studies suggest that lenses specifically designed to
change blur in the eye’s peripheral vision may be able to slow the increase of
nearsightedness.
“There is support for continuing to
investigate new lenses specially designed to change the blur profile on
the back of the eye in order to reduce
the increase of myopia in children,” he
said. “There is still further research to
be done, but our work is an important step in discovering the methods
needed to slow the progression of
nearsightedness.”
Stem Cells
Able to Form
Optic Cup
Human-derived stem cells can spontane-
ously form an optic cup, according to
a study published in Cell Stem Cell.
Transplantation of this 3D tissue in the
future could help patients with visual
impairments see clearly.
“This is an important milestone
for a new generation of regenerative medicine,” says senior study author Yoshiki Sasai, MD, PhD, of the
RIKEN Center for Developmental
Biology, in Kobe, Japan. “Our approach opens a new avenue to the use
of human stem cell-derived complex
tissues for therapy, as well as for other
medical studies related to pathogenesis and drug discovery.”
In the study, the optic cup spontaneously emerged from human embryonic stem cells (hESCs)—cells derived
from human embryos that are capable
of developing into a variety of tissues—
thanks to the cell culture methods op-
A human embryonic stem cell-derived optic
cup generated in culture. Bright green,
neural retina; off green, pigment epithelium;
blue, nuclei; red, active myosin (strong in
the inner surface of pigment epithelium).
timized by Dr. Sasai and his team.
The hESC-derived cells formed
the correct 3D shape and the two layers of the optic cup, including a layer
containing a large number of light-responsive photoreceptor cells. Because
retinal degeneration primarily results
from damage to these cells, the hESCderived tissue could be ideal transplantation material.
Beyond the clinical implications,
the study will likely accelerate the acquisition of knowledge in the field of
developmental biology. For instance,
the hESC-derived optic cup is much
larger than the optic cup that Dr. Sasai
and collaborators previously derived
from mouse embryonic stem cells,
suggesting that these cells contain innate species-specific instructions for
building this eye structure. “This study
opens the door to understanding human-specific aspects of eye development that researchers were not able to
investigate before,” Dr. Sasai says.
HSV Infection
Tied to AMD
A team of researchers reports that hu-
man cytomegalovirus, a type of herpes
virus, is associated with neovascular
6 | Review of Ophthalmology | July 2012
6/21/12 3:45 PM
age-related macular degeneration.
They report that human cytomegalovirus causes the production of vascular endothelial growth factor, a signal
protein that regulates the formation
of new blood vessels. The results were
published in PLoS Pathogens.
“Prior to this work, cofactors for the
development of AMD included genetics, a high-fat diet and smoking. Now,
we are adding an infectious agent as
another cofactor,” said Richard D. Dix,
professor at the Georgia State Viral
Immunology Center’s Ocular Virology and Immunology Laboratory. Affiliated research institutions include
the Duke University Eye Center, the
Bascom Palmer Eye Institute of the
University of Miami Miller School of
Medicine, the Viral Immunology Center at Georgia State, and the Department of Ophthalmology at the Emory
University School of Medicine.
Human cytomegalovirus is a common herpes virus, said Dr. Dix. About
80 percent of the population is estimated to have antibodies for the virus, and
it is often acquired during childhood.
In a normal, healthy immune system,
the virus becomes latent in the cells of
bone marrow and blood. But in the elderly, the immune system’s function is
reduced, the virus proliferates and the
production of VEGF increases.
Identifying human cytomegalovirus as a cofactor in the development
of AMD opens up new paths for the
treatment of AMD, Dr. Dix said. One
route could include reducing the viral
load—the amount of the human cytomegalovirus in the blood stream—by
treatment with an antiviral drug known
as ganciclovir.
Additional research paths include
looking at the genetics involved in the
upregulation of VEGF by human cytomegalovirus. “If we can knock down
a certain gene or genes of the virus
that stimulates VEGF production, we
might be able to decrease its production and minimize AMD,” Dr. Dix
said.
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July 2012 • Volume XIX No. 7 | revophth.com
Cover Focus
20 |
The Pros and Cons of
Topography-guided Ablation
By Christopher Kent
As surgeons anticipate the availability of this
technology in the United States, those who have
used it offer insights and advice.
32 |
Refractive Surgery Goes Intrastromal
By Walter Bethke
Avoiding trauma to the corneal surface may lead
to more stable procedures, say surgeons.
38 |
Presbyopia Surgery:
Beyond Multifocal IOLs
By Michelle Stephenson
Corneal inlays, scleral implants, and excimer and
femtosecond laser procedures show promise as
future options for presbyopia correction.
011_rp0712_toc.indd 11
6/22/12 9:58 AM
Departments
5|
Review News
15 |
Editor’s Page
16 |
Technology Update
Catching DME Earlier
Than Ever—at Minimal Cost
44
These tools may reveal which diabetic patients
are suffering pre-symptomatic retinal damage.
44 |
Therapeutic Topics
ARVO 2012 Gives Florida Our Best
Before ARVO goes west, here’s a look at some of
the best research from this year’s Florida meeting.
51 |
Glaucoma Management
Trabeculectomy:
It’s All in the Details
51
A top surgeon shares his insights, strategies and
techniques for making this surgery turn out well.
56 |
Retinal Insider
Genetic Testing for AMD Inches Forward
A look at the status of current technology and
where it fits in the management of patients with
age-related macular degeneration.
59 |
Calendar
61 |
Refractive Surgery
A Closer Look at the New EX500 Laser
56
The new excimer has features to enhance
connectivity and decrease procedure times.
64 |
Research Review
68 |
Products
70 |
Classified Ads
73 |
Advertising Index
74 |
Wills Eye Resident Case Series
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References
1. Christensen MT, Blackie CA, Korb DR, et al. An evaluation of the performance of a novel lubricant eye drop. Poster D692 presented at: The Association for Research in Vision and Ophthalmology Annual Meeting; May 2-6,
2010; Fort Lauderdale, FL. 2. Lane S, Paugh JR, Webb JR, Christensen MT. An evaluation of the in vivo retention time of a novel artificial tear as compared to a placebo control. Poster D923 presented at: The Association for
Research in Vision and Ophthalmology Annual Meeting; May 3-7, 2009; Fort Lauderdale, FL. 3. Davitt WF, Bloomenstein M, Christensen M, et al. Efficacy in patients with dry eye after treatment with a new lubricant eye drop
formulation. J Ocul Pharmacol Ther. 2010;26(4):347-353. 4. Alejandro A. Efficacy of a Novel Lubricant Eye Drops in Reducing Squamous Metaplasia in Dry Eye Subjects. Presented at the 29th Pan-American Congress of
Ophthalmology in Buenos Aires, Argentina, July 7-9, 2011. 5. Wojtowica JC., et al. Pilot, Prospective, Randomized, Double-masked, Placebo-controlled Clinical Trial of an Omega-3 Supplement for Dry Eye. Cornea 2011:30(3)
308-314. 6. Geerling G., et al. The International Workshop on Meibomian Gland Dysfunction: Report of the Subcommittee on Management and Treatment of Meibomian Gland Dysfunction. IOVS 2011:52(4).
RCCL0612_Alcon Systane.indd 1
5/24/12 2:08 PM
REVIEW
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Sometimes Less
Technology Is More
No one sets out to design a new prod-
uct that is intentionally complex and
expensive and that requires advanced
training to use—despite what you
see in every new car commercial. In
health care generally, and certainly in
ophthalmology, that seems to describe
many of the innovations that we report on nearly every month.
Now it seems that the reverse is
happening: a movement away from
adding features to technology in favor
of stripping it down to the bare essentials to make it more convenient,
cheaper and accessible to more people. This so-called “frugal innovation”
was described in a Reuters article
recently, but I was surprised when I
realized that we have two examples
of it—intentional or not, I can’t say—
right in this issue.
Proponents say the health-care segment is late to the party on this one,
but some have caught on. GE Healthcare is developing handheld mobile
ultrasound and electrocardiogram
scanners for use in regions where
health clinics are few and far between,
but the needs of the people are just
as great. Seattle-based Mobisante is
working on a smartphone ultrasound
probe called the Mobius that works
like a full-sized version but fits into
your pocket like a mobile phone. It
can be used for fetal ultrasounds and
imaging of organs like kidneys, gall
bladders, glands and soft tissue.
The device sends the image by mobile phone signal to a remote specialist to read, bringing the benefits of a
full-blown scanning clinic to rural areas where there may be no expert in
reading ultrasound scans—or even a
steady electricity supply.
Our Technology Update this month
describes a bit higher level but still
not wildly complicated method of
detecting presymptomatic diabetic
macular edema (p. 16); and a report
in June’s Ophthalmology (Review
News, p. 5) details a technique that
uses a tonometer to detect patients at
risk for stroke.
If anyone doubts the need for
widespread availablity of accessible,
inexpensive and non-professional
user-friendly technology right here in
this country, especially in the area of
diagnostics, the “Vision Problems in
the U.S.” report, released in late June
by Prevent Blindness America and the
National Eye Institute, provides a sobering picture. Since 2000, AMD is up
25 percent; cataracts, up 19 percent;
open-angle glaucoma, up 22 percent;
and diabetic retinopathy, up 89 percent. These are not going to be solved
by smartphones. But the need to connect patients, especially underserved
American patients as well as those in
Third-World contries, with doctors is
dire and will only get worse. If simpler
technology can connect more patients
to medical care and expertise, then
simplify, simplify, simplify.
015_rp0712_edit.indd 15
6/22/12 9:56 AM
REVIEW
Technology Update
Edited by Michael Colvard, MD, and Steven Charles, MD
Catching Diabetic
Macular Edema Early
Using inexpensive tools, internists may be able to tell which
diabetic patients are suffering pre-symptomatic retinal damage.
Christopher Kent, Senior Editor
iabetic macular edema and pro- Meter, both developed and manufac- lost moderate to significant vision. So
liferative diabetic retinopathy are tured by AMA Optics in Miami. (Dr. our goal should be to try to find these
a significant burden on the health care Reddy has no financial interest in the patients before they have vision loss.
“One of the ways we can do this is
system, in part because they’re usually company or products.)
diagnosed and treated after signifi“Diabetic retinopathy and diabetic to use the photo-stress test,” he concant damage has already been done. macular edema are vascular prob- tinues. “Stressing the macula with a
Now, an ophthalmologist has come lems, but there are also very subtle bright light and measuring how long it
up with an approach that may allow neurogenic or neurodegenerative takes vision to recover has been used
internists to inexpensively identify problems in the retina,” says Dr. for years to evaluate macular degendiabetic patients with early diabetic Reddy. “The problem with diabetic eration. In fact, this strategy reveals
macular edema and proliferative dia- macular edema and diabetes in gen- many kinds of macular pathology.”
betic retinopathy, prior to noticeable eral is that we catch it very late. By
impact on vision, so that treatment the time these patients come to see us How the Test Works
can be started even before symptoms or are referred to us, they’ve already
become evident.
Dr. Reddy says the test is
Shantan Reddy, MD,
accomplished using the RetMPH, who practices at the
inal Acuity Meter, BrightDuPage Medical Group in
ness Acuity Meter and a
Chicago, realized that an
stopwatch. “The patient’s
inexpensive test sometimes
best retinal acuity is meaused to detect early macusured with the Retinal Acular degeneration could also
ity Meter,” he says. “Then
detect early DME in diaone eye is exposed to bright
betic patients. The test inlight using the Brightness
volves stressing the macula
Acuity Meter set on high for
with bright light and then
30 seconds, after which the
timing the visual recovery.
patient’s vision is re-tested
Dr. Reddy uses two instruwith the RAM. The time rements to accomplish this: A Retinal Acuity Meter (inset) and a Brightness Acuity Meter can
quired for the patient to rethe Retinal Acuity Meter be used to detect macular pathology—including pre-symptomatic
turn to the best retinal acuand the Brightness Acuity diabetic macular edema and diabetic retinopathy.
ity level is the recovery time.
D
Shantan Reddy, MD, MPH
016_rp0712_tech update.indd 16
This article has no commercial sponsorship.
6/20/12 11:08 AM
Patients with early damage pathology
simply take a few seconds longer to
recover vision.
“Best of all, because of the way the
test works, it’s unaffected by the presence of cataract, which might otherwise confound the results,” he says.
“That’s where the RAM comes in. It
uses an acuity measurement process
involving the patient reading through
uniform pinholes; the letters in the
reading portion of the test are black
Snellen or ETDRS letters against an
illuminated background. The RAM
acts like a potential acuity meter, but
it’s easier to use and is more accurate
in eyes with co-morbid disease. In
fact, it’s being used right now by many
cataract surgeons looking at visual potential to decide whether a cataract
should come out. We’re just combining that with the Brightness Acuity
Meter to photostress the macula in
patients who may have diabetic macular edema.”
Dr. Reddy and colleague Kevin
Chen, MD, conducted a pilot study
to see whether this approach was
clinically viable. They compared the
results of a 30-second photostress
test on two age-matched groups; the
members of one group were those diagnosed with diabetic macular edema
using OCT and ophthalmoscopy. The
study involved 143 eyes of 84 patients,
mean age 58.2 years (range 24 to 86),
of which 48 eyes (33.6 percent) were
found to have macular edema. There
was no difference in retinal acuity between the DME and healthy groups,
indicating that the DME patients had
not suffered detectable functional loss
at the time of testing.
The data showed that healthy eyes
had a mean recovery time of 35.3
seconds (median: 32 seconds); eyes
with diabetic macular edema had a
mean photostress recovery time of
38.9 seconds (median: 34 seconds).
The difference was statistically significant (p=0.04). Other factors, such
as BCVA, central foveal thickness and
retinal acuity did not correlate with
recovery time.
Dr. Reddy notes that although the
difference in recovery times is only a
couple of seconds, they were able to
detect the difference to statistical significance in the study. “You wouldn’t
expect the difference to be huge,”
he says. “After all, we’re identifying
people who have very early macular edema. The difference would be
much larger if they had more pathology, but once they have a lot of pathology, they’ll be coming in anyway. This
will help us find the ones who need
treatment but don’t know it yet.”
Dr. Reddy says that because this pilot study involved a limited number of
eyes, the numbers didn’t allow them
to determine the sensitivity or specificity of the test. “That wasn’t the intent of our small study,” he says. “We
just wanted to see if there was sufficient statistical correlation to justify
further research. But our data clearly
shows that this test may provide warning when an exam of a diabetic patient
would otherwise show nothing wrong.
In our opinion, that makes it a potentially very valuable tool.”
Getting the Jump on DME
“Ultimately, we want internists to
use this,” says Dr. Reddy. “Internists
don’t usually check vision or look inside the eye to see if there’s any sign
of macular edema. But this test is easy
to perform, and if there’s a delayed
photostress recovery time, they can
refer the patient to an ophthalmologist. A non-mydriatic fundus camera
could serve this purpose as well, but
those are expensive and bulky, and
technicians have to be trained to use
them. They’re not really feasible for
internists to have in the office, and ultimately, internists are the front lines
in our battle against diabetic retinopathy.”
Dr. Reddy says he got the idea for
this approach when he worked at
New York University. “I saw many
public aid patients during that time,”
he recalls. “They wouldn’t come in
until they’d lost significant vision from
DME. Making matters worse, a lot
of these patients couldn’t voice their
concerns to their internist—there was
a communication gap. So we wanted to figure out a way that internists
could screen some of these patients
for us, which would allow us to intervene much earlier, saving vision and
putting less of a burden on the healthcare system. It’s possible that the test
will pick up other concerns such as
early macular degeneration, because
it’s not DME-specific. But any kind of
macular dysfunction is an important
reason to get the patient to an ophthalmologist as quickly as possible.
“This test should be easy for internists to use because they can train
their technicians to do it—or even
volunteers. It’s a very easy, non-invasive test, and the patients don’t need
to be in an exam room. A patient
could fill out his registration and then
do the screening right then and there.
The room doesn’t even have to be
dark. The patient puts on the [pinhole] glasses and you conduct the test.
That’s it. Furthermore, the equipment is relatively inexpensive—about
$1,000 for the system.”
Dr. Reddy doesn’t believe patients
will become overconfident about their
prognosis if they pass the test. “Part of
the internists’ job is to emphasize the
importance of yearly dilated exams
for diabetic patients, even if they pass
the test,” he says. “In the meantime,
internists will be able to go beyond
simply asking whether the patient has
any vision problems. They’ll be able
to capture many patients who have
no apparent vision problems but do
have macular edema that needs treatment. Those are the most vulnerable
patients, and the ones with the most
visual potential. Those are the ones
who stand to gain the most from treatment.”
016_rp0712_tech update.indd 17
6/20/12 11:03 AM
The School Year May Be Over for
the Kids, but Class is Always in
Session for Professionals!
Here’s a chance for your ophthalmic
technicians to earn continuing education
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REVIEW
Cover Focus
Topography-guided
Ablation: Pros and Cons
Christopher Kent, Senior Editor
As surgeons
anticipate the
availability of
this technology
in the United
States, those
who have used it
offer insights and
advice.
L
aser ablation is a complex operation; it depends on precision
laser and blade technology,
surgical skill and precise measurement of the eye being corrected. But
other issues are equally significant—
including the source of the measurements on which you base your ablation. Use of wavefront technology to
measure the eye’s optical system has
become commonplace, but outside
the United States ablations are often
based on corneal topography.
The technology used to accomplish
topography-based laser ablation isn’t
yet approved by the U.S. Food and
Drug Administration, but a Phase III
trial is currently under way. Early results have been reported to be good, so
this technology will likely be available
in the United States within the next
few years. Nevertheless, most American surgeons have little acquaintance
with topography-guided ablation.
With that in mind, three surgeons
who have used it extensively offer
their insights into its pros and cons,
and the circumstances in which it may
be a better approach than standard or
wavefront-guided ablation.
Addressing Corneal Issues
The hallmark of topography-guided ablation is that it’s designed to ad20 | Review of Ophthalmology | July 2012
020_rp0712_f1.indd 20
dress corneal issues exclusively, with
an emphasis on smoothing or normalizing the anterior corneal surface. As
a result, it’s often used to treat corneal abnormalities such as scars or
keratoconus. But because it relies on
topography for guidance, it arguably
accomplishes some things—such as
centering the treatment on the line
of vision—better than pupil-oriented measuring technologies such as
wavefront, even in normal eyes. In
addition, it sometimes uses ablation
schemes that are significantly different than a wavefront-guided ablation
would use to achieve a given result,
with potentially significant consequences for the cornea and the eye.
Given its ability to address corneal
abnormalities, it’s no surprise that the
technology is often used for that purpose outside the United States. R.
Doyle Stulting, MD, PhD, director
of the Stulting Research Center at
Woolfson Eye Institute in Atlanta, is
medical monitor for the FDA Phase
III trial of topography-guided ablation. (The trial uses Alcon’s Allegretto
Wave Eye-Q excimer laser.) “Published international data indicates
that this technology offers promise for
treating highly aberrated eyes, such as
post-LASIK eyes with decentered or
small optical zones,” he notes.
Surgeons outside the United States
6/20/12 4:05 PM
Topo-guided: The Advantages
A. John Kanellopoulos, MD, clinical professor of ophthalmology at
NYU Medical School and medical
director of the Laservision.gr Institute in Athens, Greece, says he has
worked with topography-guided laser treatments, using the Wavelight/
Alcon platform, for the past 10 years
(outside the United States). “This
technology has been approved in the
European Union since early 2003,”
he notes. “For years, we’ve observed
the advantages of topography-guided
treatments and how they can increase
the outcome efficacy and safety of
laser treatments to the cornea.”
Advantages of this technology—
beyond treating very abnormal corneas—include:
• It may be better for treating
astigmatism. “When we treat astigmatism in the standard way we treat
All images: A. John Kanellopoulos, MD
who have used the technology for
many years have found that it can
benefit less abnormal eyes as well.
Aleksandar Stojanovic, MD, who is
in charge of refractive surgery at the
University Hospital in North Norway and medical director at SynsLaser Clinic in Oslo, Norway, has used
topography-guided lasers since 2002.
“Norway is a small country, and our
clinic gets most of the cases of irregular astigmatism that require laser
treatment,” he says. “This has become
my niche.
“At the outset, we treated mostly
decentered LASIK cases,” he continues. “But over time, our use of this
technology has broadened. Now I use
it on most virgin eyes as well. The
purpose in these cases is not so much
to get rid of higher-order aberrations,
because in virgin eyes there are not
many to remove anyway. Instead, I
use the data acquired by topography
so the ablation will be perfectly centered and the cornea will be reshaped
in a more physiologic manner.”
A WaveLight topography-guided laser treatment plan for an eye with keratoconus. Such
treatments may involve a blend of myopic and hyperopic ablations in different areas of
the cornea in order to normalize it overall. In this case, the red circles indicate a myopic
treatment area (lower circle) and hyperopic treatment area (upper circle). The dark circle
indicates the visual axis.
a given amount of astigmatism as if
it’s exactly the same on every eye,”
Dr. Kanellopoulos points out. “Clinical experience and topography have
proven that there’s a great variation in
the way astigmatism occurs. You can
have 2 D of astigmatism with a thicker
bowl, a thinner bowl or a slightly decentered bowl. Doing topographyguided treatment addresses these differences far more elegantly than the
standard one-size-fits-all approach.”
• Surgeons are familiar with topography maps. “It’s much easier
to make sense of a topographic map
than a wavefront map, which is a very
theoretical model,” notes Dr. Kanellopoulos. “Any corneal surgeon will
be comfortable basing a treatment on
a topographic evaluation.”
• It may create smoother transition zones. In certain topographyguided laser systems, according to
Dr. Stojanovic, transition zones may
be smoother when correcting corneal higher-order aberrations. The
ablation-planning software creates a
customized connection between the
treated and untreated cornea. “I have
an option in my topography-guided
laser system to choose whether to just
correct lower-order aberrations and
customize only corneal asphericity
and centration, or to also correct the
corneal higher-order aberrations,”
he explains. “I’ve experimented with
this over the years. For example, I
tried correcting only the lower-order
aberrations, and then correcting the
higher-order aberrations to see what
the difference would be. The only big
difference I found, in treating virgin
eyes, was that my transition zones are
better if I correct the higher-order
aberrations. Apparently this addresses
the fine features in the transition area.
“It’s especially important to me to
create very smooth and wide transition zones, because I do most of
my cases with surface ablation, not
LASIK,” he continues. “That helps
avoid some epithelial remodeling issues. This may be less of a concern
in LASIK ablations, because the flap
helps smooth the transition zones,
just like putting an object under a
rug. Of course, when we remove the
epithelium and it grows back, it also
smoothes out the transition zones
somewhat, but if the transition isn’t
smooth enough, regression will easily
occur.
“The issue of epithelial smoothing
is also one of the arguments against
treating other than first-surface
higher-order aberrations registered
020_rp0712_f1.indd 21
6/20/12 4:05 PM
REVIEW
Cover
Focus
by wavefront,” he adds. “Imprinting
some fine, detailed features on the
corneal stroma is really not going to
work because of the smoothing during re-epithelialization, or due to
the smoothing effect of the flap. So,
higher-order aberrations must really
be of some significance to be worth
attempting to treat. Of course, that is
the case in irregular astigmatism.”
• Direct data input. “Topographyguided treatment involves a direct
relationship between diagnostics and
data processing on the laser,” Dr.
Kanellopoulos points out. “It’s a continuous chain. That eliminates the
potential error of treating with the
wrong patient’s data. If you import
topography data from a patient, you
know it’s the right program for the patient. It’s a nice safety feature to have
in a busy clinical environment.”
• It addresses the issue of angle
kappa. “One inherent advantage of
topography treatments is that since
they’re based on the topographic image of the cornea, whether produced
by Scheimpflug technology or placido
disc, by definition the image is centered on the apex of the cornea,” says
Dr. Kanellopoulos. “The line of sight,
or visual axis, is closer to the apex of
the cornea than the pupillary center. That means that these treatments
are more centered on the visual axis
of the patient than other treatments
that center the ablation based on the
pupil.”
Dr. Kanellopoulos points out that
this is especially important in hyperopes. “Hyperopes have a significant
angle kappa,” he says. “Our group
considers standard treatments for hyperopia grossly decentered, because
they’re centered on the pupil. If you
treat a hyperopic patient using topography-guided ablation, you’ll automatically shift your treatment more
toward the visual axis. We’ve treated
hyperopes with topography-guided
ablation for more than eight years for
this reason—not because they have
Pre- and postop topographies (left and
right, above) of the eye on the previous
page. Right: A difference map of the same
eye (preop minus postop measurements).
topographic irregularities, but because topography-guided treatment
addresses the issue of angle kappa.”
Dr. Kanellopoulos adds that some
myopes have angle kappa as well.
“We’re in an era in which we’re striving more and more for perfect outcomes,” he says. “That includes centering on the line of sight or visual
axis or corneal apex, all of which can
be deviant to the center of the pupil.
If we agree that treatments should
be centered on one of these landmarks, then we should evaluate the
distance between the center pupil
and that landmark in every patient.
To accomplish that, you can use diagnostic placido disc imaging of the
cornea, which makes it very easy to
ascertain whether there’s angle kappa.
If there’s angle kappa, the pupillary
center won’t match the center of the
placido discs.
“We use this diagnostic on every
patient,” he says. “I believe it’s a must
to use topography-guided treatment
in normal hyperopic corneas. In normal myopic corneas, it’s something to
consider. Probably only one out of 10
or 20 myopic eyes will have measurable angle kappa, but I still think that’s
a significant group—five percent of
myopic patients being more than 100
µm decentered is worth addressing.
“Beyond that,” he adds, “we use
topography-guided ablation in 20 to
30 percent of myopic astigmats.”
Addressing Spherical Error
One factor that some surgeons see
as a disadvantage of topography-guided treatment is that it may not always
produce the desired spherical refractive power outcome. “The topographic data are derived from the cornea,”
notes Dr. Kanellopoulos, “so if the
cornea is highly irregular, the main
point of the treatment is to normalize
the cornea. As a result, you may end
up with a very normal cornea—but
with added or reduced sphere. So,
in an eye that started with best corrected visual acuity of 20/50, your end
result may be a BCVA of 20/20, but
now with 2 D of myopia or hyperopia.
That’s because the actual refractive
power of the whole eye is difficult
to calculate when you normalize the
cornea. You know you’re going to get
a better sphere on that cornea, but
you don’t know exactly what spherical
power the revised cornea will be.
“There’s a little art involved in
020_rp0712_f1.indd 22
6/20/12 4:29 PM
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REVIEW
Cover
Focus
determining the likely spheriother decision must be made:
cal shift, and there are several
Which topographic source
techniques that can be used,”
should provide the data?
he continues. “For instance, if
Dr. Kanellopoulos notes
you’re enlarging a small optithat most doctors are wellcal zone in a myope, you know
acquainted with the two basic
that the treatment is going
types of topography: placido
to be a hyperopic-like abladisc and tomography. “Placido
tion, so you can predict what
disc devices analyze the prothe spherical shift in that eye
jection of mires onto the corwill be. For instance, if your
nea, while the tomographic
hyperopic-like ablation is at
devices analyze a Scheimpflug
a depth of 30 µm, you know
or slit-lamp image and derive
that this eye will shift about
an elevation map,” he ex1.5 D toward myopia. That’s an
plains. “In either case, the eleasy prediction.
evation data are input into the
“On the other hand, suppose
laser, and the laser software
you have an eye that’s plano
uses a best-fit sphere conafter LASIK and you want to This topography-guided treatment plan for a hyperopic eye
cept to normalize the cornea.
shows that the visual axis is significantly nasally decentered
enlarge the optical zone be- relative to the center of the pupil. This kind of angle kappa is
In fact, we evaluate the use
cause the patient has night often found in hyperopes; failing to take it into account can
of both types of topography
halos causing problems with result in poorer outcomes. Note that an equally decentered
when doing topography-guiddriving,” he says. “If you try to LASIK flap must be used in order to prevent the large-diameter ed ablations because there are
enlarge that optical zone, most hyperopic ablation from falling outside the flap borders.
advantages and disadvantages
topography-guided treatment
to each of them.
plans will create a ring at the edge of going to go. In that situation, a second
“One intrinsic advantage of the plathe older myopic treatment zone. If treatment may be required.”
cido disc devices,” he continues, “is
you don’t take into account the potenDr. Stojanovic acknowledges that that they’re not biased by imperfectial shift in corneal curvature, the eye topography-guided treatment may tions or opacities within the cornea;
may end up becoming -1.5 D. The not fully address the spherical compo- they analyze reflections from the tear
patient won’t have halos at night, but nent of the refraction. “I say to these film. So, they won’t deviate from acyou’ve induced 1.5 D of myopia. In patients, ‘OK, the first step is to get curacy if there’s a scar in the cornea—
that situation, a second purely spheri- your quality of vision right, to get rid something that could affect the accucal treatment may be required.
of your higher-order aberrations— racy of a Scheimpflug image. On the
“However, in most simple inter- your double vision, haloes, scattering other hand, placido disc technology
ventions such as optical zone recen- and so forth,’ ” he explains. “As much has the intrinsic disadvantage that the
trations or enlargements, you can as we can, we try to provide sphero- imaging rings leave an unmeasured
predict the spherical change that nor- cylindrical correction as well, but area in the center of the innermost
malization of the cornea will induce with the majority of these patients, ring. Scheimpflug is more accurate in
with a high level of certainty,” he says. the lower-order aberrations are not the center.”
“In that situation, all you have to do is the big problem. These people will
Dr. Kanellopoulos notes that in
add it into the treatment. A number of gladly use glasses again if they only the majority of cases, the images and
surgeons work in this way, and the re- can get rid of their higher-order ab- treatment plans derived from the two
sults in this type of situation are highly errations. The sphero-cylindrical cor- different types of devices are identipredictable. But if you’re dealing with rection is of secondary importance to cal. “I have access to four different toan extremely irregular cornea, such as these patients.”
pographers in our clinic; two placido
one that has a paracentral scar, then all
disc peripheral devices and two Penbets are off, because now you’ll have a Placido vs. Scheimpflug
tacam devices, one standard and one
very complex laser treatment that’s
high-resolution,” he says. “All of them
part hyperopic and part myopic. That
Once a surgeon decides that to- can feed into our treatment platform.
makes it very difficult to predict which pography-guided ablation is the right You have to use clinical judgment and
way the overall spherical refraction is procedure for a given patient, an- consider clinical images of the cornea
020_rp0712_f1.indd 24
6/20/12 4:29 PM
7 STUDIES
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FOR ALL YOUR PATIENTS NEEDING A PGA CONSIDER
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®
To learn more:
Visit www.travatanz.com/7studies1result
Scan the QR code using your smartphone,
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free copy of the published study.
INDICATIONS AND USAGE:
TRAVATAN Z® Solution is a prostaglandin analog indicated for the reduction
of elevated intraocular pressure in patients with open-angle glaucoma or
ocular hypertension.
Dosage and Administration:
One drop in the affected eye(s) once daily in the evening.
IMPORTANT SAFETY INFORMATION
Warnings and Precautions:
Pigmentation: Pigmentation of the iris, periorbital tissue (eyelid) and eyelashes
can occur. Iris pigmentation likely to be permanent.
Eyelash Changes: Gradual change to eyelashes including increased length,
thickness and number of lashes. Usually reversible.
©2012 Novartis
053_rp0512_alcontrav.indd 1
4/12
Adverse Reactions:
Most common adverse reaction (30% to 50%) is conjunctival hyperemia.
Use In Specific Populations:
Use in pediatric patients below the age of 16 years is not recommended
because of potential safety concerns related to increased pigmentation
following long-term chronic use.
For additional information please refer to the accompanying brief
summary of prescribing information on adjacent page.
Reference:
1. Dubiner HB, Noecker R. Sustained intraocular pressure reduction throughout the day with travoprost ophthalmic
solution 0.004%. Clin Ophthalmol. 2012;6:525-531.
TRV12070JAD
4/19/12 5:06 PM
BRIEF SUMMARY OF PRESCRIBING INFORMATION
INDICATIONS AND USAGE
TRAVATAN Z® (travoprost ophthalmic solution) 0.004% is indicated for the reduction of elevated intraocular
pressure in patients with open-angle glaucoma or ocular hypertension.
DOSAGE AND ADMINISTRATION
The recommended dosage is one drop in the affected eye(s) once daily in the evening.
TRAVATAN Z® (travoprost ophthalmic solution) should not be administered more than once daily since it
has been shown that more frequent administration of prostaglandin analogs may decrease the intraocular
pressure lowering effect.
Reduction of the intraocular pressure starts approximately 2 hours after the first administration with
maximum effect reached after 12 hours.
TRAVATAN Z® Solution may be used concomitantly with other topical ophthalmic drug products to
lower intraocular pressure. If more than one topical ophthalmic drug is being used, the drugs should be
administered at least five (5) minutes apart.
CONTRAINDICATIONS
None
WARNINGS AND PRECAUTIONS
Pigmentation
Travoprost ophthalmic solution has been reported to cause changes to pigmented tissues. The most
frequently reported changes have been increased pigmentation of the iris, periorbital tissue (eyelid) and
eyelashes. Pigmentation is expected to increase as long as travoprost is administered. The pigmentation
change is due to increased melanin content in the melanocytes rather than to an increase in the number
of melanocytes. After discontinuation of travoprost, pigmentation of the iris is likely to be permanent, while
pigmentation of the periorbital tissue and eyelash changes have been reported to be reversible in some
patients. Patients who receive treatment should be informed of the possibility of increased pigmentation.
The long term effects of increased pigmentation are not known.
Iris color change may not be noticeable for several months to years. Typically, the brown pigmentation
around the pupil spreads concentrically towards the periphery of the iris and the entire iris or parts of the
iris become more brownish. Neither nevi nor freckles of the iris appear to be affected by treatment. While
treatment with TRAVATAN Z® (travoprost ophthalmic solution) 0.004% can be continued in patients who
develop noticeably increased iris pigmentation, these patients should be examined regularly.
Eyelash Changes
TRAVATAN Z® Solution may gradually change eyelashes and vellus hair in the treated eye. These changes
include increased length, thickness, and number of lashes. Eyelash changes are usually reversible upon
discontinuation of treatment.
Intraocular Inflammation
TRAVATAN Z® Solution should be used with caution in patients with active intraocular inflammation
(e.g., uveitis) because the inflammation may be exacerbated.
Macular Edema
Macular edema, including cystoid macular edema, has been reported during treatment with travoprost
ophthalmic solution. TRAVATAN Z® Solution should be used with caution in aphakic patients, in pseudophakic
patients with a torn posterior lens capsule, or in patients with known risk factors for macular edema.
Angle-closure, Inflammatory or Neovascular Glaucoma
TRAVATAN Z® Solution has not been evaluated for the treatment of angle-closure, inflammatory or
neovascular glaucoma.
Bacterial Keratitis
There have been reports of bacterial keratitis associated with the use of multiple-dose containers of
topical ophthalmic products. These containers had been inadvertently contaminated by patients who,
in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface.
Use with Contact Lenses
Contact lenses should be removed prior to instillation of TRAVATAN Z® Solution and may be reinserted
15 minutes following its administration.
ADVERSE REACTIONS
Clinical Studies Experience
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed
in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug
and may not reflect the rates observed in practice. The most common adverse reaction observed
in controlled clinical studies with TRAVATAN® (travoprost ophthalmic solution) 0.004% and
TRAVATAN Z® (travoprost ophthalmic solution) 0.004% was ocular hyperemia which was reported in 30 to
50% of patients. Up to 3% of patients discontinued therapy due to conjunctival hyperemia. Ocular adverse
reactions reported at an incidence of 5 to 10% in these clinical studies included decreased visual acuity, eye
discomfort, foreign body sensation, pain and pruritus. Ocular adverse reactions reported at an incidence of
1 to 4% in clinical studies with TRAVATAN® or TRAVATAN Z® Solutions included abnormal vision, blepharitis,
blurred vision, cataract, conjunctivitis, corneal staining, dry eye, iris discoloration, keratitis, lid margin
crusting, ocular inflammation, photophobia, subconjunctival hemorrhage and tearing.
Nonocular adverse reactions reported at an incidence of 1 to 5% in these clinical studies were allergy,
angina pectoris, anxiety, arthritis, back pain, bradycardia, bronchitis, chest pain, cold/flu syndrome,
depression, dyspepsia, gastrointestinal disorder, headache, hypercholesterolemia, hypertension,
hypotension, infection, pain, prostate disorder, sinusitis, urinary incontinence and urinary tract infections.
In postmarketing use with prostaglandin analogs, periorbital and lid changes including deepening of the
eyelid sulcus have been observed.
054_rp0512_alcontravpi.indd 1
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C
Teratogenic effects: Travoprost was teratogenic in rats, at an intravenous (IV) dose up to
10 mcg/kg/day (250 times the maximal recommended human ocular dose (MRHOD), evidenced by an
increase in the incidence of skeletal malformations as well as external and visceral malformations, such
as fused sternebrae, domed head and hydrocephaly. Travoprost was not teratogenic in rats at IV doses up
to 3 mcg/kg/day (75 times the MRHOD), or in mice at subcutaneous doses up to 1 mcg/kg/day (25 times
the MRHOD). Travoprost produced an increase in post-implantation losses and a decrease in fetal viability
in rats at IV doses > 3 mcg/kg/day (75 times the MRHOD) and in mice at subcutaneous doses
> 0.3 mcg/kg/day (7.5 times the MRHOD).
In the offspring of female rats that received travoprost subcutaneously from Day 7 of pregnancy to lactation Day
21 at doses of ≥ 0.12 mcg/kg/day (3 times the MRHOD), the incidence of postnatal mortality was increased, and
neonatal body weight gain was decreased. Neonatal development was also affected, evidenced by delayed eye
opening, pinna detachment and preputial separation, and by decreased motor activity.
There are no adequate and well-controlled studies of TRAVATAN Z® (travoprost ophthalmic solution) 0.004%
administration in pregnant women. Because animal reproductive studies are not always predictive of
human response, TRAVATAN Z® Solution should be administered during pregnancy only if the potential
benefit justifies the potential risk to the fetus.
Nursing Mothers
A study in lactating rats demonstrated that radiolabeled travoprost and/or its metabolites were excreted in
milk. It is not known whether this drug or its metabolites are excreted in human milk. Because many drugs
are excreted in human milk, caution should be exercised when TRAVATAN Z® Solution is administered to
a nursing woman.
Pediatric Use
Use in pediatric patients below the age of 16 years is not recommended because of potential safety
concerns related to increased pigmentation following long-term chronic use.
Geriatric Use
No overall clinical differences in safety or effectiveness have been observed between elderly and other
adult patients.
Hepatic and Renal Impairment
Travoprost ophthalmic solution 0.004% has been studied in patients with hepatic impairment and also in
patients with renal impairment. No clinically relevant changes in hematology, blood chemistry, or urinalysis
laboratory data were observed in these patients.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Two-year carcinogenicity studies in mice and rats at subcutaneous doses of 10, 30, or 100 mcg/kg/day
did not show any evidence of carcinogenic potential. However, at 100 mcg/kg/day, male rats were only
treated for 82 weeks, and the maximum tolerated dose (MTD) was not reached in the mouse study. The high
dose (100 mcg/kg) corresponds to exposure levels over 400 times the human exposure at the maximum
recommended human ocular dose (MRHOD) of 0.04 mcg/kg, based on plasma active drug levels. Travoprost
was not mutagenic in the Ames test, mouse micronucleus test or rat chromosome aberration assay.
A slight increase in the mutant frequency was observed in one of two mouse lymphoma assays in the
presence of rat S-9 activation enzymes.
Travoprost did not affect mating or fertility indices in male or female rats at subcutaneous doses up to
10 mcg/kg/day [250 times the maximum recommended human ocular dose of 0.04 mcg/kg/day on a mcg/kg
basis (MRHOD)]. At 10 mcg/kg/day, the mean number of corpora lutea was reduced, and the post-implantation
losses were increased. These effects were not observed at 3 mcg/kg/day (75 times the MRHOD).
PATIENT COUNSELING INFORMATION
Potential for Pigmentation
Patients should be advised about the potential for increased brown pigmentation of the iris, which may be
permanent. Patients should also be informed about the possibility of eyelid skin darkening, which may be
reversible after discontinuation of TRAVATAN Z® (travoprost ophthalmic solution) 0.004%.
Potential for Eyelash Changes
Patients should also be informed of the possibility of eyelash and vellus hair changes in the treated eye
during treatment with TRAVATAN Z® Solution. These changes may result in a disparity between eyes in
length, thickness, pigmentation, number of eyelashes or vellus hairs, and/or direction of eyelash growth.
Eyelash changes are usually reversible upon discontinuation of treatment.
Handling the Container
Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye,
surrounding structures, fingers, or any other surface in order to avoid contamination of the solution by
common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of
vision may result from using contaminated solutions.
When to Seek Physician Advice
Patients should also be advised that if they develop an intercurrent ocular condition (e.g., trauma or
infection), have ocular surgery, or develop any ocular reactions, particularly conjunctivitis and eyelid
reactions, they should immediately seek their physician’s advice concerning the continued use of
TRAVATAN Z® Solution.
Use with Contact Lenses
Contact lenses should be removed prior to instillation of TRAVATAN Z® Solution and may be reinserted
15 minutes following its administration.
Use with Other Ophthalmic Drugs
If more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5)
minutes between applications.
Rx Only
U.S. Patent Nos. 5,631,287; 5,889,052, 6,011,062; 6,235,781; 6,503,497; and 6,849,253
ALCON LABORATORIES, INC.
Fort Worth, Texas 76134 USA
© 2006, 2010, 2011, 2012 Novartis
4/12 TRV12070JAD
4/19/12 5:07 PM
REVIEW
Cover
Focus
Predictability and Safety of Topography-guided Hyperopic Laser Ablation
Left: Predictability of topography-guided spherical error correction in 177 hyperopic eyes of 86 patients (age: 42.5 ±11.31 years) at
12-month follow-up. Right: Change in distance visual acuity at the 12-month visit.
to decide which of the technologies
you should use.
“Over time your experience tells
you which one will be more helpful for the treatment you’re trying to
make, but I’d say 90 percent of our topography-guided treatments are done
using the Scheimpflug technology,”
he says. “However, if there’s any issue
with cornea translucency or any issue
involving peripheral irregularity, we
use placido disc. As noted, Scheimpflug is more accurate in the central
five millimeters of the cornea, and
in my opinion, placido is more accurate in the area between three and six
millimeters from the corneal center.”
(Dr. Kanellopoulos points out that the
current FDA trial is being done using
placido-based images.)
“Scheimpflug-based technology
gives us solid, primary corneal elevation data, but its curvature measurements are not as detailed as placido’s,”
notes Dr. Stojanovic. “However, there
are limits to our laser systems, and limits to how much detail can be printed
on the cornea without being lost to
remodeling. So there’s no point to
using extremely detailed information
from the placido-based system when
we know that this won’t be translated
into ablation.
“In addition,” he continues, “we
know that placido measurements are
prone to so-called ‘cumulative error’ inherent in recalculation from
curvature-diopters to microns of elevation—the ‘language’ our lasers understand. For these reasons, I think
the Scheimpflug system is a more robust source of topographic information—provided that you’ve done a
well-balanced, thorough examination
and taken all the relevant factors into
account.”
Topography vs. Wavefront
Both wavefront and topographybased ablation have advantages and
disadvantages under different circumstances:
• Different ablation strategies.
When comparing outcomes using
wavefront-guided and topographyguided ablation, Dr. Kanellopoulos
notes that the two technologies use
very different ablation strategies to
achieve the desired refraction, especially when treating an irregular cornea. “There’s an intrinsic advantage
in trying to do this with topography
instead of wavefront,” he says. “With
topography, if you’re looking at peaks
and valleys, you don’t necessarily have
to bring all of the peaks to the valley level. You can buff off the tops
of the peaks and then treat adjacent
to the valleys, thus making the valleys steeper. Using that approach, the
amount of tissue removal required to
normalize an irregular cornea is much
smaller than would be required with
wavefront.
“Suppose you have a bump on the
cornea,” he continues. “Think of it as
being like a 12-story building. Wavefront technology assumes you have
to bring the 12th floor down to the
ground floor, so you have to remove
all of that tissue. With topography you
can bring the 12th floor down to the
eighth floor level and then use steepening to do the equivalent of bringing the ground level up to sixth-floor
level. That significantly reduces the
amount of tissue removal. It’s similar to the way hyperopic treatment
works. In order to steepen the cornea
we ablate a ring of tissue in the midperiphery. Even though we haven’t
touched the cornea in the center, the
center becomes steeper.
“For this reason, when a very irregular cornea is normalized using
a topography-guided ablation, the
treatment is a combination of small
myopic and hyperopic ablations
020_rp0712_f1.indd 27
6/20/12 4:32 PM
SAVE THE DATE
2012
CALENDAR
CONTINUING PROFESSIONAL EDUCATION
FOR FELLOWS & THIRD-YEAR RESIDENTS
The Continuing Professional Education (CPE) Ophthalmology programs are CME activities designed to complement
a third-year ophthalmology residency medical education as well as fellows programs (Vitreoretinal, Cornea, and
Glaucoma). Please visit www.revophth.com/ResFellowEdu2012 for more information on the dates and curriculum. These
CME programs take place in a comfortable arena for residents and fellows to exchange ideas with their peers. Faculty for
these educational programs are comprised of physicians from both university programs and private practices. The format
of the programs consists of presentations of illustrative and unusual cases, panel discussions, and a didactic lectures
as well as a state-of-the-art, hands-on wet lab experience. It is our hope that you will encourage selected residents and
fellows to attend these educational programs, which are all accredited to ensure fair balance.
August 3-4, 2012
Fort Worth, TX
August 10-11, 2012
Fort Worth, TX
September 14-15, 2012
Fort Worth, TX
COURSE DIRECTOR
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COURSE DIRECTOR
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Tommy Korn, M.D.
Anthony C. Arnold, M.D.
Midwest Center for Sight, Des Plaines, IL
Attending Ophthalmologist,
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Memorial Hospital, San Diego
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Professor of Ophthalmology, Vice Chairman
and Director of the Ocular Oncology Service,
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For more information and to register, go to:
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4/16/12 11:02 AM
REVIEW
Cover
Focus
working in synchrony to create a more
normal surface—with less tissue removal from the peaks. This is very
important, because corneal peaks are
usually associated with thinner corneas. Of course, that’s not always the
case; for instance, with a contact-lensrelated scar, the scar area is flatter and
the cornea next to it is steeper. But in
idiopathic irregularities such as keratoconus, the steeper cornea is usually the thinner part of the cornea. In
those situations it becomes a significant issue to try to avoid removing too
much tissue from the steeper areas.”
Along these lines, Dr. Stojanovic
points out that pairing topographyguided ablation with cross-linking to
treat keratoconus patients works well
because it may create a clear optical center without ablating a large
amount of corneal tissue. “The patient
gets a good central window with fewer
higher-order aberrations at the same
time as we do cross-linking to stabilize
the keratoconus,” he explains. “We’ve
done this procedure many times, and
have had very good results, similar to
those of Dr. Kanellopoulos.”1
• Reproducibility of measurements. Another difference between
wavefront-based ablation and topography-guided ablation, according to
Dr. Kanellopoulos, is the stability of
the measurements. “Topography is a
far more stable parameter to evaluate
than wavefront, because it has far less
fluctuation,” he says. “Wavefront is a
dynamic measurement, so there is no
perfect wavefront. Of course, there’s
no perfect topography either, but if
you compare serial topographies of
the same patient from a Pentacam
or high-end placido disc device, the
standard deviation of fluctuation is
miniscule compared to the fluctuation
of the parameters on wavefront maps.
“Wavefront maps,” he continues,
“are very much affected by factors
such as centroid shift; the state of the
pupil you’re measuring; the eye’s accommodative state; whether you’re
Topography and Wavefront: Together at Last?
A. John Kanellopoulos, MD, clinical professor of ophthalmology at NYU Medical School
and medical director of the Laservision.gr Institute in Athens, Greece, notes that some
companies are now researching the possibility of combining wavefront and topographyguided data as the basis for ablation. “WaveLight is working on a software package
called ‘ray tracing’ that combines wavefront topography and biometry measurements,”
he says. “There’s also a software package by Schwind, but Schwind doesn’t have FDA
approval to sell in the United States. I’m pretty sure that Zeiss is working on a similar
concept as well.”
Aleksandar Stojanovic, MD, in charge of refractive surgery at the University Hospital in
North Norway and medical director at SynsLaser Clinic in Oslo, Norway, is skeptical that
combining wavefront higher-order aberration measurements with topography-guided
ablation will improve outcomes very much. “The only thing wavefront might contribute
is helping us measure lower-order aberrations of the entire optical system,” he says. “If
the problem is on the corneal surface as the result of previous laser surgery or scars or
keratoconus, wavefront is not going to add any magical ingredient. And, if a problem is
in the lens, you don’t want to treat it at the cornea. So why would you need to add wavefront information to the equation, other than to get a good estimate of the lower-order
aberrations?”
Dr. Stojanovic adds that with the current technology, sphere and cylinder information
obtained by wavefront can easily be manually added to the topography-guided custom
ablation measurements.
—CK
measuring monocularly or binocularly; and so forth. The literature
supports the idea that there isn’t a
single, steady, reproducible wavefront
measurement. We try to make them
consistent by dilating the eye and using dark rooms, but this is not a physiologic measurement. Nobody puts a
dilating drop in before he gets in his
car to drive at night, so why would this
be an ideal wavefront for that person?
“The information you get from
wavefront technology includes the
crystalline lens, which is dynamic,”
agrees Dr. Stojanovic. “It’s kind of
a flying target; the readings will be
different at distant and close focus,
and likely so from measurement to
measurement. Besides, I would never
want to correct lenticular problems
at the corneal level, and that’s what
you’re doing in many cases if you rely
on wavefront blindly. You’re basing
your treatment on one moment in
time when the wavefront aberrometry
was taken, and it may not be representative of the optics of the eye.
“Ultimately, I believe custom ablation, in the sense of treatment of
higher-order aberrations, is really
necessary for treatment of irregular
corneas,” he says. “And if you’re going
to treat the cornea, you should measure the cornea, not the wavefront of
the whole eye.”
“Our experience has been that if
you have both modalities available
and you’re efficient at both, you’ll
probably do 100 topography-guided
treatments for every wavefront-guided treatment,” adds Dr. Kanellopoulos. “Wavefront technology is a good
tool, but there are a lot of variables
that make it less reproducible.”
• Differences in what you’re correcting. Dr. Kanellopoulos points out
that most topographers can produce
wavefront imaging based on corneal
irregularities. “More than 90 percent
of wavefront irregularities are corneal
irregularities,” he says. “So if you’re
talking about the majority of people
with regular corneas and how you determine which ones need treatment,
020_rp0712_f1.indd 29
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Focus
a topographic map does a great job of
pointing out irregularities. It’s a very
easy map to read.
“Suppose a patient has coma on
the wavefront map generated by the
topographer,” he continues. “How do
you correct that coma? You can do a
wavefront-guided ablation. But suppose you have smaller tissue reserves,
or you don’t want to manipulate the
rest of the wavefront indices that will
be implicated in coma. In that case,
you can do a topography-guided ablation. That will just correct the coma,
Zernike C-6 and C-7, and potentially
improve the asphericity, C-12. By
definition, topography-guided treatments have the ability to improve
corneal asphericity. So now you have
a ‘wavefront-guided treatment’ that
manipulates C-6, C-7 and C-12 only.
And these are probably the most reproducible indices in wavefront and
in topography.”
“You can run into big problems if
you try to correct irregular astigmatism using wavefront-guided ablation,
mostly because you’re looking at the
whole optical system—but doing so
only through the pupillary opening,”
Dr. Stojanovic points out. “You don’t
know how the treatment result is going to be influenced by what’s going
on beyond the entrance pupil—i.e.,
where and how to park the ablation
and not cause bigger problems by
making an abrupt transition towards
the periphery.”
Dr. Kanellopoulos says that he
sees improving a limited number of
Zernike factors as the biggest advantage of doing topography-guided ablation rather than wavefront-guided.
“Topography-guided ablations improve spherical aberration,” he says.
“That’s why their results are superior
to standard treatments. And that’s why
the wavefront-optimized outcomes
data submitted to the FDA were at
least equal to the wavefront outcomes
data. People say you should do wavefront-guided treatments because you
Preop (left), postop (middle) and difference (preop minus postop) maps showing
topography-guided correction of an extremely irregular cornea with keratoconus.
improve C-12, but other platforms
accomplish the same thing.”
Dr. Stojanovic agrees. “I think
the main thing wavefront is taking
credit for is optimizing the ablation
to avoid inducing spherical aberration,” he says. “The companies introduced wavefront together with
aspheric treatments, which address
the issue of corneal asphericity. They
credited wavefront with this fantastic achievement. I think most of the
improvement ascribed to the use of
wavefront technology was the result
of two things: optimizing the asphericity by creating the right ablation
profile, and centering the ablation
on the optics of the eye instead of
the center of the pupil. These were
great improvements over the standard ablation that came before it, but
I believe the wrong technology took
credit for them.”
Dr. Kanellopoulos notes another
concern: correcting aberrations that
are helpful. “Wavefront-guided ablation changes other indices that affect
vision in ways we don’t fully understand,” he says. “Some wavefront aberrations, for example, help us to see
by enhancing our ability to make out
details. We’ve seen proof of this in
studies performed on fighter pilots.
The majority of fighter pilots have
transverse coma between the two
eyes, with the dominant eye vertical
and the nondominant eye horizontal.
Do we really want to ‘correct’ that?”
“Topography-guided custom abla-
tion treatment, or T-CAT, in general
has several potential advantages over
wavefront-guided treatment, particularly in the treatment of people who
have aberrated corneas from previous
refractive surgery,” summarizes Dr.
Stulting. “First, the measurements
are more accurate than wavefront
measurements. Second, the measurements are not pupil-dependent;
topography gives us more accurate
information about the periphery of
the cornea, which is where most of
the aberrations lie. Third, topography
isn’t affected by internal optical components such as early cataract.”
However, Dr. Stulting notes that
topography-guided ablation has a few
downsides. “T-CAT won’t allow us
to correct for any intraocular aberrations, if desirable, and topographic
measurements don’t give us any information about optical correction,”
he says. “So, you have to correct the
corneal aberrations and then correct
the optical error of the eye using two
separate and independent measurements. And, it’s a lot more work to do
it correctly than it is to do conventional or wavefront treatments. It’s more
painstaking to make sure that the data
that generate the treatment algorithm
don’t contain any artifacts.”
When is Topo-guided Best?
Dr. Kanellopoulos admits that the
majority of patients don’t require topography-guided treatment. “I don’t
020_rp0712_f1.indd 30
6/20/12 4:29 PM
want to come across as saying that
most cases need this,” he says. “However, hyperopes, which represent 10
to 14 percent of the population being
treated, are a significant subgroup.
Myopes with significant astigmatism
could be added to that group. And of
course, it’s a good option in challenging cases, such as complications, corneal irregularities, corneal scars, decentered ablations, or trying to fix older technology mishaps and imperfections. However, dealing with patients
in these challenging cases requires a
certain amount of acquired skill.”
Dr. Stojanovic says he would not
use this technology to treat higherorder aberrations if the data suggests
that corneal and lenticular aberrations
are cancelling each other. “Because
that is a possibility, we measure both
crystalline lens aberrations and corneal aberrations,” he says. “In cases
where you find more corneal higherorder aberrations than total system
aberrations, topography-guided custom ablation should be used. If some
of the lenticular aberrations become
manifest after such treatment, I believe those will diminish greatly over
time, since the crystalline lens is a
dynamic structure and can adjust itself to compensate for corneal higherorder aberrations to a certain degree.
“An OPD scan, and a couple of
other systems, measure higher-order
aberrations in both locations,” he
adds. “If I find a balance between
the corneal and internal aberrations,
then I leave the corneal higher-order
aberrations alone. That’s especially
true if the patient is younger and precataract—which most laser-correction
patients are. If the patient is older and
likely to get rid of his cataract in the
near future, I’m more likely to proceed with regularizing the cornea.”
United States, there are a few pitfalls
surgeons can avoid at the outset:
• Be careful about the topography. “The most important advice I
can offer new users is to be certain
of the quality of the topography,”
says Dr. Stojanovic. “Unfortunately,
this can be difficult to achieve when
there is irregular astigmatism; the
topography is difficult to measure
and prone to artifacts. So, spend as
much time as necessary to be sure
you have good topographic information before you start basing your ablation on it. Don’t just get the topography from the technician and put
it into the software. That’s a mistake
early users often make. You have to
think more carefully and question
the data. Does it make sense with
the patient’s symptoms? Will this
treatment address the problem we
really want to treat?”
• Don’t attempt this on complex
corneas until you’ve become more
experienced with it. “If you’re going to make radical changes on the
cornea—which is required in a very
irregular cornea, a scar, a very eccentric previous ablation or a keratoconic
eye—then you have to be concerned
about the amount of sphere and cylinder you’re adding to the treatment,”
says Dr. Kanellopoulos. “The spherical change that an irregular treatment
induces is only partially predictable,
so you probably shouldn’t jump into
using topography-guided ablation with
these types of cases at the outset.”
• Take the tear film into account.
“An uneven or broken tear film will
certainly introduce artifacts into your
topography measurements,” says Dr.
Stojanovic. “If you base your treatment on artifacts you’re in trouble. To
avoid that, pretreat any dry eye and
improve the tear film.”
Pearls for Beginners
Coming Soon?
When topography-guided ablation
finally does become available in the
Dr. Stojanovic notes that, unfortunately, innovation and development
in topography-guided laser ablation
have been very limited. “Topography-guided laser ablation has been a
niche market for many years,” he observes. “The leading manufacturers
haven’t invested a lot of R&D money
into improving the technology because there’s not much money in it.
Not a lot of patients are currently
being treated with it.
“In a way, this may be a self-perpetuating cycle,” he continues. “The
software behind this technology
hasn’t been refined very much, so
the surgeon has to think carefully
about what he or she is doing and
make adjustments because the software doesn’t do everything for you.
As a result, many doctors shy away
from treating irregular astigmatism
with topography-guided custom
ablation—thus keeping the market
small. Hopefully, now that Alcon has
entered the market, they’ll refine
the software for this application.”
Despite its limitations, Dr. Kanellopoulos says topography-guided
ablation is an extraordinary tool.
“There’s no doubt in my mind that
using topography-guided treatment,
either through the placido disc pathway or Scheimpflug image pathway,
has produced excellent results, especially in the small percentage
of irregular eyes that we deal with
every day in our refractive surgery
practice,” he says. “This had been a
dead end for these patients for many
years—but it isn’t any longer.”
“I think many American surgeons
are not aware of the theoretical
advantages of topography-guided treatment,” adds Dr. Stulting.
“However, those who are familiar
with the methodology and outcomes
are anxious to have it. This technology certainly should be part of our
armamentarium.”
1. Stojanovic A, Zhang J, Chen X, Nitter TA, Chen S, Wang Q.
Topography-guided transepithelial surface ablation followed by
corneal collagen cross-linking performed in a single combined
procedure for the treatment of keratoconus and pellucid marginal
degeneration. J Refract Surg 2010;26:2:145-52.
020_rp0712_f1.indd 31
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REVIEW
Cover Focus
Intrastromal Ablation
Refractive Surgery
Goes Intrastromal
Walter Bethke, Managing Editor
Avoiding trauma
to the corneal
surface may lead
to more stable
procedures, say
surgeons.
I
n an effort to make surgery a
more comfortable and predictable experience for the patient,
refractive surgeons have progressed
from procedures such as RK and
PRK, which elicit a healing response
with all its attendant issues, to LASIK,
a procedure that minimizes the role of
healing. Now, some surgeons are taking this idea even further by perfecting
femtosecond intrastromal treatments
that involve minimal manipulation of
the corneal surface. Here’s a look at
how the procedures work and their
current outcomes.
Intracor
Intracor is an intrastromal treatment
for presbyopia that was originally developed by Colombian surgeon Luis
Ruiz using the Technolas Perfect Vision femtosecond laser.
In Intracor, which takes about 20
seconds to perform, the surgeon uses
the laser to create five concentric
rings of different depths, centered
on the pupil, in the cornea of the patient’s non-dominant eye. The inner
ring is approximately 0.9 mm in diameter and the outer ring is 3.2 mm.
“None of the rings perforates the cornea,” explains Intracor surgeon Tobias Neuhann, MD, of Munich, Germany. “They are beneath Bowman’s
032_rp0712_f2.indd 32
and above Descemet’s membrane, so
they’re truly intrastromal. The goal of
the rings is to create a little steepening of the central cornea.”
Intracor currently is indicated for
emmetropic presbyopes, though it can
work for patients with between +0.5
and +1.5 D of error. “If the patient is
more hyperopic than that or is myopic, we can’t do it,” Dr. Neuhann says.
“This is because the treatment induces
a little myopia.”
Researchers from Heidelberg,
Germany, did a prospective, multicenter study on 63 presbyopes who
underwent Intracor.1 The researchers
report that the median uncorrected
distance visual acuity of 20/25 (r: 20/63
to 20/20 preoperatively and 20/63 to
20/16 postoperatively) and the bestcorrected distance acuity of 20/20 (r:
20/32 to 20/12.5 preop and 20/40 to
20/16 postop) remained stable. Median spherical equivalent changed from
+0.63 D preop to plano postop. The
median uncorrected near visual acuity increased significantly from 20/100
preop (r: 20/200 to 20/32) to 20/32
postop (r: 20/125 to 20/16) and eyes
gained a median of four lines (r: one
to nine lines). The study surgeons
noted a loss of two lines of bestcorrected vision in 7.1 percent of
eyes, and that the rings were faintly
visible at a year postop.
6/20/12 3:58 PM
ReLEx FLEx and SMILE
Technolas Perfect Vision
The procedure also doesn’t have
a negative effect on future intraocular lens calculations the way LASIK
does. “We haven’t specifically studied
Intracor in patients with cataracts or
who are having cataract surgery, because cataract is an exclusion criterion
for our Intracor studies,” explains Dr.
Neuhann. “But if an Intracor patient
develops a cataract later on, we have
found that the use of a customized
aspheric, monofocal IOL, corrected
for distance as usual, works well. Plus,
we can just use the normal IOL calculation formulas.”
Dr. Neuhann says the main challenge now is dealing with those patients who have minimal or no effect,
a group he calls the “underperformers.” He says he can tell if someone is
an underperformer within two hours
postop. “When the procedure works,
you’ll know it within two hours,” he
says. It’s not a true monovision because
with Intracor you want to keep distance vision and enhance near vision.
In many patients you achieve that, but
in some you don’t get a real effect. The
rate of underperformers in our series is
between 5 and 10 percent.
Ideally, when you create the five
circular rings, you will separate each
layer from the next. In these underperformers, however, there are a lot
of tissue bridges that seem to keep the
corneal layers in place. So the problem becomes, how can you break apart
the layers without being able to touch
the incisions? After studying these patients, we’ve begun an enhancement
procedure that involves massaging the
cornea in an effort to break the tissue
bridges. In two underperforming patients, we got a dramatic enhancement
with the massage. However, these results are just a clinical observation at
this point, and the massage enhancement technique isn’t CE-marked.”
Dr. Neuhann says that, in one of the
underperformers, the postop massage
took his reading vision from J7 to between J1 and J2 in one day.
The Intracor procedure’s rings induce some
myopia to boost near vision.
The challenge with the massage enhancement technique is standardizing
it. “Based on my favorable clinical impression, we now ask, ‘OK, how can
we develop a treatment protocol that
everyone can do?’ ” says Dr. Neuhann.
“In other words, right now, I do a hard
massage while some surgeons might
do a soft one—this isn’t the way to go.
We have to find a simple, effective procedure to use on non-performers at
one or two weeks postop.” He says it’s
also not feasible to massage everyone’s
cornea because that would result in the
successful patients actually experiencing an overcorrection.
Looking to the future, Dr. Neuhann
says one of the next steps is developing
an Intracor treatment for low myopes.
“For them, we add intrastromal, radiallike incisions in the corneal periphery,” he explains. “However, it doesn’t
work very well right now. It seems to
be the same problem as with the underperformers: We do a nice incision
but have no effect, probably because
there are tissue bridges that form due
to the cornea being much thicker in
the periphery.”
Though postoperative problems
such as tissue bridges persist, Dr.
Neuhann thinks they’ll eventually be
overcome with the art of surgery as
well as the science. “There’s a lot of
‘music’ in this technique,” he says. “It
takes time.”
Another approach to intrastromal
ablations is refractive lenticule extraction, an approach taken by users of the
Carl Zeiss Meditech VisuMax laser.
ReLEx uses the laser to carve out an
intrastromal lenticule, which is then
removed in one of two ways in order
to bring about a change in refraction.
The first ReLEx method that was
devised, known as femtosecond lamellar extraction or FLEx, involves using
a LASIK-like flap to gain access to the
lenticule in order to remove it. The
second method, called small-incision
lenticule extraction, is less invasive,
and involves teasing out the lenticule
through a small corneal incision, between 2 and 4 mm wide, leaving the
rest of the cornea intact.
“FLEx has started to disappear,” says
Marburg, Germany’s Walter Sekundo,
MD, who, along with Marcus Blum,
MD, of Erfurt, Germany, introduced
the ReLEx FLEx procedure around
five years ago. “People are extremely
keen on going through a small-incision
for ReLEx, because that’s what makes
the procedure so attractive and truly
different from LASIK. In some ways,
FLEx is a transitional procedure that
was developed first and was further
elaborated upon to create ReLEx
SMILE.” Currently, ReLEx can treat
myopia up to approximately -11 D and
astigmatism up to about -5 D.
“I like the SMILE procedure better
than FLEx because, from a biomechanical standpoint, it leaves a much
stronger cornea compared to one in
which you’ve made a flap,” says Aarhus, Denmark, surgeon Jesper Hjortdal, MD, PhD, who has done hundreds of ReLEx procedures. “Also,
studies will soon begin to emerge that
show that you have a better preservation of corneal sensitivity in the first
weeks or months after surgery with
SMILE, which probably will result in
less dry eye. And then there are the potential complications related to having
032_rp0712_f2.indd 33
6/20/12 3:58 PM
a flap on the eye: late trauma; flap dislocation; epithelial downgrowth with a
large flap, etc. You won’t have any of
these potential complications after a
SMILE procedure.”
Surgeons say experience has
brought a knowledge of tips and
tricks to improve outcomes. “SMILE
is slightly more manual compared
to femto-LASIK or microkeratomebased LASIK because you have to get
into this small corneal tunnel to extract
the lenticule,” says Dr. Hjortdal. “If
the lenticule isn’t completely free, you
have to go in with a small spatula and
break the remaining small tissue bridges, so this process involves some manual manipulation. It can help to place
the removed lenticule on top of the
cornea to make sure you’ve removed
every part of it. Also, if you have to go
in and loosen a lenticule, it’s important
to loosen the tissue above the lenticule
first before loosening it below. This is
because if the lenticule is sort of stuck
on the anterior cap, it can be difficult
to free it.”
Dr. Sekundo says though SMILE
seems to be closer to the ideal intrastromal procedure, it’s good to keep
FLEx in your bag of tricks. “I do FLEx
on cases with high astigmatism [over
2 D], because there’s a higher chance
of enhancement with such cases, just
as with excimer-based surgery,” he explains. “It’s much easier to enhance
the cornea if you’ve created the flap
already than if you don’t have a flap. If
you don’t have a flap to work with, you
then have to do a superficial ablation or
open the cap in order to create a flap.
“For patients in whom I’m doing a
SMILE procedure, I still use a 4-mm
incision,” adds Dr. Sekundo. “Some
surgeons use 2-mm incisions, but if
you run into trouble, a 2-mm incision
might become difficult to handle.”
Surgeons say the results of FLEx
and SMILE are comparable to LASIK,
and may have the potential to be better. In one study, surgeons performed
SMILE on 51 eyes of 41 patients with
Jesper Hjortdal, MD, PhD
REVIEW
Cover
Focus
In small-incision lenticule extraction, the
surgeon induces a refractive change by
removing an intrastromal lenticule without
having to create a flap.
a mean spherical equivalent of -4.87 D.
Six months postop, the SE was +0.03
D, and refractive stability had been
achieved by the first month. Seventynine percent of the eyes saw 20/25 or
better uncorrected, and the surgeons
say the six-month postop best-corrected vision was the same or better than
the preop best-corrected vision in 95
percent of eyes. Two eyes lost a line of
best-corrected vision.2
Dr. Hjortdal thinks ReLEx is an attractive option for high myopes because, though it has a certain amount
of error associated with it, as any treatment would, the small amount of error stays constant from low to high
myopes. “So you can’t say it’s more
precise with low myopia,” he says. “But
you can turn it around and say that it’s
as precise with high myopia as it is with
low. At my center, we predominantly
treat high myopia with it, -6 D to -11,
so if there’s one group that could benefit from this more than the others it
would be the high myopes.” He says in
his practice, in the 800 ReLEx patients
he’s done (mean error: -7.5 D) there’s
been an undercorrection of 0.1 ±0.4
D. For astigmatism, he says it undercorrects by 25 percent of the target
value on average, but adds that this
could be improved upon by modifying
the nomogram down the road.
Dr. Sekundo says his long-term outcomes have been very stable, possibly
surpassing LASIK. “After five years,
regression in my ReLEx patients is
only 0.07 D,” he says. “I’m not saying
femto-LASIK can’t provide these numbers—you could get close with it—but
you probably couldn’t achieve this low
level of regression with LASIK, as it is
essentially nothing. The problem with
excimer ablation is the higher you go
in terms of refractive error, the more
keratocyte activation there is because
it’s not a cold laser. It warms up tissue.
When you start to cook keratocytes,
they react by producing extracellular
collagen, which thickens the cornea
and gives you regression. With ReLEx
surgery, when I do -10 D, I get the
result of -10 D without having to fight
the regression to the extent I would if I
had performed excimer laser ablation.”
As surgeons have mentioned, one
of the possible challenges is handling an enhancement in a SMILE
patient, since there is no flap to lift.
“In SMILE, one option is to do PRK
on top of the cornea, because it’s usually a low amount of correction,” says
Dr. Hjortdal. “We’ve done that in two
cases. We’ve also done one case using femto-LASIK where we make a
traditional LASIK flap and treat the
bed. The last possibility, which we
haven’t tried, is to cut down to that
space where you removed the SMILE
lenticule and then lift up the flap.”
The next frontier with ReLEx is hyperopic treatments, and Dr. Sekundo
and Dr. Blum have already applied for
approval to begin a second study of it.
“For hyperopia, the lenticule’s shape is
different,” Dr. Sekundo explains. “It’s
thicker on the edge than in the center,
so, theoretically, it should be easier to
grasp. But the challenge is the transition zone. You don’t need a transition
zone for myopia, but you do for hyperopia, and it’s probably a key issue in
terms of preventing regression.”
Intrastromal AK
In the spring of 2012, AMO/Visx’s
IntraLase laser received 510(k) clearance to perform intrastromal astigmatic keratotomy, giving surgeons a
032_rp0712_f2.indd 34
6/20/12 3:57 PM
Laser Refractive Cataract Surgery is
Now a Reality with Alcon’s LenSx® Laser.
Cataract Surgery Will Change
in a Femtosecond.
With Alcon’s LenSx® Laser, the Possibilities Have Just Begun.
Delivering the precision of a femtosecond laser to Refractive Cataract Surgery, the LenSx® Laser is designed to reproducibly perform many of the
most challenging aspects of traditional cataract surgery. Creating highly reproducible capsulotomy, lens fragmentation and all corneal incisions
including arcuate incisions with image-guided surgeon control, Alcon’s LenSx® Laser is Putting the Future in Motion.
CAUTION: United States Federal Law restricts this device to sale and use by or on the order of a physician or licensed eye care practitioner.
United States Federal Law restricts the use of this device to practitioners who have been trained in the operation of this device.
Please see adjacent page for brief summary information.
The LenSx® Laser is indicated for use in patients undergoing cataract surgery for removal of the crystalline lens.
Intended uses in cataract surgery include anterior capsulotomy, phacofragmentation, and the creation of single
plane and multiplane arc cuts/incisions in the cornea, each of which may be performed either individually or
consecutively during the same procedure.
For Important Safety Information and Full Directions for Use, please reference the LenSx® Laser Directions for Use.
To learn more about LenSx® Laser technology for Laser Refractive Cataract Surgery, visit lensxlasers.com.
© 2011 Novartis
RP0112_Alcon Lensx.indd 1
9/11
LSX11503JAD
12/14/11 11:28 AM
REVIEW
LenSx® Laser
Indication:
The LenSx® Laser is indicated for use in patients undergoing cataract surgery for
removal of the crystalline lens. Intended uses in cataract surgery include anterior
capsulotomy, phacofragmentation, and the creation of single plane and multiplane arc cuts/incisions in the cornea, each of which may be performed either
individually or consecutively during the same procedure.
Caution:
United States Federal Law restricts this device to sale and use by or on the
order of a physician or licensed eye care practitioner. United States Federal Law
restricts the use of this device to practitioners who have been trained in the
operation of this device.
Restrictions:
t 5IJTEFWJDFJTOPUJOUFOEFEGPSVTFJOQFEJBUSJDTVSHFSZ
t 1BUJFOUTNVTUCFBCMFUPMJFnBUBOENPUJPOMFTTJOBTVQJOFQPTJUJPO
t 1BUJFOUNVTUCFBCMFUPVOEFSTUBOEBOEHJWFBOJOGPSNFEDPOTFOU
t 1BUJFOUTNVTUCFBCMFUPUPMFSBUFMPDBMPSUPQJDBMBOFTUIFTJB
t 1BUJFOUTXJUIFMFWBUFE*01TIPVMEVTFUPQJDBMTUFSPJETPOMZVOEFS
close medical supervision.
Contraindications:
t $PSOFBMEJTFBTFUIBUQSFDMVEFTBQQMBOBUJPOPGUIFDPSOFBPS
transmission of laser light at 1030 nm wavelength
t %FTDFNFUPDFMFXJUIJNQFOEJOHDPSOFBMSVQUVSF
t 1SFTFODFPGCMPPEPSPUIFSNBUFSJBMJOUIFBOUFSJPSDIBNCFS
t 1PPSMZEJMBUJOHQVQJMTVDIUIBUUIFJSJTJTOPUQFSJQIFSBMUPUIF
intended diameter for the capsulotomy
t $POEJUJPOTXIJDIXPVMEDBVTFJOBEFRVBUFDMFBSBODFCFUXFFO
the intended capsulotomy depth and the endothelium
(applicable to capsulotomy only)
t 1SFWJPVTDPSOFBMJODJTJPOTUIBUNJHIUQSPWJEFBQPUFOUJBMTQBDF
into which the gas produced by the procedure can escape
t $PSOFBMUIJDLOFTTSFRVJSFNFOUTUIBUBSFCFZPOEUIFSBOHFPG
the system
t $PSOFBMPQBDJUZUIBUXPVMEJOUFSGFSFXJUIUIFMBTFSCFBN
t )ZQPUPOZHMBVDPNBPSUIFQSFTFODFPGBDPSOFBMJNQMBOU
t 3FTJEVBMSFDVSSFOUBDUJWFPDVMBSPSFZFMJEEJTFBTFJODMVEJOHBOZ
corneal abnormality (for example, recurrent corneal erosion, severe
basement membrane disease)
t 5IJTEFWJDFJTOPUJOUFOEFEGPSVTFJOQFEJBUSJDTVSHFSZ
Attention:
'PS*NQPSUBOU4BGFUZ*OGPSNBUJPOBOE'VMM%JSFDUJPOTGPS6TFQMFBTFSFGFSFODFUIF
-FO4Y¥-BTFS%JSFDUJPOTGPS6TF
Warnings:
The LenSx® Laser System should only be operated by a physician trained in its
use.
The LenSx® Laser delivery system employs one sterile disposable LenSx® Laser
1BUJFOU*OUFSGBDFDPOTJTUJOHPGBOBQQMBOBUJPOMFOTBOETVDUJPOSJOH5IF1BUJFOU
Interface is intended for single use only. The disposables used in conjunction
XJUI"-$0/¥JOTUSVNFOUQSPEVDUTDPOTUJUVUFBDPNQMFUFTVSHJDBMTZTUFN6TF
of disposables other than those manufactured by Alcon may affect system
performance and create potential hazards.
The physician should base patient selection criteria on professional experience,
published literature, and educational courses. Adult patients should be
scheduled to undergo cataract extraction.
Precautions:
t %POPUVTFDFMMQIPOFTPSQBHFSTPGBOZLJOEJOUIFTBNFSPPNBT
the LenSx® Laser.
t %JTDBSEVTFE1BUJFOU*OUFSGBDFTBTNFEJDBMXBTUF
AEs/Complications:
t $BQTVMPUPNZQIBDPGSBHNFOUBUJPOPSDVUPSJODJTJPOEFDFOUSBUJPO
t *ODPNQMFUFPSJOUFSSVQUFEDBQTVMPUPNZGSBHNFOUBUJPOPSDPSOFBM
incision procedure
t $BQTVMBSUFBS
t $PSOFBMBCSBTJPOPSEFGFDU
t 1BJO
t *OGFDUJPO
t #MFFEJOH
t %BNBHFUPJOUSBPDVMBSTUSVDUVSFT
t "OUFSJPSDIBNCFSnVJEMFBLBHFBOUFSJPSDIBNCFSDPMMBQTF
t &MFWBUFEQSFTTVSFUPUIFFZF
ª/PWBSUJT
032_rp0712_f2.indd 36
Cover
Focus
less-invasive option for patients with astigmatism.
Steven Schallhorn, MD, is medical director for the
U.K.-based refractive surgery chain Optical Express, and
says the company’s centers have performed more than 100
intrastromal AKs. “My initial take is that it works. It’s titratable and safe, and it effectively reduces cylinder, at least in
our analysis of it,” he says.
Dr. Schallhorn took part in a study of 110 eyes of 93 patients with astigmatism after cataract or refractive surgery
who underwent intrastromal AK. Their mean preop cylinder was -1.27 D (r: -3.5 to -0.5 D). The IntraLase created
the incisions beginning at 60 µm below the surface down to
80 percent depth at a 7-mm optical zone. At three months,
the mean cylinder was -0.61 ±0.5 D (r: -2.75 to 0), and 55
percent of the eyes could see 20/20 or better uncorrected
vs. 17 percent preop. Fifty-nine percent had no more
than 0.5 D of cylinder postop. On average, the treatments
achieved 78 percent of the intended cylinder correction.
“It indicates an undercorrection,” says Dr. Schallhorn. “But
it was similar across the different levels of preop cylinder,
which means we could titrate the results.” (Schallhorn J, et
al. IOVS 2012;53:ARVO E-Abstract 1504)
Dr. Schallhorn says intrastromal AK may find a niche. “In
cataract surgery, you have patients in that low to moderate
range of astigmatism where you may not want to place
a toric lens but where the corneal astigmatism is visually
significant,” he says. “The advantage of intrastromal incisions is that there’s no epithelial break, which means fast
recovery and stability. However, the potential advantage
of incisions that go from the epithelium downward is that
if you don’t get the effect you like, you can go back a week
later, for example, and open the incisions with a Sinskey
hook and you’re likely to get more of an effect. With that
approach, though, I’m concerned about the predictability.”
Dr. Schallhorn notes that, because of the way the IntraLase is doing the incisions, in a non-cataract patient the
spherical equivalent refraction must be zero or close to zero
preop, because the incisions’ coupling effect will leave the
SE the same.
The next step for intrastromal AK will be honing the nomogram. “It needs refinement,” says Dr. Schallhorn. “But it
shows the procedure is titratable, meaning you can correct
more cylinder in a controlled fashion than with the simple
nomogram we’re using. My approach to this has been to
use a simple nomogram, evaluate it carefully and scientifically, then move on to the next step. We’re in the process of
seeing how we can refine the treatment now that we have a
substantial amount of data.”
1. Holzer MP, Knorz MC, Tomalla M, Neuhann TM, Auffarth GU. Intrastromal femtosecond laser
presbyopia correction: One-year results of a multicenter study. J Refract Surg 2012;28:3:182-188.
2. Shah R, Shah S, Sengupta S. Results of small incision lenticule extraction: All-in-one femtosecond
laser refractive surgery. J Cataract Refract Surg 2011;37:1:127-37.
-49+"%
6/20/12 3:57 PM
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PROGRAMS OFFERED
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Nurse, Technician & Office Staff Program
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055_rp0612AlcSanAnt.indd 55
5/22/12 11:29 AM
REVIEW
Cover Focus
Presbyopia Surgery
Presbyopia Surgery:
Beyond Multifocal IOLs
Michelle Stephenson, Contributing Editor
Corneal inlays,
scleral implants,
and excimer and
femtosecond
laser procedures
show promise
as future options
for presbyopia
correction.
T
hree new options for presbyopia correction are currently
under investigation: corneal
inlays, scleral implants and laser procedures. Although these procedures
are not yet FDA-approved for use
in this country, they may soon become attractive alternatives for
younger presbyopic patients who do
not have cataracts or who desire a
less-invasive procedure than refractive lens exchange.
“I think there is a place for a lot of
different presbyopia surgeries. It’s not
a one-size-fits-all thing,” says Barrie
Soloway, MD, director of vision correction surgery at the New York Eye
and Ear Infirmary.
Corneal Inlays
Currently, three different corneal
inlays are under investigation. Each
offers a different principle of action.
The Kamra (AcuFocus, Irvine, Calif.)
corneal inlay uses a pinhole effect.
A recent study conducted in Turkey
found that Kamra intracorneal inlay
implantation is an effective, safe and
reversible procedure for the longterm surgical treatment of presbyopia.1 This study included patients
with emmetropic or post-LASIK
presbyopia. Patients had an uncorrected near visual acuity of 20/40 or
038_rp0712_f3.indd 38
worse that was correctable to 20/25 or
better at distance. The study included
39 patients aged 45 to 60 years, and
at the four-year follow-up, all patients
had two or more lines of improvement in uncorrected near visual acuity with no significant loss in distance
vision. The mean final uncorrected
near visual acuity was 20/20, and 96
percent of patients could read J3 or
better. Uncorrected distance visual
acuity was 20/40 or better in all eyes.
Another study with three years of
follow-up supports the safety and efficacy of the Kamra corneal inlay to
correct presbyopia.2 This study included 32 naturally emmetropic presbyopic patients, and the corneal inlay
was implanted in the non-dominant
eye. Patients’ mean uncorrected near
visual acuity improved from J6 preoperatively to J1 at three years, and
the mean uncorrected intermediate
visual acuity improved from 20/40 to
20/25 at three years. Additionally, at
three years, 97 percent of eyes had
an uncorrected near visual acuity of
J3 or better, and 91 percent had an
uncorrected intermediate visual acuity of 20/32 or better. The mean uncorrected distance visual acuity was
20/20, with all eyes achieving 20/32 or
better. Nine eyes lost one line of corrected distance visual acuity, one eye
lost more than two lines, and three
6/20/12 4:09 PM
has the capability of doing it, and surgeons seem to like the procedure.”
Another inlay under investigation
is the PresbyLens (ReVision Optics,
Lake Forest, Calif.), which is a 2-mm
corneal inlay that is designed to improve near and intermediate vision by
microscopically changing the shape of
the eye’s surface. “The inlay is placed
under a flap and creates a hyperprolate shape to the cornea, creating
negative spherical aberration and an
increased depth of field,” says Michael Gordon, MD, in private practice in La Jolla, Calif.
AcuFocus
eyes gained one line.
“Based on reports and presentations, near vision can be improved
while retaining distance visual acuity with the Kamra presbyopic inlay,” says San Diego surgeon Steven
Schallhorn, MD. “From limited data
available for the other two inlays under investigation, it appears that they
also improve near vision while retaining distance vision. But all of these
presbyopic inlays represent a compromise. For the Kamra, light entering the eye is restricted, which may
reduce contrast and night vision, and
there can be optical side effects.”
He believes that patients who can
adjust to monovision are more likely
to tolerate an inlay. “Presbyopic inlays
are only placed in one eye, and, similar to monovision, the near vision improvement is monocular. But unlike
monovision, the inlay eye can retain
distance vision,” Dr. Schallhorn says.
Two-year follow-up data from the
clinical trial of the Kamra were reported at the ASCRS meeting. “The
follow-up data showed that distance
vision was preserved and averaged
20/20 in the inlay eye,” says Dan
Durrie, MD, AcuFocus’ chief medical officer. “Near vision averaged J2,
which is good enough to read without
glasses. We saw some variability from
patient to patient during the clinical
study, and in analyzing the results, we
did find that there was a difference depending on how the pocket was made
for putting the inlay in, and some of
the modern femtosecond lasers had
better results than the early ones. So,
internationally, now that it has been
commercially approved, people are
using the modern femtosecond lasers
to create pockets in the cornea, and
they are getting even better results
than we saw in the clinical trials.”
Dr. Durrie, who is also in private
practice with Durrie Vision in Overland Park, Kan., says placing the inlay is an easy procedure to perform.
“Anyone who can do LASIK surgery
The Kamra corneal inlay.
The third inlay is the Flexivue Microlens (Presbia, Los Angeles), which
is a refractive inlay, according to Dr.
Gordon. “This means that it has a different refractive index than the cornea. It has a central clear area surrounded by an area of add that can be
varied according to patient needs. It
works in a monovision situation in the
non-dominant eye by providing add in
that eye, and it is pupil-dependent,”
he says.
One benefit of the inlays is that they
are removable, so the effect is reversible. “If patients develop a cataract
down the road, they have other options, and that just kind of makes it
interesting, compared to having your
lens replaced, which is not something
that is removable. Another benefit is
that it uses the same technology that
everybody already has, so surgeons
don’t have to go buy a new laser,” Dr.
Durrie says.
Dr. Schallhorn believes that, in the
future, an excimer laser procedure to
target a specific refractive error will
be performed along with an inlay to
improve the results. “For instance,
the Kamra inlay works on a depth of
field principle using a small aperture,”
he says. “If a patient has no refractive error and the inlay is implanted,
distance vision will be retained, and
there will be some near vision improvement. However, if the refractive error was slightly near-sighted,
then the depth of focus range should
provide better near vision while retaining distance vision. Targeting a
very specific refractive error should
result in better visual performance
after the inlay.”
A recent study conducted in Japan
found that simultaneous intracorneal
inlay implantation and LASIK to treat
presbyopia with emmetropia, hyperopia or myopia was safe and effective.3
This study included 360 eyes of 180
patients with a mean age of 52.4 years
±5.1. Patients had bilateral LASIK
with simultaneous implantation of a
corneal inlay in the non-dominant eye
to treat presbyopia and ametropia. At
the six-month postoperative visit, 64
patients were available for evaluation.
Mean uncorrected near visual acuity
in the eye with the inlay improved
seven lines in hyperopic eyes, six lines
in emmetropic eyes, and two lines
in myopic eyes. Mean uncorrected
distance visual acuity improved by
three lines in hyperopic eyes, one line
in emmetropic eyes, and 10 lines in
myopic eyes.
Scleral Implants
Another option that is currently under investigation is the PresVIEW
scleral implant, which is a two-part
clear plastic device that is approximately the size of a grain of rice.
038_rp0712_f3.indd 39
6/20/12 4:09 PM
REVIEW
Cover
Focus
Presbyopia Surgery
Mendel Communications
“I’m pretty encouraged by the
scleral implants because I like the
fact that it’s not surgery on the visual
axis. The implants are removable, and
the effect is totally reversible,” Dr.
Soloway says.
Dr. Gordon agrees, noting that the
PresVIEW scleral implant (Refocus
Group, Dallas) shows promise. “It is
currently in Phase III trials and has
been around for a long time,” he adds.
In the Phase II study, approximately
90 percent of the patients who received the PresVIEW scleral spacing
procedure reported that their closeup vision was either better than or significantly better than before surgery.
Laser Procedures
Slit-lamp view of the Flexivue Microlens.
Barrie Soloway, MD
According to Dr. Schallhorn, monovision with an excimer laser remains
popular among refractive surgeons.
A recent study conducted in Spain
found that monovision correction by
LASIK improved functional near vision in presbyopic patients.4 However,
although distance visual acuity was
good, contrast sensitivity and stereoacuity diminished significantly. In this
study, LASIK was performed with the
Allegretto Wave Eye-Q 400 Hz laser.
The dominant eye was corrected for
distance vision, and the non-dominant eye was corrected for near vision
by targeting -1.25 D of myopia. The
study included 50 eyes of 25 patients
with a mean age of 49.3 years ±4.5.
Postoperatively, more than 90 percent
of patients had a binocular uncorrected distance and near visual acuity of
0.0 logMAR or better. However, the
contrast sensitivity function diminished, especially in the non-dominant
eye and with binocular vision. All patients experienced significantly worse
stereoacuity. Visual discrimination capacity declined in non-dominant eyes
and under binocular conditions. No
significant changes occurred in dominant eyes.
Additionally, presbyLASIK and a
A patient one day after PresVIEW scleral implant placement.
femtosecond laser procedure called
Intracor (Technolas, St. Louis) are
under investigation. Neither is currently FDA-approved for use in the
United States. “Intracor works by
creating concentric rings in the cornea centrally to weaken the central
cornea so you get a push forward,
creating a hyperprolate shape,” Dr.
Gordon says. “Hopefully, we are going to have a group of procedures
that will be available, and then we, as
surgeons, will have to decide which
procedure is going to be best for a
given individual based on whether
he has a refractive error, the patient’s
age, the patient’s occupation, what
she does recreationally, and her iris
038_rp0712_f3.indd 40
6/20/12 4:10 PM
RP0412_Allergan Restasis.indd 1
3/8/12 3:17 PM
REVIEW
Cover
Focus
Presbyopia Surgery
color,” Dr. Gordon says.
A recent study found that presbyLASIK is a valuable
option for presbyopic patients considering refractive
surgery.5 In this study, 103 patients with an average age of
53.3 years underwent treatment with the VISX S4 system
and follow-up from 1.1 to 3.9 years. Preoperative refraction ranged from -9.75 D to +2.75 D. Non-dominant eyes
underwent peripheral presbyLASIK, and dominant eyes
underwent monofocal refraction-based LASIK, wavefront-guided LASIK, limbal relaxing incisions or no treatment to optimize distance vision. At the last follow-up
visit, 91.3 percent of all patients, 89 percent of hyperopes,
and 92 percent of myopes reported complete spectacle
independence, and 7.8 percent used glasses for less than
one hour per week. Distance unaided visual acuity was
at least 20/20 in 67.9 percent of hyperopes and in 70.7
percent of myopes.
“I’m not very enthusiastic about presbyLASIK in general. It cannot be undone, whereas inlays can be taken
out,” Dr. Durrie says.
A recent study has found that Intracor safely and effectively treats presbyopia.6 The study was conducted
in Croatia and included 95 eyes (49 patients had their
non-dominant eyes treated and 23 patients underwent
bilateral treatment). In this study, all eyes gained several
lines of uncorrected near visual acuity and achieved good
uncorrected distance visual acuity. A statistically significant improvement in both uncorrected near and distance
visual acuity was noted at all visits.
Dr. Schallhorn notes that all of the technology that
is currently available is a compromise. “Monovision is
a compromise. We can provide good near vision in one
eye, but that eye won’t have good distance vision, and the
other eye will have good distance vision but not good near
vision. And, accordingly, patient adaption is important.
There is an optical compromise in providing essentially
a multifocal effect. That applies also for excimer laser
procedures. There is an element of compromise. The
same thing goes for inlays. Some people are going to be
more than willing to put up with that compromise. The
watershed moment is when we can get away from this
compromise,” Dr. Schallhorn adds.
1. Yilmaz OF, Alagoz N, Pekel G, et al. Intracorneal inlay to correct presbyopia: Long-term results. J
Cataract Refract Surg 2011;37:1275-1281.
2. Seyeddain O, Hohensinn M, Riha W, et al. Small-aperture corneal inlay for the correction of
presbyopia: 3-year follow-up. J Cataract Refract Surg 2012;38:35-45.
3. Tomita M, Kanamori T, Waring GO 4th, et al. Simultaneous corneal inlay implantation and laser
in situ keratomileusis for presbyopia in patients with hyperopia, myopia, or emmetropia: Six-month
results. J Cataract Refract Surg 2012;38:495-506.
4. Alarcon A, Anera RG, Villa C, Jimenez del Barco L, Gutierrez R. Visual quality after monovision
correction by laser in situ keratomileusis in presbyopic patients. J Cataract Refract Surg
2011;37:1629-1635.
5. Epstein RL, Gurgos MA. Presbyopia treatment by monocular peripheral presbyLASIK. J Refract
Surg 2009;25:516-523.
6. Bohac M, Gabric N, Anticic M, Draca N, Dekaris I. First results of Intracor procedure in Croatia. Coll
Antropol 2011;35 Suppl 2:161-166.
038_rp0712_f3.indd 42
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5/21/12 4:32 PM
REVIEW
Therapeutic Topics
ARVO 2012 Gives
Florida Our Best
Highlights from the final Fort Lauderdale meeting of the
Association for Research in Vision and Ophthalmology.
Mark B. Abelson, MD, CM, FRCS, FARVO and Ora staff, Andover, Mass.
his year’s ARVO meeting in Fort
Lauderdale marked the end of an
era, as a fixture on the Florida convention calendar begins its nomadic cycle
of west coast to east, beginning with
next year’s meeting in Seattle. As we
bid adieu to the Sunshine State, we
look forward to new adventures across
the country. Before we go though,
here’s a look at some of the best research from this year’s meeting.
T
Retina Update
Last year saw the release of interim findings from the Comparison
of Age-related macular degeneration
Treatments Trials, the head-to-head
comparison of Avastin and Lucentis for treatment of wet AMD. This
year’s meeting opened with a twin
bill that included both results from
the completed CATT and an interim
analysis of results from the alternative
treatments to Inhibit VEGF in Agerelated choroidal Neovascularization
study.1,2 The latter was a head-to-head
comparison of the two VEGF monoclonal antibody therapies that employed a four-treatment-arm protocol
similar to the one used in the CATT
044_rp0712_ttops.indd 44
study. Monthly injections of each drug
were compared to each other, and to
“as needed” treatments arms. The
p.r.n. criteria in both studies were the
same: Any evidence of fluid, either intraretinal, subretinal or below the retinal pigment epithelium (assessed by
optical coherence tomography) was
an indication for treatment. As with
the interim results from the CATT
study, improvement in best-corrected
vision was the primary endpoint for
the IVAN trial.
Results of the IVAN study mirrored
those from the CATT: Acuity changes
were comparable for Avastin and Lucentis, and while monthly injections
were numerically superior to p.r.n.
therapy, the difference wasn’t significant. The IVAN study group also conducted a meta analysis by including
one-year data from CATT, again with
similar results.
In the second year of the CATT
study, a group of subjects receiving
monthly treatments were randomized to the p.r.n. regimen, allowing
investigators to assess potential effects
of switching patients from one injection schedule to another; this protocol
design demonstrated that the small
benefit accompanying monthly injections is lost when patients transition
to p.r.n. dosing. Analysis of secondary
endpoints reinforced the notion that
there are differences between the two
drugs: While the monthly Lucentis
group showed the highest percentage of patients without retinal fluid as
measured by OCT, this same group
also exhibited the highest rates of geographic atrophy.
Ocular Imaging
As in years past, imaging technologies and their applications were ubiquitous at this year’s ARVO meeting,
with applications that cover the eye
from front to back all on display.
Significant progress has continued
in the development of technologies
and protocols for ocular surface imaging, and these advances were wellrepresented at this year’s meeting.
A major focus was in vivo confocal
microscopy, with several poster sessions focusing particularly on corneal
imaging methods. One study correlated the density of Langerhans’
cells, an indicator of inflammation,
with a course of cyclosporine A in
6/20/12 4:14 PM
patients with severe keratoconjunctivitis sicca. HRT imaging of the
central cornea showed a significant
decrease in Langerhans’ cell density
following treatment, and this was correlated with tear-film breakup time
increases (but not with tear osmolarity or Schirmer’s tests). (Jacobi C, et
al. IOVS 2012;53:ARVO E-Abstract
2355) Another group described their
use of confocal imaging to assess agerelated changes in normal meibomian glands. They noted two major
changes in the glands over time: a
decrease in gland density and a decrease in homogeneity of acinar structures and secretions. (Canton V, et al.
IOVS 2012;53:ARVO E-Abstract 86)
Studies such as these should be useful in distinguishing the natural aging
process from pathological conditions
associated with meibomian gland dysfunction.
Improvement in imaging technologies has also made its way to the
posterior segment, with the use of
adaptive optics in combination with
other technologies. These technologies are helping us correlate structural
changes with visual function, a key
step in advancing our understanding
of degenerative retinal diseases. New
surrogate endpoints for visual acuity
based on enhanced imaging should
aid in future clinical development
programs. For example, adaptive optics scanning laser ophthalmoscopy
provides high-resolution images for
clear visualization of individual photoreceptor cells, and the high number of retinal imaging abstracts at the
2012 ARVO meeting evidenced the
burgeoning interest in this technology. Imaging the retina in real time,
AOSLO utilizes adaptive optics to remove optical aberrations from images.
In one proof-of-concept study designed to examine whether structural
parameters derived from using AOSLO on AMD patients are related
to the participants’ AMD disease severity, AOSLO was able to produce
In vivo confocal microscopy of the ocular surface is becoming increasingly popular for
following the course of diseases and monitoring treatment. For example, in this image the
normal conjunctival vasculature appears on the left. At right, confocal microscopy shows
infiltrating white cells in the vasculature following allergen exposure.
high-resolution images. In patients
with early to intermediate AMD, the
cone photoreceptors showed reduced
reflectivity and moderately increased
cell spacing, while in patients with
an advanced stage of the disease the
cone mosaic was severely disrupted,
and cone density and reflectivity were
significantly decreased compared to
that of normal subjects. (Zhang Y, et
3174) This study opens the door for
future research seeking to examine
the relationship between the statistical structural parameters of the photoreceptors.
AOSLO was also used to characterize hallmark diabetic retinopathy
lesions and then compare the findings
with those from fundus photography
and spectral domain optical coherence tomography. Microaneurysms
were not clearly distinguished from
small dot hemorrhages on ETDRS
photos and SD-OCT, but some were
identified using AOSLO by observing
red blood count flow within feeding
vessels, as well as by observing red
blood count flow within the microaneurysms themselves. AOSLO technology allows for highly detailed in
vivo imaging of diabetic retinopathy
lesions at the cellular level and is useful for discovering new morphological characteristics of various hallmark
pathologies. (Prager G, et al. IOVS
2012;53:ARVO E-Abstract 5654)
Dry Eye
Last year, we noted the growing
interest in osmolarity as a test for dryeye disease, and the continued interest in this measure was reflected in
many poster and slide presentations
at ARVO 2012. Some of these studies were efforts to identify correlations between osmolarity measures
and established dry-eye metrics such
as corneal staining, Schirmer’s testing, tear-film breakup and information from patient questionnaires such
as the Ocular Surface Disease Index
or the five-item Dry Eye Questionnaire (DEQ-5). (Bhosai SJ, et al.
IOVS 2012;53:ARVO E-Abstract 547;
Yang Y, et al. IOVS 2012;53:ARVO
E-Abstract 548; See CW, et al. IOVS
2012;53:ARVO E-Abstract 549; Messmer EM, et al. IOVS 2012; 53:ARVO
E-Abstract 556; Willmann G, et al.
IOVS 2012;53:ARVO E-Abstract
557; Torricelli AA, et al. IOVS
2012;53:ARVO E-Abstract 558) The
goal of these efforts was to identify
a test or combination of tests that
can reliably predict or otherwise be
used to diagnose dry eye. From this
year’s presentations, it doesn’t seem as
though current methods of osmolarity
6/20/12 4:14 PM
REVIEW
Therapeutic
Topics
The results of the 2011 Antibiotic Resistance Monitoring in Ocular Microorganisms study
found fluoroquinolones to be very effective against S. pneumoniae isolates.
measurement can meet that goal at
present. Several presentations reported statistically significant correlations
between these measures, while others
suggest that associations are insignificant, sporadic or both. The take-home
message is a familiar one: As one presenter stated in his conclusion “the
clinical presentation of dry-eye disease is multifactorial, thus correlation
between different tests should not be
expected.” (Sullivan BD, et al. IOVS
Another study of dry-eye metrics
examined diurnal variation in tear
osmolarity, and showed that tears
are significantly more dilute in the
morning (mean 265 mOsms/L) when
compared to tears from the same
patients measured later in the day
(mean 299 mOsms/L). (Niimi J, et
560) Such variations may contribute
to the inability to correlate osmolarity with other dry-eye metrics. Several other presentations examined the
potential impact of hyper-osmolarity
on ocular surface health: One group
reported an effect of hyper-osmolarity
on cytokine production (Jeong S, et
563), while others concluded that although increasingly solute concentra-
tions may alter frictional forces during blink, they don’t seem to have an
“adverse effect on physical properties
or stability of the tear film,” (Samsom M, et al. IOVS 2012;53:ARVO
E-Abstract 551; Mudgil P, et al. IOVS
2012;53:ARVO E-Abstract 555), this
suggests that hyper-osmolarity itself
isn’t contributing to changes in tearfilm stability of dry-eye patients.
Meanwhile, the search for additional dry-eye therapies continues.
Positive data surrounding MIM-D3
as a potential dry-eye therapy was
presented by Mimetogen Pharmaceuticals’ Karen Meerovitch, PhD,
and her colleagues. MIM-D3 is a proteolytically stable cyclic peptidomimetic identified as a selective TrkA
receptor agonist. TrkA receptor agonists are a novel pharmacological class
for ocular disease, as nerve growth
factor signaling plays a critical role in
regulating the proliferation, survival
and differentiation of neurons and
many other non-neuronal cell types,
and is mediated via both the TrkA
receptor and the p75NTR receptor.
NGF has multiple activities that may
be beneficial for dry eye, including
neurotrophic effects, corneal healing and mucin secretion. MIM-D3
has demonstrated similar activities
to NGF and is under investigation as
a pharmacologic agent to stimulate
mucin secretion for the treatment of
dry eye. In a multicenter, randomized, double-masked, placebo-controlled study utilizing the Controlled
Adverse Environment model to assess the safety and efficacy of 1% and
5% MIM-D3 compared to placebo
for the treatment of signs and symptoms of dry eye, both doses appeared
safe and well tolerated. The study
achieved significant improvements
in key approvable sign and symptom
endpoints, as MIM-D3 minimized
the exacerbation of staining postCAE exposure compared to placebo,
and significant improvements were
observed for ocular dryness during
the 28-day dosing period. A more
symptomatic subgroup of patients
showed even greater improvements
in symptoms compared to placebo
for both the 1% and 5% dose. Of the
150 subjects in the safety population,
56 reported a total of 87 treatment
emergent adverse events, 26 of which
were ocular TEAs; the majority of the
ocular TEAs were mild to moderate
in severity. (Meerovitch K, et al. IOVS
Another potential treatment for
dry eye includes the use of Thymosin Beta 4. Recent preclinical evaluations have demonstrated that Tβ4
promotes improved corneal epithelial intercellular adhesions following
injury in animal models of dry eye.
(Allan CB, et al. IOVS 2011;52:ARVO
E-Abstract 3782) Given that the results from these studies show that Tβ4
reduced corneal staining more than
positive controls and demonstrated
a statistically significant decrease
in staining compared to the vehicle
group, it was anticipated that RegeneRx Biopharmaceuticals’ RGN259 (0.1% Tβ4 ophthalmic solution)
would be a novel, safe and effective
therapeutic treatment for dry eye. In
a Phase II study comprising six study
visits and using the CAE to assess the
6/20/12 4:15 PM
safety and efficacy of RGN-259 compared to placebo,
subjects receiving the drug saw statistically significant
improvements in both the signs and symptoms. (The
study was conducted by employees of RegeneRx and
other researchers.) There was a statistically significant
reduction in central corneal fluorescein staining at visit
five from baseline compared to placebo and also a greater
reduction in exacerbation of ocular discomfort at visit
four during a 75-minute CAE challenge compared to the
placebo group. (Sosne G, et al. IOVS 2012;53:ARVO EAbstract 577)
Staff and consultants of Novagali Pharma used a post
hoc analysis to evaluate the efficacy of Novagali’s drug Cyclokat (0.1% cyclosporine cationic emulsion) in Sjögren’s
syndrome and non-Sjögren’s syndrome patients with
moderate to severe dry eye. Sjögren’s syndrome is an
autoimmune disorder characterized by lacrimal gland
destruction that leads to prominent clinical features of
dry eye and dry mouth. The researchers administered
the drug q.d. and compared it with its cationic emulsion
vehicle. Of the 379 analyzed patients, the improvement in
dry-eye symptoms in the Cyclokat group compared to vehicle was greater in both the Sjögren’s and non-Sjögren’s
groups and was similar across all levels of dry-eye severity
at baseline as defined by corneal fluorescein staining. That
being said, non-Sjögren’s patients treated with Cyclokat
showed greater improvement in dry-eye symptoms than
those with Sjögren’s, supporting the clinical notion that
dry eye in Sjögren’s patients is more difficult to treat.
(Buggage R, et al. IOVS 2012;53:ARVO E-Abstract 576)
Contact Lenses and Drug Delivery
A topic that’s generating a lot of buzz in ophthalmic
circles is that of drug delivery via contact lens wear. With
continued growth in technologies of polymer chemistry
and manufacture, the contact lens is poised for use in a
host of new therapeutic ways. Studies employing lenses
for therapeutic use in allergy and dry eye are ongoing, but
cutting-edge polymers and other innovations have paved
the way for their use in treatment areas such as glaucoma
and anti-infectives. Combinations of drug delivery and
lenses were a common thread among the presentations
at this year’s meeting, including innovative studies such as
the investigation of hydrogel lenses molecularly imprinted
with hyaluronic acid and timolol maleate. (Guidi G, et al.
IOVS 2012; 53:ARVO E-Abstract 458) Another example
of novel lens use was a pre-clinical study using lenses as a
vehicle for drug delivery of latanoprost for the treatment
of glaucoma. Using this approach, researchers were able
to show that the lens was more effective at delivery of
drug to the anterior chamber over a 14-day period than
6/20/12 4:15 PM
REVIEW
Therapeutic
Topics
the control drug, topical latanoprost.
(Ciolino J, et al. IOVS 2012;53:ARVO
E-Abstract 479) Other innovations
in contact lens technology included
a poster that described a new hydrogel lens material that was capable of
providing a continuous, sustained
release of antibiotics. A comparison performed by a researcher and
employees of SEED Co., the lens’s
maker, showed that lens drug delivery
was superior to that of gatifloxacin
0.3% or moxifloxacin 0.5% delivered
by drops. (Kobayakawa S, et al. IOVS
with an update from the Antibiotic
Resistance Monitoring in Ocular Microorganisms 2011 surveillance study.
The ARMOR study results displayed
resistance trends among ocular bacterial pathogens such as S. pneumoniae
at 32 sites using antibiotic susceptibility testing. The 2011 results showed
that while almost 46 percent of S.
pneumoniae isolates were resistant to
azithromycin, all isolates were susceptible to fluoroquinolones. Among the
fluoroquinolones, the researchers say
besifloxacin had the lowest MIC90.
(Haas W. IOVS 2012;53: ARVO E-
Anti-Infectives
Another aspect of contact lens use
presented this year was a focus on
the mechanisms underlying the linkage between poor compliance and
the contamination of lenses and lensrelated materials. Classic examples
of this association are the recent outbreaks of ocular infections attributed
to dangerous pathogens such as Acanthamoeba or Fusarium. One study
from AMO determined the comparative rates of Acanthamoeba trophozoite growth on contact lens storage
cases by seeding gram-negative bacteria from contact lens cases and Escherichia coli on non-nutrient agar plates
and inoculating with cysts of A. castellanii or A. polyphaga. Results showed
that contact lens case bacterial contaminants may support the growth of
Acanthamoeba and can provide a food
source for the organism in the development of amoebic keratitis. (Lam
A. IOVS 2012;53:ARVO E-Abstract
6172)
Other highlights from the antiinfective segment included many
posters that discussed the increasing
popularity of fluoroquinolone therapy
due to concerns of antibiotic resistance. A poster presentation by employees of and consultants to Bausch
+ Lomb examined the antibiotic resistance profile of ocular pathogens,
One study found that
contact lens case
bacterial contaminants
may support the growh
of Acanthamoeba and
can provide a food
source for the organism
in the development of
amoebic keratitis.
Abstract 6195)
In a survey designed to assess ocular
pathogen prevalence and emerging
antibiotic therapy, one study examined
the in vitro activity of a novel isothiazoquinolone (ITQ), ACH-0139586,
against common ocular pathogens (S.
aureus, S. epidermidis, S. pneumoniae, H. influenza, M. catarrhalis and
P. aeruginosa) compared with moxifloxacin and gatifloxacin. ITQs are a
new class in the quinolone family that
has been found to have good in vitro
and in vivo activity against pathogens
such as S. aureus, including MRSA
isolates.3 Fluoroquinolones typically
inhibit both DNA gyrase and topoisomerase IV, which are required for
the DNA replication process, whereas
ITQs add a third mechanism of action
as potent DNA primase inhibitors.3-8
Inhibition of DNA primase increases
efficacy and decreases the chances for
developing resistance compared with
fluoroquinolones. The study demonstrated that ACH-0139586 was more
potent relative to gatifloxacin and
moxifloxacin, regardless of methicillin
and fluoroquinolone resistance, and
that this was most apparent against
evaluated gram-positive pathogens.
(Shapiro A. IOVS 2012;53 ARVO EAbstract 6259)
Though we had to bid a fond farewell to our sunny center of research in
Ft. Lauderdale, we’re looking forward
to greeting friends and colleagues at
ARVO’s new venues, and we can’t
wait to see what study results they’ll
have in store next year. We’ll see you
in Seattle!
Dr. Abelson is a clinical professor
of ophthalmology at Harvard Medical
School and senior clinical scientist at
the Schepens Eye Research Institute.
1. Martin DF, Maguire MG, Fine SL, et al. Ranibizumab and
Bevacizumab for Treatment of Neovascular Age-Related Macular
Degeneration: Two-Year Results. Ophthalmology May 1, 2012.
[epub ahead of print]
2. 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 May 10, 2012 [epub ahead of print]
3. Pucci MJ, Podos SD, Thanassi JA, Leggio MJ, Bradbury
BJ, Deshpande M. In vitro and in vivo profiles of ACH-702, an
isothiazoloquinolone, against bacterial pathogens. Antimicrob
Agents Chemother 2011;55:6:2860-2871.
4. Agarwal A, Louise-May S, Thanassi JA, et al. Small molecule
inhibitors of E. coli primase, a novel bacterial target. Bioorg Med
Chem Lett 2007;17:10:2807-2810.
5.Cheng J, Thanassi JA, Thoma CL, Bradbury BJ, Deshpande M,
Pucci MJ. Dual targeting of DNA gyrase and topoisomerase IV:
target interactions of heteroaryl isothiazolones in Staphylococcus
aureus. Antimicrob Agents Chemother 2007;51:7:2445-2453.
6. Molina-Torres CA, Ocampo-Candiani J, Rendon A, Pucci MJ,
Vera-Cabrera L. In vitro activity of a new isothiazoloquinolone,
ACH-702, against Mycobacterium tuberculosis and other
mycobacteria. Antimicrob Agents Chemother 2010;54:5:2188.
7. Vera-Cabrera L, Campos-Rivera MP, Escalante-Fuentes WG,
Pucci MJ, Ocampo-Candiani J, Welsh O. In vitro activity of ACH702, a new isothiazoloquinolone, against Nocardia brasiliensis
compared with econazole and the carbapenems imipenem
and meropenem alone or in combination with clavulanic acid.
Antimicrob Agents Chemother 2010;54:5:2191-2193.
8. Zhang MQ, Haemers A. Quinolone antimicrobial agents:
Structure-activity relationships. Pharmazie 1991;46:10:687-700.
6/20/12 4:15 PM
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REVIEW
Glaucoma Management
Edited by Kuldev Singh, MD, and Peter A. Netland, MD, PhD
Trabeculectomy:
It’s All in the Details
A top surgeon shares his insights, strategies and techniques for
making this surgery turn out well.
By Bradford Shingleton, MD, Boston
rabeculectomy is a very different
procedure than it was 10 years ago.
Perhaps the best way to summarize
the difference is to note that we can
now customize the surgery to meet
the needs and characteristics of each
eye that we operate on. In the past,
trabeculectomy was regimented fairly
strictly into a standardized procedure
that involved a conjunctival flap, a
scleral flap and a certain number of
stitches. Today, based on the individual findings of the patient, we can
modify many aspects of the procedure.
Probably the biggest change in
the way we perform trabeculectomy
is titration of our antimetabolite
application. We’re more consistent;
we now know that the application
should be much broader, producing a
more diffuse bleb. We also appreciate
that modifying the duration of exposure can significantly increase our
chances of getting a lower pressure.
So when a patient needs a really low
pressure we’ll be more aggressive
in our use of mitomycin, while for
other patients we may choose not to
use an antimetabolite at all. Also, we
now appreciate that the tightness of
scleral flap closure is very important,
All images: Bradford Shingleton, MD
T
A Kelly Descemet’s Membrane Punch is an effective tool for creating a sclerectomy.
and thanks to laser suture lysis and
more advanced and thoughtful releasable suture techniques, we can now
modulate the flow postoperatively
better than we ever could before.
Here, I’d like to offer some strategies and observations regarding trabeculectomy, based on my experience
performing the surgery over the years.
Preoperative Considerations
The success of trabeculectomy can
be profoundly influenced by certain
051_rp0712_gm.indd 51
issues that need to be addressed prior
to surgery:
• Previous use of topical medications. This is an issue we appreciate
far more today than we did in the
past. Research has shown that chronic
use of any glaucoma medications,
whether beta blockers, alpha agonists,
prostaglandin analogues, miotics
or topical aqueous suppressants,
really does have an effect on the
cells of the conjunctiva. As a result,
healing is altered, bleeding can be
more problematic, and if the patient
6/20/12 1:40 PM
REVIEW
Glaucoma
Management
develops even a mild allergy it can be
a real problem in terms of good bleb
development.
A very common example of this,
particularly with topical alpha agonists
and carbonic anhydrase inhibitors, is
a follicular change on the conjunctiva.
Such a change can exacerbate a tendency toward postoperative conjunctival scarring. This possibility needs to
be taken into account by the surgeon;
sometimes it needs to be treated preoperatively with cessation of the offending agent and supplemental use
of topical steroids and other adjuncts.
• Previous problems with the
fellow eye. If the other eye has had
a failed filter or problematic response
to filtration surgery, I take that very
seriously. I also check to see whether
the patient has had any other previous
surgeries that could be a problem.
Make sure you’ve researched these
issues before you plan your surgery.
• Neovascular glaucoma. This
used to be the toughest glaucoma to
treat because active neovascularization
led to such a significant scarring response postoperatively. Today, things
have changed greatly with the use
of intravitreal anti-VEGF agents and
injections. Now, the key is to identify
the neovascular changes in the patient
and treat them aggressively before
attempting filtration surgery. In the
past, we were dependent on panretinal photocoagulation and panretinal cryotherapy for this purpose,
and they may still be used in very aggressive, difficult neovascular glaucomas. However, intravitreal antiVEGF agents are much more effective.
• Uveitic glaucoma. Active uveitis is still a problem, and it’s very
important to get it under control—
particularly when cataract surgery is
involved. Depending on the degree
of inflammation, we may treat with
preoperative topical steroids, but
systemic steroids are often necessary.
Today, with many immunological
Use of underwater diathermy to minimize bleeding is critical to filtration success.
pathways being identified, even
immunosuppressant therapy is sometimes used preoperatively when a
patient has recalcitrant uveitis. Note:
When glaucoma surgery is being done
in conjunction with cataract surgery,
we’ll do the glaucoma operation first
and only do the cataract operation at
a later time when the uveitis is quiet.
• Choice of anesthesia. The type
of anesthesia you choose is important
because it will impact your ability
to move the eye in the direction
you want, allowing you to get good
exposure to the trabeculectomy filtration zone. Sometimes it’s an advantage to have the patient be able to
move the eye; in that situation, topical
anesthesia is a good choice. On the
other hand, if the eye is completely
anesthetized, as with a peribulbar
approach, you may be able to position
it any way you need to.
I think it would be a mistake to
say that either method is better; this
is an area of surgeon preference. (I
myself am more comfortable with a
peribulbar approach, and then using
sutures that allow me to get good
exposure for the eye.)
Intraoperative Strategies
Here are a few of the key issues to
consider during the surgery itself:
• Choosing the conjunctival site.
Successful filtration surgery depends
on selecting an area with mobile
conjunctiva. This is particularly
important when the patient has had
previous surgery and/or any type of
scarring caused by medications or
other trauma. Also, the surgery should
be done superiorly. Most surgeons do
not do inferior filtering procedures
any more because the exposed bleb is
more prone to infection.
• Fornix or limbal flap? There’s
no simple answer here. I think either
flap is effective, and you can find
support in the published literature for
either one. There was some concern
that there might be more localization
and demarcation of blebs with limbalbased flaps, but if you achieve broad
application of an antimetabolite intraoperatively, it greatly reduces any
localization that might occur in this
situation. So either fornix or limbusbased flaps are appropriate.
I published a study of a series of
combined procedures in 47 patients
in which I alternated between limbal
and fornix-based flaps. We saw no
difference in terms of visual acuity
improvement, IOP reduction, postoperative glaucoma medication requirements or bleb configuration. It’s
possible that there might be fewer
bleb leaks with a limbal-based closure
051_rp0712_gm.indd 52
6/20/12 1:40 PM
than a fornix-based closure, but that depends on the
technique used for closure. Overall, I think this is a matter
of surgeon preference.
• Conjunctival manipulation. You should always seek
to minimize conjunctival manipulation; doing so will help
to minimize scarring.
• Getting intraoperative exposure. I like to use
an inferior limbal suture that I tuck underneath the lid
speculum for this purpose. It allows me to get excellent
exposure without any violation or suture placement in the
area of the conjunctival flap.
• Excision of Tenon’s fascia. The key thing here is
the exuberance of the fascia. Younger patients, black
patients and patients who have had previous surgery often
have a more exuberant fascia, and that may need to be
excised. The key thing with excision is to try to be above
the episcleral vascular plexus so as to minimize bleeding.
Basically, you want to fashion a conjunctival flap that’s not
too thin or too thick.
• Use of cautery. Underwater diathermy is a godsend
for glaucoma surgeons. Bleeding is anathema, and
underwater diathermy allows us to be very precise in
eliminating it. Diathermy also avoids scarring and charring
of the scleral tissue. Above all, we want to assiduously
avoid having blood in the area of the filtration zone.
• Creating the sclerectomy. Location and size are
important. The main thing is to position the sclerectomy
anteriorly, so as to avoid iris incarceration or other obstructions postoperatively, and so that when you do your
iridectomy, you avoid the peripheral iris vessels. Beyond
that, you want to be uniform and consistent in the size of
the sclerectomies you make. This will help you to know
exactly what kind of IOP reduction will result.
When it comes to the scleral flap, the shape of the
flap—triangle, rectangle or something else—probably
doesn’t make too much difference. Most important are
thickness, tightness of closure and posterior extent of the
flap; these can affect scleral flap mobilization and outflow.
For example, if the edge of your scleral flap is very close to
the sclerectomy site, then when you do laser suture lysis or
releasable sutures, the scleral flap will scroll up and there
will be less tamponade. If the edge of the flap extends
well past the sclerectomy, even if you do laser suture lysis
there will be less release and elevation of the flap over the
scleral flap.
• Consider using deep sclerectomy flap mobilization and unroofing Schlemm’s canal. When I do
a routine trabeculectomy, I often create a sclerectomy
flap underneath my traditional trabeculectomy flap,
to unroof and expose Schlemm’s canal. Though not
necessary in a standard trabeculectomy, I’m interested in
the alternative Schlemm’s canal-based procedures such
051_rp0712_gm.indd 53
6/20/12 1:44 PM
REVIEW
Glaucoma
Management
as canaloplasty and viscocanalostomy,
and performing these steps allows
me to improve my technique and become more comfortable with them.
Doing this doesn’t compromise the
trabeculectomy in any way; indeed,
there are theoretical reasons it may
enhance it by generating increased
outflow through Schlemm’s canal.
• Use of antimetabolites. Advanced glaucomatous damage with
significant visual field loss has been
shown to require significant IOP lowering. To get a low pressure, we use
broad application of an antimetabolite
in a fixed dosage with a duration of up
to three minutes or more. For other
patients not requiring such a low pressure, the dosage or time of application
might be reduced, or antimetabolites
might not be used at all.
• Releasable sutures or laser suture lysis? Whether to use releasable
Closure of limbal-based conjunctival flap high up in the fornix.
sutures or use laser suture lysis is a
matter of surgeon preference. I find
them to be equally effective. I have a
laser available to me in my clinic, so I
favor laser suture lysis, but releasable
sutures are also highly effective.
They’re basically used in the same
way as laser suture lysis.
The key thing is to use the tightness
of closure to modulate flow. We titrate
the flow on the table by deepening the
anterior chamber with balanced salt
solution and then assessing the flow
underneath the flap. We’re striving
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051_rp0712_gm.indd 54
6/20/12 1:44 PM
for slow, steady egress of aqueous
underneath the scleral flap while
the anterior chamber is formed. We
also may use digital massage and the
Traverso maneuver, where we push
on the side of the flap with a cottontipped applicator to test the flow.
• Positioning the sutures. The
conjunctival sutures should be as far
away from the action zone as possible.
If I do a limbal-based flap, I want the
incision to be as high up in the fornix
as possible and as small as possible.
If it’s a fornix-based flap, I like to use
wing sutures of inert material that will
not stimulate more scarring.
If possible, I favor scleral flap sutures
parallel to the limbus as opposed to
perpendicular to the limbus. Sutures
that are perpendicular tend to create
more astigmatism, which can affect
visual recovery. This is particularly
important for combined procedures.
• Creating the peripheral iridectomy. I favor creating iridectomies
in all phakic eyes. I like to have the
peripheral iridectomy be broad and
basal to avoid iris obstruction and
incarceration of the sclerectomy
postoperatively, and to minimize the
chance of pupillary block. A PI may
not be required in every combined
glaucoma cataract operation, and we
don’t do iridectomies when we use
the ExPRESS shunt.
• Conjunctival closure. This is a
complicated subject, in part because
there are multiple closure techniques.
Limbal-based flap closure can involve
running and interrupted closure
techniques that may or may not
incorporate Tenon’s fascia. Fornixbased flaps closure techniques usually
depend on whether you have retained
a limbal remnant. If you do an anterior dissection of your fornix flap
and do not leave a limbal remnant,
most surgeons will use wing sutures; I
often use horizontal mattress sutures
in addition. If you’re leaving a limbal
remnant, most surgeons will do a
running closure of the conjunctival
A completed trabeculectomy with a diffuse, 360-degree filtration bleb.
flap to the limbal remnant.
The take-home message here is
that there are multiple ways to close
conjunctiva. You need to develop a
technique that works in your hands.
• Test for bleb leaks on the
table. It’s very important to test for
leaks intraoperatively and close them
while you’re in the OR. Also, look for
leaks postoperatively using 2% fluorescein, and treat those appropriately.
At the Close of Surgery
For basic postoperative care, I routinely use topical cycloplegics to put
the ciliary body at rest and to tighten
the zonules to help maintain the anterior chamber depth. We routinely
have the patient use topical prednisolone acetate six times a day—more often in high-risk eyes. We also use a topical antibiotic for a couple of weeks.
In many cases, you’ll want to release the sutures to modulate the
flow postoperatively. The big issue
with either releasable sutures or laser
suture lysis is the timing of release. If
we’ve used intraoperative metabolites,
we favor delaying the release of the
sutures or performing laser suture lysis for at least a week postoperatively,
to minimize the chance of converting
a high pressure to a low pressure with
a shallow chamber and choroidal attachment formation. If we didn’t use
intraoperative metabolites, we prefer
to do laser suture lysis or releasable
sutures a little earlier; in that situation
you can get scarring very quickly, and
we want to enhance flow underneath
the flap to elevate the bleb.
It’s a New Day
Having the ability to modify all of
the factors described above allows us
to choose and achieve a target pressure
to a far greater extent than in the
past. That’s very important, because
glaucoma is not a single disease entity.
Some patients truly need a pressure
in the single digits, while others are
fine with a pressure in the high teens.
Depending on what the patient needs,
we can now significantly modify our
choice of operation and exactly how
we execute it.
Dr. Shingleton is an associate
clinical professor of ophthalmology
at Harvard Medical School and a
clinical instructor at Tufts University
School of Medicine. He has performed
more than 50,000 cataract, glaucoma,
surgical and laser operations.
051_rp0712_gm.indd 55
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REVIEW
Retinal Insider
Edited by Carl Regillo, MD and Emmett T. Cunningham Jr., MD, PhD, MPH
Genetic Testing for
AMD Inches Forward
A look at the status of current technology and where it fits in the
management of patients with age-related macular degeneration.
Ivana K. Kim, MD, Boston
ver the past six years, we have
made great progress in understanding the complex genetics underlying age-related macular degeneration. At this point more than 25
genes have been reported to influence
AMD risk, and the identification of
the major genetic risk factors has elucidated new therapeutic targets, such
as the alternative complement pathway.1 This knowledge, combined with
advances in technology allowing for
rapid and precise genotyping, make it
now possible to profile an individual’s
genetic risk for AMD.
O
Genetic Tests for AMD Risk
There already are several commercially available tests for determining
an individual’s genetic risk for AMD as
listed in Table 1. The various tests differ in the numbers of genetic markers
and methods used for calculating risk.
The two main tests currently directed
to ophthalmic providers for patient
risk stratification are Macula Risk (ArcticDx) and RetnaGene (Sequenom).
The Macula Risk test uses markers in
four genes as well as smoking history to
predict an individual’s risk of advanced
056_rp0712_rtinsider.indd 56
AMD and categorizes patients into
five risk groups (one to five, with five
representing highest risk). Sequenom’s
RetnaGene test employs an independently validated model using 13 single nucleotide polymorphisms in the
major AMD-associated genes and is
geared specifically for predicting risk of
the neovascular form of AMD. A risk
score is generated and the patient is
categorized into three risk groups: low;
medium; or high. DeCODE genetics
offers AMD risk screening as part of its
Complete scan which analyzes genetic
risk factors for 50 conditions and must
be ordered through a physician. The
23andMe test is a retail product available directly to the general population.
The ACCE Model
Now that these tests are available, it
is necessary to determine whether it
is worthwhile to perform genetic testing. The Centers for Disease Control
and Prevention sponsored the development of the ACCE model for evaluating scientific data on emerging genetic tests. This model considers four
components: 1) analytic validity; 2)
clinical validity; 3) clinical utility; and
4) ethical/legal/social implications.2
Analytic Validity
The criterion of analytic validity refers to the technical accuracy of the
test. Current technology makes genotyping very accurate. Therefore, determining whether an individual has the
high-risk or low-risk allele at a specific
single nucleotide polymorphism is performed quite reliably. The main source
of error with the current tests available
would be likely due to problems with
sample handling.
Clinical Validity
The measure of clinical validity asks
how well a test can actually discriminate
between high- and low-risk groups. A
method for calculating this discriminative ability is plotting true positives
vs. false positives, which is called a
receiver operating curve (ROC) (See
Figure 1). The area under this curve
(AUC) is a measure of discriminative
ability, with a perfect test giving an
AUC of one. The recommended AUC
of a model for screening a population
at increased risk of disease is >0.75.3
6/20/12 4:11 PM
Figure 1. Genetic Risk Models
1.0
0.8
TPF
0.6
Three gene model
CFH + LOC model
CFH model
LOC model
C2 model
Null model
0.4
0.2
0.0
0.0
0.2
0.4
0.6
FPF
0.8
1.0
Figure 1. Examples of receiver
operating curves (ROC) for AMD models
using differing numbers of genetic variants.
The grey line represents “chance.” The
farther away a curve is from the chance line,
the better the predictive value of the model
and the closer the area under the curve
(AUC) is to 1. In this plot, the AUC=0.79 for
the three-gene model. TPF=True Positive
Frequency, FPF=False Positive Frequency.
(See endnotes for source.)
Current models for predicting AMD
risk that include various combinations
of epidemiologic, clinical and genetic
factors give AUC’s of approximately
0.8.4,5,6 Therefore, these models appear to have sufficient accuracy for
predicting advanced AMD in those
already at increased risk based on age
or evidence of early AMD.
How much does genotyping add
to our ability to predict advanced
AMD? A previous analysis by Johanna
Seddon, MD, and colleagues demonstrated that a model of AMD risk
including age, gender, education, baseline AMD grade, smoking and body
mass index had an AUC of 0.757.6 The
addition of genetic factors (SNPs in
CFH, ARMS2, C2, CFB and C3) increased the AUC to 0.821. In these
models, the baseline grade of AMD
was the strongest predictor of risk of
progression to advanced AMD. More
recently, work by Michael Klein, MD,
et al. confirmed that an individual’s
macular phenotype, represented by
the AREDS Simple Scale score (See
Figure 2. An eye with large drusen and pigmentary abnormalities. This eye would receive
two points on the AREDS Simple Scale, as described in Table 2. If the other eye had similar
findings or advanced AMD, it would also receive two points and the total score for the
patient would be four.
Table 2 and Figure 2), has the greatest
predictive value.7 The predictive models in this analysis included age, family
history, smoking, the AREDS Simple
Scale score, the presence of very large
drusen, the presence of advanced
AMD in one eye, and two polymorphisms in CFH and ARMS2 strongly
associated with risk of AMD. The AUC
was 0.872 with genetic factors included
and 0.865 without. These data indicate
that it is possible to provide accurate
assessment of risk of advanced AMD
without necessarily doing genetic testing. The authors have made their risk
calculator available online at caseyamdcalc.ohsu.edu.
One other measure of clinical validity is positive predictive value (PPV) or
the percentage of individuals identified
as high-risk who will actually develop
advanced disease. This value correlates
with disease prevalence. With regard
to the AMD scenario, the PPV of any
genetic test will be better if applied to
elderly individuals with early stages of
AMD rather than young, unaffected
individuals.
Clinical Utility
The measure of clinical utility considers how the test results will affect
clinical management of the individual.
What can we do for those individuals
whose genetic testing indicates that
they are at high risk for vision loss from
AMD? Currently, we do not have preventive measures other than high-dose
antioxidant and zinc supplements as
demonstrated by the Age-Related Eye
Disease Study.8 Experience from genetic testing for Alzheimer’s disease
revealed that those who knew that they
carried the risk variant in the ApoE
gene reported that they were more
likely to use dietary supplements as
a preventive measure against the development of the disease.9 The same
might hold true for those determined
to be at high-risk for advanced AMD.
However, some evidence suggests that
6/20/12 4:11 PM
REVIEW
Retinal
Insider
Table 1. Genetic Tests for AMD
Test
Markers
Sample
Macula Risk
CFH, ARMS2, C3, ND2, Smoking
Cheek swab
RetnaGene
(CNV risk)
CFH/CFHR region, C2, CFB, ARMS2, C3
Cheek swab or
blood
deCode Complete Scan
CFH, ARMS2/HTRA1, C2, CFB, C3
(East Asians: ARMS2/HTRA1 only)
Cheek swab
ARUP Laboratories
CFH, ARMS2
Blood
23andMe
CFH, ARMS2, C2
Saliva
those with the CFH Y402H risk allele
might have a reduced benefit from taking the AREDS supplements.10
We might also suggest more frequent monitoring for high-risk patients
and possibly recommend home monitoring devices. Preferential hyperacuity perimetry has been demonstrated
to detect early neovascular AMD with
high sensitivity and specificity.11,12 This
technology has been developed for
home monitoring, and other applications are being developed for smartphones and computers. The impact of
recommending such monitoring for
high-risk patients will need to be assessed.
What about using genetics to guide
therapy? So far, there have been no
consistent associations between response to anti-VEGF therapy and genotype.13-15 However, associations may
new diagnosis. However, the impact
of being predicted to be at high-risk of
vision loss from AMD should not be
underestimated and options for counseling should be available, as recommended for all other genetic testing.
Where We Stand Today
emerge in the future as new therapeutic pathways are targeted, for example
the complement pathway. Also, the
studies to date have been performed
to a limited number of polymorphisms.
As genotyping technology continues
to improve and becomes more affordable, more extensive analyses may be
performed revealing new associations.
Ethical/Legal/Social Implications
Currently there do not appear to
be any particular ethical or social issues associated with genetic testing
for AMD. As noted previously, genetic testing for AMD should only
be considered for patients with earlystage disease and not for young, presymptomatic individuals. Therefore,
the results of this testing should not
necessarily label individuals with a
Table 2. AREDS Simplified Severity Scale
Severity Score
Rate of Advanced AMD (five-year)
0
0.5 percent
1
3 percent
2
12 percent
3
25 percent
4
50 percent
Severity score determined by presence of large drusen (1 point) and pigment changes (1
point) in each eye.
Ferris FL, Davis MD, Clemons TE, Lee LY, Chew EY, Lindblad AS, Milton RC, Bressler SB, Klein R; Age-Related Eye Disease Study
(AREDS) Research Group. A simplified severity scale for age-related macular degeneration: AREDS Report No. 18. Arch Ophthalmol.
2005 Nov;123(11):1570-4.
Should we offer genetic testing in
routine clinical practice? In terms of
the ACCE paradigm, the analytic validity of AMD genetic tests is good,
meaning there are no technical difficulties in genotyping the major risk
variants. Clinical validity is also good in
terms of being able to accurately identify high-risk patients. However, we
must keep in mind that the accuracy is
highest if we apply these tests to those
with early-stage disease rather than the
general population. In terms of clinical
utility, we are still exploring how the
results of testing will be applied to the
management of patients with AMD.
At the present time, there do not appear to be significant ethical, legal and
social implications of genetic testing
for AMD, but these issues should be
reassessed as utilization increases.
The most significant impact of
the identification of genetic risk
factors for AMD has been the insight provided regarding potential
therapeutic targets as a result of the
elucidation of pathways involved
in disease pathogenesis. Genotyping will remain a critical element of
ongoing and future clinical trials as
more information regarding genetics
and specific disease manifestations
(genotype-phenotype correlations)
as well as genetics and response to
therapy (pharmacogenetics) remains
to be discovered. Outside of the trial
setting, given the growing availability of commercial genetic tests for
AMD, clinicians will require some
knowledge about these tests in order
to have an informed discussion with
patients who are interested in knowing their genetic profile.
6/20/12 4:11 PM
REVIEW
Dr. Kim is an associate professor of
ophthalmology at the Harvard Medical School and on the Retina Service at
Massachusetts Eye and Ear Infirmary.
Contact her at (617) 573-3367; fax:
(617) 573-3678 or ivana_kim@meei.
harvard.edu.
Figure 1 adapted from Jakobsdottir J et al. PLoS Genet.
Feb;5(2):e1000337. Epub 2009 Feb 6. doi:10.1371/journal.
pgen.1000337.g003.
Calendar
JULY
21 - 25
BERLIN
The 20th Biennial Meeting of the International Society for Eye Research will present clinicians and vision researchers from all
over the world with the latest scientific achievements and research in the field. For more information, visit kenes.com/iser.
AUGUST
8 - 11
CANCUN, MEXICO
The 18th International Course on Cornea and Refractive Surgery, a joint meeting of the World Keratoconus Society and the
Pan-American Cornea Society, will be held in Cancun. Topical issues will include technological developments, advances in
surgical techniques and international multicenter studies in the field of cornea and external diseases. For more information,
visit convention-center.net/cornea2012.
SEPTEMBER
1. DeAngelis MM, Silveira AC, Carr EA, Kim IK. Genetics of
age-related macular degeneration: current concepts, future
directions. Semin Ophthalmol 2011 May;26(3):77-93.
2. Centers for Disease Control and Prevention. ACCE. http://
www.cdc.gov/genomics/gtesting/ACCE/FBR/index.htm
3. Janssens AC, Moonesinghe R, Yang Q, Steyerberg EW, et
al. The impact of genotype frequencies on the clinical validity
of genomic profiling for predicting common chronic diseases.
Genet Med 2007;9:528-535.
4. Jakobsdottir J, Gorin MB, Conley YP, Ferrell RE, Weeks DE.
Interpretation of genetic association studies: Markers with
replicated highly significant odds ratios may be poor classifiers.
PLoS Genet 2009 Feb;5(2):e1000337. Epub 2009 Feb 6.
5. Hageman GS, Gehrs K, Lejnine S, et al. Clinical validation of
a genetic model to estimate the risk of developing choroidal
neovascular age-related macular degeneration. Human
Genomics 2011 July;5(5):1-21.
6. Seddon JM, Reynolds R, Maller J, Fagerness JA, et al. Prediction model for prevalence and incidence of advanced agerelated macular degeneration based on genetic, demographic,
and environmental variables. Invest Ophthalmol Vis Sci 2009
May;50(5):2044-53.
7. Klein ML, Francis PJ, Ferris FL 3rd, Hamon SC, Clemons
TE. Risk assessment model for development of advanced
age-related macular degeneration. Arch Ophthalmol 2011
Dec;129(12):1543-50. Epub 2011 Aug 8.
8. Age-Related Eye Disease Study Research Group. A
randomized, placebo-controlled, clinical trial of high-dose
supplementation with vitamins C and E, beta carotene, and zinc
for age-related macular degeneration and vision loss: AREDS
report no. 8. Arch Ophthalmol 2001;119:1417-36.
9. Green RC, Roberts JS, Cupples LA, Relkin NR, et al; REVEAL
Study Group. Disclosure of APOE genotype for risk of Alzheimer’s
disease. N Engl J Med 2009 Jul 16;361(3):245-54.
10. Klein M, Francis P, Rosner B, et al. CFH and LOC387715/
ARMS2 Genotypes and Treatment with Antioxidants and
Zinc for Age-Re-lated Macular Degeneration. Ophthalmology
2008;115:1019-1025.
11. Alster Y, Bressler NM, Bressler SB, Brimacombe JA, et al;
Preferential Hyperacuity Perimetry Research Group. Preferential
Hyperacuity Perimeter (PreView PHP) for detecting choroidal
neovascularization study. Ophthalmology 2005112:1758-65.
12. Lai Y, Grattan J, Shi Y, Young G, Muldrew A, Chakravarthy
U. Functional and morphologic benefits in early detection
of neovascular age-related macular degeneration using the
preferential hyperacuity perimeter. Retina 2011;31:1620-6.
13. Lee AY, Raya AK, Kymes SM, Shiels A, Brantley MA Jr.
Pharmacogenetics of complement factor H (Y402H) and
treatment of exudative age-related macular degeneration with
ranibizumab. Br J Ophthalmol 2009 May;93(5):610-3.
14. Kloeckener-Gruissem B, Barthelmes D, Labs S, Schindler
C, Kurz-Levin M, Michels S, Fleischhauer J, Berger W, Sutter F,
Menghini M. Genetic association with response to intravitreal
ranibizumab (Lucentis) in neovascular AMD patients. Invest
Ophthalmol Vis Sci 2011 Jul 1;52(7):4694-702.
15. McKibbin M, Ali M, Bansal S, Baxter PD, West K, Williams
G, Cassidy F, Inglehearn CF. CFH, VEGF and HTRA1 promoter
genotype may influence the response to intravitreal ranibizumab
therapy for neovascular age-related macular degeneration. Br J
Ophthalmol 2012 Feb;96(2):208-12.
5-8
WÜRZBURG, GERMANY
The Glaucoma Research Society annual meeting will foster discussion and interaction between leading glaucoma clinicians
and researchers to synthesize new and existing knowledge and to identify strategies for future clinical, translational or basic
research. For more information, visit glaucomasociety.org/2012.
12 - 15
ST. LOUIS
Envision Conference 2012, the largest multi-disciplinary low-vision rehabilitation and research conference in the United
States, takes place at the Hilton St. Louis at the Ballpark. This one-of-a-kind conference will feature clinical education,
workshops and research presentations by top experts in low-vision rehabilitation. CME credits will be available. For more
information, or to register, visit envisionconference.org.
OCTOBER
4-6
BUENOS AIRES, ARGENTINA
The biannual meeting of the Latin American Society of Cataract and Refractive Surgeons will meet for three days in Buenos
Aires. There will be sessions, paper presentations and surgical technique training, as well as courses for managers and
technicians. For more information, please visit congresos-rohr.info/alaccsa-r2012/index.php, alaccsa-r.com or email
[email protected].
10 - 13
NICE, FRANCE
The European Association for Vision and Eye Research is the leading ophthalmological research association in Europe, covering
all areas of ophthalmology and the visual sciences. EVER currently has over 750 members from 67 countries all over the world
and represented by 11 scientific sections, ranging from epidemiology to optics, the cornea to the retina and immunology to
genetics. Central conference events will include keynote lectures, special interest symposia, courses, workshops and plenary
lectures. Accreditation is offered by the European Accreditation Council for Continuing Medical Education (EACCME). For more
information, visit ever.be.
NOVEMBER
8-9
CHICAGO
The 43rd Annual Fall Science Symposium of the American
Society of Ophthalmic Plastic and Reconstructive Surgery
(ASOPRS) will be held at the Swissôtel in Chicago. This
meeting will provide a forum for the presentation of new
concepts, techniques and clinical experiences in orbital
disease and surgery; aesthetic surgery; and oculofacial,
orbital, and lacrimal surgery. Forum space will also be
available to discuss practice management, access to care and
physician advocacy. CME credits will be available. For more
information, visit asoprs.org.
10 - 13
CHICAGO
The American Academy of Ophthalmology’s Annual Meeting will take place in Chicago, at McCormick Place West Convention
Center. This will be a joint meeting with the Asia-Pacific Academy of Ophthalmology. APAO is a federation of national societies
whose mission is to preserve and protect the vision of the people in the Asia-Pacific region. APAO will have 45 hours of its own
programming, focusing on the current challenges facing Asia-Pacific ophthalmologists. The annual meeting will be preceded
by Subspecialty Days on the 9th and 10th. CME hours will be available. For more information, visit aao.org.
27 - 29
MANILA, PHILIPPINES
The Asia Cornea Society 3rd Biennial Scientific Meeting, held immediately prior to the Philippine Academy of Ophthalmology
annual meeting, will bring together some of the foremost leaders, innovators and visionaries in the field of cornea, external
disease, refractive surgery and eye banking from all over the world, as well as hundreds of participants especially from the
dynamic Asia Pacific Region. For more information, visit asiacorneasociety2012manila.com/index.php.
6/20/12 4:12 PM
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REVIEW
Refractive Surgery
Edited by Arturo Chayet, MD
A Closer Look at the
New EX500 Laser
The new excimer from Alcon/WaveLight has features to
enhance connectivity and decrease procedure times.
Walter Bethke, Managing Editor
t’s not often that a new excimer
laser gets approved for laser vision
correction, so when it happens, surgeons take notice. Recently, refractive
surgeons were given a new excimer
option with the Food and Drug Administration approval of the Alcon/
WaveLight EX500 laser, which brings
some new features and increased
speed to the table. Here’s a look at the
new laser and how it might fit into a
refractive practice.
I
ment ranges into higher ones, as well
as with mixed astigmatism and hyperopes, speed becomes a factor, since
desiccation becomes important with
regard to outcomes.” For comparison,
Dr. Stonecipher cites a study that compared the results of the 200-Hz Allegretto Wave to those of the 400-Hz
device in 206 eyes of 121 patients with
-6 to -12 D of error with up to 3 D of
cylinder.1 At the three- and six-month
visits in the 200-Hz group, 77 percent
(109/141) and 86 percent (121/141)
of eyes, respectively, were within
±0.50 D of the intended correction.
In the 400-Hz group, 98.5 percent
(64/65) and 100 percent (65/65) of
eyes were within ±0.50 D of the intended correction at three and six
months postoperatively.
Treatment Speed
One of the key features of the device is its ablation speed, running at
500 Hz, vs. the speed of the previous model, the Allegretto Wave IQ
400 Hz. “Granted, it’s incrementally
faster,” says Greensboro, N.C., surgeon Karl Stonecipher. “However, it
matters. With a speed of 400 Hz, the
laser ablated at a rate of two seconds
per diopter. With 500 Hz, though, it’s
speed is 1.4 seconds per diopter.” Dr.
Stonecipher says it’s been his experience that up to about -7 D, the outcomes between the 400-Hz and the
500-Hz lasers are somewhat similar.
“But when they get out of those treat-
The EX500 can be networked via a wireless connection to other Alcon instruments in the
operating room, cutting down on the number of times patient data needs to be input.
061_rp0712_rs.indd 61
6/21/12 9:37 AM
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REVIEW
Refractive
Surgery
In the 200-Hz group, at the threeand six-month follow-up 84 percent
(119/141) and 77 percent (109/141)
of eyes, respectively, saw 20/20 or better uncorrected. By contrast, in the
400-Hz group 80 percent (52/65) and
92 percent (60/65) of eyes had 20/20
or better uncorrected vision at three
and six months, respectively. At the
six-month follow-up, Dr. Stonecipher
and his colleagues found that refractive predictability and visual acuity
were statistically significantly superior
in eyes in the 400-Hz group (p<0.01).
“We found that the faster 400-Hz results were better, especially with the
higher minuses,” says Dr. Stonecipher. “And I think that’s related to
speed. This speed also increases your
throughput. Some devices run at eight
to 10 seconds per diopter, so this can
be five times faster.”
Connectivity
The EX500 is also designed in such
a way that it fits into a refractive suite
of lasers and diagnostic instruments
made by Alcon/WaveLight.
“The most interesting thing about
the new device, in my opinion, is the
connectivity features,” Dr. Stonecipher says. “You know that the most
frustrating thing for us is entering the
surgical data. You and your staff have
to enter it into the topographer, the
tomographer, the computer, the femtosecond laser and the excimer laser.
That gets old. Since it takes about
one to two minutes per unit, I have
to pay someone to sit in front of two
computers and put in basic data and
information for about half a day on
the day before those patients’ surgeries. This new laser has wireless
connectivity, so if you use the Alcon
topographer, the data you enter into
that goes to every other Alcon device in your suite. It’s a huge time
saver. Not only does this save time
and ensure I’m not losing a staff
member for half a day, it also cuts
down on data-entry errors.”
Accuracy and Safety Measures
It’s common for excimer lasers to
allow users to target refractions in
increments of 0.25 D. The EX500,
however, gives surgeons a little more
leeway, allowing them to adjust refractions in 0.01-D increments. It’s
possible that such fine adjustments
will be able to get patients closer to
20/20 vision.
“Being able to enter refractions
in 1/100 of a diopter helps you with
the accuracy of your nomogram,” Dr.
Stonecipher avers. “In some other
systems, if your nomogram called for
2.21 D of correction, you could do a
2-D treatment or a 2.25-D treatment.
With this, you can correct the 2.21 D.
It will give you that extra edge you
might need in order to get closer to
the target.”
For surgeons who want to stay on
top of even the slightest risk of ectasia,
the laser allows them to perform intraoperative, non-contact pachymetry. “It
can do the measurements both before
the procedure and during it,” says Dr.
Stonecipher. “So, for those patients
in whom you’re concerned about the
depth of the residual stromal bed, you
can make intraoperative adjustments.
For instance, if you become concerned
about the amount of tissue that the laser will have to remove, you can switch
from an 8-mm to a 6-mm optical zone.”
The eye tracker runs at 1,050 Hz and
has a latency time of 2 milliseconds,
tracks pupils from 1.5 to 8 mm and is
able to compensate for cyclotorsion.
To be sure to track the eye accurately, the EX500’s tracking system
is composed of four lights situated
in positions similar to the corners of
a rectangle, with a fifth fixation light
placed in the middle of the rectangle.
The company says that positioning
the fixation light within the other
lights helps prevent cyclotorsion and
gets the eye into the right alignment.
The system also allows the surgeon
to monitor patient fixation during the
treatment, as well.
An Eye Toward the Future
Though they’re not approved in the
United States, there are features of the
EX500 that are available elsewhere in
the world that increase its functionality
in various situations.
One of these add-ons is a topography-guided treatment module, which
works based on measurements gathered by the WaveLight topographer.
The topo-guided treatment is aimed
at patients who have asymmetric bow
ties, topographic abnormalities, decentrations or need larger treatment zones
when there’s a potential for problems
with glare and halo. “Outside of the
United States, about 85 to 90 percent
of cases on the EX500 or Allegretto
are performed with a wavefront-optimized treatment,” says Dr. Stonecipher. “Around 10 to 12 percent will be
done with the topo-guided treatment.
Finally, the use of wavefront-guided
is rare with the system, comprising
maybe 2 percent of the total.” (For a
discussion of topo-guided treatment,
see “Topography-guided Ablation:
Pros and Cons,” on p. 20.)
Dr. Stonecipher says WaveLight is
looking at ray tracing. “They’re looking at other sources of aberrations and
joining them with data points from
topography and tomography to try to
improve the outcomes of refractive
surgery,” he says. “This topo-guided
laser platform’s also being used in
conjunction with corneal cross-linking
to treat keratoconus or laser-induced
ectasia, and John Kanellopoulos,
MD, has published several papers
using the topo-guided laser with his
cross-linking treatments. Though our
cross-linking studies in the U.S. can
only cross-link the patient, in Europe
they’re also able to use the laser to correct refractive errors at the same time
as the cross-linking.”
061_rp0712_rs.indd 63
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REVIEW
Research Review
Diagnostic Capability of
SD-OCT for Glaucoma
group of researchers from Massachusetts has determined that
statistical parameters for evaluating
the diagnostic performance of the
Spectralis spectral-domain optical coherence tomography were good for
early perimetric glaucoma and were
excellent for moderately advanced
perimetric glaucoma.
Participants for this prospective,
cross-sectional study were recruited
from a university hospital clinic.
One eye of 85 normal subjects and
61 glaucoma patients with average
visual field mean deviation of -9.61
±8.76 dB was selected randomly for
the study. A subgroup of the glaucoma
patients with early visual field defects
was calculated separately.
Spectralis SD-OCT circular scans
were performed to obtain peripapillary
retinal nerve fiber layer thicknesses.
The RNFL diagnostic parameters
based on the normative database
were used alone or in combination
for identifying glaucomatous RNFL
thinning. The overall RNFL thickness
had the highest area under the
receiver operating characteristic curve
values: 0.952 for all patients and 0.895
for the early glaucoma subgroup. For
all patients, the highest sensitivity
was achieved by using two criteria:
≥1 RNFL sectors being abnormal
at the <5 percent level and overall
classification of borderline or outside
normal limits, with specificities of 88.9
A
064_rp0712_rr.indd 64
percent (CI: 95 percent) and 97.1
percent (CI: 95 percent) for these two
criteria.
Am J Ophthalmol 2012;153:815826
Wu H, de Boer J, Chen T.
Treatment Outcomes in Tube
Versus Trabeculectomy Study
esearchers report that five-year
treatment outcomes in the Tube
Versus Trabeculectomy (TVT) study
show that tube shunt surgery has a
higher success rate than trabeculectomy with MMC; both procedures
were associated with similar intraocular pressure reduction and use
of supplemental medical therapy at
five years, and additional glaucoma
surgery was needed more frequently
after trabeculectomy with MMC than
after tube shunt placement.
Seventeen clinical centers
participated in this randomized
clinical trial, with a total of 212 eyes of
212 patients enrolled, including 107
in the tube group (350-mm2 Baerveldt
glaucoma implants) and 105 in the
trabeculectomy with mitomycin-C
group. Patients, between the ages
of 18 and 85 years, had previously
had trabeculectomy and/or cataract
extraction with intraocular lens
implantation and uncontrolled
glaucoma with IOP ≥18 mmHg and
≤40 mmHg on maximum tolerated
therapy.
R
At five years, IOP (mean ±SD) was
14.4 ±6.9 mmHg in the tube group
and 12.6 ±5.9 mmHg in the trabeculectomy group (p=0.12). The cumulative probability of failure during
the five years of follow-up was 29.8
percent in the tube group and 46.9
percent in the trabeculectomy group
(p=0.002). The rate of reoperation for
glaucoma was 9 percent in the tube
group and 29 percent in the trabeculectomy group (p=0.025).
Am J Ophthalmol 2012;153:189803
Gedde S, Schiffman J, Feuer W, Herndon L, et al.
Upper Lid Blepharoplasty
Improves Contrast Sensitivity
ased on patient anecdotes of
brighter vision following upper
eyelid blepharoplasty, doctors in the
United Kingdom have demonstrated
a significant increase in contrast sensitivity in patients who have undergone
upper eyelid blepharoplasty. This information may be of use in justifying
blepharoplasty surgery in the future.
A prospective study looked at preand postoperative contrast sensitivity
measurements in patients undergoing
routine upper eyelid blepharoplasty
surgery. The patients were selected
for surgery on the basis of a functional
visual field effect from dermatochalasis; dermatochalasis is well known
to cause visual field defects in many
patients. Contrast sensitivity was mea-
B
6/20/12 4:27 PM
sured using a Pelli-Robson chart, read
at 1 m under standard lighting conditions. This produces a result in log
contrast sensitivity. Other data collected included visual acuity and an
automated 60:4 visual field. A paired
t-test was used to assess the change in
contrast sensitivity.
Twenty-eight eyes of 14 patients
underwent upper eyelid blepharoplasty surgery. The mean preoperative log contrast sensitivity was 1.49,
and the mean postoperative log contrast sensitivity was 1.64. The mean
increase in log contrast sensitivity was
0.14 (r: 0-0.45). The increase in log
contrast sensitivity was statistically
significant (p=0.00002).
Ophthal Plast Reconstr Surg
2012;28:163-165
Rogers S, Khan-Lim D, Manners R.
Aqueous Humor Variations In
Ocular Hypertension Patients
esearchers from the University
of Nebraska Medical Center in
Omaha, evaluating the interaction of
IOP pressure-lowering medications
with physiologic day and night
changes in aqueous humor dynamics
in patients with ocular hypertension,
found that latanoprost use significantly
decreased IOP during the day and
night.
Thirty patients were enrolled in
this double-masked, randomized
crossover study. Each participant underwent aqueous humor dynamics
measurement at baseline and at two
weeks of dosing in random order with
latanoprost in the evening and placebo in the morning; timolol maleate
twice daily; and dorzolamide hydrochloride twice daily. Measurements
included central corneal thickness
by ultrasound pachymetry, anterior
chamber depth by A-scan, seated and
habitual IOP by pneumatonometry,
blood pressure by sphygmomanometry, episcleral venous pressure by
venomanometry and aqueous flow
by fluorophotometry. Outflow facility
R
was assessed by fluorophotometry and
by tonography. Uveoscleral outflow
was mathematically calculated using
the Goldmann equation.
Latanoprost increased daytime
uveoscleral outflow by a mean (SD)
of 0.90 (1.46) µL/min (p=0.048), but a
nighttime increase of 0.26 (1.10) µL/
min (p=0.47) did not reach statistical
significance. Timolol use decreased
IOP during the day by reducing aqueous flow by 25 percent. Dorzolamide
use lowered IOP only at the noon
measurement and reduced daytime
aqueous flow by 16 percent. Neither
dorzolamide nor timolol use added to
the physiologic 47 percent reduction
in nighttime aqueous flow.
The daytime IOP-lowering effects
of latanoprost are mediated by an
increase in uveoscleral outflow, and
those of timolol and dorzolamide are
mediated by aqueous flow suppression. Nighttime physiologic changes
in uveoscleral outflow limit the nighttime pharmacodynamics efficacy of
latanoprost. Aqueous flow suppression with timolol and dorzolamide
was ineffective in lowering IOP at
night.
Arch Ophthalmol 2012;130;6:677684
Gulatti V, Fan S, Zhao M, Maslonka M, et al.
Serial Anti-VEGF Injections May
Lead to Persistently Elevated IOP
ccording to researchers in New
York City, clinicians should recognize that serial injections of antivascular endothelial growth factor
agents may lead to elevated IOP that
requires glaucoma therapy. This can
occur even if the patient has tolerated
multiple prior injections without IOP
elevation.
Clinical data was reviewed for 25
eyes of 23 patients with neovascular age-related macular degeneration who had increased IOP while
receiving interval doses of intravitreal
ranibizumab and/or bevacizumab.
All eyes had tolerated multiple anti-
A
VEGF injections in the past without
IOP elevations.
After a mean of 20 anti-VEGF
injections (r: 8 to 40), the mean IOP
was 28.9 mmHg (r: 22 to 58 mmHg),
compared with a baseline of 16.9
mmHg (r: 14 to 21 mmHg). The
mean highest IOP while receiving
intravitreal anti-VEGF therapy was
35.8 mmHg (r: 23 to 58 mmHg).
Overall, 23 of 25 cases required IOP
management. In the remaining two
cases, anti-VEGF dosing was switched
from regular interval dosing to an
optical coherence tomography-guided
variable regimen, with subsequent
improvement in IOP without antiglaucoma treatment.
J Glaucoma 2012;21:241-247
Tsen J, Vance S, Della Torre K, Mendonca L, Cooney M, et al.
PF Tafluprost Well-Tolerated for
Ocular Hypertension
n a randomized, double-masked
multicenter clinical trial, researchers compared the efficacy and safety
of tafluprost, a preservative-free prostaglandin analogue, with PF timolol
in patients with open-angle glaucoma
or ocular hypertension. The IOP-lowering effect of PF tafluprost was noninferior to that of the PF timolol; PF
tafluprost is an efficacious and generally well-tolerated ocular hypotensive
agent.
After discontinuation and washout
of existing ocular hypotensive
treatment, patients who had IOP
≥23 and ≤36 mmHg in at least one
eye at the 8:00 hour time point
were randomized 1:1 to 12 weeks of
treatment with either PF tafluprost
0.0015% or PF timolol 0.5%. IOP
was measured three times during the
day (8:00, 10:00 and 16:00 hours) at
baseline and at weeks two, six and 12.
It was hypothesized that PF tafluprost
would be noninferior to PF timolol
over 12 weeks with regard to change
from baseline IOP. The trial was
powered for a noninferiority margin
of 1.5 mmHg at each of the nine time
I
064_rp0712_rr.indd 65
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REVIEW
Research
Review
points assessed.
A total of 643 patients were
randomized and 618 completed
the study (PF tafluprost=306, PF
timolol=312). IOPs at the three time
points assessed during the baseline
visit ranged from 23.8 to 26.1 mmHg
in the PF tafluprost group and 23.5
to 26.0 mmHg in the PF timolol
group. IOPs at the three time points
assessed during the 12-week visit
ranged from 17.4 to 18.6 mmHg for
PF tafluprost and 17.9 to 18.5 mmHg
for PF timolol. At all nine time points,
the upper limits of the two-sided
95 percent confidence intervals for
the difference between treatments
in IOP lowering were less than the
prespecified noninferiority margin.
Similar percentages of PF tafluprost
and PF timolol patients reported
ocular pain/stinging/irritation (4.4
percent vs. 4.6 percent) and pruritus
(2.5 percent vs. 1.5 percent). The
percentages of PF tafluprost and PF
timolol patients reporting conjunctival
hyperemia were 4.4 percent vs. 1.2
percent (p=0.016).
Am J Ophthalmol 2012;153:11871196
Chabi A, Varma R, Tsai J, Lupinacci R, et al.
DLK After LASIK With
Femtosecond Laser Flap
ccording to researchers from
the University of Michigan,
diffuse laser keratitis after LASIK
with femtosecond laser flap creation
tended to be mild with little effect on
visual acuity. A case-controlled study
enrolled 801 eyes (419 patients),
with 99 eyes (12.4 percent) of 70
patients developing DLK. Most
cases comprised mild flap interface
inflammation and were treated
with a routine postoperative anti-
A
inflammatory regimen. Twenty-two
eyes (2.7 percent) required more
than one week of anti-inflammatory
treatment.
There was a statistically significant
increase in the incidence of DLK
with larger flap diameter (p=0.0171),
higher side-cut energy (p=0.0037)
and higher raster energy (p=0.0033).
Patients with DLK were less likely
to achieve corrected distance visual
acuity of 20/20 or better one day
postoperatively (p=0.0453). The
difference in acuity was no longer
present at one week. There were no
significant associations between the
incidence of DLK and preoperative
refractive error, flap thickness,
ablation depth or other treatment
parameters.
J Cataract Refract Surg
2012;38:1014-1019
de Paula F, Khairallah C, Niziol L, Musch D, Shtein R.
DUKE EYE CENTER TRUSTS
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for OPHTHALMIC STAFFING
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Duke University Eye Center
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064_rp0712_rr.indd 66
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Red Book 2013.indd 1
6/20/12 3:29 PM
REVIEW
Product News
Optos Imaging, ETDRS
Photos Comparable
ptos announced the results of a
clinical validation study comparing Optos ultra-widefield imaging to
Early Treatment Diabetic Retinopathy Study protocol fundus photography, the gold standard for assessing
severity of diabetic retinopathy. The
study, completed by the Joslin Diabetes Center, was published in the
American Journal of Ophthalmology.
ETDRS protocol seven standard
field 30-degree color fundus photography has long been the imaging benchmark for assessing diabetic
retinopathy severity. This study reports that the Optos’ ultra-widefield
non-dilated optomap images compared favorably with dilated ETDRS
photos and dilated retinal examination in determining clinical severity
of diabetic retinopathy and diabetic
macular edema.
Led by Lloyd Paul Aiello, MD,
PhD, researchers at Joslin’s Beetham
Eye Institute compared non-dilated
ultra-widefield images and ETDRS
photos in 103 patients with various
severity levels of diabetic retinopathy. The two imaging modalities
exactly matched for clinical level of
diabetic retinopathy in 84 percent of
patients and were within one level of
agreement in 91 percent. Sensitivity and specificity of ultra-widefield
images for detecting the presence
or absence of diabetic retinopathy
diagnosed on ETDRS photos were
O
068_rp0712_products.indd 68
99 percent and 100 percent.
The study also measured the
length of time to capture images using both the Optos device and a traditional digital fundus camera and
found that optomap imaging took
less than half the time of dilated ETDRS photos not including the time
needed to dilate the eyes. Thus, optomap can now allow more efficient
imaging while still maintaining the
current standards of diabetic retinopathy identification.
Dr Aiello said, “In this study,
nonmydriatic ultra-widefield imaging compared favorably with dilated
Early Treatment Diabetes Retinopathy Study protocol photography and
dilated retinal examination in determining clinical severity of diabetic
retinopathy and diabetic macular
edema. The additional benefits of
easier operation, no pupil dilation
and more rapid image acquisition
will be significant improvements if
these results are confirmed across
diverse sites and broader diabetic
populations.”
Roy Davis, CEO of Optos, added:
“We are extremely pleased with these
results which clearly demonstrate
that the ultra-widefield optomap
technology compares favorably to
current imaging standards in assessing diabetic retinopathy. We believe
that this study, combined with the
increasing body of clinical evidence,
demonstrates the benefits of ultrawidefield imaging to clinicians.”
For information, visit optos.com.
Lock Down Frame Security
ashion Optical Displays’ new Generation 2 (G2) Locking Frame
Support is designed for eye-care professionals who want to deter theft
of their inventory. Simply snap each
locking frame support onto the system’s crystal clear display tubes. Then
place a frame on the G2 support and
close the lock to keep frames in place
and secure. With this new snap-andgo lock support, it is easy to unlock
and remove the eyewear for customers to try on or to easily rearrange
the display. A unique key will unlock
all of your G2 locking frame supports. The new G2 supports are easily retrofitted into existing displays
and casework.
G2 supports are available as part
of the Display Plus Merchandising
System that makes it easy to market
F
6/21/12 9:35 AM
REVIEW
any frame with its signage display
system that directs customers to new
designer frames, or to men’s, womens’ and children’s eyewear. Display
Plus also offers straight and curved
display shelves, mirrors, graphic
holders, literature holders, chain and
cord holders, etc.
For information visit fashionoptical.com or call 1 (800) 824-4106.
Iridex Debuts Patient Website
ridex Corp. has announced the
launch of an educational website aimed at patients with diabetic
macular edema: treatmydme.com.
The website provides information
on MicroPulse Laser Therapy, a new
treatment option for DME patients.
It explains DME, describes MPLT
and addresses patients’ expectations
before, during and after treatment.
“The website’s launch will facilitate increased patient awareness and
education on MPLT as a viable option for the treatment of DME,” said
Sam Mansour, MD, medical director of the Virginia Retina Center in
Warrenton, Va., and a clinical professor of ophthalmology at the George
Washington University in Washington, D.C. “For patients struggling
with DME, it’s important to have
easy access to information on the disease and treatment options.”
MPLT is a retina-sparing solution
for the treatment of DME. MPLT
also can be used in conjunction with
drug therapy, allowing complete and
optimized management of DME
without laser-induced retinal damage, according to Iridex. The laser
delivery therapy works by electronically “chopping” the laser emission
into trains of microsecond pulses.
This enhances the physician’s ability
to more precisely control the laser
effects on target tissues, offering the
potential for ocular treatment with
less collateral effects than conventional laser treatments. For information, visit iridex.com.
I
Product Research News
Group Recommendations on Preservatives in Glaucoma Meds
Valeant Ophthalmics announced that the Working Group on Preservatives Toxicity in Glaucoma
Medications, an advisory panel of glaucoma treatment experts, recently issued recommendations
regarding how to avoid the potentially toxic effects of the preservatives used in many glaucoma
medications. The group is sponsored by Valeant Ophthalmics.
The working group discussed the tendency they observed for physicians to deal with ocular
surface disease symptoms by adding a steroid or other medication rather than removing the offending agents. Group members disagreed with this “additive” approach and offered “subtractive”
alternatives. “The first thing we do is take them off the multiple preserved medications,” said Stephen C. Pflugfelder, MD, Baylor College of Medicine. “My clinic is full of patients that have toxicity,
redness or severe lid margin problems. It’s a vicious cycle because the preservative destabilizes
the tear film and the whole process just escalates. I found that unless I take them off the offending
agent I’m never going to get to the bottom of the problem.”
Reviewing first-line glaucoma therapy options, group members pointed out that prostaglandins
were the first choice of most ophthalmologists because of their dosing, efficacy and safety. They
recommended a beta blocker such as timolol for additive therapy when required except in cardiovascular and pulmonary patients where contraindicated. Timolol is available in a preservative-free
formulation as Timoptic in Ocudose (timolol maleate 0.5%). Timoptic in Ocudose is a topical beta
blocker, but is absorbed systemically; therefore the same adverse reactions and contraindications
are found with topical administration. “If someone is not at their treatment goal, adding timolol
once a day can often times get them to the goal,” reported Don Budenz, MD, MPH, chair of ophthalmology at the University of North Carolina at Chapel Hill. “You can use timolol once a day and
get a good effect with similarly low side effects.”
Christophe Baudouin, MD, PhD, University of Paris, reported similar success with the use of
beta blockers, reiterated their long clinical history and reported that in Europe, preservative-free
beta blocker formulations available since 1997 are experiencing considerable growth. Robert
J. Noecker, MD, Ophthalmic Consultants of Connecticut, remarked that in the United States, in
contrast, awareness of the benefits of beta blockers and the availability of preservative-free
formulations was low among ophthalmologists.
Cornea Publishes Report on LipiFlow System for MGD
The results of a randomized, controlled clinical study of a new treatment for meibomian gland
dysfunction and evaporative dry-eye disease, using the LipiFlow Thermal Pulsation System, was
reported in Cornea to provide sustained improvement, on average, in both signs and symptoms.
Further, this study demonstrated the clinical utility, safety and effectiveness of LipiFlow in adult
patients with MGD and dry-eye symptoms.
The clinical study, supported by TearScience, involved nine U.S.-based investigational centers
and 139 patients (278 eyes). It compared results for patients treated with a single LipiFlow
treatment to a warm compress control for the treatment of MGD. The average total meibomian
gland score for patients who received a single LipiFlow treatment more than doubled from 6.3
±3.5 at the baseline to 16.7 ±8.7 at four weeks. The increase in the average total meibomian
score reflected an improvement in both the quality and quantity of meibomian glands secreting
lipids, which keep the water portion of tears from evaporating too quickly, as compared to before
the LipiFlow treatment. Two recognized symptom questionnaires were used in the study: the
Standard Patient Evaluation of Eye Dryness (SPEED) and the Ocular Surface Disease Index. The
average SPEED score for patients who received a single LipiFlow treatment decreased from
14.3 ±4.8 at the baseline to 7.6 ±5.8 at four weeks, demonstrating a mean reduction in dry-eye
symptoms. Similarly, the average OSDI score decreased from 32.0 ±20 at baseline to 16.6 ±18.1
at four weeks.
No serious device-related adverse events were reported for the LipiFlow System. Non-serious
device-related adverse events included moderate eyelid pain during treatment (three eyes) and
transient, moderate eye redness after treatment (one eye). LipiFlow, which applies heat and gentle
pressure to a patient’s eyelid, is designed to liquefy and evacuate obstructions in meibomian
glands during a 12-minute, in-office procedure. The goal of unblocking the glands is to allow them
to resume their natural production of lipids required for a healthy tear film. TearScience manufactures and sells a complete system comprising the LipiFlow and the LipiView Ocular Surface
Interferometer, which allows physicians to assess a patient’s tear film.
068_rp0712_products.indd 69
6/21/12 9:36 AM
REVIEW Classifieds
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REVIEW Classifieds
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ROPH0712.indd 71
6/11/12 5:12 PM
REVIEW
Resident Case Series
Before reading on, please see p. 74 for presenting complaint, history and examination.
Diagnosis, Workup and Treatment
From the clinical history and exam,
Laboratory values were remark- plantation of a hydroxyapatite implant
the mass appeared to be a rapidly able for a low hemoglobin, elevated with allograft.
growing lesion with extrascleral ex- BUN and creatinine, elevated lactate
The full globe specimen as well as
tension. The differential diagnosis dehydrogenase (LDH) and elevated orbital biopsies were sent for patholincluded metastasis, lymphoma and total protein. Liver enzymes, thyroid ogy. The orbital biopsies were negamelanoma. While melanoma can stimulating hormone and coagulation tive for tumor. The globe displayed
present with extrascleral extension, it factors were all within normal limits.
angle closure by peripheral anterior
generally does not present with such
Given the clinical and imaging find- synechiae. Microscopically, large
rapid growth. A limited workup for ings, the possible treatment options in- atypical lymphocytes and numerous
primary lung and prostate malignancy, cluded: fine needle aspiration biopsy; histiocytes were present, with approxithe most common locations of primary enucleation; or exenteration. Given mately 3.5 mm of optic invasion (See
tumors metastasizing to the eye, was the aggressive growth of the tumor Figure 3). There were tumor nodules
negative. Therefore, lymphoma was and the poor visual prognosis of the underneath the conjunctiva that were
considered a likely possibility.
eye, the patient underwent enucle- not contiguous with intraocular tumor,
Further imaging was necessary ation with four orbital biopsies and im- presumably seeded through the emisto characterize the extent of
sary canals. The tumor was
the mass. CT scan showed an
highly mitotically active, with
intravitreal mass with extra15 to 20 mitotic figures per
scleral extension. There were
high-powered field.
no additional tumor foci in
Immunohistochemistry
the orbit. As mentioned, the
findings (immunoglobulin
patient could not undergo an
lambda-light chain restricMRI due to a permanent pacetion, IgA heavy chain, CD20
maker, and he could not have
negative, CD79a positive,
a contrast dye injection secCD138 positive, MUM1 posiondary to renal failure. B-scan
tive, and PAX5 negative, 95
ultrasound showed an opacipercent positive Ki67 index)
fied vitreous cavity filled with
supported the diagnosis of
multiple lobules of presumed
high-grade large cell lymphosolid uveal tumor with overlyma with plasmablastic feaFigure 2. B-scan ultrasound of the left eye. Note the opacified
ing retinal detachment. Nasal
tures. Since it was an isolated
vitreous cavity filled with multiple lobules of presumed solid
extrascleral extension of tumor uveal tumor with overlying retinal detachment, as well as nasal tumor, the final diagnosis was
was found (See Figure 2).
plasmablastic lymphoma.
extrascleral extension of tumor.
Discussion
Plasmablastic lymphoma, according to the most recent World Health
Organization classification in 2008, is a
diffuse preparation of large neoplastic
cells that resemble B immunoblasts,
but have the immunophenotype of
plasma cells.1 The blastic proliferating
B cells have switched on the plasma
cell gene expression program.
While cases have been reported in
immunocompetent elderly individuals,
plasmablastic lymphoma has a high
incidence in immunocompromised
individuals, particularly those with human immunodeficiency virus and acquired immune deficiency syndrome.
In the first reported case series, 15 of
the 16 patients were HIV positive, and
in the largest literature review of 228
patients, 69 percent were HIV positive.2,3 Median age at presentation is
50 years old.
Plasmablastic lymphoma most commonly presents as an oral mass, but
extranodal sites have also been primarily involved as well, including reported
cases in the orbit. The pathogenesis is
072_rp0712_wills.indd 72
6/21/12 12:28 PM
REVIEW
Advertising
Index
For advertising opportunities contact:
Richard D. Bay (610) 492-1020 or [email protected]
Michelle Barrett (610) 492-1014 or [email protected]
James Henne (610) 492-1017 or [email protected]
Scott Tobin (610) 492-1011 or [email protected]
Figure 3. Pathology specimen, H&E stain. Note the mitotically
active fairly monomorphic-appearing neoplasm composed of
large atypical lymphocytes with round or oval nuclei and fairly
prominent nucleoli; superimposed upon this are numerous
histiocytes resembling tingible body macrophages that impart a
prominent starry-sky appearance.
unknown, but it is thought to originate from post-germinal
center, terminally differentiated B cells that are in transition
from immunoblast state of development to plasma cells.
Some have suggested a role for Epstein-Barr virus, as it was
present in HIV-associated plasmablastic lymphoma cells in
74 percent of cases in one review.4
Most cases of plasmablastic lymphoma present as advanced disease, in stage III or IV, and most patients die
within one year of presentation.3 Without chemotherapy,
the median survival is three months. There is no consensus
or standard of care for chemotherapy regimens to treat the
disease, and it is unclear if treatment with highly active antiretroviral therapy improves prognosis.5
The patient presented in this review went on to develop
multiple subcutaneous nodules. He elected not to have any
further workup, and he succumbed to the lymphoma several months after the development of ocular disease.
The author would like to thank Carol Shields, MD, and
Ralph Eagle Jr. , MD, of the Wills Eye Institute Ocular
Oncology Service and Ocular Pathology Department, respectively, for their time and assistance in preparing this
case report.
1. Jaffe ES, Pittaluga S. Aggressive B-cell lymphomas: A review of new and old entities in the WHO
classification. Hematology Am Soc Hematol Educ Program 2011;2011:506-14.
2. Delecluse HJ, Anagnostopoulos I, Dallenbach F, et al. Plasmablastic lymphomas of the oral cavity: A
new entity associated with the human immunodeficiency virus infection. Blood 1997;89:1413–20.
3. Castillo JJ, Winer, ES, Stachurski D, et al. Clinical and pathological differences between human
immunodeficiency virus-positive and human immunodeficiency virus-negative patients with plasmablastic lymphoma. Leuk Lymphoma 2010;51:2047-53.
4. Castillo J, Pantanowitz L, Dezube BJ. HIV-associated plasmablastic lymphoma: Lessons learned
from 112 published cases. Am J Hematol 2008;83:804-9.
5. Castillo JJ, Winer ES, Stachurski,D, et al. Prognostic factors in chemotherapy-treated patients with
HIV-associated plasmablastic lymphoma. Oncologist 2010;15:293-9.
Alcon Laboratories
2, 3, 4, 14, 25, 26, 35, 36
Phone
Fax
(800) 451-3937
(817) 551-4352
Allergan, Inc.
41, 42
Phone
(800) 347-4500
CareCredit
76
Phone
Fax
(800) 859-9975
(866) 874-4093
EyeQuick, LLC
53
Phone
(800) 596-8335
[email protected]
www.EyeQuick.com
HAI Laboratories
47
Phone
Fax
(781) 862-9884
(781) 860-7722
Keeler Instruments
9, 23
Phone
Fax
(800) 523-5620
(610) 353-7814
Merck Sharp & Dohme Corp.
75
Phone
1-800-NSC-MERCK
(1-800-672-6372)
Rhein Medical
7
Phone
Fax
(800) 637-4346
(727) 341-8123
Sightpath Medical
10
Phone
Fax
(800) 728-9616
(952) 881-1700
Vmax Vision, Inc.
13
Phone
(888) 413-7038
[email protected]
www.VmaxVision.com
This advertiser index is published as a convenience and not as part of the advertising
contract. Every care will be taken to index correctly. No allowance will be made for errors due to spelling, incorrect page number, or failure to insert.
6/21/12 3:13 PM
REVIEW
Wills Eye Resident Case Series
Edited by Kristina Pao, MD
When medical therapy fails to relieve an elderly patient’s pain
and decreased vision, he visits the Wills Oncology Service.
David H. Perlmutter, MD
Presentation
A 78-year-old male presented to the Wills Eye Ocular Oncology Service with a chief complaint of pain, decreased vision and fullness around his left eye. He had initially presented to his primary ophthalmologist with this complaint five
months prior and was placed on prednisolone acetate 1% four times daily without relief. He was then referred to a retina
specialist, who diagnosed him with uveitis and hemorrhagic choroidal detachments. The retina specialist escalated his
therapy to atropine 1% twice daily and prednisolone acetate 1% every hour. The patient’s pain was slightly improved. An
attempt to drain the hemorrhagic choroidal detachment at that time was unsuccessful.
A limited workup of a prostate-specific antigen level and chest X-ray were within normal limits. The patient could
not undergo magnetic resonance imaging due to his pacemaker, so a computed tomography scan of the orbits was performed, showing only vitreal hemorrhage without observable tumor. A contrast study could not be performed due to the
patient’s severe renal impairment. B-scan ultrasound was also negative for tumor.
Medical History
Past medical history was significant for diabetes mellitus, congestive heart failure status post-pacemaker placement
and end-stage renal failure. He was on numerous chronic medications for management of diabetes, hypertension and
renal failure. Family history was noncontributory.
Examination
Ocular examination revealed a visual acuity of 20/25 in the right eye
and light perception in the left eye. The right eye was unremarkable
except for mild non-proliferative diabetic retinopathy.
The abnormal features were limited to the left eye. The pupil on the
left was irregular and nonreactive with a relative afferent pupillary defect. Visual fields testing was limited by the poor visual acuity. Extraocular motility was limited by the mass lesion. An accurate intraocular pressure could not be obtained by Goldmann applanation or by Tono-pen.
External exam revealed an epibulbar mass measuring 11 mm long,
14 mm wide, and 5 mm thick on the left eye. The mass appeared to be
extending from the sclera (See Figure 1).
Slit lamp examination of the left eye was notable for a large epibulbar
mass that appeared to have internal vessels, as well as adjacent conjunctival vessels. A sentinel vessel was also present. There was corneal edema and neovascularization of the iris. The anterior chamber appeared
shallow, and there was a posterior chamber intraocular lens in place.
There was no view posteriorly on the left.
Figure 1. External photograph of the left eye. The left
eye showed a large pink epibulbar mass with apparent internal vessels, as well as adjacent conjunctival
vessels and a sentinel vessel. Additionally, there was
corneal edema and neovascularization of the iris.
The anterior chamber appeared shallow, and there
was a posterior chamber intraocular lens in place.
What is your differential diagnosis? What further workup would you pursue? Please turn to p. 72.
6/21/12 1:08 PM
Available
from Merck
Find out more today at zioptan.com
Copyright © 2012 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. OPTH-1019572-0004 03/12
RP0412_Merck.indd 1
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