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APRIL 2019

Beyond Eyedrops
7 Next-Generation Options
for the Anterior Segment

Biomarkers for Retinoblastoma

The Promise of Aqueous Humor

Pediatric Keratoplasty:
A Modified Surgical Technique

RPE65 Gene Therapy:

A Report From the Clinic
Experience IntelleChartPRO


Assisted Compliance Accurate Coding Knowledge Base



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What wavefront data do you use to select
EDOF IOLs for patients?

Integrated Wavefront
with criteria to qualify patient


Mitch Jackson, MD Cynthia Matossian, MD Larry Patterson, MD Neda Shamie, MD Toby Tyson, MD
Jackson Eye, IL Matossian Eye Associates, NJ Eye Centers of Tennessee Maloney Vision Institute, CA Tyson Eye, FL
The OPD-Scan III lets me There are fewer halo When we’re looking at the There are cases that I Though the EDOF is a
know if I have to correct and glare issues with true multi-focal lenses, the miss the opportunity to more forgiving technology,
any astigmatism. Angle EDOF lenses than their stronger their ADD, the avoid. That’s the case remember that it’s reverse
alpha and angle kappa lets predecessor, multi-focal tighter your tolerance has with any multi-focal or engineering the cornea. It’s
me know I’m in that zone IOLs. However, I still to be for angle alpha and extended depth of focus more forgiving if you have
where it’s safe to use EDOF look at the higher order angle kappa and as you lens; there will be patients regular astigmatism or if you
lenses. And the placido aberration map on my get lower power, you get a who will not necessarily have a little bit of macular
disk mires show me if the OPD-Scan III because little bit more leeway with be the best candidate pathology, but if you have
ocular surface is healthy– if that cornea is not the EDOF lenses. The OPD and you’re not always any type of corneal edema,
or identify the patients healthy, if it has a lot of is essential for this data… going to be able to predict these are the patients who
with poor ocular surfaces higher order aberrations, we depend on it and we’ve that ahead of time. This are going to surprise you.
that will not have great they may not be a good really been impressed by it. advanced OPD can lessen By simply observing the
outcomes. candidate for the EDOF the number of patients OPD placido rings, you can
lens. I use these maps to who may be disappointed. really stay out of trouble.
reinforce the points I am


LINK: 800-874-5274 |

APRIL 2019


46-52 Novel Drug Delivery Systems

What is in the anterior segment drug delivery
pipeline, and how might next-generation drug
delivery change patient care?


19-21 News in Review

Retina Lab-grown autologous RPEs for
dry AMD.
Cataract Investigating IOL tilt with SS-OCT
Glaucoma Using OCT to decode “snuff-out
Immunology Side effects of immune check-
point inhibitors.
23-27 Journal Highlights
Key findings from Ophthalmology, Ophthalmol-
ogy Glaucoma, Ophthalmology Retina, AJO,
JAMA Ophthalmology, and more.

29-35 Clinical Update

Retinoblastoma Biopsies Noninvasive liquid
biopsies could lead to improved diagnosis and
treatment of retinoblastoma. A look at this
19 29 promising avenue of inquiry.
RPE65 Gene Therapy Update The first gene
therapy came to market in the United States

33 37 a year ago. Experts talk about their experi-

ence with it and the effect it has had on their
patients’ quality of life.

37-38 Ophthalmic Pearls

Pediatric Keratoplasty Penetrating keratoplasty
in the pediatric population is more challenging
and has a higher complication rate than in
adults. A modified surgical technique for
young patients.

EyeNet® Magazine (ISSN 1097-2986) is published monthly by the American Academy of Ophthal­mology, 655 Beach St., San Francisco,
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41-42 Morning Rounds

A Mysterious Eyelid Mass A 47-year-old
noticed an area of fullness in her right upper
eyelid. She began to feel uneasy as the mass
grew and became readily visible. Then it
started feeling tender to the touch. What’s
your diagnosis?

55-56 Savvy Coder

E&M Versus Eye Visit Codes Three changes
to the rules for documenting E&M services.

57-58 Practice Perfect

Protecting Your Online Reputation Patients
will look you up online. Will your branding
and reviews leave a good impression?


61-62 Academy Notebook

New Academy mobile app. • A glimpse at AAO
2019 courses. • Grant for big data research.


12 Letters
Progress for ophthalmic research.

14 Opinion
The graying of ophthalmology.


66 Blink
What do you see?

© Peter Bollinger

EyeNet COPYRIGHT © 2019, American Academy of Ophthalmology, Inc.® All rights reserved. No part of this publication may be reproduced with-

out written permission from the publisher. Letters to the editor and other unsolicited material are assumed intended for publication and
are subject to editorial review, acceptance, and editing. Disclaimer. The ideas and opinions expressed in EyeNet are those of the authors,
and do not necessarily reflect any position of the editors, the publisher, or the American Academy of Ophthalmology. Because this publication provides information on
the latest developments in ophthalmology, articles may include information on drug or device applications that are not considered community standard, or that reflect
indications not included in ap­proved FDA labeling. Such ideas are provided as information and education only so that practitioners may be aware of alternative methods
of the practice of medicine. Information in this publication should not be considered endorsement, promotion, or in any other way encouragement for the use of any
particular procedure, technique, device, or product. EyeNet, its editors, the publisher, or the Academy in no event will be liable for any injury and/or damages arising out
of any decision made or action taken or not taken in reliance on information contained herein.

6  •   A P R I L 2019
NEW The first and only FDA-approved, single-dose,
sustained-release, intracameral steroid for the
treatment of postoperative inflammation1-3

For Post-Cataract Surgery Inflammation

Target Within 1-3

With a single injection at the end of cataract

surgery, anti-inflammatory efficacy begins as
early as day 1 and continues through day 301*
• The percentage of patients who received DEXYCU (517 mcg) who
had anterior chamber cell clearing on day 8 was 60% (n=94/156)
vs 20% (n=16/80) in the placebo group1
• The cumulative percentage of subjects receiving rescue medication
of ocular steroid or nonsteroidal anti-inflammatory drug (NSAID) at
day 30 was significantly lower in the DEXYCU (517 mcg) treatment
group (20%; n=31/156) compared to placebo (54%; n=43/80)1
*DEXYCU was studied in a randomized, double-masked, placebo-controlled trial. Patients received either DEXYCU or a vehicle administered by a physician at the
end of the surgical procedure. The primary endpoint was the proportion of patients with anterior chamber cell clearing (cell score=0) on postoperative day 8.


DEXYCU™ (dexamethasone intraocular suspension) 9% is indicated . Use of a corticosteroid in the treatment of patients with a history of
for the treatment of postoperative inflammation. herpes simplex requires caution and may prolong the course and may
exacerbate the severity of many viral infections
. Fungal infections of the cornea are particularly prone to coincidentally
CONTRAINDICATIONS develop with long-term local steroid application and must be
None. considered in any persistent corneal ulceration where a steroid has
WARNINGS AND PRECAUTIONS been used or is in use. Fungal culture should be taken when appropriate
Increase in Intraocular Pressure
. Prolonged use of corticosteroids, including DEXYCU, may result in . Prolonged use of corticosteroids may suppress the host response
and thus increase the hazard of secondary ocular infections. In
glaucoma with damage to the optic nerve, defects in visual acuity acute purulent conditions, steroids may mask infection or enhance
and fields of vision existing infection
. Steroids should be used with caution in the presence of glaucoma Cataract Progression
. The use of corticosteroids in phakic individuals may promote the
.Delayed Healing
The use of steroids after cataract surgery may delay healing and development of posterior subcapsular cataracts
increase the incidence of bleb formation
. In those diseases causing thinning of the cornea or sclera, perforations . The most commonly reported adverse reactions occurred in 5-15%
have been known to occur with the use of corticosteroids of subjects and included increases in intraocular pressure, corneal
Exacerbation of Infection edema and iritis
. The use of DEXYCU, as with other ophthalmic corticosteroids, is not
recommended in the presence of most active viral diseases of the Please see brief summary of full Prescribing Information
cornea and conjunctiva including epithelial herpes simplex keratitis on adjacent page.
(dendritic keratitis), vaccinia, and varicella, and also in mycobacterial
infection of the eye and fungal disease of ocular structures

References: 1. DEXYCU™ (dexamethasone intraocular suspension) 9% full U.S. Prescribing Information. EyePoint Pharmaceuticals, Inc. December 2018. 2. Donnenfeld E,
Holland E. Dexamethasone intracameral drug-delivery suspension for inflammation associated with cataract surgery: a randomized, placebo-controlled, phase III trial.
Ophthalmology. 2018;125(6):799-806. 3. Data on file. EyePoint Pharmaceuticals, Inc.

DEXYCU and the EyePoint logo are trademarks of EyePoint Pharmaceuticals, Inc.
©2019 EyePoint Pharmaceuticals, Inc. All rights reserved. 01/2019
480 Pleasant Street, Suite B300, Watertown, MA 02472 US-DEX-1900045
DEXYCU (dexamethasone intraocular suspension) 9%, 6.1 Clinical Trials Experience
for intraocular administration Because clinical studies are conducted under widely varying conditions,
Initial U.S. Approval: 1958 adverse reaction rates observed in the clinical studies of a drug cannot
BRIEF SUMMARY: Please see package insert for full prescribing information. be directly compared to rates in the clinical studies of another drug and
may not reflect the rates observed in practice.
DEXYCU (dexamethasone intraocular suspension) 9% is indicated The following adverse events rates are derived from three clinical trials
for the treatment of postoperative inflammation. in which 339 patients received the 517 microgram dose of DEXYCU. The
most commonly reported adverse reactions occurred in 5-15% of subjects
4 CONTRAINDICATIONS and included increases in intraocular pressure, corneal edema and iritis.
None. Other ocular adverse reactions occurring in 1-5% of subjects included,
5 WARNINGS AND PRECAUTIONS corneal endothelial cell loss, blepharitis, eye pain, cystoid macular edema,
5.1 Increase in Intraocular Pressure dry eye, ocular inflammation, posterior capsule opacification, blurred vision,
Prolonged use of corticosteroids including DEXYCU may result in glaucoma reduced visual acuity, vitreous floaters, foreign body sensation, photophobia,
with damage to the optic nerve, defects in visual acuity and fields of vision. and vitreous detachment.
Steroids should be used with caution in the presence of glaucoma. 8 USE IN SPECIFIC POPULATIONS
5.2 Delayed Healing 8.1 Pregnancy
The use of steroids after cataract surgery may delay healing and increase the Risk Summary
incidence of bleb formation. In those diseases causing thinning of the cornea There are no adequate and well-controlled studies of DEXYCU
or sclera, perforations have been known to occur with the use of corticosteroids. (dexamethasone intraocular suspension) in pregnant women. Topical ocular
5.3 Exacerbation of Infection administration of dexamethasone in mice and rabbits during the period
The use of DEXYCU, as with other ophthalmic corticosteroids, of organogenesis produced cleft palate and embryofetal death in mice and
is not recommended in the presence of most active viral diseases of the malformations of abdominal wall/intestines and kidneys in rabbits at doses
cornea and conjunctiva including epithelial herpes simplex keratitis 7 and 5 times higher than the injected recommended human ophthalmic dose
(dendritic keratitis), vaccinia, and varicella, and also in mycobacterial (RHOD) of DEXYCU (517 micrograms dexamethasone), respectively
infection of the eye and fungal disease of ocular structures. [see Data in the full prescribing information].
Employment of a corticosteroid medication in the treatment of patients In the US general population the estimated background risk of major birth
with a history of herpes simplex requires caution. Use of ocular steroids may defects and miscarriage in clinically recognized pregnancies is 2 to 4%
prolong the course and may exacerbate the severity of many viral infections and 15 to 20%, respectively.
of the eye (including herpes simplex). Fungal infections of the cornea are 8.2 Lactation
particularly prone to develop coincidentally with long-term local steroid Risk Summary
application. Fungus invasion must be considered in any persistent corneal Systemically administered corticosteroids are present in human milk and
ulceration where a steroid has been used or is in use. Fungal culture should can suppress growth, interfere with endogenous corticosteroid production,
be taken when appropriate. or cause other unwanted effects. There is no information regarding the
Prolonged use of corticosteroids may suppress the host response and presence of injected DEXYCU in human milk, the effects on breastfed infants,
thus increase the hazard of secondary ocular infections. In acute purulent or the effects on milk production to inform risk of DEXYCU to an infant during
conditions, steroids may mask infection or enhance existing infection. lactation. The developmental and health benefits of breastfeeding should
be considered, along with the mother’s clinical need for DEXYCU and any
5.4 Cataract Progression potential adverse effects on the breastfed child from DEXYCU.
The use of corticosteroids in phakic individuals may promote the development
of posterior subcapsular cataracts. 8.4 Pediatric Use
Safety and effectiveness of DEXYCU in pediatric patients have not
6 ADVERSE REACTIONS been established.
The following adverse reactions are described elsewhere in the labeling:
• Increase in Intraocular Pressure [see Warning and Precautions (5.1)] 8.5 Geriatric Use
• Delayed Healing [see Warnings and Precautions (5.2)] No overall differences in safety or effectiveness have been observed
• Infection Exacerbation [see Warnings and Precautions (5.3)] between older and younger patients.
• Cataract Progression [see Warnings and Precautions (5.4)] Manufactured for: EyePoint Pharmaceuticals US, Inc. Watertown, MA 02472



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Section Editor John D. Shepherd, MD Section Editor Editor-in-Chief
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10  •   A P R I L 2019

1. Lee BS, Chang DF. Comparison of the rotational stability of two toric intraocular lenses in 1273 consecutive eyes. Ophthalmology. 2018;0:1-7.
2. Potvin R, et al. Toric intraoclar lens orientation and residual refractive astigmatism: an analysis. Clin Ophthalmol. 2016;10:1829-1836.
Please see Important Product Information on the adjacent page.

AcrySof IQ Toric

© 2018 Novartis 7/18 US-TOR-18-E-1605


Progress for Ophthalmic Research

It was a pleasure to read “Why Advocate for Increased

Research Funding?” (Opinion, December), in which Dr.
Ruth Williams crystallized the many reasons for society to
invest in vision research. Basic and translational research
underpins development of
the treatments that future
ophthalmologists will use®

to help patients. The com-


Trends in Eye Care pletion of the human

What’s New, What’s Next
genome code in 2001 pro-
vided powerful new tools
and approaches that are
speeding our progress along. 
I also quite liked the
verbal efficiency and clarity
Pain Without Stain
When It’s Not Dry Eye used to describe the funding
environment. Medical re-
“North of 600 Microns”
Managing Challenging Macular Holes

Rhegmatogenous Retinal Detachments

search overall has done well

Diagnostic Pearls

01_Cover_F.indd 1

in recent years. Unfortunate-
11/15/18 10:59 AM

ly, much of this funding is still devoted to erasing the sparse

funding environment of the previous decade, and the current
ACRYSOF® IQ TORIC IOL IMPORTANT PRODUCT INFORMATION buying power of the NEI budget is mired at levels equivalent
CAUTION: Federal (USA) law restricts this device to the sale by or on the order of a to nearly two decades ago (2000-2002). 
As Dr. Williams noted about the BRAIN Initiative, vision
INDICATIONS: The AcrySof® IQ Toric posterior chamber intraocular lenses are
intended for primary implantation in the capsular bag of the eye for visual correction research is also front and center in trans-NIH fundamental
of aphakia and pre-existing corneal astigmatism secondary to removal of a cataractous research in neuroscience. The BRAIN Initiative currently
lens in adult patients with or without presbyopia, who desire improved uncorrected receives nearly $400 million in annual support. Of that
distance vision, reduction of residual refractive cylinder and increased spectacle
independence for distance vision. amount, 42% goes into projects involving retinal neural-
WARNING/PRECAUTION: Careful preoperative evaluation and sound clinical circuitry and brain central visual processing and projects
judgment should be used by the surgeon to decide the risk/benefit ratio before involving vision researchers who are on BRAIN project
implanting a lens in a patient with any of the conditions described in the Directions for
Use labeling. Toric IOLs should not be implanted if the posterior capsule is ruptured, if teams. This is
the zonules are damaged, or if a primary posterior capsulotomy is planned. Rotation WRITE TO US. Send your letters of remarkable and
can reduce astigmatic correction; if necessary lens repositioning should occur as early emphasizes the
as possible prior to lens encapsulation. All viscoelastics should be removed from both 150 words to EyeNet Magazine,
the anterior and posterior sides of the lens; residual viscoelastics may allow the lens to American Academy of Ophthalmolo- importance of
rotate. Optical theory suggests that high astigmatic patients (i.e. > 2.5 D) may experience gy, 655 Beach Street, San Francisco, the visual system,
spatial distortions. Possible toric IOL related factors may include residual cylindrical
error or axis misalignments. Prior to surgery, physicians should provide prospective CA 94109; or e-mail both retina and
patients with a copy of the Patient Information Brochure available from Alcon for this brain, in neurosci-
product informing them of possible risks and benefits associated with the AcrySof® ence research.
IQ Toric Cylinder Power IOLs. Studies have shown that color vision discrimination is not
adversely affected in individuals with the AcrySof® Natural IOL and normal color vision.
On the trans­lational side, I am glad the NEI Audacious
The effect on vision of the AcrySof® Natural IOL in subjects with hereditary color vision Goals Initiative in Regenerative Medicine is moving quickly
defects and acquired color vision defects secondary to ocular disease (e.g., glaucoma, toward cell therapy, gene therapy, and retinal cell replacement
diabetic retinopathy, chronic uveitis, and other retinal or optic nerve diseases) has
not been studied. Do not resterilize; do not store over 45° C; use only sterile irrigating therapies for age-related macular degeneration and glauco-
solutions such as BSS® or BSS PLUS® Sterile Intraocular Irrigating Solutions. matous vision loss.  
ATTENTION: Reference the Directions for Use labeling for a complete listing of This editorial helps all of us as ophthalmologists celebrate
indications, warnings and precautions.
the work that astute ophthalmic clinicians, basic scientists,
and clinician-scientists are accomplishing.
© 2018 Novartis 7/18 US-TOR-18-E-1605 Paul P. Sieving, MD, PhD
Bethesda, Md.

12  •   A P R I L 2019
105440 US-TOR-18-E-1605_PI EN.indd 1 2/27/19 11:38 AM
Frank Bucci Eric Donnenfeld John Hovanesian Mitch Jackson Richard Lindstrom

James Loden Cynthia Matossian Cathleen McCabe Bob Osher Sheri Rowen John Sheppard

Steve Silverstein Inder Paul Singh Denise Visco Keith Walter Your name here

These cataract surgeons use OMIDRIA®

(phenylephrine and ketorolac intraocular
solution) 1% / 0.3% for less stress, pure
success in their O.R. day1

What about you?
OMIDRIA helps your cataract surgery by inhibiting prostaglandin release to block
inflammation and maintain iris tone, preventing miosis and reducing postoperative
pain for your patients.2,3 Experience less stress in your O.R. day with OMIDRIA.1


OMIDRIA® (phenylephrine and ketorolac intraocular solution) 1% / 0.3% is added to ophthalmic irrigating solution used during
cataract surgery or intraocular lens replacement and is indicated for maintaining pupil size by preventing intraoperative miosis
and reducing postoperative ocular pain.
OMIDRIA must be added to irrigating solution prior to intraocular use.
OMIDRIA is contraindicated in patients with a known hypersensitivity to any of its ingredients.
Systemic exposure of phenylephrine may cause elevations in blood pressure.
Use OMIDRIA with caution in individuals who have previously exhibited sensitivities to acetylsalicylic acid, phenylacetic acid
derivatives, and other nonsteroidal anti-inflammatory drugs (NSAIDs), or have a past medical history of asthma.
The most commonly reported adverse reactions at ≥2% are eye irritation, posterior capsule opacification, increased intraocular
pressure, and anterior chamber inflammation.
Please see the Full Prescribing Information for OMIDRIA at
You are encouraged to report Suspected Adverse Reactions to the FDA.
Visit, or call 1-800-FDA-1088.
References: 1. Omeros survey data on file. 2. OMIDRIA [package insert]. Seattle, WA: Omeros Corporation; 2017. 3. Al-Hashimi S,
Donaldson K, Davidson R, et al; for ASCRS Refractive Cataract Surgery Subcommittee. Medical and surgical management of the
small pupil during cataract surgery. J Cataract Refract Surg. 2018;44:1032-1041.

The healthcare professionals portrayed in this advertisement are consultants of Omeros Corporation.

OMEROS®, the OMEROS logo®, OMIDRIA®, and the OMIDRIA logo®

are registered trademarks of Omeros Corporation.

© Omeros Corporation 2019, all rights reserved. 2019-001



The Graying of Ophthalmology

phthalmology is graying. The Academy’s biennial meeting of the American College of Surgeons, attendees
membership survey shows the average age of prac- were given computerized cognitive tasks that measured three
ticing ophthalmologists in the United States has in- functions: reaction time, visual learning, and visual sustained
creased by almost three years since 2013, presumably because attention and memory. Practicing surgeons aged 60 to 64
physicians are working longer. This reflects a broader trend. scored well compared to younger surgeons aged 45 to 59,
According to the American Medical Association, the number with no senior surgeon performing below the
of physicians 65 years and older has quadrupled since 1975, younger surgeons on all three tasks.3
and nearly 40% of these physicians are actively engaged in But measuring cognitive skills on
patient care.1 a computer is not surgery. Mark
I’m wondering what factors might motivate our older Daily, MD, a respected retina sur-
colleagues to continue to work. So I asked Robert Stamper, geon and the most senior oph-
MD, who was my program chair more than 30 years ago and thalmologist in our practice,
is now director of the Glaucoma Clinic at the University of pointed out that ophthalmic
California, San Francisco, why he’s still working. surgeons consistently self-
Bob replied, “I like what I do. I truly help people, and that assess regarding their surgical
provides a satisfaction that can’t be replaced. My 90-year-old skills—and that the best time
patient recently lost his vision from glaucoma, but he had to retire from surgery varies
four decades of vision under my care. That’s a victory against greatly among individuals. “The
a chronic, progressive disease.” Bob also teaches residents and right time to stop surgery is when
glaucoma fellows, and he loves being around young people you are still doing superb work,” he
who “ask good questions and make me reevaluate my assump- said. “Don’t wait for your colleagues
tions.” He also mentioned the camaraderie of his colleagues: to tell you it’s time or wait for a bad Ruth D.
“The ophthalmology department is kind of like a family. They outcome to occur; make the decision Williams, MD
know me, they accept my foibles, and they show up every yourself.” Chief Medical
day.” When I asked him about retiring, he noted that he has Like Bob and Mark, many ophthal- Editor, EyeNet
other interests, especially skiing, hiking, and fly fishing, but mologists will be able to work well into
none of those are things he’d like to do full time. Right now, their Medicare years because they love what they do and are
he said, “I get to do all those things, and I get to practice still good at it. And Bob cited another—and somewhat intang­
ophthalmology. I get to do all the things I love.” ible—benefit of keeping our senior ophthalmologists in the
While Bob is still doing surgery, he’s planning to stop later workplace: “They add gravitas.” He said, “Our most experi-
this year, “while I’m still facile and skilled.” Is that necessary? enced physicians provide perspective for young and mid-
Do surgical skills decline with age? career physicians, especially when a case is unusual. They
It’s difficult to assess ongoing surgical competence, but also can give wise career advice.” As it turns out, wisdom and
several studies have taken a look at the issue. Recently, a experience can benefit patients and younger colleagues alike.
population-based cohort study of nearly 500,000 cataract
surgeries found that late-career surgeons are performing a 1 Competency and retirement: Evaluating the senior physician. Chicago:
significant percentage of cataract procedures (28.6%) with American Medical Association; June 23, 2015.
low adverse event rates. Importantly, complication rates management/physician-diversity/competency-and-retirement-evaluating-
were similar when mid-career surgeons were compared to senior-physician. Accessed Feb. 22, 2019.
late-career surgeons.2 2 Campbell RJ et al. JAMA Ophthalmol. 2019;137(1):58-64.
Outside of ophthalmology, several years ago, at the annual 3 Drag LL et al. J Am Coll Surg. 2010;211(3):303-307.

14  •   A P R I L 2019

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IOP control
What makes once-daily Rhopressa® different1

Consistent IOP reduction up to 5 mmHg

in patients across a range of baseline IOPs

Once-daily dosing to simplify dosing regimens

Mild ocular adverse events and no known

contraindications opens up treatment options

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IOP, intraocular pressure.


Rhopressa (netarsudil ophthalmic solution) 0.02% is
The most common ocular adverse reaction observed in
indicated for the reduction of elevated intraocular pressure in controlled clinical studies with Rhopressa® dosed once daily
patients with open-angle glaucoma or ocular hypertension. was conjunctival hyperemia, reported in 53% of patients.
Other common (approximately 20%) adverse reactions were:
corneal verticillata, instillation site pain, and conjunctival
The recommended dosage is one drop in the affected eye(s) hemorrhage. Instillation site erythema, corneal staining,
once daily in the evening. blurred vision, increased lacrimation, erythema of eyelid,
and reduced visual acuity were reported in 5-10% of patients.
The corneal verticillata seen in Rhopressa®-treated patients
WARNINGS AND PRECAUTIONS were first noted at 4 weeks of daily dosing. This reaction did
Bacterial Keratitis: There have been reports of bacterial not result in any apparent visual functional changes. Most
keratitis associated with the use of multiple-dose containers corneal verticillata resolved upon discontinuation
of topical ophthalmic products. These containers had been of treatment.
inadvertently contaminated by patients who, in most cases,
had a concurrent corneal disease or a disruption of the ocular Please see brief summary of full Prescribing Information
epithelial surface. on the adjacent page.

Contact Lenses: Contact lenses should be removed prior to References: 1. Rhopressa Prescribing Information. Irvine, CA: Aerie
instillation of Rhopressa® and may be inserted 15 minutes Pharmaceuticals, Inc; 2017. 2. MMIT:12/2018.
following its administration.

Rhopressa® is a registered trademark of Aerie Pharmaceuticals, Inc. ©2019 Aerie Pharmaceuticals, Inc. All rights reserved. US-RHO-P-0128 3/19
RHOPRESSA (netarsudil ophthalmic solution) 0.02%
Rx Only

Consult the Full Prescribing Information for complete product information.


RHOPRESSA® (netarsudil ophthalmic solution) 0.02% is indicated for the reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular


The recommended dosage is one drop in the affected eye(s) once daily in the evening.

If one dose is missed, treatment should continue with the next dose in the evening. Twice a day dosing is not well tolerated and is not recommended. If RHOPRESSA is to be used
concomitantly with other topical ophthalmic drug products to lower IOP, administer each drug product at least 5 minutes apart.


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 previously contaminated
by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface.

Use with Contact Lenses

RHOPRESSA contains benzalkonium chloride, which may be absorbed by soft contact lenses. Contact lenses should be removed prior to instillation of RHOPRESSA and may be
reinserted 15 minutes following its administration.

Clinical Trials 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 ocular adverse reaction observed in controlled clinical studies with RHOPRESSA dosed once daily was conjunctival hyperemia which was reported in 53% of
patients. Other common (approximately 20%) ocular adverse reactions reported were: corneal verticillata, instillation site pain, and conjunctival hemorrhage. Instillation site erythema,
corneal staining, blurred vision, increased lacrimation, erythema of eyelid, and reduced visual acuity were reported in 5-10% of patients.

Corneal Verticillata
Corneal verticillata occurred in approximately 20% of the patients in controlled clinical studies. The corneal verticillata seen in RHOPRESSA-treated patients were first noted at 4 weeks
of daily dosing. This reaction did not result in any apparent visual functional changes in patients. Most corneal verticillata resolved upon discontinuation of treatment.


There are no available data on RHOPRESSA use in pregnant women to inform any drug associated risk; however, systemic exposure to netarsudil from ocular administration is low.
Intravenous administration of netarsudil to pregnant rats and rabbits during organogenesis did not produce adverse embryofetal effects at clinically relevant systemic exposures.

Animal Data
Netarsudil administered daily by intravenous injection to rats during organogenesis caused abortions and embryofetal lethality at doses ≥0.3 mg/kg/day (126-fold the plasma exposure
at the recommended human ophthalmic dose [RHOD], based on Cmax). The no-observed-adverse-effect-level (NOAEL) for embryofetal development toxicity was 0.1 mg/kg/day
(40-fold the plasma exposure at the RHOD, based on Cmax).

Netarsudil administered daily by intravenous injection to rabbits during organogenesis caused embryofetal lethality and decreased fetal weight at 5 mg/kg/day (1480-fold the plasma
exposure at the RHOD, based on Cmax). Malformations were observed at ≥3 mg/kg/day (1330-fold the plasma exposure at the RHOD, based on Cmax), including thoracogastroschisis,
umbilical hernia and absent intermediate lung lobe. The NOAEL for embryofetal development toxicity was 0.5 mg/kg/day (214-fold the plasma exposure at the RHOD, based on Cmax).

There are no data on the presence of RHOPRESSA in human milk, the effects on the breastfed infant, or the effects on milk production. However, systemic exposure to netarsudil
following topical ocular administration is low, and it is not known whether measurable levels of netarsudil would be present in maternal milk following topical ocular administration.
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for RHOPRESSA and any potential adverse effects on the breastfed
child from RHOPRESSA.

Pediatric Use
Safety and effectiveness in pediatric patients below the age of 18 years have not been established.

Geriatric Use
No overall differences in safety or effectiveness have been observed between elderly and other adult patients.

Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies in animals have not been performed to evaluate the carcinogenic potential of netarsudil. Netarsudil was not mutagenic in the Ames test, in the mouse lymphoma test,
or in the in vivo rat micronucleus test. Studies to evaluate the effects of netarsudil on male or female fertility in animals have not been performed.

Manufactured for: Aerie Pharmaceuticals, Inc., Irvine, CA 92614, U.S.A.

For more information, go to or call 1-855-AerieRx (1-855-237-4379).

RHOPRESSA is a registered trademark of Aerie Pharmaceuticals, Inc.

U.S. Patent Nos.: 8,450,344; 8,394,826; 9,096,569; 9,415,043
News in Review C O M M E N TA R Y A N D P E R S P E C T I V E

RETINA the photoreceptors

Targeting and the dying RPE
layer in rodents and
Dry AMD With pigs. The patch size
Lab-Grown RPEs was 2 mm × 4 mm in
the pigs, the same size
as a human clinical
demonstrated a method for converting Bharti said.
human blood progenitor cells into Functional results.
stem cells that, in turn, differentiate Imaging, molec­ular, IN THE LAB. A scanning electron micrograph image
into retinal pigment epithelial (RPE) and electrical studies shows a polarized RPE mono­layer on a biodegradable
cells capable of keeping photoreceptors during up to nine scaffold. The image is colored to highlight the scaffold
healthy.1 months of follow-up (blue), three RPE cells (brown), and the apical process
The ultimate goal is to protect at- found that the patch- of cells in the RPE monolayer (light green).
risk photoreceptors by transplanting es of transplanted
patient-specific sheets of functioning cells functioned well and without evi- clinical trial, which the researchers hope
RPE cells into eyes with dry age-related dence of toxicity. The laboratory-grown will begin this year. Planning is under-
macular degeneration (AMD), said RPE cells integrated appropriately into way for a phase 1/2a trial in patients
principal investigator Kapil Bharti, the animals’ retinas as the biopolymer with geographic atrophy and visual
PhD, at the NEI. scaffold degraded. They also expressed acuity of no better than 20/200, he said.
Animal model. The researchers RPE65 (the gene that drives regener­ation If this and further clinical studies
described a painstaking process for of the ocular photopigment rhodopsin), were to demonstrate safety and efficacy,
transforming progenitor cells into performed the RPE’s crucial function transplants of this lab-grown RPE tissue
induced pluripotent stem cells (iPSCs), of pruning photoreceptors through could be submitted to the FDA for
then inducing differentiation into RPE phagocytosis, and facilitated normal commercial approval in three to five
cells, which are grown in a monolayer electrical responses from the rescued years, Dr. Bharti estimated.
atop a biodegradable scaffold. photoreceptors adjacent to the implant- Dr. Bharti said the researchers are
“We start with the patient’s own ed cells. cautiously optimistic about the poten-
blood, isolate the blood progenitor cells, Because of concerns about possible tial that this individualized approach
and reprogram them into induced plu- oncogenic potential in tissue derived eventually could have for AMD patients
ripotent stem cells—that is, cells that from stem cells, the researchers also with geographic atrophy. “If implanted
can make any type of cell in the body,” performed genetic analyses of the in the right place, [these cells] would
Dr. Bharti said. “And you can imagine iPSCs and found no mutations that stop the disease from progressing
the advantage, then, if you make a are known to be associated with tumor further—and this is in a disease where
tissue out of these cells: It becomes the growth, they reported. there currently is no treatment avail-
patient’s own tissue, so the immune Planning for clinical trial. Dr. Bharti able.” —Linda Roach
system would not reject it.” said the group’s cellular production
Using a specially designed transplant processes strictly followed “good manu­ 1 Sharma R et al. Sci Transl Med. 2019;11(475):
delivery cannula, the researchers insert- facturing practice” protocols, in order eaat5580.

ed single-source sheets of cells between to facilitate FDA approval of an early Relevant financial disclosures—Dr. Bharti: None.

CATARACT • repeatability
Evaluating Lens of the lens tilt
and IOL Tilt With • preoperative
SS-OCT Biometry crystalline lens
and postoperative
IOL tilt in the pa-
RESEARCHERS HAVE CONDUCTED A tients’ right eyes TILT. Preoperative crystalline lens tilt and postoperative IOL
retrospective case series study of crys- (253 phakic, 80 tilt, measured in the same eye.
talline lens and IOL tilt using a swept- pseudophakic),
source optical coherence tomography • lens tilt mirror symmetry between same day. This was assessed using two
(SS-OCT) biometer.1 the patients’ right and left eyes, param­eters: 1) the pooled within-sub-
“We found that we can reproducibly • correlation in tilt between preoper- ject standard deviations of repeated
measure crystalline lens tilt—and that ative crystalline lens and postoperative measurements, and 2) intraclass cor-
this tilt is predictive of postoperative IOL, and relation coefficient, a measure of
IOL tilt,” said Douglas D. Koch, MD, • correlation between the magnitude the correlation between repeated
at the Cullen Eye Institute in Houston. of lens tilt and ocular parameters. measurements. Repeatability using the
“Knowing this could improve the accu- Repeatability of crystalline lens SS-OCT was found to be excellent.
racy of toric IOL calculations.” tilt was calculated using participants Because of the potential mirror sym-
Study design. Dr. Koch and his with preoperative tilt data available for metry of lens tilt between right and left
colleagues evaluated 333 patients for: three repeated measurements on the eyes, the researchers used the patients’

GLAUCOMA OCT images taken after device implantation still showed

OCT Illuminates Vision Loss significant thinning of the full retinal thickness, espe-
cially in the superior macula.
After Glaucoma Surgery The second patient, an 85-year-old man, had ad-
vanced pseudoexfoliation glaucoma in his right eye.
WITH THE HELP OF OPTICAL COHERENCE TOMOGRAPHY He had previously undergone uncomplicated trabe-
(OCT), doctors at the Stein Eye Institute in Los Ange- culectomy and was referred for surgery because of his
les gained new insight into an infrequent postsurgical uncontrolled IOP. Before surgery, his IOP ranged from
complication of glaucoma filtering surgery known as 28 mm Hg to 32 mm Hg on maximal treatment, and
“snuff-out phenomenon.” The clinicians reported two his BCVA was 20/20. He received an Ahmed Glaucoma
patients who experienced significant, unexplained, and Valve (New World Medical). One week later, his VA was
permanent vision loss following placement of a drain- hand motions, and his IOP was 5 mm Hg.
age device; in both cases, OCT showed progressive At nine months, the patient’s BCVA was 20/400.
macular thinning after the procedure.1 Macular OCT imaging revealed progressive macular
It took OCT to demonstrate what had only previously thinning deemed to be consistent with progressive and
been hypothesized. “This explains one of the mecha- complete central visual field loss.
nisms of vision loss after glaucoma surgery”—that is, Can this scenario be avoided? The findings suggest
ongoing loss of the retinal ganglion cells (RGCs), said that eyes at high risk of visual loss after surgery are
Kouros Nouri-Mahdavi, MD, MS, at the Stein Eye Insti- mainly those with advanced glaucoma or extension
tute. He added that the “fairly rapid RGC loss suggests of the damage to the central field preoperatively, Dr.
the possible presence of sick cells that continue to die Nouri-Mahdavi said. But, he added, we need much
despite glaucoma surgery.” more data before making clinical recommendations.
Patient profiles. An 89-year-old woman with primary “One could imagine, though, that a very thin macula
open-angle glaucoma underwent trabeculectomy in her observed preoperatively could predict possible wors-
right eye to lower her intraocular pressure (IOP), which ening of vision after surgery.” For now, he said, doctors
was 20 mm Hg on maximal treatment prior to surgery. might consider preoperative imaging of the macula in
Pressure remained inadequate after surgery despite eyes at high risk of visual loss after surgery, followed by
escalation of therapy. The patient’s best-corrected continued postoperative monitoring. —Miriam Karmel
visual acuity (BCVA) was 20/50 before surgery. It then
fluctuated, in the 20/70 to 20/150 range, and it never 1 Mohammadzadeh V et al. J Glaucoma. Published online Jan.
Cullen Eye Institute

recovered to preoperative levels. 28, 2019.

At 12 months, the patient received a 250-mm2 Baer- Relevant financial disclosures—Dr. Nouri-Mahdavi: Heidelberg
veldt Glaucoma Implant (Johnson & Johnson). Macular Engineering: L,S.

20  •   A P R I L 2019
right eyes to assess the mean crystal- the preoperative crystalline lens tilt. The researchers stressed that further
line lens and IOL tilt magnitudes and In the 253 phakic right eyes, multi- studies evaluating incorporation of lens
directions. In 163 phakic patients and ple regression analysis revealed that the tilt in IOL power calculations in clinical
24 pseudophakic patients, there was magnitude of crystalline lens tilt was patients are needed. —Arthur Stone
significant mirror symmetry. negatively correlated with axial length
In the 65 eyes with both pre- and (AL), anterior chamber depth, and lens 1 Wang L et al. J Cataract Refract Surg. 2019;45:
postoperative tilt measurements, there thickness, and positively correlated 35-40.
was significant correlation between with angle α. In the 80 pseudophakic Relevant financial disclosures—Dr. Koch: Carl
tilt magnitude and tilt direction of right eyes, the magnitude of IOL tilt Zeiss Meditec: C. This study was funded in part
preoperative crystalline lens and post- was negatively correlated with AL and by the Sid W. Richardson Foundation and an
operative IOL. The IOL tilt magnitude positively correlated with angle α and unrestricted grant from Research to Prevent
increased significantly compared with angle κ. Blindness.

IMMUNOLOGY for clinicians is that these

Growing Problem: side effects can occur days to
weeks after the infusion of
Ocular Impact immunotherapy. Moreover,
From Cancer Rx they can appear mild at
first but later become quite
serious, Dr. Lim said. For
tinue to watch for patients who, after • One patient complained
receiving immunotherapy for cancer, of floaters that did not go
develop ophthalmic adverse effects away, and she was later
that could prove catastrophic if they go found to have melanoma-
untreated. associated retinopathy.
In a large retrospective study of • Another patient was hav-
patients treated with the immune ing difficulty in the periph-
checkpoint inhibitors ipilimumab ery of her [perceived] field VF LOSS. Ocular adverse effects following treat-
(Yervoy, Bristol-Meyers-Squibb) and/or of vision, and her initial ment with immune checkpoint inhibitors included
nivolumab (Opdivo, Bristol-Myers- visual field (VF) showed this case of profound VF loss.
Squibb), Yale researchers found that nonspecific defects, Dr.
15 of 1,474 patients (1%) developed Lim said. “A follow-up VF two to three need to know that these powerful
ophthalmic adverse events.1 months later showed profound VF loss, agents can affect the eye,” she said.
These side effects included corneal and she was found to have antiretinal Exam tips. “A complete examination
perforation, corneal punctate epithelial and antioptic nerve autoantibodies.” is warranted in patients on immu-
erosions, subconjunctival hemorrhage, (This case will be published in another notherapy, including slit-lamp and fun-
uveitis, hypotony maculopathy, cystoid report about the clinical spectrum of duscopic examination,” Dr. Lim said.
macular edema, serous retinal detach- immunotherapy patients with anti­ In addition, she said, ancillary testing
ment, choroiditis, optic neuritis, and retinal autoantibodies, she said.) based on exam findings may be needed,
melanoma-associated retinopathy. • A third case began as dry eye and such as optical coherence tomography.
Need for suspicion. “These adverse progressed to corneal perforation by She added, “I would like to stress
events are uncommon; however, we the time the patient presented to an that most of the ophthalmic adverse
need to be aware that they can occur ophthalmologist. effects can be managed locally, with
in patients undergoing immunother- Growing problem. Although the in- continuation of immunotherapy in
apy,” said coauthor Renelle Pointdu- cidence of ophthalmic immune-related select cases. However, if these ocular
jour-Lim, MD, at Yale University in adverse events from immunotherapy problems are not caught early and
New Haven, Connecticut. “Even if the is low, the total number of cases can be treated appropriately, they can be
patient has vague nonspecific ocular expected to increase, Dr. Lim said. “The visually devastating.” —Linda Roach
symptoms, the ophthalmologist should indications for use of these agents have
Renelle Pointdujour-Lim, MD

have a high suspicion of the possibility expanded to include a broader range of 1 Kim JM et al. Ophthalmology. Published online
of ophthalmic immune-related adverse malignancies, which means that more Feb. 5, 2019.
events.” and more people will be treated with Relevant financial disclosures—Dr. Pointdujour-
Varied presentation. One challenge immunotherapy, and ophthalmologists Lim: None.

See the financial disclosure key, page 10. For full disclosures, including category descriptions, view this News in Review at

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Journal Highlights N E W F I N D I N G S F R O M T H E P E E R - R E V I E W E D L I T E R AT U R E

Ophthalmology AEs between patients who did and Pneumatic Retinopexy or

Selected by Stephen D. McLeod, MD did not receive tamsulosin, and they Vitrectomy for Primary RRD
adjusted for patient-, surgeon-, and April 2019
Cataract Surgery in Tamsulosin- institution-level covariates. Outcome
Exposed Patients measures were the incidences of cap- There are many clinical circumstanc-
April 2019 sule rupture, dropped lens fragment, es under which the best technique to
retinal detachment, and suspected repair rhegmatogenous retinal detach­
Tamsulosin has been linked to intra- endophthalmitis. ment (RRD) is not clear. Hillier et al.
operative floppy iris syndrome (IFIS), More than 400,000 cataract surgery compared pneumatic retinopexy (PnR)
a risk factor for complications during cases were represented in the study. and pars plana vitrectomy (PPV) for
cataract surgery. Despite many efforts Of these, 39,144 had recent exposure primary RRD considered amenable to
to increase awareness of the risks related to tamsulosin. Overall, the risk of both PnR and PPV. They found that
to tamsulosin, it is surgical AEs declined over PnR produced superior visual acuity
uncertain whether time for patients who had
Volume 126 | Number 4 | April 2019
(VA) and less vertical metamorphopsia.
Volume 126 | Number 4 | pp. XXX–XXX

Elsevier | ISSN 0161-6420

these efforts have recent exposure to tamsu- In this prospective study, 176 patients
been effective. In a losin (odds ratio, 0.95/year), with RRD and one or more breaks in
population-based regardless of age group. the detached retina within 1 clock-hour
study, Campbell Findings were similar for the above the 8- and 4-o’clock meridians
et al. looked at the patients who did not have were assigned randomly to receive PnR

rates of adverse recent exposure to tamsu- or PPV within 24 hours (macula on)

events (AEs) losin (odds ratio, 0.96 per or 72 hours (macula off) of detection.

over time among year). Incidence rates for the The primary outcome was VA at 12
patients who did specific AEs were similar for months according to the Early Treat-
and did not have the study arms, and ranged ment Diabetic Retinopathy Study
recent exposure from 0.02% for retinal de- (ETDRS) criteria. Other outcomes of
April 2019

OPHTHA_v126_i4_COVER.indd 1
to tamsulosin. tachment (both groups) to
20-12-2018 12:20:55
interest were subjective visual function
Results showed 0.76% for posterior capsule (25-item National Eye Institute Visual
that, over an 11-year period, both rupture (tamsulosin group; vs. 0.58% Function Questionnaire [NEI VFQ-25]),
groups had a decline in the rate of no exposure group). metamorphopsia score, and primary
AEs linked to cataract surgery compli- The authors suggested that the anatomic success.
cations. concurrent decline in adverse event Twelve-month assessments showed
Study participants were men aged rates for cataract patients with and that mean ETDRS VA was better after
66 years and older (mean age, 78 years) without exposure to tamsulosin indi- PnR (79.9 ± 10.4 letters vs. 75.0 ± 15.2
who underwent cataract surgery from cates that continuing medical educa- letters after PPV; p = .024). Composite
January 2003 through December 2013 tion efforts that disseminate risk- NEI VFQ-25 scores were better for PnR
in Ontario, Canada. The time frame modifying technical adjustments have at three and six months, but similar
included periods both before and after been effective. at 12 months. At 12 months, vertical
the initial reports of tamsulosin-asso- Nevertheless, they pointed out, as metamorphopsia scores were better
ciated IFIS. The authors used linked tamsulosin exposure remains a risk for for the PnR group (0.14 ± 0.29 vs. 0.28
health care databases to compare the AEs, these adjustments must be main- ± 0.42; p = .026). Primary anatomic
evolution of the risk of cataract surgery tained and advanced. success was achieved by 12 months in

80.8% of patients who underwent PnR completed the trial; two died during that met all eligibility criteria; of these,
and in 93.2% of those who had PPV the study period. The area of neuro­ 10 were randomized controlled trials
(p = .045). Secondary anatomic success degeneration progression was found (RCTs). Overall, the RCTs were more
was attained for 98.7% and 98.6%, to be 31% larger for sham-treated eyes. likely to comply with the WGA guide-
respec­tively. Among phakic patients, At 24 months, the difference in mean lines than were the non-RCTs, with
65% of those in the PPV arm and area of photoreceptor loss was 0.05 ± 52.8% of the RCTs complying, versus
16% of those in the PnR group under- 0.03 mm2 (p = .04). Retinal sensitivity 40.8% of the non-RCTs. Problems with
went cataract surgery before month changes, as measured by microperime- study design included the following:
12 (p < .001). try, correlated strongly with changes in • The WGA guidelines recommend
The authors concluded that PnR the area of photoreceptor loss (r = 0.86; a follow-up on a defined schedule up
should be the first-line treatment for p < .0001). The mean retinal sensitivity to three years. Only four (16%) of the
RRD in patients who fulfill the recruit­ loss in the sham group was 45% greater 25 studies lasted three years or more.
ment criteria of the PIVOT study. than for patients with active treatment Nearly half of the studies had a follow-
Despite the current global popularity of (decrease of 15.81 ± 8.93 dB; p = .07). up of 12 months; two lasted only six
PPV, the relative simplicity and Although reading speed deteriorated in months.
elegance of PnR remain attractive, the sham group (–13.9 words/minute), • With regard to intraocular pressure
said the authors. it was maintained in the active-treat- (IOP), the WGA guidelines consider
ment arm (p = .02). Adverse effects two components mandatory for
Slowing Neurodegeneration occurred in 4% of each study group. demonstrating surgical success: 1)
in MacTel Type 2 Although the study results are an IOP-based survival curve with the
April 2019 promising, the authors encouraged number of patients at each time point
more research to assess longer-term and 2) an IOP scatterplot. None of
Chew et al. tested the effects of cell- clinical outcomes and safety. They not- the reviewed RCTs provided this infor-
based delivery of a neuroprotective ed that their findings are not necessar- mation. Of the non-RCTs, two had
agent on the progression of macular ily generalizable to all patients. Further a scatterplot, and seven included an
telangiectasia (MacTel) type 2. They study would be needed to understand IOP-based survival curve.
found that retinal degeneration pro- the therapeutic effectiveness of the • In 16 studies (64%), at least one
gressed more slowly in eyes that received device in different patient populations. author reported an association with
the implanted device releasing ciliary —Summaries by Lynda Seminara the industry. Furthermore, at least one
neurotrophic factor (CNTF) into the author was a shareholder in 32% of
vitreous cavity, and patients maintained Ophthalmology the studies, and 24% of studies had an
monocular reading speed. Glaucoma industry employee as an author. The
This single-masked trial included Selected by Henry D. Jampel, MD, MHS WGA guidelines suggest several tools
11 retina centers in the United States that can be used to manage potential
and Australia. The researchers enrolled Quality of MIGS Trials conflicts, including masked study
67 patients (99 eyes); study eyes were March/April 2019 design and funding from sources un­
required to have disruption in the ellip- related to the innovation.
soid zone layer (evidence of photore- Mathew et al. assessed the quality of The researchers urged authors and
ceptor loss) ranging from 0.16 to 4.00 published studies of minimally invasive journals to follow the WGA guidelines.
mm2 and best-corrected visual acuity of glaucoma surgery (MIGS) devices. They As they pointed out, the development
20/50 or better. found that a substantial proportion and use of standardized methodology
Participants were assigned randomly of MIGS trials do not adhere to the and outcomes supports transparency
(1:1) to receive a sham operation or World Glaucoma Association (WGA) of study results, facilitates comparisons
surgical implantation of an encapsu- guidelines, thus limiting comparison between trials, and allows readers to
lated system (NT-501, Neurotech) that between trials and hindering meaning- accurately evaluate study results and
provides sustained intravitreal delivery ful evaluation of these technologies. assess new technologies such as MIGS.
of human CNTF. For this study, the researchers —Summary by Jean Shaw
The main outcome was the change searched five databases for comparative
from baseline to 24 months in the MIGS trials published from Jan. 1, Ophthalmology Retina
area of neurodegeneration, measured 2000, to June 21, 2018. They then used Selected by Andrew P. Schachat, MD
by spectral-domain optical coherence the WGA guidelines—which cover
tomography in the area of ellipsoid the design, conduct, and reporting of Treatment Patterns for Diabetic
zone disruption or photoreceptor glaucoma surgical trials—to evaluate Macular Edema
loss. Secondary outcomes included the studies. Each study was assessed by April 2019
between-group differences in visual two reviewers; differences were resolved
function changes. by consensus. Using a large national database, Moulin
Sixty-five of the 67 participants The researchers identified 25 studies et al. evaluated the treatment patterns

24  •   A P R I L 2019
and the predictors of different treat-
ment standards in patients who were
American Journal of worse sensitivity; p = .003).

recently diagnosed with diabetic mac-

Ophthalmology In light of their findings, the authors
stressed the importance of considering
Selected by Richard K. Parrish II, MD
ular edema (DME). They found that environmental modifications for visu-
intravitreal injections of anti-VEGF ally impaired people. They recommend
medications have become a mainstay Predictors of Falls for Patients incorporating the delivery of modifi-
of DME treatment—and that patients With Glaucoma cation services into the routine care of
covered by private insurance received April 2019 patients with moderate or advanced
more injections than those covered by glaucoma.
Medicaid or Medicare. Falls are particularly problematic for
For this retrospective cohort study, the visually impaired, and many experts Risk of Stroke After NAION
the researchers used claims data on recommend including vision screening April 2019
more than 8 million diabetic patients in fall-prevention programs. Ramulu
who had commercial or government- et al. evaluated whether falls are more Does an association exist between stroke
provided health insurance and were common at home or away from home. and nonarteritic anterior ischemic optic
treated between Jan. 1, 2007, and March They also assessed how damage to the neuropathy (NAION)? Study findings
31, 2015. integrated visual field (VF) affects fall have been conflicting. Park et al. looked
When exclusion criteria were rates at both locations. They found that at a national database to better under-
applied, the final sample comprised most falls occurred at home and that stand whether NAION could be a pre-
96,316 patients. These patients were the risk of any step resulting in a fall cursor to stroke. Among their Korean
then divided into yearly cohorts and was highest at home. In addition, they study population, NAION itself was
followed for a full year after their index found that those patients with more not linked to greater risk of stroke.
date (defined as the date of their first severe VF damage were at particular This population-based retrospective
insurance claim with a diagnosis of risk of falling, regardless of the location. study included more than 400,000 ben-
DME). This three-year observational study eficiaries listed in the National Health
In 2009, anti-VEGF injections included 225 patients with confirmed Insurance Service–National Sample
accounted for 11.6% of all DME treat- or suspected glaucoma (average age, Cohort database (NHIS–NSC) from
ments; this percentage rose to 61.9% 70.4 years). Patients with neovascular 2002 to 2013. Time-varying covariate
in 2014. In contrast, corticosteroids or uveitic glaucoma were excluded. Cox regression models were used to
dropped from 6.1% of all treatments Fall-related data were documented on assess the relationship between incident
in 2009 to 2.8% in 2014, and focal calendars, and follow-up questionnaires NAION and the likelihood of subse-
laser procedures dropped from 75.3% were used to determine fall location quent stroke. Model 1 included only
in 2009 to 24% in 2014. The share of (home or away). The number of steps incident NAION as a time-varying
patients diagnosed with DME and taken was estimated by integrating covariate; model 2 included model 1
left untreated declined from 55.8% tracking data from accelerometers and and demographic data; and model 3
to 50.1%. global positioning systems. Main out- included model 2 as well as comor-
The researchers also found that come measures were the association of bidity, comedication, and Charlson
those patients covered entirely by integrated VF sensitivity with fall rates, Comorbidity Index score. Results were
third-party insurance had 45%, 31%, both per year and per step, stratified by expressed as the effect (hazard ratio
and 12% more anti-VEGF injections location. [HR]) of NAION on the subsequent
than those in Managed Medicare, Med- During the study period, partici- development of stroke.
icaid, and Medicare plans, respectively. pants accrued more steps away from The researchers found that NAION
—Summary by Jean Shaw their homes (2,366 outside vs. 1,524 occurred in 1,125 patients, and stroke
steps at home; p < .001). Steps taken occurred in 16,998. In model 1, NAION
NEW RETINA JOURNAL at home and away did not differ with was not associated with greater risk
respect to integrated VF sensitivity of subsequent stroke (HR, 1.31). For
Each month,
(p = .22). Fifty-seven percent of falls models 2 and 3, findings were similar
the Academy’s
occurred at home, with each step taken after adjustment for demographic and
at home being twice as likely to result confounding factors (HR, 1.19 and
Retina keeps
in a fall (rate ratio [RR] = 2.02 vs. away 1.10, respectively).
you up to date
steps; p < .001). Worse integrated VF The authors acknowledged that the
on clinical and
sensitivity was not associated with a NHIS–NSC database does not include
basic science
higher annual rate of home falls or details on metabolic profiles, physical
research rele-
away falls. In contrast, it was linked to activity, body mass index, alcohol con-
vant to the field of retina. Sub-
more home falls per step (RR = 1.34/5 sumption, or smoking—all of which
scribe at
dB worse sensitivity, p = .03) and more affect stroke risk. Even so, the study
away falls per step (RR = 1.47/5 dB sample is large and population-based,

which minimized selection bias. The eyes, the fibrosis progressed to retinal mean change from months 6 to 12 in
results of sensitivity analyses were con- schisis. Despite this, there was no dete- visual acuity letter score (VALS) was
sistent with those of the main analyses, rioration of visual performance, which 2.63 (p = .37), and the mean change in
as were results of matching based on was assessed prospectively with visual CST was 46.0 μm (p = .46). For the 35
propensity score. Thus, the authors function tests (square localization and eyes that were switched from bevaciz­
concluded, the etiologic mechanisms direction of motion). umab to aflibercept, the mean changes
of NAION and stroke appear to differ. These results show that OCT can be from months 6 to 12 were 10.27 in
—Summaries by Lynda Seminara used to detect retinal anatomic changes VALS (p < .001) and −125.4 μm in CST
after implantation of the Argus II. The (p < .001).
JAMA Ophthalmology authors acknowledged that more re- This research suggests that eyes with
Selected and reviewed by Neil M. search is needed to thoroughly inves- CRVO or HRVO that do not respond
Bressler, MD, and Deputy Editors tigate the morphologic features and well to bevacizumab may benefit from
pathogenesis of these changes. (Also see a switch to aflibercept. The authors rec-
OCT Assessment of Retinal related commentary by Julia A. Haller, ommended caution when interpreting
Changes With Retinal Prosthesis MD, in the same issue.) the study findings, particularly because
March 2019 so few eyes had a poor initial response
Effect of Medication Change on to aflibercept. The small sample and the
Little is known about postoperative ret- Eyes With Macular Edema Due lack of controls, randomization, and
inal changes at the juncture of an im- to Retinal Vein Occlusion masking preclude determining whether
plant electrode array and the retina— March 2019 a switching strategy is superior, similar,
or whether the potential alterations or inferior to continuing the original
could affect visual performance. To What happens when patients who treatment.
address these gaps, Rizzo et al. looked respond poorly to one anti-VEGF
at morphologic changes in recipients medication are switched to another? Oculomotor Response to
of a retinal prosthesis and found that In evaluating patients with macular Cumulative Subconcussive
50% had fibrosis-like hyperreflective edema, Ip et al. found that patients Trauma in Football Players
tissue at the interface between the array with an inadequate response to beva- March 2019
and retina. Although this often led to cizumab may benefit from a switch to
retinal schisis, visual performance was aflibercept, but the small sample and Repetitive subconcussive injury in
not impaired. lack of control group do not allow for athletes has become a major public
The study was a noncomparative definitive conclusions. health concern. Although most head
consecutive case series that involved This secondary analysis of SCORE2 injuries appear asymptomatic, they
review of pre- and postoperative find- data was performed at 66 centers in can have serious neurologic effects if
ings of optical coherence tomography the United States (private practice or sustained continually. The near point
(OCT) for 33 eyes (33 patients) that academic). Participants were required of convergence (NPC), denoting the
received the Argus II Retinal Prosthesis to have edema caused by central retinal closest point of focus before diplopia
System. This is the first—and, current- vein occlusion (CRVO) or hemiretinal occurrence, has been shown to detect
ly, the only—epiretinal device with vein occlusion (HRVO). Outcomes of subclinical neuronal damage. Yet the
commercial approval in Europe and interest were changes in visual acuity longitudinal pattern of NPC changes
North America for use in patients with and central subfield thickness (CST) due to subconcussive injury is unclear.
blindness due to retinitis pigmentosa. from month 6 (treatment switch) to Zonner et al. studied the NPC response
All procedures were performed by month 12 for eyes that responded to recurring subconcussive impact and
the same surgeon, at one of two centers poorly to aflibercept or bevacizumab found that initial disruption eventually
in Italy. Participants received compre- in SCORE2. Eyes that had received led to adaptation of the oculomotor
hensive exams before surgery, on post- aflibercept monthly were switched system to the subclinical brain injury.
operative day 1, and at months 1, 3, 6, to treatment with a dexamethasone The authors’ study included 12 U.S.
12, and 24. Yearly follow-up continued implant at month 6 and, if needed, at varsity football players (mean age, 16.4
thereafter. Only the patients who com- months 9, 10, or 11. Eyes treated ini- years) from a single high school, who
pleted at least six months of follow-up tially with bevacizumab were switched were followed throughout a season.
were included in the analysis. to aflibercept at months 6, 7, and 8, NPC assessments were made prior to
Of the 20 patients eligible for analy­ followed by a treat-and-extend regimen the season, before and after six games,
sis, all were white, and 12 (60%) were of aflibercept until month 12. and when the season concluded. An
male. The mean age was 57.4 years. Forty-nine patients (49 eyes) were embedded accelerometer mouth guard
OCT findings showed fibrosis-like included in the study; aflibercept failed measured the frequency of impact to
hyperreflective tissue, limited to the in 14, and bevacizumab failed in 35. the head and the magnitude of impact
interface between the array and the ret- Among the 14 eyes that were switched from practices and games.
ina, in 10 eyes (50%). In nine of these from aflibercept to dexamethasone, the During the games, players wore

26  •   A P R I L 2019
chest-strap heart monitors to record and were given compounded triam- between diabetes and CCT has pro-
heart rate and to estimate excess cinolone-moxifloxacin from the same duced conflicting results, and few stud-
postexercise oxygen consumption, preparation. When postoperative ies have addressed the effect of serum
accounting for possible physical-exer- complications arose, the patients were glucose or hemoglobin A1c (HbA1c) on
tion effects on NPC values. The players evaluated at the University of Texas the cornea. In a cross-sectional analy-
participated in practices and games Southwestern Medical Center. Imme- sis of the Singapore Epidemiology of
with no restrictions. diately after the surgery, best-corrected Eye Diseases (SEED) study, Luo et al.
During the football season, there visual acuity in the study eye ranged observed a correlation between thicker
were 8,009 head impacts, 177,907 g of from 20/40 to counting fingers at 4 feet CCT and the presence of diabetes or
peak linear acceleration, and 16,123,371 (average, 20/220). hyperglycemia.
radians per second squared (rad/s2) of The presenting symptoms of toxicity This study included 8,846 adults
peak rotational acceleration. NPC rose included flashes, floaters, glare, halos, aged 40 years or older (mean, 58
significantly until midseason (5.25 cm photophobia, and problems assessing years), who were of Chinese, Malay, or
at baseline vs. 6.42 cm before game 3; p colors. In three patients, changes in Indian ethnicity. The researchers also
= .01), which correlated highly with the foveal retinal pigment epithelium were performed a meta-analysis—which
frequency and magnitude of impact. detected by dilated fundus exams. In included 12 previous clinical and
However, NPC began normalizing five patients, ellipsoid zone loss was population-based studies—to estimate
toward baseline after midseason (5.75 observed with optical coherence tomog­ the overall association of diabetes with
cm before game 6; p = .32), despite the raphy. Electrophysiology testing was CCT. Standardized clinical exams were
continuation of such injuries. A signifi- performed in five eyes, all of which conducted, and questionnaires were
cant quadratic trend also was observed demonstrated similar findings of re- administered to collect demographic,
(β = −0.002 cm/d; p = .003). duction in full-field electroretinogram systemic, and ocular information. The
These results indicate that although (ERG), oscillatory potentials, pattern main outcome was CCT, measured
NPC can be perturbed for an initial ERG, multifocal ERG, and visual evoked using ultrasound pachymetry.
period of repetitive subconcussive potential. One patient received a dexa- The CCT profile of participants with
trauma, it may normalize over time, methasone implant, but visual acuity and without diabetes was similar (mean
even with additional injury. did not improve. CCT, 545.3 vs. 544.8 μm, respectively;
The authors acknowledged that the To the authors’ knowledge, this p = .39). After adjusting for age, sex,
mechanism by which this apparent is the first case series of TPSS linked ethnicity, corneal curvature, axial length,
“tolerance” develops is uncertain and to intracameral use of compounded and body mass index, the mean CCT
warrants exploration. (Also see related triamcinolone-moxifloxacin in cataract was 4.9 μm greater for patients with di-
commentary by Ann C. McKee, MD, surgery. The FDA has attributed the abetes. According to the meta-analysis,
and Michael L. Alosco, PhD, in the toxicity to abnormally high levels of CCT was 12.8 μm greater in patients
same issue.) poloxamer 407, the agent used for with diabetes. Multivariable analyses
—Summaries by Lynda Seminara binding the medications. For topical showed that greater CCT also was
administration, the maximum con­ associated with higher levels of random
Other Journals centration for poloxamer 407 set by glucose readings (per 10 mg/dL, β =
Selected by Deepak P. Edward, MD the FDA is 0.1% to 0.2%; the concen- 0.3; p < .001) and higher HbA1c (per
tration of poloxamer 407 in these cases percentage, β = 1.5; p < .001). These
Toxic Posterior Segment Syn- was 12%. associations were significant for pa-
drome After Dropless Cataract The authors also noted that mini- tients with diabetes but not for those
Surgery mal research has been conducted on without diabetes.
Retina interactions between poloxamer 407 Findings of this study may be useful
Published online Jan. 24, 2019 and retinal tissue. Until ample informa- for estimating CCT more accurately.
tion exists, the authors advise against Strengths of this research include the
Patel et al. described seven cases of toxic intraocular use of this binding agent. large sample size and use of standard-
posterior segment syndrome (TPSS) ized assessments, enabling adjustment
secondary to intracameral use of com- More Evidence That Diabetes for potential confounders and substan-
pounded triamcinolone-moxifloxacin Is Linked to Greater CCT tiating the validity of findings. Study
during cataract surgery. The toxicity JAMA Network Open limitations include the lack of fasting
was attributed to high levels of the 2019;2(1):e186647 glucose measurements.
binding agent, poloxamer 407. The As a result, the authors recom-
authors emphasized that clinicians High intraocular pressure (IOP) is the mended caution when interpreting the
need to be aware of this potential most treatable risk factor for glaucoma, findings, and they acknowledged that
problem with compounded drugs. but the degree of central corneal thick­ further research is needed to explore
All seven patients had undergone ness (CCT) may impede accurate causal factors for the associations.
uneventful “dropless” cataract surgery estimation of IOP. Research on links —Summaries by Lynda Seminara

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Liquid Biopsy in Retinoblastoma Research

raditional biopsy of retinoblas- regimen while the other
toma has long been contraindi- won’t at all? How can we
cated due to the risk of extraoc- prognosticate better for
ular spread. But in a new application of these children?”
liquid biopsy research, aqueous humor
is showing promise as a surrogate Novel Hypothesis
marker for retinoblastoma. During her search for a
In a groundbreaking study published better diagnostic and
in 2017, researchers found that the prognostic tool, Dr. Berry
aqueous humor of eyes with retinoblas- hypothesized that while the
toma can carry enough tumor-derived tumors form in the back of
DNA to perform genetic analysis of the the eye, the aqueous humor
tumor.1 A second study, published in in the front of the eye might
2018, identified a potential biomarker carry tumor-derived DNA.
for the disease in aqueous humor.2 “They’re very necrotic tu-
mors, so they undergo a lot
The Clinical Challenge of cell lysis, releasing their ULTIMATE GOAL. This line of research opens the
At present, retinoblastoma diagnosis DNA into the eye,” she said. door to in vivo diagnosis of retinoblastoma, said
and treatment decisions are based on Proof of principle. Initially, Dr. Berry (shown here).
clinical findings alone. “For advanced Dr. Berry and her colleagues
retinoblastoma, the prediction of wheth- analyzed six aqueous humor sam- across the vitreous face and makes its
er our treatment will save these eyes is ples from three children aged 7 to 28 way into the aqueous humor—and
about 50/50—and flipping a coin in months, looking for genetic material in some of that DNA material floats into
front of a parent is really frustrating these eyes, which were undergoing sal- the anterior chamber, where it is then
both for me as a surgeon and for the vage therapy.1 They found that tumor accessible for a biopsy, said J. William
parents,” said Jesse L. Berry, MD, at DNA could be detected in the aqueous Harbour, MD, at Bascom Palmer Eye
Children’s Hospital in Los Angeles. humor—and that it could be found Institute in Miami. “Previously, that
Moreover, she said, “If two kids with not only in cases of large, active tumors was just a theory, but Dr. Berry has
retinoblastoma come in with the same but also in those that involved much proved that this is possible.”
clinical features, they’re going to get the smaller tumors that had already been Molecular analysis. In a second study,
same treatment, often intra-arterial treated, Dr. Berry said. “This opened Dr. Berry and her colleagues evaluated
chemotherapy or intravenous chemo­ the door for us to investigate this whole the tumor DNA in eyes that had been
therapy, but these are general [not broader realm of aqueous humor as a removed and in those that were saved.2
personalized] chemotherapy regimens.” liquid biopsy for retinoblastoma.” For this study, the researchers evaluated
She added, “Why do two kids look The concept underpinning aqueous 63 samples of aqueous humor from
identical clinically, but one child responds sampling is that some tumor cells die 29 eyes. “After comparing the groups,
really well to our current therapeutic and rupture; the DNA then diffuses we found a potential biomarker of
Jesse L. Berry, MD

aggressive tumors: a gain of 6p,” Dr.

Berry said.
BERRY, MD, DAN S. GOMBOS, MD, FACS, AND J. WILLIAM HARBOUR, MD. —or copies—of part of the small arm

of chromosome 6. “In our study, the ma to other parts of the body, but we particular modality or agent correlating
6p gain was associated with nearly 10 would eventually like to incorporate a with [effective treatment of] a specific
times increased odds of that eye need- liquid biopsy platform,” he said. genetic fingerprint.”
ing to be removed,” said Dr. Berry. This would be of particular benefit Moreover, he said, aqueous sam-
These results raise the possibility in cases that involve small tumors, pling has potential risk for infection
that researchers might finally have a “where biopsy can be challenging, and and damage to ocular structures. “The
biomarker that would allow them to tell we may want to biopsy at multiple hope is that this research would serve
parents which eyes contain an aggres- times,” Dr. Harbour said. In these in- as a bridge to a noninvasive or purely
sive tumor and thus have a far lower stances, he said, “It would be ideal if we hematogenous biomarker.”
likelihood of responding to therapy— could just take a sample of fluid from Next steps in retinoblastoma. Dr.
and which eyes may experience better the anterior chamber.” Berry has three research initiatives under­
outcomes, Dr. Berry said. Other researchers are investigating way, including a multicenter trial to
the use of liquid biopsy in vitreoretinal collect aqueous humor samples from
Giant Steps Forward lymphoma.3 patients with retinoblastoma across
What’s really novel about aqueous the United States. “For parents who are
humor sampling, Dr. Berry said, is that Looking Ahead willing, we’ll also take aqueous humor
it allows for in vivo diagnosis. “Before, Precision medicine. “This genetic test- samples at diagnosis, to gather critical
if the eye was saved, we never saw what ing is for what we’re now calling ‘pre- data about what the tumor profile in
was happening at the molecular level cision medicine,’ which is staging the the aqueous looks like at diagnosis and
of the tumor,” she said. “We’re allowing patient in terms of prognosis and then what biomarkers we can find,” she said.
researchers—and hopefully, one day, predicting which treatment will be the “In the future, I hope to see a child at
doctors—to discover information about best for the patient,” Dr. Harbour said. diagnosis, take aqueous humor, and
the tumor while the child still has the “If we could find that certain genetic have that be informative to me and the
eye and is being treated.” markers can guide us as to which eyes parents.” She’ll also begin evaluating
And it’s only when studies identify need to be removed and which can be the potential of blood as another form
biomarkers that researchers are able to safely treated with chemotherapy, that of liquid biopsy for retinoblastoma.
begin moving toward targeted therapy would be a powerful way to use this
and precision medicine. As with so much liquid biopsy technology.” 1 Berry JL et al. JAMA Ophthalmol. 2017;135:
current cancer research, the ultimate He added, “What’s exciting is that (11)1221-1230.
aim in retinoblastoma research is to the current technology we have for 2 Berry JL et al. Mol Cancer Res. 2018;1-12.
find targetable biomarkers that pro- sequencing genetic material is so exqui- 3 Cani AK et al. Oncotarget. 2017;8(5):7989-7998.
mote tumorigenesis. sitely sensitive that it allows us to detect
This avenue of research moves these and analyze genetic material from can- Dr. Berry is associate director of ocular oncology
quests forward. “In some cases where cers in much smaller quantities than we at Children’s Hospital Los Angeles and associate
Dr. Berry had to remove the eye, she would have ever imagined in the past. professor of clinical ophthalmology at the Keck
did the liquid biopsy and compared We can make progress in treating pa- School of Medicine at the University of South-
it to analysis of the tumor and found tients, using liquid biopsy techniques, ern California. Relevant financial disclosures:
very similar results,” Dr. Harbour said. in a way that minimizes harm and risk American Cancer Society: S; Knights Templar Eye
“That was critical as well, to show that to the patients while getting sufficient Foundation: S; Larry & Celia Moh Foundation: S
not only can we do a liquid biopsy and material to guide their therapy.” (in-kind support); National Cancer Institute: S;
get genetic information, but that that Cautious optimism. Despite the Wright Foundation: S; Research to Prevent Blind-
genetic information reflects what is in promise of aqueous sampling, Dr. Berry ness: S (in-kind support).
the tumor. These are both very import- cautioned, many questions remain to Dr. Gombos is professor and chief, Section of
ant breakthroughs.” be answered. Dan S. Gombos, MD, Ophthalmology, Department of Head and Neck
FACS, at MD Anderson Cancer Center Surgery at MD Anderson Cancer Center in
Elsewhere in the Eye in Houston, agreed: “These advances Houston. He is also clinical codirector of The
While Dr. Berry is focusing on retino- have enormous potential in further Retinoblastoma Center of Houston, a consortium
blastoma, Dr. Harbour is looking at the stratifying prognosis and therapy, but of MD Anderson, Baylor College of Medicine,
potential of liquid biopsy for uveal there is lack of uniformity in the man- Texas Children’s Hospital, and Methodist Hospi-
melanoma. “Unlike retinoblastoma, agement of retinoblastoma and many tal. Relevant financial disclosures: None.
melanomas do not spread very easily” variables influencing therapy.” Dr. Harbour is director of ocular oncology, vice
from the point of fine-needle biopsy As Dr. Gombos pointed out, “Even chairman for translational research, and director
into the tumor, he said. within the same center, an eye with a of the Ocular Oncology Laboratory at Bascom
“We currently look at genetic mark- particular retinoblastoma grouping Palmer Eye Institute in Miami. Relevant financial
ers from tumor biopsy and can estimate may receive a different modality, with disclosures: None.
whether the patient is at low, medium, different agents, cycles, and doses. So See disclosure key, page 10. For full disclosures,
or high risk of spread of their melano- it may be challenging to identify a see this article at

30  •   A P R I L 2019

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RPE65 Gene Therapy:

A Report From the Clinic

ust weeks after Caspian Soto’s vision.” Together,
birth, his parents started noticing they walked into
something was awry: Their baby an exhibit where
stared constantly at lights but avoided LED stars dotted
making eye contact. “We were new par- the ceiling. “He
ents and weren’t sure how concerned was so excited
we should be,” said his mother, Krista because he’d
Soto. Then his eyes began to roll up and never been able
down, and his parents’ worry increased. to see anything
After an emergency evaluation ruled like it,” said Ms.
out a tumor, an electroretinogram later Soto. “For an
spotted the telltale signs of Leber con- hour, we just
genital amaurosis (LCA). Genetic test- lay on the floor IN THE OR. Subretinal delivery of voretigene with bleb
ing confirmed that both parents carried together and visible with intraoperative video (left) and intraoperative
a copy of a mutation in the RPE65 gene looked up.” OCT (right).
and that Caspian was deficient in both
copies. Caspian officially joined the How Luxturna Works Researchers hypothesize that earlier
1,000 to 2,000 Americans with RPE65 Approved for patients 12 months treatment is better because the retina is
mutation–associated retinal dystrophy.1 and older, Luxturna is an adeno- likely to have less severe damage, said
Without treatment, his prognosis was associated virus vector-based gene Dr. Bailey. In phase 1 Luxturna trials,
dim. therapy that delivers a normal copy the final level of visual sensitivity was
Fortunately, Caspian was a candi­date of the RPE65 gene under the retina, significantly better in 8- to 11-year-olds
for Luxturna (voretigene neparvovec-rzyl, said Ninel Z. Gregori, MD, at Bascom compared with 19- to 44-year-olds, said
Spark Therapeutics), approved in De­ Palmer Eye Institute in Miami. The Dr. Gregori. “But in the phase 3 trial,
cem­ber 2017 for both LCA and early- gene provides instructions for making even the most advanced patients had
onset retinitis pigmentosa (RP). In the an enzyme essential for normal vision, some improvement in vision.”2,3
fall of 2018, at the age of 4, he became allowing retinal cells to function more
one of the youngest patients to be treated normally. Before the Procedure
with Luxturna, the first FDA-approved “We don’t treat the entire retina,” According to Spark Therapeutics, more
gene therapy for a genetic disease. said Steven T. Bailey, MD, one of the than 35 patients have received treat-
About two weeks after Luxturna surgeons who treated Caspian at the ment since FDA approval. Currently,
treatment in the second eye, Caspian’s Oregon Health & Science University the surgeries are done at only seven
parents began noticing some surprising (OHSU) Casey Eye Institute in Port- ocular gene therapy treatment centers,
changes in his ability to navigate his land. “But we try to shore up central using a well-defined Spark protocol,
environment. His mother took him to areas, where the treatment can be most said Dr. Gregori. The first step is to
a nearby children’s museum to “test his useful.” identify the best surgical candidates.
Confirm the diagnosis. “Other in-
Steven T. Bailey, MD

herited retinal diseases [IRDs] can have

BAILEY, MD, NINEL Z. GREGORI, MD, CHRISTINE N. KAY, MD, AND KRISTA “So we need to ensure that we’re tar-
SOTO. geting the right disease with this gene

therapy. Genetic testing confirms that Dr. Gregori. “Once we separate the gel delivery-of-luxturna.)
the patient is deficient in both copies of from the retina, we’re very cautious With OCT in the OR, said Dr.
the RPE65 gene.” that we don’t cause peripheral breaks Gregori, “we’re able to confirm that
Rule out poor candidates. It’s also or detachments when we remove the we’re injecting into the subretinal, rath-
essential to select only patients who vitreous. Elevating the vitreous off the er than suprachoroidal, space. More
have viable retinal cells. “We use optical macula at the proposed injection site important, the macula stretches with
coherence tomography [OCT] to assess allows the needle to penetrate the retina injection of this large volume of medi-
for viable cells during the patient selec- without being caught on the vitreous.” cine, putting it at risk of a macular hole
tion process,” said Dr. Gregori. Removal of the sticky peripheral vit- and loss of the virus into the vitreous
Arrange approval. “The manufac- reous can be challenging in these eyes, cavity. We can observe any overstretch-
turer has a team of liaisons who help she added, explaining that it is some- ing, wait a few minutes while the fluid
physicians communicate with patients, times preferable to leave it, rather than is absorbed, and then inject more. Or
billing departments, and insurers to doing a full vitrectomy and risking an we can form a second bleb to cover the
achieve approval,” said Dr. Gregori, iatrogenic retinal break. seeing area, watching to confirm that a
“but it’s not an instantaneous approval Dr. Bailey emphasized that inspect- hole has not formed.”
process.” The $850,000 price tag might ing for any retinal breaks should not Intraoperative OCT also allows the
have something to do with this. wait until the end of the procedure surgeon to see how much pressure he
Ms. Soto’s first question was: How as with standard vitrectomies. “We or she is applying to the retina with the
do we raise a million dollars? “In my perform scleral indentation to look subretinal cannula during initial bleb
wildest dreams, I never anticipated it for peripheral retinal breaks prior to formation, said Dr. Bailey.
would be covered by insurance,” she the subretinal delivery of Luxturna. Injection: manual or machine. In the
said. And up until a few days before Because gene product in the vitreous Luxturna clinical trials, the surgeon
surgery, she didn’t know what their cavity poses the risk of an inflammato- had a surgical assistant manually inject
out-of-pocket fee would be. In the end, ry response, the idea is to limit ocular 300 mL of the medicine, said Dr. Bailey.
their insurer covered most of the cost, manipulations that may result in gene “We switched to a foot pedal delivery
and Spark covered the rest. product escaping the subretinal space device because we found it can deliver
Begin steroids. Because injection and entering the vitreous cavity.” the product in a slower, more controlled
of the virus puts the eye at risk for Injection site and blebs. “Avoiding manner.” With either method, the
inflammation, patients are started on vessels, we go along the major arcade, surgical assistant must give feedback to
oral prednisone three days before sur- but we must inject at least 2 mm from the main surgeon about the volume of
gery—21 days in total, said Dr. Gregori. the fovea,” said Dr. Gregori. “You can medicine that has been injected, said
Local corticosteroids are also used at do this in one of two ways: Either inject Dr. Gregori. She added that both meth-
the time of and after surgery. Luxturna directly without elevating the ods have their advantages, and surgeons
retina, or first elevate the retina with a may decide which they prefer.
The Procedure small subretinal balanced salt solution Do an air-fluid exchange. An air-
The patient’s eyes are treated on separate [BSS] bleb and then inject Luxturna fluid exchange is recommended to
days, with a recommended minimum into that space.” remove any gene product that may
interval of six days. On the day of sur- The second of these options is be in the vitreous cavity to reduce the
gery, the pharmacy prepares two sterile beneficial in two ways, said Dr. Bailey. risk of an inflammatory response, said
syringes of the drug, said Dr. Gregori. “You’re less likely to inject Luxturna Dr. Bailey. “I have an assistant aim the
Choosing anesthesia. Depending on into the vitreous cavity during initial infusion line more peripherally, not
the patient, the procedure is done under bleb formation, and you can confirm in the direction of the bleb,” he said.
general anesthesia or local ane­sthesia the bleb is extending toward the fovea “Otherwise, pressure from the infusion
with IV sedation, said Dr. Gregori. prior to injection. If the bleb moves line may push Luxturna out of the
Visualize the vitreous. Although the away from the fovea, the surgeon can retinotomy.”
vitrectomy has been tolerated quite well stop the injection and select one or After the procedure, patients should
in these patients, surgeons have made more alternative sites to ensure the avoid airplane travel until the air is
certain alterations to ensure best out- entire macula is treated,” he said. reduced to 10% or less, which may take
comes, said Dr. Bailey. “For example, Observe with OCT. Dr. Gregori and up to two weeks in eyes with retinal
I’ve found that using a dilute Kenalog Janet L. Davis, MD, pioneered the use degeneration, said Dr. Gregori.
solution is useful for visualizing the of intraoperative OCT during a choroi-
vitreous and ensuring that we’ve suc- deremia gene therapy trial a few years After the Procedure
cessfully induced a posterior vitreous ago. Now, surgeons use intraoperative Surgeons see these patients the first
Ninel Z. Gregori, MD

detachment.” OCT during Luxturna surgeries. (View day, week, and month after surgery,
Gently remove the vitreous. “With a a video from Dr. Gregori and Dr. Davis, at which point they are usually sent
23- or 25-gauge vitrectomy, we remove “OCT-Assisted Delivery of Luxturna,” back to the referring retina specialist,
the vitreous in a standard fashion,” said at said Christine N. Kay, MD. She’s a

34  •   A P R I L 2019
vitreoretinal specialist in Gainesville, Müller cells, not just retinal pigment
Florida, who has sent three patients to epithelial cells,” she said. “The enhanced
Dr. Gregori and colleagues at Bascom retinal milieu may improve the func-
Palmer. She sees these patients as need- tion of the cones as well.”
ed postoperatively, typically right after Long-term prognosis? “We have
they are released from their treatment about three years of data proving sus-
center and one month, three months, tained responses using the trials’ out-
and six months after treatment. “Spark come measures,” said Dr. Kay. Despite
also requests that patients return to the improvement in visual function after
surgical treatment center at six months this gene therapy, however, photorecep-
for repeat outcomes testing,” she said. tor degeneration continues at about the
Tests and monitoring. The first same rate as the natural history, said
postoperative visit includes checking Dr. Gregori. “The question is: What
vision and intraoperative pressure and happens later on? How long do the cells
looking for inflammation, said Dr. continue making this protein? Will we
Bailey. “With subsequent visits, we use TREATED EYE. Fundus photograph of a need to reinject at some point?”
OCT to make sure all subretinal fluid patient with biallelic RPE65 mutations Ms. Soto said that unknowns like
has been absorbed and to assess the who received voretigene therapy in these are definitely the most difficult
retinal anatomy.” Subsequent visits may both eyes. part of the process. Still, she says she’s
include repeat visual fields and electro­ incredibly grateful that her child’s
retinograms to assess the treatment happier, there are many adjustments surgeons fully prepared her to have
effect, he said. that come along with seeing better, such realistic expectations. “The journey
Potential complications. Patients as being able to stay out later at night doesn’t end here, but there is so much
continue with postop oral prednisone to play with peers and other social or exciting stuff happening in this field,”
and corticosteroids drops on a relatively behavioral considerations,” said Dr. she said. “It’s pretty amazing.”
rapid taper over several weeks, said Dr. Kay. “It’s important to help the patient
Bailey, and cases of inflammation have and family navigate that process.” 1 Shaberman B. Hum Gene Ther. 2017;28(12):
been minor so far. “As with any surgery, Visual sensitivity. Two patients 1118-1121.
we worry about retinal detachment,” Dr. Kay has seen postoperatively have 2 Bennett J et al. Lancet. 2016;388(10045):661-
he said. “We may assess the peripheral experienced dramatic improvements in 672.
retina with ultrasound if an indirect visual sensitivity. “Within two weeks of 3 Russell et al. Lancet. 2017;390(10097):849-860.
ophthalmoscopy exam is too challeng- surgery, the 10-year-old had significant
ing to do in a young child.” If retinal improvement in his ability to navi- Dr. Bailey is associate professor of ophthalmolo-
holes are visible, added Dr. Gregori, it’s gate in dimly lit rooms, play outside gy and a vitreoretinal specialist at Oregon Health
important to laser those right away. at night, and ride a bike home in the & Science University Casey Eye Institute in Port-
dark,” said Dr. Kay. “Easter eggs were land. Relevant financial disclosures: None.
Patients’ Quality of Life brighter, and he saw a rainbow for the Dr. Gregori is associate professor of clinical
“I can’t even describe how Caspian’s life first time.” Although the patient’s visual ophthalmology at Bascom Palmer Eye Institute at
has changed,” said Ms. Soto, explaining function subjectively improved overall the University of Miami Health System and chief
that he started preschool a couple of —indeed, he had objective improve- of the ophthalmology section at Miami Veterans
weeks after his treatment. “I no longer ment in visual acuity in one eye—there Affairs Medical Center in Miami. Relevant finan-
felt scared that he wouldn’t be able to was a slight decline postoperatively in cial disclosures: None.
see the classroom space and be ostra- visual acuity in the nondominant eye Dr. Kay is a vitreoretinal specialist at Vitreoretinal
cized because of it. I didn’t worry that (possibly due to foveal detachment). Associates in Gainesville, Fla. Relevant financial
he would feel ‘othered’ because of his However, the patient is unaware of this. disclosures: Spark Therapeutics: C; Foundation
headlamp [which he used to rely on Visual fields. The second patient Fighting Blindness: S.
before treatment].” that Dr. Kay referred to Bascom Palmer Ms. Soto is the mother of Caspian Soto, a patient
A time of transition. She hastened —a 17-year-old with a milder pheno- at OHSU Casey Eye Institute in Portland. Rele-
to add that Caspian still faces obstacles. type of RPE65-associated LCA—expe- vant financial disclosures: None.
For example, being reintroduced to so- rienced a dramatic improvement in his See the disclosure key, page 10. For full disclo-
cial situations with improved vision has visual fields with a return of one isopter sures, view this article at
brought its own set of challenges, such of light. Dr. Gregori considers the boy’s
as learning to read facial cues. At first, results the best of the patients she’s MORE ONLINE. For informa-
Caspian was scared about the adjust- treated so far. “Even his central acuity tion about how to identify
ment, and he balked at letting go of his function improved, which is interesting patients who may benefit from gene
headlamp and walking cane. since foveal detachment was avoided in therapy, view this article at
“Although patients are often much this patient, and the cone cells rely on eyenet.

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Pediatric Keratoplasty:
Strategies to Optimize Outcomes

ediatric keratoplasty can have Isolated acquired corneal 1A 1B
a profound impact on a child’s scarring or ectasia has the
life. Full-thickness corneal trans- most favorable prognosis,
plantation in the pediatric population while congenital disease,
is more challenging and has a higher especially when associat-
complication rate than in adults. Car- ed with glaucoma, has the
ing for children with corneal disease poorest prognosis.2
requires a multidisciplinary approach
including the pediatrician, pediatric Preparation
1C 1D
ophthalmologist, and cornea specialist, When considering surgery,
among others. In some complex cases, the physician should screen
glaucoma, retina, and oculoplastics spe- for any social circumstances
cialists may also be involved. The child’s
that would preclude proper
caregivers are particularly important postoperative manage-
members of this team, and they need ment. Caregivers need to be
to have realistic expectations about the prepared for the extensive
outcomes, challenges, and long-term ophthalmic care required for
SURGICAL TECHNIQUE. (1A) Suturing the host
care that is required. pediatric transplant recipi-
cornea (pink) back on to itself during dissection.
Careful preoperative, intraoperative, ents, including frequent clin-
(1B) Placing the donor cornea (blue) on a visco-
and postoperative protocols for pedi- ic visits, long-term eyedrop
elastic interface over the host cornea. (1C) Placing
atric penetrating keratoplasty (PK) are use, amblyopia treatment,
the cardinal sutures. (1D) Removing the host cor-
essential in reducing the risk of surgical
and multiple trips to the OR
nea only after the first three donor corneal sutures
complications in children. Here, we de- for exams, suture removal,
have been placed. (See text for further detail.)
scribe the modified surgical technique and possibly other surgical
we use in young patients. interventions.
It is important to discuss realistic with the pediatrician and other special-
Indications expectations about outcomes—in par- ists to minimize the number of exams
Pediatric corneal disease can be divided ticular, that vision will most likely be under anesthesia.
into congenital and acquired pathol- closer to 20/200 than 20/20—as well as An ocular exam under anesthesia
ogies. In the United States, congenital the lifelong risk of transplant rejection should be considered preoperatively
corneal disease is the most common and infection. to identify other eye abnormalities
indication for pediatric PK, but in Evaluation. Children with congenital that might preclude surgical success
some countries, infections and scar- corneal abnormalities should undergo or require additional intervention.
ring are more common indications.1 a systemic evaluation, and they often Ultrasound biomicroscopy or anterior
It is important to consider the reason require genetic testing. For children segment optical coherence tomography
for surgery as well as associated ocular with additional systemic concerns, the can help with surgical planning in cases
pathology when counseling the family. ophthalmologist should coordinate with a limited view of the anterior
chamber. Other assessment techniques,
Timothy Phelps

including B-scan, visual evoked poten-

BY OLIVIA DRYJSKI, MD, AND CHRISTINA RAPP PRESCOTT, MD, PHD. tials, and corneal topography, may also

Timing. The timing of surgery is it is possible that the child will need of pain or appear uncomfortable (al-
controversial. Earlier intervention is multiple surgeries during his or her though they usually dislike the shield).
better in terms of amblyopia manage­ lifetime. For infants, we typically use
ment; however, the risks of general a 6-mm host trephine with a graft tre- Postoperative Management
anesthesia are higher for infants, espe- phine that is 0.5 mm larger. For older Suture removal starting as early as
cially those under the age of 3 months. children, a 7-mm host trephine with a 3 weeks after surgery is indicated in
Graft survival is generally better for graft trephine 0.5 mm larger is usually pediatric transplants to reduce the risk
older children, although this may be appropriate. of corneal neovascularization. With
related to differences in indication 5. Using a 15-degree blade, the surgeon infants, all sutures should be removed
rather than to the timing of surgery.2 incises the cornea along the trephina- by 3 months postoperatively.
tion incision and injects viscoelastic Children tend to have a strong
Surgical Technique into the anterior chamber. inflammatory response following PK;
General anesthesia is required. Supple- 6. We then proceed with a modified thus, a topical steroid should be admin-
mental retrobulbar anesthesia may be technique for removal of the host istered frequently and tapered slowly. In
added to reduce general anesthesia re- cornea to reduce the risk of lens patients with complex surgery, especial-
quirements and to help with early post- extrusion or expulsive hemorrhage. ly in combination with glaucoma, cata-
operative pain. Pediatric patients are This technique requires cutting the ract, or retinal surgery, a short course of
more likely than adults to experience host tissue with corneal scissors in the oral steroids may be considered if there
positive posterior vitreous pressure fol- same fashion as with an adult trans- are no systemic contraindications.
lowing retrobulbar injection. The use plant. However, as each quadrant is cut, Compared with adult patients,
of a Honan balloon prior to surgery, a suture is placed in the host cornea children more commonly experience
pilocarpine 1% or 2%, and/or reverse approximately 45 degrees from the graft rejection, infection, and glaucoma
Trendelenburg positioning during cardinal positions (Fig. 1A). following PK.1 For this reason, caregiv-
surgery may be helpful in reducing the 7. Once the host cornea is completely ers should be taught how to perform a
risk. Preoperative intravenous mannitol separated from the host bed and held penlight exam, which should be done
may be considered, depending on the in place with four 10-0 nylon sutures, it daily. They should also be educated
child’s weight and systemic health, and is covered with a cohesive viscoelastic, about signs such as fussiness, photo-
should be given as an infusion over at and the donor tissue is placed on top of phobia, and tearing that might indicate
least 15 minutes rather than as a bolus. the viscoelastic (Fig. 1B). complications.
Following is our preferred surgical 8. Three cardinal sutures are used to
approach for PK in children (Fig. 1). secure the donor tissue to the host bed Ongoing Follow-up
It is a modification of the “Price graft- (Fig. 1C). Corneal transplantation can lead to
over-host” technique.3  9. The host corneal sutures are then cut profound improvements in a child’s
1. Pediatric sclera is less rigid than and the host cornea is gently removed vision and quality of life, but even a
adult sclera, and we recommend the from under the donor tissue through clear graft does not ensure clear vision.
use of a Flieringa ring to stabilize the the area where the last cardinal suture Amblyopia therapy must be initiated
iris-lens diaphragm. Moreover, because will be placed. During this process, the as soon as possible and is usually man-
the sclera is thinner in children, the surgeon should take care to maintain aged in conjunction with the pediatric
surgeon must be careful not to perfo- a layer of viscoelastic between the host ophthalmologist. Information about
rate the globe. and donor corneas (Fig. 1D). services such as low vision aids for
2. The donor tissue is trephined in the 10. The donor cornea is then sutured school and home should be provided to
same manner as for an adult PK. Use using 16 interrupted 10-0 nylon sutures, families. Finally, it is important to work
of tissue from donors over the age of 4 with all the knots buried. A running with the patient’s pediatrician and
years is recommended, as tissue from suture is contraindicated in pediatric other specialists to help ensure proper
younger donors is more difficult to patients, since such sutures loosen development.
manage during surgery. more quickly.
3. We routinely perform at least one 11. Finally, we typically inject dexa- 1 Trief D et al. Curr Opin Ophthalmol. 2017;
peripheral iridotomy because children methasone (Decadron) and cefazolin 28(5):477-484.
are more likely than adults to develop subconjunctivally and then apply pred- 2 Karadag R et al. Am J Ophthalmol. 2016;171:95-
postoperative angle closure. nisolone 1% and gentamicin ophthal- 100.
4. We mark the center of the cornea mic drops. If the child is monocular, we 3 Loden JC, Price FW Jr. J Cataract Refract Surg. 
and use an eight-pronged radial ker- place a clear shield on the eye; if binoc- 1998;24(6):736-738.
atotomy marker to mark the cardinal ular, we apply erythromycin ointment
meridians. We then use a vacuum or and a patch and metal shield. Dr. Dryjski is a corneal fellow and Dr. Prescott is
handheld trephine to incise the cornea We recommend oral acetaminophen an assistant professor of ophthalmology; both are
to approximately 50% to 75% of its for postoperative pain control but find at the Wilmer Eye Institute, Johns Hopkins Uni-
depth. We prefer a smaller graft, as that children typically do not complain versity, in Baltimore. Financial disclosure: None.

38  •   A P R I L 2019

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A Mysterious Eyelid Mass

aura Lee* was growing increas- mass in the extraconal space
ingly concerned. Several months of the right upper quadrant.
earlier, the 47-year-old had It measured 30 × 16 × 21
noticed an area of fullness in her right mm and had at least one
upper eyelid (Fig. 1). Although she 5-mm cyst within its borders.
didn’t think much of it at the time, she Although the features of
began to feel uneasy as the mass grew this mass were consistent
and became readily visible. When it with pleomorphic adenoma
started feeling tender to the touch, she (PA), they were not specific
decided to make an appointment with enough to exclude other PRESENTATION. Preoperative appearance of pa­
her local ophthalmologist. He subse- types of lacrimal gland neo- tient showing swelling of the right upper eyelid.
quently referred her to our clinic. plasms, possibly malignant.
Mass removal. We excised the lesion carcinoma ex pleomorphic adenoma,
We Get a Look using a right lateral orbito­tomy approach and aggressive salivary neoplasm not
History. During her visit to our oculo­ under laryngeal mask anesthesia and otherwise specified. Salivary tumor
plastics clinic, Ms. Lee reported no preserved it for examination (Fig. 2). was included in the differential because
significant medical history or recent Ms. Lee tolerated the procedure well of the histologic similarity between
ocular trauma. She also denied a history and, within two weeks, reported no salivary and lacrimal gland tumors as
of past eyelid lesions, diplopia, visual residual pain or swelling. well as previously documented cases
changes, or eye surgery. She was worried Pathology report. Microscopic of spontaneous emergence of salivary
that the growing mass was indicative evaluation demonstrated a mitotically tumors in the orbital region.1
of cancer. Given the lesion’s tenderness active basaloid epithelial neoplasm To better characterize the lesion,
and relatively rapid growth, we were lining an expanded lacrimal duct with pathology then performed a panel of
similarly concerned about the possibility multiple squamous eddies. Reduplica- immunohistochemical stains. A posi-
of an orbital neoplasm. tion of basement membrane–like ma- tive staining pattern for SOX10, S100,
Exam. On initial exam, we confirmed terial within and around the periphery CK5/6, and p63 generally supported the
a mass in the right upper lid in the area of the tumor provided further evidence morphologic impression of a lacrimal
of the lacrimal gland as well as mild to support a diagnosis of PA, also salivary gland tumor. A fluorescence
right proptosis. The remainder of her known as benign mixed tumor (Fig. 3). in situ hybridization study with the
external and anterior segment ophthal- However, the increased rate of mitosis, EWSR1 separation probe was negative
mic exam was within normal limits. in addition to the interspersed central for the separation of 5´ and 3´ EWSR1
areas of fibrosis and necrosis, made us signals, providing no further sup-
Testing concerned about aggressive behavior. port for a diagnosis of myoepithelial
Courtesy of Rona Z. Silkiss, MD, FACS.

Imaging. Following her appointment, The pathology results were inconclu- neoplasm. The combined histologic,
we ordered magnetic resonance imaging sive, and other options on our broad immunostaining, and cytogenetic pat-
(MRI), which showed a well-circum- differential diagnosis included basal tern were most supportive of a benign
scribed, heterogeneously enhancing cell neoplasm, myoepithelial neoplasm, mixed tumor with aggressive features.

BY MICHAEL PAAP, BA, AND RONA Z. SILKISS, MD, FACS. EDITED BY STEVEN Lacrimal gland masses can broadly
J. GEDDE, MD. be classified as inflammatory lesions,

ma.4 Although features such as necrosis yond mixed tumor with aggressive fea-
2 and increased mitosis are suggestive of tures. Given the uncertainties inherent
malignancy, they are not definitive, and in managing poorly defined tumors, we
classification of this type of tumor may believe this case underscores the need
be difficult.4 for conservative treatment and frequent
Differentiation. Despite these chal- follow-up.
lenges, it’s important to differentiate
between benign and malignant lacrimal Our Patient
tumors given their drastically different Ms. Lee healed well following excision
prognoses. Immunohistochemistry of the mass. Because of the possibility
can be a helpful tool, as many different of recurrence and residual malignancy,
tumors exhibit association with specific we referred her for an evaluation for
3 stains. For example, myoepithelial postoperative radiation therapy. This
carcinomas are associated with CK5/6, treatment was declined by the patient.
p63, and S100.5 However, as in this She will be monitored with regular
case, staining patterns can indicate MRI imaging and follow-up for any
more than one possibility such as evidence of recurrence.
mixed tumor. The value of imaging
studies is also limited; although a lesion * Patient name is fictitious.
that appears well circumscribed on
MRI or computed tomography is typi- 1 Kuo YL et al. Eur Arch Otorhinolaryngol. 2011;
cally benign, an early-stage malignancy 268(7):1035-1040.
may have a similar appearance.6 2 Font RL et al. Arch Ophthalmol. 1998;116(5):
Several general clinical features are 613-616.
also suggestive of lacrimal neoplasm 3 Harrison W et al. Saudi J Ophthalmol. 2018;
malignancy, including rapid onset 32(1):13-16.
of symptoms and presence of pain,7 4 Rose GE, Wright JE. Br J Ophthalmol. 1992;
both of which were present in Ms. Lee. 76(7):395-400.
However, benign lacrimal tumors such 5 Argyris PP et al. Head Neck Pathol. 2013;7(1):
as PAs have also been histologically 85-92.
EX VIVO. (2) Tumor following surgical diagnosed in cases in which features 6 Shields CL, Shields JA. Int Ophthalmol Clin.
excision. (3) Overview of tumor histol­ such as pain, rapid progression, and or- 1993;33(3):181-188.
ogy, showing regions of increased bital bone destruction might otherwise 7 Perzin KH et al. Cancer. 1980;45(10):2593-2606.
mitotic activity, abnormal matrix pro­ suggest a malignancy.8 8 Miyazaki T et al. Neurol Med Chir (Tokyo).
duction, squamatization, and calcifica­ 2005;45(8):407-410.
tion. H&E stain, 200× magnification. Conclusion
This case presents a challenging and Mr. Paap is a second-year medical student at
epithelial tumors, metastatic cancer, inconclusive diagnosis of a lacrimal the University of California, San Diego, in La
and lymphomas. Diagnosing epithelial gland tumor. Based on current histo- Jolla, Calif. Dr. Silkiss is Chief of Oculofacial
lacrimal tumors can present a chal- pathologic, radiographic, immunohis- Plastic Surgery at California Pacific Medical
lenge, even with histologic evaluation, tochemical, and clinical evaluation, we Center in San Francisco. Relevant financial dis­
because of the morphalogic diversity are unable to definitively classify it be- closures: None.
within each subtype of this group. Courtesy of Rona Z. Silkiss, MD, FACS. Courtesy of Nicholas Byrne, MD.

Pleomorphic adenomas. PAs are the

Write a Morning Rounds Article
most common type of epithelial tumor, Share an intriguing case report with your colleagues. Here’s how:
comprising 41% of cases.2 Although
1) Introduce the patient (fictitious names only) and describe his or her
they are classically characterized micro-
personal story and baffling symptoms.
scopically by heterogeneous inclusion
of epithelial, myoepithelial, and mes- 2) Then move on to any of the following areas: early misdiagnoses, your
enchymal tissue, PAs exhibit signifi- observations, differential diagnosis, results of tests, the eventual definitive
cant variation in the appearance and diagnosis, treatment, and the patient’s progress.
proportion of their cell components.3 3) Add a few short paragraphs about the disease to augment readers’
Diagnosis of PA is further complicated knowledge base (pathophysiology, etiology, etc).
by the possibility of malignant trans- To get started, visit
formation, which occurs in 10% to Are you a resident? A resident article published in the Morning Rounds
20% of cases, most frequently develop- section will satisfy the RRC requirements for resident scholarly activity.
ing into a pleomorphic adenocarcino-

42  •   A P R I L 2019
Discoveries and
Analysis from
Experts You
Can Rely On
The Academy’s growing family
of journals keeps you in tune with
the most impactful research and
breakthroughs in ophthalmology.

Ophthalmology® is the most read original-

research journal in our field and has an
impressive 7.5 Impact Factor.*
First published January 2017, Ophthalmology®
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ophthalmic journals and is read cover to
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partnership with the American Glaucoma
Society, is the newest and most promising
journal for this dynamic subspecialty.
*Source: Kantar Media

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turnkey program that takes care of the rest. It’s your optical, only better. • 800.346.7486
46  •   A P R I L 2019
Drug Delivery
What is new in drug delivery systems for
the front of the eye, and how might next-generation
devices change patient care and outcomes?

By Lori Baker-Schena, MBA, EdD, Contributing Writer

administer properly. In one report, researchers found that 92% of
eyedrop-naive postoperative cataract patients improperly administered
their drops—including missing the eye, instilling an incorrect number of drops,
contaminating the bottle tip, and failing to wash hands before drop instillation.1
Because of the inherent difficulty with eyedrops (not to mention forgetting to
take drops as prescribed), medications designed to lower intraocular pressure
(IOP), decrease inflammation, and lessen pain can be rendered ineffective.
As drug delivery is the holy grail of anterior segment treatment, much
research and development has been taking place in this arena, and novel approaches
to delivery are coming to market. What is new in anterior segment drug delivery
systems, and how is next-generation drug delivery changing patient care and
outcomes? EyeNet turned to Emmett T. Cunningham, MD, PhD, MPH, founder
of the Ophthalmic Innovation Summit, to identify a few of the current and
emerging technologies; and several EyeNet editorial board members helped
round out the list.
© Peter Bollinger

For each product—starting with those that have recently received FDA
approval—an ophthalmologist familiar with the product (see financial dis­-
closures, page 52) provided insight and opinions.

Manufacturer: EyePoint Pharmaceuticals
Status: FDA approved Feb. 9, 2018
Interviewing Edward J. Holland, MD

How does this technology work?

Dexycu is an anterior chamber intracameral dexa-
methasone drug delivery suspension that provides
medication for up to 21 days with a single appli-
cation to treat postoperative inflammation in
patients undergoing cataract surgery. The sus-
pension is delivered in a single injection through 517 µg of the drug. Corneal edema was reported
a cannula into the sulcus immediately following in 10% of placebo patients, 6.3% of patients who
cataract surgery. Dexycu utilizes the company’s received 342 µg of the drug, and 7.6% of patients
proprietary bioerodable Verisome technology, who received a 517-µg dose. Iritis was more
which allows for sustained release of small mol- common in the placebo group (13.8%) than in
ecules in a suspension that can be customized to the 342-µg group (2.5%) or 517-µg dosage group
release between one and six months. (3.2%). No serious ocular adverse events were
reported up to 90 days following surgery.2
What are the benefits of this device?
Dexycu is an alternative to topical corticosteroids How has the device affected patient
and has two major benefits. First, the dexametha- quality of life?
sone is placed directly where the inflammation is I have listened to patients over the years, and they
located, so the patient receives a higher concentra- just don’t like eyedrops. They need three different
tion of the drug. Second, because Dexycu is used medications following cataract surgery, and a
in place of steroid eyedrops, it avoids many of the significant number of patients have problems with
issues with topical medications, such as patient them. We should all strive for solutions to drug
difficulties with adherence to the dosing regimen delivery challenges. Dexycu, as a possible alterna-
and potential ocular surface complications. tive to corticosteroid drops, is a great start.
In addition, Dexycu was granted pass-through
status (effective Oct. 1, 2018) and assigned a
J-code (J1095; effective Jan. 1, 2019). Dextenza
Manufacturer: Ocular Therapeutix
What are the research findings? Status: FDA approved Dec. 3, 2018
Results from a randomized, placebo-controlled Interviewing Joseph P. Gira, MD
phase 3 trial involving 394 patients found that the
dexamethasone drug delivery suspension was safe How does this technology work?
and effective in treating inflammation after cat- This sustained-release, preservative-free insert,
aract surgery.2 Patients were randomized to 5-µL which contains a 0.4-mg dose of dexamethasone,
injections of placebo or 5-µL injections of 342-µg is implanted into the lacrimal canaliculus immedi-
or 517-µg dexamethasone drug delivery suspen- ately following cataract surgery. The insert swells
sion. Anterior chamber cell and flare clearing at on contact with moisture from the tear fluid, and
postoperative day 8 was achieved in 33.8% of eyes it continues to expand until firmly secured in the
in the placebo group and 63.1% and 67.3% of canaliculus. The proprietary hydrogel plug-like
eyes in the 342-µg and 517-µg groups, respectively. device is designed to remain in the vertical cana-
liculus for 30 days as it delivers the drug. During
What are the drawbacks to this device? the monthlong period, the dexamethasone insert
The most common adverse reactions within the softens, liquefies, and is cleared through the naso-
first 90 days postoperatively were an increase in lacrimal duct—eliminating the need for removal.
IOP, corneal edema, and iritis. In no group did
mean IOP surpass 21 mm Hg, and increases of What are the benefits of this device?
10 mm Hg or more over baseline were reported The outcomes with the insert are similar to eye-
in 13% of placebo patients, 21% of patients who drops, yet the patient does not need to take drops,
received 342 µg, and 29% of patients who received thus eliminating the risk of poor patient compli-

48  •   A P R I L 2019
ance. Other benefits include the constant low-dose
drug load on the ocular surface, the absence of Bimatoprost SR
preservatives, and improved bioavailability. Manufacturer: Allergan
Status: Phase 3 trial data submitted to the FDA,
What are the research findings? and NDA filing expected mid-2019
Results from a parallel-arm, double-masked phase Interviewing E. Randy Craven, MD
3 study involving 438 patients at 21 sites who were
randomized to receive the sustained-release intra­ How does this technology work?
canalicular dexamethasone insert or a placebo Bimatoprost SR is the first-in-class sustained-
demonstrated the insert was safe and effective in release, biodegradable implant for the reduction
treating ocular pain and inflammation following of intraocular pressure (IOP) in patients with
cataract surgery.3 At day 14 after placement, 52.3% open-angle glaucoma and ocular hypertension.
of patients in the insert group had an absence of It is placed in the anterior chamber through an
anterior chamber cells compared with 31.1% in injector system using a 27-gauge needle, much
the placebo group. Additionally, at day 8, 79.6% like doing a paracentesis. Then it drifts down to
of patients in the insert group had an absence of the inferior iridocorneal angle, where it slowly
ocular pain compared with 61.3% in the placebo dissolves over many months. Interestingly, the
group. Patients in the insert group experienced a total weight of the drug in the implant is equal to
decrease in inflammation as early as day 4 after one drop of the topical Lumigan.
surgery and a decrease in pain as early as day 1.
What are the benefits of this implant?
What are the drawbacks to this device? I see this as having huge potential benefit to glau-
The insert is contraindicated for active corneal, coma patients who do not want to deal with drops
conjunctival, or canalicular infections. and are fearful of a laser or incisional surgery.
Pseudophakic patients are ideal. Additionally, this
How has the device affected patient biodegradable device reassures me that patients
quality of life? are receiving medication, which alleviates my
We conducted a qualitative survey evaluating the noncompliance fears.
experience of 25 patients after Dextenza implan-
tation.4 Most patients (92%) reported the highest What are the research findings?
level of overall product satisfaction. They described Results from the phase 1/2 clinical trial demon-
the insert as comfortable and convenient. Com- strated that Bimatoprost SR provided rapid,
pared to previous topical therapy, 96% of the par- sustained IOP lowering.5 The Bimatoprost SR
ticipants rated their experience with the insert as dose strengths were 6-μg, 10-μg, 15-μg, or 20-μg,
“very” or “extremely” convenient, with 88% saying and the overall mean IOP reduction from baseline
they would request the insert again if they were at four months in the Bimatoprost SR eyes ranged
to undergo another cataract surgery. While more from 7.2 mm Hg to 9.5 mm Hg while topical
extensive evaluation is needed, it appears that bimatoprost-treated fellow eyes had a reduction
patients prefer the insert over topical alternatives. of 8.4 mm Hg. In the phase 3 trials, we found
It is comfortable and convenient. dosing between 10-μg and 15-μg worked well.
In addition, we were surprised to learn that for
Note: The company reports that it applied to CMS one in four patients, a single injection worked for
for pass-through status and a J-code. 24 months.

What are the drawbacks to this implant?

After insertion, I look for a 30% pressure reduc-
tion. However, once the pressure creeps up, the
patient may need more treatment. We can insert
another implant, and we have had a few patients
with a couple of these stacked up in the angle.
The implant slowly dissolves over time. However,
many patients have residual implant visible for
over a year and others do not. We need to figure
out how many of them can be placed in the eye.
It is nice having the drops as a backup.

Also, anytime you insert something in the eye, drug dose and preservative delivery to the eye.6
it can cause side effects, so we are watching the Microdose delivery avoids problems associated
long-term data to see if the product is safe. with drug overflow and systemic absorption,
and it may increase local drug bioavailability and
How has the device affected patient absorption in the eye.
quality of life?
Most strikingly, while long-term bimatoprost What are the research findings?
drops can cause red, irritated eyes, the implant Results from a phase 2 study of a 0.4-µg micro-
does not cause reddening, much to the delight of dose of latanoprost demonstrated significant IOP
my patients. And, of course, patients can benefit reduction.7 In the study, 60 eyes of 30 healthy
from sustained drug control without having to volunteers received single 8-µL microdoses of
deal with drops. 0.005% latanoprost on the mornings of days 1
and 2. Diurnal IOP was measured before and two
days after microdosing. The microdose of latano-
Piezo-Print Microdose Delivery prost reduced the baseline IOP by 26% at day 1
Manufacturer: Eyenovia post­administration and by 30% at day 2. All the
Status: Phase 3 trial studying topical latanoprost patients were able to self-administer the micro-
(MicroProst) is expected in 2019. Other microdose doses following training, and no adverse effects
drugs for mydriasis, myopia, and dry eye are in the were reported. In addition, no part of the dispenser
pipeline. touched the eye or periocular area.
Interviewing Robert N. Weinreb, MD
What are the drawbacks to this device?
How does this technology work? One drawback is that the technology has not been
The concept of piezo-print technology is reminis- used in large numbers of patients to demonstrate
cent of how inkjet printers deliver a pixel-sharp efficacy, safety, and tolerability. In addition, the
fluid spray of droplets to create images. This microdose needs to be directly compared to the
ophthalmic dispenser releases a precisely calibrated 1.6-µg dosing of a standard eyedropper in a ran-
and tightly collimated stream of aqueous ocular domized controlled study.
medication microdroplets. The medication is
dispersed at the micron level, using electrostatic How has the device affected patient
droplet charging for high-adhesive ocular surface quality of life?
coating. Piezo-print microdosing delivers drugs The technology directly addresses the challenges
in less than 80 milliseconds, faster than the eye’s set forth in a quote by C. Everett Koop, MD, for-
100-ms blink reflex. mer U.S. Surgeon General: “Drugs don’t work in
patients who don’t take them.”
Lewis RA et al. Am J Ophthalmol. 2017;175:137-147.

What are the benefits of this device?

It offers a tremendous opportunity to
provide safer, better-tolerated, and effec-
tive medications that can be more readily
and reliably delivered to the patient. Two
previous phase 2 clinical trials studying
topical phenylephrine showed that mi-
crodosing achieved a pharmacodynamics
effect equivalent to conventional eyedrop
dosing, but with a 75% reduction in total

50  •   A P R I L 2019
dure. Our decision may be guided by duration of
iDose efficacy of the device. As far as long-term efficacy,
Manufacturer: Glaukos the phase 3 studies should provide the informa-
Status: Currently in phase 3 trials tion, as the studies have a three-year follow-up.
Interviewing Mark J. Gallardo, MD
How has the device affected patient
How does this technology work? quality of life?
iDose is a titanium implant (1.8 mm × 0.5 mm) There are multiple flaws in asking patients to
loaded with a proprietary formulation of travo- perpetually use drops to manage their glaucoma.
prost. It is designed to continuously elute thera- The cost of medications is rising; compliance
peutic levels of the drug into the anterior cham- decreases as the number of medications increas-
ber. Phase 2 data suggest potential efficacy up to es; and topical therapy has been associated with
12 months, after which the implant is designed multiple adverse side effects of the eye and ocular
to be removed and replaced with a new iDose adnexa. This device provides us with another tool
device. The implant is placed through a clear to battle glaucoma and improve a patient’s quality
corneal incision using an injector similar to the of life by minimizing the need for topical therapy.
iStent inject (two stents placed during a single
procedure). The device has an anchor that is
placed through Schlemm’s canal into the sclera
to maintain the device in a fixed location.

What are the benefits of this device?

The most compelling aspect of the iDose is that
by implanting the device intracamerally, we are
avoiding all the adverse effects of topical prosta-
glandin analogs: periorbital fat atrophy, blephari- Bimatoprost Ring
tis, hypertrichosis, conjunctival hyperemia. Manufacturer: Allergan
Minimizing the need for topical therapy also Status: Phase 2 and open-label extension (OLE)
reduces the eyes’ exposure to benzalkonium complete
chloride, which has been shown to exacerbate Interviewing James B. Brandt, MD
ocular surface disease and induce apoptosis of
the endothelial cells lining trabecular columns. How does this technology work?
Once the efficacy of the device has diminished, The technology is deceptively simple. The ring
it can be grasped, removed, and then replaced. is a soft, flexible ocular insert containing 13 mg
bimatoprost mixed into a silicone matrix placed
What are the research findings? over an inner polypropylene support structure.
In a Jan. 10, 2018, press release, the company The drug release occurs when the patient’s tears
reported that it was conducting a 154-patient, come in contact with the device, causing molec-
randomized double blind phase 2 trial, which ular diffusion of the drug through the silicone
evaluated two models of the iDose delivery sys- matrix. Manufactured in diameters ranging from
tem with two different travoprost elution rates, 24 to 29 mm, the ring sits circumferentially in
compared to topical timolol ophthalmic solution, the fornices on top of the conjunctiva and elutes
0.5%. Results from a 12-month interim cohort bimatoprost for up to six months at a time. Inser-
of 49 implant patients showed that they achieved tion can be compared to placing a contact lens.
an approximate 30% reduction in mean IOP vs.
baseline IOP during the first 12 months, with a What are the benefits of this device?
favorable safety profile.8 My concern about the injectable devices is that
inserting needles inside eyes is not without risk,
What are the drawbacks to this device? even if this risk is small. The biggest advantage
Because a corneal incision and anterior cham- to this platform over injectable devices is safety
ber maintenance with viscoelastic is required and reversibility. It is also quite easy to insert, and
for device implantation, we must perform this virtually all the patients in the study hardly felt the
procedure in an OR. So we have to weigh the risk device after a few days. In addition, the patient is
and benefits of subjecting the patient to a minor aware if the device is dislodged or falls out, and he
surgical procedure if done as a stand-alone proce- or she can seek attention immediately.

free life because none of these platforms allows for
loading of more than one drug. The ring platform
has the potential to carry more than one drug, but
we’re probably years away from commercialization
of multidrug rings. In the meantime, patients can
take another drop on top of the ring.

What are the research findings? How has the device affected patient
Results from the phase 2 study demonstrated a quality of life?
clinically relevant reduction in mean IOP over The safety-efficacy balance is ideal for the large
a six-month period with the bimatoprost ring.9 population of patients with ocular hypertension
Patients with open-angle glaucoma or ocular or early glaucoma who respond to prostaglandins
hypertension were randomized to receive either a but are inconsistent with eyedrops. Interestingly, a
bimatoprost insert and twice-daily artificial tears side effect of the ring is the production of mucus,
or a placebo insert and twice-daily timolol drops and in patients with a history of dry eyes, patients
(0.5% solution) for six months. A mean reduc- find that their dry eye symptoms improve as the
tion of 3.2 to 6.4 mm Hg from baseline IOP was device stimulates more mucin to enter the tear film.
observed with the ring group compared with 4.2
to 6.4 mm Hg for the timolol group. A 13-month 1 An JA et al. J Cataract Refract Surg. 2014;40:1857-1861.
open-label extension of the study showed a median 2 Donnenfeld E, Holland E. Ophthalmology. 2018;125:799-806.

© American Academy of Ophthalmology

IOP reduction of 4 mm Hg, with the rings re- 3 Tyson SL et al. J Cataract Refract Surg. 2019;45(2):204-212.
maining in place for 95% of patients.10 4 Gira JP et al. Patient Prefer Adherence. 2017;11:487-494.
5 Lewis RA et al. Am J Ophthalmol. 2017;175:137-147.
What are the drawbacks to this device? 6 Ianchulev T et al. Ther Deliv. 2018;9(1):17-27.
The challenge for the sustained-release devices 7 Pasquale LR et al. Clin Ophthalmol. 2018;12:2451-2457.
under development for glaucoma is that many 8 Go to
patients need more than one drug to achieve their Jan. 10, 2018.
clinical target IOP. As exciting as sustained-release 9 Brandt JR et al. Ophthalmology. 2016;123:1685-1694.
medicines are, we cannot promise patients a drug- 10 Brandt JR et al. Ophthalmology. 2017;124:1565-1566.

Meet the Experts

James D. Brandt, Ivantis: C; Santen: C. professor of ophthalmology at
MD Professor Mark J. Gallardo, the University of Cincinnati. Fi­
of ophthalmol- MD Glaucoma nancial disclosures: EyePoint: C.
ogy, director of specialist at El Robert N. Weinreb, MD Distin-
the Glaucoma Paso Eye Sur- guished professor
Service, and vice chair for In- geons in Texas. of ophthalmology
ternational Programs and New Financial disclosures: Alcon: and bioengineer-
Technology at the University L; Ellex: C,L; Glaukos: C,L; ing and the chair
of California, Davis. Financial New World Medical: S. of ophthalmology
disclosures: Allergan (and For- Joseph P. Gira, at the University of California,
Sight Vision Labs, which MD Refractive San Diego, as well as direc-
Allergan acquired in 2016): and anterior tor of the Shiley Eye Institute
C,S; Glaukos: O. segment surgeon and director of the Hamilton
E. Randy Craven, practicing at Glaucoma Center. Financial
MD Glaucoma Ophthalmology Consultants in disclosures: Aerie: C; Allergan:
specialist and St. Louis, Mo. Financial disclo- C; Bausch + Lomb: S; Carl
vice chair of sures: Bausch + Lomb: L; Kala: Zeiss Meditec: P,S; CenterVue:
Practice Network L. (2015-16 Ocular S; Eyenovia: C; Genentech: S;
at Wilmer Eye Institute and Therapeutix: S) Heidelberg: S; Konan: S; Na-
Johns Hopkins University in Edward J. Holland, tional Eye Institute: S; Optos:
Baltimore. Financial disclo- MD Director of S; Optovue: S; Tomey: S; Toro-
sures: Aerie: C; Alcon: C; Aller- Cornea Services medes: O; Unity: C.
gan: C; Gore: C; Haag-Streit: C; at Cincinnati Eye Institute and See disclosure key, page 10.

52  •   A P R I L 2019





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E&M Codes Versus Eye Visit Codes:

Here’s What’s New for 2019

hen billing for an office Less documentation for home Per CMS guidelines, when docu-
visit, you can choose to use visits. Effective Jan. 1, 2019: If you menting the history for an established
Evaluation and Manage- use the E&M codes for home visits patient E&M code, you can indicate the
ment (E&M) codes (99XXX) or Eye (99341-99350), you no longer have to status of three chronic or inactive con-
visit codes (92XXX). This article high- document the medical necessity for ditions, instead of documenting current
lights recent changes to the documen- furnishing the service at the home elements of the history of the present
tation requirements for E&M codes. rather than at the office or as an out­ illness (HPI).
(Note: CMS plans sweeping changes patient visit. CMS notes that the
to E&M codes in 2021. To keep track patient doesn’t have to be confined to E&M Versus Eye Visit Codes:
of the latest developments, check your the home in order to be eligible for Differences in Documentation
email each week for Washington Report such a visit. (Source: Federal Register For E&M codes, documentation guide-
Express and, if you are an AAOE mem- 83:59630.) lines are standardized and recognized
ber, Practice Management Express.) Less documentation for teaching nationally by all payers. Furthermore,
physicians. Effective Aug. 14, 2018: since 1997, there have been ophthal­
Three Changes to How You Physicians may review, rather than mology-specific exam element require-
Document E&M Codes redocument, a medical student’s doc- ments for E&M codes.
Less redundancy when staff or the umentation of the physical exam and For Eye visit codes, document the
beneficiary have documented the chief decision-making activity. The teaching services listed in the CPT descriptors.
complaint. Effective Jan. 1, 2019: For physician is responsible for performing These descriptors were established
E&M codes, new CMS rules state that (or reperforming) the exam and the many years before E&M’s ophthalmol-
physicians don’t have to “re-enter in the medical decision-making components ogy-specific exam elements, mentioned
medical record information on the pa- and also needs to sign and date the stu- above. There are no national guidelines
tient’s chief complaint and history that dent’s documentation. (Source: MLN and no state Medi­care Local Carrier
has already been entered by ancillary Matters: MM10627.) Determination (LCD) policies for
staff or the beneficiary.” Instead, phy- documenting Eye visit codes.
sicians should indicate that they have Tips for Documenting E&M Never apply E&M documentation
reviewed and verified this information. Established Patient Codes requirements to Eye visit codes or
This new policy applies to both new When you use E&M codes 99212- vice versa. When you are determining
and established patients. 99215, you are required to document the level of E&M code, you can use
This change is optional. CMS states medical decision-making plus at least an audit tool that takes into account
that you can continue your earlier doc- one of these two elements: a number of factors, including the
umentation processes. (Source: Federal • history level of history and the complexity of
Register 83:59635.) • exam decision-making that are documented.
However, you should not use that audit
tool when determining which level of
X. REPKA, MD, MBA, ACADEMY MEDICAL DIRECTOR OF GOVERNMENT chart on the next page, which lists the
ING AND REIMBURSEMENT. code 99204 and Eye visit code 92004.

Coming in the next E&M Code Versus Eye Visit Code: Example
® E&M Code: 99204: New Patient, Eye Visit Code: 92004:
Comprehensive Exam, Decision- New Patient, Comprehensive
Making of Moderate Complexity Ophthalmological Services
Documenting history: Documenting history:
Feature • Chief complaint. • Chief complaint. The patient’s
Alternative Delivery • Four elements to the HPI. chief complaint assists in identify-
Part 2 of coverage of • Past, family, and social history ing which elements of the exam are
novel drug delivery (PFSH). medically necessary to perform.
systems focuses on the • Review of 10 or more body • History. CPT does not list specific
posterior segment. systems. Note if the patient has a requirements. History should include,
positive response (e.g., has seasonal at a minimum, HPI and relevant por-
allergies), document any action tions of the past medical history.
Clinical Update
that had been taken (e.g., patient • General medical observation.
Cataract A look at two new
uses over-the-counter medication). CPT does not provide specifics.
technologies—miLoop and
Note: When seeing established You should document a review of
Zepto. How are they being
patients, you may not need a com- systems relevant to the problem(s)
plete review of systems or PFSH, being addressed.
Cornea In a break with which can overinflate the service.
traditional keratoplasty Documenting exam: Documenting exam:
techniques, DSO (Descem- • All 12 elements of the exam. • All 12 elements of the exam.
et stripping only) skips the • Mental assessment. Note: The CPT code’s description
graft. Note: Dilation is required for 99204 states, “It often includes, as indicated:
(and for codes 99205 and 99215). . . . examination with cycloplegia
Pearls or mydriasis . . .” However, the
Serpiginous Choroiditis auditor will look for documentation
How to recognize and man- for dilation. If you don’t dilate
age this elusive, recurrent indicate why.
retinal disorder that strikes Documenting medical decision- Documenting initiation of diagnostic
healthy adults. making: and treatment programs: Medical
• Must be moderate level of com- decision-making is inherent to this
Practice Perfect plexity (see below). Include these component. It may include, but is
Apps That Save Money three components: not limited to, the following:
and Time Three ophthal- 1. New problem with additional work- • prescription of medication,
mologists share tips on up planned • arranging for special ophthal-
their favorite practice 2. Order and/or review tests, labs, mological diagnostic or treatment
management apps. outside consult, review past records services,
3. Table of risk • consultations,
Blink What is a moderate level of com- • laboratory procedures, and
Take a guess at the next plexity? CMS provides the following • radiological services.
issue’s mystery image. • One or more chronic illnesses with
mild exacerbation, progression, or What are comprehensive ophthal-
side effects of treatment mological services? Such services
For Your Convenience • Two or more stable chronic ill- involve a general evaluation of the
These stories also will be nesses complete visual system. The CPT
• Undiagnosed new problem with section for Eye visit codes gives
available online at
uncertain prognosis (e.g., lump in breast) this example: “The comprehensive
• Acute illness with systemic symp- services required for diagnosis and
FOR ADVERTISING INFORMATION toms treatment of a patient with symp-
• Acute complicated injury toms indicating possible disease of
Mark Mrvica or Kelly Miller • Minor surgery with identified risk the visual system, such as glaucoma,
M. J. Mrvica Associates Inc. factors
• Elective major surgery, with no cataract, or retinal disease, or to rule
identified risk factors out disease of the visual system, new
• Prescription drug management or established patient.”

56  •   A P R I L 2019


Keys to Promoting—and Protecting—

Your Online Reputation

nline reviews are rapidly lends the brand credibility.1 quarter. A Google search of your name
replacing traditional word- Dr. Goel recommended using one will most likely prioritize Healthgrades,
of-mouth recommendations professional photo that is consistent Google My Business, Yelp, and Vitals.
for service industries—and health care across all websites. The image should Since these sites appear first, they will
is no exception. As more patients turn reflect the tone you want to set for your also be the most popular with patients
to the internet to help them choose a practice, so think about whether you and potential patients, so they require
doctor, “the biggest mistake a practice want a photo that is more patient- particular attention.
can make is ignoring its online pres- focused and personable, more expert- To correct mistakes and keep
ence,” said Ravi D. Goel, MD, compre- focused and professional, etc. He your profile current, you must claim
hensive ophthalmologist and social emphasized that using more than one your page on the review site. (There
media lecturer in Cherry Hill, New central photo for your brand could is typically an option to do so at the
Jersey. Fortunately, managing your confuse potential clients. bottom or top of your page.) Once you
prac­tice in the online realm requires Create online accounts. Cultivating have editing privileges, make it easy
no more than a few branding funda- your brand also requires that you: 1) for potential patients to learn about
mentals. have a high-quality website that is ac- your practice by providing a current
cessible and appealing across devices; 2) business phone number, work hours,
Build Your Brand create a Facebook page that is updated accepted types of insurance, and a busi-
The first step to a great online presence regularly; and 3) claim your account on ness address accessible through Google
is creating and maintaining a clear physician review sites, according to Dr. Maps, said Dr. Goel.
individual brand, which encompasses Melendez. One site to start with is Health-
all the attributes that patients associate In addition to using Facebook, you grades, which has an account for nearly
with you, said Robert F. Melendez, MD, should post content on Instagram, every U.S. physician. “At the very least,
MBA, comprehensive ophthalmologist LinkedIn, Twitter, and YouTube, Dr. all physicians should claim this account
in Albuquerque, New Mexico. Melendez said. Blog posts and videos and post a professional photo,” said Dr.
Choose an image. The easiest way can elevate your brand because they Goel. “Unclaimed accounts and those
to become recognizable is to “establish serve as a reminder of your expertise. lacking a photo can cause potential pa-
a visual brand, much like you would a They are also a great marketing tool tients to question whether the informa-
logo, and use it on everything asso- since interesting posts will make read- tion is even accurate,” added Dr. Wong.
ciated with your practice so that it ers more inclined to click on your bio
is instantly recognized online,” said and learn about your practice, he said. Reviews: Prevent Negative,
Randall V. Wong, MD, retina specialist Manage external profiles. Being Promote Positive
and internet marketing consultant in a professional in the digital realm Online reviews reflect offline behavior,
Bethesda, Maryland. Market research requires that you are aware of what is said Dr. Melendez. Your online rep-
has consistently shown that the average published about you and that you take utation is established while you are in
person is far more likely to engage steps to ensure that facts about your the clinic, performing surgery, on call,
with a product or service online if they practice are accurate. Dr. Goel suggest- and interacting in your community,
recognize it; this is because familiarity ed Googling yourself at least once per so focusing on patient satisfaction is
Know the reasons behind negative
GOEL, MD, ROBERT F. MELENDEZ, MD, MBA, AND RANDALL V. WONG, MD. you or your practice can potentially

deter others from seeking your services. indexed by Google via Google Alerts
According to Dr. Wong’s observations, (, a free service
unhappy ophthalmology patients that notifies you whenever a review is
typically write reviews to complain posted about you or your practice. All

about excessive wait times, customer reviews, positive or negative, merit a
service issues, billing, inadequate response, said Dr. Wong.
exams, and poor outcomes. Actionable Addressing positive reviews.

Gives You online feedback provides information

for improving patient communications,
Ac­knowl­edging positive reviews is
important, said Dr. Wong. “If you come

the Full
operations, and office policies and pro- upon a site where every time a review is
tocols that can enhance your patients’ left or comment is made someone from
experiences. “No matter what type of the office thanks the writer, others will

Picture feedback you get from a patient, it is

important to reflect on it and find its
core cause. One patient review could
be inspired to review as well.”
Addressing negative reviews. Your
response to negative reviews should be
Poll-topping, digestible equal five or 10 unspoken sentiments,” crafted such that it acknowledges the
coverage of all things said Dr. Goel. complaint and seeks an equitable reso-
ophthalmologic Ask patients for reviews. The easiest lution. “Delegate this task to your office
way to obtain positive reviews is to manager or someone who can remain
ask patients. Dr. Melendez said that he objective and respond in a supportive,
typically asks a patient for a review a thankful, and accurate manner,” said
week after cataract surgery since that Dr. Wong. In creating your reaction
is when patients tend to be the most plan, follow these guidelines:
satisfied with his performance. “When • Wait 24 hours to respond so that
they are already complimenting my you have time to think about what you
work in the examination room, I take are going to say.
this as an opportunity to both express • Keep it professional.
my appreciation for the compliment • Never say anything negative about
and ask for a review. Then I instruct the person.
them where to go online in order to • Always thank the person for bring-
post it,” he said, though he cautioned ing the issue to your attention.
that physicians and their staff should • Acknowledge the problem.
never ask for a particular comment or • Offer a solution.
rating, nor should they offer rewards in • Never disclose anything about a
exchange for reviews. patient’s identity or condition.
If you need help getting started, • Be honest and transparent.
Your one-stop shop for the Healthgrades offers registered physicians
free materials that can be printed and 1 Malik M et al. International Journal of Business
• In-depth clinical information
distributed to patients in your office and Science. 2019;4(5):167-171.
in Pearls, Clinical Updates, and
Features. indicating where to post a review.
• Bite-sized research summaries Know the expectation. Physicians Dr. Goel is a comprehensive ophthalmologist at
in News in Review and Journal need only as many reviews as their Regional Eye Associates in Cherry Hill, N.J., and
Highlights. closest competitors. For example, if you a regular lecturer on topics related to physicians’
• Intriguing mystery cases in are one of two glaucoma specialists in online presence. Financial disclosures: None.
Morning Rounds and Blink. a small town, and the other physician Dr. Melendez is a comprehensive ophthalmol-
• Practice management tips from has 15 great reviews, your goal should ogist at Eye Associates of New Mexico, and
the experts in Practice Perfect and
be 16. Perfect scores are nice but are not operates Social Media Page Creators, a social
Savvy Coder.
necessary. In fact, too many five-star media management company, in Albuquerque,
• Thought-provoking editorials in
Opinion and Current Perspective. ratings could seem unrealistic and fake, N.M. Financial disclosures: Social Media Page
said Dr. Melendez. “As long as your rat- Creators: O.

Visit Us Online
ings are four stars or better, it is likely Dr. Wong is a retina specialist at Dressler Oph- that you are doing okay.” thalmology Associates in Bethesda, Md., and is
founder of Medical Marketing Enterprises, an in-
Write to Us Respond to Reviews ternet marketing consulting company for health
To maintain a positive online image, care professionals, in Bethesda, Md. Financial
you will need to track feedback. You disclosures: Medical Marketing Enterprises: O.
can and should monitor all review sites See the disclosure key, page 10.

58  •   A P R I L 2019

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Easy login. To speed the login collection of ophthalmic artifacts on orated in launching Ophthalmology
process, initial sign-on can be done permanent display in the United States, Glaucoma.
through Touch ID or a face scan (if as well as the only medical museum This journal provides an oppor-
your device has those features enabled) in San Francisco. This innovative new tunity to disseminate your glaucoma
or by manually typing your username center is designed to feature interactive research directly to those who find it
and password. With your mobile and technological displays to introduce most relevant. Joining the ranks of the
device’s ability to remember your visitors from around the world to the Academy’s esteemed Ophthalmology
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Academy Makes the Case That IRIS
practice an opportunity to harness Registry Can Transform Federal Policies
the power of big data—but you must
submit your application soon. The Academy continues to build a powerful case in D.C. for the IRIS
The H. Dunbar Hoskins Jr., MD, Registry’s capacity to improve quality of care and reduce administrative
Center for Quality Eye Care IRIS Regis- burdens at the federal level. 
try Research Fund will support at least Academy urges new MIPS head to increase IRIS Registry credit in
four IRIS Registry analytics projects in quality-performance measurement. After hearing about the IRIS Reg-
2019. istry from a Michigan ophthalmologist, the new head of MIPS, Michelle
Learn more about the eligibility re- Schreiber, MD, connected with the Academy’s Medical Director of Health
quirements and the application process Policy, William L. Rich III, MD, to get a deep look into the IRIS Registry’s
at potential for burden reduction and for improving quality care.
hoskins-center-research-fund. This meeting furthered the Academy’s continued effort to secure more
program credit for registry participants. 
FOR THE RECORD Beyond MIPS. The IRIS Registry has data on more than 52 million
patients (about 16% of the U.S. population), making it a powerful resource
Notice of Resignation During for research. It can, for example, be used to assess drug safety and effec-
an Ethics Investigation tiveness in a real-world setting, and the Academy has made a case to the
At a recent meeting, the Academy’s FDA for the role that registry data can play in regulatory decision-making
Board of Trustees approved a recom- and in initiatives, such as the agency’s proposed Real World Evidence
mendation to publish the following Program. The IRIS Registry’s real-world data sets also can provide the
information about an Academy Fellow’s Academy with persuasive support for its policy positions.
resignation. Christopher Lyon, MD,
PhD, of 1401 Avocado Ave., Suite 402,
Newport Beach, California, resigned ing Session on Sunday, Oct. 13. As the Diagnostic Technology in the Pediatric
effective Oct. 11, 2018. A challenge director of the Division of Epidemiol- Patient (cosponsored by the American
pursuant to the Code of Ethics was ogy and Clinical Applications and the Association of Pediatric Ophthalmolo-
pending at the time of the resignation.   deputy clinical director at the National gy and Strabismus); and
Eye Institute, National Institutes of • The Millennial Movement: How
MEMBERS AT LARGE Health, Dr. Chew is inspired by current Gender Equality, Big Data, and Tech-
        research. Her lecture is titled “Age- nology Will Be Embraced by the Young
Hal Foster Award Related Macular Degeneration: Nutri- Ophthalmologist (cosponsored by
The Kansas City Society of Ophthal- tion, Genes, and Deep Learning.” the Academy Young Ophthalmologist
mology & Otolaryngology (KCSO&O) Find more on AAO 2019 lectures Committee).
gave the 2019 Hal Foster Award to starting June 12 at Find more information about AAO
former Missouri Society of Eye Physi- 2019 at
cians & Surgeons (MoSEPS) President Inspired by Technology
and present Membership Chair John C. San Francisco’s reputation as the home Members Register for Free
Hagan III, MD, on Feb. 8, 2019.  of technological innovation is inspiring Academy and American Academy of
Dr. Hagan previously served as many AAO 2019 symposia, including Ophthalmic Executives members can
president of the Clay-Platte County the following: register for AAO 2019 and reserve hotel
Medical Society and the Kansas City • The Impact of Artificial Intelligence rooms starting June 12. Registration for
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and is associate editor of the Kansas Information Technology); Not a member? Become one
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MEETING MATTERS for Global Ophthalmology (cospon-
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Attend the Jackson tion and Outreach Committee); Heading to the Association for Research
Memorial Lecture • Picture This: Imaging for the Anteri- in Vision and Ophthalmology (ARVO)
Emily Y. Chew, MD, will give the 76th or Segment Specialist (cosponsored by Annual Meeting in Vancouver, Cana-
annual Edward Jackson Memorial the Cornea Society); da? Visit the Academy at Booth 1714.
Lecture during the AAO 2019 Open- • How to Use the Latest Imaging and Exhibits will be open April 28-May 1.

62  •   A P R I L 2019
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Royal Alexandra Hospital Eye Clinic

to make your diagnosis in the


Giant Full-Thickness Macular Hole

Associated With Alport Syndrome

49-year-old man with chronic poor vision 1 2
in both eyes presented with worsening
vision in his right eye. His past medical
history was significant for glomerulonephritis, two
kidney transplants, and sensorineural hearing loss.
There was no history of trauma or ocular disease. 3 4
The patient’s best-corrected visual acuity was
20/150 in his right eye and 20/60 in his left. Fun-
dus examination revealed a giant full-thickness
macular hole (FTMH) in the right eye (Fig. 1) and Giant macular hole associated with Alport
a partial-thickness macular hole in the left eye. syndrome is thought to be caused by collagen
Autofluorescence imaging of the right eye (Fig. abnormalities in the internal limiting membrane,
2) showed a typical bull’s-eye appearance, with a Bruch membrane, or retinal pigment epithelium.
central area of hypoautofluorescence and a sur- Surgical treatment offers limited results.1
rounding rim of hyperautofluorescence. Optical
coherence tomography of the right eye demon- 1 Miller JJ et al. Retin Cases Brief Rep. 2007;1(3):153-155.
strated a FTMH measuring 3,900 μm in diameter
(Fig. 3) and retinoschisis involving the macula and WRITTEN BY NATALIE HUANG, MD, AND SANDRA R.
the midperipheral retina (Fig. 4). Next-generation MONTEZUMA, MD. PHOTOS BY DREW MILLER. ALL
sequencing testing revealed a pathogenic COL4A5 ARE AT UNIVERSITY OF MINNESOTA DEPARTMENT
mutation consistent with Alport syndrome, a sys- OF OPHTHALMOLOGY AND VISION NEUROSCIENCES,
temic disease that also affected his daughter. MINNEAPOLIS.

66  •   A P R I L 2019
6.2 Clinical Studies Experience 6.3 Immunogenicity
Because clinical trials are conducted under widely varying conditions, adverse As with all therapeutic proteins, there is the potential for an immune response
reaction rates observed in one clinical trial of a drug cannot be directly in patients treated with LUCENTIS. The immunogenicity data reflect the
compared with rates in the clinical trials of the same or another drug and may percentage of patients whose test results were considered positive for
not reflect the rates observed in practice. antibodies to LUCENTIS in immunoassays and are highly dependent on the
The data below reflect exposure to 0.5 mg LUCENTIS in 440 patients with sensitivity and specificity of the assays.
neovascular AMD in Studies AMD-1, AMD-2, and AMD-3; in 259 patients The pre-treatment incidence of immunoreactivity to LUCENTIS was 0%-5%
with macular edema following RVO. The data also reflect exposure to 0.3 mg across treatment groups. After monthly dosing with LUCENTIS for 6 to 24
Brief summary–please see the LUCENTIS® package LUCENTIS in 250 patients with DME and DR at baseline [see Clinical Studies (14 months, antibodies to LUCENTIS were detected in approximately 1%-9% of
insert for full prescribing information. in the full prescribing information)]. patients.
Safety data observed in Study AMD-4, D-3, and in 224 patients with mCNV The clinical significance of immunoreactivity to LUCENTIS is unclear at this time.
1 INDICATIONS AND USAGE were consistent with these results. On average, the rates and types of adverse Among neovascular AMD patients with the highest levels of immunoreactivity,
LUCENTIS is indicated for the treatment of patients with: reactions in patients were not significantly affected by dosing regimen. some were noted to have iritis or vitritis. Intraocular inflammation was not
1.1 Neovascular (Wet) Age-Related Macular Degeneration (AMD) Ocular Reactions observed in patients with DME and DR at baseline, or RVO patients with the
Table 1 shows frequently reported ocular adverse reactions in LUCENTIS- highest levels of immunoreactivity.
1.2 Macular Edema Following Retinal Vein Occlusion (RVO)
treated patients compared with the control group. 6.4 Postmarketing Experience
1.3 Diabetic Macular Edema (DME) The following adverse reaction has been identified during post-approval use
1.4 Diabetic Retinopathy (DR) Table 1 Ocular Reactions in the DME and DR, AMD, and RVO Studies of LUCENTIS. Because this reaction was reported voluntarily from a population
1.5 Myopic Choroidal Neovascularization (mCNV) DME and DR AMD AMD RVO of uncertain size, it is not always possible to reliably estimate the frequency or
2-year 2-year 1-year 6-month establish a causal relationship to drug exposure.
4 CONTRAINDICATIONS • Ocular: Tear of retinal pigment epithelium among patients with




4.1 Ocular or Periocular Infections neovascular AMD

0.3 mg

0.5 mg

0.5 mg

0.5 mg



LUCENTIS is contraindicated in patients with ocular or periocular infections. 7 DRUG INTERACTIONS
4.2 Hypersensitivity Drug interaction studies have not been conducted with LUCENTIS.
LUCENTIS is contraindicated in patients with known hypersensitivity to Adverse Reaction n=250 n=250 n=379 n=379 n=440 n=441 n=259 n=260 LUCENTIS intravitreal injection has been used adjunctively with verteporfin
ranibizumab or any of the excipients in LUCENTIS. Hypersensitivity reactions photodynamic therapy (PDT). Twelve (12) of 105 (11%) patients with
may manifest as severe intraocular inflammation. Conjunctival
hemorrhage 47% 32% 74% 60% 64% 50% 48% 37% neovascular AMD developed serious intraocular inflammation; in 10 of the 12
5 WARNINGS AND PRECAUTIONS patients, this occurred when LUCENTIS was administered 7 days (± 2 days)
Eye pain 17% 13% 35% 30% 26% 20% 17% 12% after verteporfin PDT.
5.1 Endophthalmitis and Retinal Detachments
Intravitreal injections, including those with LUCENTIS, have been associated Vitreous floaters 10% 4% 27% 8% 19% 5% 7% 2% 8 USE IN SPECIFIC POPULATIONS
with endophthalmitis and retinal detachments. Proper aseptic injection Intraocular 8.1 Pregnancy
technique should always be used when administering LUCENTIS. In addition, pressure increased 18% 7% 24% 7% 17% 5% 7% 2% Risk Summary
patients should be monitored following the injection to permit early treatment Vitreous There are no adequate and well-controlled studies of LUCENTIS administration
should an infection occur [see Dosage and Administration ((2.6, 2.6, 2.7
2.7)) in the full detachment 11% 15% 21% 19% 15% 15% 4% 2% in pregnant women.
prescribing information and Patient Counseling Information (17)].
Intraocular Administration of ranibizumab to pregnant monkeys throughout the period
5.2 Increases in Intraocular Pressure inflammation 4% 3% 18% 8% 13% 7% 1% 3% of organogenesis resulted in a low incidence of skeletal abnormalities at
Increases in intraocular pressure have been noted both pre-injection and post- intravitreal doses 13-times the predicted human exposure (based on maximal
injection (at 60 minutes) while being treated with LUCENTIS. Monitor intraocular Cataract 28% 32% 17% 14% 11% 9% 2% 2%
serum trough levels [Cmax]) after a single eye treatment at the recommended
pressure prior to and following intravitreal injection with LUCENTIS and manage Foreign body clinical dose. No skeletal abnormalities were observed at serum trough levels
appropriately [see Dosage and Administration ((2.7 in the full prescribing sensation in eyes 10% 5% 16% 14% 13% 10% 7% 5% equivalent to the predicted human exposure after a single eye treatment at the
information)]. Eye irritation 8% 5% 15% 15% 13% 12% 7% 6% recommended clinical dose [see Animal Data].
5.3 Thromboembolic Events Lacrimation Animal reproduction studies are not always predictive of human response,
Although there was a low rate of arterial thromboembolic events (ATEs) increased 5% 4% 14% 12% 8% 8% 2% 3% and it is not known whether ranibizumab can cause fetal harm when
observed in the LUCENTIS clinical trials, there is a potential risk of ATEs administered to a pregnant woman. Based on the anti-VEGF mechanism of
following intravitreal use of VEGF inhibitors. ATEs are defined as nonfatal stroke, Blepharitis 3% 2% 12% 8% 8% 5% 0% 1%
action for ranibizumab [see Clinical Pharmacology (12.1 in the full prescribing
nonfatal myocardial infarction, or vascular death (including deaths of unknown Dry eye 5% 3% 12% 7% 7% 7% 3% 3% information)], treatment with LUCENTIS may pose a risk to human embryofetal
cause). Visual disturbance development.
Neovascular (W (Wet) Age-Related Macular Degeneration or vision blurred 8% 4% 18% 15% 13% 10% 5% 3% LUCENTIS should be given to a pregnant woman only if clearly needed.
The ATE rate in the three controlled neovascular AMD studies (AMD-1, AMD-2, Eye pruritus 4% 4% 12% 11% 9% 7% 1% 2%
AMD-3) during the first year was 1.9% (17 of 874) in the combined group of Data
patients treated with 0.3 mg or 0.5 mg LUCENTIS compared with 1.1% (5 of Ocular hyperemia 9% 9% 11% 8% 7% 4% 5% 3% Animal Data
441) in patients from the control arms [see Clinical Studies (14.1 in the full Retinal disorder 2% 2% 10% 7% 8% 4% 2% 1% An embryo-fetal developmental toxicity study was performed on pregnant
prescribing information)]. In the second year of Studies AMD-1 and AMD-2, the cynomolgus monkeys. Pregnant animals received intravitreal injections of
Maculopathy 5% 7% 9% 9% 6% 6% 11% 7% ranibizumab every 14 days starting on Day 20 of gestation, until Day 62 at
ATE rate was 2.6% (19 of 721) in the combined group of LUCENTIS-treated
patients compared with 2.9% (10 of 344) in patients from the control arms. Retinal doses of 0, 0.125, and 1 mg/eye. Skeletal abnormalities including incomplete
In Study AMD-4, the ATE rates observed in the 0.5 mg arms during the first degeneration 1% 0% 8% 6% 5% 3% 1% 0% and/or irregular ossification of bones in the skull, vertebral column, and
and second year were similar to rates observed in Studies AMD-1, AMD-2, and Ocular discomfort 2% 1% 7% 4% 5% 2% 2% 2% hindlimbs and shortened supernumerary ribs were seen at a low incidence
AMD-3. in fetuses from animals treated with 1 mg/eye of ranibizumab. The 1 mg/eye
Conjunctival dose resulted in trough serum ranibizumab levels up to 13 times higher
In a pooled analysis of 2-year controlled studies (AMD-1, AMD-2, and a study of hyperemia 1% 2% 7% 6% 5% 4% 0% 0% than predicted Cmax levels with single eye treatment in humans. No skeletal
LUCENTIS used adjunctively with verteporfin photodynamic therapy), the stroke Posterior capsule abnormalities were seen at the lower dose of 0.125 mg/eye, a dose which
rate (including both ischemic and hemorrhagic stroke) was 2.7% (13 of 484) in opacification 4% 3% 7% 4% 2% 2% 0% 1% resulted in trough exposures equivalent to single eye treatment in humans.
patients treated with 0.5 mg LUCENTIS compared to 1.1% (5 of 435) in patients No effect on the weight or structure of the placenta, maternal toxicity, or
in the control arms (odds ratio 2.2 (95% confidence interval (0.8-7.1))). Injection site
hemorrhage 1% 0% 5% 2% 3% 1% 0% 0% embryotoxicity was observed.
Macular Edema Following Retinal Vein Occlusion 8.2 Lactation
The ATE rate in the two controlled RVO studies during the first 6 months was Non-Ocular Reactions Risk Summary
0.8% in both the LUCENTIS and control arms of the studies (4 of 525 in the Non-ocular adverse reactions with an incidence of ≥ 5% in patients receiving There are no data available on the presence of ranibizumab in human milk, the
combined group of patients treated with 0.3 mg or 0.5 mg LUCENTIS and 2 LUCENTIS for DR, DME, AMD, and/or RVO and which occurred at a ≥ 1% higher effects of ranibizumab on the breastfed infant or the effects of ranibizumab on
of 260 in the control arms) [see Clinical Studies (14.2 in the full prescribing frequency in patients treated with LUCENTIS compared to control are shown milk production/excretion.
information)]. The stroke rate was 0.2% (1 of 525) in the combined group of in Table 2. Though less common, wound healing complications were also
LUCENTIS-treated patients compared to 0.4% (1 of 260) in the control arms. Because many drugs are excreted in human milk, and because the potential for
observed in some studies. absorption and harm to infant growth and development exists, caution should
Diabetic Macular Edema and Diabetic Retinopathy be exercised when LUCENTIS is administered to a nursing woman.
Safety data are derived from studies D-1 and D-2. All enrolled patients had Table 2 Non-Ocular Reactions in the DME and DR, AMD, and RVO Studies
DME and DR at baseline [see Clinical Studies (14.3, 3 14.44 in the full prescribing
3, The developmental and health benefits of breastfeeding should be considered
information)]. along with the mother’s clinical need for LUCENTIS and any potential adverse
2-year 2-year 1-year 6-month
effects on the breastfed child from ranibizumab.
In a pooled analysis of Studies D-1 and D-2 [see Clinical Studies (14.3 in the




full prescribing information)], the ATE rate at 2 years was 7.2% (18 of 250) with 8.3 Females and Males of Reproductive Potential
0.3 mg

0.5 mg

0.5 mg

0.5 mg




0.5 mg LUCENTIS, 5.6% (14 of 250) with 0.3 mg LUCENTIS, and 5.2% (13 of Infertility
250) with control. The stroke rate at 2 years was 3.2% (8 of 250) with 0.5 mg No studies on the effects of ranibizumab on fertility have been conducted. and it
LUCENTIS, 1.2% (3 of 250) with 0.3 mg LUCENTIS, and 1.6% (4 of 250) with is not known whether ranibizumab can affect reproduction capacity. Based on
Adverse Reaction n=250 n=250 n=379 n=379 n=440 n=441 n=259 n=260 the anti-VEGF mechanism of action for ranibizumab, treatment with LUCENTIS
control. At 3 years, the ATE rate was 10.4% (26 of 249) with 0.5 mg LUCENTIS
and 10.8% (27 of 250) with 0.3 mg LUCENTIS; the stroke rate was 4.8% (12 Nasopharyngitis 12% 6% 16% 13% 8% 9% 5% 4% may pose a risk to reproductive capacity.
of 249) with 0.5 mg LUCENTIS and 2.0% (5 of 250) with 0.3 mg LUCENTIS. Anemia 11% 10% 8% 7% 4% 3% 1% 1% 8.4 Pediatric Use
5.4 Fatal Events in Patients with DME and DR at baseline Nausea 10% 9% 9% 6% 5% 5% 1% 2% The safety and effectiveness of LUCENTIS in pediatric patients have not been
Diabetic Macular Edema and Diabetic Retinopathy established.
Cough 9% 4% 9% 8% 5% 4% 1% 2%
Safety data are derived from studies D-1 and D-2. All enrolled patients had 8.5 Geriatric Use
DME and DR at baseline [see Clinical Studies (14.3, 14.4 in the full prescribing Constipation 8% 4% 5% 7% 3% 4% 0% 1% In the clinical studies, approximately 76% (2449 of 3227) of patients randomized
information)]. Seasonal allergy 8% 4% 4% 4% 2% 2% 0% 2% to treatment with LUCENTIS were ≥ 65 years of age and approximately 51%
A pooled analysis of Studies D-1 and D-2 [see Clinical Studies (14.3 in the full Hypercholesterolemia 7% 5% 5% 5% 3% 2% 1% 1% (1644 of 3227) were ≥ 75 years of age [see Clinical Studies (14 in the full
prescribing information)], showed that fatalities in the first 2 years occurred in prescribing information)]. No notable differences in efficacy or safety were seen
Influenza 7% 3% 7% 5% 3% 2% 3% 2% with increasing age in these studies. Age did not have a significant effect on
4.4% (11 of 250) of patients treated with 0.5 mg LUCENTIS, in 2.8% (7 of 250)
of patients treated with 0.3 mg LUCENTIS, and in 1.2% (3 of 250) of control Renal failure 7% 6% 1% 1% 0% 0% 0% 0% systemic exposure.
patients. Over 3 years, fatalities occurred in 6.4% (16 of 249) of patients treated Upper respiratory 10 OVERDOSAGE
with 0.5 mg LUCENTIS and in 4.4% (11 of 250) of patients treated with 0.3 tract infection 7% 7% 9% 8% 5% 5% 2% 2% More concentrated doses as high as 2 mg ranibizumab in 0.05 mL have been
mg LUCENTIS. Although the rate of fatal events was low and included causes Gastroesophageal administered to patients. No additional unexpected adverse reactions were
of death typical of patients with advanced diabetic complications, a potential reflux disease 6% 4% 4% 6% 3% 4% 1% 0% seen.
relationship between these events and intravitreal use of VEGF inhibitors cannot 17 PATIENT COUNSELING INFORMATION
be excluded. Headache 6% 8% 12% 9% 6% 5% 3% 3%
Advise patients that in the days following LUCENTIS administration, patients are
6 ADVERSE REACTIONS Edema peripheral 6% 4% 3% 5% 2% 3% 0% 1% at risk of developing endophthalmitis. If the eye becomes red, sensitive to light,
The following adverse reactions are discussed in greater detail in other sections Renal failure chronic 6% 2% 0% 1% 0% 0% 0% 0% painful, or develops a change in vision, advise the patient to seek immediate
of the label: Neuropathy care from an ophthalmologist [see Warnings and Precautions (5.1)].
• Endophthalmitis and Retinal Detachments [see Warnings and Precautions peripheral 5% 3% 1% 1% 1% 0% 0% 0%
• Increases in Intraocular Pressure [see Warnings and Precautions (5.2)] Sinusitis 5% 8% 8% 7% 5% 5% 3% 2%
• Thromboembolic Events [see Warnings and Precautions (5.3)] Bronchitis 4% 4% 11% 9% 6% 5% 0% 2%
• Fatal Events in patients with DME and DR at baseline [see Warnings and Atrial fibrillation 3% 3% 5% 4% 2% 2% 1% 0%
Precautions (5.4)] LUCENTIS®
Arthralgia 3% 3% 11% 9% 5% 5% 2% 1% [ranibizumab injection]
6.1 Injection Procedure
Serious adverse reactions related to the injection procedure have occurred Chronic obstructive Manufactured by: Initial US Approval: June 2006
in < 0.1% of intravitreal injections, including endophthalmitis [see Warnings pulmonary disease 1% 1% 6% 3% 3% 1% 0% 0% Genentech, Inc. Revision Date: LUC/021815/0050(4) 2017
and Precautions (5.1)], rhegmatogenous retinal detachment, and iatrogenic Wound healing A Member of the Roche Group LUCENTIS® is a registered
traumatic cataract. complications 1% 0% 1% 1% 1% 0% 0% 0% 1 DNA Way trademark of Genentech, Inc.
South San Francisco, CA ©2017 Genentech, Inc.
0 . 3 M G LU C E N T I S P R E F I L L E D SY R I N G E



The efficacy and safety of LUCENTIS in DR, studied in 3 clinical trials,
available in a sterile glass prefilled syringe.1




60 (n=41)

37 39 37.8
(n=117) (n=117) (n=148)

20 7
(n=115) 4
LUCENTIS® (ranibizumab injection) is indicated for ≥3-STEP IMPROVEMENTS AT 2 YEARS1:
the treatment of patients with:
• Diabetic retinopathy (DR) RISE AND RIDE PROTOCOL S
• Diabetic macular edema (DME) • LUCENTIS 0.3 mg: 9% (n=117) • Patients without DME:
and 17% (n=117), respectively 28.4% (n=148)
IMPORTANT SAFETY INFORMATION • Sham arms: 0% (n=115) and 2% • Patients with DME: 31.7% (n=41)
(n=124), respectively
• LUCENTIS is contraindicated in patients with ocular or Confidence intervals (95%): ≥2-step—RISE: 31% (21%, 40%); RIDE: 35% (26%, 44%). Protocol S
periocular infections or known hypersensitivity to (DR with DME): 58.5% (43.5%, 73.6%); (DR without DME): 37.8% (30%, 45.7%). ≥3-step—RISE:
ranibizumab or any of the excipients in LUCENTIS. 9% (4%, 14%); RIDE: 15% (7%, 22%). Protocol S (DR with DME): 31.7% (17.5%, 46%); (DR
without DME): 28.4% (21.1%, 35.6%).1
Hypersensitivity reactions may manifest as severe
intraocular inflammation ADVERSE EVENTS
WARNINGS AND PRECAUTIONS • Serious adverse events related to the injection procedure that occurred in <0.1%
• Intravitreal injections, including those with LUCENTIS, have of intravitreal injections included endophthalmitis, rhegmatogenous retinal
been associated with endophthalmitis, retinal detachment, detachment, and iatrogenic traumatic cataract
and iatrogenic traumatic cataract. Proper aseptic injection • In the LUCENTIS Phase III clinical trials, the most common ocular side effects
technique should always be utilized when administering included conjunctival hemorrhage, eye pain, vitreous floaters, and increased
LUCENTIS. Patients should be monitored following the injection intraocular pressure. The most common non-ocular side effects included
to permit early treatment, should an infection occur nasopharyngitis, anemia, nausea, and cough
• Increases in intraocular pressure (IOP) have been noted both • As with all therapeutic proteins, there is the potential for an immune
pre-injection and post-injection (at 60 minutes) with LUCENTIS. response in patients treated with LUCENTIS. The clinical significance
Monitor intraocular pressure prior to and following intravitreal of immunoreactivity to LUCENTIS is unclear at this time
injection with LUCENTIS and manage appropriately Please see Brief Summary of LUCENTIS full Prescribing
• Although there was a low rate of arterial thromboembolic events Information on following page.
(ATEs) observed in the LUCENTIS clinical trials, there is a potential risk
*The following clinical trials were conducted for the DR & DME indications:
of ATEs following intravitreal use of VEGF inhibitors. ATEs are defined RISE & RIDE—Two methodologically identical, randomized, double-masked,
as nonfatal stroke, nonfatal myocardial infarction, or vascular death sham injection–controlled, Phase III pivotal trials (N=759) that studied the
(including deaths of unknown cause) efficacy and safety of LUCENTIS 0.3 mg and 0.5 mg administered monthly
• In a pooled analysis of Studies DME-1 and DME-2, the ATE rate at 2 to patients with DR and DME at baseline. The primary outcome was the
years was 7.2% (18 of 250) with 0.5 mg LUCENTIS, 5.6% (14 of 250) proportion of patients gaining ≥15 letters at 2 years. Protocol S—
A randomized, active-controlled study that evaluated LUCENTIS 0.5 mg vs
with 0.3 mg LUCENTIS, and 5.2% (13 of 250) with control. The stroke
panretinal photocoagulation in DR patients with and without DME. All eyes
rate at 2 years was 3.2% (8 of 250) with 0.5 mg LUCENTIS, 1.2% (3 of in the LUCENTIS group (n=191) received a baseline 0.5 mg intravitreal
250) with 0.3 mg LUCENTIS, and 1.6% (4 of 250) with control. At 3 years, injection followed by 3 monthly injections. Further treatments were guided
the ATE rate was 10.4% (26 of 249) with 0.5 mg LUCENTIS and 10.8% (27 by prespecified retreatment criteria. FDA approval was based on an
of 250) with 0.3 mg LUCENTIS; the stroke rate was 4.8% (12 of 249) with analysis of the LUCENTIS arm of Protocol S. The primary outcome
0.5 mg LUCENTIS and 2.0% (5 of 250) with 0.3 mg LUCENTIS was mean change in visual acuity from baseline to 2 years.2-3
• Fatal events occurred more frequently in patients with DME and DR at LUCENTIS 0.3 mg is recommended to be administered by
baseline treated monthly with LUCENTIS compared with control. A pooled intravitreal injection once a month (approximately 28 days).1
analysis of Studies D-1 and D-2, showed that fatalities in the first 2 years
DME, diabetic macular edema.
occurred in 4.4% (11 of 250) of patients treated with 0.5 mg LUCENTIS, in 2.8%
(7 of 250) of patients treated with 0.3 mg LUCENTIS, and in 1.2% (3 of 250) of REFERENCES: 1. LUCENTIS [package insert]. South San
Francisco, CA: Genentech, Inc; 2018. 2. Brown DM, et al; RISE and
control patients. Over 3 years, fatalities occurred in 6.4% (16 of 249) of patients RIDE Research Group. Ophthalmology. 2013;120:2013-2022.
treated with 0.5 mg LUCENTIS and in 4.4% (11 of 250) of patients treated with 3. Gross JG, et al; Writing Committee for the Diabetic Retinopathy
0.3 mg LUCENTIS. Although the rate of fatal events was low and included causes Clinical Research Network. JAMA. 2015;314:2137-2146.
of death typical of patients with advanced diabetic complications, a potential
relationship between these events and intravitreal use of VEGF inhibitors cannot
be excluded

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