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APRIL 2019
Beyond Eyedrops
7 Next-Generation Options
for the Anterior Segment
Pediatric Keratoplasty:
A Modified Surgical Technique
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OPD-SCAN III
Integrated Wavefront
with criteria to qualify patient
for EDOF IOLs
A LIVE SYMPOSIUM DISCUSSING THE BENEFITS DERIVED FROM INTEGRATED WAVEFRONT TECHNOLOGY
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
discussing.
VISIT MARCO
May 4-6 , 2019 TO VIEW THE POWER FORUM III: PART 2
ASCRS/ASOA • 1537
▲
FEATURE
CLINICAL INSIGHTS
EyeNet® Magazine (ISSN 1097-2986) is published monthly by the American Academy of Ophthalmology, 655 Beach St., San Francisco,
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VIEWPOINTS
12 Letters
Progress for ophthalmic research.
14 Opinion
The graying of ophthalmology.
MYSTERY IMAGE
66 Blink
What do you see?
COVER ILLUSTRATION
© Peter Bollinger
66
xx
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
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.
1 INDICATIONS AND USAGE
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
DEX0019
I AM
LEARN MORE AT
MODMED.COM/CATARACT-REFRACTIVE TOGETHER, WE ARE MODERNIZING MEDICINE.
10 • A P R I L 2019
FOR ROTATIONAL STABILITY,
THERE’S NO COMPARISON
1,2
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
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ASTIGMATISM-CORRECTING IOL
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Steve Silverstein Inder Paul Singh Denise Visco Keith Walter Your name here
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RUTH D. WILLIAMS, MD
O
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. www.ama-assn.org/practice-
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
SMART is Better AI-DRIVEN EHR & PM FOR
OPTIMAL EFFICIENCY
SEE IT LIVE.
AScrs annual meeting. B00TH #3013
www.compulinkadvantage.com/oNETAB | 800.456.4522
Foundation
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
BRIEF SUMMARY
Consult the Full Prescribing Information for complete product information.
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.
ADVERSE REACTIONS
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.
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).
Lactation
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.
NONCLINICAL TOXICOLOGY
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.
ed single-source sheets of cells between to facilitate FDA approval of an early Relevant financial disclosures—Dr. Bharti: None.
EYENET MAGAZINE • 19
CATARACT • repeatability
Evaluating Lens of the lens tilt
measurement,
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’
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
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.
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 aao.org/eyenet.
EYENET MAGAZINE • 21
The One and Only Indicator of
MMP-9 for Dry Eye Inflammation
InflammaDry is the only test that detects elevated levels of MMP-9, a key inflammatory
marker for dry eye. This rapid, point-of-care test produces results in 10 minutes allowing
patients to be tested and treated in the same office visit. The test is easy to perform, is
minimally invasive and requires no additional equipment. InflammaDry utilizes innovative
patented technology, is CE marked, and CLIA waived.
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
T
ER
DV
rates of adverse recent exposure to tamsu- or PPV within 24 hours (macula on)
A
RT
events (AEs) losin (odds ratio, 0.96 per or 72 hours (macula off) of detection.
OPHTHALMOLOGY
SE
IN
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
EYENET MAGAZINE • 23
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).
EYENET MAGAZINE • 25
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
EYENET MAGAZINE • 27
41% of refractive or cataract surgery
patients have ocular surface dysfunction
levels requiring some treatment beyond
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ONCOLOGY
CLINICAL UPDATE
T
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
EYENET MAGAZINE • 29
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 aao.org/eyenet.
30 • A P R I L 2019
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CLINICAL UPDATE
J
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
EYENET MAGAZINE • 33
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 aao.org/clinical-video/oct-assisted- 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 aao.org/eyenet.
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 aao.org/
“Although patients are often much this patient, and the cone cells rely on eyenet.
EYENET MAGAZINE • 35
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CORNEA
OPHTHALMIC PEARLS
Pediatric Keratoplasty:
Strategies to Optimize Outcomes
P
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
EYENET MAGAZINE • 37
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
OPHTHALMOLOGY JOB CENTER
MORNING ROUNDS
L
aura Lee* was growing increas- mass in the extraconal space
1
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.
Discussion
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,
EYENET MAGAZINE • 41
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.
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.
Delve deeper at
aao.org/journals
UNLEASH THE POWER
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46 • A P R I L 2019
Novel
Drug Delivery
Systems
What is new in drug delivery systems for
the front of the eye, and how might next-generation
devices change patient care and outcomes?
E
YEDROPS ARE NOTORIOUSLY HARD FOR PATIENTS TO
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.
EYENET MAGAZINE • 47
Dexycu
Manufacturer: EyePoint Pharmaceuticals
Status: FDA approved Feb. 9, 2018
Interviewing Edward J. Holland, MD
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.
EYENET MAGAZINE • 49
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.
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.
EYENET MAGAZINE • 51
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.
52 • A P R I L 2019
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W
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
BY JENNY EDGAR, ACADEMY MANAGER, CODING AND REIMBURSEMENT; Eye visit code to bill.
DAVID GLASSER, MD, ACADEMY SECRETARY OF FEDERAL AFFAIRS; Want an example of how the docu-
CHERIE MCNETT, ACADEMY DIRECTOR OF HEALTH POLICY; MICHAEL mentation requirements differ? See the
X. REPKA, MD, MBA, ACADEMY MEDICAL DIRECTOR OF GOVERNMENT chart on the next page, which lists the
AFFAIRS; AND SUE VICCHRILLI, COT, OCS, ACADEMY DIRECTOR OF COD- documentation requirements for E&M
ING AND REIMBURSEMENT. code 99204 and Eye visit code 92004.
EYENET MAGAZINE • 55
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)
used?
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.
examples:
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
aao.org/eyenet. 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
856-768-9360
identified risk factors out disease of the visual system, new
mjmrvica@mrvica.com
• Prescription drug management or established patient.”
56 • A P R I L 2019
MARKETING & BUSINESS DEVELOPMENT
PRACTICE PERFECT
O
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
crucial.
Know the reasons behind negative
BY LESLIE BURLING, CONTRIBUTING WRITER, INTERVIEWING RAVI D. reviews. A single negative review about
GOEL, MD, ROBERT F. MELENDEZ, MD, MBA, AND RANDALL V. WONG, MD. you or your practice can potentially
EYENET MAGAZINE • 57
deter others from seeking your services. indexed by Google via Google Alerts
According to Dr. Wong’s observations, (www.google.com/alerts), 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
EyeNet
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.
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
Visit Us Online
ings are four stars or better, it is likely Dr. Wong is a retina specialist at Dressler Oph-
aao.org/eyenet 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
eyenet@aao.org
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
PATIENT EDUCATION
Patient Brochures
Order Today
aao.org/espanol
866.561.8558
STATE ADVOCACY
“To become a retinal surgeon, I devoted long hours to prepare for split-
second judgment calls that are of critical benefit to my patients. Long
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And it’s why I contribute to the Surgical Scope Fund.”
JULIA A. HALLER, MD
Ophthalmologist-in-Chief, Wills Eye Hospital, Philadelphia
EYENET MAGAZINE • 61
Apply Now for a Big Data
Research Grant D.C. REPORT
A research fund established last year
gives Academy members in private
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 aao.org/iris-registry/data-analysis/ 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 aao.org/2019. Find more information about AAO
former Missouri Society of Eye Physi- 2019 at aao.org/2019.
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
Medical Society; has been editor of the (AI) on Ophthalmology (cosponsored the Academy’s annual meeting is free
Missouri Medicine journal since 2000; by the Academy Committee on Medical for members.
and is associate editor of the Kansas Information Technology); Not a member? Become one
City Medicine journal. • Artificial Intelligence (AI) and Ma- by visiting aao.org/member-services
chine Learning: Promise and Purpose and scrolling to the “Join” links.
MEETING MATTERS for Global Ophthalmology (cospon-
sored by the Academy Global Educa- Visit the Academy at ARVO
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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MYSTERY IMAGE
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A
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
LUCENTIS
LUCENTIS
LUCENTIS
LUCENTIS
4.1 Ocular or Periocular Infections neovascular AMD
0.3 mg
0.5 mg
0.5 mg
0.5 mg
Control
Control
Control
Control
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
DME and DR AMD AMD RVO
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
LUCENTIS
LUCENTIS
LUCENTIS
LUCENTIS
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
Control
Control
Control
Control
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%
(5.1)]
• 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.
94080-4990
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
REGRESSION DELIVERED 1
58.5
PATIENTS (%)
60 (n=41)
37 39 37.8
(n=117) (n=117) (n=148)
40
20 7
(n=115) 4
(n=124)
0
INDICATIONS RISE RIDE PROTOCOL S
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
CONTRAINDICATIONS
• 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