CAPSULOTOMY DOES MAKE A DIFFERENCEBy Lynda Charters

SALT L AKE C I T Y : : FEMTOSECOND

LASER capsulotomies provide sig-

nificantly more predictable effec-

tive lens positions compared with

manual procedures.

Robert J. Cionni, MD, discussed the

superiority of the femtosecond laser for

creating capsulotomies compared with

the conventional manual method and

re-optimization of lens constants for

accurate laser refractive lens surgery.

“The capsulotomy does make a dif-

ference,” said Dr. Cionni, medical di-

rector of The Eye Institute of Utah, Salt

Lake City. He cited a study in which it

was found that a 4-mm capsulotomy

tends to position an IOL slightly more

posteriorly compared with a 6-mm

capsulotomy.

( See story on page 36 )

Refractive

In This IssueMarch 1, 2013

VOL. 38, NO. 5

EDITORIAL 4

Truth be toldWhy honesty in the physician-patient

relationship is not what it seems

GLAUCOMA 12

The next step in drug deliveryHow a topical micro-droplet system

targets direct application to the

ocular surface

GENERAL 32

Innovation abounds at OISRegulatory and investment climate

fosters drug, device opportunities

FOLLOW US ONLINE:

By Cheryl Guttman KraderReviewed by Mark S. Humayun, MD, PhD

SYLMAR, CA ::

AFTER 20 YEARS of research and develop-

ment and many clinical trials, patients in the United

States with retinitis pigmentosa (RP) will now have

the ability to regain limited vision, allowing them

to read, have unassisted mobility, and have facial

recognition.

On Feb. 14, the FDA granted approval to Second

Sight Medical Products to market its

retinal prosthesis (Argus II Retinal

Prosthesis System) for patients with

late-stage RP. The system is the first

and only retinal prosthesis commer-

cially available anywhere in the world.

The regulatory agency’s decision

comes after the 19 members of the FDA Ophthal-

mic Devices Advisory Panel voted unanimously

in September 2012 to recommend approval. The

prosthesis has been approved and sold in Europe

since October 2011.

The retinal prosthesis is designed to bypass the

eye structure damaged by RP with electrical stim-

ulation of the retina to induce visual perception in

blind individuals. Retinal diseases destroy the light-

sensing cells, or photoreceptors, in the retina. The

( Continues on page 7 : Prosthesis )

OphthalmologyTimes.com

FDA approval of retinal prosthesis

brings limited sight to individuals

with retinitis pigmentosa

SPECIAL REPORT // RETINAVMA ADVANCES : WET AMD 'BEST RESPONDERS'

WhatThe retinal prosthesis

is designed to

bypass the eye

structure damaged

by RP with electrical

stimulation of the

retina to induce

visual perception in

blind individuals.

When Commercial launch

planned for later

this year

(Photo courtesy of Second Sight)

FDA APPROVAL

Hope for patientswith late-stage RP

C L I N I C A L N E W S & A N A L Y S I S

Welcome to the March 01, 2013, issue of Ophthalmology Times magazine.

This digital edition is brought to you by Advanstar Communications Inc.

Below you’ll find an alphabetical index of the advertisers in this issue. If you’d like more information about the

advertiser, you can click on the name or the page number to see their ad.

Allergan Inc 22-23, 24*

Bausch + Lomb 13, 14, 15

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Fera offers the broadest line of prescription ophthalmic ointments, all of which are

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your health care partner and go-to resource for specialty pharmaceuticals.

Generic alternative

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32 INNOVATION ABOUNDS AT OISRegulatory and investment climate

fosters drug, device opportunities

36 ACCURACY DOES MAKEA DIFFERENCEProcedure provides signifi cantly more

predictable effective lens positions

12 THE NEXT STEPIN DRUG DELIVERYTopical micro-droplet system targets

direct application to the ocular surface

37 EXCHANGE-TRADED FUNDS:THE NEW MUTUAL FUNDS?Latest investment vehicle offers structure

of a fund, but is traded like stock

42 REDESIGN PLACES FOCUS ON PRACTICE EFFICIENCYImproved layout and patient education

lead to increased pass-through rates

Refractive

Glaucoma

In Every Issue 4 EDITORIAL 6 OPHTHALMIC NEWS 39 MARKETPLACE

General

Practice Management

16 POINT/COUNTERPOINTDefi ning the 'ideal' DME treatment

18 PROGNOSIS FOR AQUICKER DIAGNOSISNonmydriatic ultra-wide-fi eld imaging shows

promise for evaluating diabetic retinopathy

20 COMBINATION THERAPYA BOON FOR AMDPhase IIb neovascular AMD study shows robust

benefi t for anti-PDGF/anti-VEGF therapy

21 INTREPID IDENTIFIES'BEST RESPONDERS'Fewer anti-VEGF injections among benefi ts

of stereotactic radiotherapy for wet AMD

22 IMAGING THE CHOROID:THE NEW FRONTIERHow OCT assessment of choroidal

thickness may prove valuable in the future

24 GENE THERAPY TRIALSIN PROGRESSResearchers turn focus to non-viral and

viral vectors to deliver DNA to cells

25 PARADIGM SHIFTFOR TREATING DMEOphthalmologist uses pattern laser

treatment in conjunction with anti-VEGF

26 NEW KID ON THE BLOCKPivotal trial results demonstrate effi cacy of

newest anti-VEGF agent in treating CRVO-

related macular edema

28 HIGH RESOLUTION RATES SEEN FOR VMAOcriplasmin joins observation,

vitrectomy as treatment options

29 OPTOGENETICS A NEW APPROACH TO RPNovel method brings back light perception,

possibly vision, to patients

RETINA

Special Report

18

Advances in imaging technology

mean patients may benefi t from

faster image acquisition and

disease evaluation.

3MARCH 1, 2013 :: Ophthalmology Times

contentscontents

4

PRINTED IN

U.S.A.

MARCH 1, 2013 :: Ophthalmology Times

editorialeditorial

AS A YOUNGSTER, George Washing-

ton famously chose to tell the truth rather than

to prevaricate in the hopes of escaping pun-

ishment: “Father, I cannot tell a lie. I chopped

down the cherry tree.” We don’t have many

George Washingtons around these days.

We doctors should probably always think the

best of our patients, honoring and respecting

them. But that can be hard sometimes, because

they are a bunch of liars. Does this seem a bit

harsh to you? Well, a recent review of studies on

patient veracity reveals some striking findings:

> In a 2009 survey of 2,000 patients and 1,200

physicians, 29% of patients admitted lying to

their doctors.

> Twenty-eight percent of physicians thought the

majority of patients lie to them on occasion.

> Younger patients (25 to 34 years of age) are

more likely to lie than older patients, and men lie

twice as much as women.

> They lie about smoking, about whether they are

taking their medicines, about how often they exer-

cise, about alcohol intake, and apparently about

anything that might be embarrassing or they other-

wise don’t want included in their medical records.

Doctors also lie. One-tenth of respondents in

a survey of 1,800 physicians admit saying un-

true things to patients, more than half have

given patients unrealistically positive prognoses,

and 20% don’t come clean about mistakes they

have made because they fear malpractice suits.

A friend of mine, a high-ranking official in a

professional medical society, once told me why

his organization had stopped surveying its sur-

geons about volumes and complication rates.

“Every time we’ve done a survey and com-

pared it with OR records, we’ve found that the

surgeons claim they are doing three times the

number of procedures they are actually per-

forming,” he said. “And the complication rate is

at least twice what my colleagues self-report.”

F U Z Z Y M A T H

Many doctors do what I was taught as a medi-

cal student learning about physical diagnosis;

they double the number of alcoholic beverages

that a patient admits to imbibing. A dentist

named Sam Weisz reports that he divides in

two the number of times that his patients claim

to floss their teeth. The sobering underpinning

of these strategies is that, on average, we can-

not trust our patients to be honest.

After a long day in the office, I had com-

pleted my usual daily hour-long exercise regi-

men, including 5 miles on the treadmill and

100 sit-ups. After a dinner of tasty salad (or-

ganic greens) and a glass of pomegranate juice,

I flossed my teeth and settled down to ponder

the implications of such shameless mendacity

in the American public.

In my opinion, there are two major logical

consequences from the fact that the Washingto-

nian obsession with truth is largely extinct:

1. It is unrealistic of physicians to expect patients

to comply fully with long-term medical therapy

(pills or drops) for chronic diseases, such as dia-

betes and glaucoma. We should make it a priority

to develop surgical procedures with acceptable

safety and efficacy profiles or sustained-release

drug platforms that will make frequent drug ad-

ministration over years a thing of the past.

2. Anticipating that our internists will multiply by

two whatever we say, we should divide by four

when answering their questions about alcohol

consumption. Q

Referencet ‘I don’t smoke, Doc’ and other patient lies. Health and

Wellness section, Wall Street Journal, Feb. 19, 2013.

Truth be toldHonesty in the physician-patient relationship not what it seems

MARCH 1, 2013 ◾ VOL. 38, NO. 5

By Peter J. McDonnell, MD

director of the Wilmer Eye Institute,

Johns Hopkins University School of

Medicine, Baltimore, and chief medical

editor of Ophthalmology Times.

He can be reached at 727 Maumenee Building

600 N. Wolfe St. Baltimore, MD 21287-9278

Phone: 443/287-1511 Fax: 443/287-1514

E-mail: pmcdonn1@jhmi.edu

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Grand Rounds Robert Ritch, MD

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Ophthalmic Heritage Norman B. Medow, MD

Panretinal View Allen C. Ho, MD

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Ophthalmology Times Industry Council

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President and CEO

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Director of Market Development, Americas

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Director of Global Marketing and Sales

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Ophthalmology Times Mission Statement

Ophthalmology Times is a physician-driven publication that disseminates news and information of

a clinical, socioeconomic, and political nature in a timely and accurate manner for members of the

ophthalmic community.

In partnership with our readers, we will achieve mutual success by:

◾ Being a forum for ophthalmologists to communicate their clinical knowledge, insights, and discoveries.

◾ Providing management information that allows ophthalmologists to improve and expand their practices.

◾ Addressing political and socioeconomic issues that may either assist or hinder the ophthalmic

community, and reporting those issues and their potential outcomes to our readers.

Chief Medical Editor

Peter J. McDonnell, MDWilmer Eye Institute

Johns Hopkins University

Baltimore, MD

Associate Medical Editors

Dimitri Azar, MDUniversity of Illinois, Chicago, Chicago, IL

Anne L. Coleman, MDJules Stein Eye Institute/UCLA

Los Angeles, CA

Allen C. Ho, MDWills Eye Institute, Thomas Jefferson

University, Philadelphia, PA

Ernest W. Kornmehl, MDHarvard & Tufts Universities, Boston, MA

Robert K. Maloney, MDLos Angeles, CA

Joan Miller, MDMassachusetts Eye & Ear Infirmary

Harvard University, Boston, MA

Randall Olson, MDUniversity of Utah, Salt Lake City, UT

Robert Osher, MDUniversity of Cincinnati, Cincinnati, OH

Anterior Segment/CataractCornea/External Disease

Ashley Behrens, MDWilmer Eye Institute, Johns Hopkins University

Baltimore, MD

Rubens Belfort Jr., MDFederal University of São Paulo

São Paulo, Brazil

Elizabeth A. Davis, MDUniversity of Minnesota, Minneapolis, MN

Uday Devgan, MD

Jules Stein Eye Institute/UCLA

Los Angeles, CA

I. Howard Fine, MDOregon Health & Science University

Portland, OR

Howard V. Gimbel, MDGimbel Eye Centre, Calgary, Canada

Richard S. Hoffman, MDOregon Health & Science University, Portland, OR

Jack T. Holladay, MD, MSEE, FACSBaylor College of Medicine, Houston, TX

Manus Kraff, MDNorthwestern University, Chicago, IL

Samuel Masket, MDJules Stein Eye Institute/UCLA, Los Angeles, CA

Bartly J. Mondino, MDJules Stein Eye Institute/UCLA, Los Angeles, CA

Mark Packer, MDOregon Health & Science University, Portland, OR

Walter J. Stark, MDWilmer Eye Institute, Johns Hopkins University

Baltimore, MD

Glaucoma

Robert D. Fechtner, MDUniversity of Medicine & Dentistry of New Jersey

Newark, NJ

Neeru Gupta, MDUniversity of Toronto, Toronto, Canada

Jeffrey M. Liebmann, MDManhattan Eye, Ear & Throat Hospital

New York, NY

Richard K. Parrish II, MDBascom Palmer Eye Institute, University of Miami

Miami, FL

Harry A. Quigley, MDWilmer Eye Institute, Johns Hopkins University

Baltimore, MD

Robert Ritch, MDNew York Eye & Ear Infirmary, New York, NY

Joel Schuman, MDUniversity of Pittsburgh Medical Center

Pittsburgh, PA

Kuldev Singh, MDStanford University, Stanford, CA

George L. Spaeth, MDWills Eye Institute, Thomas Jefferson University

Philadelphia, PA

Robert N. Weinreb, MDHamilton Glaucoma Center

University of California, San Diego

Neuro-Ophthalmology

Andrew G. Lee, MDMethodist Hospital, Texas Medical Center

Houston, TX

Oculoplastics/ Reconstructive Surgery

Richard L. Anderson, MDCenter for Facial Appearances, Salt Lake City, UT

Robert Goldberg, MDJules Stein Eye Institute/UCLA, Los Angeles, CA

John T. LiVecchi, MDSt. Luke’s Cataract & Laser Institute

Tarpon Springs, FL

Shannath L. Merbs, MDWilmer Eye Institute, Johns Hopkins University

Baltimore, MD

Pediatric Ophthalmology

Norman B. Medow, MDManhattan Eye, Ear & Throat Hospital

New York, NY

Jennifer Simpson, MDUniversity of California, Irvine

Irvine, CA

H. Jay Wisnicki, MDNew York Eye & Ear Infirmary, Beth Israel Medical

Center/Albert Einstein College of Medicine

New York, NY

Refractive Surgery

Eric D. Donnenfeld, MDNew York University Medical Center

New York, NY

Daniel S. Durrie, MDKansas City, KS

Kenneth A. Greenberg, MDDanbury Hospital, Danbury, CT/ New York

University, New York, NY

Peter S. Hersh, MDUniversity of Medicine & Dentistry of New Jersey

Newark, NJ

Ioannis G. Pallikaris, MDUniversity of Crete, Crete, Greece

Theo Seiler, MDUniversity Hospital of Zurich, Zurich, Switzerland

Jonathan H. Talamo, MDHarvard University, Boston, MA

George Theodossiadis, MDAthens, Greece

Kazuo Tsubota, MDKeio University School of Medicine, Tokyo, Japan

George O. Waring III, MDAtlanta, GA

Retina/Vitreous

Mark S. Blumenkranz, MDStanford University, Stanford, CA

Neil M. Bressler, MDWilmer Eye Institute, Johns Hopkins University

Baltimore, MD

Stanley Chang, MDColumbia University, New York, NY

David Chow, MDUniversity of Toronto, Toronto, Canada

Sharon Fekrat, MDDuke University, Durham, NC

Stuart Fine, MDUniversity of Pennsylvania, Philadelphia, PA

Julia Haller, MDWills Eye Institute, Thomas Jefferson University

Philadelphia, PA

Hilel Lewis, MDColumbia University, New York, NY

Carmen A. Puliafito, MDKeck School of Medicine, USC, Los Angeles, CA

Carl D. Regillo, MDWills Eye Institute, Thomas Jefferson University

Philadelphia, PA

Lawrence J. Singerman, MDCase Western Reserve University, Cleveland, OH

Lawrence Yannuzzi, MDManhattan Eye, Ear & Throat Hospital

New York, NY

Uveitis

Emmett T. Cunningham Jr., MD, PhDStanford University, Stanford, CA

Chief Medical Editors- Emeritus

Jack M. Dodick, MDNew York University School of Medicine

New York, NY (1976-1996)

David R. Guyer, MD

New York, NY (1996-2004)

EDITORIAL ADVISORY BOARD

editorial advisory boardeditorial advisory board5MARCH 1, 2013 :: Ophthalmology Times

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SAN FRANCISCO ::

Economic uncertainties and disrup-

tive innovations, not to mention

anticipated and unanticipated

technologies, are likely to shape

ophthalmology and make future

predictions difficult.

“It’s hard to find the [crystal] ball . . . [to

see] 20 to 30 years from now,” said H. Dunbar

Hoskins Jr., MD, FACS, former

executive vice president of the

American Academy of Oph-

thalmology, and who currently

maintains a glaucoma prac-

tice in San Francisco. “Clearly,

predictions are hazardous.

“As Yogi Berra, the great

philosopher, once said: ‘The

one thing you can’t do is predict the

future.’ And I’ve learned that over

and over again,” Dr. Hoskins said.

What is known is that there

will be a few trends, including:

Reduced compensation per

unit of care that will demand

increased productivity and effi-

ciency for practices.

Increased consolidation of prac-

tices, which is going on already.

An increasing team approach.

“Those trends are obvious,” Dr.

Hoskins said. “The main changes

that will occur, however, will prob-

ably be a little unpredictable, just

like economic impact and the enor-

mous uncertainties that exist.”

D I S R U P T I V E

I N N O V A T I O N S

Innovations—actual and antici-

pated—will shape the future of ophthalmol-

ogy, Dr. Hoskins continued.

“We’ve all been through phacoemulsification,

the IOL, and the excimer laser,” he said. “We’ve

seen how they changed our practices, as have the

advent of new therapies, such as ranibizumab

and bevacizumab [Lucentis and Avastin, Ge-

nentech], that pop up on the screen and all of a

sudden, the entire management of age-related

macular degeneration (AMD) changes.”

One must also factor in anticipated technolo-

gies—such as information technology (IT) and

telemedicine, therapeutic breakthroughs in AMD,

glaucoma, and uveitis, and functioning retinal

prosthesis, for example—when trying to predict

the future. But just as importantly, there will

also be unanticipated technologies, he noted.

“For example, when timolol popped up back

in the 1980s, trabeculectomy dropped dramati-

cally,” he said. “Our inability to predict those

unanticipated technologies will

affect what is going to happen

in the future.”

Not only innovations, but also

how they are implemented will

have an effect on predictions and

actualities in the future.

“You’ve heard that IT will

change the way we practice in

the future,” he said. “I predict that

by the year 2020 or 2030, it will

change it dramatically.”

In addition, fee-for-care in-

stead of fee-for-service is inevi-

table, and the number of group

practices will increase, with ex-

panded team activities.

“I predict that by 2020 or 2030,

we will see hands-on technicians

and limited license practitioners

instead of hands-on doctors,” Dr.

Hoskins said. “Many of the things

that we now do by ourselves will be turned

over to technicians and other practitioners.”

> Reduced

compensation per

unit of care that will

demand increased

productivity and

efficiency for

practices.

> Increased

consolidation of

practices, which is

going on already.

> An increasing team

approach.

Key trends F O R

health care

ophthalmic newsophthalmic news6 MARCH 1, 2013 :: Ophthalmology Times

FUNDUS CAMERA EARNS 510(K) CLEARANCEOptovue has received 510(k) clearance for

the iCam Non-Mydriatic compact fundus

camera, which includes a variety of func-

tions and features that produce high-quality

image documentation and management of

ocular health. http://bit.ly/Z0orK2

LASER PLATFORM APPROVED FOR CORNEAL ARCUATE CUTSThe Victus Femtosecond Laser Platform

from Bausch + Lomb has received 510(k)

clearance from the FDA for the creation

of penetrating arcuate cuts/incisions in the

cornea of patients undergoing cataract

surgery or other ophthalmic treatment.

http://bit.ly/15TPxcs

SYSTEM UPGRADES ALLOW AUTOMATED IOL DELIVERYThe latest hardware and software up-

grades for Alcon's Infiniti Vision System

are expected to provide surgeons greater

control during cataract surgery, including the

Intrepid AutoSert IOL injector, which enables

automated delivery of the IOL.

http://bit.ly/XFCI1S

ALLERGAN LAUNCHES PRESERVATIVE-FREE DROPSRefresh Optive Advanced Preservative-Free

Lubricant Eye Drops (Allergan) feature the

same formula as Refresh Optive Advanced,

but without the use of a preservative.

http://bit.ly/13r9R55

TRIAL EVALUATES AFLIBERCEPT FOR DME IN RUSSIA, ASIARegeneron Pharmaceuticals Inc. and Bayer

HealthCare have initiated a new phase III

trial to evaluate the efficacy and safety of

aflibercept (Eylea) injection in the treatment

of diabetic macular edema (DME) in Russia,

China, and other Asian countries.

http://bit.ly/YCAPyY

HEADLINES YOU MIGHT HAVE MISSED. As seen in Ophthalmology Times'

weekly eReport. Sign up at

http://www.modernmedicine.com/

OphthalmologyTimes/enewssignup

Dr. Hoskins

Foreseeing the

ophthalmologist

of the futureInnovation, technology will shape the way physicians practice By Liz Meszaros

Continues on page 7 : Future

FROM STAFF REPORTS

( In Brief )

prosthesis allows patients with RP with barely

to no light perception vision to detect light and

perform tasks, to assist them with their orien-

tation, mobility, and letter recognition.

“The prosthesis stimulates the remaining ret-

inal neurons, despite the fact that there are no

photoreceptors, and the information from the

stimulation is sent to the brain, via the optic

nerve,” said Mark S. Humayun, MD, PhD, the

Cornelius Pings Professor of Biomedical Sci-

ences, professor of ophthalmology, biomedi-

cal engineering, cell and neurobiology, Keck

School of Medicine and Viterbi School of En-

gineering, University of Southern California,

Los Angeles. Dr. Humayun also is the leader

of the research team for the Argus project.

“I have dedicated my career to restoring sight

to the blind because my grandmother went

blind,” said Dr. Humayun in an interview with

Ophthalmology Times. “Although the Argus was

not developed in time to help her, I am happy

that it will be able to provide useful vision to

some blind patients. To this day, it is amazing

how much the otherwise totally blind patients

can see with the Argus II.”

Robert Greenberg, MD, PhD, president and

chief executive officer of Second Sight, has

been working on the development of the reti-

nal prosthesis for more than 20 years.

“It is also an incredible day for patients with

RP, who no longer have to be told that they

have a progressive blinding disease with no

option for restoring vision,” Dr. Greenberg told

Ophthalmology Times. “Seeing the project to

fruition and finally having something avail-

able to offer patients in the United States is

enormously rewarding for me, for the 100 or

so employees of Second Sight, many of whom

have been with us since the company’s incep-

tion, and for the hundreds of others who have

worked with us through part-

nerships with academic and

national laboratories.”

The retinal prosthesis sys-

tem features a spectacle-

mounted video camera for

receiving visual input that

is then converted to a stim-

ulation pattern by an externally worn video

processor. The processor transmits data and

power wirelessly to a 60-electrode epiretinal

array implanted, via a pars plana approach, in

a procedure similar in nature to scleral buck-

ling with vitrectomy.

The electronics are packaged to withstand

the intraocular environment with an expected

lifetime of at least 5 to 10 years after implanta-

tion, and in vitro tests demonstrate that the de-

vice may last much longer, said Dr. Greenberg.

Efficacy and safety of the retinal prosthe-

sis was investigated in an international trial

that enrolled 30 patients at 10 centers in the

United States, the United Kingdom, France, and

Switzerland. Eligible subjects had severe-to-

profound, outer retinal degeneration second-

ary to RP, or related dystrophies with visual

acuity worse than 2.3 logMAR in both eyes.

The number of physician assistants is in-

creasing, especially in rural states, and this

will continue, he added.

Another prediction from Dr. Hoskins cen-

ters on whether accountable care organiza-

tions will survive.

“I don’t know if they will, but I predict that

there will be integrated care organizations that

will survive, and we will have to react to those

by probably having integrated ophthalmic prac-

tices that allow for one-stop shopping for eye

care,” he said.

T Y P I C A L P R A C T I C E O F T H E

F U T U R E

The prediction of what a typical ophthalmic

practice will be like in 2040 is tough, Dr. Hoskins

noted. He suggested, however, that the typical

future practice will be part of a group prac-

tice, with electronic medical records and data

analysis systems in place to help understand

how physicians are practicing medicine com-

pared with peers.

Telemedicine will be prevalent locally and

beyond the practice area, increased subspe-

cialization will be the norm, and the ratio of

workers per physician will change dramati-

cally, Dr. Hoskins continued.

He projects two optometrists, four physi-

cian assistants, six technicians, and only one

clerk, because IT will replace filers, scribes,

billers, and schedulers.

“This could allow for two to three times the

current patient volumes per physician and will

be more than adequate to meet the projected

demands, but I don’t know about the needs,”

Dr. Hoskins said.

The typical ophthalmologist in 2040 will be

a 47-year-old mother of two children and who

will be working 40 hours per week from home

via Web holograms for consults. Optometrists,

nurse practitioners, physician assistants, and

technicians will see her patients, but she may

go in to the office for a particularly compli-

cated case, Dr. Hoskins predicted.

He predicted that this ophthalmologist of

the future will have one surgical bay, and on a

weekly surgical day, she will perform 40 cata-

ract surgeries, with each one lasting 5 minutes

to inject and aspirate the nucleus and the cor-

tex, using an in-the-bag accommodative poly-

mer that restores full accommodation. Included

in this work load will also be three glaucoma

implants and one strabismus surgery.

“She’ll do all of this by using her robotic

reach from home! And she’ll be finished by

noon, so she has time to feed the kids. The

retina docs will finish by 1 p.m.,” he said,

adding, “Or maybe the cataract prevention pill

will come along and we’ll all be playing golf.”

Dr. Hoskins’ final prediction is hopeful,

however.

“Clearly, it’s going to be a different world,”

he said. “Economic uncertainties and disrup-

tive innovations plus disruptive implementa-

tion equal disrupted predictions.

“The one certain[ty] is [that] protecting, pre-

serving, and restoring vision will always be a

rewarding and satisfying career,” Dr. Hoskins

said. “Nobody thanks you the way patients

do. So enjoy the future, identify the trends,

be flexible, be able to move with the waves,

and have a good time.” Q

FUTURE( Continued from page 6 )

PROSTHESIS( Continued from page 1 )

Continues on page 8 : Retinal

ophthalmic newsophthalmic news7MARCH 1, 2013 :: Ophthalmology Times

Dr. Greenberg

OphthalmologyTimes.comValue-added web content and news

RETINAL PROSTHESIS IN ACTION Go to http://ow.ly/ijY4j for a video

demonstration of how the retinal prosthesis

works. (Video courtesy of Second Sight)

Of the 30 patients enrolled, 29 had RP and

one had choroideremia. Visual acuity was bare

light perception in 29 patients and no light

perception in one individual.

Follow-up for patients with the retinal pros-

thesis implanted ranged from a minimum of

almost 3.5 years to almost 6 years, and cumu-

lative subject-years of follow-up exceeds 125

years. The safety and reliability of the system

has remained excellent in this cohort.

Explantation of the epiretinal array was per-

formed in one patient who experienced recur-

rent conjunctival erosion. In a second subject,

intermittent communications failure with the

implant began to occur at 10 months postop-

eratively and was believed to be a result of

damage to the telemetry coils induced during

implantation. The epiretinal electrode array

has not been explanted.

“With increasing improvement in design and

also more experience with the procedure, it

is anticipated that the surgical risks will be

further reduced,” Dr. Humayun said. “Hav-

ing said this, although implanting an Argus

II involves a number of routine vitreoretinal

steps, which cumulatively can take only about

2 hours, it also requires that the surgeon take

some time to understand the few steps that

are not part of routine vitreoretinal surgery,

(i.e., use of a retinal tack).”

C O M M E R C I A L A V A I L A B I L I T Y

P L A N S

With the FDA approval, Second Sight is work-

ing actively with Medicare (CMS) to establish

reimbursement for the prosthesis and hopes

that will be completed soon—although it may

not be accomplished before the commercial

launch, planned for later in 2013. The com-

pany is also working with private insurers to

make the device available with coverage to

patients who are not Medicare beneficiaries.

Upon commercial launch, the retinal prosthe-

sis will be available only through 10 to 12 U.S.

centers, including several that were involved

in the pre-marketing clinical trial. Those are

located in San Francisco, New York, Los An-

geles, Baltimore, Dallas, and Philadelphia. Ad-

ditional training is already under way at those

sites, and the company expects to open four

to six more centers in the United States soon,

although they are not yet identified.

“Our plan is to make the prosthesis available

only through select ‘centers of excellence,’ ”

Dr. Greenberg said.

Outside the United States, the retinal pros-

thesis is available at a number of centers in

Germany, Italy, the United Kingdom, France,

and Saudi Arabia. Dr. Greenberg said that pa-

tients who received the implant at many of

these sites are enrolled in a post-marketing

study, and, as expected, the initial safety re-

sults are even better than those of the pre-

marketing trials.

M O R E D A T A A N D

D E V E L O P M E N T S

Currently, researchers are also working on soft-

ware modifications that will enhance the ca-

pabilities of the existing prosthesis platform.

“One of the fantastic features of the Argus

II is that it is software upgradeable, just like a

smartphone,” Dr. Greenberg said. “Therefore,

patients with the device already implanted and

those receiving it now that it is commercially

available in the United States can benefit from

future improvements.”

He added that changing the software is a

safer, easier, and more reliable way to im-

prove the prosthesis than introducing hard-

ware modifications.

With regard to upgrades, Second Sight re-

ports it has been collaborating with research-

ers in Europe to develop software based on

modulation of the stimulus frequency that

allows color perception (the current version

operates in a black-white-gray scale). In addi-

tion, a modification is being engineered using

digital zoom techniques for the camera and

software to create virtual electrodes that will

increase resolution.

Whereas about 30% of patients with the cur-

rent model of the Argus II implanted regain

measurable visual acuity (up to 20/1260), a

patient tested with the new software achieved

20/200 visual acuity.

“It is very encouraging to see this level of vi-

sual acuity achieved without modifying spacing

of the electrodes,” Dr. Humayun said. “In the

current embodiment, this increase in acuity

comes at the expense of visual field, but Second

Sight is working on even more advanced soft-

ware that may be able to compensate for this.”

While the focus for improving the Argus II

is on software upgrades, researchers at Second

Sight are also working on an entirely new ar-

tificial vision platform that will be placed in

the visual cortex area of the brain.

“We are very excited about this brain-im-

planted device because it would represent a

treatment for blindness from all causes, not

just RP, and potentially benefit nearly 8 mil-

lion patients,” Dr. Greenberg said. Q

ophthalmic news8

ophthalmic newsMARCH 1, 2013 :: Ophthalmology Times

RETINAL( Continued from page 7 )

MARK S. HUMAYUN, MD, PHD

E: mhumayun@aol.com

Dr. Humayun is a consultant and a minority equity/share holder in Second Sight Medi-

cal Products. The Argus II Retinal Prosthesis System (Second Sight Medical Products

Inc.) is designated as a humanitarian-use device, which refl ects orphan product status.

The components The retinal prosthesis consists of a

surgically implanted 55-electrode, stimulating microelectrode array

made up of 200-μm diameter disc electrodes, an inductive coil link

used to transmit power and video data to the implant, an external

belt-worn video processing unit, and a miniature video camera

mounted on a pair of glasses. (Images courtesy of Second Sight)

For a look at how the retinal

prosthesis works, see page 10.

OphthalmologyTimes.com

Advertisement not available for this issue of the digital edition

ophthalmic news10

ophthalmic newsMARCH 1, 2013 :: Ophthalmology Times

Prosthesis team leader outlines components, procedure, follow-upBy Mark S. Humayun, MD, PhD; Special to Ophthalmology Times

THE RETINAL PROSTHESIS

consists of a surgically implanted

55-electrode, stimulating micro-

electrode array made up of 200-

μm diameter disc electrodes, an

inductive coil link used to transmit

power and video data to the im-

plant, an external belt-worn video

processing unit (VPU), and a min-

iature video camera mounted on

a pair of glasses.

The video camera captures a por-

tion of the visual scene in front of the

patient and relays the information

to the VPU. The VPU digitizes the

signal in real-time, applies a series

of image processing filters, and cre-

ates a series of stimulus pulses on

the surface of the retina based on

pixel brightness values and look-up

tables customized for each subject.

H O W I T W O R K S

The stimulus pulses are delivered

EDITOR’S NOTE: Mark S. Humayun, MD, PhD, is the team leader

behind the Argus Retinal Prosthesis project. He and his team have been working

on the prosthesis for 20 years. In this exclusive article to Ophthalmology Times, Dr.

Humayun outlines the components of the prosthesis, how the prosthesis works, the

surgical procedure, and patient expectations.

Electronics Case

Receiver Electrode Array

(FIGURE 1) The implant is an epiretinal

prosthesis surgically implanted in and

on the eye that includes an antenna, an

electronics case, and an electrode array.

(Image courtesy of Second Sight)

to the microelectrode array via ap-

plication-specific circuitry and a su-

perior-temporally placed inductive

radio frequency coil link, allowing

for wireless forward and reverse te-

lemetry between intra and extraoc-

ular portions of the system.

These pulses are intended to stim-

ulate the retina’s remaining cells to

create phosphenes, or perceptions of

light. Each electrode activates over-

lying cells based on encoded inten-

sity, and collectively the electrodes

can form an image similar to a gray-

scale digital scoreboard, resulting in

perception of patterns of light in the

brain. Patients then learn to inter-

pret these visual patterns, thereby

regaining some functional vision.

Historical challenges to bioelec-

tronics implants include safe surgi-

cal implantation and long-term sta-

bility. We recently published our

6 months results (Ophthalmology.

2012;119:779-788). Three-year follow-

up data on the Argus II show simi-

lar results and continued to show

improved visual performance and

an acceptable safety record.1

This multicenter, prospective trial

included 30 patients with a mean age

of 58 + 10 years, 97% (n = 29) of

which had bare light perception and

3% (n = 1) had no light perception at

baseline. Patients had been followed

for an average of 3.6 + 1.0 years, with

one device explanted at 14 months

due to recurrent conjunctival erosion

and one device failing at 10 months

due to communication failure with

the implant, but it was left in the eye.

Subjects performed statistically

better with the system on versus off

in the following tasks: object local-

ization, motion discrimination, and

discrimination of oriented gratings.

Other tests of visual function (ori-

entation and mobility tasks, and ac-

tivities of daily living), and a third-

party assessment of the impact of

the system on quality of life, also

showed meaningful improvements.

Reliability also was high. Over the

follow-up period of this study, all but

one device remained implanted and

the vast majority of electrodes (94.4%)

remained functional.

One of the first cases included

in the study was a female patient

who had been blind for more than

30 years due to RP. Her surgery was

successful with no adverse events.

The device helps her navigate in

unfamiliar environments, or if she

drops something in a known envi-

ronment. The device has been stable,

the electrodes all continue to func-

tion nearly 6 years post-surgery, there

has been no infection or bleeding,

and she is doing remarkably well.

T H E P R O C E D U R E

The procedure itself is something that

most retinal surgeons can perform,

as it is for the most part a combi-

nation of common techniques. The

surgery begins with the removal of

the lens, via clear corneal incision,

in phakic eyes.

This is followed by a 360° limbal

conjunctival peritomy and isolation

of the rectus muscles with a scleral

buckle. The coil antenna is placed

temporally on the globe and the electronics

package is centered in the superior temporal

quadrant and then sutured to the sclera.

Following the placement of the antenna and

hardware, core and peripheral vitrectomies are

performed, as well as dissection of any epireti-

nal membrane in the area where the surgeon

intends to tack the array. Once the vitreous is

removed, the electrode array is inserted via a

temporal sclerotomy, placed over the macula,

and micro-tacked to the retina.

Once it is in place on the retina, all of the scle-

rotomies and the conjunctiva are sutured. The

eye is injected with postoperative antibiotics.

F O L L O W - U P

While the surgical implantation of the device

is an accessible skill, the follow-up to surgery

is more involved and time-consuming than for

an average vitreoretinal surgery.

Nanduri and colleagues published their find-

ings that increased stimulation frequency in-

creases brightness, while increasing stimula-

tion amplitude generally affects both size and

brightness of phosphenes.2

Thus, independently manipulating pulse train

frequency and amplitude is part of the process

of “fitting” the prosthesis to the patient. Dedi-

cated engineers using custom instrumentation

wirelessly communicate with the implanted part

of the device, activating a few electrodes at a

time and syncing this to the camera to deter-

mine the optimal frequency and amplitude of

each electrode for an individual patient. After

fitting is completed, patients work with occu-

pational or low-vision rehabilitation therapists

to help them understand their new vision and

how to use it to achieve their goals.

Potential patients must be willing to wear

the glasses and the VPU (which also houses the

battery that powers the system). Patients will

need to commit to about 3 months of fitting

and rehabilitation, along with annual clinical

follow-up (after the first year).

The system might not be indicated for every

patient with severe RP. Refer to the product

insert for contraindications. For the right pa-

tient, restoring some level of vision and thereby

improving mobility and independence is an

amazing prospect. Q

References1. Greenberg R, et al. Results update from Second Sight’s

Argus II Retinal Prosthesis Study. Presented at the

annual meeting of the Association for Research in Vision

and Ophthalmology. May 2012, Fort Lauderdale, FL.

2. Naduri D, et al. Frequency and amplitude modulation

have different effects on the percepts elicited by retinal

stimulation. IOVS. 2012:53:205-214.

ophthalmic newsophthalmic news11MARCH 1, 2013 :: Ophthalmology Times

OphthalmologyTimes.comValue-added web content and news

PATIENT TESTIMONIAL Go to

http://ow.ly/ijY9M for a video of a patient

describing his experience with the retinal

prosthesis system. (Video courtesy of Second Sight)

See More...Treat MoreOptos has more than 100 completed and ongoing clinical studies

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SAN FRANCISCO ::

Anew topical micro-droplet de-

livery system (Micro-Droplet

Piezoelectric Ejection System,

Corinthian Ophthalmic) may

be an improvement first step

over the eye dropper to deliver

topical medications.

Such a drug-delivery system might standardize

instillation of drugs and prevent over-treatment

and improper instillation, thus aiding patient

compliance, according to Sean Ianchulev, MD,

MPH, clinical associate professor, University

of California, San Francisco.

Dr. Ianchulev identified some major chal-

lenges encountered with the conventional eye

dropper, such as overflow, inability to deliver

inside the eye, and uneven distribution to the

ocular surface. Even when instilled correctly

into the eye, the vast majority of a single eye

drop is lost within the first 15 to 30 seconds

after instillation, either by lid overflow or via

the nasolacrimal duct system. In stark con-

trast with most other pharmacologic deliv-

ery methods (e.g., pills, intravenous), there

is little control on what amount of drug is ac-

tually delivered to the target tissue (i.e., the

ocular surface) when a physician prescribes

a topical formulation.

To overcome this problem, investigators have

attempted to deliver medications by spraying

the drug onto the eye, but initial efforts with

such systems as atomizer sprays have failed

due to inability to control droplet size and flow

dynamics for consistent and predictable ad-

ministration. Major problems related to the

physics of droplet ejection, such as dispersion,

droplet evaporation, drag, and non-collimated

flow turbulence, have held back such new ap-

proaches until recently.

“There is a reason why we have been using

the conventional eye dropper for more than

100 years, even though we are well aware of

its deficiencies,” Dr. Ianchulev said.

The micro-droplet piezoelectric ejection sys-

tem may overcome these obstacles. The device,

he explained, provides collimated flow in a

manner similar to ink-jet printers.

“This facilitates depositing of the drug on

the ocular surface and the result differs mark-

edly from eye dropper instillation or spray,”

Dr. Ianchulev said.

The delivery is based on

the piezoelectric fluid ejec-

tion system, which monitors

every application of a drug.

“Using sophisticated

technology, the system is

able to control the dosing

and ejection of micro-drop-

lets to enable direct appli-

cation on the ocular sur-

face,” he said. “It can be

used across a platform of

topical medications. Glau-

coma, antibiotic, and myd-

riatic drops have been suc-

cessfully sprayed using this

delivery system.”

The technology has a light-emitting-diode op-

tical targeting system that eliminates the need

for the patient to tilt his or her head and delivers

the spray within less than 30 to 40 ms, which is

faster than the blink reflex.

C L I N I C A L A S S E S S M E N T

A clinical study of the delivery system was per-

formed to compare the dilating effect of a topi-

cal medication (2.5% phenylephrine and 1%

tropicamide) delivered via the micro-droplet

ejection device and an eye dropper. The study

included 102 patients; one eye of each patient

served as the control for which an eye drop-

per delivered the drug and the delivery system

was used to deliver the drug to the fellow eye.

The patients were randomly assigned to one of

three study arms in which 34 patients received

a 1.5-μl dose, 33 patients received 6 μl, and 35

patients two doses of 3 μl each.

The pupils were monitored by digital pu-

pillometry at 10, 20, and 60 minutes follow-

ing dosing.

“The results showed that the micro-droplet

ejection system provided similar dilation and

pharmacodynamics effect to that achieved to

the drug instilled using the eye dropper—even

though the spray administered one tenth of

the volume of the eye drop,” Dr. Ianchulev

said. “This is important because we can re-

duce ocular surface exposure to preservatives

and for some drugs, such as beta blockers,

systemic side effects can be avoided. The re-

sults made us very confident about investigat-

ing other drugs.”

When a glaucoma drug was tested in a simi-

lar manner in a canine model, the investiga-

tors achieved the same efficacy curves to those

achieved with eyedropper instillation, he noted.

The advantage of the ejection system is that

a much lower volume of drug can be ejected

onto the ocular surface to achieve the same

effect as that using eye drops. Q

The next step in drug deliveryTopical micro-droplet system targets direct application to the ocular surfaceBy Lynda Charters; Reviewed by Sean Ianchulev, MD, MPH

A new topical micro-droplet delivery

system (Micro-Droplet Piezoelectric

Ejection System, Corinthian

Ophthalmic) facilitates depositing

of the drug on the ocular surface.

TAKE-HOME

SEAN IANCHULEV, MD, MPH

E: tianchul@yahoo.com

Dr. Ianchulev is a scientific advisor and member of the board of directors for Corinthian

Ophthalmic. This article was adapted from Dr. Ianchulev’s presentation at the 2012

meeting of the American Academy of Ophthalmology.

(FIGURE 1) The micro-droplet piezoelectric ejection system provides

collimated flow of topical medication in a manner similar to ink-jet

printers. (Photo courtesy of Sean Ianchulev, MD, MPH)

glaucoma12 MARCH 1, 2013 :: Ophthalmology Times

glaucoma

RETISERT is a registered trademark of Bausch & Lomb Incorporated. ©2012 Bausch & Lomb Incorporated. PH4560 4/12

RETISERT® offers continuous control of inflammation1,2

s RETISERT® is the first approved intravitreal implant for chronic non-infectious uveitis affecting the posterior segment designed to deliver corticosteroid therapy for approximately 2.5 years1

s Approximately 80% of patients experienced a 3-year recurrence-free period in 2 pivotal trials1,*

References: 1. RETISERT [package insert]. Rochester, NY: Bausch & Lomb Inc; March 2009. 2. Callanan DG, Jaffe GJ, Martin DF, Pearson PA, Comstock TL. Treatment of posterior uveitis with a fluocinolone acetonide implant: three-year clinical trial results. Arch Ophthalmol. 2008;126(9):1191-1201. 3. Nguyen QD, Callanan D, Dugel P, Godfrey DG, Goldstein DA, Wilensky JT. Treating chronic noninfectious posterior segment uveitis: the impact of cumulative damage. Proceedings of an expert panel roundtable discussion. Retina. 2006;(suppl 8):1-16. 4. Jabs DA. Treatment of ocular inflammation [editorial]. Ocul Immunol Inflamm. 2004;12(3):163-168.

If you have any questions about RETISERT®, please call 1-800-323-0000 or visit www.retisert.com.

Please see RETISERT® full prescribing information on adjacent pages.

* Two randomized, double-masked, multicenter controlled clinical trials of the 0.59-mg fluocinolone acetonide intravitreal implant in 224 patients.1

Important Risk Information about RETISERT®

s�3URGICAL�PLACEMENT�OF�2%4)3%24® is contraindicated in active viral, bacterial, mycobacterial or fungal infections of the eye.

s��"ASED�ON�CLINICAL�TRIALS�WITH�2%4)3%24®, during the 3-year post-implantation period, nearly all phakic eyes are expected to develop cataracts and require cataract surgery. As with any surgical procedure, there is risk involved. Potential complications accompanying intraocular surgery to place RETISERT® into the vitreous cavity may include, but are not limited to, the following: cataract formation, choroidal detachment, temporary decreased visual acuity, endophthalmitis, hypotony, increased intraocular pressure, exacerbation of intraocular inflammation, retinal detachment, vitreous hemorrhage, vitreous loss, wound complication, wound site erythema and wound dehiscence.

s��&OLLOWING�IMPLANTATION�OF�2%4)3%24®, nearly all patients will experience an immediate and temporary decrease in visual acuity in the implanted eye which lasts for approximately one to four weeks post-operatively.

s��5SE�OF�CORTICOSTEROIDS�MAY�RESULT�IN�ELEVATED�)/0�AND�OR�GLAUCOMA��"ASED�ON�CLINICAL�TRIALS�WITH�2%4)3%24®, within 3 years post-implantation, APPROXIMATELY�����OF�PATIENTS�WILL�REQUIRE�)/0�LOWERING�MEDICATIONS�TO�CONTROL�INTRAOCULAR�PRESSURE�AND�����OF�PATIENTS�WILL�REQUIRE�lLTERING� procedures to control intraocular pressure.

s��0ATIENTS�SHOULD�BE�ADVISED�TO�HAVE�OPHTHALMOLOGIC�FOLLOW UP�EXAMINATIONS�OF�BOTH�EYES�AT�APPROPRIATE�INTERVALS�FOLLOWING�IMPLANTATION�OF� RETISERT®. Physicians should periodically monitor the integrity of the implant by visual inspection.

s��4HE�MOST�FREQUENTLY�REPORTED�OCULAR�ADVERSE�EVENTS�IN�CLINICAL�TRIALS�WITH�2%4)3%24® occurring in 50-90% of patients included: cataract, INCREASED�INTRAOCULAR�PRESSURE��PROCEDURAL�COMPLICATIONS�AND�EYE�PAIN��4HIRTY�lVE�TO�FORTY�PERCENT���� ����OF�PATIENTS�REPORTED�OCULAR� conjunctival hyperemia, reduced visual acuity and conjunctival hemorrhage. The most common non-ocular event reported was headache (≥33%).

Chronic inflammation associated with non-infectious posterior uveitis requires continuous control1-4

FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE RETISERT is indicated for the treatment of chronic non-infectious uveitis affecting the posterior segment of the eye. 2 DOSAGE AND ADMINISTRATION 2.1 Dosing Information RETISERT (fluocinolone acetonide intravitreal implant) 0.59 mg is implanted into the posterior segment of the affected eye through a pars plana incision. The implant contains one tablet of 0.59 mg of fluocinolone acetonide. RETISERT is designed to release fluocinolone acetonide at a nominal initial rate of 0.6 μg/day, decreasing over the first month to a steady state between 0.3-0.4 μg/day over approximately 30 months. Following depletion of fluocinolone acetonide as evidenced by recurrence of uveitis, RETISERT may be replaced. 2.2 Handling of Implant Caution should be exercised in handling RETISERT in order to avoid damage to the implant, which may result in an increased rate of drug release from the implant. Thus, RETISERT should be handled only by the suture tab. Care should be taken during implantation and explantation to avoid sheer forces on the implant that could disengage the silicone cup reservoir (which contains a fluocinolone acetonide tablet) from the suture tab. Aseptic technique should be maintained at all times prior to and during the surgical implantation procedure. RETISERT should not be resterilized by any method. 3 DOSAGE FORMS AND STRENGTHS 0.59 mg fluocinolone acetonide intravitreal implant.

4 CONTRAINDICATIONS 4.1 Viral, Bacterial, Mycobacterial and Fungal Infections of Ocular Structures Surgical placement of RETISERT is contraindicated in active viral diseases of the cornea and conjunctiva including epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, and varicella, and also in active bacterial, mycobacterial or fungal infections of the eye. 5 WARNINGS AND PRECAUTIONS 5.1 Cataract Formation Use of corticosteroids may result in posterior subcapsular cataract formation. Based on clinical trials with RETISERT, during the 3-year post implantation period, nearly all phakic eyes are expected to develop cataracts and require cataract surgery. 5.2 Endophthalmitis and Surgical Complications Late onset endophthalmitis has been observed. These events are often related to the integrity of the surgical wound site. Careful attention to assure tight closure of the scleral wound and the integrity of the overlying conjunctiva at the wound site is important. Potential complications accompanying intraocular surgery to place RETISERT into the vitreous cavity may include, but are not limited to, the following: cataract formation, choroidal

detachment, endophthalmitis, hypotony, increased intraocular pressure, exacerbation of intraocular inflammation, retinal detachment, vitreous hemorrhage, vitreous loss, and wound dehiscence. Following implantation of RETISERT, nearly all patients will experience an immediate and temporary decrease in visual acuity in the implanted eye which lasts for approximately one to four weeks post-operatively.

5.3 Increase in Intraocular Pressure Prolonged use of corticosteroids may result in elevated IOP and/or glaucoma with damage to the optic nerve, defects in visual acuity and fields of vision. Steroids should be used with caution in the presence of glaucoma. Patients must be monitored for elevated IOP. Based on clinical trials with RETISERT, within 3-years post implantation, approximately 77% of patients will require IOP lowering medications to control intraocular pressure and 37% of patients will require filtering procedures to control intraocular pressure. (see 6.1 Clinical Trials Experience - Ocular Events section). 5.4 Separation of Implant Components In vitro stability studies show that the strength of the adhesive bond between the silicone cup reservoir and the suture tab is reduced with prolonged hydration, indicating a potential for the separation of these components. Physicians should periodically monitor the integrity of the implant by visual inspection. 5.5 Other Corticosteroid Induced Adverse Reactions RETISERT should be used with caution in patients with a history of a viral, bacterial, mycobacterial or fungal infection of the cornea and conjunctiva including epithelial herpes simplex keratitis (dendritic keratitis), vaccinia and varicella. Use of ocular steroids may prolong the course and may exacerbate the severity of many viral infections of the eye (including herpes simplex). Employment of a corticosteroid medication in the treatment of patients with a history of herpes simplex requires great caution. Prolonged use of corticosteroids may suppress the host response and thus increase the hazard of secondary ocular infections (bacterial, fungal, and viral) . In acute purulent conditions of the eye, steroids may mask infection or enhance existing infection. Fungal and viral infections of the cornea are particularly prone to develop coincidentally with long-term application of steroids. The possibility of fungal invasion should be considered in any persistent corneal ulceration where steroid treatment has been used. Since resistance to infections is known to be reduced by corticosteroids, simultaneous bilateral implantation should not be carried out, in order to limit the potential for bilateral post-operative infection. Ocular administration of corticosteroids has also been associated with delayed wound healing and perforation of the globe where there is thinning of the sclera. The use of steroids after cataract surgery may delay healing and increase the incidence of bleb formation.

FULL PRESCRIBING INFORMATION: CONTENTS*1. INDICATIONS AND USAGE2. DOSAGE AND ADMINISTRATION 2.1 Dosing Information 2.2 Handling of Implant3. DOSAGE FORMS AND STRENGTHS4. CONTRAINDICATIONS 4.1 Viral, Bacterial, Mycobacterial and Fungal Infections of Ocular Structures5. WARNINGS AND PRECAUTIONS 5.1 Cataract Formation 5.2 Endophthalmitis and Surgical Complications 5.3 Increase in Intraocular Pressure 5.4 Separation of Implant Components 5.5 Other Corticosteroid Induced Adverse Reactions6. ADVERSE REACTIONS 6.1 Clinical Trials Experience - Ocular Events

6.2 Clinical Trials Experience - Non-Ocular Events 8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use11. DESCRIPTION12. CLINICAL PHARMACOLOGY 12.1 Mechanism Of Action 12.3 Pharmacokinetics13. NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility14. CLINICAL STUDIES16. HOW SUPPLIED/STORAGE AND HANDLING17. PATIENT COUNSELING INFORMATION*Sections or subsections omitted from the full prescribing information are not listed

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use RETISERT safely and effectively. See full prescribing information for RETISERT. RETISERT (fluocinolone acetonide intravitreal implant) 0.59mg Initial U.S. Approval: 1963 ------------------------------------------INDICATIONS AND USAGE-----------------------------------------RETISERT is a corticosteroid indicated for the treatment of chronic non-infectious uveitis affecting the posterior segment of the eye.(1)--------------------------------------DOSAGE AND ADMINISTRATION------------------------------------- RETISERT is surgically implanted into the posterior segment of the affected eye through a pars plana incision. (2.1) RETISERT is designed to release fluocinolone acetonide at a nominal initial rate of 0.6 μg/day, decreasing over the first month to a steady state between 0.3-0.4 μg/day over approximately 30 months. (2.1) Aseptic technique should be maintained at all times prior to and during the surgical implantation procedure. (2.2)

-------------------------------------DOSAGE FORMS AND STRENGTHS------------------------------------- 0.59 mg fluocinolone acetonide intravitreal implant.

--------------------------------------------CONTRAINDICATIONS---------------------------------------------Surgical placement of RETISERT is contraindicated in active viral, bacterial, mycobacterial and fungal infections of ocular structures. (4.1)

------------------------------------------WARNINGS AND PRECAUTIONS------------------------------------Cataract formation: Nearly all phakic patients are expected to develop cataracts and require cataract surgery. (5.1) Endophthalmitis: Late onset endophthalmitis has been observed. (5.2) Increase in intraocular pressure: Use of corticosteroids may result in elevated IOP and/or glaucoma. (5.3) IOP lowering medications were required in > 75% of patients; filtering surgeries were required in > 35% of patients. (6.1) Separation of implant components: Physicians should periodically monitor the integrity of the implant by visual inspection. (5.4)

-----------------------------------------------ADVERSE REACTIONS-------------------------------------------Ocular adverse events included procedural complications, and eye pain (> 50%). Thirty-five to forty percent of patients reported ocular/conjunctival hyperemia, reduced visual acuity, and conjunctival hemorrhage. (6.1)The most common non-ocular event reported was headache (≥33%). (6.2)

To report SUSPECTED ADVERSE REACTIONS, contact Bausch & Lomb at 1-800-323-0000 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

See 17 for PATIENT COUNSELING INFORMATION Revised March 2009

6 ADVERSE REACTIONS 6.1 Clinical Trials Experience - Ocular Events The available safety data includes exposure to RETISERT in patients with chronic non-infectious uveitis affecting the posterior segment in two multicenter controlled clinical trials. Patients were randomized to dosage regimens of 0.59 mg or 2.1 mg implants. The most frequently reported ocular adverse events were cataract, increased intraocular pressure, procedural complication, and eye pain. These events occurred in approximately 50 - 90% of patients. Cataract includes aggravated cataract, and posterior capsular opacification. Procedural complications includes post-op complication, post-op wound complication, post-op wound site erythema, and wound dehiscense. Based on clinical trials with RETISERT, during the 3-year post-implantation period, nearly all phakic eyes are expected to develop cataracts and require cataract surgery. IOP lowering medications to lower intraocular pressure were required in approximately 77% of patients; filtering surgeries were required to control intraocular pressure in 37% of patients. Ocular adverse events occurring in approximately 10 - 40% of patients in decreasing order of incidence were ocular/conjunctival hyperemia, reduced visual acuity, glaucoma, conjunctival hemorrhage, blurred vision, abnormal sensation in the eye, eye irritation, maculopathy, vitreous floaters, hypotony, pruritus, ptosis, increased tearing, vitreous hemorrhage, dry eye, eyelid edema, macula edema and visual disturbance. Ocular adverse events occurring in approximately 5 - 9% of patients in decreasing order of incidence were eye discharge, photophobia, blepharitis, corneal edema, iris adhesions, choroidal detachment, diplopia, eye swelling, retinal detachment, photopsia, retinal hemorrhage and hyphema. 6.2 Clinical Trials Experience - Non-Ocular EventsThe most frequently reported non-ocular adverse event was headache (33%). Other non-ocular adverse events occurring in approximately 5-20% of patients in decreasing order of incidence were nasopharyngitis, arthralgia, sinusitis, dizziness, pyrexia, upper respiratory tract infection, influenza, vomiting, nausea, cough, back pain, limb pain, and rash. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C No adequate animal reproduction studies have been conducted with fluocinolone acetonide. Corticosteroids are generally teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Fluocinolone acetonide when administered subcutaneously at a dose of 0.13 mg/kg/day (approximately 10,000 times the daily clinical dose of RETISERT), during days 6 to 18 of pregnancy in the rabbit, induced abortion at the end of the third and at the beginning of the fourth gestational week. When administered subcutaneously to rats and rabbits during gestation at a maternal toxic dose of 50 μg/kg/day (approximately 4,000 times the clinical dose of RETISERT), fluocinolone acetonide caused abortions and malformations in a few surviving fetuses. There are no adequate and well-controlled studies in pregnant women. RETISERT should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 8.3 Nursing Mothers It is not known whether ocular administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Systemic steroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Caution should be exercised when RETISERT is implanted in a nursing woman. 8.4 Pediatric Use Safety and effectiveness in pediatric patients below the age of 12 years have not been established. 8.5 Geriatric Use No overall differences in safety and effectiveness have been observed between elderly and younger patients. 11 DESCRIPTION RETISERT® (fluocinolone acetonide intravitreal implant) 0.59 mg is a sterile implant designed to release fluocinolone acetonide locally to the posterior segment of the eye at a nominal initial rate of 0.6 μg/day, decreasing over the first month to a steady state between 0.3-0.4 μg/day over approximately 30 months. The drug substance is the synthetic corticosteroid fluocinolone acetonide, represented by the following structural formula:

C24H

30F

2O

6 Mol. Wt. 452.50

Chemical Name: Pregna-1,4-diene-3,20-dione,6,9-difluoro-11,21-dihydroxy- 16,17-[(1-methyl-ethylidene)bis(oxy)]-,(6Į,11ȕ‚ 16Į)-.Fluocinolone acetonide is a white crystalline powder, insoluble in water, and soluble in methanol. It has a melting point of 265-266ºC. Each RETISERT consists of a tablet containing 0.59 mg of the active ingredient, Fluocinolone Acetonide, USP, and the following inactives: microcrystalline cellulose, polyvinyl alcohol, and magnesium stearate. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism Of Action Corticosteroids inhibit the inflammatory response to a variety of inciting agents and probably delay or slow healing. They inhibit the edema, fibrin deposition, capillary dilation, leukocyte migration, capillary proliferation, fibroblast proliferation, deposition of collagen, and scar formation associated with inflammation. There is no generally accepted explanation for the mechanism of action of ocular corticosteroids. However, corticosteroids are thought to act by the induction of phospholipase A

2 inhibitory proteins, collectively called lipocortins. It is postulated that

these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor

arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A

2. Corticosteroids are capable of producing a rise in intraocular pressure.

12.3 Pharmacokinetics In a subset of patients who received the intravitreal implant, and had blood samples taken at various times (weeks 1, 4 and 34) after implantation, plasma levels of fluocinolone acetonide were below the limit of detection (0.2 ng/mL) at all times. Aqueous and vitreous humor samples were assayed for fluocinolone acetonide in a further subset of patients. While detectable concentrations of fluocinolone acetonide were seen throughout the observation interval (up to 34 months), the concentrations were highly variable, ranging from below the limit of detection (0.2 ng/mL) to 589 ng/mL. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility Long-term animal studies have not been performed on RETISERT to evaluate the carcinogenic potential or the effect on fertility of fluocinolone acetonide. Fluocinolone acetonide was not genotoxic in vitro in the Ames test, the mouse lymphoma TK assay, or in vivo in the mouse bone marrow micronucleus assay. 14 CLINICAL STUDIES In two randomized, double-masked, multicenter controlled clinical trials, 224 patients with chronic (a one year or greater history) non-infectious uveitis affecting the posterior segment of one or both eyes were randomized to receive a 0.59 mg RETISERT. The primary efficacy endpoint in both trials was the rate of recurrence of uveitis affecting the posterior segment of the study eye in the 34 week pre-implantation period compared to the rate of recurrence in the 34 week post-implantation period. Uveitis recurrence rates at 1, 2, and 3 year post-implantation were also compared to the 34 week pre-implantation period. Detailed results are shown in Table 1 below: Table 1: Uveitis Recurrence Rates

TIME POINT

STUDY 1 STUDY 2

N=108 N=116

Uveitis Recurrence Rates1,2 N (%)

34 Weeks Pre-implantation 58 (53.7) 46 (39.7)

34 Weeks Post-implantation 2 (1.8) 15 (12.9)

1 Year Post-implantation 4 (3.7) 15 (12.9)

2 Years Post-implantation 11 (10.2) 16 (13.8)

3 Years Post-implantation 22 (20.4) 20 (17.2)

3 Years3 Post-implantation 33 (30.6) 28 (24.1)

1 Recurrence of uveitis for all post-implantation time points was compared to the 34 weeks pre-implantation time point.2 p-value<0.01 from McNemar’s �2 test.3 Results presented include imputed recurrences. Recurrences were imputed when a subject was not seen within 10 weeks of their final scheduled visit.

16 HOW SUPPLIED/STORAGE AND HANDLING The implant consists of a tablet encased in a silicone elastomer cup containing a release orifice and a polyvinyl alcohol membrane positioned between the tablet and the orifice. The silicone elastomer cup assembly is attached to a polyvinyl alcohol suture tab with silicone adhesive. Each RETISERT is approximately 3 mm x 2 mm x 5 mm. Each implant is stored in a clear polycarbonate case within a foil pouch within a Tyvek peelable overwrap. Each packaged implant is provided in a carton which includes the package insert.NDC 24208-416-01 Storage: Store in the original container at 15° - 25°C (59° - 77°F). Protect from freezing. 17 PATIENT COUNSELING INFORMATION Patients should be advised to have ophthalmologic follow-up examinations of both eyes at appropriate intervals following implantation of RETISERT. As with any surgical procedure, there is risk involved. Potential complications accompanying intraocular surgery to place RETISERT into the vitreous cavity may include, but are not limited to, the following: cataract formation, choroidal detachment, temporary decreased visual acuity, endophthalmitis, hypotony, increased intraocular pressure, exacerbation of intraocular inflammation, retinal detachment, vitreous hemorrhage, vitreous loss, and wound dehiscence. Following implantation of RETISERT, nearly all patients will experience an immediate and temporary decrease in visual acuity in the implanted eye which lasts for approximately one to four weeks post-operatively. Based on clinical trials with RETISERT, within 3 years post-implantation, approximately 77% of patients will require IOP lowering medications to control intraocular pressure and 37% of patients will require filtering procedures to control intraocular pressure. (see 6.1 Clinical Trials Experience - Ocular Events section). Based on clinical trials with RETISERT, during the 3-year post-implantation period, nearly all phakic eyes are expected to develop cataracts and require cataract surgery. Marketed by: Bausch & Lomb Incorporated Rochester, NY 14609 Manufactured by: Bausch & Lomb Incorporated Waterford, Ireland U.S. Patent # 6,217,895 U.S. Patent # 6,548,078 ™/® denote trademarks of Bausch & Lomb Incorporated. © Bausch & Lomb Incorporated Based on full prescribing information revised March 2009. 9164000

RETINASpecial Report )

16

ADVANCES CONTINUE TO PROGRESS FOR THE TREATMENT AND MANAGEMENT OF RETINAL DISEASE

PHIL ADELPHIA ::

Solid scientific rationale exists for

anti-vascular endothelial growth

factor (VEGF) treatment of dia-

betic macular edema (DME).Results of clinical trials show it has efficacy and safety

advantages compared with other modalities.

“We know that VEGF is a primary pathological driver of

DME, and blocking VEGF activity effectively treats DME

and limits the progression of diabetic

retinopathy as well,” said Julia A. Haller,

MD, ophthalmologist-in-chief, Wills Eye

Hospital, and professor and chairwoman,

Department of Ophthalmology, Jeffer-

son Medical College of Thomas Jefferson

Medical College, Philadelphia.

“In addition, anti-VEGF therapy has

fewer side effects than the other avail-

able treatments for DME, which are laser photocoagula-

tion and steroids,” she said.

W H Y A N T I - V E G F ?

Discussing the scientific rationale for anti-VEGF treatment

of DME, Dr. Haller explained that an alternative name for

VEGF when first described was vascular permeability fac-

tor because it caused edema. Results of preclinical studies,

including experiments performed in a guinea pig cheek

model and in the monkey eye, showed injection of VEGF

stimulated vascular leakage. Studies in which vitreous fluid

was sampled from patients with DME showed increased

VEGF immunoreactivity in retinal vessels.

Briefly reviewing some anti-VEGF clinical treatment

trials, Dr. Haller observed that studies investigating dif-

ferent anti-VEGF agents consistently show that intravit-

real anti-VEGF injection is an effective treatment for DME

and provides superior anatomic and functional outcomes

than the active comparators.

“Whether in the DRCR network protocol I trial compar-

ing ranibizumab (Lucentis, Genentech) with deferred or

prompt laser against triamcinolone or laser, or the READ 2

study comparing ranibizumab alone, laser, or ranibizumab

plus laser, mean reductions in central subfield thicken-

ing and final visual acuities achieved in eyes treated with

other modalities never measure up to the levels achieved

in those treated with anti-VEGF injections,” Dr. Haller said.

“In the DRCR network trial, the anti-VEGF treated eyes

also won out in analyses of worsening of diabetic reti-

nopathy, and in the DA VINCI trials, eyes treated with af-

libercept (Eylea, Regeneron) benefited with more thinning

than those treated with focal laser,” she said.

Safety data from the controlled trials also show the few-

est side effects occurred in eyes in the anti-VEGF treat-

ment groups, and in the available DME treatment trials

for ranibizumab and aflibercept, there were no significant

differences in serious adverse event rates

comparing the anti-VEGF and sham groups.

“Laser treatment leaves burns that re-

sult in permanent scotomata, which can

spread,” Dr. Haller said. “This effect may

partly explain why eyes treated with laser

only have the worse visual acuity out-

comes across the controlled DME studies.

With steroids, there are risks of glaucoma

and cataract.”

She cited results from the DRCR.net proto-

col I study showing that overall 50% of eyes

treated with triamcinolone experienced IOP

increase of at least 10 mm Hg from baseline, IOP ≥30 mm

Hg, and/or required initiation of an IOP-lowering medica-

tion. In parallel treatment arms that did not receive corti-

costeroid treatment, only 7% to 11% of eyes experienced

one or more of the IOP-related adverse events.

In an interview after the debate, Dr. Haller emphasized

that her remarks have to be taken in the context of the

format of the program.

“Although in fact anti-VEGFs have become the first line

for DME treatment in many cases, laser and steroids do

have a role as well, and are key weapons in the armamen-

tarium used to combat DME,” she said. Q

PRO anti-VEGF therapy

Fewer sight-limiting side

effects than other available

treatments for DME

Superior visual acuity

outcomes

JULIA A. HALLER, MD

E: jhaller@willseye.org

Dr. Haller has been a consultant in the past for Allergan, Genentech, and Regeneron. This article was

adapted from Dr. Haller’s presentation during Retina 2012 at the annual meeting of the American Academy

of Ophthalmology, where, in an Oxford-style debate, she provided her perspective on whether anti-vascular

endothelial growth factor therapy is the ideal treatment for diabetic macular edema.

By Cheryl Guttman Krader; Reviewed by Julia A. Haller, MD

Superior effi cacy, safety profi les

support anti-VEGF therapy

Dr. Haller

POINT

DEFINING THE ‘IDEAL’ DME TREATMENT

IRV INE, CA ::

Despite the emergence of anti-vas-

cular endothelial growth factor

(VEGF) agents as treatment for

diabetic macular edema (DME),

corticosteroid and/or laser treatment is preferred

for many patients.“Injection of an anti-VEGF agent is certainly effective for treat-

ing DME in many patients, but not in all, and efficacy depends

on the treatment protocol and frequency of re-

peat injections,” said Baruch D. Kuppermann,

MD, PhD, professor of ophthalmology and bio-

medical engineering, and chief, Retina Ser-

vice, Gavin Herbert Eye Institute, University

of California, Irvine.

“Additionally, I have concerns about the treat-

ment costs, burden, and systemic safety that

I think are shared by many others,” he said.

“While corticosteroids are not without side effects, they are a

great option for [patients with] pseudophakia and better than

anti-VEGF treatment for eyes with chronic DME. Furthermore,

we should not forget about laser for focal DME, where it can pro-

vide very good results for low cost and low treatment burden.”

A T W H A T C O S T ?

Reviewing the evidence, Dr. Kuppermann noted that anti-VEGF

treatment for DME carries a “huge” treatment and cost burden,

considering that maximizing the visual acuity improvement

requires ongoing monthly injections. Whereas in the pivotal

trials for exudative age-related macular degeneration, patients

treated with an anti-VEGF agent achieved rapid vision gains

that peaked after 3 monthly injections, in the phase III ranibiz-

umab DME trials, visual acuity continued to improve over 2

years with ongoing monthly anti-VEGF injections.

In addition, it appears that a p.r.n. treatment approach may

not be that effective for DME.

“Results from ranibizumab clinical trials show you have to

be aggressive when treating DME to achieve good results,” Dr.

Kuppermann said. “With ongoing monthly injections in RISE

and RIDE, about 40% of [patients with] DME treated with rani-

bizumab 0.3 mg gained 3 or more lines of best-corrected visual

acuity at 24 months. However, using a p.r.n. approach in a DRCR.

Dr. Kuppermann

RETINASpecial Report )

MARCH 1, 2013 :: Ophthalmology Times 17

Therapy carries cost burden

for ongoing monthly injectionsBy Cheryl Guttman Krader; Reviewed by Baruch D. Kuppermann, MD, PhD

net study, less than 30% of patients were three-line gainers at

the end of year 2.”

Three years of follow-up in RISE and RIDE also indicate that

reduced efficacy in patients with chronic DME is another limita-

tion of anti-VEGF therapy. Patients originally assigned to sham

treatment in RISE and RIDE were crossed over to ranibizumab

after 2 years years, but had only a meager response, he said.

“In contrast, in the study of the fluocino-

lone acetonide intravitreal insert (Iluvien,

Alimera Sciences), patients with chronic

DME were the most responsive, with 34%

achieving a three-line improvement,” he said.

Concerns about systemic safety of anti-

VEGF treatment are heightened in the vas-

culopathic DME population. In the phase III

RISE and RIDE trials that compared rani-

bizumab 0.3 and 0.5 mg, the higher dose

was associated with more deaths without

providing any efficacy advantage compared

with the lower dose. Therefore, rani bizumab

was approved for treatment of DME using the 0.3-mg dose.

“However, patients with bilateral disease will be getting higher

doses, and there is concern that these severe systemic side effects

might be even greater with bevacizumab due to its longer sys-

temic half life and the reduction in systemic VEGF levels noted

with bevacizumab but not ranibizumab in the IVAN trial for wet

AMD,” Dr. Kuppermann said.

Discussing alternatives, Dr. Kuppermann noted that in the

DRCR protocol I study enrolling pseudophakic patients, efficacy

outcomes were similar at 1 year in the group that received in-

jections of triamcinolone every 4 months as needed compared

with eyes receiving ranibizumab as often as monthly. Visual

acuity results were also similar in the second year when in-

jections for both agents were only given as needed, but more

injections were given in the ranibizumab group. Q

BARUCH D. KUPPERMANN, MD, PHD

E: bdkupper@uci.edu

Dr. Kuppermann is a consultant and clinical investigator with Alimera, Allergan, Genentech, and Regeneron, manufac-

turers of intravitreal anti-vascular endothelial growth factor therapies (VEGF) and steroid therapies, either approved

for diabetic macular edema (DME) or being investigated for DME. This article was adapted from Dr. Kuppermann’s

presentation during Retina 2012 at the annual meeting of the American Academy of Ophthalmology, where, in an

Oxford-style debate, he provided his perspective on whether anti-VEGF therapy is the ideal treatment for DME.

DEFINING THE ‘IDEAL’ DME TREATMENT

COUNTERPOINT

CON anti-VEGF therapy

Reduced efficacy in

patients with chronic DME

Effective alternatives

may be preferred in specific

patients

BOSTON ::

ADVANCES IN IMAGING technology

mean patients may benefit from faster image

acquisition and disease evaluation.

Nonmydriatic ultra-wide-field imaging (Optos

P200MA, Optos) compares favorably with di-

lated ETDRS protocol fundus photography and

dilated fundus examination in determining the

severity of both diabetic retinopathy (DR) and

diabetic macular edema (DME), according to

the results of a clinical validation study per-

formed by researchers at the Beetham Eye In-

stitute, Joslin Diabetes Center, Harvard Medi-

cal School, Boston.

The ultra-wide-field retinal imaging sys-

tem combines scanning laser (green 532-nm

and red 633-nm) ophthal-

moscope technology with

a large ellipsoidal mirror

to image up to 200° (82%)

of the retina in a single,

0.25-second scan. A high-

resolution mode (ResMax,

Optos) scans a 100° area of

the retina (25%), but offers

increased image resolution (11 μm).

“Compared with ETDRS 30° color fundus

photography, the new imaging technology has

several advantages as it avoids the need for

pupil dilation, offers a wider imaging field, has

faster acquisition time, and may penetrate bet-

ter through media opacity and smaller pupils,”

said Paolo S. Silva, MD, lead author of a pub-

lished paper on the study [Am J Ophthalmol.

2012;154:549-559] and assistant chief, Center

for Ocular Telehealth, Beetham Eye Institute.

“If our findings on its use for evaluating DR

are confirmed in larger studies in broader di-

abetic populations, nonmydriatic ultra-wide-

field imaging may prove to be beneficial in

research and clinical settings,” Dr. Silva said.

“To determine whether additional prognostic

information can be obtained from peripheral

retinal lesions, ultra-wide-field images of dia-

betic and non-posterior pole will need to be

evaluated carefully over time in a defined pop-

ulation. These peripheral findings may or may

not provide additional prognostic information

for DR progression.”

V A L I D A T I O N S T U D Y

The validation study enrolled 103 patients with

type 1 or 2 diabetes who were attending a regu-

larly scheduled clinic appointment. At a single

visit, each patient underwent imaging of both

eyes, using the nonmydriatic ultra-wide-field

technology (100° and 200° fields), as well as

dilated ETDRS photography and dilated fun-

dus examination. The nonmydriatic imaging

was performed first by a certified imager; the

ETDRS photographs were acquired by an ETDRS-

certified photographer; and the dilated fundus

examination was performed by a retina specialist.

All of the images acquired were graded in

masked fashion for DR and DME severity by

two independent readers. Any discrepancies

between the two readers were adjudicated by

a third retina specialist.

ETDRS photography was completed for 200

eyes and the readings showed the group rep-

resented the full spectrum of DR from none

(12.5%) to proliferative (2.5%); the majority of

eyes were graded as having mild or moderate

nonproliferative DR (54%). The majority of eyes

had no DME (57%), and nearly one-fourth were

determined to have clinically significant DME.

Results from grading of the ultra-wide-field

100° images showed exact agreement with the

ETDRS , photography-based interpretations in

84% of eyes and there was a difference of just

1 severity level in another 7%. When com-

pared with clinical examination, the readings

from the nonmydriatic ultra-wide-field images

were an exact match in 70% of eyes and were

within 1 level in 93%.

The ultra-wide-field images had 99% sensitiv-

ity for detecting and identifying DR on ETDRS

photographs and 100% specificity. Sensitivity

and specificity for detecting and identifying PDR

on ETDRS photographs using the ultra-wide-

field imaging were 100% and 92%, respectively.

The researchers also noted that acquisi-

tion of the nonmydriatic ultra-wide-field im-

ages took less than half the time needed for

ETDRS photography, even excluding the time

for pupil dilation.

Although the ultra-wide-field imaging cap-

tures peripheral lesions, their implications on

DR severity are unknown at this time.

“Current knowledge of DR progression rates,

along with recommendations for DR manage-

ment, is based on lesions located within the 7

standard 30° fields following the ETDRS imaging

protocol,” he said. “It is uncertain how peripheral

lesions would [affect] these recommendations.”

Prognosis for a quicker diagnosisNonmydriatic ultra-wide-field imaging shows promise for evaluating diabetic retinopathyBy Cheryl Guttman Krader; Reviewed by Paolo S. Silva, MD

Dr. Silva

18 MARCH 1, 2013 :: Ophthalmology Times

RETINASpecial Report )

Continues on page 20 : Imaging(FIGURE 1) Optomap image showing diabetic

retinopathy. (Photo courtesy of Optos)

(FIGURE 2) LEFT: A 30° retinal image centered on the macula. RIGHT: A 200° ultra-wide-field retinal image.

The green circle represents the approximate area covered by a 30° retinal image. The system combines

scanning laser ophthalmoscope technology with a large ellipsoidal mirror. (Images courtesy of Paolo S. Silva, MD)

OphthalmologyTimes.com

Advertisement not available for this issue of the digital edition

Dr. Dugel

PRAVIN U. DUGEL, MD

E: pdugel@gmail.com

Dr. Dugel is a consultant to and minor shareholder in Ophthotech. This article was

adapted from Dr. Dugel’s presentation at Retina 2012 during the annual meeting of

the American Academy of Ophthalmology.

PAOLO S. SILVA, MD

E: paoloantonio.silva@joslin.harvard.edu

Dr. Silva discloses no relevant financial interests. Grant funding was provided to the

Joslin Diabetes Center for performance of the study.

20 MARCH 1, 2013 :: Ophthalmology Times

RETINASpecial Report )

IMAGING( Continued from page 18 )

PHOENIX ::

PATIENTS WITH WET age-related

macular degeneration (AMD) may benefit from

treatment that combines anti-platelet-derived

growth factor (PDGF)/anti-vascular endothe-

lial growth factor (VEGF) therapy.

Results from a large phase IIb randomized

clinical trial show combination therapy with

E10030 (Fovista, Ophthotech), an investiga-

tional 50-kD DNA aptamer directed against

PDGF-B (subunit B), plus ran i biz u mab (Lu-

centis, Genentech), is superior to ran i biz u mab

monotherapy for treating neovascular AMD.

“There is no doubt that anti-VEGF monother-

apy treatment is effective for neovascular AMD,

but there is equally no doubt that chronic anti-

VEGF monotherapy treatment induces resistance,

and that is why we have to

treat perhaps indefinitely,” said

Pravin U. Dugel, MD, study

investigator and managing

partner, Retinal Consultants

of Arizona, Phoenix.

“It makes good physiologic

sense to combine anti-PDGF and

anti-VEGF agents, and this is

well-supported in the oncology literature,” he said.

“If the results of the Fovista phase IIb neovascular

AMD study are confirmed in a larger pivotal phase

III trial, the combined approach has the potential

to change dramatically and profoundly our treat-

ment model for patients with neovascular AMD.”

The rationale for the anti-PDGF combination

is based on evidence that anti-VEGF monother-

apy treatment induces PDGF upregulation, peri-

cyte recruitment, and neovascular membrane

maturation. These pericytes form a protective

armor around the neovascular complex, but are

stripped away with the addition of

an anti-PDGF agent, thereby render-

ing the neovascular complex more

vulnerable to anti-VEGF therapy.

The E10030 phase IIb trial of anti-

PDGF combination therapy randomly

assigned 449 treatment-naive patients

equally into three treatment arms

to receive ran i biz u mab plus E10030

0.3 mg, ran i biz u mab plus E10030 1.5

mg, or ran i biz u mab monotherapy.

“There are two important things

to note about the study,” Dr. Dugel

said. “It was designed as a superi-

ority study, and it was the largest phase II su-

periority study ever done in retina.”

Both the 0.3-mg and 1.5-mg E10030 combi-

nation groups met their pre-specified primary

endpoint by achieving superior mean visual acu-

ity improvement from baseline to week 24 com-

pared with ran i biz u mab monotherapy. The vision

improvement at week 24 was 10.6 letters in the

1.5-mg E10030 combination group, 8.8 letters in

the 0.3-mg E10030 combination group, and 6.5

letters in the ran i biz u mab monotherapy group.

“The data for visual acuity improvement

also showed a classic dose response and con-

tinued divergence of the efficacy curves over

time,” Dr. Dugel said.

Pre-specified subgroup analyses were per-

formed to determine whether any particular pa-

tient subgroup(s) drove the superior results for

the combination treatment. With patients strati-

fied by neovascular membrane size or baseline

vision, the combination arms were always su-

perior to ran i biz u mab monotherapy.

Combination treatment was also

superior to control in an analysis of

the disappearance of subretinal hy-

perreflective material as seen on op-

tical coherence tomography (OCT),

and a comparison of the two com-

bination groups showed a clear and

predictable dose-related effect.

“We were especially interested in

this parameter that was felt to rep-

resent the entire lesion and lesion

components,” Dr. Dugel said.

When the relationship of OCT

thickness and vision was studied, regardless

of the initial lesion thickness, the combination

arms always proved superior. When fluorescein

angiograms were studied, there was a consis-

tent and predictable relationship between le-

sion regression and vision improvement.

The safety data showed no differences in the

rate or type of ocular adverse events or seri-

ous systemic adverse events among the three

study arms, and mean IOP was not signifi-

cantly different even though patients received

two injections in the combination groups. Q

Combination therapy a boon for AMDPhase IIb neovascular AMD study shows robust benefit for anti-PDGF/anti-VEGF therapyBy Cheryl Guttman Krader; Reviewed by Pravin U. Dugel, MD

The imaging technology has some limita-

tions, Dr. Silva noted. The cost is substantially

higher compared with traditional methods of

retinal imaging, and there is the potential for

imaging artifacts not seen in traditional fun-

dus photography due to the mirror, lashes,

motion, and reflections. In addition, the com-

posite color image is based on red and green

wavelengths only. Due to the curvature of the

globe and the mirror, in 200° images there is

some loss of resolution beyond the superior

and inferior vascular arcades. Due to the large

contiguous area of retina that is acquired in

a single image, it is necessary to zoom in to

sufficient magnification in order to obtain an

adequate view necessary to appreciate subtle

retinal lesions.

“With the 200° image there is good resolu-

tion along a central horizontal band that en-

compasses the disc and macula and extends

to the temporal and nasal periphery,” Dr. Silva

concluded. Q

> Designed as

superiority study

> Largest phase II

superiority study

in retina

Study power pointS

LONDON ::

PATIENTS UNDERGOING stereotactic

radiotherapy for wet age-related macular de-

generation (AMD) may experience a reduced

need for anti-vascular endothelial growth fac-

tor (VEGF) injections, along

with visual acuity benefits.

Findings from post-hoc

analyses of data collected

through 12 months in the

INTREPID trial indicate eyes

with lesions that are actively

leaking, fully within the ra-

diotherapy treatment zone,

and without significant fibrosis achieve the

greatest benefit. The randomized,

sham-controlled, double-masked

trial is investigating stereotactic

radiotherapy using a proprietary

device (IRay, Oraya) in patients

receiving anti-VEGF injections for

exudative AMD.

“These ‘best responders’ rep-

resent about 25% to 50% of the

enrolled population, depending

on the number of defining crite-

ria used,” explained Timothy L.

Jackson, PhD, FRCOphth, consul-

tant ophthalmic surgeon, King’s

College Hospital, London. “Over-

all, the data indicate that they can

expect to need about 50% fewer

anti-VEGF injections over the course of a year

following the radiotherapy and achieve sig-

nificantly better visual acuity improvements

than their counterparts receiving anti-VEGF

monotherapy.

“However, these subset analyses need to be

interpreted with caution and, of course, fur-

ther follow-up is needed,” he added.

The stereotactic radiotherapy is delivered

using a slit lamp-type system. It delivers three

X-ray beams that pass through the inferior sclera

and overlap at the macula, coalescing over a

4-mm zone.

P A T I E N T E N R O L L M E N T

Patients were eligible to be enrolled in INTREPID

if they had exudative AMD diagnosed within

the past 3 years, had received at least three

anti-VEGF injections in the prior year, were

deemed to require further anti-VEGF therapy,

and had a lesion measuring 6 mm or less.

A total of 230 patients were randomly assigned

to three groups to receive radiotherapy with a

16-Gy dose, 24-Gy dose, or sham exposure. The

radiotherapy was administered as a one-time

treatment and patients were seen monthly there-

after. Need for further anti-VEGF injection (rani-

bizumab; Lucentis, Genentech) was assessed based

on predefined re-treatment criteria.

For the responder analysis, eyes with ac-

tively leaking lesions were defined as those

with macular volume >7.4 mm2, the macular

volume which represented the median volume

for the study population. Within

this particular subgroup, patients

who received stereotactic radio-

therapy had a 45% reduction in the

number of anti-VEGF injections re-

ceived during the first 12 months of

INTREPID along with a 5-letter greater

gain in best-corrected visual acuity

(BCVA) compared with the sham-

treated controls.

As a reference in the overall

study population, stereotactic ra-

diotherapy significantly reduced

the number of anti-VEGF injec-

tions needed, but by only 32%,

and was associated with a 1.6 let-

ter BCVA benefit, which was not

statistically significant.

Eyes with both macular volume >7.4 mm2

and lesion diameter <4 mm represented about

one-fourth of the study population. Within

this subgroup, the radiotherapy-treated eyes

required 54% fewer anti-VEGF injections than

the sham-treated controls and had close to a

7-letter greater gain in visual acuity.

Among eyes with lesions that were both ac-

tively leaking and that was within the treat-

ment zone, only 20% of those receiving radio-

therapy compared with 70% of controls re-

ceived four or more anti-VEGF injections over

the course of 12 months; while 100% of con-

trol eyes received at least one additional anti-

VEGF injection after the mandatory baseline

treatment, only 33% of the eyes in the radia-

tion arm required anti-VEGF re-treatment, Dr.

Jackson noted. Q

INTREPID identifies ‘best responders’Fewer anti-VEGF injections among benefits of stereotactic radiotherapy for wet AMDBy Cheryl Guttman Krader; Reviewed by Timothy L. Jackson, PhD, FRCOphth

Dr. Jackson

take-home The INTREPID trial

results showed a

significant benefit

of stereotactic

radiotherapy

for reducing the need

for further anti-vascular

endothelial growth

factor injections

in eyes with active wet

age-related macular

degeneration.

TIMOTHY L. JACKSON, PHD, FRCOPHTH

E: t.jackson1@nhs.net

Dr. Jackson receives lecture fees and grant support from Oraya. The proprietary

stereotactic radiotherapy device is CE marked and investigational in the United

States. This article was adapted from Dr. Jackson’s presentation at Retina 2012

during the annual meeting of the American Academy of Ophthalmology.

> LOW-ENERGY X-R AY TUBE . Although

similar to a portable chest X-ray machine, the tube

utilized by the IRay produces a highly collimated,

narrow beam. It is designed to affect only the

target area or lesion, with minimal scatter onto

surrounding healthy tissue.

> S E L F - C ON TA I N E D AU T OM AT E D

B E A M P O S I T I O N I N G S Y S T E M . The

positioning mechanism ensures the precise

entry of energy into the eye, avoiding critical

structures, such as the lens and optic nerve.

> O R A Y A T H E R A P Y S O F T WA R E .

Specialized software includes treatment planning,

treatment monitoring and control, and treatment

verification. The treatment-planning model uses

axial length of the eye, obtained via immersion

ultrasonography or optical biometry, to calculate

the exact required beam positioning.

> I - G U I D E E Y E S T A B I L I Z A T I O N

DEV ICE . This component has been designed

to stabilize and align the eye. It includes a

sterile, disposable contact lens that uses a

small amount of vacuum to hold the eye in the

appropriate treatment orientation. The I-Guide

also contains optical reflectors that work with

the beam positioning system to enable precise

localization and tracking of the eye.

> E Y E-T R ACK I NG SY ST E M . The IRay

system has been designed to monitor movement

of the patient’s eye continuously and enable

immediate shut-down of treatment in the event

of excessive eye motion. (Source: Oraya)

Utilizing the radiotherapy system

21MARCH 1, 2013 :: Ophthalmology Times

RETINASpecial Report )

*Branch or central retinal vein occlusion.

BECAUSE THERE ARE NO TIME-OUTS

IN MACULAR EDEMA DUE TO RVO*

Indication and Usage

Retinal Vein Occlusion: OZURDEX® (dexamethasone intravitreal implant) is a corticosteroid indicated for the treatment of macular edema following branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO).

Dosage and Administration

FOR OPHTHALMIC INTRAVITREAL INJECTION ONLY. The intravitreal injection procedure should be carried out under controlled aseptic conditions. Following the intravitreal injection, patients should be monitored for elevation in intraocular pressure and for endophthalmitis.

Patients should be instructed to report any symptoms suggestive of endophthalmitis without delay.

IMPORTANT SAFETY INFORMATION

Contraindications

Ocular or Periocular Infections: OZURDEX® (dexamethasone intravitreal implant) is contraindicated in patients with active or suspected ocular or periocular infections including most viral diseases of the cornea and conjunctiva, including active epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, varicella, mycobacterial infections, and fungal diseases.

� Every case of retinal vein occlusion (RVO) is different

� Every patient responds differently to therapy

� Every office visit is an opportunity to assess macular edema

due to RVO and treat appropriate patients with OZURDEX®

Keep the Opportunity in Sight©2013 Allergan, Inc., Irvine, CA 92612 ® marks owned by Allergan, Inc. www.Ozurdex.com

APC07BY12 122961

IMPORTANT SAFETY INFORMATION (continued)

Contraindications (continued)

Advanced Glaucoma: OZURDEX® (dexamethasone intravitreal implant) is contraindicated in patients with advanced glaucoma.

Aphakic Eyes with Rupture of the Posterior Lens Capsule: OZURDEX® is contraindicated in patients who have aphakic eyes with rupture of the posterior lens capsule.

ACIOL and Rupture of the Posterior Lens Capsule: OZURDEX® is contraindicated in eyes with ACIOL (Anterior Chamber Intraocular Lens) and rupture of the posterior lens capsule.

Hypersensitivity: OZURDEX® is contraindicated in patients with known hypersensitivity to any components of this product.

Warnings and Precautions

Intravitreal Injection-related Effects: Intravitreal injections have been associated with endophthalmitis, eye inflammation, increased intraocular pressure, and retinal detachments. Patients should be monitored regularly following the injection.

Potential Steroid-related Effects: Use of corticosteroids may produce posterior subcapsular cataracts, increased intraocular pressure, glaucoma, and may enhance the establishment of secondary ocular infections due to bacteria, fungi, or viruses.

Corticosteroids should be used cautiously in patients with a history of ocular herpes simplex.

Risk of Implant Migration: Patients in whom the posterior capsule of the lens is absent or has a tear are at risk of implant migration into the anterior chamber.

Adverse Reactions

The most common ocular adverse reactions reported by greater than 2% of patients in the first 6 months following injection of OZURDEX® for retinal vein occlusion and posterior segment uveitis include: intraocular pressure increased (25%), conjunctival hemorrhage (22%), eye pain (8%), conjunctival hyperemia (7%), ocular hypertension (5%), cataract (5%), vitreous detachment (2%), and headache (4%).

Increased IOP with OZURDEX® peaked at approximately week 8. During the initial treatment period, 1% (3/421) of the patients who received OZURDEX® required surgical procedures for management of elevated IOP.

Please see Brief Summary of full Prescribing Information on adjacent page.

It may be time for OZURDEX®

(dexamethasone intravitreal implant) 0.7 mg

Brief Summary—Please see the OZURDEX® package insert for full Prescribing Information.

INDICATIONS AND USAGERetinal Vein Occlusion: OZURDEX® (dexamethasone intravitreal implant) is a corticosteroid indicated for the treatment of macular edema following branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO). Posterior Segment Uveitis: OZURDEX® is indicated for the treatment of non-infectious uveitis affecting the posterior segment of the eye.CONTRAINDICATIONSOcular or Periocular Infections: OZURDEX® (dexamethasone intravitreal implant) is contraindicated in patients with active or suspected ocular or periocular infections including most viral diseases of the cornea and conjunctiva, including active epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, varicella, mycobacterial infections, and fungal diseases. Advanced Glaucoma: OZURDEX® is contraindicated in patients with advanced glaucoma.Aphakic Eyes with Rupture of the Posterior Lens Capsule: OZURDEX® is contraindicated in patients who have aphakic eyes with rupture of the posterior lens capsule.ACIOL and Rupture of the Posterior Lens Capsule: OZURDEX® is contraindicated in eyes with ACIOL (Anterior Chamber Intraocular Lens) and rupture of the posterior lens capsule.Hypersensitivity: OZURDEX® is contraindicated in patients with known hypersensitivity to any components of this product.WARNINGS AND PRECAUTIONSIntravitreal Injection-related Effects: Intravitreal injections have been associated with endophthalmitis, eye inflammation, increased intraocular pressure, and retinal detachments. Patients should be monitored regularly following the injection [see Patient Counseling Information].Potential Steroid-related Effects: Use of corticosteroids may produce posterior subcapsular cataracts, increased intraocular pressure, glaucoma, and may enhance the establishment of secondary ocular infections due to bacteria, fungi, or viruses. Corticosteroids should be used cautiously in patients with a history of ocular herpes simplex. Risk of Implant Migration: Patients in whom the posterior capsule of the lens is absent or has a tear are at risk of implant migration into the anterior chamber.ADVERSE REACTIONSClinical Studies Experience: Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.Adverse reactions associated with ophthalmic steroids include elevated intraocular pressure, which may be associated with optic nerve damage, visual acuity and field defects, posterior subcapsular cataract formation, secondary ocular infection from pathogens including herpes simplex, and perforation of the globe where there is thinning of the cornea or sclera.The following information is based on the combined clinical trial results from 3 initial, randomized, 6-month, sham-controlled studies (2 for retinal vein occlusion and 1 for posterior segment uveitis):Adverse Reactions Reported by Greater than 2% of Patients in the First Six Months

MedDRA Term OZURDEX® N=497 (%)

ShamN=498 (%)

Intraocular pressure increased 125 (25%) 10 (2%)

Conjunctival hemorrhage 108 (22%) 79 (16%)

Eye pain 40 (8%) 26 (5%)

Conjunctival hyperemia 33 (7%) 27 (5%)

Ocular hypertension 23 (5%) 3 (1%)

Adverse Reactions Reported by Greater than 2% of Patients in the First Six Months (continued)

MedDRA Term OZURDEX® N=497 (%)

ShamN=498 (%)

Cataract 24 (5%) 10 (2%)

Vitreous detachment 12 (2%) 8 (2%)

Headache 19 (4%) 12 (2%)

Increased IOP with OZURDEX® (dexamethasone intravitreal implant) peaked at approximately week 8. During the initial treatment period, 1% (3/421) of the patients who received OZURDEX® required surgical procedures for management of elevated IOP.Following a second injection of OZURDEX® in cases where a second injection was indicated, the overall incidence of cataracts was higher after 1 year.USE IN SPECIFIC POPULATIONSPregnancyTeratogenic Effects: Pregnancy Category C: Topical dexamethasone has been shown to be teratogenic in mice producing fetal resorptions and cleft palate. In the rabbit, dexamethasone produced fetal resorptions and multiple abnormalities involving the head, ears, limbs, palate, etc. Pregnant rhesus monkeys treated with dexamethasone sodium phosphate intramuscularly at 1 mg/kg/day every other day for 28 days or at 10 mg/kg/day once or every other day at 3 or 5 days between gestation days 23 and 49 had fetuses with minor cranial abnormalities. A 1 mg/kg/dose in pregnant rhesus monkeys would be approximately 85 times higher than an OZURDEX® injection in humans (assuming 60 kg body weight). There are no adequate and well-controlled studies in pregnant women. OZURDEX® (dexamethasone intravitreal implant) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers: It is not known whether ocular administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Caution should be exercised when corticosteroids are administered to a nursing woman. Pediatric Use: Safety and effectiveness of OZURDEX® in pediatric patients have not been established.Geriatric Use: No overall differences in safety or effectiveness have been observed between elderly and younger patients.NONCLINICAL TOXICOLOGYCarcinogenesis, Mutagenesis, Impairment of FertilityNo adequate studies in animals have been conducted to determine whether OZURDEX® (dexamethasone intravitreal implant) has the potential for carcinogenesis.Although no adequate studies have been conducted to determine the mutagenic potential of OZURDEX®, dexamethasone has been shown to have no mutagenic effects in bacterial and mammalian cells in vitro or in the in vivo mouse micronucleus test. PATIENT COUNSELING INFORMATIONIn the days following intravitreal injection of OZURDEX®, patients are at risk for potential complications including in particular, but not limited to, the development of endophthalmitis or elevated intraocular pressure. If the eye becomes red, sensitive to light, painful, or develops a change in vision, the patient should seek immediate care from an ophthalmologist. Patients may experience temporary visual blurring after receiving an intravitreal injection. They should not drive or use machines until this has resolved.

©2012 Allergan, Inc., Irvine, CA 92612, U.S.A. ® marks owned by Allergan, Inc.Patented. See: www.allergan.com/products/patent_noticesMade in Ireland Based on 72212US14APC52EA12

OZURDEX®

(dexamethasone intravitreal implant) 0.7 mg

Continues on page 26 : DME

take-home A new technology

(Endpoint Management,

Topcon Medical

Laser Systems), when

combined with Topcon’s

PASCAL scanning laser,

allows physicians very

precise management of

two important elements

of laser treatment:

duration and power,

relates one

ophthalmologist.

MARCH 1, 2013 :: Ophthalmology Times

RETINASpecial Report )

25

DIABETIC RETINOPATHY (DR) and

diabetic macular edema (DME) are the most

common causes of blindness among the work-

ing-age populations of the developed world.

Yet, treatment for these patients represents a

large unmet need.

The Early Treatment Diabetic Ret-

inopathy Study (EDTRS) set focal/

grid laser photocoagulation as the

standard of care for treatment more

than two decades ago,1 but the under-

standing of laser therapy is evolving

and treatment modalities changing.

Concurrently, there has been a large

focus on therapy with anti-vascular

endothelial growth factor (VEGF),

and study results suggest the ben-

efits of combined therapy.2

Numerous studies have shown

positive results with anti-VEGF in-

jections. In the drcr.net study, pa-

tients were treated every 4 weeks

until week 16, at which point 25%

met the criteria not to receive an

injection. Of those 25% that could

skip a treatment, 90% had recurrences that

required future treatment.

Overall, the first time that a patient met the

criteria not to be examined every 4 weeks was

at week 64. Thus, the requirement is to see pa-

tients with DME every 4 weeks for more than

a year, which is not sustainable or realistic.

Many patients are young, have jobs and busy

lives, and may not be able to be compliant. If

patients are not seen every 4 weeks, that may

compromise the study results.

In spite of having been the standard of care for

decades, there are several misconceptions that

have marred the reputation of laser treatment.

Initial studies showed that laser photocoagula-

tion stabilized patients but did not necessarily

improve vision (Original DRS Study in 1980s).

However, closer analysis of these results show

that many patients actually started with suffi-

ciently good vision, so that gaining 3 lines of

visual improvement was not possible. Among

those patients that did have potential for greater

than 3 lines of improvement, more than 40%

achieved this. The results for laser treatment

were actually very good, but this finding was

misunderstood because of the study design.

In addition to better interpretation of ex-

isting studies of laser photocoagulation, the

treatment itself is also changing. It was pre-

viously thought that laser photocoagulation

provided its therapeutic benefit, via the de-

struction of microaneurysms. Large and intense

laser burns were applied that not

only caused destruction initially,

but also tended to expand over

time, impacting the surround-

ing tissues.

However, recent studies have

suggested that laser treatment

can best be used as a stimula-

tor of retinal pigment epithelial

(RPE) cells, creating a cascade

of events which release chemi-

cal factors that then allow the

edema in patients with DME to be

resolved.3 Consequently, therapy

is evolving to be less destructive

and more precise by manipulat-

ing the duration and power of the

laser energy applied.

Micropulse and subthreshold

laser therapies have been developed that allow

physicians to provide less destructive treatment,

and studies have shown that these modalities

are at least as effective as the modified EDTRS

recommendations for focal/grid laser photoco-

agulation.4,5 We are on the tip of an evolution

that will change the vocabulary from destruc-

tive photocoagulation to photostimulation of

RPE cells.

D U R A T I O N A N D P O W E R

One treatment option is a new technology (End-

point Management, Topcon Medical Laser Sys-

tems) that, when combined with Topcon’s PAS-

CAL scanning laser, allows physicians very pre-

cise management of two important elements of

laser treatment: duration and power. The soft-

ware uses advanced mathematical algorithms

to guide laser output in controlled, repeatable

doses as a percentage of the initial settings

determined by the physician during titration.

The technology allows user flexibility in a

range the desired endpoints from 95% of the

titrated lesion down to subvisible treatment lev-

els less than 50%. This control capability can

allow RPE cells to get precise, focused-energy

delivery, resulting in minimal collateral dam-

age while still maintaining clinical efficacy.

DME can be divided into three different cat-

egories, among which there is significant over-

lap. The first category is true focal DME, with a

very precise location of the leak which is away

from the fovea. The second category is diffuse

DME, in which there is widespread leakage,

even under the fovea. The third category is

ischemic DME, characterized by swelling due

to insufficient blood flow.

C A T E G O R I Z I N G P A T I E N T S

The vast majority of patients can be catego-

rized into the second or third groups, and I

treat with a combination of laser therapy and

anti-VEGF injections. Anti-VEGF works imme-

diately and continues to help as long as it is

administered. However, when treatment stops,

edema recurs, and maintaining frequent in-

jections is often not sustainable. Laser photo-

stimulation is the perfect complement to anti-

VEGF treatment because it does not provide

an immediate improvement, but rather has a

slow, steady and sustainable positive effect.

For patients who fall into the first category,

I would treat using only laser therapy. How-

ever, focal DME with a distinct round circle of

exudate or a particular microaneurysm tends

to occur early in the disease state and is seen

only in a minority of patients.

Laser photostimulation using the software

technology is much like photocoagulation in

that the physician programs a certain percent-

age of treatment effect so that a burn on the

retinal pigment epithelium can barely be visu-

alized. Once that benchmark it set, the treat-

ment effect is titrated down by selecting the

percentage level of the energy to be delivered.

I currently use the 50% level in my patients

and studies. Once I choose my percentage level,

the software automatically adjusts both power

and duration to achieve this energy level.

Another capability of Endpoint Management

is the “landmark” patterns, where the edges

of a pattern can be selected to remain barely

visible and provide reference points, while the

remainder of the pattern itself cannot be seen.

These patterns are useful to identify the treated

zones and prevent overlapping.

Paradigm shift for treating DMEOphthalmologist explains his use of pattern laser treatment in conjunction with anti-VEGFBy Pravin U. Dugel, MD; Special to Ophthalmology Times

26 MARCH 1, 2013 :: Ophthalmology Times

RETINASpecial Report )

BORDEAUX, FRANCE ::

A NEW OPTION FOR macular edema

following central retinal vein occlusion (CRVO)

is showing consistent, statistically significant

treatment benefits.

Six-month results from a multicenter, ran-

domized, double-masked, sham-controlled trial

show that fixed monthly injections of aflibercept

(Eylea, Bayer/Regeneron Pharmaceuticals) 2 mg

in treatment-naïve patients with macular edema

secondary to CRVO results in

rapid and sustained gains in

visual acuity, said Jean-Fran-

cois Korobelnik, MD.

The efficacy and safety of

aflibercept for the treatment

of macular edema second-

ary to CRVO is being inves-

tigated in twin international studies—GALI-

LEO and COPERNICUS. Dr. Korobelnik, pro-

fessor of ophthalmology, University Hospital

Bordeaux, France, presented outcomes from

the GALILEO study that enrolled 177 patients

at 62 centers in Europe and Asia.

Eligible patients had central retinal thick-

ness (CRT) of at least 250 μm and ETDRS best-

corrected visual acuity (BCVA) ranging from

20/40 to 20/320. They were randomly assigned

at baseline 3:2 to receive aflibercept 2 mg every

4 weeks (n = 106) or sham injection (n =

71). After 24 weeks, patients were treated as

needed according to pre-specified re-treatment

criteria, and after 52 weeks, sham patients be-

came eligible for treatment with aflibercept.

P R I M A R Y , S E C O N D A R Y

E F F I C A C Y A N A L Y S E S

The proportion of eyes at 24 weeks with a

BCVA gain from baseline of 3 or more lines

was analyzed as the primary efficacy endpoint

and showed a significant difference favoring

the aflibercept arm over the sham-treated con-

trols (60% versus 22%). Secondary efficacy out-

comes pertaining to functional and anatomic

improvements also showed a significant treat-

ment benefit, and adverse event data showed

aflibercept had a favorable safety profile.

GALILEO and COPERNICUS studies are the

last studies in CRVO with placebo control arms

in CRVO. In the future, this will not be ethical, as

anti-vascular endothelial growth factor (VEGF)

agents have demonstrated a strong benefit com-

pared with natural history, Dr. Korobelnik noted.

The two treatment arms in GALILEO were

similar in baseline characteristics. Patients had

a mean age of about 60 years and there was a

slight predominance of men. Mean BCVA was

about 52 letters; mean CRT was 639 μm in the

sham arm and 683 μm in the aflibercept patients.

Eighty percent of sham patients completed

follow-up at week 24 as did 91.5% of aflibercept

patients. Mean change from baseline BCVA was

18 letters for the aflibercept arm versus 3.3 let-

ters in the control group. Mean change in CRT

was more than two-fold greater in the afliber-

cept arm compared with the controls, and the

proportion of eyes with a dry retina (CRT <250

μm) was about three-fold higher for the active

versus sham group (80% versus 26%). Analyses

of time to first sustained 15-letter gain in BCVA

and time to first sustained dryness were also

highly in favor of the aflibercept arm.

“The most frequent ocular serious adverse

events in the aflibercept arm were macular edema

and reduced visual acuity, but these events are

related to the disease being treated rather than

to the anti-VEGF treatment. There were no APTC

events reported,” Dr. Korobelnik said. Q

New kid on the blockPivotal trial results demonstrate efficacy of newest anti-VEGF agent in treating CRVO-related macular edema

Dr. Korobelnik

By Cheryl Guttman Krader; Reviewed by Jean-Francois Korobelnik, MD

Titration can also be fine-tuned to allow treat-

ment over the entire macula. We are currently

titrating to 50% energy, but experimentation is

still in the early stages, and there is the possibility

of greater reductions and going to lower levels.

While it is not at this point yet, there is even po-

tential to be able to treat directly over the fovea.

This is a very exciting time in the develop-

ment of laser therapy, and there are phenom-

enal possibilities for the future of combined

treatment algorithms. The more precision we

have with our laser treatments, the greater

our ability will be to fine tune treatment and

achieve even better results. If photostimulation

continues to show that it is a safe and effective

modality, we may even see the use expanded

as a compliment to other treatment modali-

ties for diseases such as branch retinal vein

occlusion, central serous choroidopathy and

other pathologies that involve fluid leakage. Q

References1. Early Treatment Diabetic Retinopathy Study Research

Group. Treatment techniques and clinical guidelines

for photocoagulation of diabetic macular edema.

Early Treatment Diabetic Retinopathy Study Report

Number 2. Early Treatment Diabetic Retinopathy Study

Research Group. Ophthalmology. 1987;94:761-774.

2. Diabetic Retinopathy Clinical Research Network.

Randomized trial evaluating ranibizumab plus prompt

or deferred laser or triamcinolone plus prompt

laser for diabetic macular edema. Ophthalmology.

2010;117:1064-1077.

3. Sramek C, Mackanos M, Spitler R, et al. Non-damaging

retinal phototherapy: dynamic range of heat shock

protein expression. IOVS. 2010;52:1780-1787.

4. Vujosevic S, Bottega E, Casciano M, Pilotto E,

Convento E, Midena E. Microperimetry and fundus

autofluorescence in diabetic macular edema:

Subthreshold micropulse diode laser versus modified

early treatment diabetic retinopathy study laser

photocoagulation. Retina. 2010;30:908-916.

5. Luttrull JK, Sramek C, Palanker D, Spink CJ, Musch

DC. Long-term safety, high-resolution imaging, and

tissue temperature modeling of subvisible diode

micropulse photocoagulation for retinovascular macular

edema. Retina. 2012;32:375-386.

DME( Continued from page 25 )

JEAN-FRANCOIS KOROBELNIK, MD

E: jean-francois.korobelnik@chu-bordeaux.fr

Dr. Korobelnik is a consultant and advisory board member for Bayer. The 6-month

results of the GALILEO Study were published online in January 2013 (Holz FG, et

al. VEGF Trap-Eye for macular oedema secondary to central retinal vein occlusion:

6-month results of the phase III GALILEO Study. Br J Ophthalmol. 2013 Jan 7. [Epub

ahead of print]). This article was based on Dr. Korobelnik’s presentation at the 2012

meeting of the American Academy of Ophthalmology.

PRAVIN U. DUGEL, MD, is managing partner, Retinal

Consultants of Arizona, Phoenix, and clinical associate professor,

Department of Ophthalmology, Doheny Eye Institute, University

of Southern California, Los Angeles. He has no financial interest

in Topcon Medical Laser Systems.

Education Research Technology Public Health Brien Holden Vision Institute Foundation (formerly ICEE) is a Public Health Division of Brien Holden Vision Institute

Brien Holden Vision Institute is one of the largest DQG�PRVW�VXFFHVVIXO�QRQ�SURÀW�VRFLDO�HQWHUSULVHV�in the history of eye care. By applying commercial strategies to vision research and product development the Institute has generated income for research and public health programs that provide quality eye care solutions and sustainable services for the most disadvantaged people in our world.

The concern for the devastating shortfall in eye care education in developing communities, especially for correction of refractive error, became action in 1998 for those at the Institute. The lack of training institutes and educational opportunities was creating a human resource gap and a critical eye care shortage for hundreds of millions of people in need of services. The concern and willingness to address the issue gave rise to the International Centre for Eyecare Education (ICEE).

Almost 15 years later, and acknowledging that 640 million people are still without access to

visionfor everyone...

everywhere

brienholdenvision.orgShare the vision

permanent eye care, concern has galvanised into action again. To advance the process of addressing the challenge, both ICEE and Brien Holden Vision Institute will more closely align, share one common purpose and one name.

Together, we believe if we harness our efforts and broaden our scope we can achieve much more.

Together, we aim to drive, innovate, educate, collaborate, advocate and negotiate what is needed so that hundreds of millions, even billions, of people worldwide can enjoy the right to sight. Whether it’s research to develop the technology to slow the progress of myopia, investment in new systems for diagnosis of disease, delivery of sustainable access to services or provision of eye care education in the most marginalised and remote communities in the world, the Institute will focus on the quality of vision people experience and equity in eye care access worldwide.

We believe in vision for everyone...everywhere.

The Durban community in South Africa, arrives in hundreds to support the Brien Holden Vision Institute’s initiative Drive for Sight,

part of the World Sight Day celebrations in October 2012. All attendees were offered free eye examinations, access to free or

affordable low cost spectacles and referrals for further eye care where necessary. Photo by Graeme Wyllie.

SAN FRANCISCO ::

THE BASELINE FEATURES that are

positive predictors of pharmacologic resolution

of vitreomacular adhesion (VMA) following

ocriplasmin treatment (Jetrea, ThromboGen-

ics) are smaller adhesion base

size, absence of an epiretinal

membrane (ERM), presence of

a full-thickness macular hole,

patient age below 65 years,

and phakic status.

Subhransu K. Ray, MD,

PhD, outlined the results of

the phase III Ocriplasmin Pro-

gram on behalf of the MIVI-Trust Study Group.

“Two treatment options are available for symp-

tomatic VMA: observation or vitrectomy,” said

Dr. Ray, a partner at Bay Area Retina Associ-

ates in northern California, and an associate

clinical professor of Ophthalmology, Univer-

sity of California, San Francisco.

However, in October 2012, the FDA approved

the use of ocriplasmin to treat symptomatic

VMA. The drug targets fibronectin and lam-

inin and induces liquefaction and subsequent

release of the VMA, Dr. Ray explained.

M I V I - T R U S T S T U D I E S

Ocriplasmin was tested clinically in two phase

III trials (MIVI-006 and MIVI-007) in a total of

652 patients. The patients received either one

intravitreal injection of ocriplasmin or a placebo

injection of saline. The primary endpoint was

the effectiveness at 28 days after the injection.

The MIVI-Trust Study group then conducted

additional analyses to determine which base-

line features were predictive of the most suc-

cessful VMA release rates, Dr. Ray explained.

“The positive predictors of VMA resolution

are adhesion size <1,500 μm, the absence of

an ERM, presence of a full-thickness macular

hole, patient age below 65 years, and phakic

status,” he said.

The combined data from both MIVI-Trust

studies showed that across all populations,

ocriplasmin treatment induced a higher rate

(26.5%) of VMA resolution compared with pla-

cebo (10.1%).

“This corresponded to a significant improve-

ment in the number of patients who gained 2

or more lines of best-corrected visual acuity

[BCVA] 6 months after treatment,” Dr. Ray said.

“The number of patients who gained 3 or more

lines of BCVA vision was also sustained at the

6-month time point in those who

achieved VMA resolution, compared

with patients who did not achieve

VMA resolution.”

P R E D I C T I V E F A C T O R S

Non-anatomic predictive baseline fac-

tors were treatment group and age.

Analysis showed, not surprisingly,

that treatment with ocriplasmin re-

sulted in a higher rate of VMA release.

Similarly, age below 65 years was

a positive predictor of higher rates

of VMA resolution. However, even

among the patients who were over 65

years of age, the rate of VMA release

was also significantly (p < 0.001)

higher among the patients treated with

ocriplasmin compared with placebo

(22.1% versus 6.2%, respectively).

Detailed analysis of the anatomic features also

revealed the impact of ocriplasmin on VMA re-

lease. Ocriplasmin treatment resulted in a rate

of VMA release of 50% among patients with a

full-thickness macular hole. However, even in

patients who did not have a full-thickness mac-

ular hole, the VMA release rate was higher in

patients treated with ocriplasmin as compared

with placebo (19.6% versus 5.0%, respectively).

“This overall resulted in a four-fold higher

rate of macular hole closure rate in those pa-

tients treated with ocriplasmin (40.6% versus

10.6%, respectively),” Dr. Ray said. At 6 months,

76.7% of patients with macular hole closure

had a sustained and significant improvement

in visual acuity of at least two lines and 51.2%

had at least a three-line gain in visual acuity.

Adhesion size <1,500 μm resulted in VMA re-

lease in 34.7% of treated patients compared with

14.6% of those randomly assigned to placebo.

Nevertheless, even in patients with adhesions

exceeding 1,500 μm, 5.9% achieved VMA release

when treated with ocriplasmin as compared with

0% among the placebo-treated patients.

The absence of an ERM was an overwhelm-

ing positive predictor for successful VMA re-

lease following ocriplasmin treatment; 34.7%

of patients without ERM had VMA release with

ocriplamin versus 14.3% with placebo. Once

again, though, even in those with an ERM,

ocriplasmin resulted in a higher

VMA release compared with pla-

cebo (8.7% versus 1.5%), though

at an overall lower rate.

The adverse events associated

with ocriplasmin treatment in-

clude significant rates of vitre-

ous floaters, photopsia, blurred

vision, transient visual acuity de-

crease, transient visual impair-

ment, retinal edema, and macular

edema. Many of these might be

attributed to the process of VMA

release itself and not specifically

to an unrelated adverse effect of

the drug, Dr. Ray noted.

“When determining whether

to incorporate this treatment into

your clinical practice, it is im-

portant to note that ocriplasmin had a posi-

tive effect across all VMA subgroups,” he said.

“Specific baseline features were predictive of

a higher success rate.

“Each patient must be evaluated and edu-

cated about the relative benefits of the three

treatment options available for symptomatic

VMA, namely, observation, ocriplasmin, and

vitrectomy,” Dr. Ray concluded. Q

High resolution rates seen for VMAOcriplasmin joins observation, vitrectomy as treatment options for vitreomacular adhesionBy Lynda Charters; Reviewed by Subhransu K. Ray, MD, PhD

Dr. Ray

take-home High success rates

of vitreomacular

adhesion release using

ocriplasmin (Jetrea,

ThromboGenics) are

associated with smaller

adhesion size, absence

of an epiretinal

membrane, presence

of a full-thickness

macular hole, patient

age below 65 years,

and phakic status.

28 MARCH 1, 2013 :: Ophthalmology Times

RETINASpecial Report )

SUBHRANSU K. RAY, MD, PHD

E: retina01@gmail.com

Dr. Ray has no financial interest in the subject matter. This article was adapted

from Dr. Ray’s presentation during Retina 2012 at the annual meeting of the

American Academy of Ophthalmology.

19.6% vs 5.0% VMA release rate was higher in

patients treated with ocriplasmin

as compared with placebo

LUK H. VANDENBERGHE, PHD

E: luk_vandenberghe@meei.harvard.edu

Dr. Vandenberghe is a co-founder of GenSight Biologics, which may develop the discussed therapy, and

holds patents with GlaxoSmithKline and ReGenX Biosciences. This article was adapted from Dr. Vandenber-

ghe’s presentation during Retina 2012 at the annual meeting of the American Academy of Ophthalmology.

BOSTON ::

A NEW LABORATORY development

may be the key to a new therapy for retini-

tis pigmentosa (RP).

Luk H. Vandenberghe, PhD, discussed the

progress in optogenetics.

“In most cases, RP results

in the loss of photorecep-

tors due to a single gene

defect,” said Dr. Vanden-

berghe, a lecturer in oph-

thalmology, Schepens Eye

Research Institute, Massa-

chusetts Eye and Ear Infirmary, Harvard

Medical School, Boston.

“There are two main strategies to address

RP, i.e., protective means and restorative

means,” he said. “Ideally, we

would like to be at the inter-

face of the two.”

Optogenetic therapy for RP,

according to Dr. Vandenberghe,

is the re-sensitization of the ret-

ina to light by the introduction of

a genetically encoded molecular

light sensor that is coupled to

the neural circuitry of the de-

generated retina for functional

restoration of light perception

and ultimately vision.

The restorative methods that

have been attempted previously

that are currently in clinical trials involve

retinal implants, cell replacement, and gene

augmentation.

“All of these have advantages and disad-

vantages,” Dr. Vandenberghe said. “Using

optogenetics, we are aiming to overcome

some of the limitations of these strategies,

such as the retinal coupling needed for

implanted devices, grafting required for

photoreceptor cell replacement, and a one

gene/one drug regimen and a small win-

dow of intervention associated with gene

augmentation.”

Three molecules—melanopsin, channel-

rhodopsin, and halorhodopsin—are studied

to re-sensitize the retina to light.

“These have created a great deal of ex-

citement in the field of neuroscience,” Dr.

Vandenberghe said. “Upon the influx of

light, a neuron that expresses one of these

molecules is triggered.”

Channelrhodopsin, for example, is a chan-

nel protein that opens when light hits it and

depolarizes the cell, he explained.

A few approaches can be used to place

the molecules in the retina.

“The sensors can be placed either in ret-

inal ganglion cells or deeper in the retina

which would capture more of the endoge-

nous retinal processing capacity and may

restore a more natural form of vision,” he

said. “The molecules can be placed in am-

acrine cells, bipolar cells, or remnant cone

photoreceptors.”

While this endeavor may sound like sci-

ence fiction, Dr. Vandenberghe

said, “we have proof-of-concept

data for at least four strategies

in animal models, several of

which can restore fairly com-

plex vision.”

Optogenetics has a few lim-

itations and hurdles to over-

come that presently prevent ap-

plication in a clinical setting.

These include overcoming the

host immune response, creation

of possible undesirable forms of

vision, the sensitivity and dy-

namic range of the molecules

that require a great deal of light and are

only active in about one or two orders of

magnitudes compared with normal vision

that can adapt to seven orders of magnitude,

pupillary reflex, and nystagmus.

Dr. Vandenberghe pointed out that ini-

tially the therapy will be combined with a

head-mounted display device that will ac-

tivate the gene therapy in the retina. The

patient or a computer will be able to modu-

late the increased sensitivities and adapta-

tion to the surrounding light environment.

This technology is presently in the

preclinical stage in primate and animal

safety studies.

“We need four fairly developed fields to

come together: retinal gene therapy, reti-

nal circuitry, improved optogenetics, and

engineering,” he concluded. Q

Optogenetics a new approach to RPNovel method brings back light perception, possibly vision, to patientsBy Lynda Charters; Reviewed by Luk H. Vandenberghe, PhD

Dr. Vandenberghe

Optogenetics, the brainchild of Botond Roska, from the

Friedrich Miescher Institute for Biomedical Research,

Basel, Switzerland, may hold the key to therapy for

patients with retinitis pigmentosa.

The principal players in this technologic tool set are

the molecules melanopsin, channelrhodopsin, and

halorhodopsin. All three molecules share the same

activity, that is, when exposed to light, a single molecule

can engage the phototransduction cascade in a neuron,

according to Luk H. Vandenberghe, PhD.

1. Melanopsin is derived from vertebrates. Retinal ganglion

cells use this for circadian rhythm and pupillary reflex.

2. Channelrhodopsin is derived from algae (Chlamydomonas

reinhardtii). The molecule, a channel protein, opens when

exposed to light and depolarizes the cell.

3. Halorhodopsin is derived from archaebacteria

(Natronomonas pharaonis). This molecule has a

hyperpolarizing effect.

Both halorhodopsin and channelrhodopsin have a role

in phototropism, which is the movement of single-cell

organisms toward light.

Importantly, the deeper into the retina the molecules

are placed, the more retinal processing that can be

captured. The same tools are used as those that have

been clinically validated in gene therapy trials, that is,

the sensors can be put into retinal ganglion cells by an

intravitreal approach, in amacrine cells or bipolar cells

using an intravitreal or subretinal approach, and in residual

photoreceptor cells by a subretinal approach. “The hope

is to achieve a more natural vision,” he commented.

Three biotech ventures are interested in this technology

and helping to move it forward: Retro Sense, EOS

Neuroscience, and GenSight. Q

Potential for light perception for patients with RP

take-home Optogenetic therapy

is the re-sensitization

of the retina to light

by the introduction of

a genetically encoded

molecular light

sensor coupled to the

neural circuitry of the

degenerated retina.

MARCH 1, 2013 :: Ophthalmology Times

RETINASpecial Report )

29

This activity is supported by an unrestricted educational grant from Bausch + Lomb

Release Date: March 1, 2013 Expiration Date: March 1, 2014

Learning Objectives

�� Select the most appropriate topical ocular anti-LQIHFWLYH�RU�DQWL�LQÁDPPDWRU\�DJHQW�IRU�WKH�treatment of ocular infection or post-surgical LQIHFWLRQ�SURSK\OD[LV�EDVHG�RQ�ULVN�EHQHÀW�GDWD

�� Identify existing as well as emerging treatment options for pre- and post-ocular surgery prophylaxis and treatment

Ophthalmologist Accreditation

The Institute for Continuing Healthcare Education is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Institute for Continuing Healthcare Education designates this enduring material for a maximum of 0.75 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Optometrist Accreditation

7KLV�FRXUVH�LV�&23(�TXDOLÀHG�IRU�����KRXU�RI �&(�credit. Please check with your state licensing board to see if this approval counts toward your actual SC requirements for relicensure. (COPE-ID # 36478-SP)

Claiming Credit

3OHDVH�JR�WR�ZZZ�LFKH�HGX�H\H���WR�FODLP�$0$�RU�COPE credit. You will be directed to a host site for further instruction. A complete set of references can also be found online.

Disclosures

Relationships are abbreviated as follows: E, Educational Planning Committee; G, Grant/research support recipient; A, Advisor/review panel member; C, Consultant/Independent Contractor; SS, Stock shareholder; SB, Speaker bureau; PE, Promotional Event Talks; H, Honoraria; O, Other.

Faculty

Eric D. Donnenfeld, MD, FACS: Allergan Inc., Bausch + Lomb, Alcon/C

Mark T. Dunbar, OD, FAAO: Allergan, Carl Zeiss Meditec, Inc., Alcon Nutritional, ArticDX /A, C, SB; Reed Exposition (Vision Expo)/A, C

Marc R. Bloomenstein, OD, FAAO: Allergan Inc., RPS, AMO/A, AOA/E; Bausch + Lomb, Allergan Inc., Odyssey/G; Alcon, Bausch + Lomb, ISNA, RPS, Odyssey, Reichert/SB

Clark Springs, MD: Alcon, Merck/A

Peer Reviewer

Donald L. Budenz, MD, MPH: Alcon, Santen/A, Alcon, Allergan Inc., Alimera/C, Merck, Lumenis/SB

Medical Writer

Dominique W. Brooks has no relationships to disclose.

Activity Development and Management Team

Cathy Pagano, CCMEP; Allison A. Muller, Pharm.D, D.ABAT; Scott Kober, MBA, CCMEP; April Reynolds, MS, ELS; Sandra Davidson; and Tina Chiu, MEd are employees of the Institute and have no relationships to disclose.

Off-Label Product Disclosure:

This educational activity includes discussion of published and/or investigational uses of agents that are not indicated by the U.S. Food and Drug Administration. Please refer to WKH�RIÀFLDO�SUHVFULELQJ�LQIRUPDWLRQ�IRU�HDFK�product for discussion of approved indications, contraindications, and warnings.

Infection and Inflammation Associated with Ocular Surgery

is a 55-year-old man who has noted a gradual decrease in vision in his right eye over the past year. He has no history of any ocular disease or systemic health problems, such as diabetes or high

blood pressure. Slit lamp examination shows a moderate nuclear sclerotic cataract in his right eye, and vitreous and retinal examinations are within normal limits. He is interested in cataract surgery. The potential risks of surgery are discussed with him as well as any dangerous symptoms that may occur after the procedure, such as decreased vision, red eye, pain, and discharge. These could all be signs of infection or other potentially dangerous visual complications.

EndophthalmitisEndophthalmitis is a serious and vision-threatening ocular complication that can occur after a surgical procedure, trauma, or a systemic infection.���,W�LV�DQ�LQÁDPPDWRU\�FRQGLWLRQ�RI �WKH�DTXHRXV�RU�YLWUHRXV�cavities caused by a bacterial or fungal agent; however, noninfectious endophthalmitis can also be caused by toxic agents, pharmacologic treatments, or post-operative retained native lens material.2,3

While endophthalmitis is always a risk associated with ocular surgery, it is rare and varies with the type of surgery performed���VHH�7DEOH�����$�VWXG\�E\�.HD\�HW�DO�IRXQG�WKDW�WKH�RYHUDOO�LQFLGHQFH�RI �HQGRSKWKDOPLWLV�LQ������ZDV������SHU�������VXUJHULHV������&,�������������DQG�GHFUHDVHG�WR������SHU�������VXUJHULHV������&,�������������LQ������4

A.L.

cmearticle series

Table 1. Incidence of Endophthalmitis by Surgical Procedure

Surgical Procedure Incidence

Aqueous shunt surgery or trabeculectomy5 1% to 3% and 0.3% to 1.8%, respectively

Pars plana vitrectomy6 0.011% to 0.039%

Cataract Surgery7 0.028%

Penetrating keratoplasty7 0.108%

LASIK8 Post-operative infections are rare

Photorefractive keratectomy 9 Rare and usually involves an infectious keratitis, not endophthalmitis

Diagnosing endophthalmitis quickly is important to preserve vision.� Obtaining an accurate history – including any surgical procedures or LQIHFWLRQV��VXFK�DV�HQGRFDUGLWLV�²�LV�WKH�ÀUVW�VWHS�in diagnosis. The course of the condition may vary based on the cause of the infection; for example, bacterial causes generally present more acutely, while fungal infections may take several days before becoming evident.2 Symptoms of HQGRSKWKDOPLWLV�LQFOXGH�D�UHG�DQG�LQÁDPHG�H\H��vision loss, photophobia, eye pain, and ocular discharge. Eyelid swelling and headache may also be present. An ocular examination may show keratic precipitates, anterior chamber cell and ÁDUH��DQG�D�VLJQLÀFDQW�YLWULWLV�LQ�WKH�DIIHFWHG�H\H�and/or a hypopyon in the anterior chamber.���

Disease progression due to endophthalmitis may lead to corneal perforation, vision loss or phthisis bulbi.� Treatment depends upon the causative organism and may include a diagnostic vitreous tap or vitrectromy with intravitreal injections of antimicrobial agents. Treatment may also include V\VWHPLF�DQWLELRWLFV�VXFK�DV�RUDO�ÁXRURTXLQRORQHV��YDQFRP\FLQ��D�FHSKDORVSRULQ��ÁXFRQD]ROH��or amphotericin B. Treatment should begin immediately after cultures are obtained depending on the suspected cause of the condition.2 If the condition does not improve after treatment is initiated, clinicians should obtain repeat anterior chamber or vitreous samples to determine the

causative organism, if possible, because knowing the causative organism is essential in directing treatment.����� Since the outcome of endophthalmitis can be poor, prevention before and after the surgery often serves as the best defense.�

Toxic Anterior Segment SyndromeToxic anterior segment syndrome (TASS) is a post-operative condition caused by an LQÁDPPDWRU\�UHDFWLRQ�WR�D�QRQLQIHFWLRXV�substance that enters the eye during a surgical SURFHGXUH��7$66�W\SLFDOO\�RFFXUV�ZLWKLQ���to 2 days after cataract or anterior segment surgery; signs are limited to the anterior segment of the eye.�� Cultures taken from the eye are always negative after gram staining, and blurred vision and ocular pain are often present. On examination, there is usually severe DQWHULRU�VHJPHQW�LQÁDPPDWLRQ��RIWHQ�ZLWK�D�hypopyon and profound corneal edema. The iris and trabecular meshwork may also become permanently damaged in TASS, which may lead to an irregularly shaped pupil or elevated intraocular pressure.�� TASS typically responds to aggressive corticosteroid therapy.��

Iritis/UveitisPreexisting or undiagnosed uveitis can be exacerbated by ocular surgery. Uveitis is LQÁDPPDWLRQ�RI �WKH�XYHDO�WUDFW��ZKLFK�LQFOXGHV�the iris, ciliary body, and the choroid. Most

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s� 0ROPHYLACTIC�ANTIBIOTICS�CAN�BE�GIVEN�TOPICALLY�BEFORE�AND�AFTER�OCULAR�SURGERY��

s� &OR�SOME�SURGERIES��SUCH�AS�CATARACT�SURGERY��ANTIBIOTICS�MAY�BE�GIVEN�INTRACAMERALLY�DURING�THE�PROCEDURE��

s� ,ID�SCRUBS�CAN�LOWER�BACTERIAL�CONCENTRATIONS�AND�MAY�BE�BENEFICIAL�FOR�MOST�OCULAR�PROCEDURES�

cases are idiopathic, but a thorough history is necessary to ascertain whether further work-up is needed. Symptoms of anterior uveitis include pain, blurred vision, and photophobia. Posterior uveitis is associated with blurred vision and is not typically associated with pain or photophobia.�� Treatment for both types of uveitis consists of corticosteroid use (topical and systemic) and cycloplegics for anterior uveitis.�� Intravitreal injections of corticosteroids and sustained-release corticosteroid implants are also available. Other immunotherapies, such as anti-TNF alpha agents, can also be used.��

Other Causes of Vision Loss After Ocular SurgeryIn the days after an ocular surgery, other FRQGLWLRQV�VXFK�DV�SRVW�RSHUDWLYH�LQÁDPPDWLRQ�and vitreous hemorrhage may also present with similar symptoms to endophthalmitis. Surgical WUDXPD�FDQ�FDXVH�DQ�LQÁDPPDWRU\�FDVFDGH�WKDW�JHQHUDWHV�SURVWDJODQGLQV��ZKLFK�FDQ�LQÁXHQFH�intraocular pressure, cause miosis, and increase vascular permeability, thereby increasing the levels of protein in the aqueous.��

3RVWRSHUDWLYH�LQÁDPPDWLRQ�XVXDOO\�UHVSRQGV�WR�topical ocular corticosteroids and/or nonsteroidal medications.���/DUJH�DPRXQWV�RI �LQÁDPPDWLRQ�can be confused with infectious endophthalmitis and may be treated as such. With vitreous hemorrhage, the patient complains of decreased YLVLRQ��ÁRDWHUV��SKRWRSKRELD��DQG�LPDJHV�RI �cobwebs, but generally no pain��; however, since the patient is postoperative, he or she may actually have some discomfort from the procedure not associated with the hemorrhage. On examination, the clinician will be able to see hemorrhage in the posterior chamber. This may not be the complete diagnosis in every case, as endophthalmitis may have an unusual presentation (such as vitreous hemorrhage), but there are typically other ÀQGLQJV��VXFK�DV�D�SRVLWLYH�VPHDU�RU�FXOWXUH��WKDW�point to the proper diagnosis.��

Endophthalmitis Prevention StrategiesSince treatment of endophthalmitis may not yield positive ocular outcomes, prevention before and after surgery has become a hallmark of ophthalmic treatment regimens.5 It is commonly DFFHSWHG�WKDW�WKH�SDWLHQW·V�SHUVRQDO�ÁRUD�LV�responsible for most cases of postoperative infection.20 Lid cleaning prior to surgical procedures may lower the amount of bacteria available to cause infection, as evidenced in a study by Bucci and colleagues that found that a combination of lid scrubs and antibiotics lowered the amount of bacteria around the eye prior to cataract surgery.�� Lid hygiene prior to surgery can EH�EHQHÀFLDO�LQ�DOO�VXUJLFDO�SURFHGXUHV��HVSHFLDOO\�if the patient has blepharitis or meibomian gland dysfunction, which may increase the levels of bacteria on the eyelids.22,23 Application of both preoperative and postoperative topical antibiotics, WKH�XVH�RI ����SRYLGRQH�LRGLQH�LQ�WKH�RFXODU�FXO�GH�VDF�DQG�����SRYLGRQH�LRGLQH�RQ�WKH�periocular skin, as well as sterile draping in the operating room, are all potential ways to lower the rates of infection.23

Many clinicians have preferences for antibiotic use, but newer antibiotics such as ÁXRURTXLQRORQHV�PD\�KDYH�FOLQLFDO�EHQHÀW�GXH�to a broader spectrum of action.24 Whatever the choice, the selected antibiotic should be active DJDLQVW�JUDP�SRVLWLYH�EDFWHULD�DQG�KDYH�VXIÀFLHQW�bioavailability for absorption.���0R[LÁR[DFLQ��JDWLÁR[DFLQ��EHVLÁR[DFLQ��DQG�OHYRÁR[DFLQ�DOO�UHGXFHG�RFXODU�ÁRUD�EDFWHULD�OHYHOV�LQ�QRQFOLQLFDO�DQG�clinical trials.25,26 %HVLÁR[DFLQ�PD\�SURYLGH�DGGLWLRQDO�FRYHUDJH�IRU�RFXODU�SDWKRJHQV�VXFK�DV�FLSURÁR[DFLQ��and methicillin- resistant staphylococci.27

Some clinicians start topical antibiotics at least one day before ocular surgery, while others may give multiple drops at the time of the procedure.28 There has been some debate as to whether starting antibiotics days before the procedure HUDGLFDWHV�EDFWHULDO�ÁRUD�DV�FRPSDUHG�ZLWK�RQO\�one day before the surgery or when compared with use of povidone-iodine alone.����� Despite this debate, many clinicians use topical antibiotics prior to most ocular procedures and continue antibiotic drops after the procedure. Research has shown that endophthalmitis typically occurs within one week after ocular surgery, so antibiotics are often continued for at least that long.25 Controlled studies evaluating prophylaxis IRU�HQGRSKWKDOPLWLV�KDYH�EHHQ�GLIÀFXOW�WR�complete partly because of the low incidence of the condition and the differences in practice

patterns among clinicians23; however, a large, randomized study of the European Society of Catraract and Refractive Surgery by Barry and colleagues evaluated intraocular antibiotics and found that intracameral cefuroxime administered DW�WKH�WLPH�RI �VXUJHU\�VLJQLÀFDQWO\�ORZHUHG�WKH�risk for developing endophthalmitis after cataract surgery.�� Other nonrandomized studies have also evaluated the effectiveness of intracameral antibiotic injections after cataract surgery, and a survey of cataract surgeons in Sweden suggested that intracameral cefuroxime may be responsible for the lower levels of endophthalmitis.32

Patient Case ConclusionTo lower the risk of endophthalmitis before cataract surgery, we started A.L. on a ÁXRURTXLQRORQH�GURS�RQH�GD\�SULRU�WR�WKH�cataract surgery. We also started him on a WRSLFDO�QRQVWHURLGDO�DQWL�LQÁDPPDWRU\�GUXJ�(NSAID) and steroid drop to lower the risk RI �LQÁDPPDWLRQ��3ULRU�WR�WKH�SURFHGXUH�LQ�WKH�operating room, povidone-iodine was used to clean the eyelid skin and was placed in the cul de sac as well. During the cataract extraction, intracameral cefuroxime was administered, and the surgery was a success. A.L. was instructed WR�FRQWLQXH�WKH�ÁXRUTXLQRORQH�GURS�4,'�IRU���weeks after the procedure in addition to topical NSAIDs and steroid drops.

s� 3EVERAL�OCULAR�CONDITIONS�MAY�PRESENT�LIKE�HERPETIC�KERATITIS��THUS��IT�IS�IMPORTANT�TO�MAKE��THE�APPROPRIATE�DIAGNOSIS�TO�DECREASE�THE�RISK�OF�OCULAR�DAMAGE�

s� #ORTICOSTEROIDS�MAY�WORSEN�ACTIVE�HERPETIC�KERATITIS�AND�SHOULD�BE�ADMINISTERED�IN��CONJUNCTION�WITH�AN�ANTIVIRAL�MEDICATION�AND�CLOSE�SUPERVISION�

s� 4RIFLURIDINE�AND�GANCYCLOVIR�CAN�BOTH�BE�EFFECTIVE�TREATMENTS��BUT�GANCYCLOVIR�CARRIES�LESS��CORNEAL�TOXICITY�AND�MAY�BE�PREFERABLE�FOR�LONG TERM�USE�

RefresherIn the previous article on herpetic keratitis, we learned the following key learning points:

Post-surgical endophthalmitis caused by gram-positive bacteria.

Close-up of the cornea showing large keratic precipitates on the endothelium in a patient with a 4+ anterior chamber reaction due to postoperative endophthalmitis.

Claiming Credit3OHDVH�JR�WR�ZZZ�LFKH�HGX�H\H���WR claim AMA or COPE credit. A complete set of references can be found online.

CHICAGO ::

A favorable regulatory and invest-

ment climate in ophthalmology

means that ophthalmologists and

patients can expect more expedi-

tious drug and device approvals

in 2013 and beyond, said speak-

ers at the recent Ophthalmology

Innovation Summit (OIS) held here.

For starters, experts expect recent FDA changes

to streamline the drug and device approval

process. In late 2012, as part of the FDA Safety

and Innovation Act (FDASIA), Congress autho-

rized the Medical Device User Fee Amendment

III and the Prescription Drug User Fee Amend-

ment. Both aim to increase FDA funding and

personnel to provide more timely reviews of

drug and device applications. These measures

expire in October 2017.

The FDA also has pledged to make specific

changes in areas ranging from staff levels and

training to how it communicates with appli-

cants—from pre-submission to post-marketing.

One executive who welcomes the changes

is Edward Peterson, president and chief exec-

utive officer (CEO) of AcuFocus Inc., which is

developing a device (Kamra) to increase depth

of focus for patients with presbyopia. Meet-

ings between AcuFocus representatives and

the FDA are always very productive, he said.

Afterward, he said, “You know exactly what

you need to do.”

However, he said, scheduling a meeting can

take 3 to 5 months.

“With more staff, the agency could host more

meetings with industry throughout the process,”

he said. “This kind of interaction between the

industry and the FDA has the potential to im-

prove the process dramatically.”

For example, Peterson said, being able to

work collaboratively throughout the investi-

gational device exemption and premarket ap-

proval submission process with the FDA’s input

upfront would improve the quality of submis-

sions and could further expedite the process.

Also, simply increasing the number of FDA

reviewers likely will help the agency process

applications faster, he added.

In 2012, said Malvina Eydelman, MD, direc-

tor of the FDA’s Division of Ophthalmic, Neu-

rologic, and Ear Nose and Throat Devices, the

FDA received 1,441 submissions, including 447

for ophthalmic devices.

C A P T U R I N G V E N T U R E

C A P I T A L

Overall, the FDA changes aim to increase the

accountability, predictability, and transparency

of the review process. Achieving these goals

will reduce the risk related to FDA submissions

and increase the availability of venture capital

in ophthalmology and other specialties, said

William Link, PhD, a Versant Ventures man-

aging director who specializes in early-stage

medical device investments.

Quinton Oswald, CEO of SARcode Biosci-

ence, added that how potential investors view

early-stage drug and device companies hinges

largely on the predictability of the FDA.

To that end, “For the FDA to provide earlier

and more frequent feedback is very helpful for

a company like mine,” he said.

Moreover, Dr. Link and Oswald said they

hope that increased funding especially will ben-

Innovation abounds at OIS

Regulatory and investment climate fosters drug, device opportunitiesBy Peter Sonnenreich, MA, and John Jesitus, MA

A favorable regulatory and

investment climate in ophthalmology

means that ophthalmologists and

patients can expect more expeditious

drug and device approvals in 2013 and

beyond, said speakers at the recent

Ophthalmology Innovation Summit.

TAKE-HOME

Continues on page 34 : Innovation

News Makers in Ophthalmology 2012

DATE COMPANY PRODUCT NEWS

10/12Sigma-Tau

Pharmaceuticals Inc. Cystaran

Approved by FDA for corneal

cystine crystal accumulation

10/12 Sarcode Bioscience SAR 1118 Successful phase III dry eye data

8/12 Roche LucentisApproved by FDA for diabetic

macular edema

7/12 LuxBio Sciences Luveniq Completed enrollment phase III study

6/12 Ophthotech Fovista

Statistically significant phase IIb

data (REGN dropped 12% on day

of data announcement)

2/12 Merck ZioptanApproved by FDA for lowering

of IOP

Source: Company filings and Wall Street research.

Ophthalmologists and

patients can expect

more expeditious drug

and device approvals

in 2013 and beyond.

general32 MARCH 1, 2013 :: Ophthalmology Times

general

PRGHUQPHGLFLQH�FRP�L7HFK5HVRXUFH�&HQWHU�IRU�7HFKQLFLDQ�(GXFDWLRQ

1

BUILDING THE OPHTHALMIC TECH’S COMMUNITY OF PRACTICE

What is it that almost

all of my ophthalmologist

and optometrist

colleagues lament not

having more of? No, not

shares in a Gold Exchange

Traded Fund. But close.

The correct answer is

something worth its

weight in gold — highly

skilled, knowledgable and

motivated ophthalmic

technicians.

We all know that there is a

nationwide shortage of trained

ophthalmic technicians. We also know

that excellent technicians have major

benefits in our practices. When we

partner with skilled technicians, we

can help more patients in less time, our

patient satisfaction scores are higher, and

we finish our work days happier and less

fatigued. We do more things that our

years of specialized training permit us to

do, and less things that a motivated and

well-trained technician can do at least as

f ot better).

Our lives are much, much better

when we have an ample supply of

engaged technicians in our practices, and

when we can retain them long term.

So we need to keep them happy. As is

typical of most employees, technicians

are happiest when they know they are

valued and in a position that allows them

the opportunity to constantly learn and

enhance their skills.

Toward this end, Advanstar

Communications is pleased to present

a series of educational offerings that

you will hopefully eagerly bring to the

attention of your technicians. These will

help with learning new skills, refining

and improving upon previously learned

information, instructional case studies,

and pearls on how to work effectively

with their doctors to enhance the

practice. And, coming soon, an online

community will afford the opportunity

to connect with and share best practices

with colleagues.

In my opinion, these materials help

address an important unmet need for

our technicians. Aware that they are

constantly learning and growing in

their careers, mastering new skills and

becoming more effective at working with

their doctors and enhancing our practices,

they will ideally experience more job

satisfaction and want to remain long-

term partners in our practices. ◗

SUPPLEMENT TO

AND

OCULAR

ALLERGIE

S

The incredibly mild winter

that much of the United States

experienced may mean that

ophthalmic technicians are going

to be on the front line helping

to manage a wave of patients

with ocular allergies.

The iTech program

is dedicated to

burnishing the

skills, knowledge

and community

of ophthalmic

technicians

everywhere, to

broaden their

comprehension

of their physician-

colleagues’ practice

and patient care

behaviors, and to

ensure technicians’

skills mastery and

growing value in an

ever more dynamic

and thriving eye

practice.

When we

partner

with skilled

technicians,

...Our lives

are much,

much better—Peter

McDonnell, MD

ence

Pho

to L

ibra

ry/S

TEVE

GSC

HMEI

SSNE

R/SP

L/JG

I/Jam

ie Gr

ill/B

lend

Imag

es

AnEye on

Page 2

Peter McDonnell, MD

A NEW EDUCATIONAL OFFERING

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efit the FDA device review process—because

its funding has fallen in recent years, while

its complexity and duration have increased.

Compared with drug approvals, Oswald noted,

the device process seemed to be “a moving

target. Every time people would try to satisfy

the FDA, something else—such as a need for

additional data—popped up.”

It’s too soon to tell whether beefier budgets

are facilitating smoother device reviews, Dr.

Link said. But already, as several of his com-

panies interact with Dr. Eydelman and her

staff, “I’m seeing improved responsiveness,”

he noted.

Since the FDASIA passed, added Richard L.

Lindstrom, MD, “The FDA and its representa-

tives are much more available, responsive, and

helpful in giving guidance to companies who

are trying to create clinical trials, or nearing

submission of clinical trial data. We are start-

ing to see some more rapid approvals as well.”

As founder and attending surgeon at Minne-

sota Eye Consultants, and adjunct clinical pro-

fessor emeritus at the University of Minnesota,

Department of Ophthalmology, Dr. Lindstrom

frequently consults with early-stage ophthal-

mology companies.

U N T A P P E D O P H T H A L M I C

O P P O R T U N I T I E S

Regarding financing, large pharmaceutical and

device companies, along with public share-

holders, would like more access to ophthalmol-

ogy, added Anthony J. Gib-

ney, managing director, East

Coast biopharma at Leerink

Swann LLC.

It offers healthy profit mar-

gins, the ability to launch

drugs ef fect ively with

smaller sales forces, and

a generally consistent FDA

evaluation process, which

builds confidence in clini-

cal trial data, he explained.

Accordingly, he said, the

receptivity of investors,

merger/acquisition experts,

and even regulators to oph-

thalmology creates very fer-

tile ground for innovation.

The global drug and

medical device market is

expanding modestly, with

sales growth expected to

match the rate of popula-

tion increase (15.8%) through

2017, Gibney said.

Meanwhile, ophthalmol-

ogy’s share of this market

will grow from 2% presently

to 2.3%, he predicted.

Ophthalmology’s modest market share high-

lights the specialty’s many untapped oppor-

tunities—namely, diseases that remain un-

treatable because treatments have not been

approved or, in some cases, even attempted,

Gibney said. Such indications one day may

dwarf wet age-related macular degeneration

(AMD), which represents nearly half of oph-

thalmology sales, he said, because wet AMD

treatments are largely biologics. Regarding

stock activity, he said, “It was a breakout year

for Regeneron, which posted a 166% jump in

its stock price in 2012. The vast majority of the

growth came from [aflibercept].”

Elsewhere, he said, the most commercially

relevant data to emerge in 2012 involved Fo-

vista (Ophthotech), which, in combination with

ran i biz u mab (Lucentis, Genentech) showed

significantly better visual gain over ran i biz-

u mab alone in a phase IIb study in wet AMD.

Fovista’s active ingredient blocks platelet-de-

rived growth factor-B.

Among products under development, SAR

1118 (SARcode) successfully completed a phase

III dry eye study. Conversely, voclosporin (Lu-

veniq, Lux Biosciences) failed in its phase III

trial for noninfectious uveitis. Q

DISCLOSURES

Dr. Lindstrom is medical director of Sightpath Medical and

Refractec, and chief medical officer of TLCVision. He serves

on the board of directors of AcuFocus, Encore, Refractec,

RevitalVision, TearLab, TLCVision, and Wavetec.

In addition to being president and CEO of AcuFocus,

Peterson serves on the board of directors for Accelerated

Vision Group and AqueSys.

Dr. Link's Versant investments include AcuFocus, Cameron

Health, ForSight, Glaukos, Inogen, LenSx, NeoVista,

Neurotech Pharmaceuticals, Rox Medical, Second Sight,

and Wavetec.

MARCH 1, 2013 :: Ophthalmology Times

general34

INNOVATION( Continued from page 32 )

Source: Cowen Therapeutic Categories Outlook research report.

Ophthalmology Sales CURRENT vs. PROJECTED

IN 2011Drug sales

totalled

$486 BILLIONOF THAT

$10 BILLIONwere from

ophthalmology

drug sales

THAT'S 2%

IN 2017Drug sales are

projected to hit

$563 BILLIONOF THAT

$13 BILLIONwill be from

ophthalmology

drug sales

THAT'S 2.3%

A PROJECT INCREASE OF 0.3%

2ND ANNUAL OPHTHALMOLOGY

INNOVATION SUMMIT

AT THE ASCRS MEETING

APRIL 18, 2013 IN SAN FRANCISCO

The Ophthalmology Innovation Summit

(OIS) unites leaders in the development

of ophthalmic products, drugs, and

devices. www.oisascrs.com

For $100 off the registration fee, use

the discount code OISOPT

5TH ANNUAL OPHTHALMOLOGY

INNOVATION SUMMIT

AT THE AAO MEETING

NOVEMBER 14, 2013 IN NEW ORLEANS

The purpose of OIS is to create an

ecosystem of clinical, technology, and

business. www.oisaao.com

For an executive summary on

the 2012 OIS AAO meeting, see

ophthalmologytimes.com/ois

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SALT L AKE CI T Y ::

Femtosecond laser capsulotomies

provide significantly more pre-

dictable effective lens positions

(ELPs) compared with manual

procedures.

Robert J. Cionni, MD, discussed

the superiority of the femtosecond

laser for creating capsulotomies compared with

the conventional manual method and reopti-

mization of lens constants for accurate laser

refractive lens surgery.

“The capsulotomy does make a difference,”

said Dr. Cionni, medical director of The Eye In-

stitute of Utah, Salt Lake City. He cited a study

in which it was found that a 4-mm capsulotomy

tends to position an IOL slightly more posteri-

orly compared with a 6-mm capsulotomy. When

performing manual cases, the capsulotomies

will vary and so, too, will the

spherical refractive results.

Dr. Cionni also discussed a

non-randomized prospective

study in which he performed

all surgeries between March

and June 2011. One IOL (Acry-

Sof SN60WF, Alcon Laborato-

ries) was implanted in 48 pa-

tients, for 26 of whom he created a manual cap-

sulotomy and for 22 a laser capsulotomy using

the LenSx femtosecond laser system (Alcon). In

the manual group, he used a 5.75-mm Mastel

marker to guide a 5-mm capsulorhexis.

Patients were followed up at 1 and 6 months

postoperatively and the targeted refractions and

the uncorrected visual acuities were compared

between the two groups. He also measured

the true lens position in all patients using an

all-in-one optical biometer (LenSTAR LS 900,

(Haag-Streit). Dr. Cionni used a refractive ver-

gence formula (Jack Holladay, MD) to calcu-

late the predicted ELP and then compared that

with the true lens position.

When he compared the mean absolute error,

he pointed out that he had used a personal-

ized lens constant in both groups; however,

further optimization of the lens constant was

needed for both groups. He also compared the

regression of the preoperative anterior cham-

ber depth (ACD) with the true postoperative

ACD at both time points.

G O O D C O R R E L A T I O N

At 1 month postoperatively, the femtosecond

laser group had good correlation between the

predicted ELP and the true postoperative lens

position, Dr. Cionni noted. There was poor cor-

relation between the two in the manual group.

The results at 6 months were similar; there was

slightly less variability in the manual group at 6

months compared with the manual group at 1

month. However, the high correlation was seen only

in the femtosecond laser group (89%, R2 = 0.80,

p < 0.000 versus 41%, R2 = 0.17, p = 0.09).

“The mean absolute error was better in the

laser group compared with the manual group

(0.26 ± 0.16 versus 0.34 ± 0.21, respectively),”

Dr. Cionni said. “Significantly more patients

were within 0.25 D of the intended target in

the laser group compared with manual group

(77% versus 54%, respectively).”

When he evaluated the A-constant sepa-

rately, he found that the laser group had a

mean 0.05 increase in the A-constant and the

manual group had a 0.05 decrease.

M O R E V A R I A B I L I T Y

“This shows that in the manual group even

though the target is a 5-mm capsulotomy in

each case, there is more variability with some

capsulotomies smaller or larger than 5 mm

and some as large as 6 mm,” he said.

The calculated new prediction error at 1 month

still showed favorable results and predictability

that favored the laser group. Some improvement,

however, was seen in the manual group with

re-optimization of the A-constant, he noted.

This was also true at the 6-month evaluation.

“It was interesting that the manual group

had improved predictability and was close to

the target refraction at 6 months,” Dr. Cionni

said. “This demonstrated that there was a shift

in the lens position that was greater in the

manual group than the laser group.”

When he compared the ACDs preoperatively

and 1 month postoperatively, there was good

correlation in the laser group but not in the

manual group (87%, R2 = 0.76, p < 0.000 ver-

sus 12%, R2 = 0.0142, p = 0.56, respectively).

The results were similar at 6 months.

In terms of the uncorrected visual acuity, the

laser group fared better at all time points than

the manual group. At 1 month, 73% and 46%,

respectively, achieved 20/20 or better, and 82%

and 54% achieved 20/25 or better. The results

were similar at 6 months, although Dr. Cionni

noted some improvement in the manual group.

“The ELP is more predictable and more highly

correlated with the postoperative ACD in laser

capsulotomy compared with manual capsulot-

omy,” he concluded. “Optimization of the lens

constant is essential for better predictability of

the ELP, which means better refractive accu-

racy. The lens constant for laser cases should

be optimized separately from manual cases.” Q

Femtosecond laser capsulotomy:

Accuracy does make a difference

Procedure provides significantly more predictable effective lens positions, study findsBy Lynda Charters; Reviewed by Robert J. Cionni, MD

Femtosecond laser capsulotomies

provide significantly more predictable

effective lens positions compared

with manual procedures.

TAKE-HOME

ROBERT J. CIONNI, MD

Dr. Cionni is on the LenSx medical advisory board and a consultant to Alcon Labo-

ratories. This article was adapted from Dr. Cionni’s presentation during Refractive

Surgery 2012 at the annual meeting of the American Academy of Ophthalmology.

Dr. Cionni

77% vs 54%More patients were within 0.25 D

of the intended target in the laser

group compared with manual group

refractive36 MARCH 1, 2013 :: Ophthalmology Times

refractive

An investment sea change has

been occurring in the past

few years: Mutual fund inves-

tors have been shifting some or

all of their assets to passively

managed vehicles.1 For many,

exchange-traded funds (ETFs)

have become the vehicle of choice.

“An increasing number of investors are turn-

ing to ETFs to gain exposure to specific mar-

kets or to complement other holdings in their

portfolios,” said Mariana F. Bush, CFA, a senior

analyst with Wells Fargo Advisors.

Many of those investors have found plenty

to like in the rapidly maturing field of ETFs.

Since the first ETF was launched in 1993, the

field has grown to nearly 1,200 different ETFs,

with combined assets of $1.193 trillion as of

March 31, 2012, according to the Investment

Company Institute.2

T R A D E D L I K E A S T O C K

ETFs are a type of exchange-traded product

(ETP), which is essentially what it sounds like:

an investment that trades on exchanges. ETFs

are generally designed to mirror the perfor-

mance of certain market indexes, so they tend

to be passively managed. A few actively man-

aged ETFs exist, but when most people discuss

ETFs, they’re referring to the index-based type.

Like mutual funds, most ETFs are registered

investment companies. And like index mutual

funds, passively managed ETFs attempt to mir-

ror the performance of an index. Those indexes

may reflect exposure to domestic or interna-

tional markets; equity, fixed income, commod-

ity or currency markets; or a broad or narrow

exposure to those markets.

Unlike mutual funds, however, ETFs trade

on exchanges and can be bought and sold at

market prices throughout the day during mar-

ket hours, like stocks. ETFs typically list their

current holdings on a daily basis, whereas

mutual funds generally disclose their hold-

ings every quarter.

“This transparency and trading flexibility

are important to investors

who want to know how much

an ETF costs and what it is

investing in before they buy

or sell shares,” Bush pointed

out. “These advantages can

be particularly critical in

highly volatile markets,

since investors can place ETF

trades using limit and stop

orders to potentially mitigate

risk and minimize losses.”

ETFs can also offer an easy

way to gain exposure to par-

ticular areas of the market.

“Some investors just want to integrate a broad

mix of stocks, such as those included in the

S&P 500 index,” explained Bush. “Others are

interested in taking a targeted—but still cost-

efficient—approach to an investing theme, such

as the potential for a region, country or indus-

try to outperform the market. ETFs can offer

a way for an investor to achieve potentially

diverse exposure to that particular segment

of the market.”

O T H E R U S E S — A N D

C O N S I D E R A T I O N S

Another advantage of ETFs is that the invest-

ment minimum is one share.3 This makes it

easy for investors to try out investment themes

or create targeted allocations without a signifi-

cant investment of capital.

ETFs may be more tax-efficient than ac-

tively managed funds. ETFs may create and

redeem their shares in kind, rather than in

cash, which can help them avoid distributing

year-end capital gains the way many mutual

funds do. This is particularly true for more

seasoned and liquid ETFs.

But like any powerful tool, ETFs need to be

handled carefully. In particular, investors should

understand exactly what a given ETF holds and

how its underlying index really works during

particular market environments.

“For example, investors must understand

the different return components of futures-

based ETFs,” Bush cautioned. “The way fu-

tures contracts work is different from how

stocks behave. The same goes for ETFs that

involve leverage. They can magnify or min-

imize market movements, and the mecha-

nisms for how they do that can be complex.

Investors must understand the drivers of per-

formance (or causes of underperformance)

with those more complicated ETFs.”

You should take the time to understand ex-

actly what you’re buying and how it’s likely

to behave under different conditions. Work-

ing with your financial advisor to select ap-

propriate ETFs is likely to involve more than

just a review of performance and expenses.

Among other things, you’ll want to look at an

Are exchange-traded funds

the new mutual funds?

Latest investment vehicle offers the structure of a fund, but is traded like stockMoney Matters By John J. Grande, CFP; Traudy F. Grande, CFP; and John S. Grande, CFP

Investors should understand

exactly what a given ETF holds

and how its underlying index

really works during particular

market environments.

Investors are shifting assets to

passively managed vehicles. For

many, exchange-traded funds (ETFs)

have become the vehicle of choice.

ETFs are investments that trade

on exchanges, and are designed to

mirror the performance of certain

market indexes, so they tend to be

passively managed.

TAKE-HOME

Continues on page 38 : ETF

37MARCH 1, 2013 :: Ophthalmology Times

practice managementpractice management

JOHN J. GRANDE, CFP®; TRAUDY F. GRANDE, CFP®; AND

JOHN S. GRANDE, CFP®are co-editors of Money Matters. They are owners

Grande Financial Services Inc., Oakhurst, NJ, and registered principals of Wells

Fargo Advisors Financial Network Inc., member FINRA/SIPC.

The Grandes lecture at Johns Hopkins University School of Medicine, and they

advise ophthalmologists across the country on a diverse range of investment

and financial matters. Readers may submit their financial questions to them at

800/722-1258 or e-mail john.s.grande@wfafinet.com

Readers also may access the Grande’s website at www.grandefinancialservices.com

Investments in securities and insurance products are: Not FDIC-insured/not

bank-guaranteed/may lose value. [PCG / ISG:] Wells Fargo Advisors, LLC, Member

SIPC, is a registered broker-dealer and a separate non-bank affiliate of Wells Fargo

& Co. Investment products and services are offered through Wells Fargo Advisors

Financial Network, LLC (WFAFN), Member SIPC. Grande Financial Services Inc. is a

separate entity from WFAFN.

MARCH 1, 2013 :: Ophthalmology Times

practice management38

individual ETF’s exposure and how it fits into

the rest of your portfolio.

You’ll also want to examine a given ETF’s

liquidity. This tends to be less of an issue for

popular, heavily traded ETFs, but less liq-

uid ETFs may be thinly traded and difficult

to trade at a price that makes sense for your

investment strategy. Your financial advisor,

who has access to the traders, can guide your

trading execution.

ETFs may be an attractive option if you want

to diversify your portfolio with exposure to

additional asset classes and market sectors,

but it’s important for you to understand their

unique characteristics.

When asked directly whether she believes

ETFs are the new mutual funds, Bush answered

with a qualified, “yes.”

“For investors who take the time to under-

stand what ETFs can and can’t do and what

they hold, ETFs offer benefits that justify mak-

ing them a cornerstone of an individual’s port-

folio,” Bush said.

Shares of ETFs are bought and sold at

market price which may differ significantly

from the ETF’s net asset value and are not

individually redeemed from the fund. Only

“authorized participants” can purchase and

redeem directly in the funds creation units,

typically consisting of a block of 50,000 shares.

Ordinary brokerage commissions for pur-

chases and sales may apply which could

reduce returns.

Index-based ETFs seek investment results

that, before expenses, generally correspond

to the price and yield of a particular index.

There is no assurance that the price and

yield performance of the index can be fully

matched. Q

References

1. Tom Lydon, “Are Shifting Demographics Driving ETF

Growth?” Yahoo! Finance, 10 May 2012, http://finance.

yahoo.com/news/shifting-demographics-driving-etf-

growth-133555434.html.

2. Investment Company Institute, “Exchange-Traded Fund

Assets, March 2012,” 24 April 2012, http://www.ici.org/

etf_resources/research/etfs_03_12.

3. NYSE Euronext. ETFs FAQ, 2009, http://www.amex.com/

etf/FAQ/et_etffaq.htm#4

ETF( Continued from page 37 )

The stakes are even higher for security breaches of health

information, according to new rules for the Health Insurance

Portability and Accountability Act of 1996 (HIPAA).

HIPAA rules complicate compliance, could up fines

EDITOR’S NOTE:

ETFs are subject to risks similar to those of stocks.

Investment returns may fluctuate and are subject to

market volatility, so that an investor’s shares, when

redeemed, or sold, may be worth more or less than

their original cost.

THE FINA L RULE:

> makes business associates of covered entities directly

liable for compliance with certain requirements;

> strengthens limitations on the use of personal health

information for marketing and fundraising purposes;

> prohibits the sale of a patient’s personal health information

without specific individual authorization to do so;

> expands patients’ rights to request and receive electronic

copies of their personal health information; and

broadens patients’ ability to restrict, in some instances,

disclosure of their personal health information to health

insurance plans;

> requires modification to, and redistribution of, a covered

entity’s notice of privacy practices;

> simplifies reporting requirements of child immunizations

to schools;

> expands the Health Information Technology for Economic

and Clinical Health (HITECH) Act to address enforcement

due to willful neglect; and

> adopts changes to increase and tier civil monetary penalties.

OCR Director Leon Rodriguez says

the rules “strengthen the ability of

my office to vigorously enforce the

HIPAA privacy and security protections,

regardless of whether the information

is being held by a health plan, a health-

care provider, or one of their business

associates.”

The final omnibus rule is based on

statutory changes under the HITECH

Act and the Genetic Information

Nondiscrimination Act of 2008, which

clarifies that genetic information is

protected under the HIPAA privacy rule

and prohibits most health plans from

using or disclosing genetic information

for underwriting.

In fact, the U.S. Department of Health

and Human Services (HHS) recently

unveiled these rules in the Federal

Register, which are described as the

most sweeping changes to HIPAA since

its birth more than 15 years ago. Slated

to take effect March 26 and with a

compliance deadline of Sept. 23, the

rules are thought to make compliance

for physicians more difficult while

expanding the government’s latitude

in levying fines to providers from $100

to $1.5 million.

The move by government regulators

within HHS’s Office of Civil Rights (OCR)

is focused on protecting and expanding

individual rights covered by HIPAA.

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Repeating an ad ENSURES

it will be seen and

remembered!

ring either during or after treatment.1 It is

likely that continued research will find this

treatment modality to be optimal for an ex-

panding number of retinal diseases.

In our practice of four physicians, there was

often a bottleneck created by patients waiting

to be moved from the exam lane to the laser

room to receive treatment. To address this,

we designed three of our twelve exam rooms

to accommodate lasers (IQ 577, Iridex Corp.)

directly into the exam lanes. We initially in-

stalled two lasers and we are anticipating add-

ing a third in the near future.

The lasers are mounted on a swing arm that

allows the physician to treat the patient either

in the sitting position or with the chair reclined.

The laser console is positioned and the laser out-

put settings are adjusted to either micropulse

or conventional emission modes by our sup-

port staff, depending on the patient’s pathology.

By utilizing the exam room in this manner,

not only is there an additional laser available

to aid with the workflow, but not having to

move the patient to a different location for

treatment results in significant time savings

as well. Typical patients in a retina practice

are fairly elderly and often use walkers, wheel-

chairs, or some other assistance to get from

point A to point B, and they truly appreciate

not having to move back and forth as much.

We chose this laser because of its ergonomics,

versatility, and small footprint. As our knowl-

edge of micropulse laser applications grows,

we are finding that we have many more pa-

tients that may benefit from laser treatment,

and that this method of treatment may ease

case management and improve patient out-

comes. The more laser procedures that are

done, the greater the demand for efficiency

from the treatment modality.

The laser can be placed on a typical arm ap-

paratus in an exam room and the treatment set-

tings can be quickly adjusted. The integration

of the laser into our practice has significantly

improved our overall laser treatment efficiency

because of its ergonomically friendly design and

the reduction in patient movement resulting

from its use in our dual-purpose exam rooms.

The changes we made to our patient educa-

tion and practice layout, coupled with the capital

investment in additional laser equipment, have

greatly improved our patient pass-through rates.

We plan to continue in our quest for greater

efficiency this year with the adoption of elec-

tronic medical records. As we all struggle with

cost containment, it is important to remem-

ber that revenue enhancement should not be

overlooked as a means of improving practice

profitability, and we have found that to be the

case with our recent updates. Q

Referencet Luttrull JK, Sramek C, et al. Long-term safety,

high-resolution imaging, and tissue temperature

modeling of subvisible diode micropulse

photocoagulation for retinovascular macular edema.

Retina. 2012;32:375-386.

EFFICIENCY( Continued from page 42 )

PATRICK J. CASKEY, MD, is senior partner at North Bay

Vitreoretinal Consultants, Santa Rosa, CA. He has no fi nancial

disclosures or consulting relationships relevant to this article.

PATIENT EDUCATION. Audio visual

aids are an effective means of educating

patients about their disease pathology and

treatment. An update to our exam lanes included

adding 32-inch, flat-screen monitors on each

wall that allow projection of optical coherence

tomography and angiograpic images, as well

as educational images.

PATIEN T FLOW. Create a circular flow

throughout the office, where patients check in

at one location and check out at another. Keep

walkways wheelchair- and walker-friendly. Have

a staff member stationed at the exam door and

ready to escort patients to the check-out desk. This

enables the staff member to address additional

questions or concerns, while the physician moves

on to the next patient.

ADDITIONAL LASER TREATMENT

CAPABILIT Y. Avoid a bottleneck for patients

waiting to be moved from the exam lane to

the laser room. One option is to design exam

rooms to accommodate lasers directly into the

exam lanes. By utilizing the exam room in this

matter, there is an additional laser available to

aid with the workflow. In addition, significant

time savings result from not having to move

patients to a different location for treatment.

A check list for your practice redesign

41MARCH 1, 2013 :: Ophthalmology Times

practice management

Alcon Laboratories Inc. 9-10, 19

Tel: 800/862-5266Internet: www.alcon.com

Allergan Inc. 22-24*

Tel: 714/246-4500Customer Service: 800/433-8871Fax: 714/246-4971Internet: www.allergan.com

Bausch + Lomb 13-15

Tel: 800/227-1427Customer Service: 800/323-0000Internet: www.bausch.com

Brien Holden Vision Institute 27

Tel: 612/9385-7441Internet: www.brienholdenvision.org

Fera Pharmaceuticals Inc. CV2

Tel: 414/434-6604Fax: 414/434-4603Internet: www.ferapharma.com

ICHE 30-31

Internet: www.bizmedicine.org

Advertiser Page

Advertiser I ndex

Marco CV4

Tel: 800/874-5274Internet: www.marco.com

Optos 11

Internet: www.optos.com

Regeneron Pharmaceuticals 6A-B*

Tel: 914/345-7400Internet: www.regeneron.com

Rhein Medical 5

Tel: 800/637-4346Internet: www.rheinmedical.com

ThromboGenics CV3

Tel: 732/590-2900Internet: www.thrombogenics.com

This index is provided as an additional service.

The publisher does not assume any liability for errors

or omissions.

*Indicates a demographic advertisement.

Advertiser Page

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While the future is never

certain, inescapable in-

fluences bear down on

the field of ophthalmol-

ogy. Perhaps most cer-

tain is that fewer num-

bers of ophthalmologists

will have to treat an ever-growing population.

The first of the baby boomers are just start-

ing to reach the age of needing glaucoma, cat-

aract, and retinal treatments, and many more

are on their heels. In addition, there is steady

pressure from health-care reform to treat a

greater number of patients at a lower level of

reimbursement.

When my partners and I remodeled our

practice last year, it was with an eye toward

efficiency in preparation for what is to come.

A U D I O V I S U A L U P D A T E S

Patient education is an essential task that also

has the potential to eat up a lot of physician

time. However, an effective means of educat-

ing patients about retinal difficulties can help

the patient understand the pathology better, as

well as save the physician valuable chair time.

Audio visual aids in one form or another

are incredibly helpful in that regard. There-

fore, the update to our exam lanes included

adding 32-inch, flat-screen monitors on each

wall that allow projection of optical coherence

tomography and angiographic images as well

as educational materials.

The quick and seamless display of patient

diagnostic images allows the physician to ex-

plain to both the patient and the family mem-

bers what pathology is present and what treat-

ment options are available. The use of images

increases patient understanding significantly,

reducing the time physicians spend on educa-

tion while increasing patient knowledge and

overall satisfaction.

P A T I E N T F L O W

The remodel to our practice also had to address

patient flow concerns and eliminate gridlock in

the daily examination and treatment of patients.

One component of this was creating a circular

flow throughout the office where patients check

in at one location and check out at another.

All walkways are wheelchair- and walker-

friendly. A crisp and pleasant end to the pa-

tient encounter is created by stationing a staff

member at the exam door ready to escort the

patient to the check-out desk. The staff mem-

ber is then able to provide answers to any ad-

ditional questions or concerns, while the phy-

sician smoothly moves on to the next patient.

A D D E D L A S E R C A P A B I L I T Y

An important addition to our office was addi-

tional laser treatment capability. Retinal photo-

coagulation can be used to treat a variety of

ischemic, inflammatory, and degenerative reti-

nal diseases.

In addition, the science behind micropulse

laser technology has introduced the concept

of providing a positive treatment benefit while

avoiding visible intraretinal damage or scar-

Redesign places focus

on practice efficiency

Improved layout and patient education lead to increased pass-through ratesBy Patrick J. Caskey, MD; Special to Ophthalmology Times

Continues on page 41 : Efficiency

In our practice of four physicians, there was often a bottleneck created by

patients waiting to be moved from the exam lane to the laser room to receive treatment. To address

this, we designed three of our twelve exam rooms to accommodate lasers directly into the exam

lanes. The lasers are mounted on a swing arm that allows the physician to treat the patient either in

the sitting position or with the chair reclined. The laser console is positioned and the laser output

settings are adjusted to either micropulse or conventional emission modes by our support staff,

depending on the patient’s pathology. (Photo courtesy of Patrick J. Caskey, MD)

MARCH 1, 2013 :: Ophthalmology Times42

practice management

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Learning Method and MediumThis educational activity consists of a supplement and ten (10) study questions.The participant should, in order, read the learning objectives contained at thebeginning of this supplement, read the supplement, answer all questions in thepost test, and complete the Activity Evaluation/Credit Request form. To receivecredit for this activity, please follow the instructions provided on the post testand Activity Evaluation/Credit Request form. This educational activity shouldtake a maximum of 1 hour to complete.

Content SourceThis continuing medical education (CME) activity captures content from a CMEsymposium held on November 10, 2012, in Chicago, Illinois.

Activity DescriptionThe management of patients with ocular hypertension or glaucoma increasesin complexity as comorbid conditions such as ocular surface disease andcataract present. The goal of this program is to improve the knowledge and clinical performance of glaucoma specialists and comprehensiveophthalmologists by disseminating new information on ocular surface healthin patients on glaucoma therapy, and providing expert clinical insight on themanagement of challenging cases.

Target AudienceThis educational activity is intended for glaucoma specialists andcomprehensive ophthalmologists.

Learning ObjectivesUpon completion of this activity, participants should be better able to:

=��'(17,)<�2&8/$5�685)$&(�',6($6(�,1�7+(,5�3$7,(176�:,7+�*/$8&20$�or ocular hypertension

=��(6&5,%(�7+(�())(&76�2)�35(6(59$7,9(6�,1�*/$8&20$�0(',&$7,216�on ocular health

=��/$1�())(&7,9(�0(',&$/�5(*,0(16�)25�3$7,(176�:,7+�*/$8&20$�25�2&8/$5hypertension and complex presentations including ocular surface disease

Accreditation StatementThis activity has been planned and implemented in accordance with the�66(17,$/��5($6�$1'��2/,&,(6�2)�7+(��&&5(',7$7,21��281&,/�)25��217,18,1*��(',&$/Education through the joint sponsorship of The New York Eye and Ear Infirmaryand MedEdicus LLC. The New York Eye and Ear Infirmary is accredited by theACCME to provide continuing medical education for physicians.

AMA Credit Designation StatementThe New York Eye and Ear Infirmary designates this enduring material for amaximum of 1.0 AMA PRA Category 1 Credit>���+<6,&,$16�6+28/'�&/$,0�21/<�7+(credit commensurate with the extent of their participation in the activity.

Grantor StatementThis continuing medical education activity is supported through anunrestricted educational grant from Merck & Co, Inc.

Disclosure Policy StatementIt is the policy of The New York Eye and Ear Infirmary that the faculty andanyone in a position to control activity content disclose any real or apparentconflicts of interest relating to the topics of this educational activity, and alsodisclose discussions of unlabeled/unapproved uses of drugs or devices duringtheir presentation(s). The New York Eye and Ear Infirmary has establishedpolicies in place that will identify and resolve all conflicts of interest prior to this educational activity. Full disclosure of faculty/planners and theircommercial relationships, if any, follows.

Expert Consultations in Diseases of the

Aging EyeGlaucoma, Ocular Surface Disease, and BeyondHighlights from a CME Symposium held during the American Academy of Ophthalmology 2012 meeting

CME MONOGRAPH

Original Release: March 1, 2013 Last Review: February 15, 2013 Expiration: March 31, 2014

Jointly sponsored by The New York Eye and Ear Infirmary and MedEdicus LLC.

This continuing medical education activity is supported throughan unrestricted educational grant from Merck & Co, Inc.

This CME symposium was not affiliated with the official program of theAAO/APAO Joint Meeting.

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Richard K. Parrish II, MD�662&,$7(��($1�)25��5$'8$7(��(',&$/��'8&$7,21�52)(6625�2)��3+7+$/02/2*<University of Miami Miller School of Medicine�$6&20��$/0(5��<(��167,787(Miami, Florida

Faculty

Program Chair

Brian A. Francis, MD, MS�$/3+�$1'��1*(/<1��,))(1%85*+��52)(6625�2)��/$8&20$�2+(1<��<(��167,787(Keck School of MedicineUniversity of Southern CaliforniaLos Angeles, California

Cindy M.L. Hutnik, MD, PhD�52)(6625���(3$570(176�2)��3+7+$/02/2*<����$7+2/2*< &+8/,&+� &+22/�2)��(',&,1(����(17,675<Ivey Eye InstituteSt. Joseph’s Health Center"1,9(56,7<�2)�#(67(51��17$5,2�21'21���17$5,2���$1$'$

Steven L. Mansberger, MD, MPHSenior Scientist, Legacy Health�,5(&725�2)��/$8&20$� (59,&(6�(9(56��<(��167,787(�257/$1'���5(*21

Stephen C. Pflugfelder, MD�52)(6625�2)��3+7+$/02/2*<James and Margaret Elkins ChairBaylor College of MedicineHouston, Texas

Visit http://www.MedEdicus.com/ foronline testing and instant CME certificate.

Disclosures Brian A. Francis, MD, MS, had a financial agreement or affiliation during thepast year with the following commercial interests in the form of SpeakersBureau: Merck & Co, Inc.

Cindy M.L. Hutnik, MD, PhD, has no relevant commercial relationships to disclose.

Steven L. Mansberger, MD, MPH, had a financial agreement or affiliation during the past year with the following commercial interests in the form ofConsultant/Advisory Board: Alcon, Inc; Allergan, Inc; and Santen PharmaceuticalCo, Ltd; Speakers Bureau: Merck & Co, Inc; Contracted Research: Allergan, Inc;American Glaucoma Society; Centers for Disease Control and Prevention; andMerck & Co, Inc.

Richard K. Parrish II, MD, had a financial agreement or affiliation during thepast year with the following commercial interests in the form of Consultant/Advisory Board: Aerie Pharmaceuticals, Inc; Alimera Sciences, Inc; Allergan, Inc;AqueSys, Inc; Bausch + Lomb Incorporated; Glaukos Corporation; InnFocus, Inc;Innovia LLC; and Merck & Co, Inc.

Stephen C. Pflugfelder, MD, had a financial agreement or affiliation during the past year with the following commercial interests in the form ofConsultant/Advisory Board: Allergan, Inc; Bausch + Lomb Incorporated; andGlaxoSmithKline; Contracted Research: Allergan, Inc; and GlaxoSmithKline.

Peer Review Disclosures Ted Gerszberg, MD, has no relevant commercial relationships to disclose.

Editorial Support DisclosuresDerek Dore, PharmD; Cynthia Tornallyay, RD, MBA, CCMEP; Kimberly Corbin,CCMEP; Barbara Aubel; and Barbara Lyon have no relevant commercialrelationships to disclose.

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DisclaimerThe views and opinions expressed in this educational activity are those of thefaculty and do not necessarily represent the views of The New York Eye and EarInfirmary; MedEdicus LLC; Merck & Co, Inc; or Ophthalmology Times.

Introduction

For patients with glaucoma or ocular hypertension, the end goal is

preserving vision by medically and/or surgically lowering intraocular

pressure (IOP). An underappreciated factor than can affect treatment

outcomes is preexisting or concurrent ocular surface disease (OSD).

Recently, 5 leading ophthalmologists convened at a continuing medical

education (CME) symposium to present complex clinical cases focusing on

the intersection of IOP management and ocular surface health. This CME

activity summarizes highlights from the case presentations and includes

panel discussion in 2 of the cases, to share with you the particular debate

and varied perspectives those cases engendered. We hope the evidence

presented and the panel’s insight on this topic will be helpful to you in

managing patients with glaucoma or ocular hypertension.

—Richard K. Parrish II, MD

Evaluating the Ocular Surface in Patients With

Glaucoma or Ocular Hypertension

—Stephen C. Pflugfelder, MD

Case 1: The patient is a 64-year-old female with a several-year historyof eye irritation and intermittent tearing that worsens uponawakening. Glaucoma was diagnosed a year ago and she is currentlybeing treated with generic latanoprost preserved with benzalkoniumchloride (BAK). Over the past 3 months, redness and burning havebeen noted throughout the day, with worsening after eveninglatanoprost instillation.

The patient’s tear break-up time (TBUT), as measured by standardfluorescein testing, is 3 seconds. She has inferior corneal fluoresceinstaining and poorly expressible meibomian glands with ductalkeratinization and posterior lid margin neovascularization. Externalexamination with lissamine green dye finds lid parallel conjunctivalfolds, which is indicative of conjunctivochalasis. (Figure 1A) Anteriorsegment optical coherence tomography (OCT) shows her tearmeniscus height centrally to be 378 μm, approximately 50% higherthan the normal height of 250 μm. (Figure 1B)

What are the factors contributing to this patient’spresentation of ocular surface signs and symptoms?

There are several factors that may be contributing to the patient’spresentation: preexisting and persistent OSD, deleterious effects ofBAK, and abnormal tear dynamics and delayed tear clearance.

Preexisting and Persistent OSD

Prior to the initiation of ocular hypotensive therapy, the patient’sseveral-year history of eye irritation and tearing is consistent withOSD. Her current signs and symptoms—reduced TBUT, corneal

2

Figure 1A. External examination of Case Patient 1 showing lid parallel conjunctival folds.

Figure 1B. Increased tear meniscusheight in Case Patient 1 visualizedby OCT.

This CME activity is copyrighted to MedEdicus LLC ©2013. All rights reserved.

378 μm

Photos Courtesy of Stephen C. Pflugfelder, MD

fluorescein staining, meibomian gland dysfunction, redness andburning in the eyes—indicate persistent OSD.

Deleterious Effects of BAK on the Ocular Surface

BAK, the most commonly used preservative in ocular medications, is aquaternary ammonium chloride compound with surfactant anddetergent properties.1 The toxicity of BAK has been studied extensively.BAK disrupts corneal epithelial tight junctions,1-3 leading toaccelerated desquamation, or loss of the apical corneal andconjunctival epithelium.3,4 BAK can trigger apoptosis at concentrationsof 0.01% and necrosis at concentrations of 0.05%.5 BAK also has beenfound to be proinflammatory, increasing expression of inflammatorymarkers on the ocular surface epithelial cells,6 promotinginflammatory cell infiltration6 and goblet cell loss.7,8 The disruption ofboth goblet cell mucin production and meibomian gland secretion ofthe lipid component of tears results in an unstable tear film andincreased tear film evaporation, and thereby contributes to the dry eyeoften seen in patients with glaucoma.9 BAK has been detected in thecorneal and conjunctival tissues for 7 days following instillation of asingle 30-μL drop.1 Chronic use of BAK may lead to an increased risk ofcorneal complications such as punctate epitheliopathy,10 a decrease infunctional vision, and may affect tasks that require extendedconcentration, such as reading.11 BAK-induced toxicity may lead todecreased productivity and overall quality of life.12

Abnormal Tear Dynamics and Delayed Tear Clearance

This patient has conjunctivochalasis, a condition that increases withage.13 Conjunctivochalasis can compartmentalize the tear film in thecenter of the eye, which results in pooling and stagnation of thecentral tear meniscus.13 Her abnormal tear dynamics is increasingBAK’s concentration in the precorneal tear layer, which is likelyresponsible for the finding of punctate epitheliopathy of the inferiorcornea. The conjunctivochalasis also is causing delayed tearclearance, resulting in retention of the ocular hypotensive in theprecorneal tear meniscus.

Glaucoma and OSD

This case is representative of the common problem of coexisting OSDin patients with glaucoma. Leung and colleagues found that 59% ofpatients with glaucoma or ocular hypertension complained ofsymptoms of OSD.14 In addition, they found that for each additionalBAK-preserved ocular hypotensive used, there were approximately 2 times higher odds of showing abnormal results on corneal andconjunctival lissamine green staining.14

Identifying patients at risk for ocular hypotensive toxicity

It is prudent to perform an ocular surface assessment in patientswith glaucoma in order to determine if the condition of their ocularsurface places them at greater risk for ocular surface toxicity with theuse of ocular hypotensives. (See Sidebar.)

Managing patients with glaucoma and OSD

First, I switch the patient to a BAK-free ocular hypotensive. If thepatient’s OSD is not improved, I initiate an ocular hypotensive dropholiday, and treat the patient’s glaucoma with an oral carbonicanhydrase inhibitor. I consider instituting dry eye therapy with apreservative-free, low-dose ocular steroid, such as dexamethasone0.01%, which can be compounded by a specialty pharmacy. Other dryeye therapies to consider include ocular cyclosporine A 0.05%; low-dose oral doxycycline (20 mg twice a day or 40 mg once daily), whichinhibits desquamation in the corneal epithelium17,18; or punctalocclusion plugs (only after the patient has discontinued the BAK-preserved ocular hypotensive). For ocular hypotensive-naïve patients,the decision to avoid ocular hypotensives containing BAK canmitigate the risk of developing ocular surface problems. Rossi andcolleagues found that initiating IOP-lowering therapy with apreservative-free ocular hypotensive in ocular hypotensive-naïvepatients resulted in no new cases of OSD and maintained the qualityof life of treated patients.19

Recognizing the Issue of Poor Adherence in

Patients Treated With Ocular Hypotensives

—Steven L. Mansberger, MD, MPH

Case 2: The patient is an 85-year-old female who reports that she is“doing fine.” IOP in both eyes is 10 mm Hg (her baseline IOP in botheyes before beginning IOP-lowering therapy was 18 mm Hg). Hermedication regimen includes timolol twice daily, brimonidine 3 timesdaily, and dorzolamide 3 times daily. Fundoscopy finds evidence ofdisc hemorrhage inferiorly. (Figure 2)

Disc hemorrhage in patients with glaucoma

There should be concern when disc hemorrhage is observed in thesetting of good IOP readings. Just as hemoglobin A1C may be used asan indicator of glucose control in patients with diabetes, the presenceof disc hemorrhage in patients with glaucoma may indicate pooradherence with ocular hypotensives. Disc hemorrhages persist, onaverage, for 3 to 6 months, and can be a sign that either patients arepoorly adherent to their medications or that their glaucoma isworsening. The finding of a disc hemorrhage should promptophthalmologists to ask patients about adherence.

3

Dr Pflugfelder’s Ocular Surface Assessment

1. Inquire about ocular irritation symptoms:Although there are many validated questionnaires available, theiradministration can be quite cumbersome and time consuming. Ihave found a single question to be just as valuable as a set ofmany questions. Identifying OSD can be as simple as asking yourpatients 1 question, “Are you experiencing eye irritation?”

2. Examine the ocular surface: 4��2�'#(��."��*/(�.����)�."�3�"�0�����'��),�-.�()-#-��4��2�'#(��."��&#��'�,!#(-���)�."�3�*,�-�(.�1#."�'�#�)'#�(

gland disease, ectropion, or conjunctival injection orchalasis? I have found chalasis to be prevalent in patientsaged older than 45 years, and I have become much attunedto its presence.

4��"��%�.��,�-.��#&#.3�1#."� &/),�-��#(���(-.#&&� &/),�-��#( 1�#.��� �1�-��)(�- ��-%�."��*�.#�(.�.)��&#(%���(��."�(�

check the TBUT.4��)(-#��,��2�'#(#(!�."��#( �,#),�.��,�'�(#-�/-���(-.#&&#(!��3�

in the eye makes it fairly simple to examine the meniscus�(��1#&&�#(�#��.��# �."��.��,�'�(#-�/-�#-�&)1��(),'�&�elevated, or blocked by conjunctivochalasis.

4��)(-#��,�'��-/,#(!�.��,�*,)�/�.#)(���4���'),��-)*"#-.#��.����**,)��"�#-�.)�'��-/,��.��,)-')&�,#.3���"�,��#-�()1����)''�,�#�&&3��0�#&��&�osmometer to measure tear osmolarity. The clinical value ) �."#-�.�-.�#-�-.#&&�/(%()1( �")1�0�,������&#�0��."�.�#(�."�context of prescribing ocular hypotensive therapy, it may bequite valuable. If a patient consistently has a tear osmolarity#(�."��,�(!��) �����'�-'���),�"#!"�,��1"#�"�#-�!,��.�,�."�(the range of 308 to 316 mOsm/L that has been found to be asensitive predictor of dry eye disease,15,16 then that patient-")/&�����*,�-�,#�����(�)�/&�,�"3*).�(-#0��1#.")/.�����

Figure 2. Inferior dischemorrhage in Case Patient 2.

Photo Courtesy of Steven L. Mansberger, MD, MPH

How adherent are patients with their prescribed ocular hypotensives?

Examining Adherence Patterns and Persistency of Adherence

When analyzing adherence patterns of patients with their ocularhypotensives, researchers find that patients typically are mostadherent immediately after their ophthalmologist appointment andthen immediately before they return for another office visit. Therefore,the level of adherence to medications is lower in between visits.20 Oneway to combat this dip in adherence, especially in patients withsuspected poor adherence, is to increase the frequency of office visits.

We also know that with time, we can expect a considerable decrease inour patients’ adherence to their ocular hypotensives. Reardon andcolleagues examined the persistency of patients with glaucoma inadhering to their ocular hypotensive regimens over time. When theylooked at latanoprost refill records, they found that only approximately50% of patients were refilling their medications at 6 months.21

Therapy adherence and visual function

Stewart and colleagues assessed factors associated with decreased orstable visual function in patients with glaucoma and end-stagecupping of the optic disc. Grading patients as either poorly adherentor adherent to glaucoma treatment, the researchers found that ofthose who were adherent, approximately 90% were graded as stablein their disease progression, whereas only approximately 50% of the poorly adherent group were stable.22 Consequences of pooradherence in these patients can be worsening of the visual field orthe requirement of surgical intervention to manage IOP.

Determining adherence to ocular hypotensive therapy

If patients admit they are poorly adherent, they probably are, andinterventions should be employed to improve adherence. But whatabout patients who claim they never miss a drop? The finding of dischemorrhage in this patient may suggest poor adherence to ocularhypotensive therapy despite a stable IOP reading at the office visit. To obtain a more accurate history, I have found it effective to helppatients admit to poor adherence by suggesting an overestimate ofnonadherence in a “safe” environment. For example, you might say, “It can be difficult to use eye drops every day. How often do you missyour drops? …about half the time?” By suggesting this high rate ofpoor adherence, patients may be more comfortable discussing theirdifficulty with drop administration.

Improving adherence to ocular hypotensive therapy

A useful tool for determining the factors related to patient adherenceto ocular hypotensives is the Health Belief Model. (Figure 3) Thefactors are broadly classified into 1 of 2 groups:

1) Factors that affect individual perception: the patient/doctorrelationship, patient demographic features, social supports, patientpersonality, and patient knowledge of the disease.

2) Modifiable factors: perceived severity of disease, perceived benefitsof adherence, perceived barriers to adherence, and perceivedsusceptibility to blindness. This category includes “Cues to Action”that refer to the external reminders some patients may need tohelp them remember to use their medication.

By identifying and addressing the following factors, patientadherence may be improved.

B��Patient Demographic Features: Elderly patients often have poorcorneal sensation. Refrigerating their ocular hypotensive maymake the drop more obviously felt when hitting their eye,allowing them to know that they were successful in dropadministration.

B��Social Supports: Patients should consider inviting familymembers into the examination room. Having a family memberin the room both reinforces the severity of the disease andprovides an opportunity to enlist family members’ help withremembering the counseling relevant to medication adherence.

B��Perceived Barriers to Adherence: Barriers to ocular hypotensivesinclude medication adverse effects and inconvenience of dropadministration.23 Medication adverse effects are a commonreason for poor adherence23; thus, switching to ocularhypotensives that are gentler to the eye, such as those withoutBAK, may improve adherence. Decreasing the frequency of dropadministration, by using once-daily prostaglandin analogs,21 orby using fixed-combination drops,24 also could improveadherence.

B��Perceived Susceptibility to Blindness and Perceived Severity ofDisease: If patients neglect their ocular hypotensives becausethey perceive there is a low risk of vision loss, adherence may beimproved through education. Also, patients may be poorlyadherent when they do not have a measure for, and thereforecannot quantify, the degree of their susceptibility to blindness.These 2 scenarios may be addressed by keeping patientsinformed of the results of their glaucoma assessments.

B��Cues to Action: Consider providing patients with cues to action;suggest they set their container of ocular hypotensive near theirtoothbrush to help them remember to instill their drops in muchthe same routine as brushing their teeth.

In summary, poor adherence to ocular hypotensives is common;recognizing and managing the issue may improve patient outcomes.

Recognizing Subtle Ocular Surface Disease

Before Management of Intraocular Pressure

—Cindy M.L. Hutnik, MD, PhD

Case 3: A 68-year-old male without a significant medical history isreferred by an optometrist who had been following him for elevatedIOP and was concerned about his recent optic disc changes. Thepatient felt he was doing well, had no visual or ocular complaints, andwas still phakic.

The ocular examination showed the following:

The patient’s visual fields were noncontributory, but he wasdiagnosed with open-angle glaucoma based on IOP elevation, opticdisc changes, and open angles on gonioscopy. Imaging revealed a thinretinal nerve fiber layer consistent with the diagnosis.

He was started on a BAK-preserved prostaglandin analog. Five daysafter initiation of therapy, the patient reported discontinuing theocular hypotensive because of eye discomfort. He admitted that prior

4

Figure 3. Health Belief Model (developed by the US Public Health Service in the 1950s).

Patient/DoctorRelationship,

Demographic Features,

Social Supports.Personality,Knowledge

PerceivedSeverity of

Disease

PerceivedBenefits—PerceivedBarriers toAdherence

PerceivedSusceptibility to

Blindness

Cues to Action:(���� ���������#���"(���$��#���

Likelihood ofAdherence

������������'

IndividualPerception Modifiable Factors

OD OS

IOP (mm Hg) 24 22

CCT (microns) 553 550

BCVA 20/25 20/25

Angle III III

BCVA=best corrected visual acuity; CCT=central corneal thickness; IOP=intraocular pressure.

to starting the BAK-preserved ocular hypotensive, his eyes were “a bitteary,” but after starting therapy he complained his eyes were “veryscratchy and uncomfortable,” and worsened when he read. Hedescribed the discomfort as “unbearable.”

Neither a switch to another prostaglandin analog nor a switch toanother class of ocular hypotensives helped relieve his eye discomfort.Selective laser trabeculoplasty was offered as an early therapeuticoption; the patient, however, refused this procedure.

At the 3-month office visit (after multiple ocular hypotensive trials), afull ocular surface workup was ordered. The clinical test findings werediagnostically borderline of OSD, demonstrating few superficialpunctate erosions, an equivocal 9-second TBUT in each eye, 14 mmSchirmer test in each eye, and some reflex tearing. Externalexamination showed numerous collarettes on his eyelash bases,inspissation of his meibomian glands with minimal expression uponcompression, and lower lid laxity. (Figure 4)

Treating the patient with equivocal OSD findings

Dr Pflugfelder: I would attempt to quickly rehabilitate the ocularsurface with a topical corticosteroid and preservative-free artificialtears, and also to implement longer-term treatment with nutritionalsupplementation: fish oil (omega-3 fatty acid)25,26,27 and gamma-linolenic acid (omega-6 fatty acid).28 Another option is to treat withdoxycycline. Doxycycline and other tetracyclines are potent anti-inflammatory agents, protease inhibitors, and metalloproteaseinhibitors.17,18 Doxycycline is dosed at 20 mg twice daily in the genericstrength, or 40 mg once daily in the branded product. I typically treatpatients with doxycyline at these dosages for a month, reassess, andthen perhaps reduce the dose if improvement is observed.

Dr Francis: I would treat the patient’s blepharitis with warmcompresses and his dry eye with artificial tears, and also take thepatient off BAK-preserved drops.

Dr Mansberger: I would ensure the patient is properly hydrated,drinking at least 8 to 12 cups of water per day, because dehydrationmay be contributing to dry eye. My tendency is to avoid using asteroid unless there are no options remaining. I also would suggestthe patient take nutritional supplements, and switch him to apreservative-free ocular hypotensive.

What are the BAK-free ocular hypotensive options available in the United States?

In the United States, there are 2 commercially available non–BAK-preserved ocular hypotensives and 3 preservative-freeocular hypotensives. (Table 1)

Comparative ocular surface effects of ocular hypotensiveswithout BAK vs BAK-preserved ocular hypotensives

Nakagawa and colleagues compared the effects of travoprost withsofZia™ to latanoprost with BAK and to phosphate-buffered salinecontrols on human corneal epithelial cells. The cell cultures exposedto travoprost with sofZia and those of the controls both exhibited100% viability at 6 hours, whereas the BAK-exposed cells had 0%viability (P<.05 vs control).29

Removing BAK from ocular hypotensives has also been found to beclinically beneficial. Horsley and Kahook evaluated patients’ ocularsurface signs and symptoms during latanoprost with BAK therapy, and then reevaluated the patients 8 weeks after switching fromlatanoprost with BAK to travoprost with sofZia. The authors foundimprovements in TBUT, inferior corneal staining, and OSDI (OSD index)scores after patients switched to travoprost with sofZia.30 (Table 2)Likewise, Janulevi●ien� and colleagues found that switching patientsfrom latanoprost with BAK to preservative-free tafluprost led tonormalization of tear osmolarity, improved ocular comfort and TBUT,and decreased corneal staining.31 (Figure 5, Table 3)

5

BAK=benzalkonium chloride; OSDI=ocular surface disease index; TBUT=tear break-up time.aStudent’s t-test

Table 1. Ocular Hypotensives Without BAK Available in the United States

Table 2. Mean TBUT, Inferior Corneal Staining Score, and OSDI Score onLatanoprost With BAK and at 8 Weeks After Switch to Travoprost With sofZia(P<.001) in a Prospective, Open-label, Single-center Study Involving 20 Patients(40 Eyes)30

Figure 5. Mean osmolarity at baseline (latanoprost with BAK) and at 2 weeks(P=.002 vs baseline), 6 weeks (P<.001 vs baseline), and 12 weeks (P<.001 vsbaseline), after changing medication to preservative-free tafluprost in aprospective, observer-masked study involving 30 patients (60 eyes).31

Adapted from Janulevi●ien� I et al. Clin Ophthalmol. 2012;6:103-109.

290

295

300

305

310

315

320

Baseline Week 2 Week 6 Week 12

P<.001 vs baseline

Me

an

Osm

ola

rity

(m

Osm

/L)

Figure 4. External examinationof Case Patient 3 showingnumerous collarettes on eyelashbases, inspissation of meibomianglands, and lower lid laxity.

Photo Courtesy of Cindy M.L. Hutnik, MD, PhD

Generic Name Brand Name Medication Class

Non–BAK-Preserved

Brimonidine tartrateophthalmic solutionwith Purite 0.1% or 0.15%

Alphagan® P Alpha-adrenergicreceptor agonist

Travoprost ophthalmicsolution with sofZia®(boric acid, propyleneglycol, sorbitol, zincchloride) 0.004%

Travatan Z® Prostaglandin analog

Preservative-Free

Dorzolamidehydrochloride/timololmaleate ophthalmicsolution 2%/0.5%

Cosopt® PF Carbonic anhydraseinhibitor/Beta-adrenergic receptorantagonist

Tafluprost ophthalmicsolution 0.0015%

Zioptan™ Prostaglandin analog

Timolol maleateophthalmic solution0.25% or 0.5%

Timoptic® in Ocudose® Beta-adrenergicreceptor antagonist

Latanoprost With BAK

Travoprost WithsofZia (8 weeks after switch)

P value (8 weeks after switch)

TBUT (seconds) 2.02 ± 0.71 6.34 ± 1.31 <.001a

Inferior cornealstaining

2.40 ± 0.87 1.38 ± 0.59 <.001a

OSDI score 26.31 ± 8.25 16.56 ± 6.19 <.001a

BAK=benzalkonium chloride.

The results of the study by Janulevi●ien� and colleagues emphasizethe importance of setting realistic expectations for patients aboutwhen they should expect to see improvements in OSD symptomsafter switching from a BAK-preserved to a preservative-free ocularhypotensive. Improvements in all OSD measures began to appear atweek 2, although significant improvements were not seen until week12. (Table 3) Indeed, in this patient, after the recognition andtreatment of his subtle OSD, he was started on a preservative-freeocular hypotensive, which he has tolerated well.

Managing Advanced Glaucoma and

Severe Ocular Surface Disease

—Brian A. Francis, MD, MS

Case 4: The patient is a 79-year-old female with a chief complaint ofdecreasing vision. She has a history of primary open-angle glaucoma,OSD, non-neovascular age-related macular degeneration, andcataract extraction with intraocular lens implantation in each eye.Her visual fields have progressively worsened over the last 3 years. Hermedications, the only 2 ocular hypotensives she can tolerate, includebranded latanoprost with BAK at bedtime and dorzolamide twicedaily in each eye. She is also using artificial tears during the day andan artificial tear ointment at night.

The ocular examination finds the following:

Fundoscopy finds obvious advanced cupping and optic nerve damage in both eyes. She also has conjunctival injection bilaterally. Externalexamination finds advanced OSD and eyelid disease: considerablelagophthalmos, which prevents complete closure of the eyes. She alsohas exposure keratopathy and pannus inferiorly in the cornea. (Figure 6)

How should this patient with advanced glaucoma and severe OSD be managed?

Dr Hutnik: Certainly, this patient must become less dependent onocular anithypertensives, particularly agents with BAK. A surgicaloption may need to be considered. Before undergoing a surgical

procedure, her ocular surface and eyelids need time to heal, and her IOP could be managed with ocular antihypertensives without BAK or with an oral carbonic anhydrase inhibitor whileawaiting the procedure.

Dr Mansberger: This patient has a high chance of going blind, basedon her presentation of uncontrolled IOP and visual decline. I have notfound trabeculoplasty to be effective in patients with implantedanterior chamber lenses. Trabeculectomy also may not be a goodoption, given the patient’s poor lid closure and conjunctivalinflammation. Switching ocular hypotensives may be effective, but Iwould not choose this option because the patient’s visual field hasbeen declining despite various attempts at maximal medical therapy.Minimally invasive glaucoma surgery (MIGS) also may not reducepressures sufficiently. Most of these procedures will lower IOP to thehigh teens, which is not that different from the patient’s current IOP. Iwould likely consider implanting a tube, a Baerveldt tube or anAhmed valve implant.

Dr Francis: This patient has reached the end of the line in terms ofglaucoma medical treatment. I would avoid trabeculectomy in thiscase because there is a high risk that the procedure would beassociated with poor outcomes because of her considerable OSD.32

Baudouin and colleagues found that long-term use of ocularhypotensives, particularly BAK-preserved ocular hypotensives, inducesconsiderable histopathologic and inflammatory changes in the ocularsurface and also in the trabecular meshwork. In addition, theresearchers found that as the number of ocular hypotensivesincreased, so did the inflammatory markers and disruption of thenormal conjunctival architecture.33 I would avoid MIGS-basedprocedures because of potentially insufficient IOP lowering.

Instead of these surgical options, it was decided to manage thispatient with an aqueous tube shunt (Baerveldt implant) because ofits efficacy in lowering IOP and the minimal need for postoperativeocular hypotensive use or additional surgical interventions followingits implantation.34

Conclusion

It is important to be mindful of the deleterious effects of BAK onocular tissues and its potential to limit medical and surgicalinterventions in patients with glaucoma or ocular hypertension.Identifying preexisting or coexisting OSD in patients with glaucomacan assist clinicians in determining the therapeutic options that caneffectively and safely manage IOP, without compromising ocularsurface health. Today, the ophthalmologist's toolbox has expanded toinclude non–BAK-preserved and preservative-free IOP-loweringtherapies that effectively treat patients with or at risk for glaucoma.

6

OD OS

IOP (mm Hg) 12 20

BCVA 20/50 20/100

RAPD +

Gonioscopy 3+ SS 3+ SS with PAS temp

BCVA=best corrected visual acuity; IOP=intraocular pressure;PAS=peripheral anterior synechiae; RAPD=relative afferent papillary defect; SS=scleral spur.

TBUT=tear break-up time.aMcNemar testbPaired t-testAdapted from Janulevi●ien� I et al. Clin Ophthalmol. 2012;6:103-109.

Table 3. Patients’ Dry Eye Complaints, Mean TBUT, and Abnormal CornealFluorescein Staining at Baseline (Latanoprost With BAK), and at 2, 6, and 12Weeks After Changing to Preservative-free Tafluprost in a Prospective, Observer-masked Study Involving 30 Patients (60 Eyes)31

Baseline Week 2 Week 6 Week 12 P value (12 weeks vs baseline)

Dry eyecomplaints (n= 30, patients)

30 (100%) 19 (63.3%) 11 (36.7%) 11 (36.7%) <.05a

TBUT (seconds)(n= 60, eyes)

3.7 ± 1.1 4.1 ± 1.0 5.2 ± 1.5 6.5 ± 1.5 <.001b

Abnormalfluoresceinstaining of the cornea (n= 60, eyes)

45 (75.0%) 35 (58.3%) 21 (35%) 7 (12%) <.005a

Figure 6. External examinationof Case Patient 4 showingadvanced OSD and eyeliddisease (lagophthalmos),preventing closure of the eyes.

Photos Courtesy of Brian A. Francis, MD, MS

1. What is the prevalence of OSD symptoms in patients with glaucoma or ocularhypertension?

a. 29%b. 39%c. 49%d. 59%

2. Which of the following is likely the LEAST efficient method of identifying a patient who isat risk for ocular hypotensive toxicity?

a. Examine the punctab. Administer an ocular surface assessment questionnairec. Examine the lid margind. Administer a tear film stability test with fluorescein

3. Which of the following is FALSE about BAK?a. BAK can cause clinically significant IOP elevationb. BAK can trigger apoptosis at concentrations of 0.01% and necrosis at concentrations

of 0.05%c. BAK has been found in corneal and conjunctival tissues for 7 days following

instillation of a single 30-μL drop d. BAK-induced toxicity can cause decreased patient quality of life

4. Which of the following is consistent with conjunctivochalasis?a. Central tear meniscus height of 225 μmb. Enhanced tear clearancec. Pooling of tearsd. Tear osmolarity 300 mOsm/L

5. According to Reardon and colleagues, approximately what percent of patients refill theirlatanoprost at 6 months’ time?

a. 25%b. 50%c. 75%d. 100%

6. Which of the following is an appropriate strategy to improve adherence to ocularhypotensive therapy?

a. Suggest patients attend office visits alone to minimize distraction during counseling

b. Decrease the frequency of drop administration by prescribing fixed-combination drops

c. Avoid providing patients with details of their glaucoma assessmentsd. Recommend patients simplify ocular hypotensive administration by avoiding

administering the doses close to other routine tasks

7. For each additional BAK-preserved eyedrop used, Leung and colleagues found that therewere approximately _____ higher odds of showing abnormal results on corneal andconjunctival lissamine green staining.

a. 2 timesb. 3 timesc. 4 timesd. 5 times

8. In patients at 8 weeks’ post-switch from latanoprost with BAK to travoprost with sofZia,Horsley and Kahook found all of the following, EXCEPT:

a. Increased TBUTb. Decreased inferior corneal staining c. Increased tear osmolarityd. Decreased OSDI score

9. A 72-year-old male with glaucoma presents with signs and symptoms of OSD. Ocularexamination finds an IOP of 12 mm Hg in both eyes and a newly found disc hemorrhage.The patient is treated with timolol twice daily and brimonidine 3 times daily. Which of thefollowing is the most likely cause of this patient’s presentation?

a. The patient has undiagnosed hypertension or diabetes that has led to the dischemorrhage

b. Timolol and brimonidine are not adequately effective to provide the aggressive IOPmanagement necessary to prevent disc hemorrhage

c. BAK-induced OSD has caused the patient to become poorly adherent with his ocularhypotensive, with resulting disc hemorrhage

d. Chronic brimonidine usage has induced disc hemorrhage

10. In patients who were switched from BAK-preserved latanoprost to preservative-freetafluprost, Janulevi●ien� and colleagues found that, at 12 weeks, patients’ eyesexperienced significantly:

a. Decreased TBUTb. Increased corneal stainingc. Decreased dry eye complaintsd. Increased tear osmolarity

7

CME Post Test QuestionsReferences

1. Pflugfelder SC, Baudouin C. Challenges in the clinical measurement of ocular surfacedisease in glaucoma patients. Clin Ophthalmol. 2011;5:1575-1583.

2. Pauly A, Meloni M, Brignole-Baudouin F, Warnet JM, Baudouin C. Multiple endpointanalysis of the 3D-reconstituted corneal epithelium after treatment with benzalkoniumchloride: early detection of toxic damage. Invest Ophthalmol Vis Sci. 2009;50(4):1644-1652.

3. Kaur IP, Lal S, Rana C, Kakkar S, Singh H. Ocular preservatives: associated risks and neweroptions. Cutan Ocul Toxicol. 2009;28(3):93-103.

4. Denoyer A, Ossant F, Arbeille B, et al. Very-high-frequency ultrasound corneal imaging as anew tool for early diagnosis of ocular surface toxicity in rabbits treated with a preservedglaucoma drug. Ophthalmic Res. 2008;40(6):298-308.

5. De Saint Jean M, Brignole F, Bringuier AF, Bauchet A, Feldmann G, Baudouin C. Effects ofbenzalkonium chloride on growth and survival of Chang conjunctival cells. Invest

Ophthalmol Vis Sci. 1999;40(3):619-630.6. Baudouin C, Riancho L, Warnet JM, Brignole F. In vitro studies of antiglaucomatous

prostaglandin analogues: travoprost with and without benzalkonium chloride andpreserved latanoprost. Invest Ophthalmol Vis Sci. 2007;48(9):4123-4128.

7. Liang H, Baudouin C, Labbe A, Riancho L, Brignole-Baudouin F. Conjunctiva-associatedlymphoid tissue (CALT) reactions to antiglaucoma prostaglandins with or without BAK-preservative in rabbit acute toxicity study. PLoS One. 2012;7(3):e33913.

8. Yalvaç IS, Gediko●lu G, Karagöz Y, et al. Effects of antiglaucoma drugs on ocular surface.Acta Ophthalmol Scand. 1995;73(3):246-248.

9. Bron AJ, Tiffany JM, Gouveia SM, Yokoi N, Voon LW. Functional aspects of the tear film lipidlayer. Exp Eye Res. 2004;78(3):347-360.

10. Liang H, Pauly A, Riancho L, Baudouin C, Brignole-Baudouin F. Toxicological evaluation ofpreservative-containing and preservative-free topical prostaglandin analogues on athree-dimensional-reconstituted corneal epithelium system. Br J Ophthalmol. 2011;95(6):869-875.

11. Ishida R, Kojima T, Dogru M, et al. The application of a new continuous functional visualacuity measurement system in dry eye syndromes. Am J Ophthalmol. 2005;139(2):253-258.

12. Skalicky SE, Goldberg I, McCluskey P. Ocular surface disease and quality of life in patientswith glaucoma. Am J Ophthalmol. 2012;153(1):1-9.e2.

13. Gumus K, Pflugfelder SC. Increasing prevalence and severity of conjunctivochalasis withaging detected by anterior segment optical coherence tomography. Am J Ophthalmol.

2012 Oct 1. [Epub ahead of print]14. Leung EW, Medeiros FA, Weinreb RN. Prevalence of ocular surface disease in glaucoma

patients. J Glaucoma. 2008;17(5):350-355.15. Lemp MA, Bron AJ, Baudouin C, et al. Tear osmolarity in the diagnosis and management of

dry eye disease. Am J Ophthalmol. 2011;151(5):792-798.e1.16. Tomlinson A, Khanal S, Ramaesh K, Diaper C, McFadyen A. Tear film osmolarity:

determination of a referent for dry eye diagnosis. Invest Ophthalmol Vis Sci. 2006; 47(10):4309-4315.

17. De Paiva CS, Corrales RM, Villarreal AL, et al. Corticosteroid and doxycycline suppress MMP-9 and inflammatory cytokine expression, MAPK activation in the corneal epitheliumin experimental dry eye. Exp Eye Res. 2006;83(3):526-535.

18. Kim HS, Luo L, Pflugfelder SC, Li DQ. Doxycycline inhibits TGF-beta1-induced MMP-9 viaSmad and MAPK pathways in human corneal epithelial cells. Invest Ophthalmol Vis Sci.

2005;46(3):840-848.19. Rossi GC, Pasinetti GM, Raimondi M, et al. Efficacy and ocular surface tolerability of

preservative-free tafluprost 0.0015%: a 6-month, single-blind, observational study onnaïve ocular hypertension or glaucoma patients. Expert Opin Drug Saf. 2012;11(4):519-525.

20. Kass MA, Meltzer DW, Gordon M, Cooper D, Goldberg J. Compliance with topicalpilocarpine treatment. Am J Ophthalmol. 1986;101(5):515-523.

21. Reardon G, Schwartz GF, Mozaffari E. Patient persistency with topical ocular hypotensivetherapy in a managed care population. Am J Ophthalmol. 2004;137(1 suppl):S3-S12.

22. Stewart WC, Chorak RP, Hunt HH, Sethuraman G. Factors associated with visual loss inpatients with advanced glaucomatous changes in the optic nerve head. Am J Ophthalmol.

1993;116(2):176-181.23. Friedman DS, Hahn SR, Gelb L, et al. Doctor-patient communication, health-related beliefs,

and adherence in glaucoma results from the Glaucoma Adherence and Persistency Study.Ophthalmology. 2008;115(8):1320-1327, 1327.e1-3.

24. Tsai JC, McClure CA, Ramos SE, Schlundt DG, Pichert JW. Compliance barriers in glaucoma:a systematic classification. J Glaucoma. 2003;12(5):393-398.

25. Miljanovi●B, Trivedi KA, Dana MR, Gilbard JP, Buring JE, Schaumberg DA. Relation betweendietary n-3 and n-6 fatty acids and clinically diagnosed dry eye syndrome in women. Am J

Clin Nutr. 2005;82(4):887-893.26. Rashid S, Jin Y, Ecoiffier T, Barabino S, Schaumberg DA, Dana MR. Topical omega-3 and

omega-6 fatty acids for treatment of dry eye. Arch Ophthalmol. 2008;126(2):219-225.27. Macsai MS. The role of omega-3 dietary supplementation in blepharitis and meibomian

gland dysfunction (an AOS thesis). Trans Am Ophthalmol Soc. 2008;106:336-356.28. Kokke KH, Morris JA, Lawrenson JG. Oral omega-6 essential fatty acid treatment in contact

lens associated dry eye. Cont Lens Anterior Eye. 2008;31(3):141-146.29. Nakagawa S, Usui T, Yokoo S, et al. Toxicity evaluation of antiglaucoma drugs using

stratified human cultivated corneal epithelial sheets. Invest Ophthalmol Vis Sci. 2012;53(9):5154-5160.

30. Horsley MB, Kahook MY. Effects of prostaglandin analog therapy on the ocular surface ofglaucoma patients. Clin Ophthalmol. 2009;3:291-295.

31. Janulevi●ien� I, Derka●I, Grybauskiene L, Paulauskait� R, Gromnickaite R, Kuzmien� L.Effects of preservative-free tafluprost on tear film osmolarity, tolerability, and intraocularpressure in previously treated patients with open-angle glaucoma. Clin Ophthalmol. 2012;6:103-109.

32. Broadway DC, Grierson I, O’Brien C, Hitchings RA. Adverse effects of topical antiglaucomamedication. II. The outcome of filtration surgery. Arch Ophthalmol. 1994;112(11):1446-1454.

33. Baudouin C, Pisella PJ, Fillacier K, et al. Ocular surface inflammatory changes induced bytopical antiglaucoma drugs: human and animal studies. Ophthalmology. 1999;106(3):556-563.

34. Gedde SJ, Schiffman JC, Feuer WJ, Herndon LW, Brandt JD, Budenz DL; Tube versusTrabeculectomy Study Group. Treatment outcomes in the Tube Versus Trabeculectomy(TVT) study after five years of follow-up. Am J Ophthalmol. 2012;153(5):789-803.e2.

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Activity Evaluation/Credit RequestExpert Consultations in Diseases of the Aging Eye—Glaucoma, Ocular Surface Disease, and Beyond

Original Release: March 1, 2013

Last Review: February 15, 2013

Expiration: March 31, 2014