ophthalmology update - cleveland clinic · er-generation femtosecond lasers, so that most...

For patients with endothelial disease necessitating corneal

transplantation, Descemet’s stripping and automated

endothelial keratoplasty (DSAEK) represents an alterna-

tive to penetrating keratoplasty (PKP) with several major

advantages.

DSAEK is a modifi cation of the Descemet’s stripping and

endothelial keratoplasty (DSEK) technique fi rst intro-

duced by Dutch ophthalmologist Gerritt Melles, M.D.,

and that has been brought to the forefront in the United

States by Francis Price, M.D. In DSAEK, described by

Mark Gorovoy, M.D., Descemet’s membrane is stripped

from the recipient host and replaced with a posterior

lamellar graft that is harvested on an artifi cial anterior

chamber using a mechanical microkeratome. Then the

graft is folded and inserted into the eye through a small

(≤5.0-mm) clear corneal incision.

In March 2005, Cleveland Clinic Cole Eye Institute

ophthalmologist David M. Meisler, M.D., was among

the fi rst corneal transplant surgeons in the United States

to offer DSAEK to appropriate candidates. He believes

it is an excellent option for patients with corneal endo-

thelial disorders.

“DSAEK is a new procedure that is continuing to evolve as

surgeons introduce modifi cations to overcome some of its

technical challenges. In addition, longer-term follow-up is

needed to address unanswered questions about its poten-

tial benefi ts and limitations. However, we are very encour-

aged by our results so far, which demonstrate some very

good success as measured by visual recovery outcomes

and impression of patient satisfaction,” says Dr. Meisler.

At the Cole Eye Institute, all DSAEK procedures have

been performed in an IRB-approved prospective study. In

Cole Eye Institute Experience: DSAEK Has Advantages Over Penetrating Keratoplasty Leads to modifi cations for enabling better outcomes

Cole Eye Institute Spring 2007

Ophthalmology Update

Continued on page 2

David M. Meisler,M.D.

Histologic study provides insight into mechanisms of femtosecond laser-induced infl ammationPage 4

Breakthroughs on corneal biomechanics may have broad-ranging clinical consequencesPage 8

Novel technique being applied to improve effi ciency of stem cell differentiation 0

Cole Eye Institute welcomes neuro-ophthalmologist Lisa D. Lystad, M.D.Page 20

addition to Dr. Meisler, the participating surgeon-investi-

gators in that study also include staff members William J.

Dupps, Jr, M.D., Ph.D., and Bennie H. Jeng, M.D.

In an article in press in Cornea, data from the early cases

performed by Dr. Meisler were pooled with data from a se-

ries of cases performed by Steven B. Koenig, M.D., at the

Medical College of Wisconsin. The results showed that at

6 months, mean BSCVA had improved signifi cantly from

20/99 preoperatively to 20/42, and two-thirds of patients

achieved BSCVA of 20/40 or better. There was no signifi -

cant change in astigmatism, and the refraction showed a

mean hyperopic refractive shift of 1.2 D.

Dr. Meisler notes the outcomes in that series highlight

some of the advantages of DSAEK relative to PKP.

“Wound healing and integrity have always been major con-

cerns with PKP. It can take a year, sometimes longer, for

good vision to be realized after the full-thickness proce-

dure, and even when post-PKP healing is complete, there

are refractive surprises and a remaining risk of refractive

instability and late wound dehiscence,” Dr. Meisler says.

“In contrast, since DSAEK leaves the anterior surface of

the cornea undisturbed, it results in more predictable

refractive outcomes compared with PKP. In addition,

with its cataract-like small incision, DSAEK is associated

with much faster visual recovery as well as better overall

corneal integrity. Most patients who have undergone

DSAEK and who do not have visually disabling, comorbid

disease usually achieve good vision by 3 months post-

operatively and sometimes as early as within 1 month.”

Dr. Meisler, in collaboration with Dr. Dupps and their

Medical College of Wisconsin colleagues Dr. Koenig and

Douglas J. Covert, M.D., M.P.H., have also introduced

technique innovations designed to address some of the

challenges of DSAEK and improve its results. In an article

in the May 2007 issue of The Journal of Cataract and

Cole Eye Institute Experience:DSAEK Has Advantages Over Penetrating Keratoplasty

0

2

Continued from page 1

Refractive Surgery, they describe their technique for

minimizing the occurrence of early graft separation.

The method is designed to maintain a controlled

tamponade pressure using an air-fl uid exchange

pump attached to a 30-gauge needle. The sustained

pressure buoys and pushes the graft up against the

recipient stroma, and it may also help force fl uid out

of the interface. Dr. Meisler and colleagues reported

experiencing no cases of early graft dislocation in

the fi rst 12 eyes in which this system was used.

Another innovation introduced by Drs. Koenig and

Meisler and colleagues aims to assist in the intraocular

unfolding of the graft and employs a modifi ed 30-gauge

needle attached to an air syringe [J Cataract Refract

Surg 2007;33:189-90]. The barbed, bent needle tip

is inserted through a limbal paracentesis or temporal

wound and is used to engage the graft and pin it up

against the host tissue. Then, air is injected posterior to

the graft, causing it to unfold in the correct orientation.

“This technique helps to fi xate the tissue and as-

sures that it unfolds properly,” notes Dr. Meisler.

Ongoing concerns exist with DSAEK; one is endo-

thelial cell loss. The endothelial cell losses may be

attributed in part to an initial steep surgeon learning

curve. However, there remain multiple opportunities

for causing endothelial trauma during the graft har-

vesting, preparation and insertion steps of DSAEK.

“Longer follow-up is needed to see if endothelial cell attri-

tion is greater after DSAEK compared with PKP and to

determine how that phenomenon may affect long-term

graft survival,” Dr. Meisler says. Further, he suggested

that efforts should be directed to modify the technique

in order to minimize endothelial trauma during the

procedure.

3

A patient with pseudophakic bullous keratopathy before (top left) and 1 month after (bottom left and at right) Descemet’s stripping and auto-

mated endothelial keratoplasty at Cleveland Clinic Cole Eye Institute. The cornea is clear with minimal induced refractive error and an improve-

ment in best-corrected visual acuity from 20/200 to 20/30 was achieved.

The good news, however, is that if the graft fails, it can be removed and replaced with a new lenti-

cule. In fact, Dr. Meisler notes he completed a repeat DSAEK without diffi culty in one patient

2 years after the primary procedure. By 1 month after the second surgery, the patient achieved

BSCVA of 20/30.

“Removing the DSAEK donor tissue and replacing it with a new lenticule was not diffi cult, and the

outcome in this patient alleviates concerns that lenticule removal would lead to signifi cant interface

scarring limiting the visual outcome after graft replacement,” Dr. Meisler says.

4

Steven E. Wilson,M.D.

When the femtosecond laser fi rst became available, LASIK surgeons immediately appreciated its ben-

efi ts for creating fl aps of more predictable thickness compared with mechanical microkeratomes and

for minimizing the risks of certain microkeratome-related fl ap complications, including buttonholes,

free caps and partial fl aps. However, with initial clinical experience using the 15-kHz Model II device,

it soon became apparent those advantages were accompanied by some drawbacks. Eyes operated on

with the femtosecond laser manifested a greater infl ammatory response after LASIK along with more

discomfort and a slower visual recovery than those undergoing fl ap creation with a microkeratome.

Postulating that those fi ndings were due to an exacer-

bated corneal wound healing response, Steven E. Wilson,

M.D., and colleagues at the Cole Eye Institute undertook

a study in groups of rabbit eyes to characterize cellular

differences after lamellar fl ap creation with the 15-kHz

femtosecond laser and a mechanical microkeratome

(Hansatome, Bausch & Lomb). The effects of the newer

30-kHz and 60-kHz Model II femtosecond lasers, which

have been associated with less infl ammation in clinical

use than the 15-kHz device, were also studied.

Corneas were excised 24 hours after fl ap creation and

evaluated using a TUNEL assay and immunocytochemi-

cal techniques. Those analyses showed eyes operated

on with the 15-kHz femtosecond laser had signifi cantly

greater infl ammatory infi ltrate compared with the

mechanical microkeratome controls, along with relatively

more stromal cell proliferation and death. However, the

magnitude of the differences in those parameters between

the femtosecond laser and mechanical microkeratome

groups was progressively minimized with each of the new-

er-generation femtosecond lasers, so that most histologic

fi ndings were essentially similar comparing eyes operated

on with the 60-kHz femtosecond laser and the mechani-

cal microkeratome, reported Dr. Wilson and colleagues,

including Marcelo Netto, M.D., in a paper in press in

The Journal of Refractive Surgery.

“When we fi rst began using the 15-kHz femtosecond

laser for LASIK surgery, we noticed immediately that the

eyes had excessive infl ammation on postop day 1 and

some even developed central diffuse lamellar keratitis

(DLK). Therefore, while we believed this new device held

promise, we felt it was appropriate for use only in patients

for whom we could not use a mechanical microkeratome,”

Dr. Wilson says.

“The histologic fi ndings from this preclinical study demon-

strate that upgrades to the femtosecond laser allowing fl ap

creation with lower side-cut and lamellar-cut energies (and,

importantly, lower total energy delivery) have successfully

reduced the augmented infl ammatory and wound healing

responses associated with the 15-kHz version of the laser

and are consistent with our more favorable clinical experi-

ence using the newer models. We anticipate that improved

understanding of laser-tissue interactions with studies such

as ours will enable additional technologic refi nements that

may further expand the applications of the femtosecond

laser and enhance clinical outcomes.”

Histologic Study Provides Insight into Mechanisms of Femtosecond Laser-Induced Infl ammation

5

Cell death caused by the femtosecond laser in

making a LASIK fl ap is much greater with the 15-kHz

laser (arrows in A) than the 30-kHz (arrows in B) or

60-kHz laser, not shown. Even though this cell death

was detected using the TUNEL assay that detects

fragmented DNA usually associated with apoptosis,

subsequent transmission electron microscopy studies

showed that the mode of cell death generated by the

femtosecond laser is actually necrosis [400X].

The researchers also examined the corneas using trans-

mission electron microscopy, and those studies revealed

that necrosis was the primary mode of stromal cell death

in the eyes operated on with the femtosecond laser. Rela-

tive to the eyes operated on with the 15-kHz laser, there

were far fewer necrotic cells in eyes treated with the

30-kHz femtosecond laser and even less with use of the

60-kHz device.

Those fi ndings provide an explanation for understanding

why infl ammation was greatest in eyes operated on with

the 15-kHz femtosecond laser, says Dr. Wilson.

“Cell death by necrosis is associated with release of intra-

cellular contents that trigger infl ammation, and we found

that the number of necrotic cells present was greatest in

eyes operated on with the 15-kHz device and decreased

with the newer devices as the amount of energy delivered

to the cornea was reduced. In contrast, death of stromal

cells after fl ap creation with a mechanical microkeratome

occurs predominantly via apoptosis, which incites a much

lower infl ammatory response,” he explains.

The researchers have also theorized that because the

15-kHz femtosecond laser uses higher side-cut energies

than the 30-kHz and 60-kHz models, it induces relatively

more epithelial cell injury that also contributes to an over-

all greater wound healing and infl ammatory response.

“Injured corneal epithelial cells also release cytokines, like

interleukin-1, that would be expected to bind to surface

receptors on keratocyte cells and upregulate the produc-

tion of chemokines, which up-regulate the infl ammatory

response in the cornea,” notes Dr. Wilson.

B

A

6

“With the approval of ranibizumab (Lucentis, Genen-

tech) in 2006, and the use of bevacizumab (Avastin,

Genentech) off-label, we now have two outstanding treat-

ments that have allowed us not only to offer patients a

good chance for maintaining vision, but that even result

in improved vision in about 40% of patients. However,

these anti-VEGF (vascular endothelial growth factor)

agents are not ideal,” says Cole Eye Institute retinal

specialist Peter K. Kaiser, M.D.

“Both medications require frequent visits and intravitreal

injections, and of course neither is 100% effective. A

number of novel agents are in or about to enter clinical

trials, and our hope is that this investigational work

will identify the next generation of treatments for AMD,

offering advantages compared with available treatment

options.”

Dr. Kaiser also notes that many of the agents now

being developed for AMD work through molecular

mechanisms that are distinct from existing anti-VEGF

therapies. Therefore, they are of interest not only for their

potential activity when administered as monotherapy,

but also because they might offer opportunities for better

effi cacy and safety outcomes achieved through use in

combination regimens.

“By targeting multiple aspects of the complex angiogene-

sis cascade with different treatment modalities, it may be

possible to achieve better results and with lower doses of

each agent relative to what is required in monotherapy,”

Dr. Kaiser explains.

Cole Eye Institute has been the optical coherence

tomography (OCT) reading center for a Phase II study

of the VEGF Trap (Regeneron), a receptor decoy that

traps VEGF and permanently nullifi es the action of

that angiogenic growth factor in the extracellular space.

While the VEGF Trap is also administered by intravit-

real injection and has a mechanism of action somewhat

analogous to that of ranibizumab and bevacizumab, it

has unique pharmacokinetics features that may translate

into potential advantages.

“The VEGF Trap is a smaller molecule that confers better

penetration characteristics. In fact, after intravitreal

injection, it has been found to penetrate fully all of the

retinal layers and to gain access into the subretinal

space where it is required for therapeutic activity. In

addition, because the VEGF Trap binds VEGF at a low

concentration and with very high affi nity, it may have a

longer duration of action and therefore allow a reduction

in treatment frequency. That possible benefi t is being

Peter K. Kaiser,M.D.

Research on Pharmacologic Treatment of AMD Continues with Multitude of Compounds Offering Diverse Mechanisms of Action

Management of age-related macular degeneration (AMD) has taken a major step forward thanks to

recent pharmacologic advances. Since the beginning of this era of drug development, the Cole Eye

Institute has been actively involved in clinical trials, and it is continuing to have an important role as

research continues to identify additional and even better treatment options.

7

investigated in clinical studies,” Dr. Kaiser explains.

The Cole Eye Institute was also one of the fi rst centers in

the world to treat a patient with a small interfering RNA

using the compound AGN211745 (previously known as

SIRNA-027). AGN211745 (Allergan) prevents expres-

sion of the VEGF receptor-1 by blocking production of

its mRNA. It is now in Phase 2 testing, and the Cole Eye

Institute is one of the centers participating in that trial.

“One of the attractive features about this compound is

that it could theoretically be used in combination with

the existing anti-VEGF agents because it acts through an

independent mechanism,” Dr. Kaiser notes.

Cole Eye Institute will also be participating in the Phase

I studies of two other novel investigational agents. One

compound being developed by Quark Biotech acts to

block the production of hypoxia-inducible factor 1alpha

(HIF1alpha), a transcriptional factor that regulates the

expression of a variety of genes that encode for VEGF

and other proangiogenic proteins.

“By working upstream, this agent may provide better

blockade of VEGF relative to ranibizumab and bevaci-

zumab,” Dr. Kaiser says.

The compound from Quark is being tested as an intravit-

real injection. The other compound about to enter Phase

I testing at the Cole Eye Institute is a small molecule

multitargeted tyrosine kinase inhibitor from TargeGen.

It is of signifi cant interest because it is being developed

as a solution for topical administration.

The multitargeted tyrosine kinase inhibitor works down-

stream of VEGF and related growth factors that bind

to cell surface receptors with an intracellular tyrosine

kinase domain. By blocking tyrosine kinase, it prevents

the signaling cascade that is activated when the surface

receptor binds its ligand.

AMD research is also focusing on new ways to optimize

outcomes with existing therapies. The DENALI study

is one such trial under way, and Dr. Kaiser is serving as

chair of that research program.

Sponsored by Novartis, it is designed to see if two cur-

rently available treatments – verteporfi n photodynamic

therapy (Visudyne PDT, Novartis) and ranibizumab

– can be used in combination to control exudative

AMD with a reduced number of intravitreal injections

compared with ranibizumab alone. DENALI is a 2-year

study enrolling approximately 300 patients who are be-

ing randomly assigned 2:1 to ranibizumab plus PDT at

full or half light doses or ranibizumab monotherapy. All

patients in the combination arm initially undergo PDT

and receive three monthly injections of ranibizumab.

Then, the need for further treatments will be based on

monthly assessments of disease activity.

“Various independent investigators have reported achiev-

ing good results with this combination therapy, but

their data are from limited case series. In this rigorous

study, we are hoping that the combination will result in

similar effi cacy compared with ranibizumab alone and

lessen the frequency of the intravitreal injections,”

Dr. Kaiser says.

8

At Cleveland Clinic’s Cole Eye Institute, William J.

Dupps, Jr., M.D., Ph.D., is actively involved in corneal

biomechanics research, including the development of

some innovative measurement techniques.

“Several methods for assessing corneal biomechanics are

in development, and together they have the potential to

provide entirely new ways of studying the structural behav-

ior of the cornea in surgery and disease. Part of the chal-

lenge researchers face moving forward is to determine how

to use the various techniques and the data they provide

to bring us closer to our goal of patient-specifi c surgical

modeling and improved patient care,” says Dr. Dupps.

The understanding of corneal biomechanics and

development of measurement tools promises to deliver

a variety of diagnostic, therapeutic and prognostic ap-

plications, including several relevant to refractive surgery

patients. One area of interest relates to the potential

for improving early diagnosis of corneal ectatic disease,

considering that eyes with forme fruste keratoconus—

and even some with no apparent risk factors—are at

increased risk for a poor outcome after corneal ablative

procedures.

“Ectasia is an overtly biomechanical disease, yet its patho-

genesis is poorly characterized in biomechanical terms.

If biomechanical abnormalities are key features of these

pathologic phenotypes, then they should also be the

target of diagnostic testing. Some patients who develop

post-LASIK ectasia appear to have no prior risk factors,

and perhaps application of biomechanical measure-

ments could identify abnormalities prior to development

of topographic signs of ectasia,” explains Dr. Dupps.

By giving rise to a better clinical defi nition of keratoco-

nus, understanding of the mechanics of ectasia could

also improve comprehension of the pathogenesis of that

disease as well as improve its classifi cation, linkage

analysis efforts and the development of tissue or animal

research models.

A device being developed by Dr. Dupps and colleagues

may ultimately provide a more sensitive approach for

diagnosing subclinical biomechanical abnormalities

in refractive screening exams. The technology uses

high-speed optical coherence tomography to measure

strain within the layers of the cornea during exposure to

a variety of stresses. The data are analyzed with advanced

software and represented in maps that display the cor-

neal biomechanical properties. A study performed by Dr.

Dupps and colleagues demonstrated there are variations

in stiffness across the cornea’s diameter and depth.

William J. Dupps, Jr., M.D., Ph.D.

Breakthroughs on Corneal Biomechanics May Have Broad-Ranging Clinical Consequences

One of the fi rst acknowledgements that the biomechanical properties of the eye have clinical relevance

came in 1937 when Dr. Jonas S. Friedenwald proposed the ocular rigidity function. Seventy years

later, the biomechanical properties of the normal, in situ cornea remain poorly understood. However,

the fi eld is now being rapidly advanced with the development of tools that allow non-invasive, in vivo

assessment of corneal biomechanics. In parallel with this technological revolution, concepts of clinical

applications are also expanding.

9

“The biomechanical properties of the cornea are het-

erogeneous throughout different layers and regions of

the tissue, and these differences could be even greater

in eyes with keratoconus. A technique such as this

that allows regional mapping is critical because global

measurements may obscure local variations and lead to

inaccurate predictions of tissue behavior and less sensi-

tive screening tools,” Dr. Dupps explains.

Understanding of corneal biomechanics is also expected

to provide a foundation for improving outcomes of kera-

torefractive surgery since the intrinsic material proper-

ties of the cornea are thought to modulate individual

responses to LASIK or surface ablation procedures.

For example, measurement of corneal biomechanical

properties preoperatively may allow surgeons to predict

the likelihood of over- or undercorrection after standard

LASIK or surface ablation.

Mapping of stiffness in eyes with post-keratoplasty

astigmatism might also be applied to refi ne the outcome

of treatment with LASIK or astigmatic keratotomy, both

of which can be unpredictable in corneal grafts due to

asymmetric corneal stresses and heterogenous wound

healing. In addition, characterizing the corneal biome-

chanics prior to surgery could help surgeons optimize

the ablation profi le based on the anticipated biomechan-

ical response and improve the predictability of outcomes

of customized ablations.

“Achieving that goal has taken on added importance in

the current era of wavefront-guided refractive surgery

where the outcomes bar has been raised higher than ever

before. The ability to better predict the cornea’s response,

together with improved understanding of wound healing,

could lower existing barriers to more accurate correction

of lower- and higher-order aberrations,” Dr. Dupps says.

Improved accuracy of IOP measurement is another major

implication of better understanding of corneal biome-

chanics, and it has led researchers to develop alternative

technologies for tonometry. Characterization of “true

Continued on page 10

The Ocular Response Analyzer monitors

the pressure (green) of an air puff at

two corneal applanation events (red),

one with indentation, and the other

with recovery from concavity. The

numerical output provides a measure

of viscoelastic absorptive capacity or

corneal hysteresis (CH), overall corneal

resistance (CRF), Goldmann-equivalent

pressure (IOPg) and an IOP that is less

dependent on corneal biomechani-

cal properties (IOPcc). While CH and

CRF are almost identical in the two

eyes of this patient with keratoconus,

the second eye is much more severely

affected clinically. Signifi cant differ-

ences are seen in the morphology of

the measurement signal waveforms

between the two eyes and point to the

importance of studies that dissect the

signal into other potential measures

of disease.

10

IOP” is important for optimizing patient management in a variety

of clinical settings, such as in situations where there appears to be

a mismatch between the measured IOP and ocular pathology. For

example, some patients may be found to have optic nerve damage

but a seemingly normal IOP while others may have an elevated

IOP without any evidence of structural or functional glaucomatous

damage. The ability to measure IOP accurately in those cases

would enable appropriate diagnosis and management.

Availability of a technique for accurately measuring IOP is also im-

portant in patients with a history of keratorefractive surgery since

IOP is factitiously lowered after corneal ablative surgery.

“Considering the number of people who are undergoing those

procedures underlines the importance of developing technology

for properly measuring IOP and allowing the correct identifi ca-

tion of patients who go on to develop ocular hypertension and

glaucoma,” Dr. Dupps says.

Determinations of corneal biomechanical properties may also hold

the key to understanding the relationship between IOP, central

corneal thickness and glaucoma risk as recent evidence indicates

corneal elasticity may be more important than corneal thickness

as a source of error in IOP measurement. A recent report that

biomechanics measurements obtained with the Ocular Response

Analyzer (Reichert) correlate to glaucoma progression in a relation-

ship that is independent of IOP suggests biomechanical features of

the eye may also have value for predicting which glaucoma patients

are at risk for worsening and whose disease might remain stable.

“That information could then be used to help decide which patients

might be appropriate candidates for intervention and who might

be assigned instead to careful surveillance,” Dr. Dupps says.

Defi ning the biomechanical properties of the normal cornea is

also expected to provide researchers with material benchmarks for

developing stable, mechanically compatible corneal prostheses and

bioengineered tissue equivalents.

Stem cell transplantation is

considered to have enormous

potential as a therapeutic strategy

for restoring vision lost second-

ary to a number of common

ophthalmologic diseases. To

date, proof of principle studies

performed in animal models

have yielded encouraging results in demonstrating that

neural stem cells transplanted into the eye survive and

can be driven to differentiate into phenotypes, including

photoreceptor cells and retinal pigment epithelial cells.

It has also been shown that stem cells can be used to

reverse processes such as abnormal neovasculariza-

tion in the eye. However, success has been measured

mostly through histologic evaluation; in most of these

studies, there is not suffi cient effi ciency of rescue that

would translate into restoration of visual function.

There are many questions to be answered and challenges

to overcome in this fi eld. Recognizing that the effi cacy

of stem cell transplantation depends in part on numbers

– the ability to harvest large numbers of stem cells and

then to generate from them large numbers of appropri-

ately differentiated cells − researchers at Cleveland Clin-

ic’s Cole Eye Institute have been focusing on developing

techniques for optimizing stem cell isolation and for in-

creasing the effi ciency of retinal stem cell differentiation.

“The ability to drive stem cell differentiation into cells

of desired lineage has been demonstrated by assessing

expression of cell-specifi c markers. However, in order

for stem cell transplantation to be a clinically viable

technique, we need to be able to control the maturation

process so it is more reliable and effi cient,” says Nadia K.

Waheed, M.D., M.P.H.

Nadia K. Waheed,M.D., M.P.H.

Novel Technique Being Applied to Improve Effi ciency of Stem Cell Differentiation

Breakthroughs on Corneal Biomechanics May Have Broad-Ranging Clinical Consequences


11

The research interests of Dr. Waheed and colleagues are

centered on two areas − the use of stem cell transplanta-

tion as a technique for replacing photoreceptor cells

lost as a result of neurodegenerative diseases and also

as a treatment for ocular neovascular diseases, where

stem cell therapy would be used to induce regres-

sion of existing neovascular membranes and promote

the growth of normal vessels by driving stem cell

differentiation along an endothelial cell pathway.

In previous work presented by Dr. Waheed at the

Association for Research in Vision and Ophthalmol-

ogy annual meeting, she found that retinal stem

cells, in their natural environment, commit to dif-

ferentiation earlier than was previously thought.

“Even though retinal stem cells have been isolated and

cultured more than a week postnatally in mice, we

found that a signifi cant number of these cells commit

to differentiation within 3 to 5 days. This research

suggests that the most effi cient time to isolate stem cells

would be within a few days of birth,” she explains.

To promote more effi cient stem cell differentiation

along the photoreceptor lineage, Dr. Waheed and col-

leagues are studying whether the maturation process

can be enhanced by coadministering transcription

factors that are known to be integral in promoting

stem cell differentiation along specifi c pathways.

“These transcription factors are produced intracel-

lularly and drive the transcription of proteins critical

for cell development. We know from previous research

on knock-out animals that maturation of specifi c cell

phenotypes does not occur when these transcription

factors are absent. Now, we will be testing the hypothesis

that introducing those same factors may enhance the

effi ciency of stem cell maturation,” Dr. Waheed explains.

Transcription factors, however, are usually produced

within cells, and if introduced outside the cell, do

not penetrate intracellularly in suffi cient concentra-

tions to exert pharmacologic activity. To overcome this

obstacle, Cole Eye Institute investigators are collaborat-

ing with colleagues in Cleveland Clinic’s Department

of Cardiology. Using cardiac stem cells, the cardiology

team has developed a proprietary method whereby

additional amino acid sequences are attached to the

transcription factors. The sequences are recognized

by the stem cells as “uptake sequences” and signal

the cell to transport the extracellular protein, includ-

ing the transcription factor, across its membrane.

“The feasibility of this technique was demonstrated

through pilot testing using cardiac stem cells. Now we

hope to apply this technology to retinal stem cells,” say Dr.

Waheed, who is also collaborating with fellow Cole Eye

Institute researcher Bela Anand-Apte, Ph.D., M.B.B.S.

The ophthalmic research will be performed in murine

models of retinal degeneration and neovascularization

and uses postnatal stem cells derived from the same

species that are being injected simultaneously into the

eye with the modifi ed transcription factors. The animals

will be followed to determine if the transcription fac-

tors provide the necessary push to encourage stem cell

differentiation along the desired maturation pathways.

Rhodopsin-green fl uorescent protein (GFP) fusion (rho-gfp) mice had their native rhodopsin gene replaced by the human rhodopsin gene with its C terminus modifi ed to encode an enhanced GFP fusion. GFP expression in these mice serves as a sensitive indicator of rod-cell structure and integrity. It may also serve as a mark-er for rod specifi c progenitor cells in the retina of these mice. Nadia Waheed, M.D., M.P.H., and colleagues examined GFP expression in vivo and in vitro in the retina of the rho-gfp mice.

At top, GFP expression in the photoreceptor layer of a rho-gfp mouse.

Middle photo, a fi ve-day postnatal mouse retina. Some GFP expression is seen in the photoreceptor layer.

Bottom photo, a seven-day postnatal mouse retina. GFP expression is seen in the photoreceptor layer.

12

A new multiauthored textbook on ophthalmic

oncology includes two Cole Eye Institute ophthal-

mologists, Arun D. Singh, M.D., and Julian D.

Perry, M.D., among its fi ve editors.

Entitled Clinical Ophthalmic Oncology, it is the

largest textbook ever published on this topic and

is a comprehensive reference source on the diagno-

sis and management of all types of ocular cancers.

The book contains more than 100 chapters and

over 650 pages. The chapters are written by 124

contributing authors representing experts in the

fi eld from 18 countries.

The textbook’s contents cover all aspects of clinical

ophthalmic oncology, including eyelid, conjunc-

tival, intraocular and orbital tumors. In addition,

the volume includes a section on basic sciences that reviews the latest

information on tumor angiogenesis, basic principles of radiation and

radiation complications.

Dr. Singh says the textbook is designed to be user-friendly. The content is

presented in a practical format with a clinical focus and is easy to search

for desired information. Numerous graphics supplement

the written text. The book contains more than 700 clinical

photographs, histolopathologic microphotographs and

imaging studies along with tables, algorithms and illustra-

tions highlighting key information.

Packaged with the book is a CD-ROM containing fi gures

from the text that can be downloaded for use in Power-

Point presentations.

Clinical Ophthalmic Oncology is published by Saun-

ders Elsevier and has a list price of $199.

In other news from the publishing world, Dr. Singh was also

recently named editor of the British Journal of Ophthalmology

(USA). The British Journal of Ophthalmology is a monthly publi-

cation with an international circulation. It features peer-reviewed articles

for ophthalmologists and vision scientists reporting on clinical investiga-

tions, clinical observations and clinically relevant laboratory studies.

Textbook a Defi nitive Resource on Ocular Tumor Diagnosis, Management

Arun D. Singh,M.D.

The following studies are currently enrolling. All

studies have been approved by the Institutional

Review Board.

GENETICS

Studies of the Molecular

Genetics of Eye Diseases

Objective: To map the genes for inherited eye diseases. To screen candidate genes for muta-tions in a variety of genetic ocular disorders, including ocular malformations, congenital cataracts and retinal dystrophies.

Contact: E. Traboulsi, M.D., at 216.444.4363 or S. Crowe, C.O.T., at 216.445.3840

The Genetics of Strabismus

Objective: To discover the genes that cause some strabismus syndromes, including those for accommodative esotropia, congenital esotropia, congenital ocular fi brosis syndrome, intermittent exotropia, Brown syndrome and Duane syndrome.

Contact: E. Traboulsi, M.D., at 216.444.4363

or S. Crowe, C.O.T., at 216.445.3840

PEDIATRICS

Infant Aphakia Treatment Study

Objective: To determine whether infants with a unilateral congenital cataract are more likely to develop better vision following cataract extrac-tion surgery if (1) they undergo the primary implantation of an IOL or (2) they are treated primarily with a contact lens.

Contact: E. Traboulsi, M.D., at 216.444.4363 or S. Crowe, C.O.T., at 216.445.3840

CLINICAL TRIALS

Julian D. Perry,M.D.

13

RETINAL DISEASES

Protocol B7A-MC-MBDL Reduction

in the Occurrence of Center-Threatening

Diabetic Macular Edema

Objective: The primary objective of this study is to test the hypothesis that oral administration of 32 mg per day of ruboxistaurin for ap-proximately 36 months will reduce, relative to placebo, the occurrence of center-threatening diabetic macular edema as assessed by fundus photography in patients with non-clinically signifi cant macular edema and nonproliferative diabetic retinopathy at baseline.

Contact: P. Kaiser, M.D., at 216.444.6702 or L.

Schaaf, R.N., at 216.445.4086

Protocol B7A-MC-MBCU The Effect

of Ruboxistaurin on Clinically Signifi cant

Macular Edema in Patients with

Diabetes Mellitus, as assessed by

Optical Coherence Tomography

Objective: The primary objective of this study is to test the hypothesis that oral administra-tion of 32 mg per day of ruboxistaurin for 18 months will reduce the baseline to endpoint changes in central macular thickness, as mea-sured by OCT in patients with CSME.


Schaaf, R.N., at 216.445.4086

A Six-Month Phase 3, Multicenter, Masked,

Randomized, Sham-Controlled Trial (with Six-

Month Open-Label Extension) to Assess the

Safety and Effi cacy of 700 μg and 350 μg

Dexamethasone Posterior Segment

Drug Delivery System

Objective: To evaluate the safety and effi cacy of the 700 μg DEX PS DDS Applicator System and 350 μg DEX PS DDS Applicator System

compared with a Sham DEX PS DDS Applicator System (needle-less applicator) for six months in patients with macular edema following branch retinal vein occlusion or central retinal vein occlusion. The safety of the 700 μg DEX PS DDS Applicator System will be assessed for an additional 6 months in patients who qualify for treatment in an open-label safety extension.

Contact: P. Kaiser, M.D., at 216.444.6702 or L. Schaaf, R.N., at 216.445.4086

A Randomized Trial Comparing

Intravitreal Triamcinolone Acetonide

and Laser Photocoagulation for

Diabetic Macular Edema

Objective: To determine whether intravitreal triamcinolone acetonide injections at doses of 1 mg or 4 mg produce greater benefi t, with an acceptable safety profi le, than macular laser photocoagulation in the treatment of diabetic macular edema.


Holody, C.O.A., at 216.445.3762

A 3-Year, Phase 3, Multicenter,

Masked, Randomized, Sham-Controlled Trial

to Assess the Safety and Effi cacy of 700

μg and 350 μg Dexamethasone Posterior

Segment Drug Delivery System (DEX PS

DDS) Applicator System in the Treatment of

Patients with Diabetic Macular Edema

Objective: To evaluate the safety and effi cacy of the 700 μg DEX PS DDS Applicator System and 350 μg DEX PS DDS Applicator System compared with a Sham DEX PS DDS Applicator System (needle-less applicator) in patients with diabetic macular edema.

Contact: P. Kaiser, M.D., at 216.444.6702

or L. Schaaf, R.N., at 216.445.4086

A Phase IIIb, Multicenter Study To Evaluate

the Safety and Tolerability of Ranibizumab in

Naïve and Previously Treated Subjects with

Choroidal Neovascularization Secondary to

Age-Related Macular Degeneration

Objective: To estimate the incidence of ocular and non-ocular serious adverse events in sub-jects treated for 12 months with 0.3 mg or 0.5 mg intravitreal ranibizumab.

Contact: P. Kaiser, M.D., at 216.444.6702 or

Lynn Bartko, R.N., at 216.444.7137

GLAUCOMA

Advanced Imaging for Glaucoma

Objective: Advanced Imaging for Glaucoma (AIG) is a multi-center bioengineering partner-ship sponsored by the National Eye Institute to develop advanced imaging technologies to improve the detection and management of glaucoma. The advanced imaging technolo-gies include optical coherence tomography, scanning laser polarimetry and scanning laser tomography. The technologies will be evaluated in a longitudinal fi ve-year clinical trial composed of glaucoma suspects, glaucoma patients and normal subjects.

Contact: S. Smith, M.D., M.P.H., at 216.444.4821 or L. Holody, C.O.A., at 216.445.3762

Programs in Ophthalmic Education 2006-2007

14

Thursday and Friday, June 21-22, 2007

5:00 p.m. to 7:30 p.m. (Thursday);

7:30 a.m. to 6:00 p.m. (Friday)

Course Directors:

Hilel Lewis, M.D.

Chairman, Division of Ophthalmology

Director, Cleveland Clinic Cole Eye Institute

Careen Y. Lowder, M.D., Ph.D.

Director, Uveitis Department

Cleveland Clinic Cole Eye Institute

Keynote Speaker:

Paul A. Sieving, M.D., Ph.D.

Director, National Eye Institute,

National Institutes of Health

Bethesda, MD

Annual Research, Residents & Alumni Meeting

Description/Objectives:

This program provides a scientifi c forum to present original,

thought-provoking clinical research papers and basic science

research of the Cole Eye Institute residents, fellows, staff, alum-

ni and invited ophthalmologists. In addition to the educational

aspects of the program and learning about new and ongoing

investigations, this event offers an excellent opportunity to meet

current residents, fellows, new faculty and invited ophthalmolo-

gists, and to make and renew friendships.

At the conclusion of the meeting, participants should be able to:

1. Recognize the most up-to-date concepts and treatments in research

and clinical ophthalmology.

2. Identify current basic science research in age-related macular

degeneration.

3. Review the rationale and status of the most current treatments for

uveitic and diabetic macular edema.

4. Discuss outcomes of complicated glaucoma and cataract surgery.

5. Describe the latest techniques in refractive surgery.

15

Physicians are invited to attend the following ophthalmic continuing medical education courses at Cleveland Clinic’s Cole Eye Institute. All courses will be held in the James P. Storer Conference Center on the fi rst fl oor of the Eye Institute.

For more information, contact Jane Sardelle, program coordinator, at 216.444.2010 or 800.223.2273, ext. 42010, or [email protected].

September 29, 2007

Biomechanics of Strabismus

Course Director:

Elias I. Traboulsi, M.D.

October 27, 2007

Cerebrovascular Diseases and the Eye

Course Directors:

Gregory S. Kosmorsky, D.O.

Lisa D. Lystad, M.D.

January 12, 2008

Glaucoma Management in 2007-2008: Pearls and Pitfalls

Course Directors:

Edward J. Rockwood, M.D.

Scott D. Smith, M.D., M.P.H.

February 9, 2008

Ophthalmic Oncology Update

Course Director:

Arun D. Singh, M.D.

March 8, 2008

Innovations in Ocular Infl ammatory Diseases

Course Director:


March 23 through 28, 2008

Innovations in Ophthalmology:Spring Break in Los Cabos, Mexico

Course Director:

Hilel Lewis, MD

May 31, 2008

Posterior Segment Complications of Anterior Segment Surgery

Course Director:

Andrew P. Schachat, M.D.

June 7, 2008

Innovations in Refractive Surgery

Course Directors:

Ronald R. Krueger, M.D.

Steven E. Wilson, M.D.


June 19 and 20, 2008

Annual Research, Residents & Alumni Meeting

Course Directors:


Hilel Lewis, M.D.

Mark your calendar!

Programs in Ophthalmic Education, 2007-2008

I N F O R M A T I O N

For information regarding

these courses, please contact

Jane Sardelle at [email protected]

or 216.444.2010.

July 19, 2007

Pathogenesis of Dry AMD:

Role of Smoking and RPE Injury

Scott W. Cousins, M.D.

Professor of Ophthalmology

Duke Center for Macular Disease

Duke University Eye Center

Durham, NC

September 27, 2007

Modeling Age-Related Macular

Degeneration Using a Multifactorial

Murine Model

Catherine Bowes Rickman, Ph.D.

Assistant Professor

Departments of Ophthalmology and Cell Biology

Duke University Medical Center

Durham, NC

October 18, 2007

Role of VEGF in Blood Vessel Growth

and Stability Implications for

Anti-Angiogenic Therapies

Patricia A. D’Amore, Ph.D.

Senior Scientist

Ankeny Scholar of Retinal

Molecular Biology

Professor, Harvard Medical School

The Schepens Eye Research Institute

Boston MA

November 15, 2007

Macular Degeneration and the

Metabolic Demands of Vision

Robert B. Barlow, Ph.D.

Professor of Ophthalmology

Director, Center for Vision Research

SUNY Upstate Medical University

Syracuse, NY

16

DISTINGUISHED LECTURE SERIES

Cleveland Clinic’s Cole Eye Institute Distinguished Lecture Series provides a forum for renowned researchers in the visual sciences to present

their latest fi ndings. This series features advances in many areas of ophthalmic research, from noted basic and clinical scientists throughout

the world. There will be ample opportunity for questions and discussion. Please join us for these insights into discoveries in ophthalmology

research and the promises they hold for patient care. All programs are held in the James P. Storer Conference Center on the fi rst fl oor of the

Cole Eye Institute from 7 to 8 a.m.

There is no registration required. If you have any questions, please call 216.444.5832.

17

COLE EYE INSTITUTE STAFF

Hilel Lewis, M.D.

Chairman, Division of Ophthalmology

Director, Cole Eye Institute

Specialty/Research Interests: Vitreoretinal

surgery for complicated retinal detachment and

trauma, age-related macular degeneration,

diabetic retinopathy, retinal photocoagulation,

instrument development

Bela Anand-Apte, M.B.B.S., Ph.D.

Ophthalmic Research Department

Research Interest: Angiogenesis

John W. Crabb, Ph.D.


Research Interests: Age-related macular

degeneration, inherited retinal diseases


Cornea and External Disease Department

Specialty/Research Interests: Cornea, cataract

and refractive surgery

Marc A. Feldman, M.D.

Ophthalmic Anesthesia

Specialty Interests: Ophthalmic surgery

anesthesia, preoperative assessment, resident

education

Richard E. Gans, M.D., F.A.C.S.

Comprehensive Ophthalmology Department

Specialty Interests: Cataract, glaucoma,

diabetes

Philip N. Goldberg, M.D.


Specialty Interests: Cataract, glaucoma

Froncie A. Gutman, M.D.

Vitreoretinal Department

Specialty Interests: Retinal vascular diseases,

laser therapy, diabetic retinopathy

Stephanie A. Hagstrom, Ph.D.


Research Interests: Inherited forms of retinal

degeneration, including macular degeneration

and retinitis pigmentosa

Joe G. Hollyfi eld, Ph.D.


Research Interests: Retinal degeneration,

retinal diseases

Bennie H. Jeng, M.D.


Specialty/Research Interests: Corneal

transplantation, ocular surface disease, limbal

stem cell transplantation, artifi cial corneas,

eyebanking, cataracts

Peter K. Kaiser, M.D.


Specialty/Research Interests: Vitreoretinal

diseases, age-related macular degeneration,

retinal detachment, diabetic retinopathy,

endophthalmitis, posterior segment

complications of anterior segment surgery

Gregory S. Kosmorsky, D.O.

Neuro-Ophthalmology Department

Specialty Interests: Neuro-ophthalmology,

cataract, refractive surgery

Ronald R. Krueger, M.D., M.S.E.

Refractive Surgery Department

Specialty/Research Interests: Refractive

surgery, lasers, refractive corneal pathology,

lamellar corneal transplants, investigational

clinical trials

Roger H.S. Langston, M.D.


Specialty Interests: Cornea and external

disease, corneal transplantation


Uveitis Department

Specialty/Research Interests: Uveitis,

intraocular infl ammatory diseases, pathology

Continued on page 18

18



Neuro-Ophthalmology and Comprehensive

Ophthalmology

Specialty Interests: Neuro-ophthalmology,

general eye care

Andreas Marcotty, M.D.

Pediatric Ophthalmology and

Strabismus Department

Specialty Interests: Pediatric ophthalmology,

adult strabismus

Shari Martyn, M.D.



diabetes

David M. Meisler, M.D.


Specialty/Research Interests: Corneal and

external disease, infl ammatory and infectious

diseases of the cornea, corneal transplantation,

refractive surgery

Michael Millstein, M.D.



refractive surgery

Neal S. Peachey, Ph.D.


Research Interests: Visual loss associated with

hereditary retinal degeneration

Julian D. Perry, M.D.

Oculoplastic and Orbital Surgery Department

Specialty/Research Interests: Aesthetic facial

surgery/fat transplantation and repositioning,

acellular human dermal graft matrix, new

bovine hydroxyapatite orbital implant,

thyroid eye disease/rate of strabismus

after decompression surgery for dysthyroid

orbitopathy

Edward J. Rockwood, M.D.

Glaucoma Department

Specialty/Research Interests: Glaucoma,

glaucoma laser surgery, combined cataract and

glaucoma surgery, glaucoma fi ltering surgery

with antimetabolite therapy, glaucomatous

optic nerve damage, congenital glaucoma

Allen S. Roth, M.D.


Specialty Interests: Corneal transplantation,

refractive surgery, cataract and implant surgery

Andrew P. Schachat, M.D.


Vice Chairman of Clinical Affairs

Specialty/Research Interests: Age-related

macular degeneration, diabetic retinopathy,

medical retina

Jonathan E. Sears, M.D.


Specialty/Research Interests: Pediatric and

adult vitreoretinal diseases, pediatric retinal

detachment, inherited vitreoretinal disorders,

retinopathy of prematurity, other acquired

proliferative diseases

David B. Sholiton, M.D.


Specialty Interests: Cataract and implant

surgery, glaucoma, oculoplastics

Arun D. Singh, M.D.

Ophthalmic Oncology Department

Specialty/Research Interests: Adult and

pediatric ocular tumors, uveal melanoma,

genetics of retinoblastoma, retinal capillary

hemangioma, von Hippel-Lindau disease.


19


Scott D. Smith, M.D., M.P.H.

Glaucoma Department

Specialty/Research Interests: Glaucoma,

cataract, prevention of eye disease,

international ophthalmology, congenital

glaucoma

Elias I. Traboulsi, M.D.

Pediatric Ophthalmology and

Strabismus Department

Center for Genetic Eye Diseases

Specialty/Research Interests: Ocular diseases

of children, genetic eye diseases, strabismus,

retinoblastoma, congenital cataracts,

childhood/congenital glaucoma

Nadia K. Waheed, M.D., M.P.H.


Specialty/Research Interests:

Medical and surgical retina

Steven E. Wilson, M.D.

Cornea and External Disease and Refractive

Surgery Departments

Specialty/Research Interests: Refractive

surgery, corneal healing

216.444.2020Cleveland Clinic

Cole Eye Institute

www.clevelandclinic.org/eye

Lisa D. Lystad, M.D., Joins Cole Eye Institute Staff


Ophthalmology Update, a publication of The Cleveland Clinic Cole Eye Institute, provides information for ophthalmologists about state-of-the-art diagnostic and man-agement techniques and current research.

Please direct any correspondence to:

Steven E. Wilson, M.D.Cole Eye Institute / i32The Cleveland Clinic Foundation9500 Euclid AvenueCleveland, Ohio 44195

Phone 216.444.5887Fax 216.445.8475

Director and Division ChairmanHilel Lewis, M.D.

Editor-in-ChiefSteven E. Wilson, M.D.

Managing EditorBeth Thomas Hertz

Art DirectorChip Valleriano

PhotographersDon GerdaDeborah Ross, C.R.A.

The Cleveland Clinic Foundation is an indepen-dent, not-for-profi t, multispecialty academic medical center. It is dedicated to providing quality specialized care and includes an outpatient clinic, a hospital with more than 1,000 available beds, an education division and a research Institute.

Ophthalmology Update is written for physicians and should be relied upon for medical education purposes only. It does not provide a complete overview of the topics covered and should not replace the independent judgment of a physician about the appropriateness or risks of a procedure for a given patient.

Physicians who wish to share this information with patients need to make them aware of any risks or potential complications associated with any procedures.

© The Cleveland Clinic Foundation 2007

07-EYE-006

The Cleveland Clinic FoundationCole Eye Institute9500 Euclid Avenue / W14Cleveland, OH 44195

Non-Profi t Org.U.S. Postage

PAIDCleveland, OH

Permit No. 4184

Lisa D. Lystad, M.D., joined Cleveland Clinic’s Cole Eye

Institute in January. Previously, she had practiced in

the Greater Cleveland area for nearly 15 years. She is

a comprehensive ophthalmologist with a subspecialty

in neuro-ophthalmology. She is interested in the visual

complications of systemic diseases such as multiple

sclerosis, myasthenia gravis, brain tumors and stroke.

“I am excited to have joined the Cole Eye Institute and

have the opportunity to work closely with a team of

specialists with access to state-of-the-art diagnostic equipment, treatment and research

facilities,” says Dr. Lystad.

She will see patients on the main campus and at Cleveland Clinic’s suburban Beachwood

ophthalmology offi ce.

Dr. Lystad is a graduate of Tufts University School of Medicine in Boston, where she also

served her residency. She completed a fellowship in neuro-ophthalmology at University

Hospitals of Cleveland in 1991-1992. She holds a bachelor’s degree from Johns Hopkins

University in Baltimore and a masters degree from Johns Hopkins’ Whiting School of

Engineering.

To reach Dr. Lystad, please call 216.444.2020 (main campus) or 216.831.0120 (Beachwood).

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