best glaucoma aao 2008

A S U P P L E M E N T T O E Y E N E T M A G A Z I N EEyeNet

S E L E C T I O N S

The Best of CATARACT SURGERY

The Best of CATARACT& REFRACTIVE SURGERY

The Best of REFRACTIVE SURGERY

The Best of RETINA

The Best of PRACTICEMANAGEMENT

e y e n e t s e l e c t i o n s 5

Dear Glaucoma Subspecialty Day Attendee, The glaucoma community is witness-

ing a quiet paradigm shift, away from therigid absolutes of IOP and toward a morenuanced understanding of pressure fluc-tuations and optic nerve sensitivities.This year’s Glaucoma Subspecialty Day meeting, “The Pendulum Swings,”explores these nuances, including thenew thinking around normal-tensionpatients and the impact of perfusionpressure and central corneal thickness.

It’s a perfect time to review the state

of glaucoma science with a perusal ofEyeNet Selections, our best glaucoma stories from the past year. Enjoy yourSubspecialty Day as well as the AtlantaMeeting’s additional offerings on con-temporary glaucoma medicine!

L e t t e r F r o m t h e E d i t o r

EyeNetGLAUCOMA SUBSPECIALTY DAY

ATLANTA 2008

S E L E C T I O N S

Glaucoma Eyedrops: A Fresh Look at PreservativesDo preservatives in eyedrops harm the cornea? Four glaucomaspecialists weigh in.

7

Neuroprotection Research, Part OneA survey of fresh ideas and new research suggests that glaucoma may be more than one disease.

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Neuroprotection Research, Part TwoInteresting new targets—axonal degeneration, gliosis and pressure injury—may lead to promising glaucoma therapies.

13

clinical update

17feature

ON THE COVER: Retinal ganglion cells in a mouse marked red by gamma-synuclein mRNA, and their axonsgreen by the TUJ-1 antibody. Nuclei of surrounding cells are blue. Nicholas Marsh-Armstrong, PhD

The Incision Decision: When Glaucoma ProgressesFive experts discuss their criteria to proceed with surgery whenglaucoma hasn’t responded (or patients weren’t adherent) tomedications.

Richard P. Mills, MD, MPHChief Medical Editor

EyeNet Magazine/EyeNet Selections

e y e n e t s e l e c t i o n s 7

Benzalkonium chloride (BAK)is generally regarded as aneffective agent for preventingbacterial contamination ofglaucoma eyedrops. However,

its advantages and disadvantages areunder scrutiny for possible effects onmedical and surgical management.

“BAK is a mixed bag,” said RichardA. Lewis, MD, glaucoma specialist inprivate practice in Sacramento, Calif.,and former president of the AmericanGlaucoma Society. “For years, it wasthought that BAK helped penetrationso there was better drug effect. In theold days, when pilocarpine was com-monly used for glaucoma, it had suchpoor penetration that BAK was added toget more drug effect. But more recently,prostaglandin eyedrops, such as latano-prost, bimatoprost and travoprost, pen-etrate so very well that there is no needfor BAK to get penetration,” Dr. Lewissaid. He suggested that this renders anyhazards of the preservative unnecessary.“You don’t need BAK if you can get equalefficacy without the side effects of BAK.”

Prostaglandins have become formany clinicians the preferred first-linetherapy.

Some ophthalmologists are emphaticabout the hazards posed by the preserv-ative. “BAK is bad for the conjunctiva,the cornea and perhaps even the trabec-ular meshwork,” said John R. Samples,MD, professor of ophthalmology at theOregon Health & Science University in

Portland. “It is a toxic detergent. Itattracts monocytes and lymphocytesinto the conjunctiva and it makes thetissue thicken up.”

Bad BAK? Dr. Samples contends that BAK can havenegative consequences that extend fromthe ocular surface all the way to the pos-terior pole. “BAK makes dry eye worsein some patients; it is toxic to cornealepithelial cells and, according to ourlaboratory work, it is toxic to cornealendothelial cells and trabecular cellswhen it enters the anterior chamber;it gives us a dysfunctional conjunctivawhen it comes time to consider filtra-tion; it has a complex role in setting upallergic reactions in the eye. It has evenbeen implicated in the occurrence ofcystoid macular edema,” he noted.

Cumulative damage. “There’s someevidence that total lifetime eye exposureto BAK is important in the late-occur-ring follicular conjunctivitis that appearswith long-term use of adrenergic ago-nists,” added Dr. Samples.

Dr. Lewis agreed. “The greater theexposure to the preservative, the greaterthe effect and that effect is cumulative.There are a lot of dry eye problems withBAK,” he said. “There are eyelid andconjunctival problems, irritation andredness, with the whole ocular surfaceaffected by these preservatives.” He findsit affects tear function and that evenminor exposure may induce cell-growtharrest and death by necrosis or apoptosis.

Surgery made riskier. Dr. Lewis alsosaid that patients who have been on

long-term therapy with BAK-preservedeyedrops may pose surgical problemsstemming from ocular surface changesand dry eye. “The conjunctiva is moretoxic from BAK, which causes increasedscar tissue that is more reactive andinflammatory and may affect the suc-cess rate of trabeculectomies.”

Dr. Samples added that prior expo-sure to BAK is more likely to cause blebfailure and that the blebs created by fil-tration surgery are more likely to scardown, although it is difficult to measureor see. He added that more research isneeded in this area.

Association with failure. One Frenchstudy found that failure of surgical treat-ment is mainly linked to the duration

Glaucoma Eyedrops:A Fresh Look at Preservatives

G L A U C O M A

Clinical Updatetools and t echn iques

by pat phillips, contributing writer

Some physicians are concerned aboutthe long-term effects of eyedroppreservatives on various ocular tissues.

1 g t t o u q h s

This article originally appeared in the January

2008 issue of EyeNet Magazine.

8 s u p p l e m e n t

and the extent of previous medicaltreatment with preservative-containingglaucoma eyedrops. The study suggestedthat failure was associated with inflam-mation of the ocular surface structures.1

The study also compared the toxicityof eyedrops with and without preserva-tives, and found that ocular symptomsin the conjunctiva, cornea and eyelidswere less prevalent with preservative-free eyedrops, adding that “the benefitsof reducing microbial contaminationthrough use of preservative are offset bythe known ocular side effects of preser-vatives.”

Medicine or Marketing?But many in the ophthalmic communityregard BAK as a safe preservative thatdoes a good job in protecting againstbacteria, according to Alan Sugar, MD,professor and associate chairman ofophthalmology and visual sciences at theUniversity of Michigan, Ann Arbor.

“Recently, there’s been an upswing of interest in the issue of preservatives,”Dr. Sugar said. “Some of the attention isdue to marketing. Companies want tomarket a glaucoma drug that does nothave BAK, as a marketing edge. Some ofthe attention is increased awareness thattoxicity can occur, even though in mymind, it doesn’t occur that frequently.”

Richard P. Mills, MD, MPH, agreed.“I find it hard to believe that for mostpatients a single drop of BAK-contain-ing preservative per day will cause sig-nificant surface problems. Certainlythat has been my experience after yearsof observation.”

Toxicity to BAK does develop in somepatients, but not in most, according toDr. Sugar. “For most patients it’s notthat big a deal. There’s less to the issueof BAK than meets the eye.”

Dr. Mills, who is in private practicein Seattle, noted that each patient shouldbe approached as a separate case.“Obvi-ously, there are sensitive patients, and, ofcourse, it’s quite another matter whentherapy involves multiple drops per day.”

No-Preser vative Approach Dr. Lewis recently conducted a study ofthe prostaglandin drug travoprost, withand without BAK.2 The BAK-free for-

mulation is sold as Travatan Z (Alcon).The study involved 700 open-angle glau-coma or ocular hypertension patientswith pressures between 24 and 36 mmHg.In this double-masked, randomizedstudy, the medication was used once inthe evening and IOP was measured atthree different intervals throughout the day.

“Our study results show that youdon’t need BAK for drug penetration,”Dr. Lewis said. “There was equal efficacywith the IOP changes between Travatanwith and without BAK. Now, glaucomaspecialists have choices.”

Ophthalmic researchers will probablybe getting rid of BAK and substituting a more benign preservative wheneverpossible, according to Dr. Samples. Hesaid this should have been done already.As long as 20 years ago, he analyzed BAKand identified its disadvantages. “It issurprising how often I will encounterolder ophthalmologists who recall notingthe toxic effects of BAK and discussingit with manufacturers and colleagues.”

Future directions. “The pipeline fordevelopment of glaucoma drugs is veryrich,” said Dr. Samples. “There are manynew classes of glaucoma medications,perhaps four or five, in the pipeline,” hesaid. “Companies such as Alcon, Aller-gan, Merck, Ista and Pfizer all have newglaucoma treatments under develop-ment.” He added that many companiesare looking at modifications of theprostaglandins, and he is hopeful thatthese will come without the addition ofBAK.

Drop the Drops Altogether?One new treatment approach underdevelopment for glaucoma uses a com-pletely different delivery system: injec-table medication. Anecortave acetate,for example, is a modified steroid thatappears to control high IOP for at leastthree months with only a single injec-tion, and it is currently under clinicalinvestigation as a glaucoma treatment.3

(Alcon has also been studying anecor-tave acetate depot suspension to treatwet AMD.)

Dr. Samples views anecortave acetateas a possible solution to the continuingproblem of patient compliance with

eyedrops. “Now here’s a drug you caninject and you don’t have to worry aboutcompliance anymore.”

“It’s an interesting concept that wouldtake the preservative problem out of thepicture,” agreed Dr. Lewis.

Beyond lowering the IOP. Variousneuroprotective drugs are also underinvestigation and ultimately may becomeused as injectables in the treatment ofglaucoma. Glatiramer acetate, a drugcurrently used to treat multiple sclero-sis, is under study as a possible neuro-protective agent to prevent damage tothe optic nerve.

In the future, Dr. Lewis said he ishopeful for both better preservativesand new routes of administration. “Iwant to see drugs that have a longerduration of action so that we get bettercompliance and less exposure,” he said.“And we need to get beyond ocularpressure-lowering medications to theneuroprotective drugs.”

1 Pisella, P. J. et al. Br J Ophthalmol 2002;

86(4):418–423.

2 Lewis, R. A. J Glaucoma 2007;161:98–103.

3 Robin, A. L. Anecortave Acetate Lowers

IOP in Patients With Glaucoma. Association

for Research in Vision and Ophthalmology,

2006; abstract 1541.

Dr. Lewis is a consultant for Alcon and is

on the speaker’s bureau for Allergan, Merck

and Pfizer. Dr. Samples receives lecture

honoraria from Alcon, Allergan and Merck.

Drs. Sugar and Mills have no related finan-

cial interests.

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Reminder bracelets, alarm watches,buddy patients and visual fielddefects etched into eyeglasses: Thoseare among the motivational and deter-rent ideas for improving compliancewith glaucoma medications, assolicited in a contest by the AmericanGlaucoma Society last year.

The results were published in areport titled “Pearls to Improve Com-pliance.” The AGS can be contactedat [email protected].

A d h e r e n c e P e a r l s

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Glaucoma research has evolvedfrom a focus on the front of the eye—the so-calledplumbing problems—to afocus on similarities with

other neurodegenerative diseases, suchas Alzheimer’s and Parkinson’s. Nolonger defined simply by increasedintraocular pressure, glaucoma is nowalso considered a problem of progres-sive neurodegeneration.

This new view resulted in part fromthe realization that the disease cannotalways be arrested by IOP-loweringtreatment. For about one-third of idio-pathic open-angle glaucoma patients,in fact, vision slowly worsens despitethe best treatment efforts of ophthal-mologists.1 There is a silver lining here,however. Slow progression opens up the therapeutic window very wide—for years or even decades, according toGeorge A. Cioffi, MD, professor of oph-thalmology at Oregon Health & ScienceUniversity and chairman of the DeversEye Institute in Portland.

In this two-part series, EyeNet takes a look at how notions explored by a newgeneration of researchers have illumi-nated the potential of neuroprotectionin glaucoma management.

Neuro Disease, Neuro Research“The concept of neuroprotection forglaucoma has been around for morethan a decade,” said Robert N. Weinreb,MD, director of the Hamilton Glaucoma

Center and professor of ophthalmologyat the University of California, San Diego.Neuroprotection is being developed as atherapeutic regimen for slowing, pre-venting or reversing the death of neu-rons following an initial insult, said Dr.Weinreb. For most patients, it is likelythat it will complement IOP-loweringtherapy, not replace it, he said. In somecases, however, neuroprotective agentsmay also become an alternative forthose who can’t tolerate IOP-loweringtherapy or for whom they have beenineffective.

Neuro research. David J. Calkins,PhD, associate professor of ophthalmol-ogy and visual science at Vanderbilt Uni-versity in Nashville, said that makingcomparisons to other neurodegenera-tive diseases will allow researchers tobetter understand the optic nerve’sresponse to glaucoma. “Reasoningthrough analogy, researchers have beenable to identify different components of the disease,” said Dr. Calkins.

One injured neuron looks a lot likeanother. Although glaucoma is notassociated with cognitive or motordeficits, it is, at the cellular level, struc-turally comparable to other neuro-degenerative processes. “Nothing is fun-damentally different in glaucoma thanwith other neurodegenerative diseases,”said Monica L. Vetter, PhD, professor ofneurobiology and anatomy at the Uni-versity of Utah in Salt Lake City. “Theinitial triggering events are distinct, andthere is clearly a different initial pathol-ogy,” she said. “But at a certain point,neurons are responding to stress, and

other cell populations are recruited,and, in the cross talk between them,I think there are a lot of shared mecha-nisms during progression.”

Work by Drs. Calkins, Vetter and colleagues has thus far supported thenotion of shared disease mechanismsamong neurological disorders. Forexample, while identifying changes ingenetic expression related to increasesin IOP, researchers found that one ofthe most robust changes occurs in afamily of genes associated with inflam-mation and involved in pathologies ofthe brain like Alzheimer’s.2

The eye as a window on the brain.Not only is Dr. Vetter hopeful that glau-coma researchers can learn a lot fromdiseases such as Alzheimer’s and Par-kinson’s, but she considers glaucoma anattractive reciprocal model for figuringout what’s happening temporally andspatially with neural degeneration inother diseases. “In the brain, you have a

Neuroprotection Research, Part One

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by annie stuart, contributing writer

Microglia (stained blue) become acti-vated in the vicinity of damaged axonsand RGCs (stained yellow).

C e l l u l a r S n a p s h o t

This article originally appeared in the March


1 2 s u p p l e m e n t

very complex architecture—neurons,axons and synapses—that is not alwayseasily accessible,” said Dr. Vetter. “But inthe eye, everything is compartmentalizedin a way that’s not possible in the brain.You have a very distinct neuronal popu-lation with highly laminated tissue; thesynapses are organized in discrete layers;and you have this beautiful axon bundlethat exits the eye and traverses the restof the brain.”

Strategies for NeuroprotectionOne disease or several? Dr. Calkins andmany other researchers consider glau-coma a multifaceted disease, or a collec-tion of diseases.“Glaucoma can start outin one spatial region and then spreadspatially and temporally,” added Dr.Vetter.

Dr. Cioffi, in contrast, describes him-self “more as a lumper than a splitter.I know there are those who try to splitglaucoma and glaucoma’s optic neu-ropathy into a half-dozen different dis-eases. But my bias is that there is a verycharacteristic optic neuropathy weknow as glaucoma and that has retinalganglion cell death.”

Glaucoma experts appear to agree,though, that glaucoma processes callforth both destructive and protectivecomponents. “There are protective cas-cades that are inducted in response toglaucomatous injury,” said Dr. Calkins.“The nervous system responds to thedisease as though it is trying to rescuethe cells from death, and so the diseasetakes time to finish its course.”

Block damage or boost repair.Whether glaucoma is one disease or sev-eral, there are at least two broad neuro-protective drug-development strategies.One is to try to neutralize the effects ofnerve-derived toxic factors; the otherwould work to boost the body’s ownrepair mechanisms.3 Dr. Cioffi describedsome of the neurodynamics behind thetwo strategies.

Genes that help, genes that hurt.Functions of Bax gene expression aredetrimental and promote cell death,while functions of the Bcl gene andnerve growth factors promote survivalor enhance repair. “These offer us twoapproaches to neuroprotection,” said

Dr. Cioffi. “We can either block cell-death promoters or enhance cell-sur-vival signals. If we decided to enhancesurvival signals, do we try to turn on the cells’ innate protection systems—prompt a cell to make more nervegrowth factor—or do we try to providethe end product? We could provide theretinal ganglion cells with a growth fac-tor or other macromolecule via an intra-vitreal injection or sustained releasesystem and thereby enhance survival.”

Robert W. Nickells, PhD, professor ofophthalmology and visual science at theUniversity of Wisconsin in Madison, isfocusing on the Bax gene. “We think it is a really important step in preventingapoptosis because it blocks the involve-ment of mitochondria,” he said.“As longas you can keep the mitochondria frombecoming involved, you’ve stopped celldeath before the point of no return.”

In any case, success requires thatresearchers understand the basic biologyfirst, said Dr. Vetter, so they know whichpathways are involved.“It may require—just as with HIV or cancer treatment—that you’ve got to hit multiple pathways,”she said. “That’s manageable if we cancome up with a reasonable model.”

Dying little deaths. One challenge is that the compartments of the retinalganglion cell—the axon, synapse, den-drites and cell body—can die indepen-dently, said Dr. Nickells.4 “Each com-partment has its own molecularprogram it can turn on that doesn’trequire the previous deaths of othercompartments,” said Dr. Nickells,adding that this may require agents toaddress the deaths of all these differentcompartments.

Is a silver bullet then out of the ques-tion? It probably is, according to Dr.Calkins, who argued that multiplesequential or simultaneous interventionsare a more likely scenario, particularlywhen the disease is not caught early.

Where Best to Inter veneIOP elevation and the factors promot-ing disease progression may be very dif-ferent processes, said Dr. Vetter. She andother researchers are focused on earlyand middle stages of the disease.

First stop, nerve head. Dr. Cioffi

suggested that focusing on early initiat-ing events will prove most productive.“We’ve gotten better in recent years atbeing more sensitive to early functionaland structural changes—better visualfield tests for function and better waysof looking at the optic nerve and nervefibers structurally—and so we’re pick-ing up problems earlier and earlier,”said Dr. Cioffi. “I think we’ll learn a lotmore by looking at models that mimicearly disease as opposed to models thatmimic late blown-out terrible disease.I believe the initial insult is at the opticnerve head and, therefore, it’s morefruitful to go after the axon.”

Downstream damage. In addition to the primary insult, however, a sec-ondary cascade of events can causedeath of retinal ganglion cells. Trans-synaptic degeneration may act likedominoes, toppling connected neuronsone after another. That might explainwhy IOP-lowering medications aresometimes ineffective.5

The immune system: hero or hellion?“I think that a lot of recent research hasshown that neural inflammation plays areally critical role in how the neuronsrespond,” said Dr. Nickells. A student of Dr. Nickells’ has shown how macro-phages can stimulate ganglion cells.

“There are resident surveillancemacrophage-like cells called microgliain the nervous system,” explained Dr.Vetter. “They act very locally in terms of detecting damage and changes in thenervous system. We think that these areplaying an important role at that junc-ture. They may not be the triggeringstep, but I actually think they do play an important role in this progression.”

Dr. Weinreb is a consultant for Alcon, Aller-

gan, Merck and Pfizer. The other experts

report no related financial interests.

1 www.willsglaucoma.org/eduneu.htm.

2 Steele, M. R. et al. Invest Ophthalmol Vis Sci

2006;47:977–985.

3 Ritch, R. Can J Ophthalmol 2007;42(3):425

–438.

4 Nickells, R. W. Can J Ophthalmol 2007;42

(2):278–287.

5 Weinreb, R. N. Can J Ophthalmol 2007;42

(3):396–398.

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Last month EyeNet began atwo-part examination of newtheories in glaucoma patho-genesis and treatment. Thismonth we look at the specifics

of neuroprotective agents, as researchersface many opportunities—and manyquestions: Will the ideal interventioninvolve sequential or simultaneous ther-apies? Will treatments be easy for patientsto use? Will they address mechanismsspecific to retinal ganglion cells? Willthey avoid inflammatory responses?

Challenges of Dr ug DevelopmentApproved only for lowering intraocularpressure, today’s glaucoma medicationsmay also have neuroprotective proper-ties, but none has definitively demon-strated that in humans. Neuroprotectionwas simply not a part of their initial ther-apeutic rationale or their subsequentapproval by the FDA, said Robert N.Weinreb, MD, director of the HamiltonGlaucoma Center and professor of oph-thalmology at the University of Califor-nia, San Diego. Because each IOP-low-ering medication has distinct biologicalproperties, it is difficult to know how orwhether they also provide neuroprotec-tion independent of their IOP effects.One such medication, brimonidine, hasbeen under study to answer that ques-tion, but results are not yet available.

As agents are reviewed for their neuro-protective properties, noted Dr. Wein-reb, some criteria must be considered:

● Does the drug have a specific receptortarget in the retinal nerve cells or theoptic nerve? ● Does activation of the drug’s targetstrigger pathways that enhance neuronalsurvival or decrease neuronal damagein animal models?● Can it actually reach the retina oroptic nerve in pharmacologically effec-tive concentrations?● Has neuroprotection been demon-strated in an appropriately designedclinical trial—a randomized, controlledstudy in patients?

A number of agents have been testedin the lab and have demonstrated poten-

tial for clinical neuroprotection, said Dr.Weinreb. In cell culture models, manyhave enhanced the viability of culturedretinal ganglion cells. And in experimen-tal models, a significant number of drugshave demonstrated neuroprotectiveproperties.

Clinical trials. But the last criterion—human trials —is an incredibly expen-sive hurdle, said George A. Cioffi, MD,professor of ophthalmology at OregonHealth & Science University and chair-man of the Devers Eye Institute in Port-land. There are two reasons why.

1. Study size and duration. Glaucomais a very slowly progressing disease. At

Neuroprotection Research,Part Two

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by annie stuart, contributing writer

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Retinal ganglion cells in a mouse can be marked red by gamma-synuclein mRNA,and their axons green by the TUJ-1 antibody, which labels beta 3-tubulin. Nucleiof surrounding cells are blue.

T h e C o l o r s o f R e s e a r c h

This article originally appeared in the April



birth, the human eye has approximatelyone million retinal ganglion cells andoptic nerve fibers, and it is estimatedthat healthy individuals lose fewer than20 cells per day, said Dr. Weinreb. Withglaucoma, that loss multiplies several-fold but still is not always noticeable, hesaid. Therefore, progressive glaucoma-tous injury is difficult to detect, andclinical trials must then be lengthy andenroll many patients.

2. Definition of study endpoints.Study goals remain problematic, said Dr.Weinreb, because regulatory agenciesequate glaucoma progression with stan-dard visual field loss. Thus far, they havenot permitted a surrogate to serve as an endpoint, he said, such as a selectivefunctional test or change in the opticdisc or retinal nerve fiber. Dr. Cioffibelieves this will change as researchersget better at detecting structural andfunctional changes. “As we convinceregulatory agencies that these are goodbarometers of disease, we’ll be able totest drugs much faster,” he said.

Memantine:The first neuroprotector?One glutamate receptor antagonist,memantine, is a good example of thesechallenges. Approved by the FDA in 2003to treat Alzheimer’s disease, it is the onlydrug demonstrating glaucoma neuro-protection in primates. In monkeys, itprotected against optic nerve fiber loss,neuronal shrinkage within the centralvisual pathway and visual function loss.1

These results may be due to its ability tomitigate excitotoxicity and the release ofexcess glutamate into the extracellularspace, which causes ganglion cells to dieby apoptosis from secondary damage.2

Human trials of memantine foropen-angle glaucoma have producedconfusing and disappointing results.Progression of disease in studies lastyear appeared to be lower in patientsreceiving the higher dose of the drugcompared to those receiving a low dose.But in January Allergan announced thatfinal analysis of a memantine phase 3trial revealed that overall the drug didnot perform any better than a placebo.3

Despite these inconclusive results,Dr. Cioffi remains optimistic about thememantine trials. “Going into suchstudies we don’t know if we are testing

the right drug, but we’re going to learnsomething from each trial, includingthe memantine trial,” he said, pointingto the large number of patients—2,000—who were followed for four years withstate-of-the-art structure and functionmeasures. “That’s a huge step for us inglaucoma,” he added. “It sets the stageand teaches us how to do these thingsbetter in the future.”

New Theor ies, New TargetsIn the past few years, researchers havebegun to formulate new theories aboutthe role of neurodegeneration in glau-coma. Some of the most exciting workhas focused on three ideas, best encap-sulated as axonal degeneration, gliosisand pressure injury.

1. Axonal degeneration. A precursorto eventual vision loss, changes begin tooccur months or even years before reti-nal nerve cells die. Retinal ganglion cells(RGCs) sample the microenvironmentof the brain via the axon. However, thetransport machinery used to bringnourishment from the brain to the RGCsbecomes dysfunctional—long beforethe cells die—as first shown by the labof Donald J. Zack, MD, PhD, at JohnsHopkins University.4 The axon alsoallows the retina to communicate withthe brain. So if the axon becomes dam-aged, the retina cannot send visualinformation to the brain, even if theRGC is still alive, explained Monica L.Vetter, PhD, professor of neurobiologyand anatomy at the University of Utahin Salt Lake City.

Researchers have also discovered thatdeficits in transport have early, middleand late-stage components. “This allowsresearchers to break down the progres-sion and home in on particular modelsinvolved in each stage,” said David J.Calkins, PhD, associate professor ofophthalmology and visual science atVanderbilt University in Nashville.

The drug minocycline has been shownto improve retrograde transport andmorphology of the optic nerve. If deliv-ered at stages well before evidence ofdisease, it can suppress activation ofmicroglia, said Dr. Vetter. This showsthat axonal changes are coupled withactivation of microglia. “We wanted to

capture this window before microgliaget activated and cranky,” she said,acknowledging that the picture is con-siderably more complex than this, likelyinvolving many cellular players.

2. Gliosis. Dr. Calkins added thatrecent research continues to unearth themultiple roles of glial cells. Thought ofin the past as only support cells for theneurons, glial cells have begun to earngreater respect in recent years. Forexample, researchers have found that, inresponse to pressure at the optic head,glial cells release proteins that may betoxic to neurons. In fact, changes in glialcells are the earliest known event in theprogression of glaucoma, happeningwell before vision loss occurs. Thismakes them another potential thera-peutic target.4

Two other main models exist forhow glial changes affect RGCs, saidRobert W. Nickells, PhD, professor ofophthalmology and visual science at theUniversity of Wisconsin in Madison.“Cells may pump out neuropeptidesthat affect vascular flow, creating a kindof microischemic event at the optic nervehead,” he said. “Or the cells themselvesmay become stressed, losing their abili-ty to accommodate the axons they’resurrounding.”

In any event, some of the first changesthat can be seen in the level of geneexpression or morphology are glialchanges, said Dr. Vetter. In early stagesof the mouse model, she said, there arechanges in gene expression. There is clear optic nerve pathology, but theretinal ganglion cells are still there untillate in the game. Studies by the lab ofPhilip J. Horner, MD, at the Universityof Washington in Seattle, documentthat the ganglion cells persist for a longtime, detectable by the expression of ageneral neuronal marker.5 “There is stillthe potential for rescue because the cellsare simply quiescent or atrophied—notgone,” said Dr.Vetter. In addition to otherfactors, loss of neurotrophic supportmay eventually contribute to cell bodydeath. “But apoptosis is not the drivingforce for quite a while in this disease,”she added.

3. Pressure injury. Designed to sensepressure, a family of molecules called

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mechanicoreceptors is located through-out the brain and retina. These moleculesmight allow cells in the retina and opticnerve to respond directly to ocular pres-sure. “This could be similar to how neu-rons in the spinal cord respond to pres-sure from walking, sitting and keepingbalance,” said Dr. Calkins. Pressureinjury may overload the cells with calci-um, which can cause a direct degenera-tive cascade, he said. Researchers suggestthat the molecules sensing pressuremight be the factor translating pressureinto neuronal damage. If so, blockingthe pressure-sensitive calcium channelmight restore contact with the brain.

Dr. Vetter and other researchersexpress excitement about these andother theories concerning glaucomaand neuroprotection. “We do feel thatwe’ve learned enough to have somecandidate pathways to target, and we’rehopeful that in the next couple of yearswe’ll be able to figure out—along with anumber of other excellent labs—whichones are responding.”

Dr. Weinreb is a consultant for Alcon,

Allergan, Merck and Pfizer. The other

experts report no related financial interests.

1 Hare, S. et al. Invest Ophthalmol Vis Sci

2004;25:2640–2641.

2 Nickells, R. W. Can J Ophthalmol 2007;42:

278–287.

3 http://agn360.client.shareholder.com/relea

sedetail.cfm?ReleaseID=227679#

4 Pease, M. E. et al. Invest Ophthalmol Vis Sci

2000;41:764–774.

5 Buckingham, B. P. et al. Progressive Gan-

glion Cell Degeneration Precedes Neuronal

Loss in a Mouse Model of Glaucoma. J Neu-

rosci 2008, in press.

The valuable work of three of the re-searchers interviewed for this two-partstory, Drs. Vetter, Calkins and Horner,as well as researcher Nicholas Marsh-Armstrong, PhD, who contributed theimages, is sponsored by the Glauco-ma Research Foundation. For moreinformation, visit www.glaucoma.org.

G l a u c o m a R e s e a r c h F o u n d a t i o n

sk four glaucoma specialists

when to move from eyedrops

to the operating room and

you’re likely to get eight

different opinions, said Dale K. Heuer,

MD, professor and chairman of oph-

thalmology at the Medical College

of Wisconsin in Milwaukee. One

thing, though, is clear. The reluctance

to perform incisional surgery runs

deep. Doctors resist it. Patients resist

it. Some physicians never do surgery

without trying medication. And some

patients will try anything before

agreeing to surgery.

There are many factors to consider

before progressing to surgery, from

the severity of the glaucoma to the

patient’s age, ability to adhere to and/

or afford medication and coincident

morbidities. The surgical procedure

itself gives doctors and patients pause.

Despite all the tweaking to perfect

it, the gold standard trabeculectomy

is risky. As Dr. Heuer explained, it’s

not like cataract surgery, for example,

which is so successful and which

A

This article originally appeared in the April 2008 issue of EyeNet Magazine.



If there is too much scarring on the con-junctiva anteriorly, or if Dr. Feitl doesn’tthink a trabeculectomy has a reasonableprognosis, she puts in a tube shunt 8 to10 mm posterior to the limbus. Shouldtrabeculectomy or tube shunt fail, thendiode laser photocoagulation is an option.“We always try to temporize. It’s alwaysworth trying medication, for at least a briefperiod of time.” Dr. Feitl selects patientscarefully to avoid hypotony from anti-metabolites.

MarianneFeitl, MDIn private practicewith Arbor Centersfor Eye Care inChicago.

“The guiding principle is we want to savevision as best we can,” Dr. Gaasterlandsaid. “Most of the studies pay attentionto eye pressure, but eye pressure doesn’tmatter to the patient. What the patientscare about is whether they can see thenewspaper and read. Reduce the eyepressure from the level associated withdamage and you can keep them that way.That’s the name of the game these days—it has been forever.”

Douglas E.Gaasterland,MDClinical professor of ophthalmology at Georgetown University.

Various Routes

SAME GOAL

Our glaucoma specialists do

not disagree with each other’s

essential goals for incisional

surgery. But their particular

strategies, concerns and

patient criteria may very

much affect how aggressively

or frequently their threshold

for surgery is reached.

typically transforms the patient’s vision with minimal risk ofserious complications. Similarly, retina surgeons faced withdetached retinas have an easier decision. “If you don’t fixthose, the vision will get worse,” he said. “Even the thresholdfor cornea transplant has been lowered. The decision to doglaucoma surgery, at least where pressure is not way off themap, is difficult.”

A RISK/BENEFIT RATIO. So when to resort to surgery?“When is a hard question to answer because some people dovery well with medicines and some don’t,” said Douglas E.Gaasterland, MD, clinical professor of ophthalmology atGeorgetown University. “When you’re sitting there in thechair with a patient, you can’t tell how they’re going to dowith medication until they try them.”

The mantra has been and continues to be: medicationfirst.

“Our standard approach to glaucoma is to begin withmedical therapy and escalate by adding drops or using com-bined agents,” said Steven J. Gedde, MD, professor of ophthal-mology at Bascom Palmer Eye Institute. “When that fails toadequately control IOP, traditionally we use laser trabeculo-plasty. We reserve surgical intervention for patients who haveinadequately controlled glaucoma, despite maximum toleratedmedical therapy and appropriate laser treatment.”

The move toward surgery, as Dr. Heuer put it, comes “whenthe risk of continuing to observe outweighs the risk of doingsurgery.” And what is that threshold? Determining the answerto that, Dr. Heuer said, “is more often art than science.”

Reconsidering the StandardOver the years, there have been challenges to the traditionalstepped regimen of medication then laser trabeculoplasty.The Glaucoma Laser Trial (GLT) demonstrated that initiallaser is at least as effective as medication.

And while doctors seldom, if ever, do glaucoma surgerybefore trying medication, a case has been made for surgeryfirst—at least in newly diagnosed open-angle glaucomapatients with advanced visual field loss. The CollaborativeInitial Glaucoma Treatment Study (CIGTS) found that low-ering intraocular pressure with initial filtering surgery is aseffective as medical therapy for inhibiting progression ofvisual field damage. In fact, surgery yielded a slightly greaterreduction. The data derive from a subanalysis of the CIGTSdata, reported by Paul Lichter, MD, and colleagues. It didn’tmatter whether subjects with mild baseline visual field loss(mean deviation –2 dB or better) had surgery first or medica-tion. But the subanalysis found that patients with moreadvanced visual field loss at baseline (mean deviation worsethan –10 dB) fared better with initial surgery, compared withthe medication-first group. The complete analysis has beensubmitted for publication.

OLD STANDARD STILL IN PLACE. Though the GLTand CIGTS studies showed that laser and surgical treatmentwere essentially equivalent to initial medical therapy, “Theydidn’t create a shift in the paradigm,” said Dr. Gedde. Medica-tion continued to trump surgery as a first-line treatment. “Igenerally will give patients at least a trial of medical therapy,”

Dr. Gedde said. “If they can be compliant and have access tomedication, even people with advanced glaucoma will receivea trial with medical therapy.”

MAKING EXCEPTIONS. On the other hand, Dr.Gedde will consider surgical intervention as initial therapy in patients who have limited access to medications or whoadmit to poor compliance with other medications. Generallyspeaking, he said there is no magic IOP number—no cutoffpoint—that mandates surgical intervention. “You have toindividualize to the patient,” Dr. Gedde said. “It requires judg-ment on the part of the clinician. It’s not easy to know whento pull the trigger.”

Marianne Feitl, MD, agrees. “ALT (argon laser trabeculo-plasty), or SLT (selective laser trabeculoplasty), or surgicalintervention has to be tailored to the individual patient,which is how we’ve always approached the issue,” she said.“There’s not been a huge shift in thought process about it.”Dr. Feitl is in private practice in Chicago.

“We’re inclined to use medications first, primarily becauseif you get into trouble, you can stop them,” Dr. Gaasterlandsaid. “If you get into trouble with surgical intervention, it’sdone. You can’t undo it,” he said. The result is, “We tend to beconservative.”

Are We Too Conservative?In patients with moderately advanced glaucoma, said Dr.Heuer, “We’re probably not operating enough.” Ophthalmol-ogists are conservative because although trabeculectomy is

safer than ever, he said, “It’s still not totally predictable, and it doesn’t always work, even when done well.”

THE FEARFUL PATIENT. Dr. Heuer, who has alwaysbeen prone to operating when he sees moderate disease pro-gression, is caught in a kind of catch-22 when it comes to earlysurgical intervention. On the one hand, he is talking to patientsearlier about surgery. But he’s also very open with them aboutpotential complications. As a result, he isn’t operating sub-stantially more than in the past because many patients, afterhearing the options, decide to stick with medication.

LASER BEFORE SURGERY. He’s not alone. “There arepatients who will refuse to have surgery, even when we decidedthat medical therapy is not working,” said Dr. Feitl. They’ll trylaser, and even oral carbonic anhydrase inhibitors, despitetheir potentially serious complications. “They’d still rather do that than have a surgical procedure.” She added that laser,though it doesn’t achieve pressures as low as trabeculectomyand doesn’t lower pressure much for about 15 percent ofpatients, is a good option after exhausting the prescriptiondrug armamentarium. “If we do move on to needing a surgi-cal procedure, patients and I are more comfortable knowingthat we did try other reasonable avenues first.”

“Though laser trabeculoplasty doesn’t work as long aswe’d like, it can buy time,” said Andrew G. Iwach, MD.“If that’syour objective and you have been able to avoid the more inva-sive step of trabeculectomy, you’ve done the patient a service.” Dr. Iwach is associate clinical professor of ophthal-mology at the University of California, San Francisco.


If a patient is developing glaucomatousdamage despite apparent IOP control, Dr. Gedde considers that IOP measure-ments in a patient with an extremely thincornea might be under true IOP. So he issure to check central corneal thickness.

He is also mindful that the patientmay be more compliant prior to officevisits, and that diurnal fluctuations maymean that peak IOP measures may beoccurring at times other than normaloffice hours.

Steven J.Gedde,MDProfessor of ophthalmology atBascom PalmerEye Institute inMiami.

Surgery first is an option in a patient witha mean defect worse than 10 dB, accord-ing to Dr. Heuer. “As a glaucoma special-ist, I’ve had a little lower threshold forsurgery,” he said, adding that the report(submitted for publication) from CIGTS“crystallized that for me.” But he saidthe decision to operate should be basedon visual field testing, not on changes in GDx, HRT or OCT images. He alsoavoids surgery on ocular hypertensives or glaucoma suspects.

Dale K.Heuer, MD Chairman of oph-thalmology, Med-ical College ofWisconsin anddirector, Froedtertand the MedicalCollege of Wis-consin Eye Insti-tute, Milwaukee.

Dr. Iwach emphasized the uniqueness ofeach patient, and the importance of tai-loring the results of studies to eachpatient’s clinical situation.

“All these studies report in averagesand means. But we don’t treat averagesor means. We treat individuals. Our jobas clinicians is to determine an accuraterisk assessment for that individual, draw-ing on studies and being aware that youneed to customize the treatment.”

Andrew G.Iwach, MDAssociate clinicalprofessor of oph-thalmology, Uni-versity of Califor-nia, San Francisco,and executivedirector of theGlaucoma Centerof San Francisco.

LASER BEFORE DROPS? Dr. Iwach warned againstrushing to surgery. “Glaucoma is, in general, a slow-movingdisease, so you have the time to collect data, establish trendsand then make a decision before you do something.” That’swhere laser trabeculoplasty has a role, perhaps even morethan eyedrops. “It can delay taking a patient to surgery. Insome patients, it can delay the need for medication.”

Dr. Feitl agreed, noting that medication has a downside.Aside from cost and compliance issues, drugs can inducechanges to the conjunctiva that may reduce surgical successdown the road. She added that not doing surgery has its risks.“We have to tell patients that there’s a higher risk of losingyour vision from uncontrolled glaucoma,” Dr. Feitl said.

Each Patient Case by Case“For some people, it’s going to be plain as day that you’ve gotto do surgery. For some people it’s going to be a puzzle,” Dr.Gaasterland said. The obvious case involves a patient on max-imum medication, with a high pressure and a deterioratingoptic nerve or visual field. “The puzzling one is the one who’snot getting worse,” he said. That patient may have a pressureof 23, with a target pressure in the teens, but the visual fieldand optic nerve measures are holding steady. “You have achoice to escalate medication because they’re not yet on max-imum treatment. That’s the person who you have to thinkabout and decide about individually. Will they be able toadhere to a more complex medical schedule? Will more med-

ication work? There is no easy guidance on this. It depends onthe patient and the doctor.”

USE LOGICAL CRITERIA. Dr. Feitl’s criteria for oper-ating include noncompliance and an inability to afford med-ication. Also, if a patient is getting worse, in spite of medicaltherapy, even if the pressure looks reasonable, “surgery is war-ranted because that approach may get a lower pressure,” saidDr. Feitl.

LOOK AT THE WHOLE PATIENT. There are no easyanswers. “People like a cookie-cutter formula,” Dr. Iwach said.But a lot of patients fall into a gray area between monitoringand more aggressive treatment. That’s where being MDscomes in pretty handy, he said. Ophthalmologists have all theskills to assess the patient’s overall health and base treatmentdecisions on that information.

DON’T BE OVERLY CAUTIOUS. “It’s so individual, bypatient, that it’s hard to articulate a precise point at whichyou’ll do surgery,” Dr. Heuer said. “What my colleagues and Istruggle to realize is that in some of our patients we’re actual-ly a little late to operate. With moderate to advanced glauco-ma, we need to be a little more aggressive than most of ushave historically been. At least with patients with advanceddisease, we need to have a little lower threshold. We ought tooperate more than we have.”

And clearly, doctors would operate more if they had a bet-ter surgery. “If we had the equivalent of clear cornea phacowith foldable IOL surgery, we would probably operate a lot


Dr. Peng Khaw’s fornix-based trabeculectomy (see “Trabeculectomy and theFornix-Based Flap”) is depicted here from the conjunctival incision to creatingthe scleral flap, preparing the iridectomy, applying antimetabolites, securing

releasable sutures and closing the conjunctiva. The final panel shows how Dr. Khaw’sadjustable scleral sutures can be be manipulated after surgery to moderate the flowof aqueous.

Strategy Under Pressure

2 3 4

1

5 6 7


sooner. But so far we don’t,” Dr. Heuer said.Dr. Feitl, who has never treated a patient initially with

incisional surgery, agrees. “If we had the perfect surgical pro-cedure, with zero complications, I think we’d be doing a lotmore surgery. But we haven’t got the perfect surgery yet.”

Drs. Feitl, Gaasterland and Gedde report no related financial interests.

Dr. Heuer has received consulting and speaker honoraria from Alcon,

Allergan, Carl Zeiss and Pfizer. Dr. Iwach has served on speaker bureaus

for Alcon, Allergan, Iridex, Ista, Lumenis, Merck and Carl Zeiss.

If you could avoid creatingan ischemic, localizedbleb, would you be more

inclined to do surgery earlier?Dr. Feitl said it’s probable.“We’d be more comfortablemoving on to earlier surgical intervention,” she said,explaining that the benefits would outweigh the burden ofpatient adherence, the costs and the potential for localizedand systemic side effects that are associated with medicaltherapy. “Traditionally, in the United States, surgery wasconsidered a treatment of last resort because of the risk ofinfection,” Dr. Feitl said. “Some of the bias against surgerywas in knowing that you often could end up with theseischemic, localized blebs.”

Trabeculectomy is still risky, but Dr. Feitl has adopted asurgical technique intended to create healthier blebs. TheMoorfields Safer Surgery System, advanced by Peng T. Khaw,MD, PhD, involves a fornix-based flap with adjustablesutures and a diffuse application of antimetabolites. Theresulting bleb is healthier appearing, flatter and more dif-fuse, as opposed to the elevated, ischemic and localizedblebs that result from limbus-based flaps, Dr. Feitl said.

Dr. Heuer also has adopted the fornix-based flap, but henoted that Dr. Khaw’s technique involves two changes to thetraditional surgery. One, he changed the flap technique.Two, he went from a local to more diffuse application ofmitomycin C. “I think it’s more the latter that has changedthe bleb morphology,” Dr. Heuer said.

Dr. Feitl stressed the importance of applying theantimetabolite over a large area. But she is so sold on Dr.Khaw’s technique that she no longer creates limbus-basedflaps.

Dr. Khaw is a consultant ophthalmic surgeon at MoorfieldsEye Hospital in London and professor of glaucoma and ocu-lar healing at University College London. For a video presen-tation of Dr. Khaw’s surgical technique, “Advances in Tra-beculectomy Surgery: The Moorfields Safer Surgery System,”go to http://aao.scientificposters.com/vodAbstract.cfm?id=25,click on “videos on demand” and type “Khaw” into theauthor field.

Trabeculectomyand the Fornix-Based Flap

best glaucoma aao 2008

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