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Best Glaucoma AAO 2008 Best Glaucoma AAO 2008 Document Transcript

  • EyeNet SELECTIONS G L AU C O M A S U B S P E C I A LT Y D AY AT L A N TA 2 0 0 8 clinical update 7 Glaucoma Eyedrops: A Fresh Look at Preservatives Do preservatives in eyedrops harm the cornea? Four glaucoma specialists weigh in. 11 Neuroprotection Research, Part One A survey of fresh ideas and new research suggests that glaucoma may be more than one disease. 13 Neuroprotection Research, Part Two Interesting new targets—axonal degeneration, gliosis and pressure injury—may lead to promising glaucoma therapies. feature The Incision Decision: When Glaucoma Progresses 17 Five experts discuss their criteria to proceed with surgery when glaucoma hasn’t responded (or patients weren’t adherent) to medications. Letter From the Editor Dear Glaucoma Subspecialty Day Attendee, of glaucoma science with a perusal of The glaucoma community is witness- EyeNet Selections, our best glaucoma ing a quiet paradigm shift, away from the stories from the past year. Enjoy your rigid absolutes of IOP and toward a more Subspecialty Day as well as the Atlanta nuanced understanding of pressure fluc- Meeting’s additional offerings on con- tuations and optic nerve sensitivities. temporary glaucoma medicine! This year’s Glaucoma Subspecialty Day meeting, “The Pendulum Swings,” explores these nuances, including the new thinking around normal-tension patients and the impact of perfusion Richard P. Mills, MD, MPH pressure and central corneal thickness. Chief Medical Editor It’s a perfect time to review the state EyeNet Magazine/EyeNet Selections ON THE COVER: Retinal ganglion cells in a mouse marked red by gamma-synuclein mRNA, and their axons green by the TUJ-1 antibody. Nuclei of surrounding cells are blue. Nicholas Marsh-Armstrong, PhD e y e n e t s e l e c t i o n s 5
  • Clinical Update tools and techniques GLAUCOMA Glaucoma Eyedrops: A Fresh Look at Preservatives by pat phillips, contributing writer B enzalkonium chloride (BAK) Portland. “It is a toxic detergent. It is generally regarded as an attracts monocytes and lymphocytes 1 gtt ou qhs effective agent for preventing into the conjunctiva and it makes the bacterial contamination of tissue thicken up.” glaucoma eyedrops. However, its advantages and disadvantages are Bad BAK? under scrutiny for possible effects on Dr. Samples contends that BAK can have medical and surgical management. negative consequences that extend from “BAK is a mixed bag,” said Richard the ocular surface all the way to the pos- A. Lewis, MD, glaucoma specialist in terior pole. “BAK makes dry eye worse private practice in Sacramento, Calif., in some patients; it is toxic to corneal and former president of the American epithelial cells and, according to our Glaucoma Society. “For years, it was laboratory work, it is toxic to corneal thought that BAK helped penetration endothelial cells and trabecular cells so there was better drug effect. In the when it enters the anterior chamber; old days, when pilocarpine was com- it gives us a dysfunctional conjunctiva monly used for glaucoma, it had such when it comes time to consider filtra- poor penetration that BAK was added to tion; it has a complex role in setting up get more drug effect. But more recently, allergic reactions in the eye. It has even Some physicians are concerned about prostaglandin eyedrops, such as latano- been implicated in the occurrence of the long-term effects of eyedrop prost, bimatoprost and travoprost, pen- cystoid macular edema,” he noted. preservatives on various ocular tissues. etrate so very well that there is no need Cumulative damage. “There’s some for BAK to get penetration,” Dr. Lewis evidence that total lifetime eye exposure long-term therapy with BAK-preserved said. He suggested that this renders any to BAK is important in the late-occur- eyedrops may pose surgical problems hazards of the preservative unnecessary. ring follicular conjunctivitis that appears stemming from ocular surface changes “You don’t need BAK if you can get equal with long-term use of adrenergic ago- and dry eye. “The conjunctiva is more efficacy without the side effects of BAK.” nists,” added Dr. Samples. toxic from BAK, which causes increased Prostaglandins have become for Dr. Lewis agreed. “The greater the scar tissue that is more reactive and many clinicians the preferred first-line exposure to the preservative, the greater inflammatory and may affect the suc- therapy. the effect and that effect is cumulative. cess rate of trabeculectomies.” Some ophthalmologists are emphatic There are a lot of dry eye problems with Dr. Samples added that prior expo- about the hazards posed by the preserv- BAK,” he said. “There are eyelid and sure to BAK is more likely to cause bleb ative. “BAK is bad for the conjunctiva, conjunctival problems, irritation and failure and that the blebs created by fil- the cornea and perhaps even the trabec- redness, with the whole ocular surface tration surgery are more likely to scar ular meshwork,” said John R. Samples, affected by these preservatives.” He finds down, although it is difficult to measure MD, professor of ophthalmology at the it affects tear function and that even or see. He added that more research is Oregon Health & Science University in minor exposure may induce cell-growth needed in this area. arrest and death by necrosis or apoptosis. Association with failure. One French This article originally appeared in the January Surgery made riskier. Dr. Lewis also study found that failure of surgical treat- 2008 issue of EyeNet Magazine. said that patients who have been on ment is mainly linked to the duration e y e n e t s e l e c t i o n s 7
  • Glaucoma and the extent of previous medical mulation is sold as Travatan Z (Alcon). eyedrops. “Now here’s a drug you can treatment with preservative-containing The study involved 700 open-angle glau- inject and you don’t have to worry about glaucoma eyedrops. The study suggested coma or ocular hypertension patients compliance anymore.” that failure was associated with inflam- with pressures between 24 and 36 mmHg. “It’s an interesting concept that would mation of the ocular surface structures.1 In this double-masked, randomized take the preservative problem out of the The study also compared the toxicity study, the medication was used once in picture,” agreed Dr. Lewis. of eyedrops with and without preserva- the evening and IOP was measured at Beyond lowering the IOP. Various tives, and found that ocular symptoms three different intervals throughout the neuroprotective drugs are also under in the conjunctiva, cornea and eyelids day. investigation and ultimately may become were less prevalent with preservative- “Our study results show that you used as injectables in the treatment of free eyedrops, adding that “the benefits don’t need BAK for drug penetration,” glaucoma. Glatiramer acetate, a drug of reducing microbial contamination Dr. Lewis said. “There was equal efficacy currently used to treat multiple sclero- through use of preservative are offset by with the IOP changes between Travatan sis, is under study as a possible neuro- the known ocular side effects of preser- with and without BAK. Now, glaucoma protective agent to prevent damage to vatives.” specialists have choices.” the optic nerve. Ophthalmic researchers will probably In the future, Dr. Lewis said he is Medicine or Marketing? be getting rid of BAK and substituting hopeful for both better preservatives But many in the ophthalmic community a more benign preservative whenever and new routes of administration. “I regard BAK as a safe preservative that possible, according to Dr. Samples. He want to see drugs that have a longer does a good job in protecting against said this should have been done already. duration of action so that we get better bacteria, according to Alan Sugar, MD, As long as 20 years ago, he analyzed BAK compliance and less exposure,” he said. professor and associate chairman of and identified its disadvantages. “It is “And we need to get beyond ocular ophthalmology and visual sciences at the surprising how often I will encounter pressure-lowering medications to the University of Michigan, Ann Arbor. older ophthalmologists who recall noting neuroprotective drugs.” “Recently, there’s been an upswing the toxic effects of BAK and discussing of interest in the issue of preservatives,” it with manufacturers and colleagues.” 1 Pisella, P. J. et al. Br J Ophthalmol 2002; Dr. Sugar said. “Some of the attention is Future directions. “The pipeline for 86(4):418–423. due to marketing. Companies want to development of glaucoma drugs is very 2 Lewis, R. A. J Glaucoma 2007;161:98–103. market a glaucoma drug that does not rich,” said Dr. Samples. “There are many 3 Robin, A. L. Anecortave Acetate Lowers have BAK, as a marketing edge. Some of new classes of glaucoma medications, IOP in Patients With Glaucoma. Association the attention is increased awareness that perhaps four or five, in the pipeline,” he for Research in Vision and Ophthalmology, toxicity can occur, even though in my said. “Companies such as Alcon, Aller- 2006; abstract 1541. mind, it doesn’t occur that frequently.” gan, Merck, Ista and Pfizer all have new Richard P. Mills, MD, MPH, agreed. glaucoma treatments under develop- Dr. Lewis is a consultant for Alcon and is “I find it hard to believe that for most ment.” He added that many companies on the speaker’s bureau for Allergan, Merck patients a single drop of BAK-contain- are looking at modifications of the and Pfizer. Dr. Samples receives lecture ing preservative per day will cause sig- prostaglandins, and he is hopeful that honoraria from Alcon, Allergan and Merck. nificant surface problems. Certainly these will come without the addition of Drs. Sugar and Mills have no related finan- that has been my experience after years BAK. cial interests. of observation.” Toxicity to BAK does develop in some Drop the Drops Altogether? patients, but not in most, according to One new treatment approach under Adherence Pearls Dr. Sugar. “For most patients it’s not development for glaucoma uses a com- that big a deal. There’s less to the issue pletely different delivery system: injec- Reminder bracelets, alarm watches, of BAK than meets the eye.” table medication. Anecortave acetate, buddy patients and visual field Dr. Mills, who is in private practice for example, is a modified steroid that defects etched into eyeglasses: Those in Seattle, noted that each patient should appears to control high IOP for at least are among the motivational and deter- be approached as a separate case. “Obvi- three months with only a single injec- rent ideas for improving compliance ously, there are sensitive patients, and, of tion, and it is currently under clinical with glaucoma medications, as course, it’s quite another matter when investigation as a glaucoma treatment.3 solicited in a contest by the American therapy involves multiple drops per day.” (Alcon has also been studying anecor- Glaucoma Society last year. tave acetate depot suspension to treat The results were published in a No-Pr eser vative Approach wet AMD.) report titled “Pearls to Improve Com- Dr. Lewis recently conducted a study of Dr. Samples views anecortave acetate pliance.” The AGS can be contacted the prostaglandin drug travoprost, with as a possible solution to the continuing at and without BAK.2 The BAK-free for- problem of patient compliance with 8 s u p p l e m e n t
  • Clinical Update tools and techniques GLAUCOMA Neuroprotection Research, Part One by annie stuart, contributing writer G laucoma research has evolved Center and professor of ophthalmology from a focus on the front at the University of California, San Diego. Cellular Snapshot of the eye—the so-called Neuroprotection is being developed as a plumbing problems—to a therapeutic regimen for slowing, pre- focus on similarities with venting or reversing the death of neu- other neurodegenerative diseases, such rons following an initial insult, said Dr. as Alzheimer’s and Parkinson’s. No Weinreb. For most patients, it is likely longer defined simply by increased that it will complement IOP-lowering intraocular pressure, glaucoma is now therapy, not replace it, he said. In some also considered a problem of progres- cases, however, neuroprotective agents sive neurodegeneration. may also become an alternative for This new view resulted in part from those who can’t tolerate IOP-lowering the realization that the disease cannot therapy or for whom they have been Microglia (stained blue) become acti- always be arrested by IOP-lowering ineffective. vated in the vicinity of damaged axons treatment. For about one-third of idio- Neuro research. David J. Calkins, and RGCs (stained yellow). pathic open-angle glaucoma patients, PhD, associate professor of ophthalmol- in fact, vision slowly worsens despite ogy and visual science at Vanderbilt Uni- other cell populations are recruited, the best treatment efforts of ophthal- versity in Nashville, said that making and, in the cross talk between them, mologists.1 There is a silver lining here, comparisons to other neurodegenera- I think there are a lot of shared mecha- however. Slow progression opens up tive diseases will allow researchers to nisms during progression.” the therapeutic window very wide— better understand the optic nerve’s Work by Drs. Calkins, Vetter and for years or even decades, according to response to glaucoma. “Reasoning colleagues has thus far supported the George A. Cioffi, MD, professor of oph- through analogy, researchers have been notion of shared disease mechanisms thalmology at Oregon Health & Science able to identify different components among neurological disorders. For University and chairman of the Devers of the disease,” said Dr. Calkins. example, while identifying changes in Eye Institute in Portland. One injured neuron looks a lot like genetic expression related to increases In this two-part series, EyeNet takes another. Although glaucoma is not in IOP, researchers found that one of a look at how notions explored by a new associated with cognitive or motor the most robust changes occurs in a generation of researchers have illumi- deficits, it is, at the cellular level, struc- family of genes associated with inflam- NICHOLAS MARSH-ARMSTRONG, PHD nated the potential of neuroprotection turally comparable to other neuro- mation and involved in pathologies of in glaucoma management. degenerative processes. “Nothing is fun- the brain like Alzheimer’s.2 damentally different in glaucoma than The eye as a window on the brain. Neuro Disease, Neuro Resear ch with other neurodegenerative diseases,” Not only is Dr. Vetter hopeful that glau- “The concept of neuroprotection for said Monica L. Vetter, PhD, professor of coma researchers can learn a lot from glaucoma has been around for more neurobiology and anatomy at the Uni- diseases such as Alzheimer’s and Par- than a decade,” said Robert N. Weinreb, versity of Utah in Salt Lake City. “The kinson’s, but she considers glaucoma an MD, director of the Hamilton Glaucoma initial triggering events are distinct, and attractive reciprocal model for figuring there is clearly a different initial pathol- out what’s happening temporally and This article originally appeared in the March ogy,” she said. “But at a certain point, spatially with neural degeneration in 2008 issue of EyeNet Magazine. neurons are responding to stress, and other diseases. “In the brain, you have a e y e n e t s e l e c t i o n s 11
  • Glaucoma very complex architecture—neurons, Dr. Cioffi. “We can either block cell- suggested that focusing on early initiat- axons and synapses—that is not always death promoters or enhance cell-sur- ing events will prove most productive. easily accessible,” said Dr. Vetter. “But in vival signals. If we decided to enhance “We’ve gotten better in recent years at the eye, everything is compartmentalized survival signals, do we try to turn on being more sensitive to early functional in a way that’s not possible in the brain. the cells’ innate protection systems— and structural changes—better visual You have a very distinct neuronal popu- prompt a cell to make more nerve field tests for function and better ways lation with highly laminated tissue; the growth factor—or do we try to provide of looking at the optic nerve and nerve synapses are organized in discrete layers; the end product? We could provide the fibers structurally—and so we’re pick- and you have this beautiful axon bundle retinal ganglion cells with a growth fac- ing up problems earlier and earlier,” that exits the eye and traverses the rest tor or other macromolecule via an intra- said Dr. Cioffi. “I think we’ll learn a lot of the brain.” vitreal injection or sustained release more by looking at models that mimic system and thereby enhance survival.” early disease as opposed to models that Strategies for Neuroprotection Robert W. Nickells, PhD, professor of mimic late blown-out terrible disease. One disease or several? Dr. Calkins and ophthalmology and visual science at the I believe the initial insult is at the optic many other researchers consider glau- University of Wisconsin in Madison, is nerve head and, therefore, it’s more coma a multifaceted disease, or a collec- focusing on the Bax gene. “We think it fruitful to go after the axon.” tion of diseases. “Glaucoma can start out is a really important step in preventing Downstream damage. In addition in one spatial region and then spread apoptosis because it blocks the involve- to the primary insult, however, a sec- spatially and temporally,” added Dr. ment of mitochondria,” he said. “As long ondary cascade of events can cause Vetter. as you can keep the mitochondria from death of retinal ganglion cells. Trans- Dr. Cioffi, in contrast, describes him- becoming involved, you’ve stopped cell synaptic degeneration may act like self “more as a lumper than a splitter. death before the point of no return.” dominoes, toppling connected neurons I know there are those who try to split In any case, success requires that one after another. That might explain glaucoma and glaucoma’s optic neu- researchers understand the basic biology why IOP-lowering medications are ropathy into a half-dozen different dis- first, said Dr. Vetter, so they know which sometimes ineffective.5 eases. But my bias is that there is a very pathways are involved. “It may require— The immune system: hero or hellion? characteristic optic neuropathy we just as with HIV or cancer treatment— “I think that a lot of recent research has know as glaucoma and that has retinal that you’ve got to hit multiple pathways,” shown that neural inflammation plays a ganglion cell death.” she said. “That’s manageable if we can really critical role in how the neurons Glaucoma experts appear to agree, come up with a reasonable model.” respond,” said Dr. Nickells. A student though, that glaucoma processes call Dying little deaths. One challenge of Dr. Nickells’ has shown how macro- forth both destructive and protective is that the compartments of the retinal phages can stimulate ganglion cells. components. “There are protective cas- ganglion cell—the axon, synapse, den- “There are resident surveillance cades that are inducted in response to drites and cell body—can die indepen- macrophage-like cells called microglia glaucomatous injury,” said Dr. Calkins. dently, said Dr. Nickells.4 “Each com- in the nervous system,” explained Dr. “The nervous system responds to the partment has its own molecular Vetter. “They act very locally in terms disease as though it is trying to rescue program it can turn on that doesn’t of detecting damage and changes in the the cells from death, and so the disease require the previous deaths of other nervous system. We think that these are takes time to finish its course.” compartments,” said Dr. Nickells, playing an important role at that junc- Block damage or boost repair. adding that this may require agents to ture. They may not be the triggering Whether glaucoma is one disease or sev- address the deaths of all these different step, but I actually think they do play eral, there are at least two broad neuro- compartments. an important role in this progression.” protective drug-development strategies. Is a silver bullet then out of the ques- One is to try to neutralize the effects of tion? It probably is, according to Dr. Dr. Weinreb is a consultant for Alcon, Aller- nerve-derived toxic factors; the other Calkins, who argued that multiple gan, Merck and Pfizer. The other experts would work to boost the body’s own sequential or simultaneous interventions report no related financial interests. repair mechanisms.3 Dr. Cioffi described are a more likely scenario, particularly some of the neurodynamics behind the when the disease is not caught early. 1 two strategies. 2 Steele, M. R. et al. Invest Ophthalmol Vis Sci Genes that help, genes that hurt. W her e Best to Inter vene 2006;47:977–985. Functions of Bax gene expression are IOP elevation and the factors promot- 3 Ritch, R. Can J Ophthalmol 2007;42(3):425 detrimental and promote cell death, ing disease progression may be very dif- –438. while functions of the Bcl gene and ferent processes, said Dr. Vetter. She and 4 Nickells, R. W. Can J Ophthalmol 2007;42 nerve growth factors promote survival other researchers are focused on early (2):278–287. or enhance repair. “These offer us two and middle stages of the disease. 5 Weinreb, R. N. Can J Ophthalmol 2007;42 approaches to neuroprotection,” said First stop, nerve head. Dr. Cioffi (3):396–398. 12 s u p p l e m e n t
  • Clinical Update tools and techniques GLAUCOMA Neuroprotection Research, Part Two by annie stuart, contributing writer L ast month EyeNet began a two-part examination of new The Colors of Research theories in glaucoma patho- genesis and treatment. This month we look at the specifics of neuroprotective agents, as researchers face many opportunities—and many questions: Will the ideal intervention involve sequential or simultaneous ther- apies? Will treatments be easy for patients to use? Will they address mechanisms specific to retinal ganglion cells? Will they avoid inflammatory responses? Challenges of Dr ug Development Approved only for lowering intraocular pressure, today’s glaucoma medications may also have neuroprotective proper- ties, but none has definitively demon- strated that in humans. Neuroprotection was simply not a part of their initial ther- Retinal ganglion cells in a mouse can be marked red by gamma-synuclein mRNA, apeutic rationale or their subsequent and their axons green by the TUJ-1 antibody, which labels beta 3-tubulin. Nuclei approval by the FDA, said Robert N. of surrounding cells are blue. Weinreb, MD, director of the Hamilton Glaucoma Center and professor of oph- ● Does the drug have a specific receptor tial for clinical neuroprotection, said Dr. thalmology at the University of Califor- target in the retinal nerve cells or the Weinreb. In cell culture models, many nia, San Diego. Because each IOP-low- optic nerve? have enhanced the viability of cultured ering medication has distinct biological ● Does activation of the drug’s targets retinal ganglion cells. And in experimen- properties, it is difficult to know how or trigger pathways that enhance neuronal tal models, a significant number of drugs NICHOLAS MARSH-ARMSTRONG, PHD whether they also provide neuroprotec- survival or decrease neuronal damage have demonstrated neuroprotective tion independent of their IOP effects. in animal models? properties. One such medication, brimonidine, has ● Can it actually reach the retina or Clinical trials. But the last criterion been under study to answer that ques- optic nerve in pharmacologically effec- —human trials —is an incredibly expen- tion, but results are not yet available. tive concentrations? sive hurdle, said George A. Cioffi, MD, As agents are reviewed for their neuro- ● Has neuroprotection been demon- professor of ophthalmology at Oregon protective properties, noted Dr. Wein- strated in an appropriately designed Health & Science University and chair- reb, some criteria must be considered: clinical trial—a randomized, controlled man of the Devers Eye Institute in Port- study in patients? land. There are two reasons why. This article originally appeared in the April A number of agents have been tested 1. Study size and duration. Glaucoma 2008 issue of EyeNet Magazine. in the lab and have demonstrated poten- is a very slowly progressing disease. At e y e n e t s e l e c t i o n s 13
  • Glaucoma birth, the human eye has approximately the right drug, but we’re going to learn capture this window before microglia one million retinal ganglion cells and something from each trial, including get activated and cranky,” she said, optic nerve fibers, and it is estimated the memantine trial,” he said, pointing acknowledging that the picture is con- that healthy individuals lose fewer than to the large number of patients—2,000 siderably more complex than this, likely 20 cells per day, said Dr. Weinreb. With —who were followed for four years with involving many cellular players. glaucoma, that loss multiplies several- state-of-the-art structure and function 2. Gliosis. Dr. Calkins added that fold but still is not always noticeable, he measures. “That’s a huge step for us in recent research continues to unearth the said. Therefore, progressive glaucoma- glaucoma,” he added. “It sets the stage multiple roles of glial cells. Thought of tous injury is difficult to detect, and and teaches us how to do these things in the past as only support cells for the clinical trials must then be lengthy and better in the future.” neurons, glial cells have begun to earn enroll many patients. greater respect in recent years. For 2. Definition of study endpoints. New Theor ies, New Targets example, researchers have found that, in Study goals remain problematic, said Dr. In the past few years, researchers have response to pressure at the optic head, Weinreb, because regulatory agencies begun to formulate new theories about glial cells release proteins that may be equate glaucoma progression with stan- the role of neurodegeneration in glau- toxic to neurons. In fact, changes in glial dard visual field loss. Thus far, they have coma. Some of the most exciting work cells are the earliest known event in the not permitted a surrogate to serve as has focused on three ideas, best encap- progression of glaucoma, happening an endpoint, he said, such as a selective sulated as axonal degeneration, gliosis well before vision loss occurs. This functional test or change in the optic and pressure injury. makes them another potential thera- disc or retinal nerve fiber. Dr. Cioffi 1. Axonal degeneration. A precursor peutic target.4 believes this will change as researchers to eventual vision loss, changes begin to Two other main models exist for get better at detecting structural and occur months or even years before reti- how glial changes affect RGCs, said functional changes. “As we convince nal nerve cells die. Retinal ganglion cells Robert W. Nickells, PhD, professor of regulatory agencies that these are good (RGCs) sample the microenvironment ophthalmology and visual science at the barometers of disease, we’ll be able to of the brain via the axon. However, the University of Wisconsin in Madison. test drugs much faster,” he said. transport machinery used to bring “Cells may pump out neuropeptides Memantine: The first neuroprotector? nourishment from the brain to the RGCs that affect vascular flow, creating a kind One glutamate receptor antagonist, becomes dysfunctional—long before of microischemic event at the optic nerve memantine, is a good example of these the cells die—as first shown by the lab head,” he said. “Or the cells themselves challenges. Approved by the FDA in 2003 of Donald J. Zack, MD, PhD, at Johns may become stressed, losing their abili- to treat Alzheimer’s disease, it is the only Hopkins University.4 The axon also ty to accommodate the axons they’re drug demonstrating glaucoma neuro- allows the retina to communicate with surrounding.” protection in primates. In monkeys, it the brain. So if the axon becomes dam- In any event, some of the first changes protected against optic nerve fiber loss, aged, the retina cannot send visual that can be seen in the level of gene neuronal shrinkage within the central information to the brain, even if the expression or morphology are glial visual pathway and visual function loss.1 RGC is still alive, explained Monica L. changes, said Dr. Vetter. In early stages These results may be due to its ability to Vetter, PhD, professor of neurobiology of the mouse model, she said, there are mitigate excitotoxicity and the release of and anatomy at the University of Utah changes in gene expression. There excess glutamate into the extracellular in Salt Lake City. is clear optic nerve pathology, but the space, which causes ganglion cells to die Researchers have also discovered that retinal ganglion cells are still there until by apoptosis from secondary damage.2 deficits in transport have early, middle late in the game. Studies by the lab of Human trials of memantine for and late-stage components. “This allows Philip J. Horner, MD, at the University open-angle glaucoma have produced researchers to break down the progres- of Washington in Seattle, document confusing and disappointing results. sion and home in on particular models that the ganglion cells persist for a long Progression of disease in studies last involved in each stage,” said David J. time, detectable by the expression of a year appeared to be lower in patients Calkins, PhD, associate professor of general neuronal marker.5 “There is still receiving the higher dose of the drug ophthalmology and visual science at the potential for rescue because the cells compared to those receiving a low dose. Vanderbilt University in Nashville. are simply quiescent or atrophied—not But in January Allergan announced that The drug minocycline has been shown gone,” said Dr. Vetter. In addition to other final analysis of a memantine phase 3 to improve retrograde transport and factors, loss of neurotrophic support trial revealed that overall the drug did morphology of the optic nerve. If deliv- may eventually contribute to cell body not perform any better than a placebo.3 ered at stages well before evidence of death. “But apoptosis is not the driving Despite these inconclusive results, disease, it can suppress activation of force for quite a while in this disease,” Dr. Cioffi remains optimistic about the microglia, said Dr. Vetter. This shows she added. memantine trials. “Going into such that axonal changes are coupled with 3. Pressure injury. Designed to sense studies we don’t know if we are testing activation of microglia. “We wanted to pressure, a family of molecules called 14 s u p p l e m e n t
  • mechanicoreceptors is located through- out the brain and retina. These molecules might allow cells in the retina and optic nerve 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 keeping balance,” said Dr. Calkins. Pressure injury may overload the cells with calci- um, which can cause a direct degenera- tive cascade, he said. Researchers suggest that the molecules sensing pressure might be the factor translating pressure into neuronal damage. If so, blocking the pressure-sensitive calcium channel might restore contact with the brain. Dr. Vetter and other researchers express excitement about these and other theories concerning glaucoma and neuroprotection. “We do feel that we’ve learned enough to have some candidate pathways to target, and we’re hopeful that in the next couple of years we’ll be able to figure out—along with a number of other excellent labs—which ones 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 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. Glaucoma Research Foundation The valuable work of three of the re- searchers interviewed for this two-part story, Drs. Vetter, Calkins and Horner, as well as researcher Nicholas Marsh- Armstrong, PhD, who contributed the images, is sponsored by the Glauco- ma Research Foundation. For more information, visit e y e n e t s e l e c t i o n s 15
  • sk four glaucoma specialists A 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 This article originally appeared in the April 2008 issue of EyeNet Magazine. e y e n e t s e l e c t i o n s 17
  • typically transforms the patient’s vision with minimal risk of Reconsidering the Standard serious complications. Similarly, retina surgeons faced with Over the years, there have been challenges to the traditional detached retinas have an easier decision. “If you don’t fix stepped regimen of medication then laser trabeculoplasty. those, the vision will get worse,” he said. “Even the threshold The Glaucoma Laser Trial (GLT) demonstrated that initial for cornea transplant has been lowered. The decision to do laser is at least as effective as medication. glaucoma surgery, at least where pressure is not way off the And while doctors seldom, if ever, do glaucoma surgery map, is difficult.” before trying medication, a case has been made for surgery A RISK/BENEFIT RATIO. So when to resort to surgery? first—at least in newly diagnosed open-angle glaucoma “When is a hard question to answer because some people do patients with advanced visual field loss. The Collaborative very well with medicines and some don’t,” said Douglas E. Initial Glaucoma Treatment Study (CIGTS) found that low- Gaasterland, MD, clinical professor of ophthalmology at ering intraocular pressure with initial filtering surgery is as Georgetown University. “When you’re sitting there in the effective as medical therapy for inhibiting progression of chair with a patient, you can’t tell how they’re going to do visual field damage. In fact, surgery yielded a slightly greater with medication until they try them.” reduction. The data derive from a subanalysis of the CIGTS The mantra has been and continues to be: medication data, reported by Paul Lichter, MD, and colleagues. It didn’t first. matter whether subjects with mild baseline visual field loss “Our standard approach to glaucoma is to begin with (mean deviation –2 dB or better) had surgery first or medica- medical therapy and escalate by adding drops or using com- tion. But the subanalysis found that patients with more bined agents,” said Steven J. Gedde, MD, professor of ophthal- advanced visual field loss at baseline (mean deviation worse mology at Bascom Palmer Eye Institute. “When that fails to than –10 dB) fared better with initial surgery, compared with adequately control IOP, traditionally we use laser trabeculo- the medication-first group. The complete analysis has been plasty. We reserve surgical intervention for patients who have submitted for publication. inadequately controlled glaucoma, despite maximum tolerated OLD STANDARD STILL IN PLACE. Though the GLT medical therapy and appropriate laser treatment.” and CIGTS studies showed that laser and surgical treatment The move toward surgery, as Dr. Heuer put it, comes “when were essentially equivalent to initial medical therapy, “They the risk of continuing to observe outweighs the risk of doing didn’t create a shift in the paradigm,” said Dr. Gedde. Medica- surgery.” And what is that threshold? Determining the answer tion continued to trump surgery as a first-line treatment. “I to that, Dr. Heuer said, “is more often art than science.” generally will give patients at least a trial of medical therapy,” Various Routes Marianne Feitl, MD Douglas E. Gaasterland, SAME In private practice with Arbor Centers for Eye Care in MD Clinical professor of ophthalmology GOAL Chicago. at Georgetown University. Our glaucoma specialists do not disagree with each other’s If there is too much scarring on the con- “The guiding principle is we want to save essential goals for incisional junctiva anteriorly, or if Dr. Feitl doesn’t vision as best we can,” Dr. Gaasterland think a trabeculectomy has a reasonable said. “Most of the studies pay attention surgery. But their particular prognosis, she puts in a tube shunt 8 to to eye pressure, but eye pressure doesn’t 10 mm posterior to the limbus. Should matter to the patient. What the patients strategies, concerns and trabeculectomy or tube shunt fail, then care about is whether they can see the patient criteria may very diode laser photocoagulation is an option. newspaper and read. Reduce the eye “We always try to temporize. It’s always pressure from the level associated with much affect how aggressively worth trying medication, for at least a brief damage and you can keep them that way. or frequently their threshold period of time.” Dr. Feitl selects patients That’s the name of the game these days carefully to avoid hypotony from anti- —it has been forever.” for surgery is reached. metabolites. 18 s u p p l e m e n t
  • Dr. Gedde said. “If they can be compliant and have access to safer than ever, he said, “It’s still not totally predictable, and medication, even people with advanced glaucoma will receive it doesn’t always work, even when done well.” a trial with medical therapy.” THE FEARFUL PATIENT. Dr. Heuer, who has always MAKING EXCEPTIONS. On the other hand, Dr. been prone to operating when he sees moderate disease pro- Gedde will consider surgical intervention as initial therapy gression, is caught in a kind of catch-22 when it comes to early in patients who have limited access to medications or who surgical intervention. On the one hand, he is talking to patients admit to poor compliance with other medications. Generally earlier about surgery. But he’s also very open with them about speaking, he said there is no magic IOP number—no cutoff potential complications. As a result, he isn’t operating sub- point—that mandates surgical intervention. “You have to stantially more than in the past because many patients, after individualize to the patient,” Dr. Gedde said. “It requires judg- hearing the options, decide to stick with medication. ment on the part of the clinician. It’s not easy to know when LASER BEFORE SURGERY. He’s not alone. “There are to pull the trigger.” patients who will refuse to have surgery, even when we decided Marianne Feitl, MD, agrees. “ALT (argon laser trabeculo- that medical therapy is not working,” said Dr. Feitl. They’ll try plasty), or SLT (selective laser trabeculoplasty), or surgical laser, and even oral carbonic anhydrase inhibitors, despite intervention has to be tailored to the individual patient, their potentially serious complications. “They’d still rather which is how we’ve always approached the issue,” she said. do that than have a surgical procedure.” She added that laser, “There’s not been a huge shift in thought process about it.” though it doesn’t achieve pressures as low as trabeculectomy Dr. Feitl is in private practice in Chicago. and doesn’t lower pressure much for about 15 percent of “We’re inclined to use medications first, primarily because patients, is a good option after exhausting the prescription if you get into trouble, you can stop them,” Dr. Gaasterland drug armamentarium. “If we do move on to needing a surgi- said. “If you get into trouble with surgical intervention, it’s cal procedure, patients and I are more comfortable knowing done. You can’t undo it,” he said. The result is, “We tend to be that we did try other reasonable avenues first.” conservative.” “Though laser trabeculoplasty doesn’t work as long as we’d like, it can buy time,” said Andrew G. Iwach, MD.“If that’s Are We Too Conservative? your objective and you have been able to avoid the more inva- In patients with moderately advanced glaucoma, said Dr. sive step of trabeculectomy, you’ve done the patient a Heuer, “We’re probably not operating enough.” Ophthalmol- service.” Dr. Iwach is associate clinical professor of ophthal- ogists are conservative because although trabeculectomy is mology at the University of California, San Francisco. Steven J. Dale K. Andrew G. Gedde, Heuer, MD Iwach, MD MD Chairman of oph- Associate clinical Professor of thalmology, Med- professor of oph- ophthalmology at ical College of thalmology, Uni- Bascom Palmer Wisconsin and versity of Califor- Eye Institute in director, Froedtert nia, San Francisco, Miami. and the Medical and executive College of Wis- director of the consin Eye Insti- Glaucoma Center tute, Milwaukee. of San Francisco. If a patient is developing glaucomatous Surgery first is an option in a patient with Dr. Iwach emphasized the uniqueness of damage despite apparent IOP control, a mean defect worse than 10 dB, accord- each patient, and the importance of tai- Dr. Gedde considers that IOP measure- ing to Dr. Heuer. “As a glaucoma special- loring the results of studies to each ments in a patient with an extremely thin ist, I’ve had a little lower threshold for patient’s clinical situation. cornea might be under true IOP. So he is surgery,” he said, adding that the report “All these studies report in averages sure to check central corneal thickness. (submitted for publication) from CIGTS and means. But we don’t treat averages He is also mindful that the patient “crystallized that for me.” But he said or means. We treat individuals. Our job may be more compliant prior to office the decision to operate should be based as clinicians is to determine an accurate visits, and that diurnal fluctuations may on visual field testing, not on changes risk assessment for that individual, draw- mean that peak IOP measures may be in GDx, HRT or OCT images. He also ing on studies and being aware that you occurring at times other than normal avoids surgery on ocular hypertensives need to customize the treatment.” office hours. or glaucoma suspects. e y e n e t s e l e c t i o n s 19
  • LASER BEFORE DROPS? Dr. Iwach warned against ication work? There is no easy guidance on this. It depends on rushing to surgery. “Glaucoma is, in general, a slow-moving the patient and the doctor.” disease, so you have the time to collect data, establish trends USE LOGICAL CRITERIA. Dr. Feitl’s criteria for oper- and then make a decision before you do something.” That’s ating include noncompliance and an inability to afford med- where laser trabeculoplasty has a role, perhaps even more ication. Also, if a patient is getting worse, in spite of medical than eyedrops. “It can delay taking a patient to surgery. In therapy, even if the pressure looks reasonable, “surgery is war- some patients, it can delay the need for medication.” ranted because that approach may get a lower pressure,” said Dr. Feitl agreed, noting that medication has a downside. Dr. Feitl. Aside from cost and compliance issues, drugs can induce LOOK AT THE WHOLE PATIENT. There are no easy changes to the conjunctiva that may reduce surgical success answers. “People like a cookie-cutter formula,” Dr. Iwach said. down the road. She added that not doing surgery has its risks. But a lot of patients fall into a gray area between monitoring “We have to tell patients that there’s a higher risk of losing and more aggressive treatment. That’s where being MDs your vision from uncontrolled glaucoma,” Dr. Feitl said. comes in pretty handy, he said. Ophthalmologists have all the skills to assess the patient’s overall health and base treatment Each Patient Case by Case decisions on that information. “For some people, it’s going to be plain as day that you’ve got DON’T BE OVERLY CAUTIOUS. “It’s so individual, by to do surgery. For some people it’s going to be a puzzle,” Dr. patient, that it’s hard to articulate a precise point at which Gaasterland said. The obvious case involves a patient on max- you’ll do surgery,” Dr. Heuer said. “What my colleagues and I imum medication, with a high pressure and a deteriorating struggle to realize is that in some of our patients we’re actual- optic nerve or visual field. “The puzzling one is the one who’s ly a little late to operate. With moderate to advanced glauco- not getting worse,” he said. That patient may have a pressure ma, we need to be a little more aggressive than most of us of 23, with a target pressure in the teens, but the visual field have historically been. At least with patients with advanced and optic nerve measures are holding steady. “You have a disease, we need to have a little lower threshold. We ought to choice to escalate medication because they’re not yet on max- operate more than we have.” imum treatment. That’s the person who you have to think And clearly, doctors would operate more if they had a bet- about and decide about individually. Will they be able to ter surgery. “If we had the equivalent of clear cornea phaco adhere to a more complex medical schedule? Will more med- with foldable IOL surgery, we would probably operate a lot Strategy Under Pressure 1 r. Peng Khaw’s fornix-based trabeculectomy (see “Trabeculectomy and the D Fornix-Based Flap”) is depicted here from the conjunctival incision to creating the scleral flap, preparing the iridectomy, applying antimetabolites, securing releasable sutures and closing the conjunctiva. The final panel shows how Dr. Khaw’s adjustable scleral sutures can be be manipulated after surgery to moderate the flow of aqueous. 2 3 4 5 6 7 20 s u p p l e m e n t
  • 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 lot more 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. Trabeculectomy and the Fornix-Based Flap f you could avoid creating I an ischemic, localized bleb, would you be more inclined to do surgery earlier? Dr. Feitl said it’s probable. “We’d be more comfortable moving on to earlier surgical intervention,” she said, explaining that the benefits would outweigh the burden of patient adherence, the costs and the potential for localized and systemic side effects that are associated with medical therapy. “Traditionally, in the United States, surgery was considered a treatment of last resort because of the risk of infection,” Dr. Feitl said. “Some of the bias against surgery was in knowing that you often could end up with these ischemic, localized blebs.” Trabeculectomy is still risky, but Dr. Feitl has adopted a surgical technique intended to create healthier blebs. The Moorfields Safer Surgery System, advanced by Peng T. Khaw, MD, PhD, involves a fornix-based flap with adjustable sutures and a diffuse application of antimetabolites. The resulting bleb is healthier appearing, flatter and more dif- fuse, as opposed to the elevated, ischemic and localized blebs that result from limbus-based flaps, Dr. Feitl said. Dr. Heuer also has adopted the fornix-based flap, but he noted that Dr. Khaw’s technique involves two changes to the traditional surgery. One, he changed the flap technique. Two, he went from a local to more diffuse application of mitomycin C. “I think it’s more the latter that has changed the bleb morphology,” Dr. Heuer said. Dr. Feitl stressed the importance of applying the antimetabolite over a large area. But she is so sold on Dr. Khaw’s technique that she no longer creates limbus-based flaps. Dr. Khaw is a consultant ophthalmic surgeon at Moorfields Eye 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, click on “videos on demand” and type “Khaw” into the author field. e y e n e t s e l e c t i o n s 21