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March 2011

 
Feature
Glaucoma Treatment Paradigm Driven By New Interventions
By Miriam Karmel, Contributing Writer
 
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Once regarded as a last resort, aggressive interventions to lower IOP have leapfrogged over topical drops to become innovative, first-choice recommendations for some adventuresome physicians and select patients. The rationales propelling these interventions, however, are necessarily in flux.

The glaucoma surgery armamentarium is expanding as doctors continue the search for a technique that lowers intraocular pressure without the complications associated with trabeculectomy. Some of the new techniques, some involving devices no bigger than a grain of rice, are still investigational. Others have been in use for several years. Though none gets pressures as low as trabeculectomy, their safety profiles are so appealing that surgeons may want to try them as a first-line treatment.

“Right now we’re seeing the brightest horizon I’ve ever seen for glaucoma surgical advances; technology is finally catching up to where it should have been,” said E. Randy Craven, MD. “The reason all these techniques have evolved is that trabs cause trouble.” Dr. Craven is associate clinical professor of ophthalmology at Rocky Vista University in Englewood, Colo., and codirector of the Specialty Eye Care research department there.

These procedures could generate a new treatment paradigm, said Douglas J. Rhee, MD. He predicts a shift from dependence on IOP-lowering medications to surgical, laser or incisional intervention. He cited multiple limitations to the medical approach, including adherence, cost (even for generics) and tolerability. “The initial management may move from medical management to procedural intervention first,” he said. Dr. Rhee is assistant professor of ophthalmology and associate chief of practice development at the Massachusetts Eye and Ear Infirmary.

The idea of surgery as an initial intervention gained traction with the Collaborative Initial Glaucoma Treatment Study (CIGTS), which compared medical treatment to early filtration surgery in newly diagnosed open-angle glaucoma. Patients with advanced disease, defined as greater than –10dB on the mean deviation, had better preservation of visual field with trabeculectomy than with medical management.1

Dr. Rhee added that surgery generally has the advantage of flattening the circadian rhythm more than medication, an important benefit given the recent attention to IOP fluctuation as a risk factor for progression that might equal or trump mean IOP itself.

“Depending on the degree of damage the patient has, we have specific options,” said Joel S. Schuman, MD, professor and chairman of ophthalmology at the University of Pittsburgh. But, he added, “We’re not there yet in terms of having found a great procedure to replace trabeculectomy. The problem is we have procedures where we can achieve low IOP that preserves the optic nerve, but they carry short- and long-term risk as well as occasional discomfort for the patient. On the other hand, we’ve made a lot of strides, and many of our patients are benefiting from less risky procedures. So I think we need to look both at aspects of where we’ve been and where we want to go. We’re farther down the road, but still nowhere close to where we need to go.”

What follows is a discussion of eight interventions for getting aqueous flowing. Three are not yet approved in the United States but may be soon.

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TRABECULECTOMY ASSISTS

Ex-Press Glaucoma Filtration Device

The Ex-Press (Alcon) is implanted under the conjunctiva, between the anterior chamber and the outside of the sclera, allowing aqueous to bypass the normal filtration angle of the eye.

“It’s a modified trab,” said Shan C. Lin, MD, associate professor of clinical ophthalmology at the University of California, San Francisco. Dr. Lin uses it as an alternative to trabeculectomy. The theoretical advantage is a more fixed outflow that reduces the amount of leakage around the conjunctiva, as compared with a trabeculectomy, in which the hole was cut too big, he said. By the same token, theoretically, it prevents hypotony. In trabeculectomy, the surgeon has to gauge how much aqueous will leak out, Dr. Lin said. But with the Ex-Press, the surgeon controls release of fluid by inserting a small stent into the eye.

He would not use the Ex-Press in a patient who needs a very low pressure, say, someone with normal tension glaucoma with a target pressure below 10 mmHg.

“I would say you are more likely to get that with a trabeculectomy, where you can aim for lower pressure by making a larger hole,” Dr. Lin said. He added that there is some preliminary evidence that a newer version of the device can achieve lower pressures than the standard model.

Dr. Rhee said that he does find the Ex-Press is helpful when aiming for a pressure of less than 10 mmHg or for advanced disease. He disagreed with those who contend that the Ex-Press has a lower rate of hypotony than trabeculectomy.

The final IOP depends on how tight you tie the sutures, he said. But if hypotony occurs, the Ex-Press maintains a deep chamber and thus results in fewer complications.

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Tube Shunts

This option isn’t terribly new, but there may be a new role for tube shunts depending on the outcome of the Primary Tube Versus Trabeculectomy (PTVT) study. This followed an earlier study—the Tube Versus Trabeculectomy (TVT) Study—which suggested that following previous intraocular surgery, tube shunts have an advantage with regard to long-term efficacy and safety compared with trabeculectomy. The data were so encouraging that the PTVT group is now comparing trabeculectomy with tube shunts as the primary incisional surgery for open-angle glaucoma.

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EXTERNAL APPROACHES

Canaloplasty

Canaloplasty (iScience Interventional) is a nonpenetrating surgical technique for lowering IOP by restoring the natural outflow pathway in patients with open-angle glaucoma. The procedure is completed under a scleral flap, using a microcatheter with an illuminated tip for 360-degree catheterization and viscodilation of Schlemm’s canal. A prolene suture maintains tension on the inner wall of Schlemm’s canal. The aim is to increase the flow of aqueous humor from the anterior chamber through the trabecular meshwork and Descemet’s window, into and around Schlemm’s canal, and out through the collector channels.

Canaloplasty is “a procedure in evolution. It’s not understood why it works,” Dr. Schuman said. Some think it functions as a mechanical pilocarpine. Others think it causes production of cytokines that increase aqueous outflow. Or possibly, the prolene suture may cause breaks in the inner wall of Schlemm’s canal, allowing fluid to drain more easily, he said. Dr. Schuman added that while canaloplasty is touted as blebless, it may produce a low-lying bleb in some cases.

Dr. Lin said canaloplasty is an especially challenging surgery because the surgeon is doing a dissection to Schlemm’s canal without puncturing Descemet’s membrane. “If you puncture, it’s basically a trabeculectomy.”

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Gold Micro Shunt

Still not FDA-approved in the United States, the Gold Micro Shunt (Solx) is widely used internationally, Dr. Craven said.

The 3-mm-wide by 6-mm-long drainage device is about the thickness of a human hair and is implanted through a single incision into the supraciliary space. Solx claims that while the mechanism of action is undetermined, it is assumed that increased uveoscleral outflow into and through the suprachoroidal space leads to IOP reduction.

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INTERNAL APPROACHES

Trabeculotomy Ab Interno With the Trabectome

Designed to open Schlemm’s canal and reestablish access to the eye’s natural drainage pathway, surgery with the Trabectome (NeoMedix) is performed under direct visualization with a gonioscopy lens. Electrocautery removes a 60- to 120-degree strip of the trabecular meshwork and the inner wall of Schlemm’s canal to achieve direct flow of aqueous into the canal and then into the collector channels. The advantage is that it’s quick and simple. Dr. Schuman characterized the surgery as minimally invasive and relatively low risk, since hypotony and other complications are rare. The most common complication is bleeding, due to the backflow of blood into the anterior chamber when removing the inner wall of Schlemm’s canal. Another downside is a limited reduction in pressure in most cases, with many patients still requiring medication, Dr. Schuman said.

Trabectome surgery was introduced as a stand-alone procedure, but it can be combined with phacoemulsification and an IOL implant. Dr. Schuman has done the procedure both ways but tends to reserve it for the patient who is having cataract surgery who has early to moderate glaucoma and doesn’t need a very low IOP.

As a stand-alone procedure, Dr. Rhee reserves it for the patient “who is very wary of having a bleb, someone who is very informed of relative risk of failure and is accepting of going on to the next step—trabeculectomy.” Dr. Rhee has a study in press with the Journal of Glaucoma comparing primary trabeculectomy with trabeculectomy performed after a failed Trabectome. The survival curves were the same, and the average number of IOP-lowering medications was the same. Thus, Trabectome failure does not have a negative impact on a later trabeculectomy, he said.

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iStent Mini Glaucoma Shunt

The titanium stent is placed in Schlemm’s canal to reestablish more normal flow of aqueous.

Though not U.S.-approved yet, the iStent (Glaukos) received a favorable recommendation from an FDA review committee in July 2010. It is expected to be approved but only for use in conjunction with cataract surgery to control high IOP in open-angle glaucoma patients already on glaucoma medication. “It’s got its place, but in eyes with open-angle glaucoma and not necessarily super high pressures or other issues with the angles,” said Dr. Craven, who implanted the first iStent in the United States in June 2005.

He said part of the holdup with the FDA is that iStent has to achieve better pressure reduction than cataract surgery alone. When inserted in the right place, the iStent can achieve pressures around 13 or 14 mmHg without medication, Dr. Craven said. “I was surprised how a teeny stent could allow a low pressure.” Dr. Craven predicts the iStent will be a first-line mainstay option for the patient undergoing cataract surgery. Or for the patient on one or two medications, it might be tried before selective laser trabeculoplasty. The data show the iStent reduces the medication burden over time, without the pressure drift that occurs following cataract surgery, he said.

Dr. Schuman said iStent functions much the same way as surgery with Trabectome, bypassing the major site of resistance to outflow. But since no tissue is removed, there’s less likelihood of scarring at the surgical site. Dr. Lin said the data show modest IOP reduction. Also, it requires a gonioscopic approach, something “most ophthalmologists are not comfortable doing.”

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CyPass

Approved in Europe, this supraciliary microstent for increased aqueous outflow through the uveoscleral pathway is investigational in the United States. Unlike other glaucoma surgical devices, CyPass (Transcend Medical), which is implanted through a 1.5-mm clear cornea incision, does not access Schlemm’s canal or the conventional aqueous outflow pathway. CyPass was designed to create a permanent conduit from the anterior chamber to the suprachoroidal space, to drain the aqueous internally. It is intended for use in combination with phacoemulsification or as a stand-alone for open-angle glaucoma. The company states that the device is intended to function like prostaglandin analogs.

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Endoscopic Cyclophotocoagulation

ECP (Endo Optiks) employs video endoscopy to visualize laser application and selectively ablate pigmented ciliary epithelium. It is the only incisional glaucoma procedure intended to suppress aqueous production.

While it is promoted as a first-line treatment (usually in combination with cataract surgery), Dr. Lin described this cyclodestructive procedure as suitable for eyes refractory to medication, or eyes that may have undergone previous filtering surgery. Inflammation of the anterior chamber and cystoid macular edema are potential complications.

Dr. Craven said ECP went through a phase where it was favored for almost anybody undergoing cataract surgery. “Now it’s more a niche procedure, especially for eyes with narrow angles.” For example, it could be used to treat plateau iris syndrome. The surgeon goes behind the iris and uses the endoscopic probe to visualize the ciliary process, then opens the angle by shrinking the tissue with the laser.

ECP may be combined with cataract surgery in patients with mild to moderate glaucoma. And it can be performed after failed trabeculectomy or tube shunt surgery. Dr. Rhee offers ECP in conjunction with cataract surgery in patients with chronic angle-closure glaucoma, but not open-angle glaucoma. And he offers it after failed trabeculectomy or tube shunts. As a stand-alone procedure, the data on long-term effectiveness are limited, he said.

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STEPPING-STONES

While the newer surgeries don’t achieve pressures as low as trabeculectomy, in certain patients they are a reasonable first step, glaucoma experts agreed. “We’ll be able to do this stepwise,” said Dr. Craven, who proposed a surgical decision-making approach that begins with an iStent or the CyPass before moving on to trabeculectomy or tube surgery. “We’ll walk down those steps because it’s safer for the patient than to jump straight to a trabeculectomy.”

Finessing the options. Drs. Schuman and Rhee offered their approaches to several different clinical scenaria:

  • “If I need a very low IOP now, right away, I’ll do a more standard filtering procedure, like a trabeculectomy or tube implant surgery,” said Dr. Schuman.
     
  • “If I need a low pressure, but the patient has moderate glaucoma,” Dr. Schuman continued, “I’ll do canaloplasty. There’s a chance I’ll get a low pressure with that alone, but I can convert it [to trabeculectomy].”
     
  • To convert canaloplasty to a penetrating procedure, Dr. Schuman opens up Descemet’s window with a YAG laser, allowing fluid to more easily reach the scleral flap, creating a bleb. If that isn’t adequate, he would inject mitomycin C subconjunctivally, wait one half hour for it to be absorbed, then do a needle revision of the scleral flap. This allows direct flow from the anterior chamber to the subconjunctival space. “You’ve essentially converted this nonpenetrating procedure in a stepwise way to a trabeculectomy. You’ve done it under safe conditions and in the doctor’s office.”
     
  • For the patient who needs cataract surgery and who also has early or, even, moderate glaucoma, Dr. Schuman would combine Trabectome surgery with phacoemulsification.

    Dr. Rhee offers his patients three surgical options: Trabectome, canaloplasty and trabeculectomy.

  • Trabectome has limited success rates compared with canaloplasty or trabeculectomy,” he said, but it doesn’t involve manipulating the conjunctiva, and it is relatively safe.
     
  • Canaloplasty, though more invasive than Trabectome surgery, seems to have higher success rates, Dr. Rhee said. The downside: a trabeculectomy after canaloplasty is likely to have a higher risk of failure because you have scarred conjunctiva. The TVT study results would infer that a tube would be a better choice. After a failed canaloplasty, he would implant a tube shunt.
     
  • Finally, Dr. Rhee offers trabeculectomy to “patients who want the highest chances of success and are willing to accept the risk.”

Caveats? Yes—two. There are caveats. First of all, Trabectome and canaloplasty are mutually exclusive. You can’t do one and then the other, Dr. Rhee said. And second, the target IOP for both techniques is in the mid and upper teens. Anyone who needs a target pressure in the low teens or lower should have a trabeculectomy. “Given the knowledge that we have now, this is my treatment protocol,” Dr. Rhee said. “It is different than it was a year ago. Now we know more. A year from now we’ll know even more, and my protocol might be different.”
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1 Musch, D. C. et al. Ophthalmology, 2009;116(2):200–207.

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WHERE SKILL AND NECESSITY TRUMP RESOURCES: THE CASE FOR TRABECULECTOMY

Even as the glaucoma treatment paradigm may be shifting in the United States and other resource-rich nations, it may well be in the developing world, too, but in different ways. “Our available resources, challenges and approaches to glaucoma are different in the developing world,” said Hunter Cherwek, MD, medical director of ORBIS International, a group that works to establish comprehensive, affordable and sustainable eye care in developing countries.

He called glaucoma “a huge issue in the developing world.” Severity at presentation is often advanced because of the lack of routine screening, so patients typically need lower target pressures and are often going to have surgery first.

Dr. Cherwek also said that because medical cost and compliance are significant issues, “Many ophthalmologists go straight to trabeculectomy.”

Bread & butter trabs. ORBIS teaches other procedures, including canaloplasty, pediatric glaucoma procedures and tube-shunt surgery. But its priorities are to help the neediest patients and transfer sustainable technologies to local medical personnel, so trabeculectomy is the “bread-and-butter procedure” in countries where resources are scarce, Dr. Cherwek said.

The agency focuses on teaching improved techniques for trabeculectomy, including the use of antimetabolites. It also teaches tube-shunt surgery as a next step, especially for failed trabeculectomies. ORBIS also passes on lessons learned from the large clinical trials. “The OHTS is a beautiful example,” Dr. Cherwek said, referring to the finding that central corneal thickness matters in the evaluation of glaucoma suspects. Being mindful of that finding could result in fewer premature trabeculectomies.

The value of gonio. In China, where over 30 percent of the glaucoma population has an angle-closure component, doctors are taught the importance of gonioscopy, Dr. Cherwek said. “Gonioscopy might be the most important and underperformed diagnostic skill in preventing someone from going on to develop glaucoma.”

He stressed that without optic nerve head imaging or visual field analyzers, “the key factors in the evaluation and management of the glaucoma patient become angle and optic nerve head appearance, intraocular pressure and patient history.” In parts of the world where resources are scarce, the fundamentals are key. “Your imaging machine may not work one day,” Dr. Cherwek said. “But your training and clinical skills never fail you.”

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MEET THE EXPERTS

HUNTER CHERWEK, MD Medical director, ORBIS International. Financial disclosure: None.

E. RANDY CRAVEN, MD Associate clinical professor of ophthalmology, Rocky Vista University in Englewood, Colorado. Financial disclosure: Unpaid speaker for iScience and consultant for Glaukos and Transcend. Investigator for several glaucoma devices now in clinical trials.

SHAN C. LIN, MD Associate professor of clinical ophthalmology, University of California, San Francisco. Financial disclosure: Speaker for Alcon.

DOUGLAS J. RHEE, MD Assistant professor of ophthalmology and associate chief of practice development, Massachusetts Eye and Ear Infirmary in Boston. Financial disclosure: Research funding from Allergan and Alcon; consultant to Allergan, Alcon and Santen.

JOEL S. SCHUMAN, MD Professor and chairman of ophthalmology and director of UPMC Eye Center, University of Pittsburgh. Financial disclosure: Receives royalties for intellectual property licensed by MIT to Carl Zeiss Meditec.

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