Advances in glaucoma management blur the barriers between subspecialties

Glaucoma management has undergone significant advancements in recent years. New minimally invasive surgical options have become available, filling in the gap between medical management and major surgeries such as trabeculectomy and tubes. On the diagnostic side, OCT technology has allowed a better understanding of the pathophysiology of glaucoma and more accurate monitoring of the effects of treatment, and has broadened the view to new imaging markers for progression. Glaucoma has opened up as a subspecialty to share areas of interest with other subspecialties and even other branches of medicine.

“The life of a glaucoma specialist has become a lot busier with so many options. We wear many hats now, and it is great to be able to wear a white hat with MIGS for our patients rather than the black hat we used to wear previously in many cases, when we could only offer invasive surgery with a high risk of complications,” E. Randy Craven, MD, said.

MIGS has brought radical changes in the way cataract and glaucoma treatments are combined. Cataract surgery was used previously as a stand-alone procedure to lower IOP, but now the two procedures work synergistically in a safe manner.

Image: Craven ER

“MIGS has also shifted a significant portion of glaucoma treatment in the hands of the cataract surgeon. It is tempting, and it makes sense to implant a MIGS stent in a patient who has glaucoma and needs a cataract operation,” Craven said.

While some glaucoma specialists are still reluctant to jump into the MIGS space due to efficacy concerns, cataract specialists have greatly increased the number of glaucoma patients who are managed now with MIGS.

“This is a positive aspect of the crossover between specialties. In addition, cataract surgeons have high operating skills as they perform a much higher amount of procedures and perform them in a patient population that has earlier disease and a higher likelihood of responding to surgery. So, I personally welcome the widespread use of MIGS devices by cataract surgeons,” Craven said.

Managing blebs

“Certainly a number of these devices are suitable to be used by cataract surgeons, typically the blebless MIGS that involve no bleb management postoperatively. They are safe procedures which take just a couple of extra minutes, so it is very convenient to implant these devices at the time of cataract surgery,” Ingeborg Stalmans, MD, PhD, said.

Study results show that MIGS devices consistently offer a reduction in the number of pressure-lowering medications, with some mild additional IOP-lowering effects as compared with phacoemulsification alone. According to Stalmans, these devices are suitable for patients who are on multiple medications, have glaucoma that is not advanced and need to undergo cataract surgery.

“They are an opportunity to maybe reduce the medication burden and have a slightly lower pressure, but don’t count on a massive reduction of IOP,” she said.

In patients with more advanced disease and a lower target pressure, something more than a blebless implant is needed. Besides the traditional options, such as classic trabeculectomy and tubes, ab interno, bleb-inducing MIGS is available with the Xen implant (Allergan). Prospective data with at least 1 year of follow-up have shown that the device is able to lower and maintain IOP in the low teens.

“The Xen was primarily designed to be used as a stand-alone procedure, but it can be used in combination with cataract surgery. However, some of these patients might need some bleb management such as needling, so I believe that the Xen is more suitable to be implanted by surgeons who are more experienced with bleb management. It can be a cataract surgeon, but it must be someone who is well trained to deal with blebs in the postop or someone who can count on this expertise from a colleague in case there are problems,” Stalmans said.

The Xen implant has multiplied the number of surgical interventions performed in the glaucoma department Stalmans leads at Leuven University, Belgium.

“More surgeries are done and are done earlier. We have almost 3 years of experience, and we have good efficacy with the Xen, less postoperative complications, faster visual recovery and more comfortable patients. Our threshold for doing surgery is going down,” she said.

In patients who are not well controlled with two drops, whereas previously she might have added another drop, now she considers MIGS.

“We realized that too many drops are not manageable and often cause irritation, and now we have a safer surgery option, so we move to surgery sooner. This is in line with several guidelines for glaucoma management that say that if a patient is not well controlled on two drops, another treatment option like surgery should be considered,” she said.

Need for proper training

Magda Rau, MD, runs a busy refractive cataract surgery practice with a day clinic and hospital eye department in Germany but has also dealt with glaucoma since the clinic’s inception, with argon laser trabeculoplasty, trabeculectomy as well as combining, when needed, trabeculectomy and phaco.

“The combination of trabeculectomy and cataract surgery was generally better accepted by patients than trabeculectomy alone. However, since new regional contracts no longer cover combined procedures, the number of my trabeculectomies has considerably decreased,” she said. “The willingness to undergo microstent implantation with cataract surgery is much higher. This opens the new field to cataract surgeons.”

Rau was one of the investigators of the CyCLE European study, in which the CyPass micro-stent (Alcon) was evaluated in combination with cataract surgery as well as a stand-alone procedure.

“The results of the multicenter European study correlate with my own results in 300 patients. The reduction of the IOP compared with baseline is approximately 34% ± 28%. The number of medications could be reduced by two. This effect is after 3 and even 5 years, lasting in most cases. But in some cases, because we know glaucoma is a progressive disease, trabeculectomy or nonpenetrating sclerectomy is needed. The surgery could be performed on virgin tissue at 12 o’clock because the CyPass is implanted temporarily.”

“MIGS has definitely changed the landscape of glaucoma surgery because trabeculectomy involved high intraoperative risks, a demanding postoperative management, frequent complications and a fairly high rate of long-term failures. Now we are able to provide patients with less invasive, easier and safer options,” Rau said.

However, a cataract surgeon who has never performed glaucoma surgery before should not underestimate the challenges of embarking on MIGS, she said. There are new skills to develop, such as visualizing the angle, assessing the structures, and deciding whether there are indications and requisites to implant a stent.

“I would not advise my colleagues to do this without attending a course. The CyPass implant has been recently acquired by Alcon, and they carry on the careful strategy of Transcend, offering training courses with expert instructors. They don’t want to spoil the reputation of the device by letting inexperienced surgeons implant it,” Rau said.

The number of certified CyPass users is increasing slowly but steadily, and there is growing interest around this option.

“Courses are well attended, and I have a lot of people asking questions after my presentations at meetings,” Rau said.

The iStent is a little easier to implant, but Glaukos also offers training courses, she said. She expects that the Xen gel stent will not gain the same popularity among cataract surgeons, not because of the surgical technique, but because cataract surgeons may not like to use mitomycin C and may be discouraged by the postoperative management of a bleb.

Although micro-stents are creating a lot of interest, surgeons should not forget that they are not for everyone, Rau said.

“They can only be implanted in patients with open-angle glaucoma and quite a wide angle. There are many cases with narrow angles and still many cases in which stents would not work because of high IOP. MIGS cannot cover the entire palette of glaucoma cases, and other procedures like trabeculectomy will continue to be in our armamentarium,” she said.

Success redefined

Some glaucoma specialists are reluctant to accept MIGS because what they expect from surgery is to achieve low pressures without medications. MIGS requires a more flexible approach and a paradigm change in the way surgeons think about success, according to Craven.

“If my patients are on one or two medications, have a MIGS stent implanted and the pressure is low enough so that I don’t have to do a trabeculectomy, I look at it as a success,” he said.

Choosing a MIGS option, combining it with phaco, adding some medications and possibly using more than one stent is a possibility and needs to be evaluated on a case-by-case approach.

“I found that canal-based procedures, the Hydrus (Ivantis) and iStent, work better if I do phaco at the same time. Often I implant not one but two iStents, and frequently I combine canal-based procedures with medications. I call it MIGS & Meds, and it allows me to achieve the target IOP I look for,” Craven said.

“Preoperatively, I look for clues on who might be successful with a canal-based procedure. For instance, if someone has had a good response to SLT before, or if I see there are patches of pigment on the trabecular meshwork, it tells me that the canal system is viable and I can go with an iStent or a Hydrus. If I do not see these signs, or if a patient did not respond to SLT, then I frequently look at the CyPass as the next MIGS option, or I may look at a Xen. This is the kind of process I go through, and if I choose the right patient, I do have the success I want. There is no perfect MIGS, and we need to understand who are the best candidates for each procedure. We are still working at this and don’t yet have any randomized trial to answer our questions,” he said.

Organizational changes

“When the Xen procedure was introduced in my department, it had quite an impact on the organization, and I had not anticipated this,” Stalmans said.

She soon found out that surgery was shorter than trabeculectomy, and consequently she was able to considerably increase the number of patients she could operate on in one day. In the time she used to do trabeculectomy, she could do two or more Xen procedures.

“However, this also meant we had to increase the capacity of our ward and deal with a faster turnover of patients. Initially this created a bit of an issue because our nurses did not have enough space to put the patients, did not have enough time to prepare them and had to run in and out of the OR all the time,” she said.

With more than double the number of patients, the number of postoperative visits also increased unsustainably.

“I see my trabeculectomy patients four times over the first month, and so I did with my Xen patients initially. Our clinic was bursting, and we were unable to keep up with this pace. We had to find a solution, and so we did,” Stalmans said.

After revising the number of postoperative interventions and bleb manipulations in the first month and discovering that they were considerably fewer with Xen than trabeculectomy.

“Trabeculectomy has sutures which you frequently have to adjust to get the pressure right, but with Xen you don’t have sutures, for instance. That’s why we decided we could see Xen patients less often, and we found the right balance. It works really well because we are doing surgery on more patients but can manage them with less postoperative visits and less manipulation,” Stalmans said.

OCT widens horizons

OCT has also been a game-changer for glaucoma specialists. It has changed the clinical practice, provided new insights into the pathogenesis of the disease and opened the possibility to explore new approaches to treatment.

“OCT is at the core of glaucoma examination for diagnosing and monitoring glaucoma. It provides objective and quantitative information that describes the retinal nerve fiber layer, the optic nerve and the macula. The macula in particular is of interest because it is involved in early glaucoma, and assessing it allows enhanced diagnosis and monitoring of the disease,” OSN Glaucoma Board Member Robert N. Weinreb, MD, said.

OCT angiography (OCTA) has gone a step further, allowing the investigation of vascular factors that might contribute to the development and progression of the disease.

“OCTA allows us to measure the radial peripapillary capillaries that emanate from the optic nerve head and nourish the axons of the retinal ganglion cells in the inner retina. These axons are selectively damaged in glaucoma, perhaps because they are more vulnerable to IOP changes or as a result of loss of perfusion from the local [radial peripapillary capillaries],” Weinreb said.

Several recent studies show a relationship between loss of optic nerve fibers and loss of radial peripapillary capillaries, raising “the chicken or the egg” question of what comes first. Does loss of radial peripapillary capillaries come first and subsequently cause the loss of nerve fibers or vice versa?

“There is new evidence that loss of microvascular capillary density, measured by OCTA, might precede structural loss of optic nerve fibers. This is particularly exciting because not only would it be good for diagnosing and monitoring glaucoma, but also might be a sensitive glaucoma biomarker,” Weinreb said.

“Over the next year or two we should be able to develop better predictive models to estimate the risk of glaucoma development and progression and to distinguish those individuals who have the likelihood of rapidly progressing and losing ganglion cells and [retinal nerve fibers],” he said.

Window between eye and brain

Some years ago, Francesca Cordeiro, MD, PhD, developed the detection of apoptosing retinal cells (DARC) method for imaging and tracking retinal ganglion cell apoptosis in vivo.

“We were looking specifically, we thought, at [retinal ganglion cells] apoptosis in glaucomatous disease to better elucidate the mechanisms of neurodegeneration and assessing potential neuroprotective strategies in glaucoma,” she said.

However, time spent on this research led to the discovery of a crossover with other neurodegenerative diseases.

“In a phase 1 clinical trial, we found a 1.5 times greater number of apoptotic cells in the [retinal ganglion cell] layer of eyes with glaucoma as opposed to healthy controls, which is a clear, significant difference. Later on, using the DARC test and OCT, we were able to find increased [retinal ganglion cell] apoptosis in an in vivo model of Parkinson’s disease. These changes occurred before brain changes in the substantia nigra and striatum, suggesting that retinal changes precede the classical pathological manifestations of Parkinson’s disease,” Cordeiro said.

After treatment with various doses of rosiglitazone, a neuroprotective drug, reduced neuronal loss was observed at day 20 in the retina and at day 60 in the brain.

“These very important findings demonstrate that the retina can be used as a surrogate marker for changes in the brain,” Cordeiro said.

A phase 2 trial is currently ongoing. In addition to glaucoma patients, it includes a subset of patients with neurodegenerative diseases in the form of optic neuritis, which is associated with multiple sclerosis, and also a group of Down syndrome patients who have a high risk for dementia due to amyloid deposition in the brain. In another group, patients with macular degeneration are included.

If the retina is “a window to the brain,” ophthalmologists will be able to help neurologists and neuro-ophthalmologists in the management of patients.

“We provide an easily accessible window, which is much cheaper than doing expensive PET scans or MRI, and we can do it in a noninvasive manner,” Cordeiro said.

A similar multidisciplinary project investigating the connection between changes in the retina and Alzheimer’s disease is currently being set up in Leuven.

“The retina is part of the brain and therefore can be used as a window to the brain,” Stalmans said. “The idea of the project is that retinal imaging might help in the early detection and follow-up of patients with Alzheimer’s disease.”

Several partners are involved, among them the Interuniversity MicroElectronics Center (IMEC), currently working on the development of a hyperspectral imaging sensor for retinal imaging, and the Flemish Institute for Technological Research (VITO), specialized in the development of software for automated image analysis.

“With them, the departments of ophthalmology, neurology and biology have formed a consortium to work conjunctly at this important project, which will help screening and following up patients with Alzheimer’s disease,” Stalmans said. – by Michela Cimberle

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• For more information:
• Francesca Cordeiro, MD, PhD, is professor of retinal neurodegeneration and glaucoma studies at University College London. She can be reached at UCL Institute of Ophthalmology, Bath Street, London EC1V 9EL, UK; email: m.cordeiro@ucl.ac.uk.
• E. Randy Craven, MD, is associate professor at Johns Hopkins University School of Medicine. He can be reached at Ophthalmology, Glaucoma Center of Excellence, Wilmer 233, 600 N. Wolfe St., Baltimore, MD 21287; email: erandycraven@gmail.com.
• Magda Rau, MD, is the owner and head of Augenklink Cham. She can be reached at Augenklinik Cham, Cham, Germany, 93413; email: info@augenklinik-cham.de.
• Ingeborg Stalmans, MD, PhD, is head of the glaucoma unit, University Hospitals UZ Leuven, and head of the ophthalmology research group, Catholic University KU Leuven. She can be reached at Ophthalmology Department, UZ Leuven, Herestraat 49, 3000 Leuven, Belgium; email: ingeborg.stalmans@mac.com.
• Robert N. Weinreb, MD, is distinguished professor and chair of ophthalmology at the University of California, San Diego. He can be reached at 9415 Campus Point Dr, La Jolla, CA 92037; email: rweinreb@ucsd.edu.

Disclosures: Cordeiro reports she is the named inventor of DARC technology. Craven reports he is a consultant for Allergan and Alcon. Rau reports no relevant financial disclosures. Stalmans reports she is a consultant for Allergan, AqueSys, Alcon, Santen and Glaukos. Weinreb reports he receives research support from Carl Zeiss Meditec, Heidelberg Engineering, Optovue, Optos and the National Eye Institute.

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