New Distinctions Between Controlled and Refractory Glaucoma

MIGS could redefine how glaucoma specialists stage disease.


As minimally invasive glaucoma surgery (MIGS) devices proliferate, so do their indications. Minimally invasive surgical options are available for mild-to-moderate, severe, and refractory glaucoma. As these indications expand, it is also possible that the definition of controlled and refractory glaucoma will shift. In this roundtable discussion, Inder Paul Singh, MD, leads a discussion of the definition of controlled and refractory glaucoma with glaucoma specialists Carlos Buznego, MD, and Arsham Sheybani, MD.

Dr. Singh: The definition of refractory glaucoma seems to change depending on the surgeon you’re talking to. Some surgeons say glaucoma is refractory after one trabeculectomy. Some say it’s refractory if the patient is on more than 2 medications. What I want to discuss is whether you have redefined what is considered controlled glaucoma or, in other words, whether the indications for going to surgery have changed. Do you consider quality of life as part of your definition of uncontrolled glaucoma?

Dr. Buznego: I worry about compliance for patients who are on a lot of medications. Every one of my patients tells me they’re compliant, but studies confirm that probably 50% of patients are truly compliant. I think that ophthalmologists should be more skeptical that patients can keep up with complex regimens.

Dr. Sheybani: I consider whether the glaucoma is stable based on disease progression and whether the patient is stable with their treatment regimen. Patients might have years of stable fields, with pressures in the clinic that are at target, but at home things aren’t stable. They’re noncompliant with medications, and/or their quality of life is very poor on their medication regimen.

Dr. Singh: Are there patients for whom you define uncontrolled glaucoma purely on quality of life, forgetfulness, or side effects? If the disease is stable, will quality of life be the only cause for you to say glaucoma is not controlled?

Dr. Sheybani: I might not call it uncontrolled, but I might note the compliance issue. And yes, that is a reason to operate. There are also instances where I might know there is a compliance issue but I decide to back off of the target pressure goals I set. I’m not always trying to do something to drive pressure down. But it is true that, once I get the hint that a patient is not able to take the medication, then I try to do something about getting them off the medication. It could take years for allergies or ocular toxicity to build up. They might still be taking their medications, but when you start seeing conjunctival foreshortening, ectropion, entropion, or trichiasis, the disease might be stable but it’s not a stable way of living life. And up until recently we just didn’t have surgical options that carried relatively low risk.

Dr. Buznego: The conversation with the patient about compliance and side effects is key. Rather than simply adding more medications when the disease is uncontrolled, we need to make MIGS a part of the conversation. The low risk profile of MIGS changes the discussion; we weren’t talking about surgery before as an option.

Dr. Singh: For me, noncompliance occurs not only because of the side effects of medication. If I hear a patient complain about cost, I know they are likely not able to take multiple medications, or if they state they have a hard time remembering to take their meds, that to me is a cry for help. My fear is the poor compliance will eventually show up in obvious field or optic nerve head progression. Now, because the safety profiles of these MIGS devices are so good, we’re more willing to operate earlier. I think the mild-to-moderate patient is the toughest one because we often can’t use visual fields to see progression. Even the optic nerve may not show significant progression. The more advanced the disease, the easier it is to see visual field changes over time and say the patient is not controlled. It’s the mild-to-moderate patient, or a mild patient specifically, who may have a healthy field, for whom we may not be able to detect changes for years.1,2

I think we have better data now that support the idea that removing compliance issues will reduce future need for incisional surgery. The HORIZON 3-year data demonstrated 85% decreased risk of needing incisonal surgery in the Hydrus/phaco group compared to the phaco-only group.3 The LiGHT study also demonstrated that the group receiving selective laser trabeculoplasty (SLT) as first-line treatment for open-angle glaucoma and ocular hypertension had similar IOP reduction to the medication-only group, but the SLT group had significantly less chance of progressing to incisional glaucoma surgery.2 Decreasing medication burden and thus decreasing compliance issues might be the explanation for the decrease risk for needing incisonal surgery. These 2 studies were also conducted in the mild-to-moderate patient. Now MIGS gives us another option for patients with milder disease, where we can’t always use visual fields or sometimes even nerves to show progression early on, but we have evidence to support we are helping to decrease eventual progression. That’s why I think about compliance if patients tell me they can’t remember to take their medications or the medications are too expensive.

Dr. Sheybani: A recent study looked at IOP fluctuations and concluded that in the end, when there is high pressure, it’s pressure that will cause progression and vision loss.4 When pressures are in a more normal range, fluctuation matters more. So some of these devices that go in the trabecular meshwork and have a good safety profile could reduce that variability and potentially decrease progression. Now we are starting to see studies showing a decrease in secondary surgical interventions. These are in patients with mild-to-moderate glaucoma, and that’s critical.

Dr. Singh: The problem with looking at fluctuation studies like AGIS and CIGTS that studied more advanced patients5,6 is that in earlier disease it isn’t as easy to see the ramifications of fluctuating IOP. Patients can lose a significant number of ganglion cells before we can appreciate visual field loss. That’s why I prefer not to wait until there is field loss before determining if a patient’s glaucoma is progressing.

I also would like to address refractory glaucoma and how we define that. There seems to be no consistent definition among my colleagues. This is important because there are surgeries — for instance, Xen (Allergan) — for which the indication is for refractory glaucoma. The question is, what is the definition? Has it changed in the last 5 years since the introduction of MIGS?

Dr. Sheybani: For me, the disease severity is not in the equation. Refractory means patients are not at goal pressures. Refractory means that the pressure is not where it needs to be or their compliance is not where it needs to be for their disease, and therefore the disease is refractory to current treatment.

Dr. Singh: That’s a very good point. This is a change for many glaucoma specialists. We used to look at visual fields before we considered glaucoma to be refractory. However, a preperimetric glaucoma patient with a pressure of 28 mmHg on multiple medications can also be refractory; there’s nothing else nonprocedural we can do in that situation. I think that’s important because it does change the type of patients who would qualify for surgery.

In earlier disease, the target pressure does not need to be quite as low. So for a Xen surgery you might end up in the mid-teens. You are going to hit your target, and therefore your definition of success increases. It’s a catch-22. If you’re doing the surgery only for patients who have more advanced glaucoma, where the target pressure is 10 mmHg or lower, you’re going to consider yourself a failure if you don’t get to that pressure, whereas for patients with milder disease with a target pressure in the mid-teens you might be more successful. My practice has changed a lot in that area. I am doing even subconjunctival surgery like Xen for more moderate patients, because my target pressures are often in the mid-teens for those patients and thus my success rate has gone up.

Dr. Buznego: The definition of refractory glaucoma used to mean for me someone who needs a surgical procedure, which meant a trabeculectomy or a tube. Knowing the complication and reoperation rates from the TVT studies, we were hesitant to apply that label. Now when we’re looking at the definition of refractory glaucoma, we can offer MIGS, which are minimally invasive with a low risk profile. This has allowed us to expand the definition of refractory glaucoma and recommend a surgical solution.

Dr. Sheybani: Right; if a procedure got pressure down to 10 mmHg every single time with zero complications, why not do that for almost anyone that you think has glaucoma, even over medications? We’re far from reversal of optic neuropathy; however, we are seeing evidence that MIGS procedures, especially when performed at the time of cataract surgery, reduce the number of future surgical interventions compared to cataract surgery alone.

Dr. Singh: Another point to make is that angle-based surgeries do not preclude us from doing a subconjunctival surgery later. Because the safety is so high, my definition of controlled glaucoma, or even refractory, has gone down so low where there’s very little that it takes to trigger a surgical need. Within the angle, I do think about factors such as life span or need for future surgery. For instance, if a patient is younger and phakic, I may perform a viscodilating procedure to save the trabecular meshwork as much as I can in case I do want to place a stent or perform SLT later.

Dr. Sheybani: Another interesting part of this conversation is that, for clinical trials, there are set definitions and parameters for disease severity. But the term refractory seems artificial, especially if it’s coming from a government entity with probably very little modern-day input. This kind of thing can actually have sweeping changes or effects to what we do and what surgeries are done on label. I would argue that it’s time to look at this again.

Dr. Singh: Right. These definitions affect clinical trials too. The newer studies of Hydrus (SUMMIT) and iStent infinite for standalone indications have been done on refractory patients. This limits the type of patients who could qualify for these procedures as a standalone surgery.

Another thing to think about is the idea of “interventional glaucoma” and our mindset is shifting to intervening earlier. If our definitions are not consistent with our philosophy, that’s where we can get into trouble. From the perspective of general disease state and a paradigm shift in the subspecialty of glaucoma, we have to redefine disease state to be consistent with our thoughts about earlier surgical intervention. They have to go together. GP


  1. Samuelson TW, Chang DF, Marquis R, et al; HORIZON Investigators. A Schlemm canal microstent for intraocular pressure reduction in primary open-angle glaucoma and cataract: the HORIZON study. Ophthalmology. 2019;126(1):29-37.
  2. Gazzard G, Konstantakopoulou E, Garway-Heath D, et al. Selective laser trabeculoplasty versus drops for newly diagnosed ocular hypertension and glaucoma: the LiGHT RCT. Health Technol Assess. 2019;23(31):1-102.
  3. Samuelson TW. Three Year safety and efficacy outcomes from the multicenter randomized study of a Schlemm’s canal microstent (HORIZON trial). Paper presented at: the ASCRS annual meeting; May 5, 2019; San Diego, CA.
  4. Kim JH, Caprioli J. Intraocular pressure fluctuation: is it important? J Ophthalmic Vis Res. 2018;13(2):170-174.
  5. Nouri-Mahdavi K, Hoffman D, Coleman AL, Liu G, Li G, Gaasterland D, et al. Predictive factors for glaucomatous visual field progression in the Advanced Glaucoma Intervention Study. Ophthalmology. 2004;111(19):1627-1635.
  6. Musch DC, Gillespie BW, Lichter PR, Niziol LM, Janz NK. Visual Field Progression in the Collaborative Initial Glaucoma Treatment Study. The Impact of Treatment and Other Baseline Factors. Ophthalmology. 2009;116(2):200-207.
  7. Gedde SJ, Schiffman JC, Feuer WJ, Herndon LW, Brandt JD, Budenz DL; Tube versus Trabeculectomy Study Group. Treatment outcomes in the Tube Versus Trabeculectomy (TVT) study after five years of follow-up. Am J Ophthalmol. 2012;153(5):789-803.