MIGS: Tailored Treatments for Glaucoma

The introduction of minimally invasive glaucoma surgery (MIGS) offers patients with mild to moderate glaucoma a safe and effective way to reduce their intraocular pressure (IOP) with potentially fewer medications, especially where cataract surgery is required. With multiple options to choose from, it is important to understand the differences between available devices and the questions to ask to help select the best procedure for an individual patient.

 

WHY WERE MIGS DEVELOPED?

Patients with glaucoma want to avoid vision loss and maintain their independence while having treatments which are convenient, with minimal negative impact on their quality of life. Because glaucoma is largely an asymptomatic disease until advanced, the convenience and side effects of treatment are important considerations. Historically, mild to moderate glaucoma has been treated with topical glaucoma medications. These treatments are effective at lowering IOP and have been shown to slow the progression of glaucoma,¹ however more than one medication is often required. These medications frequently cause or exacerbate ocular surface disease, adherence can be a challenge for patients, and medication alone may not always be sufficient to control the disease.

patients receiving a greater number of glaucoma medications for longer periods of time have more severe signs and symptoms of ocular surface disease

Ocular Surface Disease 

In a survey of over 2,000 glaucoma patients treated with topical glaucoma medications, 47 per cent needed more than one class of medication and 62 per cent of patients reported side effects such as redness, burning, grittiness, tearing, and dry eye.² These side effects were more common in patients taking multiple medications.² Other clinical studies have found that patients receiving a greater number of glaucoma medications for longer periods of time have more severe signs and symptoms of ocular surface disease.³ Topical medications can have a deleterious effect on the ocular surface, not only through the effect of the active ingredient but also due to the presence of preservatives or excipients. Common preservatives such as benzalkonium chloride (BAK) and polyquaternium-1 (PQ) have been shown to have cytotoxic and proinflammatory effects on the ocular surface, causing squamous metaplasia of the conjunctival epithelium and a reduction in the number of goblet cells.^4-6 This is significant, not only for the patient’s comfort, but also because damage to the ocular surface and conjunctiva may compromise the success of future glaucoma filtration surgery. Long-term exposure to glaucoma medication has been found to have a deleterious effect on the conjunctiva and is a risk factor for failure of glaucoma filtration surgery.^7-9 These side effects and symptoms are not isolated to preserved medications. In patients taking preservative-free medications, up to one in five report pain or discomfort during instillation, foreign body sensation, stinging or burning, and dry eye sensation.¹⁰

Dry Eye and Quality of Life 

Co-existing eye conditions, such as dry eye, are common in patients with glaucoma. The use of glaucoma eye drops has been shown to exacerbate the signs and symptoms of dry eye and negatively affect quality of life.11 In an observational cross-sectional study, patients taking glaucoma medications were found to have more signs and symptoms of dry eye syndrome and lower quality of life scores than those not taking glaucoma medications.¹¹ The negative impact on quality of life should not be underestimated. In one study, the effect of dry eyes secondary to glaucoma medications was similar to 10dB of visual field loss.¹²

Adhering to Medical Treatment 

Adhering with daily medication use for a chronic and asymptomatic condition like glaucoma is difficult. Proper adherence requires obtaining the medication, successfully instilling the drop into the eye, using the medication at the appropriate time, and doing so consistently each day.¹³ Studies show that between 30 per cent and 80 per cent of patients are non-adherent with their glaucoma medications.^14,15 In one study, only 24 per cent of patients with newly diagnosed glaucoma persisted with treatment for two years.¹⁶ In another study, 50 per cent of patients had stopped taking their medications by six months and only 37 per cent were still filling their prescriptions after three years.¹⁷

Patients have difficulty maintaining recommended medication regimens for many reasons, including difficulties with the medication schedule, forgetfulness, difficulty with eye drop administration, cost, and life stress among others.¹⁷ Nonadherence with medication may result in periods of uncontrolled intraocular pressure and patients with poor adherence have been found to be more likely to progress,18 have severe glaucomatous damage,¹⁹ and become blind from glaucoma.^20,21

Limitations of Medical Treatment 

The only proven treatment for glaucoma is to lower intraocular pressure.²² In the Ocular Hypertension Treatment Study (OHTS), lowering intraocular pressure by 20 per cent with topical glaucoma medications reduced the risk of developing glaucoma from 9.5 per cent to 4.4 per cent.²³ However, this means a significant number of individuals still developed glaucoma despite treatment. Similarly, in the Early Manifest Glaucoma Trial (EMGT), 59 per cent of patients progressed on visual fields over a four year period, despite treatment with glaucoma medications and achieving an average IOP reduction of 25 per cent.24 By comparison, in the Collaborative Initial Glaucoma Treatment Study (CIGTS) IOP reductions of 35 per cent to 48 per cent resulted in no net glaucoma progression25 and in the Advanced Glaucoma Intervention Study (AGIS), patients who consistently had an IOP of < 18mmHg at every visit and a mean IOP of 12.3mmHg had no visual field progression on average.²² It is therefore important not only to lower IOP, but to do so effectively. For patients with advanced glaucoma, this is best performed with trabeculectomy or tube surgery because of their potent ability to lower IOP. In these cases, the risk of adverse events is outweighed by the importance of preventing vision loss. However, for patients with mild to- moderate glaucoma and borderline IOP control despite glaucoma eye drops, MIGS procedures provide effective additional IOP lowering while avoiding some of the short and long-term risks associated with traditional glaucoma surgery.

MINIMALLY INVASIVE GLAUCOMA SURGERY OPTIONS

Patients in Australia and New Zealand are fortunate to have access to a range of MIGS options to lower their IOP and reduce their dependence on glaucoma medications. These devices bypass the blocked or damaged trabecular meshwork to augment aqueous outflow. The procedures vary in efficacy and potency and are most logically classified according to where they drain aqueous.

Schlemm Canal 

iStent Inject 

One of the first MIGS devices, the iStent Inject consists of two very small titanium stents (less than 0.4mm in size) that are surgically implanted into the trabecular meshwork to assist aqueous to drain from the anterior chamber into Schlemm canal. Typically implanted at the time of cataract surgery, the stents are inserted using a preloaded injector using the same incisions as cataract surgery. Once inserted, the device’s stents open a section of the trabecular meshwork to increase the facility of outflow.

The procedure can be performed under topical or local anaesthesia. During the procedure the patient must rotate their head 45 degrees to facilitate visualisation of the angle. Because the iStent accesses a portion of Schlemm canal, it is important to target areas of the canal with the highest concentrations of the collector channels. Reflux into Schlemm canal and areas of pigmentation of the trabecular meshwork are clues to the presence of collector channels. Failure to correctly place the stent in Schlemm canal and near collector channels may result in disappointing outcomes.

Post-operatively, the management is similar to cataract surgery alone. Patients are prescribed prednisolone acetate 1 per cent four times a day for one month and many surgeons also prescribe a topical non-steroidal to prevent pain and cystoid macular oedema. Glaucoma medications are stopped after several weeks, depending on the fall in IOP.

When implanted correctly, the iStent Inject has been shown to produce modest reductions in IOP and reduce the need for glaucoma medications. The interim results of a pivotal trial comparing the iStent Inject in combination with cataract surgery to cataract surgery alone were announced at the American Society of Cataract and Refractive Surgery (ASCRS) Annual Meeting this year. At 24 months, the mean IOP reduced 31 per cent to a mean of 17.1mmHg from an unmedicated mean baseline IOP of 24.8mmHg. The full results, including safety data, are awaited with interest.

With regards to safety, blood reflux from Schlemm canal into the anterior chamber is common and can cause an early post-operative hyphaema. This can be minimised by leaving the eye pressurised at the end of the case. Other complications include stent malposition, over or under implantation, stent obstruction, IOP spikes, and failure to lower IOP requiring further surgery. Serious complications are rare and include a trabecular meshwork tear, cyclodialysis cleft, suprachoroidal implantation, and iridodialysis.²⁶

Hydrus Microstent 

The Hydrus Microstent is a crescentshaped implant made of a highly flexible, biocompatible alloy of nickel and titanium (Nitinol). The 8mm stent both bypasses the trabecular meshwork and scaffolds open Schlemm canal. Unlike the iStent Inject, which only accesses a small portion of Schlemm canal, the size of the Hydrus allows it to dilate three clock hours of Schlemm canal, thus providing access to a greater number of collector channels. The posterior part of the stent is open, which means that it will not block collector channel openings. The Hydrus has been shown to increase outflow facility and reduce outflow resistance in perfusion models of human cadaver eyes.²⁷

The Hydrus has been found to be safe and effective in the Hydrus II study. In this randomised controlled trial, 100 patients with primary open-angle glaucoma were randomised (1:1) to cataract surgery alone or cataract surgery combined with Hydrus Microstent insertion and were observed for 24 months.²⁸ In this study, the proportion of patients achieving a 20 per cent reduction in unmedicated IOP was significantly greater in those undergoing cataract surgery with Hydrus insertion compared to cataract surgery alone (80 per cent vs. 46 per cent; P = 0.0008).28 Also, the proportion of patients who were free of medication was significantly higher in the combined cataract surgery and Hydrus group (73 per cent vs. 38 per cent; P = 0.0008).²⁸ The safety profile was similar between both groups, except for a higher rate of peripheral anterior synechiae (PAS) in patients receiving the Hydrus. A larger randomised trial, Hydrus IV, is underway in which 556 patients have been randomised (2:1) to cataract surgery with Hydrus or cataract surgery alone. This pivotal trial will be used to seek FDA approval in the United States and the results are eagerly awaited.

The Hydrus is most commonly performed with cataract surgery. Insertion, postoperative care, and potential complications are similar to those of the iStent Inject. The manufacturer of Hydrus, Ivantis, is preparing for commercial release of Hydrus this year.

Supraciliary Space 

CyPass MicroStent 

One of the latest generation of MIGS procedures is the CyPass MicroStent. This device is the first and only device currently available that takes advantage of uveoscleral outflow, the same route used by the most effective glaucoma eye drops – prostaglandin analogues. Leveraging the uveoscleral outflow pathway offers a number of advantages over other MIGS procedures. One of the limitations of stentbased trabecular bypass procedures is that they only treat a small area of the outflow tract and must be placed near collector channels to work effectively. At present there is no diagnostic tool for identifying collector channels and there is therefore a chance these will be missed, resulting in suboptimal treatment. Additionally, it is unknown whether collector channels remain open as glaucoma progresses.

The CyPass MicroStent is a 6.35mm long fenestrated tube that is made of a biocompatible material called polyimide. The device is implanted just below the scleral spur into the supraciliary space to allow aqueous to drain via the uveoscleral pathway. The CyPass MicroStent can be inserted at the time of cataract surgery without the need for additional incisions, or it can be inserted without cataract surgery via a single 1.5mm clear corneal incision. As an internal blebless procedure, it eliminates the risk of blebrelated complications.

The CyPass MicroStent has some of the strongest and most-compelling evidence supporting its use for the treatment of mild-to-moderate open-angle glaucoma. The COMPASS trial was a multicentre randomised clinical trial of 505 patients, making it one of the largest MIGS trials completed to date.²⁹ Eyes were randomised (3:1) to cataract surgery with the CyPass Microstent or cataract surgery alone. A significantly greater proportion of patients in the CyPass group had an unmedicated IOP reduction of at least 20 per cent or more compared to the control group (77 per cent vs. 60 per cent; P = 0.001).²⁹ Furthermore, the CyPass group showed a sustained reduction in IOP with 61 per cent having an unmedicated diurnal IOP of between 6–18mmHg through 24 months compared to only 43.5 per cent of the control group. Additionally, 85 per cent of CyPass patients were free of medication compared to 59 per cent of control subjects.29 Avoiding many of the major risks associated with traditional glaucoma surgery, the safety profile of the CyPass MicroStent is comparable to that of cataract surgery. In the COMPASS pivotal trial, transient numerical hypotony occurred in 2.9%, all of which resolved in the first month after implantation.²⁹ Similarly, hyphaema occurred in 2.7% of patients but resolved in all cases within the first 2 weeks.²⁹ Myopic shift in the early postoperative period can occur but this is rare and typically transient.

Post-operative care is similar to cataract surgery alone. Patients are prescribed topical prednisolone acetate 1 per cent four times a day for four to six weeks after surgery and some surgeons also prescribe a non-steroidal anti-inflammatory, routinely after cataract surgery, to reduce the risk of cystoid macular oedema. Topical glaucoma medications should be discontinued at the time of surgery or in the month prior to surgery to minimise the chance of low IOPs in the early post-operative period because of the combined effect of the stent and medication. Should IOP begin to rise postoperatively, it is recommended to commence a prostaglandin analogue to maintain the aqueous lake in the supraciliary space.

Subconjunctival Space 

XEN 

The XEN is a minimally invasive glaucoma procedure that drains aqueous from the anterior chamber to the subconjunctival space, the same as trabeculectomy. It is a 6mm flexible tube made of porcine gelatine that has been cross-linked with glutaraldehyde to prevent biodegradation. It is very biocompatible and does not cause a foreign body reaction. The dimensions of the tube have been carefully selected based on the Hagen-Poisseuille equation, which predicts resistance to flow based on the length, inner diameter, and viscosity of the fluid. Given a length of 6mm and inner diameter of 45μm, the XEN provides approximately 6–8mmHg resistance, therefore minimising the risk of hypotony.

The XEN can be performed as a standalone procedure or in conjunction with cataract surgery. It is generally performed under a local anaesthetic block but can be performed under topical anaesthesia with intracameral lignocaine. To prevent fibrosis, an off-label injection of mitomycin is given under the conjunctiva prior to implantation. The XEN is inserted via a corneal incision and exits the sclera, remaining under the conjunctiva, 3mm from the limbus in the superonasal quadrant of the eye. Once implanted, the XEN becomes hydrated and malleable, which is important to prevent migration or erosion. The XEN is designed to provide effective lowering of IOP, using the same route as trabeculectomy, while avoiding the need to incise the conjunctiva, create a scleral flap, or perform an iridectomy. The aim is to provide a safer procedure with faster recovery of vision by reducing the risk of complications such as bleb leak, over filtration, or hypotony.

Post-operatively, glaucoma medications are stopped in the operated eye and topical steroids are commenced. The frequency of steroids is tapered over several months, according to the degree of conjunctival inflammation. In cases where there is significant conjunctival inflammation preoperatively, steroid may be commenced the week prior to surgery. The patient will then be seen the following day and then at one week. After this, the post-operative reviews are spaced further apart and are much less often than for trabeculectomy. If there is conjunctival scarring, a procedure called ‘needling’ may be performed at the slit lamp and if scarring is extensive, bleb revision can be performed in the operating theatre.

The XEN is indicated for glaucoma not controlled with topical medications and it is designed to offer an enhanced safety profile compared to traditional filtration surgery. While not a replacement for trabeculectomy in cases with very advanced glaucoma, it offers patients with less advanced disease a minimally invasive option where medical therapy has failed.

The XEN has been studied in the APEX trial where 215 patients with mild-to-moderate primary open angle glaucoma without a prior history of intraocular pressure surgery underwent either a standalone XEN procedure, or cataract surgery combined with the XEN. The preliminary results showed a mean IOP reduction of 7.6 } 4.8mmHg at 12 months and all patients had a reduction in IOP lowering medications. The safety profile was very good and serious complications were rare. An IOP of < 6mmHg in the first month occurred in 14.9 per cent of patients and required no intervention. Needling was required in approximately one in four patients. The 24-month data is anticipated to be published shortly. In another study, there was an average IOP reduction of 36.4 per cent following XEN insertion and a 57 per cent reduction in glaucoma medication use at 12 months.³⁰ In this study nine out of 10 patients achieved an IOP of 18 mmHg or less and 40 per cent were entirely medication free.³⁰

SELECTING THE APPROPRIATE MIGS PROCEDURE

Appropriate patient selection is the key to success in glaucoma surgery. With many MIGS options to choose from, it is important to tailor the choice of procedure to each patient. This complex decision should take into account the patient’s specific needs, preferences, and values while taking into consideration their lifestyle, type of glaucoma, disease stage, and tolerance to prior treatment. It is essential that this discussion is centred around the individual patient and not the procedures a surgeon performs as there is no ‘one size fits all’ MIGS procedure.

The first step in creating an individualised treatment plan is to carefully listen to the patient to hear their symptoms, what they hope to achieve from treatment, and any concerns they may have about glaucoma or surgery. Having examined the patient and confirmed a diagnosis of ocular hypertension or open-angle glaucoma, it is then essential to answer four important questions:

1. What is the stage of glaucoma?
2. Is there cataract?
3. Is IOP at or above target?
4. Are glaucoma medications tolerated or causing side effects?

Glaucoma can be staged as mild, moderate, severe, or advanced, based on visual fields and optic nerve appearance.31 A commonly used system is the Glaucoma Staging System (GSS) which is a modification of the earlier Hodapp-Parrish-Anderson (HPA) criteria.³² The GSS uses the visual field mean deviation (MD) to classify patients as mild (MD better than -6.00dB), moderate (MD -6.01 to -12.00dB), severe (MD -12.01 to -20.00dB), or advanced (-20.01dB or worse), in addition to taking into account point clusters and hemifield comparisons.³² Staging glaucomatous damage enhances management and enables therapy to be tailored to each patient. In addition, careful documentation of the degree of damage is essential for monitoring the stability of glaucoma.

Mild Disease 

Well Controlled 

For patients with ocular hypertension or mild open-angle glaucoma who are well-controlled with glaucoma eyes drops and tolerating treatment, continuing with existing treatment is recommended. Should visually significant cataract be present, cataract surgery can be discussed to improve vision and this may also provide a slight reduction in IOP. After cataract surgery some patients may be able to stop their glaucoma eye drops.

Uncontrolled or Intolerance to Treatment 

Where IOP is not controlled, or glaucoma eye drops are not tolerated due to symptoms such as red eyes, itching, burning, or stinging, the management depends on whether cataract is present. For patients without cataract, treatments such as selective laser trabeculoplasty (SLT) or additional/alternative glaucoma eye drops could be considered, in particular preservative-free medications, to provide better control of IOP and/ or relieve symptoms associated with glaucoma eye drops. For patients with cataract, they should be referred for consideration of cataract surgery combined with a MIGS procedure such as the iStent Inject, Hydrus, or CyPass. All of these procedures have a good safety profile and lower IOP. The degree of IOP lowering varies between devices, and the CyPass may provide greater IOP reduction and higher chance of being medication-free. This may be important for patients with higher IOP, the need for a greater number of medications, or a strong need or desire to be free of medication because of intolerance to medications. All of these devices can be combined with premium intraocular lenses (IOL) such as toric lenses to treat any refractive error and provide the best possible unaided visual acuity. However the use of multifocal IOLs is not recommended in patients with glaucoma or macular pathology.

Moderate Disease 

Patients who already have moderate visual field loss from glaucoma are at a greater risk of glaucoma progression, and therefore effective lowering of IOP is an important goal to prevent further visual loss from glaucoma. For patients with cataract and poorly controlled IOP or intolerance to glaucoma eye drops, I recommend cataract surgery combined with a supraciliary device like the CyPass MicroStent because of its proven ability to lower IOP. For patients without cataract or, for those who have already had cataract surgery, I discuss SLT or the XEN as a standalone procedure to provide better IOP control and/or reduce their need for glaucoma medications. At present the XEN is the only device both approved by the TGA and covered under Medicare for standalone use. Other devices like iStent Inject, Hydrus, and CyPass Micro-Stent are approved for standalone use however out of pocket expenses will be higher. The XEN can also be performed with cataract surgery for patients with cataract and glaucoma refractory to medications.

Severe or Advanced Disease 

Patients with severe or advanced disease require the most aggressive IOP lowering in order to avoid vision loss from glaucoma. For patients with advanced but controlled disease who require cataract surgery, there is a risk of an IOP spike causing snuff out with cataract surgery alone. Combining cataract surgery with the XEN may reduce this risk. Where IOP is not controlled, procedures like trabeculectomy or a glaucoma drainage device (such as the Baerveldt tube) should be offered because of their proven ability to lower IOP. For patients who are unwilling to accept the risks of traditional surgery, the XEN provides a less invasive option for refractory glaucoma however patients should be aware the evidence base for use in this setting is still growing.

CONCLUSION

Minimally invasive glaucoma surgery provides a new option for the treatment of glaucoma, offering safer glaucoma surgery for patients with less severe disease. With many options to choose from, optometrists will play an important role in helping educate their patients about the options available to them. There is no ‘one size fits all’ approach and options should be tailored to each patient. As many eye surgeons are in their initial phases of incorporating the latest technologies into their practice, optometrists need to be familiar with the pre-operative and post-operative expectations to best help their patients. Optometrists interested in perioperative co-management may wish to spend time in the operating theatre with a MIGS surgeon to better appreciate what is involved and what to expect postoperatively.

Today, patients want to be well-educated about their treatment choices and engaged in the decision making process. To assist optometrists and patients there are now resources like MIGS.org which provide unbiased and factual information about MIGS surgery. With the recent advances in glaucoma surgery there are now many more options designed to control IOP, reduce the need for glaucoma eye drops, and help preserve patients’ vision and quality of life.

Dr. Nathan Kerr is a fellowship-trained cataract and glaucoma surgeon in Melbourne, Australia. Dr. Kerr completed a prestigious Minimally Invasive Glaucoma Surgery (MIGS) Fellowship at Moorfields Eye Hospital in London and is one of Australia’s most experienced MIGS surgeons. He was the first Australian surgeon to be accredited to perform the XEN procedure and he performed the first commercial CyPass MicroStent operation in Australia. Dr. Kerr serves as a Glaucoma Section Editor for Clinical and Experimental Ophthalmology and is the Clinical Lead for Glaucoma Surgical Trials at the Centre for Eye Research Australia. Dr Kerr is a Consultant Ophthalmologist at the Royal Victorian Eye and Ear Hospital and consults privately at Eye Surgery Associates in East Melbourne, Doncaster, and Vermont South. doctorkerr.com.au

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