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Cutting EDGE Glaucoma Issue 4

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Glaucoma

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Contents WHAT’S NEW 1. Minimally Invasive Glaucoma Surgery: WhereWe Are, andWhat the Future Holds ............................ 1 Fareed Rifai, Crystal P. Le, Lauren Lim, Ze Zhang 2. MIGS in Special Cases ............................ 21 John Liu, Jingyi Ma, Jeb Alden Ong, Iqbal Ike Ahmed CLINICAL VIGNETTE 3. Intermediary Inflammatory Reaction After Micropulse Cyclophotocoagulation Diode Therapy: A Case Report ............................ 34 Gaëtane Ghion, Alexandra Singh, Sayeh Pourjavan 4. Waardenburg Syndrome Type 4 Coexisting with Open‑angle Glaucoma: A Case Report ............................ 43 Li Zhang, Yue Wan, Ningli Wang Videos available online: MIGS in Special Cases Video 1: H ydrus implantation. Video 2: i Stent inject W implantation. Video 3: Kahook dual blade.

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WHAT’S NEW Abstract Purpose of Review: Minimally invasive glaucoma surgery, or MIGS, has revolutionized the glaucoma surgical space in the past 15 years. The high safety profile and moderate efficacy of MIGS has enabled earlier surgical intervention for glaucoma, providing safe and sight-saving care sooner. This review aims to examine the latest evidence on available devices and techniques. Recent Findings: Trabecular outflow remains a mainstay for MIGS targets, with distal outflow enhancement and alternative drainage pathways showing efficacy. Comparisons of various MIGS devices and techniques are emerging, which will enable glaucoma surgeons to better design individualized care for their patients. While no single MIGS has emerged as significantly superior to others; some MIGS may be better suited for some types of glaucoma, however. Summary: Minimally invasive glaucoma surgeries provide safe and effective alternatives to traditional filtering glaucoma surgeries in many patients. The high safety profile of MIGS enable earlier surgical interventions, which can improve visual outcome and patients’ quality of life. There is an abundance of evidence showing the efficacy and safety of various MIGS, with innovations continuing to advance the surgical treatment of glaucoma. Keywords: MIGS, Microinvasive glaucoma surgery, Minimally invasive glaucoma surgery, Trabecular microbypass, Goniotomy, Canaloplasty, Trabeculotomy Introduction Glaucoma is a progressive optic neuropathy that can result in permanent vision loss. It affects over 60 million people (3.5% of population) worldwide and is estimated to increase to 111.8 million by year 2040 [1]. Minimally Invasive Glaucoma Surgery: WhereWe Are, andWhat the Future Holds Fareed Rifai1, Crystal P. Le1, Lauren Lim1, Ze Zhang1 Ze Zhang () e-mail: zzhang9@tulane.edu 1Department of Ophthalmology, Tulane School of Medicine, 131 S. Robertson St, 12th Floor, New Orleans, LA 70112, USA

2 • CUTTING EDGE - GLAUCOMA Fig. 1: Common surgical approach for Ab interno surgery. A Patient’s head is rotated 30° away from the surgeon and OVD is used to inflate the anterior chamber. B Gonioprism applied to the cornea to ensure proper view. C Adequate illumination and magnification to view angle structures is critical to successful MIGS. D Insertion of device/implant through temporal clear corneal incision under gonioscopic guidance. It is the leading cause of irreversible blindness in the world [2]. Risk factors for glaucoma include elevated intraocular pressure (IOP) [3-6], African ancestry [5], positive family [5], older age [3, 5] and thin central corneal thickness. [5] IOP is currently the only modifiable risk factor for glaucoma to reduce the risk of progression [7]. Treatment for glaucoma include topical medications, laser, and surgery. Usually, if medical and laser therapy is unable to adequately lower IOP to reach target levels, surgery is often required. Traditional glaucoma surgeries include trabeculectomy and glaucoma drainage device implantation. While effective, these filtering procedures require extensive post-operative followup and prolonged recovery. They are also prone to episcleral fibrosis and subsequent failure. Filtering surgeries are associated with serious risk of early and late complications including bleb Thus, there is a need to create effective but safer glaucoma surgeries. Since the early 2000s, the surgical field of glaucoma has been revolutionized by the world of minimally, or microinvasive, glaucoma surgery (MIGS). MIGS is generally defined by five key components: high safety is always used. Implantation or insertion occurs through a small clear corneal incision. The patient’s head is turned 30–45� away and the microscope rotated 30� toward the surgeon. Viscoelastic is used to fill the anterior chamber and can be used to deepen the nasal angle to facilitate the Fig. 1 Common surgical approach for Ab interno surgery. A Patient’s head is rotated 30� away from the surgeon and OVD is used to inflate the anterior chamber. B Gonioprism applied to the cornea to ensure proper view. C Adequate illumination and magnification to view angle structures is critical to successful MIGS. DInsertion of device/implant through temporal clear corneal incision under gonioscopic guidance 36 Curr Surg Rep (2022) 10:35–49

MINIMALLY INVASIVE GLAUCOMA SURGERY: WHERE WE ARE, AND WHAT THE FUTURE HOLDS • 3 leak, bleb-related infections, and device extrusion. In the Tube versus trabeculectomy study, average IOP decreased by 10.7 mmHg in the tube group and 13 mmHg in the trabeculectomy group. However, 34% of tube group and 36% of trabeculectomy group developed late complications including vision threatening complications such as hypotony, choroidal effusions, maculopathy, and erosion [8]. Thus, there is a need to create effective but safer glaucoma surgeries. Since the early 2000s, the surgical field of glaucoma has been revolutionized by the world of minimally, or microinvasive, glaucoma surgery (MIGS). MIGS is generally defined by five key components: high safety profile with rapid recovery, minimal disruption of normal anatomy, ab interno approach, efficacy in lowering IOP, and ease of use for surgeons [9•]. These procedures work by either augmenting traditional aqueous outflow through trabecular meshwork (TM) and Schlemm’s canal (SC), or creating regulated outflow into the suprachoroidal and subconjunctival space. Many of the procedures are likely not sufficient for patients with advanced disease as they do not provide the very low IOP targets required. The surgical approach for majority of MIGS is similar. An ab interno approach under direct gonioscopic guidance is always used. Implantation or insertion occurs through a small clear corneal incision. The patient’s head is turned 30–45° away and the microscope rotated 30° toward the surgeon. Viscoelastic is used to fill the anterior chamber and can be used to deepen the nasal angle to facilitate the view (Fig. 1). This review aims to summarize the latest update on MIGS available and their clinical efficacy data. Trabecular Meshwork-Based MIGS The juxtacanalicular TM represents the site of greatest outflow resistance prior to aqueous humor entering SC. Devices and surgical procedures have been designed to bypass this source of resistance. Trabecular Bypass Devices (Fig. 2) iStent and iStent Inject The iStent (G1-IS) is a L-shaped heparin-coated, titanium micro-bypass device (Glaukos, San Clemente, CA) that was FDA approved in 2012 to use in combination with cataract surgery (Table 1). It is easiest to insert with a 15° approach toward the sclera while advancing until the retention arches are within SC before deployment (Fig. 3). Blood reflux is often observed indicating correct positioning. Most common adverse events include obstruction or malposition of the iStent and temporary post-operative hyphema. No hypotony, endothelial cell loss or increased inflammation were reported. The first generation iStent has been largely replaced by the second-generation device of the same material: the iStent inject (G2-M-IS), which was developed to improve ease of implantation.

4 • CUTTING EDGE - GLAUCOMA Fig. 2: MIGS Devices. A iStent G1 (Glaukos Corporation, San Clemente, CA, USA). B iStent inject (Glaukos Corporation, San Clemente, CA, USA). C Hydrus (Ivantis, Irvine, CA, USA). D CyPass (Alcon, Fort Worth, Texas, USA). E Kahook Dual Blade (NewWorld Medical, Rancho Cucamonga, CA, USA). F TrabEx (MST, Redmond, Washington, USA). G Xen gel stent (Allergan, Dublin, Ireland). H Preserflo Microshunt (Santen, Miami, FL, US). evices (Fig. 2) L-shaped heparin-coated, titanium Glaukos, San Clemente, CA) that malposition of the iStent and temporary post-op rative hyphema. No hypotony, endothelial cell loss or increased inflammation were reported. The first generation iStent has been largely replaced by the second-generation device of the same material: the iStent inject (G2-M-IS), which was developed to improve Stent San tent n, CA, ort hook ga, T, A). o , FL, 5–49 37 Lumen Snorkel Windows Distal tip Spines Inlet 1mm 1mm Retention arches Central lumen 3 Retention Rings Proximal Collar Lumen 6.35 mm Length Side ports Head Open half-pipe Self-trephining tip

MINIMALLY INVASIVE GLAUCOMA SURGERY: WHERE WE ARE, AND WHAT THE FUTURE HOLDS • 5 Table 1: Implantable MIGS devices. Implant Device iStent iStent inject Hydrus CyPass Istent Supra Miniject Xen PreserFlow Microshunt Mechanism of action Trabecular bypass Trabecular bypass Trabecular bypass Suprachoroidal flow Suprachoroidal flow Suprachoroidal flow Subconjuncti-val outflow Subconjunctival outflow Size/dimensions 0.3 mm×1 mm 360 um×230 um with 80 um outlet 8 mm 6.35 mm with 510 um outer diameter 4 mm with 0.16–0.17 mm lumen 5 mm oblong design 6 mm with 45 um lumen 8.5 mm with 70 um lumen Material Heparincoated nonferromagnetic titanium Heparin-coated non-ferromagnetic titanium Nickel-titanium alloy (nitinol) Polyamide Polyethersulfone and titanium porous silicone STAR® material Collagen-derived porcine gelatin cross-linked with glutaraldehyde poly(styrene— block— isobutylene— block—styrene), or SIBS Manufacturer Glaukos, Laguna Hills, CA Glaukos, Laguna Hills, CA Ivantis, Irvine CA Alcon, Fort Worth, Tx Glaukos, Laguna Hills, CA iStar Medical, Wavre, Belgium Allergan, Dublin Ireland Santen, Miami, FL Indications Mild to moderate open angle glaucoma Mild to moderate open angle glaucoma Mild to moderate open angle glaucoma Currently withdrawn Investigational Investigational Moderate to severe glaucoma Patients with glaucoma not at target Investigational Potential adverse events/ risks Hyphema, malposition of stent Hyphema, malposition of stent Hyphema, malposition of stent, PAS ECD loss, corneal edema, hypotony, myopic shift, choroidal effusion, hyphema Need for bleb needling, hypotony, extrusion, bleb leak and infection

6 • CUTTING EDGE - GLAUCOMA It is 360 μm long with a 230 μm diameter and four 50 μm side outlets to maximize flow (Fig. 3). It was FDA approved in 2018 as a two-stent system to be inserted in the same ab interno approach. By inserting two stents into the TM directly two to three clock hours apart, a new patent channel into SC is created, increasing outflow to the collector channels. The latest iteration comes in the form of the iStent inject W, featuring a wider flange allowing better visualization. In initial studies, the devices were implanted after phacoemulsification. However, some surgeons prefer insertion beforehand due to a clearer cornea, less hyphema, and ability to insert before any potential complications from cataract surgery. There have not been any large studies demonstrating any difference between order of implantation. Fea et al. compared iStent with phacoemulsification to phacoemulsification alone in a prospective randomized clinical trial. At 15 months of follow-up, mean IOP in the iStent group was significantly lower compared to the PE-alone group: 14.8±1.2 mmHg and 15.7±1.1 mmHg [10]. Samuelson et al. compared iStent or iStent inject to phacoemulsification alone. At 2 years, 66% of iStent eyes achieved primary outcome (≥20% IOP reduction) versus 48% in the control group [11••]. 75.8% of iStent inject eyes versus 61% of phacoemulsification eyes achieved the primary outcome with mean IOP reduction of 7 mmHg vs 5.4 mm Hg, respectively [12]. The iStent Infinite, a three-stent, wide-flange version of the iStent inject, is currently undergoing investigational trial for standalone surgery for moderate to severe glaucoma. Hydrus The Hydrus Microstent (Ivantis Inc, Irvine, CA) is an aqueous drainage device introduced in 2011 in Europe, and in 2018 in the U.S (Table 1). The nitinol (nickel-titanium alloy) device is curvilinear, 8 mm in length with a 290-micron lumen, with three windows designed to dilate SC and function as a scaffold, increasing access to the collector channels, as well as an inlet that creates a trabecular bypass. Hydrus comes preloaded on an injector with a sharp tip used to pierce the TM to enter SC. It is then advanced into SC until the site interlock to allow release from the injector. In the Horizon study, 546 patients were randomized 2:1 to Hydrus with phacoemulsification alone and followed over 2 years. 77.3% of the Hydrus group had>20% unmedicated IOP Fig. 3: iStent G1 insertion under gonioscopic view. A Angling 15° away from TM for insertion of the G1 iStent. B Advancing into Schlemm’s canal. C Blood reflux from Schlemm’s canal after proper iStent implantation. increasing outflow to the collector channels. The latest iteration comes in the form of the iStent inject W, featuring a wider flange allowing better visualization. In initial studies, the devices were implanted fter phacoemulsification. However, some surgeons prefer insertion beforehand due to a clearer cornea, less hyphema, and ability to insert before any potential complications from cataract surgery. Ther have not been any large studies monstrating any difference between order of implantation. Fea et al. compared iStent with phacoemulsification to phacoemulsification alone in a prospective randomized clinical tri l. At 15 months of follow-up, mean IOP in the iStent group was significantly lower compared to the PE-alone group: 14.8 ±1.2 mmHg and 15.7 ±1.1 mmHg [10]. Sa elson et al. compared iStent or iStent inject to phacoemulsification alone. At 2 years, 66% of iStent eyes achieved primary outcome (C20% IOP reduction) versus 48% in the control group [11••]. 75.8% of iStent inject eyes versus 61% of phaco mulsification eyes achieved the primary outcome with mean IOP reduction of 7 mmHg vs 5.4 mm Hg, respectively [12]. The iStent Infinite, a threestent, wide-flange version of the iStent inject, is currently und rgoing investigational trial for standalon surgery for moderate to severe glaucoma. Hydrus The Hydrus Microstent (Ivantis Inc, Irvine, CA) is an aqueous drainage device introduced in 2011 in Europe, and in 2018 in the U.S (Table 1). The itinol (nickel-titanium alloy) device is curvilinear, 8 mm in length with a 290-micron lumen, with three windows designed to dilate SC and function as a scaffold, increasing access to the colle tor ch nnel , s well as an inlet th t reates a trabecular bypass. Hydrus comes preloaded on an injector with a sharp tip used to pierce the TM to enter SC. It is then advanced into SC until the site interlock to allow release from the injector. In the Horizon study, 546 patients were randomized 2:1 t Hydrus with phaco mulsific tion alo e and followed over 2 years. 77.3% of the Hydrus group had[20% unmedicated IOP reduction compared to 57.8% in the phacoemulsification group. 30% or greater reduction in unmedicated IOP at 24 months was found in 53.4% Hydrus vs. 32.1% phacoemulsification eyes [13]. At three-year follow-up, 73% of Hydrus group were medication-free compared to 48% in the phacoemulsification group. A statistically ignificant reduction in the need for s co dary incisional glaucoma surgery was demonstrated in the Hydrus group [14••]. Another prospective randomized controlled trial by Pfeiffer et al. also compared Hydrus with phacoe ulsification to phacoemulsification alone. 80% of Hydrus eyes versus 46% of phacoemulsification eyes had C20% reduction IOP at 24 months. Both groups had similar occurrence of adverse effects except for Hydrus group had 12% developing peripheral anterior synechiae [15]. Comparison of iStent Inj ct and Hydrus In the COMPARE trial, 152 eyes with primary open angle glaucoma (POAG) on multiple topical medications were randomized 1:1 to either the Hydrus or iStent inject on phakic or pseudophakic patients. At one year, 46.0% of Hydrus vs. 24.0% of iStent eyes were medication-free. Medication-free IOP B18 was reached in 30.1% Hydrus vs. 9.0% iStent eyes [16•]. A meta-analysis by Otarola et al. analyzed the trial by Pfeiffer et al. the HORIZON trial, and the COMPARE trial, concluding that there was moderate evidence that the Hydrus would increase the number of patients that would be medication-free and decrease unmedicated IOP of least 2 mmHg compared to phacoemulsification. There was low Fig. 3 iStent G1 insertion under gonioscopic view. AAngling 15� away from TM for insertion of the G1 iStent. BAdvancing into Schlemm’s canal. CBlood reflux from Schlemm’s canal after proper iStent implantation Curr Surg Rep (2022) 10:35–49 39 123

MINIMALLY INVASIVE GLAUCOMA SURGERY: WHERE WE ARE, AND WHAT THE FUTURE HOLDS • 7 reduction compared to 57.8% in the phacoemulsification group. 30% or greater reduction in unmedicated IOP at 24 months was found in 53.4% Hydrus vs. 32.1% phacoemulsification eyes [13]. At three-year follow-up, 73% of Hydrus group were medication-free compared to 48% in the phacoemulsification group. A statistically significant reduction in the need for secondary incisional glaucoma surgery was demonstrated in the Hydrus group [14••]. Another prospective randomized controlled trial by Pfeiffer et al. also compared Hydrus with phacoemulsification to phacoemulsification alone. 80% of Hydrus eyes versus 46% of phacoemulsification eyes had≥20% reduction IOP at 24 months. Both groups had similar occurrence of adverse effects except for Hydrus group had 12% developing peripheral anterior synechiae [15]. Comparison of iStent Inject and Hydrus In the COMPARE trial, 152 eyes with primary open angle glaucoma (POAG) on multiple topical medications were randomized 1:1 to either the Hydrus or iStent inject on phakic or pseudophakic patients. At one year, 46.0% of Hydrus vs. 24.0% of iStent eyes were medication-free. Medicationfree IOP≤18 was reached in 30.1% Hydrus vs. 9.0% iStent eyes [16•]. A meta-analysis by Otarola et al. analyzed the trial by Pfeiffer et al. the HORIZON trial, and the COMPARE trial, concluding that there was moderate evidence that the Hydrus would increase the number of patients that would be medication-free and decrease unmedicated IOP of least 2 mmHg compared to phacoemulsification. There was low certainty evidence from only the COMPARE trial that showed the Hydrus was more effective than iStent in reducing medications and decreasing unmedicated IOP [17]. Trabecular Excision or Ablation Trabectome Trabectome (NeoMedix, Irvine, CA) was approved by the US FDA in 2004. It is an ab interno electrosurgical device used to ablate up to 180° of TM. The Trabectome tip can be inserted through a small clear corneal incision with minimal heat dissipation to nearby tissues. It uses a bipolar 550 kHz electrode with adjustable power to ablate the TM with minimal thermal transfer to the outer wall of SC. The device contains a footplate that guides the tip and protect adjacent tissues. There is constant irrigation and aspiration that maintains the anterior chamber and removes debris. Trabectome is approved for treatment of open angle glaucoma with uncontrolled IOP regardless of lens status but is often performed in combination with phacoemulsification. Contraindications to Trabectome are active neovascular glaucoma, active uveitis, elevated EVP, angle dysgenesis, and inadequate view of the angle. Postoperative IOP typically decrease to mid-teens. Younger patients are at risk for worse outcomes [18]. Most common adverse events involve hyphema, incomplete or improper TM ablation, damage to the ciliary body, and PAS formation [19, 20••].

8 • CUTTING EDGE - GLAUCOMA The Trabectome Study Group has published the largest source of data on the Trabectome. In a prospective study on patients with OAG, mean IOP reduction of 11.9 mmHg and medication reduction of 0.8 was observed at 1 year follow-up [20••]. Trabectome appears to lead to greater IOP reduction in pseudoexfoliation glaucoma (PXG) (44%) than POAG (34%) [21]. Phacoemulsification combined with Trabectome has been extensively studied and appears to have additional IOP-lowering effect [21-23]. Francis et al. reported IOP reduction of 4.5 mmHg and medication reduction of 1.3 at 12 months [22]. Ting et al. showed mean IOP reduction of 4.3 mmHg in POAG and 7.5 mmHg in PXG (Tables 2 and 3) [21]. Kahook Dual Blade (KDB) The Kahook Dual Blade (New World Medical, Rancho Cucamonga, CA) is a single-use, disposable instrument for performing 3–5 clock hours of Ab interno Goniotomy (Table 2). Its sharp tip, two blades and footplate with a total width of 230 microns are designed to achieve near-complete excision of TM. It is approved for use as standalone or combined with cataract extraction. It is indicated for open angle glaucoma and ocular hypertension, though studies have shown efficacy in eyes with at least 3 clock hours of PAS [24•]. Potential complications include difficulty removing the TM strip, hyphema, Descemet tears, iridodialysis, PAS, and corneal edema. The newest iteration of blade is the KDB GLIDE, designed to allow more precise and smooth excision of the TM with a rounded heel. The role of KDB goniotomy combined with phacoemulsification have been reported by a number of studies, though long-term data are limited. At 6 months, IOP reduction of up to Table 2: Non-device-based MIGS procedures. Procedure GATT OMNI ABiC Trabectome KDB TrabEx Mechanism Trabecular aqueous outflow enhancement Trabecular aqueous outflow enhancement, Viscodilation of Schlemm’s canal Viscodilation of Schlemm’s canal Trabecular aqueous outflow enhancement Trabecular aqueous outflow enhancement Trabecular aqueous outflow enhancement Device or material Prolene suture or iTrack microcatheter OMNI surgical system iTrack microcatheter Trabectome KDB TrabEx Indications Open angle glaucoma (primary and secondary), congenital glaucoma, juvenile open angle glaucoma Open angle glaucoma (primary and secondary) Open angle glaucoma (primary and secondary) Open angle glaucoma (primary and secondary), some narrow angle glaucoma with limited PAS Open angle glaucoma (primary and secondary), some narrow angle glaucomas with limited PAS Open angle glaucoma (primary and secondary), some narrow angle glaucomas with limited PAS Potential adverse events/risks Hyphema, damage to nearby structures Hyphema, damage to nearby structures Hyphema, damage to nearby structures Hyphema, PAS, damage to nearby structures Hyphema, damage to nearby structures Hyphema, damage to nearby structures

MINIMALLY INVASIVE GLAUCOMA SURGERY: WHERE WE ARE, AND WHAT THE FUTURE HOLDS • 9 Table 3: Efficacy studies for various MIGS. Study/Author Type of study Number enrolled at baseline (N) Length of follow-up Mean % IOP reduction and %medication reduction from baseline iStent Fea et al. [10] Double blinded RCT 36 16 months 17.3% IOP reduction and 80% medication reduction in the iStent +PE group; 9.2% IOP reduction and 31.6% medication reduction in PE group Samuelson et al. [11••] Multicenter RCT 240 12 months 8% IOP reduction with 87% medication reduction in istent +PE group; 5.5% IOP reduction and 73% medication reduction in PE group iStent inject Samuelson et al. [12] Prospective multicenter RCT 24 months iStent inject: 31% IOP reduction in eyes that did not undergo further surgeries PE only: 27% IOP reduction in eyes that did not undergo further surgeries Hydrus Samuelson et al. [13] Multicenter RCT 546 24 months Hydrus: 29.8% IOP reduction and 82.4% medication reduction; 77.3% achieved>20% IOP reduction Hydrus +PE: 20.9% IOP reduction 58.8% medication reduction; 57.8% achieved>20% IOP reduction Horizon trial Ahmed et al. [14••] Multicenter RCT 556 48 months Hydrus:6.7% IOP reduction and 76.5% medication reduction PE:6% IOP reduction and 52.9% medication reduction Pfeiffer et al. [15] Single blinded, RCT 100 24 months 50% IOP reduction in Hydrus +PE group; 28% IOP reduction in PE group Trabectome Jea et al. [18] Retrospective cohort study 417 24 months Trabectome: 43.5% IOP reduction and 3% increase in medications Trabeculectomy: 61.3% IOP reduction 77% medication reduction Minkler et al. [20••] Consecutive prospective case series 101 30 months 40.9% IOP reduction Francis et al. [22] Consecutive prospective case series 304 12 months 22.5% IOP reduction and 45.7 medication reduction Ting et al. [21] Consecutive prospective case series 517 12 months 44% IOP reduction and 28% medication reduction in PXG, 34% IOP reduction and 21% medication reduction in POAG Ting et al. [21] Consecutive prospective case series 308 12 months 35% IOP reduction and 38% medication reduction in PXG, 22% IOP reduction and 31% medication reduction in POAG continued

10 • CUTTING EDGE - GLAUCOMA Kahook Dual Blade (KDB) Dorairaj et al. [24•] Retrospective review 42 12 months 47.2% IOP reduction and 91.7% medication reduction Greenwood et al. [26] Prospective interventional series 71 6 months 26.4% IOP reduction and 47.8% medication reduction ElMallah et al. [28] Retrospective review 42 12 months 19.3% IOP reduction and 12.5% medication reduction Laroche et al. [30] Retrospective review 63 6 months 19.5% IOP reduction and 38.5% medication reduction Berdahl et al. [31] Retrospective review 53 6 months 29.8–43.8% IOP reduction and 40% medication reduction Salinas et al. [32] Retrospective review 116 18 months KDB+PE: 12.7% IOP reduction and 45.8% medication reduction KDB alone: 31.2% IOP reduction and 13.8% medication increase GATT Grover et al. [34••] Prospective consecutive case series 85 12 months 39% IOP reduction and 53% medication reduction in GATT only group; 35% IOP reduction and 48% medication reduction in GATT/PE group Grover et al. [35] Retrospective review 35 24 months 40% IOP reduction Grover et al. [36] Retrospective review 14 12 months 45.8% IOP reduction, 67% reduction in medications OMNI Vold et al. [37] Retrospective multicenter review 48 12 months 28.4% IOP reduction in group 1 (baseline IOP>18 mm Hg) 9.7% IOP reduction in group 2 (baseline IOP≤18 mm Hg) (not statistically significant) ABiC Gallardo et al. [40••] Retrospective consecutive case series 75 12 months 34.8% IOP reduction and 60.7% medication reduction Gallardo et al. [41] Retrospective paired study 12 12 months Ab interno: 25.4% IOP reduction and 66.7% medication reduction Ab externo: 25.4% IOP reduction and 75% medication reduction Ondrejka et al. [42] Retrospective review 106 12 months Group 1 (IOP≥18 mm Hg): 41% IOP reduction and 90.4% medication reduction Group 2 (IOP<18 mm Hg), no significant change in IOP and 88.9% medication reduction Hughes et al. [43] Retrospective consecutive case series 89 18 months 36% IOP reduction and 32% medication reduction Cypass Table 3: continued continued

MINIMALLY INVASIVE GLAUCOMA SURGERY: WHERE WE ARE, AND WHAT THE FUTURE HOLDS • 11 COMPASS XT: Reiss et al. [44] Randomized controlled trial, safety extension study 282 60 months CyPass group: 34.3% IOP reduction and Control group: 32.3% IOP reduction iStent Supra Junemann et al. Prospective study 73 18 months 50.4% IOP reduction Miniject Denis et al. [48] Prospective single arm study 25 24 months 40.7% IOP reduction and 50% medication reduction Xen Grover et al. [49] Open-label prospective study 65 12 months 37% IOP reduction and 51% medication reduction Mansouri et al. [50•] Prospective interventional study 149 12 months 31% IOP reduction and 73.6% medication reduction Smith et al. [51] Interventional case series 3 24 months 49% IOP reduction in case 1, 48% IOP reduction in case 2, 81% IOP reduction in case 3 Arad et al. [52] Consecutive case series 10 13 months 41% IOP reduction Tan et al. [53] Retrospective review 50 12 months IOP reduction: Ab interno: 28.6%; Ab externo: 40.1% Medication reduction: Ab interno: 45.3%; Ab externo: 50.8% Yuan et al. [54] Retrospective review 69 8 months IOP reduction: Ab interno: 47.4%; Ab externo: 40.1% Medication reduction: Ab interno: 52.9%; Ab externo: 55.3% Gallardo et al. [55] Retrospective review 12 months IOP reduction: Ab interno: 39.3%; Ab externo: 51.1% Medication reduction: Ab interno: 69.9%; Ab externo: 63.2% Purgert et al. [56] Retrospective review 55 6 months IOP reduction: Ab interno: 30.1%; Ab externo: 30.4% Medication reduction: Ab interno: 51.7%; Ab externo: 75.9% Preserflo Microshunt Batlle et al. [57] Feasibility study, prospective consecutive case series 23 60 months 46% IOP reduction at 4 years, 48.5% IOP reduction at 5 years; 66.7% reduction in medications at 5 years Table 3: continued 26% are observed [25•, 26]. At 12 months, IOP reduction of 12.6% to 47% [27-29] are reported. Reduction of medications of 1–2 is observed at 6 months [25•, 26, 30]. As a standalone procedure, at 6 months, KDB lead to IOP reduction ranging from 22 to 43.8%. Medication reduction occurred by up to 47.8% [30-32]. Eyes with higher baseline IOP experienced greater mean IOP reductions [30].

12 • CUTTING EDGE - GLAUCOMA KDB vs iStent Studies suggest that KDB is comparable, if not superior to iStent implantation combined with cataract surgery. In a retrospective study of 77 eyes undergoing KDB or iStent in combination with phacoemulsification, there was no significant difference in overall success between iStent and KDB via a multivariable logistic regression accounting for age, sex, race, and baseline IOP. Mean IOP decreased by 1.7 mmHg in the iStent group and by 2.4 mmHg in the KDB group. Mean medication use decreased by 1.3 and 0.6, respectively [27]. In a prospective study comparing PE-KDB with PE-iStent, at 12 months, mean IOP was reduced by 3.1 mmHg in the KDB group and 3.4 mmHg in the iStent group. Mean medications were reduced by 1 in both groups. Primary outcome was attained in 93.7% of patients of KDB eyes and 83.3% of iStent eyes (Table 4) [33]. TrabEx and TrabEx+ (Previously Known as Goniotome and Goniotome I/A) TrabEx (MST, Redmond, Washington, USA) is a single-use, dual-blade device for the excision of up to 6 clock hours of TM via ab interno goniotomy. This device was formerly known as Goniotome (Neomedix USA). It is a serrated, dual-bladed device designed to completely excise TM without leaving flaps that may occlude collector channels. The TrabEx+ offers the additional feature of irrigation and aspiration ports for improved angle visualization and anterior chamber stabilization, eliminating the need for viscoelastic which can trap regurgitating blood and bubbles. The TrabEx+ is approved for use as a standalone procedure or combined with cataract extraction. Large studies on the efficacy and safety of the TrabEx devices have yet to be published. Table 4: MIGS efficacy comparison studies. Study/author Design of study Number enrolled Follow-up Mean% IOP reduction and %medication reduction from baseline KDB vs istent: ElMallah et al. [29] Retrospective review 315 12 months KDB+PE: 27.5% IOP reduction iStent +PE: 13.8% IOP reduction Hydrus vs iStent: Ahmed et al. [16•] Multicenter RCT 152 12 months Hydrus: 8.9% IOP reduction Istent: 5.2% IOP reduction KDB vs iStent: Le et al. [27] Retrospective review 77 12 months KDB: 12.6% IOP reduction and 36.4% medication reduction iStent: 14.3% IOP reduction and 65% medication reduction KDB vs Trab/360 or GATT: Hirabayashi et al. [38] Retrospective review 101 6 months Mean IOP reduction similar between KDB and Trab360/GATT group: 83.6% vs 44.5%/73% (p=0.858) *80% of KDB eyes achieved target IOP≤18 mm HG compared to 59.3% GATT eyes without additional interventions at 6 months

MINIMALLY INVASIVE GLAUCOMA SURGERY: WHERE WE ARE, AND WHAT THE FUTURE HOLDS • 13 GATT Gonioscopic-assisted transluminal trabeculotomy (GATT) was developed by Grover et al. in 2014 [34••]; it involves a circumferential goniotomy using a prolene suture or a flexible illuminated microcatheter (iTrack 250, Ellex, Australia) (Table 2). In addition to the temporal clear corneal incision, an oblique paracentesis is created superonasally or inferonasally. The catheter or suture is threaded into the anterior chamber to rest near the nasal angle. A microsurgical blade is used to create a 1–2 mm nasal goniotomy. Using microsurgical graspers, the catheter or suture is introduced into SC and advanced circumferentially for 360°. The distal end of the catheter or suture is then grasped and the proximal end pulled out of the eye to create the 360° goniotomy. GATT can be done with or without and prior to or after phacoemulsification (Fig. 4). Fig. 4: Steps of GATT and ABiC. A Creation of oblique/tangential paracentesis. B MVR blade creating 1–2 clock goniotomy nasally. C Insertion of microcatheter into SC for 360° (note the red illumination on lower left side of image). D Performing the 360 trabeculotomy by removing the catheter. Note: ABiC procedure involves panels A–C, with retraction of the catheter while viscoelastic is injected to dilate SC instead of performing the trabeculotomy. Table 4 MIGS efficacy comparison studies Study/author Design of study Number enrolled Follow-up Mean% IOP reduction and %medication reduction from baseline KDB vs istent: ElMallah et al. [29] Retrospective review 315 12 months KDB ?PE: 27.5% IOP reduction iStent ?PE: 13.8% IOP reduction Hydrus vs iStent: Ahmed et al. [16•] Multicenter RCT 152 12 months Hydrus: 8.9% IOP reduction Istent: 5.2% IOP reduction KDB vs iStent: Le et al. [27] Retrospective review 77 12 months KDB: 12.6% IOP reduction and 36.4% medication reduction iSt nt: 14.3% IOP r duction and 65% medication reduction KDB vs Trab/360 or GATT: Hirabayashi et al. [38] Retrospective review 101 6 months Mean IOP reduction similar between KDB and Trab360/GATT group: 83.6% vs 44.5%/73% (p = 0.858) *80% of KDB eyes achieved target IOP B18 mm HG compared to 59.3% GATT eyes wi out addit on l interventions at 6 months Fig. 4 Steps of GATT and ABiC. A Creation of oblique/tangential paracentesis. B MVR blade creating 1–2 clock goniotomy nasally. C Insertion of microcatheter into SC for 360� (note the red illumination on lower left side of image). D Performing the 360 trabeculotomy by removing the catheter. Note: ABiC procedure involves panels A–C, with retraction of the catheter while viscoelastic is injected to dilate SC instead of performing the trabeculotomy 44 Curr Surg Rep (2022) 10:35–49 123

14 • CUTTING EDGE - GLAUCOMA In the original study, GATT showed an IOP reduction of 7.7 mmHg and average decrease in medications of 0.9 at 6 months, and 11.1 mmHg and 1.1 at 12 months in POAG. In secondary OAG, IOP decreased by 17.2 mmHg and medications by 2.2 at 6 months. 9% required repeat glaucoma surgery at 1 year [34••]. GATT can also be used in eyes with history of previous glaucoma surgery, including trabeculectomy, tube shunts, and ECP., where mean IOP decreased by 10.2 mmHg and medications decreased by 1.2 with 60% of patients achieving definition of successful IOP control [35]. The most common complication of GATT is post-operative transient hyphema, seen in 30–50% of patients at the post-op 1 week visit [34••]. Leaving the IOP in the high teens to low 20 s at time of surgery can decrease the risk of hyphema. Contraindications to GATT include persistent use of anticoagulation medications, bleeding disorders, closed angles, and the inability to properly identify the angle anatomy. GATT is indicated for primary and secondary open angle glaucoma. It has been used in juvenile open angle and congenital glaucoma as well, with reduction of IOP up to 12.5 mmHg and reduction of medications by 1.74 [36]. OMNI VISCO360 and Trab360 (Sight Sciences, Menlo Park, CA) were designed to perform ab interno trabeculotomy and canaloplasty, respectively (Table 2). They have been combined into the OMNI surgical system, designed to perform up to 360° of trabeculotomy as well as SC viscodilation. It was FDA approved in 2017. The OMNI is introduced through the main corneal incision, advanced across the anterior chamber toward the nasal angle, and a small goniotomy is created with the cannula tip.The cannula is then inserted into the goniotomy and the microcatheter advanced into SC 180°. Retraction of the catheter injects a predetermined amount of viscoelastic into SC to provide viscodilation. Advancing the catheter again and withdrawing the device completes the trabeculotomy. This can then be repeated for the other 180° if desired. The ROMEO study found a mean IOP reduction of 6.2 mmHg and medications reduced by 0.5 in patients with preoperative IOP>18 mmHg. In patients with preoperative IOP<or equal to 18 mmHg, IOP reduction of 1.5 and medication reduction by 0.7 were observed [37]. There is no clear data indicating a clear relationship between degrees of goniotomy or trabeculotomy performed and IOP reduction. In a small study comparing KDB versus 360 trabeculotomy, IOP and medication requirements were similar between the groups (Table 4) [38]. Aqueous angiography may be helpful in the future to determine the high versus low flow regions and allow targeted outflow treatment. This has been demonstrated by a two-dye perfusion system ex vivo [39]. Schlemm Canal Dilation Traditional canaloplasty is a bleb-less, ab externo procedure that uses a sclerostomy and microcatheter to enter, circumnavigate, and viscodilate SC, ending with a tensioning suture that leads

MINIMALLY INVASIVE GLAUCOMA SURGERY: WHERE WE ARE, AND WHAT THE FUTURE HOLDS • 15 to decreased aqueous outflow resistance and IOP lowering. Gallardo introduced a modified technique, ab interno canaloplasty (ABiC) through a clear corneal incision using a microcatheter that allows viscodilation of SC [40••]. This is designed to target the distal outflow system beyond the TM (Fig. 4). A single-center retrospective review of 75 eyes compared ABiC alone vs. ABiC with phacoemulsification. At 12 months, there was a 32.8% reduction in IOP in standalone ABiC and 31.7% IOP reduction in ABiC. There was a 60% reduction in medication usage, and 40% were medication-free. No significant differences in IOP or medication reduction were observed at 12 months. At 24 months, the data demonstrated consistent IOP lowering of 6.5 mmHg. In a study comparing ab externo vs. ab interno canaloplasty, there was no significant difference in IOP lowering or medication reduction at 12 months [40••, 41]. The initial ABiC study was performed with the iTrack microcatheter (Ellex iScience, Fremont, CA), and required grasping the catheter with micro forceps to insert it into the canal 360°. Ondrekja and Körber studied ABiC using the OMNI system in mild to moderate glaucoma patients, divided into two groups based on baseline IOP. At 12 months, mean IOP reduction was 10 mmHg in group 1 (baseline IOP≥18) and 1.3 mmHg group 2 (baseline IOP<18). 86% of all eyes were medication-free [42]. Higher pre-op IOP was found to be correlated with increased IOP-lowering effect [43]. Suprachoroidal Drainage Devices The suprachoroidal space is a physiologic route for aqueous humor outflow. Because traditional subconjunctival targeted surgeries may be complicated by a lifetime risk of endophthalmitis, poor cosmesis, and variable would healing response, the suprachoroidal pathway has been investigated as an alternative treatment for glaucoma. Cypass The CyPass Micro-Stent (Alcon, Fort Worth, TX) is a polyamide fenestrated tube 6.35 mm in length, designed to create a controlled outflow pathway between the anterior chamber and the supraciliary space (Table 1). It is inserted on a small guidewire. It was FDA approved for use with cataract surgery in 2016. The COMPASS trial evaluated its effectiveness and safety in eyes randomized to phacoemulsification with or without CyPass. The five-year data demonstrated that 46% of eyes in the CyPass group had≥20% unmedicated IOP reduction at 60 months versus 32.1% of control eyes [44]. On August 29, 2018, Alcon announced a voluntary market withdrawal of the CyPass following analysis of post-surgical data from the post-approval safety study. At 5-years, CyPass-implanted eyes had a statistically significant endothelial cell density (ECD) loss of −20.4% compared with −10.1% of control eyes. There was no statistically significant difference in baseline cellular morphology. Nine adverse events may have been related to ECD loss, including three with transient focal corneal edema and four that required trimming of the device due to protrusion [45]. Data suggests a correlation between the distance the CyPass device extends into the anterior chamber,

16 • CUTTING EDGE - GLAUCOMA determined by the number of retention rings visible, and the rate of ECD loss. Of the patients with ECD data at both 2 and 5 year follow-up, mean ECD loss over this 3-year period was 3.1% when 0 rings were visible, 8.4% with 1 ring visible, 21% with 2 rings visible, and 31.4% with 3 rings visible. At this time the FDA recommends monitoring all patients whom have had CyPass-implanted undergo periodic ECDmonitoring using specular microscopy until stabilization of ECD loss [45]. Clinical findings associated with ECD loss were uncommon (3.3% of implanted eyes), suggesting that ECD may be a subclinical sequela [45, 46]. In the future, if returned to the market, the CyPass may be useful for advanced open angle glaucoma cases. Other Suprachoroidal Devices Several other devices currently undergoing clinical trials are also aimed at increasing outflow through the suprachoroidal space (Table 1). The iStent Supra (Glaukos Corporation, San Clemente, CA) is a 4 mm polyethersulfone and titanium stent with a 165-μm heparin-coated lumen. Preliminary results showed IOP reduction of 11.6 mmHg from baseline at 12 months, and 12.5 mmHg by 18 months with no major adverse events [47]. The Miniject (iStar Medical, Wavre, Belgium) is another investigational supraciliary device and is made from proprietary biocompatible silicon material containing a geometric porous microstructure to promote tissue integration with reduced fibrosis. The STAR-I trial evaluated Miniject implantation as a standalone procedure in mild to moderate glaucoma. At 24 months, the device demonstrated a mean IOP reduction of 40.7% and 48% of patients were medicationfree. No serious adverse events were reported [48]. Subconjunctival Devices Subconjunctival filtration creates a new, non-physiologic pathway for aqueous humor outflow and is used in traditional glaucoma filtering procedures such as trabeculectomy and glaucoma drainage devices. New devices targeting the subconjunctival pathway have been developed with aim to decrease complications rates of traditional filtration surgeries. Xen The Xen-45 Gel Stent (Allergan, Irvine, California) is a hydrophilic, gelatin stent approved by the FDA in 2016. It is 6 mm long with a 45um lumen and is composed of porcine gelatin cross-linked with glutaraldehyde (Table 1). Outflow is designed to follow Poiseuille’s law of laminar flow and minimizes risk of hypotony. It is designed for ab interno insertion through a small clear corneal incision. It is preloaded on a 27-gauge needle that is inserted into the superonasal angle, into the subconjunctival space. The needle is advanced until it emerges from the sclera 3 mm from the limbus, and the injector button is then advanced to deploy the stent. Ideally, the stent tip sits above tenon’s capsule and a 1 mm tip remains in the anterior chamber. The stent should move freely under the conjunctiva, and sometimes blunt instrumentation or a needle may be used to

MINIMALLY INVASIVE GLAUCOMA SURGERY: WHERE WE ARE, AND WHAT THE FUTURE HOLDS • 17 straighten the stent. Mitomycin C is applied to increase the rate of success of aqueous outflow due to the formation of a bleb. The pivotal FDA study enrolled 65 patients with refractory glaucoma for Xen implantation with mitomycin C. At 12 months, 75.4% of patients had≥20% IOP lowering from baseline with the same or fewer medications. Mean IOP reduction was 9.1 mmHg (37%) and mean medication reduction was 1.8 (51%). Adverse events included needling, non-persistent loss of best corrected visual acuity, and transient hypotony. During the 12-month follow-up period, 32.3% required needling [49]. Examination of Xen alone versus Xen combined with phacoemusification suggests standalone Xen leads to greater IOP reduction than combination surgery: 40% reduction in standalone group versus 22.9% in combination group [50•]. The use of Xen has also been evaluated in pediatric glaucoma with promising results [51, 52]. One of the major challenges for a beginner Xen surgeon is to ensure the tip of the Xen sits above Tenon’s layer and not within. There is emerging evidence for Ab externo implantation of the gel stent with and without conjunctival dissection suggesting comparable safety and effectiveness [53-56]. In a study comparing ab interno and ab externo placement, there was no statistically significant difference in mean IOP reduction, medication reduction, secondary glaucoma surgeries or adverse events at 12 months [53]. Further research involving prospective randomized trials are indicated to further evaluate the safety and efficacy of each approach. PreserFlo Microshunt The PreserFlo MicroShunt (Santen Inc., Miami, FL) is an 8.5 mm device made of a biocompatible polystyrene material with a 70 μm lumen. It is designed to be implanted ab externo under open conjunctival dissection with mitomycin C. At the time of this review, the MicroShunt is not yet FDA approved. The pivotal study enrolled 23 POAG patients. At 5 years follow-up, mean IOP was reduced by 46%. Mean number of medications was reduced by 1.6. 61.1% of patients were medication-free. The most common adverse events included corneal edema, transient hypotony, bleb-related complications, and device-iris touch. Two patients required reoperation due to bleb failures. There were no reports of chronic hypotony or endophthalmitis. There were no signs of apparent degradation after 5 years [57]. Conclusion Many MIGSs have emerged in the past 15 years, and we will likely continue to see novel surgical techniques and devices in the future. Moderate efficacy and high safety have been demonstrated by many previous studies, and new data will continue to help us better understand how to design minimally invasive glaucoma surgical treatment for our patients to provide sightsaving care. Funding: None. Declarations Conflict of interest: None of the authors have any conflicts of interest.

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