Advances in procedural management of glaucoma are challenging the long-held paradigm of using medical therapy as a mainstay of treatment. Yet, while an expanding array of laser and surgical options improve the ability to control IOP with reduced reliance on medication, treatment gaps still exist within the category of procedural options. For instance, MIGS options have grown in popularity due to their ability to achieve postoperative pressures in the mid- to upper-teens, decrease patients’ dependence on glaucoma medication, and favorable safety profile compared to external filtration surgeries.1 However, because they are not capable of delivering equivalent IOP-lowering efficacy as external filtration,2 they are generally utilized in patients with mild to moderate glaucoma.3 Options that would be suitable for patients who require greater IOP lowering than what MIGS can deliver but for whom incisional surgery is not yet indicated would be welcomed. In addition, because the majority of MIGS procedures are indicated for use at the time of cataract surgery, there remains an unmet need for standalone options that achieve a moderate to high degree of IOP-lowering efficacy, but which are associated with a favorable safety profile.

The recent emergence of a sub-category of device-based, bleb-forming procedures that are associated with minimal conjunctival disruption, and which aim to direct aqueous drainage to the subconjunctival space, would seem to fill a prominent treatment gap in glaucoma. Early experience with this new category of implants suggests an ability to reliably and predictably achieve IOP in the low teens, which is comparable to outcomes after trabeculectomy or placement of a glaucoma drainage device, but with a safety profile demonstrated in clinical trials to be more similar to MIGS than traditional incisional glaucoma surgeries.

Factors Driving Increased Use of Procedural Management

Several factors are driving the increased use of procedural management in glaucoma. For example, suboptimal adherence to medical therapy, which may be due to several issues, undermines the ability to understand the efficacy of pressure-reducing drops in real-world settings. Moreover, several studies have demonstrated an association between poor adherence and loss of visual function.4,5 Even if medications are used according to schedule, IOP variability (a risk factor for visual field deterioration),6,7 inability to achieve sufficiently low IOP while on medical therapy, and progression despite achieving the target pressure8-10 suggest a need for additional treatment options. In the Early Manifest Glaucoma Trial, 45% of treated patients experienced progression over a 6-year follow-up period despite a 25% mean reduction of IOP,11 suggesting that durably low IOP targets, irrespective of percentile reduction, may be warranted in some cases. Supporting evidence for the latter is found in the Advanced Glaucoma Intervention Study, in which eyes with post-intervention IOP greater than 17.5 mm Hg demonstrated more profound loss on VF compared to eyes with post-intervention IOP less than 14 mm Hg.7 Compared to medical management, glaucoma surgery may be superior in conferring control of diurnal IOP variation.12

Is There a Ceiling Effect with MIGS?

The MIGS category has been introduced as an alternative to traditional surgeries and can achieve postoperative pressures in the mid-teens with a favorable safety profile compared to traditional incisional surgeries.1 Devices and surgeries within the category are associated with a variety of mechanisms—or, more precisely, are targeted to differing aspects of the aqueous outflow pathway. One limitation to the class is that few have been studied in robust clinical trials as standalone options. Several of the options specifically target the trabecular meshwork (TM) or Schlemm canal (SC), which is unsurprising in light of mounting evidence showing that resistance in the juxtacanalicular TM and/or inner wall of SC is a primary causative factor in increased outflow resistance in eyes with primary open-angle glaucoma (POAG).13,14 However, it is increasingly recognized that such devices restore physiologic aqueous flow dynamics in only one part of a complex system which regulates aqueous outflow.15

Aqueous flow through the TM structures is segmental, referring to the fact that outflow is non-uniform around the circumference of the TM.15 It appears likely that several factors contribute to segmental and pulsatile flow dynamics, including the location of distal pathway structures, such as collector channels, as well as location and presence of pores in the inner wall of SC and composition of extracellular matrix proteins.15,16 While the TM is crucial to aqueous dynamics, several lines of evidence suggest that the TM, collector channels, and distal outflow pathways function collectively to regulate aqueous humor outflow, whereas resistance in more than one of these entities synergistically contributes to glaucomatous pathophysiology.15 Furthermore, there is growing evidence that distal components of the outflow pathway have a critical role in outflow and IOP regulation, with most outflow occurring near collector channels.16 Taken together, this evidence suggests that a device or surgery intended to improve trabecular flow, regardless of how perfectly placed or performed, is inherently limited in its ability to restore physiologic aqueous flow dynamics.

Emerging Options

Due to their invasive nature, traditional incisional glaucoma surgeries are most often reserved for later disease stages. However, both trabeculectomy and tube shunt surgery are associated with a not insignificant risk of intra- and postoperative complications.17,18 Even when successful, use of postoperative medications may be necessary to maintain control of IOP,19 and many patients require intensive postoperative care, including suture manipulation, revision for hypotony, bleb needling, cataract extraction, and subconjunctival 5-FU injection.20

The recent introduction of comparatively less invasive surgical options that shunt aqueous humor to the subconjunctival space, and thereby target distal flow, helps to cover existing treatment gaps in the procedural management of glaucoma. The MicroShunt* (Santen, Osaka, Japan) is a surgical device made from a highly biocompatible, bioinert material poly(styrene-block-isobutylene-block-styrene), or SIBS, that is currently being investigated in patients with POAG where IOP remains uncontrolled while on maximum tolerated medical therapy and/or where glaucoma progression warrants surgery.21 The MicroShunt device is intended for a standalone controlled ab externo filtration surgical implantation.21,22 Mitomycin C (MMC) is used at the time of surgery to inhibit the formation of scar tissue and thereby reduce the risk of failure.23,24

During implantation, the distal end of the MicroShunt is situated approximately 6 mm posterior to the limbus.25 The theoretical advantage of bleb formation in this posterior location is that it may be less prone to constant friction from eye lid blinking which could result in lower risk of bleb wall breakdown and eventual leak.25 Some observations from the pivotal clinical trial are interesting to note in this regard, specifically a lower rate of bleb leak with MicroShunt compared to trabeculectomy (8.9% vs 14.5%, respectively).26

The material design and engineering of the MicroShunt may be consequential for its performance. SIBS has demonstrated biostability through multiple studies, with a lack of biodegradation byproducts, resulting in reduced chronic inflammation and minimal scar formation.27 SIBS is an inert, soft, and flexible thermoformable elastomeric material, which allows the MicroShunt to conform to the curvature of the eye.27 SIBS has been used for over 14 years in more than 1 million patients in the TAXUS cardiac stent and has been used as an investigational product for over 10 years in the eye.28,29 The MicroShunt was designed with a 70 µm lumen size and length of 8.5 mm based on the Hagen-Poiseuille equation for laminar flow to minimize hypotony without the need for tensioning sutures.

Conclusion

Maintaining patients’ visual function to improve quality of life at a sustainable cost is a primary goal of glaucoma therapy.30 Gaining control of IOP is widely understood to be the best mechanism to slow or stop structural and functional progression of the disease.31,32 In general, device-based, procedural management of glaucoma provides an important mechanism to achieve control of pressure while reducing the reliance on medication. However, even with the expanding array of lasers and surgeries available, unmet need exists for intermediate options between medication and invasive surgeries, such as trabeculectomy and aqueous shunt devices. New and novel devices in later stages of development thus offer significant promise to alter and improve glaucoma management.

*MicroShunt is CE Marked in Europe and was recently approved in Canada by Health Canada marketed under the brand name PRESERFLOTM. It is not yet approved in the United States and is pending PMA approval from the US FDA.

1. Prum BE Jr, Rosenberg LF, Gedde SJ, et al. Primary Open-Angle Glaucoma Preferred Practice Pattern(®) Guidelines. Ophthalmology. 2016;123(1):P41-P111.

2. Francis BA, Singh K, Lin SC, et al. Novel glaucoma procedures: a report by the American Academy of Ophthalmology. Ophthalmology. 2011;118(7):1466-1480.

3. Richter GM, Coleman AL. Minimally invasive glaucoma surgery: current status and future prospects. Clin Ophthalmol. 2016;10:189-206.

4. Paula JS, Furtado JM, Santos AS, et al. Risk factors for blindness in patients with open-angle glaucoma followed-up for at least 15 years. Arq Bras Oftalmol. 2012;75(4):243-246.

5. Sleath B, Blalock S, Covert D, et al. The relationship between glaucoma medication adherence, eye drop technique, and visual field defect severity. Ophthalmology. 2011;118(12):2398-2402.

6. Nouri-Mahdavi K, Hoffman D, Coleman AL, et al. Predictive factors for glaucomatous visual field progression in the Advanced Glaucoma Intervention Study. Ophthalmology. 2004;111(9):1627-1635.

7. The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration.The AGIS Investigators. Am J Ophthalmol. 2000;130(4):429-440.

8. Jones JP, Fong DS, Fang EN, et al. Characterization of glaucoma medication adherence in Kaiser Permanente Southern California. J Glaucoma. 2016;25(1):22-26.

9. Kass MA, Meltzer DW, Gordon M, et al. Compliance with topical pilocarpine treatment. Am J Ophthalmol. 1986;101(5):515-523.

10. Musch DC, Gillespie BW, Palmberg PF, et al. Visual field improvement in the collaborative initial glaucoma treatment study. Am J Ophthalmol. 2014;158(1):96-104.e102.

11. Heijl A, Leske MC, Bengtsson B, et al. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol. 2002;120(10):1268-1279.

12. Konstas AG, Topouzis F, Leliopoulou O, et al. 24-hour intraocular pressure control with maximum medical therapy compared with surgery in patients with advanced open-angle glaucoma. Ophthalmology. 2006;113(5):761-765.e761.

13. Braunger BM, Fuchshofer R, Tamm ER. The aqueous humor outflow pathways in glaucoma: A unifying concept of disease mechanisms and causative treatment. Eur J Pharm Biopharm. 2015, 95(Pt B):173-181.

14. Tamm ER, Braunger BM, Fuchshofer R. Intraocular pressure and the mechanisms involved in resistance of the aqueous humor flow in the trabecular meshwork outflow pathways. Prog Mol Biol Transl Sci. 2015;134:301-314.

15. Carreon T, van der Merwe E, Fellman RL, et al. Aqueous outflow - a continuum from trabecular meshwork to episcleral veins. Prog Retin Eye Res. 2017;57:108-133.

16. Swaminathan SS, Oh DJ, Kang MH, Rhee DJ. Aqueous outflow: segmental and distal flow. J Cataract Refract Surg. 2014;40(8):1263-1272.

17. Gedde SJ, Herndon LW, Brandt JD, et al. Postoperative complications in the Tube Versus Trabeculectomy (TVT) study during five years of follow-up. Am J Ophthalmol. 2012;153(5):804-814.e801.

18. Gedde SJ, Feuer WJ, Shi W, et al. Treatment Outcomes in the Primary Tube Versus Trabeculectomy Study after 1 Year of Follow-up. Ophthalmology. 2018;125(5):650-663.

19. Landers J, Martin K, Sarkies N, et al. A twenty-year follow-up study of trabeculectomy: risk factors and outcomes. Ophthalmology. 2012;119(4):694-702.

20. Kirwan JF, Lockwood AJ, Shah P, et al. Trabeculectomy in the 21st century: a multicenter analysis. Ophthalmology. 2013;120(12):2532-2539.

21. Pinchuk L, Riss I, Batlle JF, et al. The use of poly(styrene-block-isobutylene-block-styrene) as a microshunt to treat glaucoma. Regen Biomater. 2016;3(2):137-142.

22. Batlle JF, Fantes F, Riss I, et al. Three-year follow-up of a novel aqueous humor MicroShunt. J Glaucoma. 2016;25(2):e58-65.

23. Yamanaka O, Kitano-Izutani A, Tomoyose K, Reinach PS. Pathobiology of wound healing after glaucoma filtration surgery. BMC Ophthalmol. 2015;15 Suppl 1(Suppl 1):157.

24. Wilkins M, Indar A, Wormald R. Intra-operative mitomycin C for glaucoma surgery. Cochrane Database Syst Rev. 2005(4):Cd002897.

25. Beckers HJM, Pinchuk L. Minimally Invasive glaucoma surgery with a new ab-externo subconjunctival bypass – current status and review of literature. European Ophthalmic Review. 2019;13(1):27-30.

26. Baker ND, Barnebey HS, Moster MR, et al; INN005 Study Group. MicroShunt versus trabeculectomy in primary open-angle glalucoma: 1-year results from a 2-year randomized, multicenter study. In Press.

27. Acosta AC, Eema EM, Yamamoto H, et al. A newly designed glaucoma drainage implant made of poly(styrene-b-isobutylene-b-styrene): biocompatibility and function in normal rabbit eyes. Arch Ophthalmol. 2006;124(12):1742-1749.

28. Silber S, Colombo A, Banning AP, et al. Final 5-year results of the TAXUS II trial: a randomized study to assess the effectiveness of slow- and moderate-release polymer-based paclitaxel-eluting stents for de novo coronary artery lesions. Circulation. 2009;120(15):1498-1504.

29. Pinchuk L, Riss I, Batlle JF, et al. The development of a micro-shunt made from poly(styrene-block-isobutylene-block-styrene) to treat glaucoma. J Biomed Mater Res B Appl Biomater. 2017;105(1):211-221.

30. European Glaucoma Society Terminology and Guidelines for Glaucoma, 4th Edition - Chapter 3: Treatment principles and options Supported by the EGS Foundation: Part 1: Foreword; Introduction; Glossary; Chapter 3 Treatment principles and options. Br J Ophthalmol. 2017;101(6):130-195.

31. Mantravadi AV, Vadhar N. Glaucoma. Prim Care. 2015;42(3):437-449.

32. Weinreb RN, Aung T, Medeiros FA. The pathophysiology and treatment of glaucoma: a review. JAMA. 2014; 311(18):1901-1911.