Expert Review of Ophthalmology

For Peer Review Only

Techniques and technologies for modulating (IOP)

Journal: Expert Review of Ophthalmology

Manuscript ID Draft

Manuscript Type: Review

Intraocular pressure, Minimally invasive surgery, neuroprotective, shunt procedure, Non-penetrating glaucoma Keywords: procedures, Laser trabeculoplasty, cyclophotocoagulation, trabeculectomy

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1 2 3 4 Techniques and technologies for modulating intraocular pressure 5 (IOP) 6 7 8 Glaucoma is a disease characterized by optic neuropathy defined by characteristic 9 optic disc damage and visual field loss for which intraocular pressure (IOP) is a major 10 modifiable risk factor. It is the second leading cause of blindness worldwide[1,2]. With 11 the aging population, the incidence and burden of glaucoma are expected to rise to 12 even more significant levels[3]. Lowering the IOP remains the only treatment option to 13 control glaucoma, and prevent further damage. This can be achieved by various 14 methods that will be discussed below. 15 16 17 IOP lowering drops (Table 1) 18 For Peer Review Only 19 Topical eye drops are the first, and most commonly used line of treatment, for ocular 20 hypertension and open angle glaucoma. They decrease IOP by increasing aqueous 21 22 drainage and/or reducing aqueous production. Treatment regimens vary depending on 23 the individual medications and the clinical response of each individual patient. 24 25 It is essential to establish the patient’s baseline untreated maximum IOP and then to set 26 a target IOP. This target value is generally set as the pressure at which the rate of loss 27 of ganglion cells is the same as the age-dependent rate of cell loss[4]. Practically, the 28 target pressure is the highest IOP with which there is no progression of clinically 29 30 detectable glaucomatous optic nerve damage from the physician’s perspective (i.e. no 31 optic disc abnormality, no visual field defects) or the patient’s perspective (i.e. no 32 noticeable reduction in vision, no impact on daily activities or quality of life)[4]. Some 33 studies aim to reduce IOP to a given value[5,6] or by a given percentage[7], regardless 34 of patient risk factors and baseline pressure. This, however, does not take into account 35 that the risk of nerve damage varies between patients. More recent strategies calculate 36 target pressures based on when other parameters change[8] (e.g. reversal of disc 37 38 cupping, improvement in visual fields), or the degree of nerve damage at baseline[9] 39 and the number and severity of other non-pressure risk factors[10]. 40 41 There are five main classes of anti-hypertensive eye drops, which are the 42 analogues, beta-blockers, sympathomimetics (alpha agonists), carbonic anhydrase 43 inhibitors and cholinergics (miotics), as well as combination formulas. There are also 44 45 new agents emerging, with novel mechanisms of action[11]. According to the UK 46 NICE guidelines for the diagnosis and management of glaucoma[12], generic 47 prostaglandin inhibitors are the first-line for patients with IOP>24mmHg and/or 48 suspected chronic open angle glaucoma (if there is a risk of visual impairment within 49 their lifetime; if not then regular visual assessments are initially advised). For patients 50 who cannot tolerate the first-line treatment, an alternative generic prostaglandin 51 analogue or a beta-blocker are second-line options. If none of the above is tolerated, 52 53 then third-line options are a non-generic , sympathomimetics, 54 carbonic anhydrase inhibitors, cholinergics, or combination treatments. Combination 55 treatments can also be used when a single agent is unable to achieve the desired IOP 56 reduction. 57 58 Prostaglandin analogues are the most commonly used medications for the reduction 59 of and the treatment of open-angle glaucoma[13,14]. They have a 60

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1 2 3 moderate speed of therapeutic effect, but have a longer duration of effect than other 4 anti-hypertensive agents and so only require once-daily dosing. Formulations of 5 6 , and are available in generic form. They have an 7 excellent systemic safety profile; however, some ocular side effects still occur[15]. 8 9 Beta-blockers are the second most commonly used class of topical ocular anti- 10 hypertensives. They were developed in the late 1970s[16,17], with being 11 approved by the FDA in 1978[18]. They have a rapid therapeutic effect, and as a result, 12 are used as the first line in acute closed-angle glaucoma and post-operative ocular 13 14 hypertension, but as a second line in chronic open angle glaucoma (or first line in 15 patients with contraindications to prostaglandin analogues). All formulations are 16 available in generic form; making them one of the least expensive medications for 17 modulation of IOP.For Topical Peer beta-blockers Review have a better Only ocular side effect profile than 18 prostaglandin analogues, however, their absorption into the general circulation, via the 19 lacrimal drainage system and conjunctival vasculature[19], causes a variety of 20 21 systemic side effects. Topical beta-blockers are therefore contraindicated in patients 22 with asthma, chronic obstructive pulmonary disease, poorly controlled congestive 23 cardiac failure, bradycardias, and severe peripheral arterial disease[20]. 24 25 Carbonic anhydrase inhibitors are another class of topical modulators of IOP. The 26 enzyme carbonic anhydrase catalyzes the conversion of carbon dioxide and water into 27 carbonic acid [21]. The secretion of aqueous humor from the epithelium is 28 29 dependent on carbonic anhydrase. Carbonic anhydrase inhibitors reduce IOP by 30 blocking this process and thereby decreasing the secretion of aqueous humor from the 31 ciliary body into the posterior chamber[22,23]. In 1954, the oral carbonic anhydrase 32 inhibitor Diamox () was shown to markedly reduce IOP in humans[24]. 33 Systemic acetazolamide reduces the secretion of aqueous humor by around 30%[25]. 34 However, oral carbonic anhydrase inhibitors have a wide range of significant systemic 35 side effects, which limits their long-term use. It was not until the mid-1990s that the 36 37 first topical carbonic anhydrase inhibitor, hydrochloride (2%) was 38 introduced[22]. Subsequently, ophthalmic suspension (1%) was 39 developed[26]. Carbonic anhydrase is present in the . Carbonic 40 anhydrase inhibitors have not been shown to cause any clinically significant change in 41 corneal thickness in subjects with normal corneas, however in subjects with 42 compromised corneas (e.g. in Fuchs’ dystrophy, or after complicated cataract surgery), 43 44 they can result in corneal decompensation that does not necessarily reverse after 45 cessation of treatment[25]. All carbonic anhydrase inhibitors are contraindicated in 46 patients with known sulphonamide allergy. Systemic and topical carbonic anhydrase 47 inhibitors are excreted mainly via the kidneys, and so should be avoided if creatinine 48 clearance < 30 ml/min. 49 50 Parasympathomimetics: is the most commonly prescribed cholinergic; it 51 52 typically reduces the IOP by 20%–30%. [27] Its mechanism of action is by increasing 53 the uveoscleral outflow, allowing another alternative route for eyes with compromised 54 conventional drainage pathway. It is short-acting, so commonly used before laser 55 treatment, or surgical iridotomy, to stretch the iris and is available in two forms as 56 drops used four times a day or as a 4% gel used once a day [28]. 57 58 The final major class of medications that modulate IOP are the alpha-adrenergic 59 60 agonists. Previously, non-selective adrenergic agonists were used for the treatment of

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1 2 3 glaucoma or ocular hypertension; however, they have been replaced by more selective 4 alpha-2-adrenergic agonists[29]. There are two alpha agonists licensed for use in the 5 6 modulation of IOP: tartrate (0.1%, 0.15%) and 7 hydrochloride (0.5%, 1%). They have similar efficacy and safety profiles in clinical 8 practice[30]. There are no absolute adult contraindications to the use of topical alpha 9 agonists for ocular hypertension[31]. Alpha agonists may be of therapeutic value in the 10 treatment of glaucoma due to factors additional to their hypotensive effect[32]. Reports 11 of the neuroprotective effect of brimonidine in humans have come from the Low- 12 pressure Glaucoma Treatment Study[33]; however, more large-scale clinical trials are 13 14 required to investigate these potential neuroprotective effects further. 15 16 Osmotic agents 17 Mannitol 20% (1.0–1.5g/KgFor Peer intravenously) Review and glycerol Only (1.0–1.5g/Kg orally) are 18 commonly used in controlling acutely raised IOP. Careful assessment of renal and 19 cardiac status must be done before their usage as they increase blood volume and 20 21 therefore increase cardiac preload. Mannitol may also alter blood glucose levels. 22 23 Novel agents are under experimental investigation and may be introduced into clinical 24 practice in the future. Rho kinase (ROCK) is an enzyme expressed in many tissues 25 [34]. It is thought that excess rho kinase activity contributes to cerebral[35] and 26 coronary[36] vasospasm and hypertension[37]. In the early 2000s, Rho kinase 27 inhibitors emerged as a potential new treatment for glaucoma[38]. Ripasudil 28 29 hydrochloride hydrate (Glanatec ophthalmic solution 0.4%) is a 30 that was developed and approved for use in the treatment of glaucoma in Japan in 31 2014[39]. It is administered on a twice-daily regimen[40]. Other Rho Kinase inhibitors 32 are currently being tested[41,42]. All rho kinase inhibitors currently in clinical trials 33 have so far shown promising safety profiles[11]. 34 35 Similar to other chronic asymptomatic diseases, adherence to treatment tends 36 37 to be relatively poor among patients with glaucoma[43]. Only an estimated 60-70% of 38 prescribed eye drop doses are taken by patients with glaucoma[43]. Reasons for poor 39 compliance and adherence to treatment are varied and complex. 40 41 Various combination medications are available as an alternative for managing patients 42 whose IOP does not respond to a single agent. Fixed-combination PGA/timolol 43 44 preparations have been shown to be more effective at reducing IOP than PGA therapy 45 alone[44]. Other fixed combinations are available, which help in improving 46 compliance. 47 48 49 Currently, the use of preservatives in ocular hypotensive formulations is widespread. 50 This most obvious advantage that preservatives confer is a longer shelf-life[45]. 51 52 Increasingly, the focus is switching to the development of entirely preservative-free 53 formulations. Several prostaglandin analogues, timolol, dorzolamide and several 54 combination agents are now available in preservative-free formulations. Surveys have 55 demonstrated that glaucoma patients on preservative-free drops have fewer symptoms 56 and signs of ocular surface disease, compared to those on preservative-containing 57 drops. Furthermore, the survey found that most of the adverse signs and symptoms 58 induced by preserved drops were reversed after the withdrawal of the preservative- 59 60 containing agent. [46] However, other studies have demonstrated little or no corneal

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1 2 3 damage resulting from a range of concentrations of Benzalkonium chloride (BAK) one 4 of the most common preservatives used in eye drops,[45] and meta-analyses have 5 6 shown that in patients taking twice the daily dose of BAK, there is no significant 7 increase in corneal staining compared to those on half the dose[47]. Regarding the 8 economic considerations of preservative and preservative-free drops, there have been 9 no studies performed to directly compare the cost-effectiveness of individual 10 medications in their BAK-preserved and preservative-free formulations[45]. 11 12 The past decade has seen increasing evidence that ocular hypertension, although a 13 14 feature of many cases of glaucoma is not the primary pathology in the disease, and that 15 neurodegeneration is the fundamental pathological process of glaucomatous disease 16 [48]. Furthermore, studies have demonstrated the similarity between the mechanism of 17 cell death in glaucomaFor and Peer neurodegenerative Review diseases suchOnly as Alzheimer’s Disease 18 [92,93] and Parkinson’s Disease[51]. As a result, neuroprotection has become a 19 significant focus of research into both the mechanisms behind glaucoma and new 20 21 medications[52]. As mentioned previously, brimonidine has also been shown to have a 22 neuroprotective effect[33,53]. Another area of research in neuroprotection in glaucoma 23 is that of glutamate-induced excitotoxicity. Although the results of some studies have 24 been called into question and generated some controversy, glutamate release in the 25 retina has been suggested as one mechanism of retinal ganglion cell death in 26 glaucoma[54–57]. Memantine is the only current glutamate inhibitor in clinical use and 27 has promising neuroprotective effects in acute and chronic animal models of 28 29 glaucoma[55–58]. 30 31 Lasers in the reduction of IOP (Table 2) 32 33 Lasers can be used in managing glaucoma to lower IOP by increasing aqueous outflow 34 35 or reducing inflow. The nature of laser delivery can be varied in terms of power, 36 wavelength, treatment area or duration. Laser treatments in glaucoma also vary in the 37 longevity of their action, with some treatments lasting a few years, while others deliver 38 permanent effects. In some cases, the use of laser can be considered a primary 39 treatment, whereas laser procedures also play an essential role in refractory glaucoma. 40 41 Increasing outflow: Laser Trabeculoplasty 42 43 44 By directly targeting the (TM), aqueous drainage from the eye 45 can be increased in order to lower IOP,[59] even if the mechanisms behind this are not 46 fully understood. Such techniques include argon laser trabeculoplasty (ALT) and the 47 newer selective laser trabeculoplasty (SLT)[60]. ALT is a non-selective treatment 48 proven to be efficacious when compared to topical timolol therapy by the Glaucoma 49 Laser Trial[61]. SLT is a technique described in 1995[62] that selectively targets 50 51 pigmented TM through which trabecular filtration is thought to occur,[63] while 52 having considerably less effect on the neighbouring non-pigmented cells and structures 53 with lower optical absorption properties[64]. 54 55 The efficacy of SLT in open-angle glaucoma has been shown to equal that of topical 56 therapies both in terms of percentage IOP reduction and lowering IOP into the ‘normal 57 58 range’[65,66] and has therefore been proposed as a primary treatment [67] eliminating 59 eyedrop adherence issues and the subsequent local and systemic side effects that may 60 occur. One study reported success rates of 63% of early glaucoma patients and in 59%

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1 2 3 of advanced patients[68] (success=IOP less than 21mmHg or a greater than 20% IOP 4 reduction) demonstrating the little effect of disease duration or severity on IOP- 5 6 lowering potential. Peak IOP and IOP fluctuation have also been reported beneficiaries 7 of SLT treatment[69]. As to whether the treatment effect is dose-dependent, the 8 comparison between 180-degree and 360-degree treatments show greater efficacy 9 where a larger proportion of the TM has been treated[70–73] and reduction in inter- 10 visit variability in the 360-degree group[74]. ‘Crossover’ effects describing enduring 11 IOP reduction in untreated contralateral eyes have been reported[75] and refuted,[76] 12 with contrasting explanations given including increased adherence to drops after laser 13 14 procedures, or migration of activated macrophages. Whether or not this is an actual 15 biological effect, this has led to the exclusion of other eyes in many of the studies. 16 Another curiosity of SLT efficacy is the observation of additional benefit to those 17 patients who areFor not using Peer prostaglandin Review analogue topical Only therapy[77,78]. However, a 18 larger prospective study refuted this finding, reporting similar efficacy regardless of 19 prostaglandin use[79]. 20 21 22 In primary angle closure, a smaller body of evidence suggests SLT may provide an 23 alternative treatment option in order to lower IOP. This can be affected by the 24 obstruction of the trabecular meshwork due to apposition or secondary causes, limiting 25 both access and visualization with laser, and efficacy due to secondary changes seen to 26 occur in the TM microstructure[80,81]. Therefore, eyes with visible or partially visible 27 TM on gonioscopy after peripheral iridotomy have been examined to gauge its 28 29 efficacy. Studies investigating IOP-lowering in eyes with a patent peripheral iridotomy 30 have reported results of up to 41% mean reduction in IOP[82]. Another group have 31 reported a 4mmHg mean reduction equal to that produced by topical travoprost 32 0.004% at 6-month follow-up[83]. Importantly for the quality of life, a further study 33 reported a reduction of eyedrop medications with SLT in PACG, with 67% of their 34 patients achieving a minimum of 3mmHg IOP-lowering[84]. In pseudoexfoliation 35 (PXF) syndrome where there is blockage of the trabecular meshwork and Schlemm’s 36 37 canal by exfoliative dandruff-like material, a limited amount of short term studies have 38 reported similar outcomes to those amongst POAG patients,[85,86] as well as when 39 using ALT[87]. 40 41 SLT has been shown to be non-inferior to ALT by way of meta-analyses[65,88] with 42 the added advantages of being a repeatable treatment. Failure rates two years after 43 44 therapy have been quoted at around 50%[89] therefore warranting further or repeat 45 treatments. In comparison to ALT where the success rate has been quoted to be around 46 33% for repeat procedures,[90] SLT fares better in terms of success rates between 36- 47 67% using similar benchmarks[91–94] and time-to-failure analysis[95]. As to the 48 magnitude of the effect of repeated treatments, results are varied with both equal[96] 49 and diminished[95] responses being reported. Tolerability of both SLT and ALT also 50 seems to be equitable, with no significant differences found in rates of anterior 51 52 chamber flare and IOP spikes between SLT and ALT, although numerically higher in 53 the latter[88]. 54 55 Quality of life and cost-benefit ratios are both endpoints that are conceivably favored 56 with SLT in comparison to continuing topical therapy. Results so far have reported 57 SLT becoming the cheaper treatment when compared to generic latanoprost in the 58 second year of treatment[97,98]. This effect is seen sooner in comparison to 59 60 combination therapy, even when two-yearly SLT is factored in. Cost analyses and

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1 2 3 quality of life are currently being studied in large prospective studies comparing SLT 4 treatment with topical therapy[99,100] with results yet to be published. 5 6 7 Micropulse laser trabeculoplasty (MLT) is a variant of SLT using a micropulse laser. 8 First described in 2005,[101] MLT is administered using a mirrored lens to deliver 9 pulses of laser treatment 300 μs in duration. When efficacy is compared to SLT, the 10 IOP outcomes are similar. One prospective head-to-head study randomised 69 patients 11 to either 360-degree SLT or MLT. Similar proportions of patients achieved success 12 criteria in both groups, with no significant differences in IOP throughout the yearlong 13 14 follow-up period. Patients reported less discomfort in the MLT group, but MLT was 15 also associated with a trend towards higher IOPs at all time points (non-statistically 16 significant)[102]. 17 For Peer Review Only 18 Reducing inflow: Cyclophotocoagulation 19 20 21 Destruction of the ciliary body in order to reduce aqueous production has traditionally 22 been reserved as a last-resort treatment in eyes with advanced disease, owing to the 23 poor side effect profile of early techniques such as cyclodiathermy and 24 cyclocryotherapy including phthisis, uveitis, pain and reduction in vision[103–105]. 25 With time, the technique has adopted new lasers and approaches to improve its safety 26 and tolerability. Transscleral cyclophotocoagulation (TSCPC) is now most commonly 27 applied using a semiconductor diode laser in the near infrared spectrum (810nm) while 28 29 localizing the ciliary body using scleral transillumination[106]. While still reserved as 30 a treatment for advanced refractory cases, it is a useful tool in achieving substantial 31 IOP lowering effects of more than 15mmHg[107–109] with rates of hypotony, usually 32 defined as chronic IOP less than 5mmHg, quoted at being between 1%-9.5%, 33 especially in patients with neovascular glaucoma and high starting pressures[107,109– 34 112]. This risk is reportedly reduced by using lower energy especially in these high- 35 risk groups[110,113,114] and in those patients where treatment sessions are restricted 36 37 to under 80J[115]. However, no clear linear relationship between power and rates of 38 hypotony have been seen, except in cases of neovascular glaucoma[110]. 39 40 An endoscopic variant of cyclophotocoagulation (ECP) has also been developed via a 41 limbal or pars plana approach, first described in 1992[116]. ECP also uses an 810nm 42 diode laser in common with the trans-scleral variant, combined with a xenon light 43 44 source,[117] a helium-neon laser aiming beam, and an endoscope offering a 110-160 45 degree field of view. The procedure is usually carried out under subtenon or 46 intracameral anaesthesia with viscoelastic inflating the ciliary sulcus to maximise 47 visualisation of the ciliary processes. 48 49 The efficacy of ECP has been compared to non-ECP techniques including TSCPC, 50 cyclocryotherapy and tube surgery in refractory cases[118,119]. A meta-analysis 51 52 compared six controlled trials (n=429), reporting no significant difference in IOP 53 outcomes between ECP and non-ECP techniques. The average IOP lowering rate 54 amongst ECP was quoted as ranging between 28.8%-49.3%. ECP is now commonly 55 similarly combined with phacoemulsification to minimally invasive glaucoma surgery 56 (MIGS)[120]. As a primary procedure in glaucoma, studies of combined procedures 57 have demonstrated an IOP reduction of 47% lasting a minimum of two years, 58 accompanied by a significant reduction in eyedrop burden[121]. 59 60

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1 2 3 A large-scale report on 5,824 ECP outcomes reported rates of complications including 4 IOP spikes (14.5%), haemorrhage (3.8%), vision loss of more than 2 lines (1.03%), 5 6 substantial choroidal effusions (0.38%) and retinal detachments (0.27%)[122]. The 7 complication profile of combined phacoemulsification-ECP procedures was also quite 8 similar, including IOP spikes (14.4%), fibrinous uveitis (7.06%), cystoid macular 9 oedema (4.34%), transient hypotony (2.17%), iris bombé (1.08%). It is thought the 10 increased tissue specificity and visible endpoint of the ECP procedure that spares the 11 choroidal circulation and ciliary muscles and allows more accurate quantification of 12 the treatment delivered may be largely protective against post-operative hypotony 13 14 found in the trans-scleral variant[123]. Mean IOP, the number of drops and visual 15 acuity have all been reported as improved, at 1 year in a retrospective review[124], 16 with 2-year success rates (defined as IOP≤21mmHg) reported at 74%-82% in a 17 different study[119,125].For Peer Although longer-term Review data are Only scanty, such results may 18 encourage wider uptake of this procedure as a second-line or primary treatment option, 19 given the favorable safety outcomes. 20 21 22 Micropulse transscleral cyclophotocoagulation (MP-TSCPC) is another variant of 23 cyclophotocoagulation described in 2010[126]. Comparing efficacy between 24 techniques is limited by the definition of ‘success’ and variations in follow-up duration 25 and frequency. However, in the original MP-TSCPC 2010 case series, mean IOP 26 reduction was quoted as 16% at 18 months with a ‘success’ rate of 72.7% (IOP 6-21 or 27 30% reduction in IOP at last follow-up visit)[126]. Another larger randomized study 28 29 comparing MP-TSCPC with continuous wave TSCPC reported a 45% reduction in 30 mean IOP at 18 months in both groups, including multiple treatments which were 31 required in 46% of eyes in the MP-TSCPC group and 58% of eyes in the continuous 32 wave group[127]. Furthermore, no difference in eyedrop requirements was found 33 between the two groups after both MP-TSCPC and continuous wave TSCPC. Other 34 studies have reported very similar rates[128,129]. In terms of complications, most 35 reports favour MP-TSCPC, with no hypotony observed with MP-TSCPC in several 36 37 studies[126,127,130]. One study reported 46% of eyes after MP-TSCPC having 38 ongoing anterior chamber inflammation 3 months after the procedure[128]. However, 39 the incidence of this complication is still reportedly reduced in MP-TSCPC (4% vs 40 30%) when compared with continuous wave TSCPC[127]. As with all types of 41 cyclophotocoagulation, further studies are needed to extensively stratify patients 42 according to energy and glaucoma type to definitively decide which factors are more 43 44 predictive of poor outcomes. 45 46 47 Surgery for lowering the IOP (Table 3) 48 49 50 When all non-surgical therapies have been exhausted glaucoma filtration surgeries, 51 trabeculectomy (trab) and tube shunts, are the most common second-line therapy[131]. 52 53 Trabeculectomy 54 55 56 First described in 1968 by Cairns and Watson, trabeculectomy remains the gold- 57 standard surgery[132] and is the most widely performed[133] followed closely by tube 58 shunt procedures[131]. 59 60 Traditional trabeculectomy has been associated with vision-threatening complications

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1 2 3 such as hypotony (early) and endophthalmitis (early, late). Long-term complications 4 such as bleb leak or failure due to fibrosis of the subconjunctival tissue around the bleb 5 6 and scleral flap can also happen[131,134]. Patients at high risk for trabeculectomy 7 failure may be younger, African ethnic origin[135], previous ocular surgeries such as 8 cataracts, pre-operative IOP greater than 20mmHg[134], uveitic glaucoma, aphakic, 9 pseudoexfoliation, advanced visual field (VF) loss at time of surgery or prolonged 10 exposure to eye drops[136–138]. Scarring (fibrosis) is the primary cause of 11 postoperative failure and can arise during the first weeks to months following surgery. 12 13 Fibrosis occurs at the site of the new conduit or the scleral flap[139] resulting in 14 reduced aqueous humor outflow in the filtration path potentially leading to 15 uncontrolled IOPs. 16 17 Multiple studiesFor have cited Peer a higher riskReview of cataracts 5 toOnly 11 years after trabeculectomy 18 with and without anti-fibrotic use. [140–143] The Collaborative Initial Glaucoma 19 Treatment (CIGTS) study found that patients who underwent initial trabeculectomy 20 21 were at higher risk of cataract extraction compared to medicated patients during the 22 first 5 years after treatment, however after 5 years, the risk did not continue to differ 23 significantly[144]. The Advanced Glaucoma Intervention Study (AGIS) described a 24 similar finding with a 78% increased risk of developing cataracts after initial 25 trabeculectomy[142]. 26 27 To maximise the benefits of trabeculectomy while minimising the risk of adverse 28 29 events, several variations and modifications of the procedure have been 30 developed[145–147]. The Moorfield’s Safer Surgery System was developed as a 31 simplified method using minimal materials, providing a more efficient, consistent and 32 effective approach[139]. This method comprised of ‘best practices’ includes cordoning 33 off surgery to the superior half of the globe to reduce inflammation and 34 endophthalmitis, using a corneal traction suture to reduce the risk of haematoma and 35 36 performing a fornix-based conjunctival flap to achieve a more diffuse bleb[148]. 37 38 Antimetabolites 39 Antimetabolites such as 5-fluorouracil (5-FU) and mitomycin-C (MMC) were 40 developed to inhibit fibrosis and are routinely administered either topically to the 41 sclera at the site of the future ostomy or pre-operatively injected into the sub-tenon 42 space and patients at higher risk of trabeculectomy failure may require higher 43 44 concentrations or more extended exposure[131]. However, due to fibroblast cell 45 inhibition, the conjunctiva covering the sclera may become thin, leading to a greater 46 outflow of aqueous humor or the drug may have a toxic effect on the epithelium and 47 reduce production of aqueous humor, both resulting in hypotony. Over time, holes may 48 form in the conjunctiva permitting bacteria into the eye resulting in 49 endophthalmitis[149]. Several systematic reviews and meta-analyses have explored the 50 51 use of anti-metabolites paired with trabeculectomy during and post 52 procedure[149,150]. A Cochrane systematic review and meta-analysis of 11 RCTs 53 (n=698 patients) assessed the effects of intraoperative MMC compared to placebo in 54 three groups of patients (patients at high risk of trab failure patients with no previous 55 surgical intervention, and patients who underwent trab with cataract surgery) at 12 56 months[149]. Mean IOP was significantly reduced in MMC compared to placebo in 57 58 the three groups of patients measured. When comparing the efficacy of IOP lowering 59 power of MMC to 5-FU, one systematic review (11 trials, n=687 eyes) reported 60 patients treated with MMC demonstrated lower IOP, however, the quality of evidence

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1 2 3 was low due to high risk of selection bias and findings being inconsistent [151]. Green 4 et al. (12 trials, n=1319 patients) assessed the effects of 5-FU administered intra and 5 6 postoperatively at 12 months demonstrating results favoring 5-FU to placebo in 7 patients with high risk of failure and primary trabeculectomy groups, yet no significant 8 difference between 5-FU and controls in the combined surgery group[152]. 9 Additionally, postoperative 5-FU in primary trabeculectomy reduced IOP greater than 10 intraoperative administration 11 12 Anti-inflammatories 13 14 Anti-inflammatories such as corticosteroids and non-steroidal anti-inflammatories 15 (NSAIDs) have also been used to reduce the production of inflammatory mediators in 16 the inflammatory phase of wound healing[153]. However, corticosteroids have been 17 associated with Foran increased Peer risk of cataractsReview and increasing Only IOP after surgery. 18 NSAIDs have not been associated with these risks, yet there is more evidence pointing 19 to lower the effectiveness of NSAIDs compared to corticosteroids[154]. In a three- 20 21 armed RCT, Breusegem et al. investigated the preoperative use of self-administered 22 topical ketorolac versus fluorometholone versus placebo eye drops; results indicated 23 that anti-inflammatories, notably steroids, may be an effective additive at decreasing 24 the incidence of bleb failure leading to more stable IOPs[155]. 25 26 Comparing steroids to placebo, Starita et al. reported that patients (n=52 eyes) who 27 used topical prednisolone 1% for 3 weeks postoperatively had significantly lower IOP 28 29 at 20 weeks follow-up[156]. When comparing postoperative topical steroids to 30 combined topical and 50mg oral prednisolone, Azuara-Blanco et al. reported no 31 statistically significant difference in IOP between the groups in 35 patients at 12 32 months[157]. 33 34 Anti-VEGF 35 More recently, anti-vascular endothelial growth factor (anti-VEGF) drugs have been 36 37 employed as a potential wound modulator. VEGF, a signal protein that stimulates the 38 formation of new blood vessels (angiogenesis), is present during the proliferative 39 phase, so it is thought that inhibiting this factor would reduce scar formation[158,159]. 40 Bevacizumab has been injected via the subconjunctival route after needling 41 revision[160,161] and preoperatively injected intravitreally resulting in functioning 42 blebs and stable IOPs at 6 months[162,163]. Although promising initial results, more 43 44 studies are needed with larger sample sizes, control arms and longer follow-up time to 45 confirm long-term safety and efficacy[153]. 46 47 Releasable sutures 48 To prevent hypotony, a technique using releasable sutures to close the scleral flap that 49 can be removed to allow greater outflow of aqueous humor was developed[164]. A 50 meta-analysis synthesizing results from 6 RCTs (n=296 eyes) comparing 51 52 trabeculectomy with and without releasable sutures reported trabeculectomies with 53 releasable sutures were associated with greater efficacy of lowering IOP compared to 54 without releasable sutures[165]. However, the various studies reported inconsistent 55 rates of complications and small sample sizes hampering the ability to draw strong 56 conclusions for clinical practice. 57 58 59 60

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1 2 3 Tubes 4 In cases where trabeculectomy fails or will likely fail, tube shunts may be indicated 5 6 [166]. The non-valved Molteno implant was the first commercially available tube 7 implant; however, currently, the most commonly used shunts are the valved Ahmed 8 implant and non-valved Baerveldt implant[167]. Valved shunts limit the flow of 9 aqueous humor in the outgoing direction, thus theoretically preventing hypotony; 10 however, antiglaucomatous eye drops are still required for many patients with the 11 Ahmed valve. 12 13 14 Most evidence points to comparable efficacy of both Baerveldt and Ahmed shunts with 15 a lean towards better IOP control and fewer side effects with the Baerveldt[167,168]. 16 A Cochrane systematic review of RCTs by Tseng et al. compared the different tubes. 17 One trial (n=57)For comparing Peer Ahmed toReview Molteno found higher Only mean IOP in the Ahmed 18 group at 24 months. Similarly, two trials (combined n=464) compared the Ahmed to 19 the Baerveldt implant, and both found a higher mean IOP in the Ahmed group at 12 20 21 months follow-up[167]. One of these studies, the Ahmed Versus Baerveldt (AVB) trial 22 continued to demonstrate superior (P<0.001) mean IOP reduction in the Baerveldt 23 group (13.2±4.7mmHg) compared to the Ahmed group (15.8±5.2mmHg) at 5 years. 24 However, the Baerveldt shunt resulted in more serious early complications[168]. 25 Finally, a systematic review of 5 systematic reviews including patients with various 26 types of glaucoma including POAG, closed-angle, neovascular, uveitic and congenital, 27 28 observed moderate evidence that Baerveldt achieves a greater IOP reduction compared 29 to Ahmed and requires fewer re-interventions[169]. These results suggest that the 30 Baerveldt implant could be more effective at moderating IOP compared to the Ahmed, 31 yet is associated with a higher risk of complications. 32 33 Trabs vs tubes 34 Multiple studies have compared trabeculectomies versus various tubes with 35 36 comparable IOP reduction between the two therapies. A systematic review of 6 37 controlled trials comparing the Ahmed valve implant to trabeculectomy reported that 38 Ahmed was comparable to trabeculectomy in IOP reduction, yet Ahmed was 39 associated with a lower frequency of adverse events[170]. Two RCTs comparing the 40 Baerveldt to trabeculectomy yielded similar results; however, Baerveldt required 41 significantly more antiglaucomatous medication and had a higher complication 42 43 rate[171]. This similarity carried over time in the Tube Versus Trabeculectomy (TVT) 44 study (n=212 eyes) which demonstrated comparable mean IOPs between Baerveldt 45 (14.4±6.9mmHg) and trabeculectomy (12.6±5.9mmHg) groups (p=0.12) and a similar 46 need for antiglaucomatous medication at 5 years follow-up[172]. However, in this 47 study, an essential inclusion criterion was that all study eyes must have either 48 undergone previous cataract extraction with intraocular lens implantation, 49 trabeculectomy or both, therefore not all trabeculectomies were primary trabs, which 50 51 could explain the lack of significant difference between the two groups[173]. To 52 clarify this relationship, the Primary Tube Versus Trabeculectomy (PTVT) study 53 reported a statistically significantly lower mean IOP in primary trabeculectomy 54 (12.4±4.4mmHg) compared to Baerveldt (13.8±4.1mmHg) at one year (p=0.01)[174]. 55 56 Non-penetrating glaucoma surgery (NPGS) 57 Examples of these procedures are deep sclerectomy and viscocanalostomy procedures. 58 59 Several randomised controlled trials (RCTs) suggested an improved safety profile, but 60

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1 2 3 there is still no consensus about their efficacy when compared to trabeculectomy [175– 4 180]. 5 6 7 Deep sclerectomy (DS): 8 A prospective study by Dahan et al. that included 43 eyes and followed patients for 30 9 months, reported a 50% mean drop in IOP, with success rates of 61.4% at 21 months, 10 36.6% at 24 months, and 18.9% at 30 months [181]. 11 Antimetabolites and implants use are suggested to improve the success rate[182,183]. 12 However, the evidence is inconclusive as some comparative studies did not report a 13 14 significant difference regarding success rates[182,184,185]. 5FU and MMC have been 15 both used in studies to assess their effect in improving the success rate [184–186]. 16 17 ViscocanalostomyFor Peer Review Only 18 It aims to improve aqueous drainage by injecting high viscosity sodium hyaluronate 19 into Schlemm’s canal [187]. 20 21 Several studies demonstrated the improved safety profile of augmented 22 viscocanalostomy in comparison to MMC augmented trabeculectomy, but failed to 23 prove similar efficacy between the two procedures [175–179,188,189]. 24 25 Express shunt (Alcon Laboratories, Inc., Fort Worth, TX) 26 Several randomized trials have compared EX-PRESS to trabeculectomy [190–193]; 27 however, only one study (n=78 patients) reported statistically significant long-term 28 29 IOP reduction with EX-PRESS[194,195]. Compared to trabeculectomy (50.0%), EX- 30 PRESS (76.9%) provided better (P=0.0193) IOP control, meaning patients required 31 fewer antiglaucomatous medications and surgical interventions[194], especially in the 32 first 3 years, however, the difference in IOP control did not remain significant at 5 33 years follow-up[195]. 34 35 36 37 Minimally invasive glaucoma surgery (MIGS) and IOP (Tables 4,5) 38 39 Minimally invasive glaucoma surgeries (MIGS) are perceived as less traumatic 40 surgical interventions for patients with mild to moderate glaucoma, for those seeking 41 less dependence on drop treatment, or are intolerant to standard medical therapy[196]. 42 The commonly accepted definition is that MIGS are procedures in which implantation 43 of a surgical device with the intention of lowering IOP is performed, this is achieved 44 45 via an outflow mechanism with either an ab interno or ab externo approach, minimal 46 trauma with very little or no scleral dissection, minimal or no conjunctival 47 manipulation, good safety profile and rapid recovery[197]. 48 MIGS devices can be trabecular, suprachoroidal and subconjunctival 49 interventions[197], that can be performed with cataract surgery or as a stand-alone 50 procedure[198]. 51 52 53 TRABECULAR MESHWORK BYPASS STENTS 54 These include iStent, iStent inject, and Hydrus, They allow the flow of aqueous from 55 the anterior chamber to Schlemm’s canal, but have the limitation that the IOP cannot 56 fall below the episcleral vien pressure. 57 58 iStent 59 60

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1 2 3 The iStent Study Group[199], is an RCT conducted by Carven et al., which compared 4 cataract surgery to cataract surgery and one iStent. In the iStent study arm, IOP was 5 6 <21mmHg with no medications in 61% of patients at 24 months, compared to 50% in 7 the cataract only group, which was statistically significant (P=0.036). There was a 8 statistically significant mean decrease in medications in the combined group, compared 9 to the cataract surgery group at 12 months, that continued to appear at 24 months, but 10 was no longer statistically significant. 11 12 The use of iStent for advanced cases has been studied by Neuhann, including cases 13 14 with previous drainage procedures and follow up of 36 month[200]. In the analysis of 15 the cohorts, the mean IOP was 15.4±2.2mmHg in eyes that had no previous 16 intervention, with 13% were on IOP medications, compared to 14.2±2.3mmHg mean 17 IOP in cases thatFor had previous Peer surgery, Review with 44% of the Onlyeyes were on IOP medications. 18 Lower IOP threshold was needed in eye with prior glaucoma surgery. In the group 19 with no previous glaucoma surgery, there was a 34% reduction in mean IOP and 20 21 93% reduction in the mean number of medications. 22 23 24 Using multiple implants as a stand-alone procedure was studied by Katz et al., and was 25 shown to enhance the IOP reduction, with further reduction in IOP with additional 26 stents (p=0.001). The mean unmedicated IOP was found to be 15.9±0.9mmHg, 27 28 14.1±1.0mmHg, and 12.2±1.1mmHg with one, two, and three stents respectively at 18 29 months of follow-up [201]. This was the motivation behind the development of a 30 second-generation iStent, the iStent Inject, which consists of two preloaded stents 31 32 33 Istent inject was studied by Voskanyan et al. showing that implantation of this device 34 resulted in IOP ≤18mmHg in 66%, and 81% of cases without medications, and with 35 36 medications respectively, at 12 months, with an encouraging safety profile[202]. 37 38 Hydrus 39 40 An RCT conducted by Pfeiffer et al. that followed 100 eyes for 24 months had 41 compared cataract surgery alone versus combined cataract surgery and Hydrus stent 42 and had shown a significant increase in cases reached 20% reduction in diurnal IOP in 43 44 the combined surgery group (80% in combined group vs. 46% in cataract only group) 45 (p=0.0008). It also showed a significant lower IOP (p=0.0093), and a significantly less 46 number of patients on IOP medications (p=0.0008) in the combined surgery group 47 [203]. In terms of safety, both groups showed a similar safety profile. Focal peripheral 48 anterior synechiae developed in six (12%) patients, and commonly situated near the 49 inlet of the device, however, it did not affect the efficacy of the device. 50 51 52 53 SUPRACHOROIDAL IMPLANTS 54 This includes CyPass, iStent supra, and the SOLX Gold micro shunt. 55 56 No published data were found on the iStent supra (ab interno) and the SOLX Gold 57 micro shunt (ab externo) at the time of this review. 58 59 60 The CyPass

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1 2 3 Several studies had assessed CyPass efficacy and safety profile, whether implanted 4 during cataract surgery or as a separate procedure. 5 6 7 Combined CyPass insertion and cataract extraction with IOL implantation 8 (CE/IOL) 9 10 The COMPASS Trial considered as the primary study to assess CyPass efficacy and 11 safety profile, it is an RCT that compared CE/IOL+CyPass to CE/ IOL alone in 505 12 eyes, with 2 years of follow-up[204]. IOP showed a reduction of 7.4mmHg and 13 14 5.4mmHg in the microstent arm, and the control arm respectively (p<0.001). 85% eyes 15 of the stent arm remained drop-free at 24 months. It also demonstrated an excellent 16 safety profile with no vision-threatening adverse events in the CyPass group at 24 17 months. 18 For Peer Review Only 19 In early September, Alcon announced the voluntary global market withdrawal of the 20 21 CyPass micro stent due to concerns of progressive endothelial cell loss (ECL), due to 22 results from the COMPASS-XT trial which is 3 years extension of Alcon’s 2 years 23 COMPASS trial, showing a significant ECL (>30%) in the combined group versus the 24 control group[205]. 25 26 Other smaller scale studies that looked into the efficacy and possible complications of 27 cypass+CE/IOL includes the multicentre prospective study conducted by Hoeh et al. 28 29 which included 57 uncontrolled POAG patients and 41 controlled POAG patients 30 undergoing CyPass+CE/IOL and showed good safety profile. It demonstrated a 31 statistically significant reduction in mean IOP and medications with 37% reduction in 32 IOP and 50% reduction in medications in the uncontrolled group at 6 months. While 33 the IOP remained controlled below 21mmHg, there was 71.4% reduction in 34 medications (p<0.001) in the controlled group [206]. No series adverse events were 35 found, with transient hypotony being the commonest to occur. 36 37 38 Höh et al. studied the efficacy and safety of combined CyPass+CE/IOL in 136 eyes 39 including controlled, and controlled cohorts. Patients were followed for 2 years 40 [207]. No sight-threatening adverse events were seen in any of the remaining 82 41 subjects at the end of the study, with transient hypotony (15.4%) and micro stent 42 obstruction (8.8%) being considered the most common complications seen. Further 43 44 glaucoma surgery was needed in fifteen eyes (11%). The mean IOP in the uncontrolled 45 group (n=23) was found significantly lower (p<0.0001) at months 6, 12, and 24. A 46 statistically significant reduction of the mean IOP from baseline was seen at months 6 47 (p=0.0188) and 12 (p=0.0356) in the controlled group (n=59). The mean decrease of 48 IOP medications from baseline was found statistically significant in both groups at all 49 points of the study. 50 51 52 53 CyPass stand-alone implantation 54 García-Feijoo et al. followed 60 eyes that underwent stand-alone CyPass implantation 55 for 1 year, and included eyes with OAG and uncontrolled IOP (>21mmHg) on topical 56 therapy [208]. IOP showed a 34.7% reduction, IOP medications were reduced from 57 2.2±1.1 medications to 1.4±1.3 medications at 12 months. Most common adverse 58 events included IOP spikes to >30mmHg that lasted beyond 1 month in 11% of cases; 59 60 cataract progression, that was seen in 12.2% of the cases at 12 months; hyphaema that

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1 2 3 occurred in 6% and resolved by the first month. In eyes that were indicated to 4 secondary glaucoma surgical intervention, further glaucoma surgery was successfully 5 6 avoided in 83% of eyes. 7 8 A study was being conducted to assess the safety and effectiveness of the use of visco- 9 assisted CyPass Micro-Stent implantation for the lowering of intraocular pressure in 10 11 subjects who have open angle glaucoma (Viscopass). It describes injecting 60 µL of an 12 ophthalmic viscosurgical device (OVD) at the end of the lumen. However, no 13 published results were found. 14 15 16 17 SUBCONJUNCTIVAL FILTRATION 18 For Peer Review Only 19 20 They are similar to traditional trabeculectomy and aqueous shunt surgery, hence 21 requiring subconjunctival MMC injection pre-insertion to optimize bleb function and 22 survival. 23 24 XEN implant 25 26 27 It is an ab interno porcine gelatin stent, which was shown that it does not get occluded, 28 and does not cause a tissue reaction in the eye [209] and is implanted via a clear 29 corneal incision, avoiding conjunctival dissection. 30 31 One of the earliest studies investigating Cataract surgery combined with the insertion 32 of a XEN implant (the 63 or 140 model) without using MMC, demonstrated a 33 34 significant reduction in IOP with a qualified success of 85.3% and a complete success 35 rate off medications of 47.1% [210]. 36 37 In another study implanting XEN 140 model + MMC as a stand-alone procedure (n=49 38 eyes) and including cases with previously failed trabeculectomy, Sheybani et al. 39 demonstrated a 36.4% reduction in IOP from baseline at 12 months, with 40% 40 complete success, while 89% qualified success [211]. No serious adverse events were 41 42 found in the study. 43 44 45 Bleb needling remains the most common complication of Xen implant, with 44.1% 46 reported to require bleb needling with MMC or surgical revision in a recent study, this; 47 however, did not affect success rate at 12 months [212]. This compares to a 14% 48 49 needling rate in the trabeculectomy arm of the Primary Tube Versus Trabeculectomy 50 Study. Postoperative loss of IOP control due to subconjunctival fibrosis is more 51 common in Xen stent compared to trab despite less conjunctical dissection[174]. 52 53 54 InnFocus 55 56 57 It is an ab externo drainage device, which resembles the trabeculectomy in the steps of 58 surgery, and is considered more invasive than other MIGS. In a study, which included 59 combined and stand-alone cases of micro shunt and MMC, 80% had IOP ≤14mmHg at 60 3 years. At 3 years, the mean IOP was 10.7±1.5mmHg; with 95 % qualified success

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1 2 3 rate and a reduction in medications from 2.6±0.9 to 0.8±1.2[213]. Transient hypotony 4 and choroidal effusion were the most frequent adverse effects, and they spontaneously 5 6 resolved. No long-term serious adverse events were reported. 7 8 9 Summary: 10 11 Glaucoma is a disease characterized by optic neuropathy defined by characteristic 12 optic disc damage and visual field loss for which intraocular pressure (IOP) is a major 13 modifiable risk factor. Lowering the IOP remains the mainstay treatment to stop the 14 progression of glaucoma. Different modalities can be used to achieve this including 15 IOP lowering medications, laser, and surgeries. Nowadays, minimally invasive 16 glaucoma surgeries and newer lasers are becoming more popular due to their safety 17 profile, and their efficacy, allowing the patients to be less dependent on life long 18 For Peer Review Only 19 medications and substituting more invasive procedures as trabeculectomy, and shunt 20 operations. This review will go through the different ways used to lower the IOP, and 21 the newest techniques, and modalities used to achieve this. 22 23 24 25 Keywords: 26 Intraocular pressure, neuroprotective, laser trabeculoplasty, cyclophotocoagulation, 27 trabeculectomy, shunt procedure, non-penetrating glaucoma procedures, minimally 28 invasive glaucoma procedures. 29 30 31 32 Expert Commentary: 33 Lowering the intraocular pressure remains the mainstay treatment for glaucoma, with 34 increasing evidence of neuroprotection rather than decreasing the intraocular pressure, 35 which is of particular importance in normal tension glaucoma, and in cases that 36 37 continue to progress despite achieving target intraocular pressure. The use of 38 preservative-free agents and combinations can help increase compliance with drops. 39 Laser procedures continue to gain popularity as being a non-invasive, safe, and 40 effective way to control the intraocular pressure, with the newer laser (Selective laser 41 trabeculoplasty, micropulse cyclophotocoagulation, endoscopic 42 cyclophotocoagulation) developed that can be used as the first line of treatment, with 43 44 minimal damage that allows repeated treatments. Some can be done with cataract 45 surgery (endoscopic cyclophotocoagulation), mimicking minimally invasive glaucoma 46 procedures. 47 Surgical intervention remains the gold standard for refractory cases, including 48 trabeculectomy, and shunt procedures, with the introduction of non-penetrating 49 glaucoma procedures which allows for less side effect profile. 50 The use of antimetabolites, anti-inflammatories and antivascular endothelial growth 51 52 factors allows for better success rate. 53 Minimally invasive glaucoma procedures are considered the newest modality to 54 control the intraocular pressure, which can be done alone or with cataract surgery. 55 Various devices are described, which shows promising success, and good safety 56 profile, but larger randomized control trials are needed with longer follow-up. 57 58 59 60

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1 2 3 4 Five-year view: 5 The authors of this review believe that in five-years time lasers and minimally invasive 6 glaucoma procedures will replace eye drops, and surgeries like trabeculectomy, and 7 shunt procedures. 8 New minimally invasive glaucoma devices will emerge, and the existing ones will 9 have better success and safety profile. 10 11 Neuroprotective medications will gain more popularity, in preventing ganglion cell 12 death in high-risk individuals. 13 14 15 16 Key issues: 17  Intraocular pressure lowering drops remains the first line of treatment of newly 18 diagnosedFor glaucoma Peer patient Review Only 19  Preservative-free agents and combination medications are gaining popularity 20  Neuroprotective drugs are a new group of medications, which shows some 21 22 hope. 23  Selective laser trabeculoplasty is a safe alternative as a first line treatment in 24 cases of open-angle closure, which shows good efficacy and safety. 25  Endoscopic cyclophotocoagulation is an option to decrease the intraocular 26 pressure, which can be combined with cataract surgery. 27  Trabeculectomy and shunt procedures remain the mainstay for refractory 28 29 glaucoma cases. 30  Minimally invasive glaucoma procedures are a popular alternative to control 31 the intraocular pressure, and decrease drop dependence. 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 4 References: 5 [1] Quigley HA. Number of people with glaucoma worldwide. Br. J. Ophthalmol. 6 [Internet]. 1996 [cited 2018 Nov 4];80:389–393. Available from: 7 http://www.ncbi.nlm.nih.gov/pubmed/8695555. 8 [2] Quigley HA, Vitale S. Models of open-angle glaucoma prevalence and incidence in 9 the United States. Invest. Ophthalmol. Vis. Sci. [Internet]. 1997 [cited 2018 Nov 10 4];38:83–91. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9008633. 11 [3] Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 12 and 2020. Br. J. Ophthalmol. [Internet]. 2006 [cited 2018 Nov 4];90:262–267. 13 Available from: http://www.ncbi.nlm.nih.gov/pubmed/16488940. 14 [4] Jampel HD. Target Pressure in Glaucoma Therapy. J. Glaucoma. 1997. p. 133–136. 15 [5] Fluorouracil T, Surgery F, Group S. Fluorouracil Filtering Surgery Study One-Year 16 Follow-up. Am. J. Ophthalmol. 2018;186:xxxiii–xlii. 17 18 [6] GlaucomaFor Laser Trial Peer Research ReviewGroup. The Glaucoma Only Laser Trial (GLT) and 19 Glaucoma Laser Trial Follow-up Study: 7. Results. Am. J. Ophthalmol. 20 1995;120:718–731. 21 [7] Gordon MO, Beiser JA, Brandt JD, et al. The Ocular Hypertension Treatment Study. 22 2002;120. 23 [8] Jay Katz L, Spaeth G, Cantor L, et al. Reversible Optic Disk Cupping and Visual Field 24 Improvement in Adults With Glaucoma. Am. J. Ophthalmol. 1989. 25 [9] Anderson DR. Glaucoma: the Damage Caused by Pressure xlvi Edward Jackson 26 Memorial Lecture. Am. J. Ophthalmol. 1989;108:485–495. 27 [10] Hodapp E, Parrish RK, Anderson DR. Clinical decisions in glaucoma. Mosby; 1993. 28 [11] Wang SK, Chang RT. An emerging treatment option for glaucoma: Rho kinase 29 inhibitors. Clin. Ophthalmol. 2014;8:883–890. 30 [12] Centre NG. Glaucoma : diagnosis and management. 2017;1–41. 31 32 [13] Golan S, Rosenfeld E, Shemesh G, et al. Original and generic latanoprost for the 33 treatment of glaucoma and ocular hypertension: Are they really the same? Clin. 34 Exp. Pharmacol. Physiol. 2015;42:220–224. 35 [14] Doucette LP, Walter MA. in the eye: Function, expression, and roles 36 in glaucoma. Ophthalmic Genet. 2017;38:108–116. 37 [15] Alm A, Grierson I, Shields MB. Side Effects Associated with Prostaglandin Analog 38 Therapy. Surv. Ophthalmol. 2008;53:93–105. 39 [16] TJ Z, HE K. Timolol: Dose response and duration of action. Arch. Ophthalmol. 40 1977;95:605–607. 41 [17] Katz IM, Hubbard WA, Getson AJ, et al. Intraocular pressure decrease in normal 42 volunteers following timolol ophthalmic solution. Invest. Ophthalmol. Vis. Sci. 43 1976;15:489. 44 [18] Realini T. A history of glaucoma pharmacology. Optom. Vis. Sci. 2011;88:36–38. 45 [19] Shields MB. Textbook of Glaucoma - 2nd Edition. 2nd ed. Baltimore: Lippincott 46 47 Williams & Wilkins; 1987. 48 [20] BNF. BETA-ADRENOCEPTOR BLOCKERS (SYSTEMIC): Contraindications. 49 [21] Lindskog S. Structure and mechanism of carbonic anhydrase. Pharmacol. Ther. 50 1997;74:1–20. 51 [22] F. Sugrue M. Pharmacological and ocular hypotensive properties of topical 52 carbonic anhydrase inhibitors. Prog. Retin. Eye Res. 2000. 53 [23] H Maren T. The rates of movement of Na+, Cl-, and HCO-3 from plasma to posterior 54 chamber: effect of acetazolamide and relation to the treatment of glaucoma. Invest. 55 Ophthalmol. 1976. 56 [24] Becker B. Decrease in Intraocular Pressure in Man by a Carbonic Anhydrase 57 Inhibitor, Diamox*: A Preliminary Report. Am. J. Ophthalmol. 1954;37:13–15. 58 [25] Holló G. The use of topical carbonic anhydrase inhibitors in glaucoma treatment. 59 In: Orgul S, Flamer J editors., editor. Pharmacother. glaucoma. Bern: Hans Huber 60

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1 2 3 [Internet]. 2013 [cited 2018 Nov 4];39:431–437. Available from: 4 http://www.ncbi.nlm.nih.gov/pubmed/23506920. 5 [207] Höh H, Grisanti S, Grisanti S, et al. Two-year Clinical Experience with the CyPass 6 Micro-Stent: Safety and Surgical Outcomes of a Novel Supraciliary Micro-Stent. 7 8 Klin. Monbl. Augenheilkd. [Internet]. 2014 [cited 2018 Nov 4];231:377–381. 9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24771171. 10 [208] García-Feijoo J, Rau M, Grisanti S, et al. Supraciliary Micro-stent Implantation for 11 Open-Angle Glaucoma Failing Topical Therapy: 1-Year Results of a Multicenter 12 Study. Am. J. Ophthalmol. [Internet]. 2015 [cited 2018 Nov 4];159:1075–1081.e1. 13 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25747677. 14 [209] Lewis RA. Ab interno approach to the subconjunctival space using a collagen 15 glaucoma stent. J. Cataract Refract. Surg. [Internet]. 2014 [cited 2018 Nov 16 4];40:1301–1306. Available from: 17 http://www.ncbi.nlm.nih.gov/pubmed/24943904.For Peer Review Only 18 [210] Sheybani A, Lenzhofer M, Hohensinn M, et al. Phacoemulsification combined with a 19 new ab interno gel stent to treat open-angle glaucoma: Pilot study. J. Cataract 20 Refract. Surg. [Internet]. 2015 [cited 2019 Mar 12];41:1905–1909. Available from: 21 https://linkinghub.elsevier.com/retrieve/pii/S0886335015010391. 22 23 [211] Sheybani A, Dick HB, Ahmed IIK. Early Clinical Results of a Novel Ab Interno Gel 24 Stent for the Surgical Treatment of Open-angle Glaucoma. J. Glaucoma [Internet]. 25 2016 [cited 2019 Mar 13];25:e691–e696. Available from: 26 http://www.ncbi.nlm.nih.gov/pubmed/26561420. 27 [212] Smith M, Charles R, Abdel-Hay A, et al. 1-year outcomes of the Xen45 glaucoma 28 implant. Eye [Internet]. 2018 [cited 2019 Jan 15]; Available from: 29 http://www.ncbi.nlm.nih.gov/pubmed/30552422. 30 [213] Batlle JF, Fantes F, Riss I, et al. Three-Year Follow-up of a Novel Aqueous Humor 31 MicroShunt. J. Glaucoma [Internet]. 2016 [cited 2018 Nov 4];25:e58–e65. 32 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26766400. 33 [214] Brubaker RF, Schoff EO, Nau CB, et al. Effects of AGN 192024, a new ocular 34 hypotensive agent, on aqueous dynamics. Am. J. Ophthalmol. 2001;131:19–24. 35 [215] Nilsson SFE, Drecoll E, Lütjen-Drecoll E, et al. The prostanoid EP2receptor agonist 36 37 butaprost increases uveoscleral outflow in the cynomolgus monkey. Investig. 38 Ophthalmol. Vis. Sci. 2006;47:4042–4049. 39 [216] Christiansen GA, Nau CB, McLaren JW, et al. Mechanism of ocular hypotensive 40 action of bimatoprost (Lumigan) in patients with ocular hypertension or 41 glaucoma. Ophthalmology. 2004;111:1658–1662. 42 [217] Dinslage S, Hueber A, Diestelhorst M, et al. The influence of Latanoprost 0.005% 43 on aqueous humor flow and outflow facility in glaucoma patients: A double- 44 masked placebo-controlled clinical study. Graefe’s Arch. Clin. Exp. Ophthalmol. 45 2004;242:654–660. 46 [218] Wan Z, Woodward DF, Cornell CL, et al. Bimatoprost, prostamide activity, and 47 conventional drainage. Investig. Ophthalmol. Vis. Sci. 2007;48:4107–4115. 48 [219] Bahler CK, Howell KG, Hann CR, et al. Prostaglandins Increase Trabecular 49 Meshwork Outflow Facility in Cultured Human Anterior Segments. Am. J. 50 51 Ophthalmol. 2008;145:114–119. 52 [220] Lim KS, Nau CB, Byrne MMO, et al. NIH Public Access. Evaluation. 2009;115:790– 53 795. 54 [221] Takagi Y, Nakajima T, Shimazaki A, et al. Pharmacological characteristics of AFP- 55 168 (), a new prostanoid FP receptor agonist, as an ocular hypotensive 56 drug. Exp. Eye Res. 2004;78:767–776. 57 [222] Toris CB, Zhan GL, Zhao J, et al. Potential mechanism for the additivity of 58 pilocarpine and latanoprost. Am. J. Ophthalmol. 2001;131:722–728. 59 [223] Schumer RA, Camras CB, Mandahl AK. Putative side effects of prostaglandin 60 analogs. Surv. Ophthalmol. 2002;47.

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1 2 3 [261] Brandão LM, Grieshaber MC. Update on Minimally Invasive Glaucoma Surgery 4 (MIGS) and New Implants. J. Ophthalmol. [Internet]. 2013 [cited 2018 Nov 5 4];2013:1–12. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24369494. 6 [262] Manasses DT, Au L. The New Era of Glaucoma Micro-stent Surgery. Ophthalmol. 7 8 Ther. [Internet]. 2016 [cited 2018 Nov 4];5:135–146. Available from: 9 http://www.ncbi.nlm.nih.gov/pubmed/27314234. 10 [263] Saheb H, Ianchulev T, Ahmed I ‘Ike’ K. Optical coherence tomography of the 11 suprachoroid after CyPass Micro-Stent implantation for the treatment of open- 12 angle glaucoma. Br. J. Ophthalmol. [Internet]. 2014 [cited 2018 Nov 4];98:19–23. 13 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23743436. 14 15 16 17 18 For Peer Review Only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 Table 1: Intraocular pressure lowering drops 4 5 Agent Mode of action Side effects 6 Prostaglandin analogues  Increase the outflow of Common ocular side effects: 7 Bimatoprost aqueous humor[214] via  Conjunctival hyperemia 8 Lumigan® 0.01% and 0.03% the unconventional  Eyelash changes 9 Latanoprost Xalatan® 0.005% uveoscleral  Darkening of the iris and 10 Tafluprost Saflutan® 0.0015% pathway[215–219] periocular skin 11 Travoprost Travatan® 0.004% 12  Might also affect the pigmentation[223]. 13 Rescula® 0.12% conventional trabecular Less common, but more 14 and 0.15% pathway[220–222]. serious, side effects: 15  Cystoid macular 16 oedema[224,225] 17 18 For Peer Review Only Iris cysts[226] 19  Anterior uveitis[225] 20  Reactivation of previous 21 herpes simplex 22 keratitis[227]. 23 24 Beta-blockers  Decrease the production Topical side effects: uncommon 25  Beta 1 selective of aqueous 26 0.25%, 0.5% humor[228,229], with no Systemic side effects: 27 Betoptic® Betoptic S® effect on outflow  Hypotension 28 Betoptima®  Bradycardia[230] 29  Non selective  Fatigue, shortness of 30 31 0.5% Betaclar® breath (in patients with 32 0.25%, 0.5% asthma or other 33 Betagan® Vistagan® respiratory 34 0.1%, 0.3% diagnoses)[231,232]. 35 Betaman® Beta-ophtiole®,  Reduced libido an 36 Optipranolol®, Turoptin® depression have been 37 Timolol 0.1%, 0.25%, 0.5% 38 reported[231] (rare) 39 Aquanil® Arutimol® 40 Cusimolol® 41 Nyogel® Opimol® Oftamolol® 42 Timoptic® Timoptic-XE® 43 Timoptol® Timabak® 44 Timogel® 45 46 Timolabak® Timosine XE® 47 Timosan® 48  With intrinsic 49 sympathomimetic activity 50 0.5%, 1%, 2% 51 Carteol® Carteabak® 52 Teoptic® Arteoptic® 53 54 Ocupress® 55 Pindolol 2% Pindoptic® 56 Carbonic anhydrase  Decrease the production Systemic side effects: 57 inhibitors of aqueous Common side effects 58 Topical humor[23,233].  Ataxia 59 Brinzolamide 1% Azopt® 60  Depression

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1 2 3 Dorzolamide 2% Trusopt®  Diarrhea 4 Systemic 5  Fatigue 6 Acetazolamide Diamox®  Headache 7 Diamox SR®  Paraesthesia 8 Diamox Retard® Odemin® Less common side effects: 9 Dichlorphenamide Antidrasi®  Anaemia 10 Daranide®  Confusion 11 Glaumid® Oralcon® 12  Dermatological adverse Neptazane® 13 drug reactions 14  Renal calculi 15  Increased renal loss of 16 17 sodium, potassium and 18 For Peer Review Only water which can cause 19 metabolic acidosis[234] 20 21 Ocular side effects of the 22 topical CAIs include 23 24  Ocular stinging, burning 25 or discomfort [235] 26 (more common in 27 Dorzolamide) 28  Visual blurring 29 immediately after 30 31 administration of 32 brinzolamide, due to the 33 viscous suspension in 34 which it is 35 formulated[233] 36  Periorbital contact 37 38 dermatitis[236,237] 39  Allergic 40 conjunctivitis[238]. 41 Parasympathomimetics  Directly stimulate the Systemic side effects: 42 (cholinergics) muscarinic receptors of  Gastro intestinal upset 43  Direct acting the ciliary muscle Local side effects: 44 45 Pilocarpine 0.5% 1% 2% 4% resulting in widening of  46 E-Pilo® Isopto Carpine® the anterior chamber  Accommodative spasm 47 Pilagan® Pilocar® angle  Pseudomyopia 48 Pilogel® Pilomann® Pilopine®  Increase outflow  Brow ache 49 Pilopine HS gel® through the trabecular  Retinal detachment 50 Pilostat® Spersacarpine® 51 meshwork  Ciliary spasm and 52 2% increased Glaucostat®Glaunorm® 53  Pupil block 54 0.75%–3% 55 Isopto Carbachol® 56 1% 57 Miochol® 58 59  Indirect acting 60 0.125%

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1 2 3 0.25% 4 Humorsol® Tosmilen® 5 6 Ecothiophate iodide 0.03% 7 0.25% Echodide® 8 Alpha-adrenergic agonists  Decrease the secretion of Common side effects: 9 Non selective aqueous humor, and  Burning sensation 10 Dipivefrin 0.1% increasing uveoscleral immediately after 11 Propine® Epinal® d-Epifrin® 12 outflow[239,240]. application 13 Glaucothil®  May have a  Disturbances to the 14 Epinephrine 0.25% 0.5% 1.0% neuroprotective effect on conjunctiva (blanching, 15 2.0% retinal ganglion follicle development, 16 Alpha-2 selective cells[241,242] infections) 17 Apraclonidine 0.5% 1.0%  Corneal staining 18 For Peer Review Only Iopidine®  Ocular hyperaemia 19 Brimonidine 0.2% Alphagan® 20  Photophobia and taste 21 0.125% 0.25% 0.5% disturbances[31] 22 Isoglaucon® Catapres® Less common side effects: 23 Glaucopres® Aruclonin®  Bradycardia[243] 24 25  Hypotension [31] 26 Combination Therapies 27  Cosopt (timolol and 28 dorzolamide) 29  Combigan (brimonidine and 30 31 timolol) 32  Simbrinza suspension 33 (brinzolamide and brimonidine) 34  Fixed-combination 35 PGA/timolol combinations 36 including: 37 38 (0.05% latanoprost/0.5% 39 timolol, 0.0004% 40 tavoprost/0.05% timolol, 41 0.0005% tafluprost/0.5% 42 timolol). 43 Novel Agents (Rho kinase  Causes a dose-depended  Conjunctival 44 inhibitors) 45 decrease in intraocular hyperaemia[11,245], due 46 Glanatec ophthalmic solution pressure, along with an to vasodilator effect. 47 0.4% increase in trabecular  Reduction of the 48 outflow facility[244]. intraocular penetration of 49 other intraocular pressure 50 modulating drops [246]. 51 52 (Of particular importance 53 if using them in multi- 54 drop regimen) 55 56 57 58 59 60

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1 2 3 Table 2: Lasers in lowering the intraocular pressure 4 5 Type of Laser Mechanism of action 6 Laser Trabeculoplasty Increasing the outflow 7  Argon laser trabeculoplasty  Causes TM contraction and 8 (ALT) increases or ensures continuity of 9 flow in Schlemm’s canal. 10  ALT is also associated with 11 12 coagulative damage, fibrin 13 deposition and damage to the 14 trabecular beams, endothelium, 15 and subsequent TM 16 remodelling.[247,248] 17 18 For Peer Review Only 19  Selective laser trabeculoplasty  Uses a frequency-doubled, short 20 (SLT) pulse, Q-switched Nd:YAG laser 21 applied at the slit-lamp 22  Act at a cellular level by inducing 23 cytokine release,[249] matrix 24 metalloproteinase (MMP) 25 26 induction to remodel the ECM, 27 and macrophage recruitment in 28 order to clear debris.[250–252] 29  Causes little to no mechanical 30 changes in the trabecular 31 meshwork,[253,254] in contrast to 32 33 ALT. 34 35  Micropulse laser  MLT is thought to induce 36 trabeculoplasty (MLT) inflammatory cytokine release 37 and lower intraocular pressure in 38 39 a similar manner to SLT.[255] 40  The micropulse laser and longer 41 wavelength (532/577nm) provides 42 advantages over ALT by being 43 less destructive in terms of 44 collateral damage and scarring of 45 the tissues,[256] however 46 47 provides a smaller pressure- 48 lowering effect.[257] 49 Cyclophotocoagulation Reducing inflow 50 51  Transscleral  The energy of TSCPC is 52 53 cyclophotocoagulation (TSCPC) selectively absorbed by the 54 melanin-containing tissues, 55 inducing necrosis of the ciliary 56 epithelium and stroma.[258,259] 57 58  Endoscopic  Using endoscopic probe held 3- 59 60 cyclophotocoagulation (ECP) 4mm away from the ciliary

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1 2 3 processes, with the surgeon 4 applying laser energy in a semi- 5 6 continuous anterior to posterior 7 fashion, circulating around 270- 8 360 degrees ablating the visible 9 ciliary epithelium, under direct 10 endoscopic view 11 12 13  Micropulse transscleral  Micropulse laser technology is 14 cyclophotocoagulation (MP- applied directly through the sclera 15 TSCPC) and absorbed by pigmented 16 tissues. 17 For Peer Review The Only on/off cycle of micropulses 18 propagates a build-up of energy 19 20 within the target tissues, whilst 21 the surrounding tissues have a 22 chance to dissipate their energy in 23 the “off” periods, and avoid 24 reaching the coagulative 25 threshold[126], this leads to less 26 27 hypotony and inflammation.[127] 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 Table 3: Different surgical approaches 4 5 6 Type of surgery Description and mechanism 7 Trabeculectomy  A fistula with a trap 8 door is created between 9 the anterior chamber 10 and sub-tenon space at 11 12 the level of the 13 trabecular meshwork 14 (TM) to allow the build 15 up of aqueous humor to 16 flow into a small 17 For Peer Review Onlyreservoir (bleb) in the 18 superior aspect of the 19 20 globe[260] thus 21 lowering IOP.[59] 22 Tube shunts:  They are flexible 23 silicone or 24 polypropylene 25 implanted tubes that 26  Valved: Ahmed’s valve 27 o Adult model S2, drain aqueous humor 28 o Pediatric model S3 from the anterior 29 o Newer model: M4 chamber to an external 30 o Others: double plates, parsplana reservoir in the 31 subconjunctival space 32 33  Non-valved: 34 o Molteno 35 o Baerveldt 36 . 250mm2 plate 37 . 350mm2 plate 38 . Parsplana 39 40 41 Non-penetrating glaucoma surgery (NPGS) They improve aqueous drainage 42 without penetrating into the 43 anterior chamber at the time of 44 the initial surgery 45 46 47  Deep sclerectomy  It involves making a 5 × 48 5 mm superficial scleral 49 flap, then removing a 50 second scleral flap 4 × 4 51 mm beneath the original 52 to leave a residual 53 54 scleral bed of 50–100 55 microns. 56  Schlemm’s canal is de- 57 roofed. 58  Viscocanalostomy  Injecting high viscosity 59 60 sodium hyaluronate

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1 2 3 (Healon GV) into 4 Schlemm’s canal as a 5 6 means of improving 7 aqueous drainage.[187] 8  The superficial scleral 9 flap is tightly sutured so 10 aqueous reach the two 11 surgically created ostia 12 13 of Schlemm’s canal, 14 travel circumferentially 15 within the canal and 16 enter the collector 17 For Peer Review Onlychannels and then the 18 aqueous veins. 19 20 21 Express shunt (Alcon Laboratories, Inc., Fort  It is a stainless-steel 22 Worth, TX) non-valved shunt 23 implanted under the 24 scleral flap and to drain 25 aqueous humor from the 26 27 AC to an intrascleral 28 space 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 Table 4: Minimally invasive glaucoma devices 4 5 Mechanism of Devices that meet the Devices that doesn’t meet 6 action definition of MIGS the definition of MIGS 7 The trabecular based Canal based (trabecular Canal based includes: 8 devices work by microbpass stents)  Ab interno 9 improving trabecular trabeculectomy: 10 outflow through  Glaukos iStent Trabectome 11 Schlemm’s canal 12 (Glaukos Corp., (NeoMedix, Tustin, 13 Laguna Hills, CA, CA, USA) 14 USA) 15  Ab interno 16  Hydrus (Ivantis Inc., trabeculotomy: 17 Irvine, CA, USA) iScience catheter 18 For Peer Review Only 19 20 21 The suprachoroidal- Suprachoroidal based (Ab Suprachoroidal based (Ab 22 based devices interno suprachoroidal externo suprachoroidal stents): 23 improve the stents) 24 uveoscleral outflow  Solx Gold Shunt 25 26 by connecting the  Glaukos iStent supra (SOLX, Waltham, 27 anterior chamber and (Glaukos Corp., MA, USA) 28 the suprachoroidal Laguna Hills, CA, 29 space USA) 30 31  Transcend CyPass 32 33 (Alcon, Fort Worth, 34 TX, USA) 35 36 The subconjunctival Subconjunctival based which Subconjunctival based (Ab 37 devices create an includes: externo transscleral filtration 38 alternative outflow devices): 39 40 pathway of the  Ab interno 41 aqueous humor to transscleral filtration  ExPress shunt (Alcon 42 the subconjunctival devices (Aquesys Laboratories, Inc., Fort 43 space.[261,262] Xen) (Allergan, Worth, TX) 44 Dublin, Ireland) 45 46 47  Ab externo 48 transscleral filtration 49 devices (InnFocus 50 Microshunt) (Santen 51 Pharmaceutical 52 Company Ltd, 53 Osaka, Japan) 54 55 56 57 58 59 60

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1 2 3 Table 5: Description of the most commonly used Minimally invasive glaucoma 4 devices. 5 6 Device Description 7 iStent  A heparin-coated, 8 nonferromagnetic titanium device 9 with a snorkel shape that is 10 implanted into Schlemm’s canal 11 12 (SC) 13 Hydrus  This is a crescent-shaped 14 trabecular bypass device made of 15 nitinol, a shape-memory alloy, 16 which when deformed, returns to 17 its original shape after being 18 For Peer Review Only 19 heated. 20  It measures 8 mm long, straddling 21 3 clock hours of SC. 22  It acts as a scaffold so that it does 23 not block the collector channel 24 ostia. 25 26 27 The CyPass  It is a polyamide implant, 6.35 28 mm in length and 510 µm in 29 external diameter t 30  Connects between the anterior 31 32 chamber and the supraciliary 33 space through the microholes 34 placed along its length. 35  The collar of the device rests in 36 the anterior chamber angle[263] 37 38 39 XEN Gel Stent  It is an ab interno gelatin stent 40  It is 6 mm in length and 41 composed of porcine gelatin 42 crosslinked with glutaraldehyde. 43  Three models with inner 44 45 diameters of 45, 63 and 140 46 µm,[209] with 45 µm being 47 recommended by the 48 manufacturer 49 InnFocus  It is an ab externo drainage device 50 51  Formed of SIBS (polystyrene- 52 blockisobutylene-block-styrene), 53 which is a biocompatible and 54 biostable thermoplastic elastomer 55 56 57 58 59 60

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