Emerging Trends in Glaucoma Research

Glaucoma is the leading cause of irreversible vision loss globally and in Australia.¹ Lowering the intraocular pressure (IOP) has been shown in randomised controlled trials to reduce the incidence and progression of glaucomatous field loss,² and at present this remains the only proven strategy for managing glaucoma.

MIGS offers moderate IOP lowering with a strong safety profile

The ideal IOP lowering treatment should be effective, simple to administer, symptom free, low risk, with a high success rate, and long duration of action. Glaucoma management still awaits this panacea. However our developing understanding of aqueous outflow and the mechanisms of trabecular dysfunction are leading to improved therapeutic options for patients with glaucoma.

Eye drops have been the central pillar of IOP lowering treatment, with drainage surgery a successful option when the risk of vision loss outweighs the risk of surgical complications. The critical limitations of eye drops are adherence and intolerance which cause a significant burden on our patients.³ Novel drug targets and delivery options, laser trabeculoplasty, and new surgical devices including Minimally Invasive Glaucoma Surgery (MIGS) have shifted the management spectrum available to patients suffering from glaucoma, and from the side effects of its treatment.

MIGS

We have an increasing understanding of the physiology of the aqueous outflow pathways, particularly the deposition of extracellular matrix and loss of trabecular meshwork (TM) cells, and the contractile properties and stiffness of the inner TM wall and Schlemms canal (SC).^4,5 Localisation of the site of outflow resistance to the inner wall of the TM and SC has led to surgical approaches to bypass or augment this pathway. This has informed the clinical success of trabecular bypass using MIGS. The general characteristics of MIGS are an ab-interno approach (from inside the eye) through a small corneal incision such as routinely used in cataract surgery, minimal tissue trauma, with no (or at least very minimal) conjunctival manipulation.⁶

Anatomically MIGS devices may act:

1. Across the trabecular meshwork to improve aqueous outflow, eg. iStent, iStent inject, Hydrus, trabectome, ab-interno canaloplasty (ABiC),
2. Into the suprachoroidal space, to divert aqueous to alternate potential spaces within the eye, eg. Cypass micro-stent, iStar Miniject, iStent Supra,
3. At the ciliary processes to reduce aqueous production, eg. endocyclophotocoagulation (ECP), and
4. Devices which access the subconjunctival space, resulting in a drainage bleb have been described as MIGS-plus, eg. Xen Glaucoma Gel Microstent (Xen-GGM), InnFocus.

Compared with traditional glaucoma drainage surgery, MIGS offers moderate IOP lowering with a strong safety profile. A transient IOP spike is the most common complication occurring in between 1–21 per cent, but this rarely has a serious impact on the patient. A recent metaanalysis found no cases of infection or loss of best corrected visual acuity (BCVA) from glaucoma in over 2,928 eyes.⁶ However there have been recent reports of endophthalmitis associated with the Xen-GGM,^7,8 and endothelial cell loss with the Cypass microstent, which highlights the need for longer term safety and efficacy data to further define the role of MIGS in the management of glaucoma.

MIGS are currently supported by the Medicare Benefits Schedule (MBS) in Australia for use in conjunction with cataract surgery. Multiple trials have demonstrated their benefit as a standalone procedure, but unfortunately the current MBS code limits patients’ access to this solution. The impact of trans-trabecular MIGS may be highlighted by the rapid uptake of MIGS combined with cataract surgery across the country (Table 1), and their introduction to the public system in many areas.

TRANS-TRABECULAR MIGS

iStent inject (Glaukos Corporation, CA, USA) is the smallest stent inserted anywhere in the human body, measuring 0.36mm in length.

Fea et al found that two iStent inject stents were at least as effective as two medications (fixed combination latanoprost/timolol) with a reduction in medication burden. The average IOP dropped from 21.1 ± 1.7mmHg (baseline IOP after washout of all medications was 25.2 ± 1.4mmHg) to 13.0 ± 2.3mmHg one year after surgery.⁹

Patients whose traditional glaucoma drainage surgery has failed may also benefit from trabecular bypass stenting. A retrospective, open-label, non-randomised study found that patients who had two iStent inject stents placed after failing one previous glaucoma filtration surgery had a mean IOP reduction from 23.8 mmHg ± 3.9 (SD) to 15.2 ± 2.7 mmHg at one year post-surgery, and those who failed more than one filtration surgery decreased from 26.1 ± 5.7 mmHg to 16.3 ± 3.3 mmHg.¹⁰

Hydrus Microstent (Irvine, CA, USA) dilates and scaffolds the Canal of Schlemm along one quarter of the anterior chamber angle (Figure 2). The 8mm long nickel-titanium device is curved to match the anatomy of the angle, and designed to provide support for aqueous egress from a greater number of collector channels (Figure 3).

A prospective interventional case-series of 56 patients comparing SLT to the Hydrus microstent found similar effective reductions in IOP, but a threefold greater reduction in medication requirements in the Hydrus group.¹¹ There were no complications for those undergoing SLT, and minimal complications with Hydrus, including three transient vision reductions and two transient IOP spikes after surgery.

SUPRACHOROIDAL MIGS STENTS

The value of the suprachoroidal space as a target for aqueous outflow has been demonstrated in the effectiveness of prostaglandin analogues which enhance the uveoscleral pathway. Surgical approaches to enhancing suprachoroidal aqueous outflow have been proposed for over a century, but recent advances in biocompatible materials have improved the chances of success.¹²

The early data from MIGS are very encouraging in offering patients significant IOP lowering, rapid recovery, and an alternative to drop dependency

CyPass Micro-Stent (Alcon, Fort Worth, Texas, USA) is a 6.35mm polyamide tube with a 300micron internal lumen and 64 fenestrations (Figure 4). It is inserted ab interno into the potential space between the sclera and ciliary body and shunts fluid into this suprachoroidal space.

While the early data seemed promising in terms of IOP lowering,¹³ Cypass was recently withdrawn from the market voluntarily by Alcon after the five year results revealed a greater rate of endothelial cell loss (ECL) amongst patients with the stent than those with cataract surgery alone. Notably, patients with optimally positioned stents did not have a statistically higher rate of ECL than control patients, but the rate of ECL increased the further into the anterior chamber the stent was visible.¹⁴

iStar Miniject has just released promising interim results from its first human trial. This suprachoroidal stent is made from a flexible bio-integratable medical grade silicone. The prospective, open-label study of 25 patients reported an average 39 per cent IOP reduction with no serious adverse events at six months. The study will be completed at two-years. (https://clinicaltrials.gov/ct2/ show/study/NCT03193736).

SUBCONJUNCTIVAL MIGS-PLUS

MIGS-plus procedures access the subconjunctival or subtenon space and appear to achieve lower IOP than other MIGS. They are indicated for moderate to severe glaucoma, compared with most MIGS which are targeted to mild to moderate disease. The main failure risk in drainage surgeries targeting the subconjunctival space for both traditional and MIGS-plus is scarring due to the activation of fibroblasts that can obstruct aqueous outflow. These surgeries are quicker to perform than a traditional trabeculectomy, have less manipulation of ocular tissues, and probably have less intensive follow up requirements, however a recent Cochrane review highlighted the need for better designed RCTs to assess both efficacy and safety.¹⁵

Xen Glaucoma Gel Microstent (Xen- GGM, Allergan Plc., Parsippany, NJ, USA) is a 6mm long flexible stent inserted ab-interno from the anterior chamber angle into the subconjunctival space. It is made from a biocompatible, cross-linked, porcine collagen. It does not require any conjunctival incision, compared with the extensive dissection required for trabeculectomy, but rather is made through a small corneal incision (Figure 6).

The four year results of the APEX trial have just been published. This prospective, non-randomised, multi-centre study of 64 consecutive patients with open angle glaucoma (OAG) who had Xen-GGM inserted without mitomycin C found a 40 per cent reduction in mean best-medicated IOP (22.5±4.2 mmHg to 13.4±3.1 mmHg, n=34, p<0.001). Medication usage decreased 50 per cent (2.4±1.3 to 1.2±1.3) postoperatively. Surgical failure rate was 10 per cent per year, comparable to established drainage surgeries.¹⁶

InnFocus microshunt (Santen Pharmaceutical Company Ltd, Osaka, Japan) is an ab externo drainage device, which is inserted after initial surgical steps similar to a trabeculectomy. It is constructed from a thermoplastic elastomer called SIBS (polystyrene-blockisobutylene- block-styrene). A prospective trial of 889 patients randomised to InnFocus or traditional trabeculectomy is due to be completed this year (visit https:// clinicaltrials.gov/ct2/show/NCT01881425). The early data from MIGS are very encouraging in offering patients significant IOP lowering, rapid recovery, and an alternative to drop dependency. However the novelty of these procedures, and the recent experience of Cypass endothelial cell loss and Xen endophthalmitis cases highlight that longer term safety and efficacy data is needed to help define the role of MIGS in the future of glaucoma management.

CLINICAL PHARMACOLOGY RESEARCH UPDATE

Contemporary research into pharmacological glaucoma management has targeted limitations of topical therapy with extra- and intra-ocular sustained release dosing. This may offer simplified adherence for our patients, while delivering a more sustained bioavailable dose than the peak and trough levels currently available with drops. Sustained-release (SR) glaucoma medications are currently only available in a clinical trial setting.

EXTRAOCULAR SR MEDICATIONS

Extraocular SR dosing currently under investigation includes:

• Punctal plugs – latanoprost and bimatoprost,
• Canalicular inserts – travoprost, and
• Periocular rings – bimatoprost.⁵

INTRAOCULAR SR MEDICATIONS

The success and safety of anti-VEGF intravitreal injections have paved the way for intraocular SR dosing of glaucoma medications. This route offers direct access to pharmacological target sites and avoids release of medications onto the ocular surface, thereby potentially minimising many of the adverse effects of topical medications. However, macular degeneration is symptomatic when intravitreal injections are indicated, while mild to moderate glaucoma is a relatively asymptomatic condition, and therefore intraocular injections are less likely to be acceptable to many glaucoma patients.

Intraocular SR systems currently under investigation include:

• Intracameral rods: bimatoprost, travoprost, and latanoprost

These devices are injected into the anterior chamber, to sit in the inferior angle. The ARTEMIS trial of bimatoprost SR for open angle glaucoma and ocular hypertension has just completed primary data collection and final results are planned for release in 2020 (visit https://clinicaltrials.gov/ct2/ show/study/NCT02250651).

The final data for the ATHENA trial randomising patients to intracameral bimatoprost or SLT with a sham control for each arm was collected in December 2019 (visit https://clinicaltrials.gov/ct2/show/ record/NCT02507687).

A phase 1/2 study of intracameral bimatroprost compared with topical administration found similar IOP lowering but a lower incidence of conjunctival hyperaemia (6.7 per cent vs 17.3 per cent) and eyelash growth (0 per cent vs 2.6 per cent).¹⁷

• Subconjunctival liposomal depot, rod or insert: latanoprost

Compared to intracameral devices, these offer a less invasive delivery, but higher ocular surface effects, and less direct target tissue delivery.

• Scleral-anchored implant: travoprost

The current clinical trials for scleralanchored implantable drugs have targeted mild to moderate open-angle glaucomas.⁵ Long term safety and efficacy data, lower cost and a longer interval between dosing requirements are likely to be the drivers of patient and eye care provider acceptability for these options.¹⁸

NEW CLASSES OF TOPICAL GLAUCOMA MEDICATIONS

We currently have access to five main classes of topical glaucoma therapy: beta blockers, prostaglandin F2alpha analogues, carbonic anhydrase inhibitors, sympathomimetics (alpha agonists), and cholinergic agonists (miotics like pilocarpine). Novel glaucoma drugs, including a completely new drug class, have emerged with promising Phase 2/3 clinical trial results:

1. Rho kinase inhibitors (repasudil and netarsudil)
2. Nitric oxide donors (latanoprostene bunod)

Both of these agents are thought to act directly at the trabecular meshwork to increase outflow facility.⁵

The development of rho kinase inhibitors demonstrates an elegant translation of laboratory physiology to clinical medicine. In 1993, physiologists Geiger and Kaufman began a collaboration which identified cytoskeletally active elements in the trabecular meshwork which could decrease aqueous humour outflow resistance. This prompted further study into the cellular mechanisms mediating this process, including the role of rho kinase. Rho kinase was found to increase the contractility and rigidity of cells, while regulating cellular processes like movement and contraction of smooth muscle.¹⁹ While no rho kinase inhibitor has proven superior to currently available first line therapies, they do appear to have an additive effect when used in combination. Repasudil is approved in Japan as an adjunctive agent. Netarsudil has additional pharmacologic actions compared with other rho kinase inhibitors, including reducing aqueous production and episcleral venous pressure in animal studies. It was non-inferior to timolol amongst patients with IOP <25mmHg.²⁰ The main reported adverse events have been conjunctival hyperaemia and corneal verticillata with an incidence currently higher than other agents.

Latanoprostene bunod (LBN) is metabolised to nitric oxide (NO) and latanoprostic acid. NO has been shown to relax ciliary smooth muscle and trabecular meshwork,²¹ and increase outflow facility of the distal outflow tract independent of the trabecular meshwork in a porcine model.²² LBN 0.24 per cent daily demonstrated superior IOP lowering to timolol 0.5 per cent bd in Phase 3 randomised, controlled, multicenter, double masked, parallel group clinical studies.^23,24

Innovation and research in clinical pharmacology, namely new drug delivery systems and classes of IOP lowering agents, are building a greater armamentarium to tailor management for our patients, and provide hope for improving outcomes in the future.

MECHANISMS OF GANGLION CELL DEATH: TREATMENT OPTIONS IN THE FUTURE

At its heart, glaucoma is a disease of accelerated aging and apoptosis and has much in common with other neurodegenerative conditions. Why retinal ganglion cells choose to die at a faster rate than normal aging is complex and multifactorial (Figure 7). This makes targeting specific risk factors and pathways to halt or slow this process particularly difficult.

It has been known for some time that raised intraocular pressure (IOP) is one of many risk factors for glaucoma, but to date controlling IOP is still the only reliable and validated way to slow or halt visual loss associated with glaucoma. This is probably why some glaucoma patients continue to progress despite well controlled IOP, leading to lifetime monocular blindness rates of around 40 per cent with around 15 per cent bilaterally blind.^25,26

Many in vitro or clinical neuroprotective studies attempting to modify non IOP related risk factors have either shown negative results or suggested them by not providing results at all.^27,28 The only successful trial to show a neuroprotective effect of a drug in glaucoma, the Low Pressure Glaucoma Treatment Study, showed that, over a 30 month period, patients treated with brimonidine had a significantly lower rate of visual field defect progression compared to subjects treated with timolol, despite similar IOPs.⁹ However this study’s significance is far from clear – does it reflect a neuroprotective effect of brimonidine or a detrimental effect of topical beta blockers? This paper has had its results questioned in two Cochrane reviews.^30,31 It may well be that some of the small effects of potential neuroprotective agents have been missed in previous trials and the emergence of new trial methodology and diagnostic techniques may reveal hitherto unknown neuroprotective effects.^32,33

Over the last few years there has been a greater understanding of the role of genetic pathways in the pathogenesis of glaucoma. Prior to this year, 14 genetic loci had been uncovered by Genome Wide Association Studies (GWAS) as being associated with increased risk of having glaucoma. They were, TMCO1, CDKN2B-AS1, SIX6, CAV1, CAV2, ABCA1, AFAP1, GMDS, ARHGEF12, TXNRD2, ATXN2, and FOXC1 and TGFBR3.34-43 In 2018 12 new loci were discovered.^41,42 It is unclear what the functionality of these loci are or what precise role they play in the pathogenesis of glaucoma. To quote the well-known aphorism: “correlation is not causality”. Additionally, it is unlikely that in any one patient, one of these genetic variants on its own is causative of glaucoma. The interaction between these regions is complex but can be mapped with simple freely accessible programs like Genebunny.^44,43 By mapping these interactive pathways more precisely we may be able to identify regions where multiple risk forming pathways converge. We may also be able to identify where the genetic region has a product that can be modified or targeted to arrest the molecular cascade that leads to glaucoma related apoptosis and eventually vision loss.

Already there has been much work on genetic modification, principally via viral vectors, on targeting areas that produce innate neuroprotective factors and halt mitochondrial dysfunction. In animal models they seem to have effect, particularly when multiple approaches are used. Human trials are also beginning on some of the more promising candidates.⁴⁴ Some of the most promising work is related to addressing the mitochondrial dysfunction associated with Lebers hereditary optic neuropathy as mitochondrial dysfunction can also play a role in glaucoma pathogenesis. With appropriate therapy, there was recovery one year after documented visual loss.⁴⁴ Experimental models and a human trial have also shown that visual loss from glaucoma can at least temporarily be recovered.^46,47

As we begin to understand the complexity of glaucoma in all of its forms we are beginning to harness new technologies that address the apoptosis of retinal ganglion cells which underlies glaucomatous visual loss. It is becoming clear that there is no single process but rather a combination, and the study of the interaction of various genetic and environmental factors is becoming increasingly important. Through a combination of genetic modification and targeted pharmacotherapy we may be able to develop new effective therapies for glaucoma, possibly ‘tailor made’ depending on genetic and environmental traits specific to each patient. New trial designs and diagnostic technologies will enable the evaluation of these treatments to be quicker and more reliable than previously possible. It will take some time but the building blocks for this new approach are in place.

GLAUCOMA AND OCULAR CO-MORBIDITIES

Several ocular co-morbidities occur commonly in conjunction with glaucoma, and can have a significant quality of life (QoL) impact for people with glaucoma. Such conditions include ocular surface disease/blepharitis, cataract, and age related macular degeneration. In many cases, particularly in people with mild optic nerve damage, these conditions have a greater impact on daily function than glaucoma itself.

Research over the past decade has focused on these co-morbidities in the context of glaucoma, and how we can modify or improve suffering from such conditions. Unlike glaucoma, some of these conditions are potentially reversible, if diagnosed and managed appropriately.

Ocular Surface Disease and Glaucoma 

Ocular surface disease (OSD) occurs in up to 59 per cent of people with glaucoma.^48,49 OSD is one of the biggest contributors to poor QoL in glaucoma, with flow on effects contributing to decreased adherence and potentially, glaucoma progression.⁵⁰ Bad OSD associated with topical medical therapy (especially with multiple daily drops) in glaucoma is the reason why there has been recent focus on new drop free treatment technologies such as minimally invasive glaucoma surgery (MIGS) and drug delivery depot preparations.^51,52

OSD is due to a variety of factors including drop preservative related surface toxicity, proinflammatory tear film cytokines and hyperosmolarity, meibomian gland dysfunction, and eyelid malposition. In particular, the commonly used preservative benzalkonium chloride (BAK), important in prolonging the shelf life of opened medication bottles with its anti-microbial and anti-fungicidal properties, reduces the stability of the pre-corneal tear film, with direct toxicity to the ocular surface (Figure 8).^53,54 This has been shown in vitro and in vivo in animal and human studies.^55-57 Female gender, increased age, duration of glaucoma therapy, and the number of drops of preservative per day are all risk factors for OSD in glaucoma.⁵⁸

All classes of topical IOP lowering medications can cause or exacerbate underlying ocular surface discomfort,^58-60 and can be associated with irreversible structural changes to the meibomian glands when used long term.⁶¹ This can result in reduced treatment adherence.50,62 In fact improvement of OSD for people treated with glaucoma medication can result in improved IOP control;⁶³ this may reflect less ocular surface inflammation, improving topical medication absorption, better treatment adherence in comfortable eyes, or reduction of a direct toxic effect of the preservative on the trabecular meshwork.⁶⁴ Topical medications result in elevated levels of inflammatory tear film cytokines; these are associated with scarring post trabeculectomy and trabeculectomy failure.^54,65

Much can be done to help glaucoma patients suffering from OSD.^66,67 Preservative free lubricants, lid hygiene, dietary intake (e.g. food containing omega 3 fatty acids) can help.^68,69 In select cases, punctual plugs or cyclosporin drops can be beneficial.^70,71 Combination IOP lowering drop preparations, preservative free preparations, and judiciously ceasing glaucoma medications when not needed are good therapeutic options for people with glaucoma and OSD.

As mentioned above, drop free options – notably selective laser trabeculoplasty (SLT and MIGS) – are now available to control the IOP in a way that is more gentle to the ocular surface. This is especially relevant for patients with OSD.

SLT (Figure 9) is a safe and effective alternative to drops.72 SLT does not have an adherence burden, but it is imperative that patients are appropriately monitored as the effect of SLT wears off over time. SLT lasts on average 3.5–4 years, and is often repeatable.

CATARACT AND GLAUCOMA

Cataract is commonly found with glaucoma for various reasons – both conditions are common with age, and they often have linked pathophysiology (e.g. angle closure). Cataract formation is often hastened by medical or surgical treatments for glaucoma.⁷³

Glare, reduced night time vision, need for increased lighting when reading, and general visual decline are common symptoms of cataracts among people with glaucoma. Many population based glaucoma studies have documented the additive visual impact of cataracts to glaucoma – such as the Blue Mountains Eye Study, Barbados Eye Study, Los Angeles Latino Eye Study, and Advanced Glaucoma Intervention Study.^73-76 Cataracts are a significant (and thankfully reversible) burden of visual dysfunction among people with glaucoma; even in cases of advanced glaucomatous disc damage, cataract surgery can potentially be a useful intervention.⁷⁷

The central mechanical role of the crystalline lens in the pathophysiology of angle closure was recently highlighted in the EAGLE study. This multi-centre trial randomised 419 patients with primary angle closure (PAC) glaucoma, and without a cataract, to have traditional care with a laser peripheral iridotomy (LPI) and topical medical therapy or clear lens extraction (CLE). It found CLE was more efficacious and cost effective than LPI, with patient reported health status on the European Quality of Life-5 Dimensions questionnaire 0.052 higher (95 per cent CI 0.015-0.088, p=0.005) and mean IOP 1.18mmHg lower (95 per cent CI -1.99 to -0.38, p=0.004) with CLE. Irreversible vision loss affected one patient after CLE and three after LPI.⁷⁸

There are several specific considerations when performing cataract surgery for people with glaucoma:

1. While prostaglandin analogues may increase the risk of post-operative cystoid macular oedema (CMO), they are generally not ceased pre-operatively except in high risk cases. Risk factors for CMO need to be considered prior to cataract surgery for patients using prostaglandin analogues.
2. As many glaucoma patients have OSD, optimisation of the ocular surface prior to biometry and cataract surgery is important to maximise refractive outcomes, and minimise surface discomfort post-operatively.
3. Pseudoexfoliation (PXF), a common cause of secondary OAG, might be present and can make cataract surgery challenging – weakened zonules, a small pupil, and increased risk of a post-operative IOP spike are associated with PXF. A meticulous and gentle surgical technique and careful removal of all viscoelastic at the case end is necessary; occasionally iris dilation rings or capsular supports are required.
4. Narrow angles associated with shallow anterior chambers can increase the risk of iris prolapse early in the operation or capsular bag shallowing later. Careful technique is required to avoid and/or manage these potential problems.
5. Meticulous post-operative IOP monitoring for all glaucoma patients undergoing cataract surgery is important.
6. MIGS should be considered when people with glaucoma undergo cataract surgery. The added improvement in IOP control and potential to cease topical medication are important therapeutic goals that MIGS offers in addition to conventional cataract surgery.

AGE RELATED MACULAR DEGENERATION AND GLAUCOMA

Age related macular degeneration (AMD) and glaucoma are both common conditions associated with ageing. The incidence of AMD can vary from 5-40 per cent among glaucoma cohorts.^79,80 Both conditions can reduce contrast sensitivity and have an effect on essential visual functions like light/dark adaptation,⁸¹ reading,^82-84 hazard detection while driving,⁸⁵ and recognising faces.⁸⁶ Visual loss from either condition can lead to social isolation from impaired driving and loss of independence.^87-89 When daily functions were specifically evaluated among a cohort with both AMD and glaucoma, patients with both conditions perceived increased difficulty walking safely compared to patients with glaucoma alone.⁹⁰ It is important to offer such patients access to visual disability services that might provide assistance through supportive devices or home modification.

People with AMD receiving regular intravitreal anti-vascular endothelial growth factor (VEGF) injections can develop IOP spikes and occasionally sustained elevated IOP. This appears to be more common among people with pre-existing ocular hypertension or glaucoma, and among those with an extended duration of anti- VEGF treatment.^91,92 The pathophysiology is incompletely understood: mechanisms proposed include obstruction of the conventional outflow pathway by foreign particles, protein aggregates or local inflammation, chronic angle closure, mechanical trauma, toxicity from repeated injections or a direct effect of VEGF on outflow facility.^93-96

 PSYCHOSOCIAL FACTORS THAT INFLUENCE QOL IN GLAUCOMA

Many other factors can influence QoL among glaucoma patients. Mental health issues such as depression and anxiety, common among any sufferer of chronic neurological disease, have increased prevalence in glaucoma and have a large impact on glaucoma related QoL.^97,98 Education level, glaucoma knowledge, socioeconomic factors, access to health services, and family support can all influence how a person perceives their condition, how it is treated, and ultimately how it influences their life.^99,100 Further research to understand such factors, and how we can modify them, is important to improve patient related outcomes in glaucoma healthcare delivery.

CONCLUSION

Better outcomes for people with glaucoma can be achieved through the development and application of new technologies to improve clinical service delivery. As clinicians we must keep abreast of new developments and trends in clinical practice, and translate the new knowledge and experience into better glaucoma care for all.

To earn your CPD points from this article, answer the assessment available at mivision.com.au/ emerging-trends-in-glaucoma-research 

Dr Hamish Dunn is an ophthalmologist with subspecialty training in glaucoma and oculoplastics. He worked with UNICEF in Guyana, South America prior to medicine. His PhD research is developing optimised ways for non-experts to examine the fundus, and he is actively involved in clinical glaucoma research. Dr Dunn is Chair of the Glaucoma Australia, Expert Advisory Panel and a member of the Local Organising Committee for the World Glaucoma Conference in Melbourne 2019. He has clinical teaching and research affiliations with Westmead Hospital, the University of Sydney and University of NSW. 

Clinical Associate Professor Andrew White is a clinician scientist ophthalmologist at Westmead Hospital with a subspecialty interest in glaucoma. He is a Clinical Senior Lecturer and has research affiliations with the University of Sydney at both the Save Sight Institute and Westmead Millennium Institute where he has an active laboratory. Clin.Assoc. Prof. White has multiple peer-reviewed scientific publications and published conference abstracts. He is a regular invited speaker at overseas conferences and is actively involved in training medical students, registrars and fellows in cataract and glaucoma. He also lectures optometrists and optometry students in Glaucoma. 

Dr Simon Skalicky FRANZCO, PhD, BSc (Med), MPhil, MMed, MBBS (Hons 1) is a Victorian ophthalmologist with subspecialty skills in glaucoma and cataract surgery. 

A University of Melbourne senior lecturer, he has published widely and remains actively involved in medical student teaching and RANZCO specialist training of ophthalmology registrars and glaucoma subspecialty fellows. Dr Skalicky is an active clinical glaucoma researcher, particularly interested in optimising patients’ treatment experience and their quality of life. 

Dr Skalicky is a strong patient advocate at a national and international level. He serves as federal Councillor and Chair of the Ophthalmology Committee for Glaucoma Australia and Victorian representative for the Australia and New Zealand Glaucoma Society. He serves on the Scientific Program Committee for the World Glaucoma Conference. 

References 

1. Dirani M, Crowston JG, Taylor PS, Moore PT, Rogers S, Pezzullo ML, et al. Economic impact of primary open-angle glaucoma in Australia. Clin Exp Ophthalmol. 2011;39(7):623-32.
2. Heijl A, Leske MC, Bengtsson B, Hyman L, Bengtsson B, Hussein M, et al. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol. 2002;120(10):1268-79.
3. Society APG. Asia Pacific Glaucoma Guidelines. Amsterdam, The Netherlands: Kugler Publications; 2016.
4. 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. Progress in molecular biology and translational science. 2015;134:301-14.
5. Adams CM, Stacy R, Rangaswamy N, Bigelow C, Grosskreutz CL, Prasanna G. Glaucoma – Next Generation Therapeutics: Impossible to Possible. Pharmaceutical research. 2018;36(2):25.
6. Lavia C, Dallorto L, Maule M, Ceccarelli M, Fea AM. Minimally-invasive glaucoma surgeries (MIGS) for open angle glaucoma: A systematic review and meta-analysis. PLoS ONE. 2017;12(8):e0183142.
7. Karri B, Gupta C, Mathews D. Endophthalmitis Following XEN Stent Exposure. J Glaucoma. 2018;27(10):931-3.
8. Olgun A, Imamoglu S, Karapapak M, Duzgun E, Kacar H. Endophthalmitis After XEN Gel Stent Implantation: 2 Cases. J Glaucoma. 2018;27(12):e191-e4.
9. Fea AM, Belda JI, Rekas M, Junemann A, Chang L, Pablo L, et al. Prospective unmasked randomized evaluation of the iStent inject ((R)) versus two ocular hypotensive agents in patients with primary open-angle glaucoma. Clin Ophthalmol. 2014;8:875-82.
10. Macher T, Häberle H, Wächter J, Thannhäuser C, Aurich H, Pham D-T. Trabecular microbypass stents as minimally invasive approach after conventional glaucoma filtration surgery. Journal of Cataract & Refractive Surgery. 2018;44(1):50-5.
11. Fea AM, Ahmed, II, Lavia C, Mittica P, Consolandi G, Motolese I, et al. Hydrus microstent compared to selective laser trabeculoplasty in primary open angle glaucoma: one year results. Clin Exp Ophthalmol. 2017;45(2):120-7.
12. Vinod K. Suprachoroidal shunts. Curr Opin Ophthalmol. 2018;29(2):155-61.
13. Vold S, Ahmed, II, Craven ER, Mattox C, Stamper R, Packer M, et al. Two-Year COMPASS Trial Results: Supraciliary Microstenting with Phacoemulsification in Patients with Open-Angle Glaucoma and Cataracts. Ophthalmology. 2016;123(10):2103-12.
14. Lane S, editor Overview of the results from the 5 year follow-up of the Cypass Microstent. ESCRS; 2018 Sept. 24; Vienna.
15. King AJ, Shah A, Nikita E, Hu K, Mulvaney CA, Stead R, et al. Subconjunctival draining minimally-invasive glaucoma devices for medically uncontrolled glaucoma. The Cochrane database of systematic reviews. 2018;12:Cd012742.
16. Lenzhofer M, Kersten-Gomez I, Sheybani A, Gulamhusein H, Strohmaier C, Hohensinn M, et al. Four-year results of a minimally invasive transscleral glaucoma gel stent implantation in a prospective multicenter study. Clin Exp Ophthalmol. 2018.
17. Lewis RA, Christie WC, Day DG, Craven ER, Walters T, Bejanian M, et al. Bimatoprost Sustained-Release Implants for Glaucoma Therapy: 6-Month Results From a Phase I/II Clinical Trial. Am J Ophthalmol. 2017;175:137-47.
18. Ozdemir S, Wong TT, Allingham RR, Finkelstein EA. Predicted patient demand for a new delivery system for glaucoma medicine. Medicine (Baltimore). 2017;96(15):e6626.
19. Tanna AP, Johnson M. Rho Kinase Inhibitors as a Novel Treatment for Glaucoma and Ocular Hypertension. Ophthalmology. 2018;125(11):1741-56.
20. Serle JB, Katz LJ, McLaurin E, Heah T, Ramirez-Davis N, Usner DW, et al. Two Phase 3 Clinical Trials Comparing the Safety and Efficacy of Netarsudil to Timolol in Patients With Elevated Intraocular Pressure: Rho Kinase Elevated IOP Treatment Trial 1 and 2 (ROCKET-1 and ROCKET-2). Am J Ophthalmol. 2018;186:116-27.
21. Cavet ME, Vittitow JL, Impagnatiello F, Ongini E, Bastia E. Nitric oxide (NO): an emerging target for the treatment of glaucoma. Invest Ophthalmol Vis Sci. 2014;55(8):5005-15.
22. Waxman S, Wang C, Dang Y, Hong Y, Esfandiari H, Shah P, et al. Structure–Function Changes of the Porcine Distal Outflow Tract in Response to Nitric Oxide. Investigative Ophthalmology & Visual Science. 2018;59(12):4886-95.
23. Weinreb RN, Scassellati Sforzolini B, Vittitow J, Liebmann J. Latanoprostene Bunod 0.024% versus Timolol Maleate 0.5% in Subjects with Open-Angle Glaucoma or Ocular Hypertension: The APOLLO Study. Ophthalmology. 2016;123(5):965-73.
24. Weinreb RN, Liebmann JM, Martin KR, Kaufman PL, Vittitow JL. Latanoprostene Bunod 0.024% in Subjects With Open-angle Glaucoma or Ocular Hypertension: Pooled Phase 3 Study Findings. J Glaucoma. 2018;27(1):7-15.
25. Peters D, Bengtsson B and Heijl A. Lifetime risk of blindness in open-angle glaucoma. Am J Ophthalmol. 2013; 156: 724-30.
26. Malihi M, Moura Filho ER, Hodge DO and Sit AJ. Long-term trends in glaucoma-related blindness in Olmsted County, Minnesota. Ophthalmology. 2014; 121: 134-41.
27. Baltmr A, Duggan J, Nizari S, Salt TE and Cordeiro MF. Neuroprotection in glaucoma – Is there a future role? Exp Eye Res. 2010; 91: 554-66.
28. Weinreb RN, Liebmann JM, Cioffi GA, et al. Oral Memantine for the Treatment of Glaucoma: Design and Results of 2 Randomized, Placebo-Controlled, Phase 3 Studies. Ophthalmology. 2018; 125: 1874-85.
29. Krupin T, Liebmann JM, Greenfield DS, Ritch R, Gardiner S and Low-Pressure Glaucoma Study G. A randomized trial of brimonidine versus timolol in preserving visual function: results from the Low-Pressure Glaucoma Treatment Study. Am J Ophthalmol. 2011; 151: 671-81.
30. Sena DF and Lindsley K. Neuroprotection for treatment of glaucoma in adults. The Cochrane database of systematic reviews. 2017; 1: CD006539.
31. Sena DF and Lindsley K. Neuroprotection for treatment of glaucoma in adults. The Cochrane database of systematic reviews. 2013: CD006539.
32. Garway-Heath DF, Crabb DP, Bunce C, et al. Latanoprost for open-angle glaucoma (UKGTS): a randomised, multicentre, placebo-controlled trial. Lancet. 2015; 385: 1295-304.
33. Yucel YH and Gupta N. A framework to explore the visual brain in glaucoma with lessons from models and man. Exp Eye Res. 2015; 141: 171-8.
34. Thorleifsson G, Walters GB, Hewitt AW, et al. Common variants near CAV1 and CAV2 are associated with primary open-angle glaucoma. Nat Genet. 2010; 42: 906-9.
35. Burdon KP, Macgregor S, Hewitt AW, et al. Genome-wide association study identifies susceptibility loci for open angle glaucoma at TMCO1 and CDKN2B-AS1. Nat Genet. 2011; 43: 574-8.
36. Wiggs JL, Yaspan BL, Hauser MA, et al. Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma. PLoS Genet. 2012; 8: e1002654.
37. Gharahkhani P, Burdon KP, Fogarty R, et al. Common variants near ABCA1, AFAP1 and GMDS confer risk of primary open-angle glaucoma. Nat Genet. 2014; 46: 1120-5.
38. Bailey JN, Loomis SJ, Kang JH, et al. Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma. Nat Genet. 2016; 48: 189-94.
39. Springelkamp H, Iglesias AI, Cuellar-Partida G, et al. ARHGEF12 influences the risk of glaucoma by increasing intraocular pressure. Hum Mol Genet. 2015; 24: 2689-99.
40. Li Z, Allingham RR, Nakano M, et al. A common variant near TGFBR3 is associated with primary open angle glaucoma. Hum Mol Genet. 2015; 24: 3880-92.
41. Gharahkhani P, Burdon KP, Cooke Bailey JN, et al. Analysis combining correlated glaucoma traits identifies five new risk loci for open-angle glaucoma. Sci Rep. 2018; 8: 3124.
42. Shiga Y, Akiyama M, Nishiguchi KM, et al. Genome-wide association study identifies seven novel susceptibility loci for primary open-angle glaucoma. Hum Mol Genet. 2018; 27: 1486-96.
43. www.genebunny.xyz/ – /shortest_path.
44. Ratican SE, Osborne A and Martin KR. Progress in Gene Therapy to Prevent Retinal Ganglion Cell Loss in Glaucoma and Leber’s Hereditary Optic Neuropathy. Neural Plast. 2018; 2018: 7108948.
45. Guy J, Feuer WJ, Davis JL, et al. Gene Therapy for Leber Hereditary Optic Neuropathy: Low- and Medium-Dose Visual Results. Ophthalmology. 2017; 124: 1621-34.
46. Fry LE, Fahy E, Chrysostomou V, et al. The coma in glaucoma: Retinal ganglion cell dysfunction and recovery. Progress in retinal and eye research. 2018; 65: 77-92.
47. Shibeeb O, Chidlow G, Han G, Wood JP and Casson RJ. Effect of subconjunctival glucose on retinal ganglion cell survival in experimental retinal ischaemia and contrast sensitivity in human glaucoma. Clin Exp Ophthalmol. 2016; 44: 24-32.
48. Leung EW, Medeiros FA and Weinreb RN. Prevalence of ocular surface disease in glaucoma patients. Journal of glaucoma. 2008; 17: 350-5.
49. Fechtner RD, Godfrey DG, Budenz D, Stewart JA, Stewart WC and Jasek MC. Prevalence of ocular surface complaints in patients with glaucoma using topical intraocular pressure-lowering medications. Cornea. 2010; 29: 618-21.
50. Lee TH, Sung MS, Heo H and Park SW. Association between meibomian gland dysfunction and compliance of topical prostaglandin analogs in patients with normal tension glaucoma. PloS one. 2018; 13: e0191398.
51. Lavia C, Dallorto L, Maule M, Ceccarelli M and Fea AM. Minimally-invasive glaucoma surgeries (MIGS) for open angle glaucoma: A systematic review and meta-analysis. PloS one. 2017; 12: e0183142.
52. Aref AA. Sustained drug delivery for glaucoma: current data and future trends. Curr Opin Ophthalmol. 2017; 28: 169-74.
53. Ghosh S, O’Hare F, Lamoureux E, Vajpayee RB and Crowston JG. Prevalence of signs and symptoms of ocular surface disease in individuals treated and not treated with glaucoma medication. Clinical & experimental ophthalmology. 2012; 40: 675-81.
54. Martinez-de-la-Casa JM, Perez-Bartolome F, Urcelay E, et al. Tear cytokine profile of glaucoma patients treated with preservative-free or preserved latanoprost. Ocul Surf. 2017; 15: 723-9.
55. Pisella PJ, Fillacier K, Elena PP, Debbasch C and Baudouin C. Comparison of the effects of preserved and unpreserved formulations of timolol on the ocular surface of albino rabbits. Ophthalmic research. 2000; 32: 3-8.
56. Ammar DA, Noecker RJ and Kahook MY. Effects of benzalkonium chloride- and polyquad-preserved combination glaucoma medications on cultured human ocular surface cells. Advances in therapy. 2011; 28: 501-10.
57. Kim JH, Kim EJ, Kim YH, et al. In Vivo Effects of Preservative-free and Preserved Prostaglandin Analogs: Mouse Ocular Surface Study. Korean J Ophthalmol. 2015; 29: 270-9.
58. Skalicky SE, Goldberg I, McCluskey P. Ocular surface disease and quality of life in patients with glaucoma. Am J Ophthalmol. 2012; 153: 1-9.
59. Saade CE, Lari HB, Berezina TL, Fechtner RD and Khouri AS. Topical glaucoma therapy and ocular surface disease: a prospective, controlled cohort study. Canadian journal of ophthalmology Journal canadien d’ophtalmologie. 2015; 50: 132-6.
60. Servat JJ and Bernardino CR. Effects of common topical antiglaucoma medications on the ocular surface, eyelids and periorbital tissue. Drugs & aging. 2011; 28: 267-82.
61. Arita R, Itoh K, Maeda S, et al. Comparison of the long-term effects of various topical antiglaucoma medications on meibomian glands. Cornea. 2012; 31: 1229-34.
62. Baudouin C. Detrimental effect of preservatives in eyedrops: implications for the treatment of glaucoma. Acta ophthalmologica. 2008; 86: 716-26.
63. Batra R, Tailor R and Mohamed S. Ocular surface disease exacerbated glaucoma: optimizing the ocular surface improves intraocular pressure control. Journal of glaucoma. 2014; 23: 56-60.
64. Ammar DA and Kahook MY. Effects of benzalkonium chloride- or polyquad-preserved fixed combination glaucoma medications on human trabecular meshwork cells. Mol Vis. 2011; 17: 1806-13.
65. Boimer C and Birt CM. Preservative exposure and surgical outcomes in glaucoma patients: The PESO study. J Glaucoma. 2013; 22: 730-5.
66. Hommer A, Schmidl D, Kromus M, et al. Effect of changing from preserved prostaglandins to preservative-free tafluprost in patients with glaucoma on tear film thickness. Eur J Ophthalmol. 2018; 28: 385-92.
67. Zhang X, Vadoothker S, Munir WM and Saeedi O. Ocular Surface Disease and Glaucoma Medications: A Clinical Approach. Eye Contact Lens. 2018.
68. Roberti G, Agnifili L, Berardo F, et al. Prospective, Randomized, Single Masked, Parallel Study Exploring the Effects of a Preservative-Free Ophthalmic Solution Containing Hyaluronic Acid 0.4% and Taurine 0.5% on the Ocular Surface of Glaucoma Patients Under Multiple Long-Term Topical Hypotensive Therapy. Adv Ther. 2018; 35: 686-96.
69. Tellez-Vazquez J. Omega-3 fatty acid supplementation improves dry eye symptoms in patients with glaucoma: results of a prospective multicenter study. Clinical ophthalmology. 2016; 10: 617-26.
70. Saini M, Dhiman R, Dada T, Tandon R and Vanathi M. Topical cyclosporine to control ocular surface disease in patients with chronic glaucoma after long-term usage of topical ocular hypotensive medications. Eye. 2015; 29: 808-14.
71. Sherwin JC, Ratnarajan G, Elahi B, Bilkiewicz-Pawelec A and Salmon JF. Effect of a punctal plug on ocular surface disease in patients using topical prostaglandin analogues: a randomized controlled trial. Clin Exp Ophthalmol. 2018; 46: 888-94.
72. Wong C, Tao LW and Skalicky SE. A Retrospective Review Comparing the Safety and Efficacy of 120 Versus 160 Applications of Selective Laser Trabeculoplasty. J Glaucoma. 2018; 27: 94-9.
73. Chandrasekaran S, Cumming RG, Rochtchina E and Mitchell P. Associations between elevated intraocular pressure and glaucoma, use of glaucoma medications, and 5-year incident cataract: the Blue Mountains Eye Study. Ophthalmology. 2006; 113: 417-24.
74. Wu SY, Hennis A, Nemesure B, Leske MC and Barbados Eye Studies G. Impact of glaucoma, lens opacities, and cataract surgery on visual functioning and related quality of life: the Barbados Eye Studies. Investigative ophthalmology & visual science. 2008; 49: 1333-8.
75. Varma R, Paz SH, Azen SP, et al. The Los Angeles Latino Eye Study: design, methods, and baseline data. Ophthalmology. 2004; 111: 1121-31.
76. Koucheki B, Nouri-Mahdavi K, Patel G, Gaasterland D and Caprioli J. Visual field changes after cataract extraction: the AGIS experience. Am J Ophthalmol. 2004; 138: 1022-8.
78. Azuara-Blanco A, Burr J, Ramsay C, Cooper D, Foster PJ, Friedman DS, et al. Effectiveness of early lens extraction for the treatment of primary angle-closure glaucoma (EAGLE): a randomised controlled trial. Lancet. 2016;388(10052):1389-97.
79. Skalicky SE, Martin KR, Fenwick E, Crowston JG, Goldberg I and McCluskey P. Cataract and quality of life in patients with glaucoma. Clinical & experimental ophthalmology. 2015; 43: 335-41.
80. Griffith JF and Goldberg JL. Prevalence of comorbid retinal disease in patients with glaucoma at an academic medical center. Clinical ophthalmology. 2015; 9: 1275-84.
81. Tarkkanen A, Reunanen A and Kivela T. Frequency of age-related macular degeneration among patients with primary chronic open-angle glaucoma and exfoliation glaucoma. Acta ophthalmologica. 2008; 86: 697-8.
82. Hogg RE and Chakravarthy U. Visual function and dysfunction in early and late age-related maculopathy. Progress in retinal and eye research. 2006; 25: 249-76.
83.Ramulu PY, West SK, Munoz B, Jampel HD and Friedman DS. Glaucoma and reading speed: the Salisbury Eye Evaluation project. Arch Ophthalmol. 2009; 127: 82-7.
84.Burton R, Crabb DP, Smith ND, Glen FC and Garway-Heath DF. Glaucoma and reading: exploring the effects of contrast lowering of text. Optom Vis Sci. 2012; 89: 1282-7.
85.Ramulu PY, Swenor BK, Jefferys JL, Friedman DS and Rubin GS. Difficulty with out-loud and silent reading in glaucoma. Investigative ophthalmology & visual science. 2013; 54: 666-72.
86. Crabb DP, Smith ND, Rauscher FG, et al. Exploring eye movements in patients with glaucoma when viewing a driving scene. PloS one. 2010; 5: e9710.
87. Glen FC, Crabb DP, Smith ND, Burton R and Garway-Heath DF. Do patients with glaucoma have difficulty recognizing faces? Investigative ophthalmology & visual science. 2012; 53: 3629-37.
88. Mitchell J, Bradley, C. Quality of life in age-related macular degeneration: a review of the literature. Health Qual Life Outcomes. 2006; 4: 97.
89. Ramulu P. Glaucoma and disability: which tasks are affected, and at what stage of disease? Curr Opin Ophtalmol 2009: 92.
90. Berman K and Brodaty H. Psychosocial effects of age-related macular degeneration. International psychogeriatrics / IPA. 2006; 18: 415-28.
91. Skalicky SE, Fenwick E, Martin KR, Crowston J, Goldberg I and McCluskey P. Impact of age-related macular degeneration in patients with glaucoma: understanding the patients’ perspective. Clin Exp Ophthalmol. 2016; 44: 377-87.
92.Dedania VS and Bakri SJ. SUSTAINED ELEVATION OF INTRAOCULAR PRESSURE AFTER INTRAVITREAL ANTI-VEGF AGENTS: What Is the Evidence? Retina. 2015; 35: 841-58.
93. Hoang QV, Tsuang AJ, Gelman R, et al. Clinical predictors of sustained intraocular pressure elevation due to intravitreal anti-vascular endothelial growth factor therapy. Retina. 2013; 33: 179-87.
94. Wen JC, Reina-Torres E, Sherwood JM, et al. Intravitreal Anti-VEGF Injections Reduce Aqueous Outflow Facility in Patients With Neovascular Age-Related Macular Degeneration. Investigative ophthalmology & visual science. 2017; 5: 1893-8.
95. Yannuzzi NA, Patel SN, Bhavsar KV, Sugiguchi F and Freund KB. Predictors of sustained intraocular pressure elevation in eyes receiving intravitreal anti-vascular endothelial growth factor therapy. Am J Ophthalmol. 2014; 158: 319-27 e2.
96. Kahook MY and Ammar DA. In vitro effects of antivascular endothelial growth factors on cultured human trabecular meshwork cells. J Glaucoma. 2010; 19: 437-41.
97. Wen JC, Cousins SW, Schuman SG and Allingham RR. Dynamic Changes of the Anterior Chamber Angle Produced by Intravitreal Anti-Vascular Growth Factor Injections. Retina. 2016; 36: 1874-81.
98. Zhang X, Olson DJ, Le P, Lin FC, Fleischman D and Davis RM. The Association Between Glaucoma, Anxiety, and Depression in a Large Population. Am J Ophthalmol. 2017; 183: 37-41.
99. Skalicky S, Goldberg, I. Depression and quality of life in patients with glaucoma: a cross-sectional analysis using the Geriatric Depression Scale-15, assessment of function related to vision, and the Glaucoma Quality of Life-15. J Glaucoma. 2008; 17: 546-51.
100. Skalicky SE, D’Mellow G, House P, Fenwick E and Glaucoma Australia Educational Impact Study C. Glaucoma Australia educational impact study: a randomized short-term clinical trial evaluating the association between glaucoma education and patient knowledge, anxiety and treatment satisfaction. Clin Exp Ophthalmol. 2018; 46: 222-31.
101. Kuo YS, Liu CJ, Cheng HC, Chen MJ, Chen WT and Ko YC. Impact of socioeconomic status on vision-related quality of life in primary open-angle glaucoma. Eye. 2017; 31: 1480-7.