Glaucoma: Informing the Way Forward

A/Professor Jamie Craig

Family History and Glaucoma
It has long been known that there is a strong hereditary component to most forms of glaucoma. Recently, much progress has been made in starting to unravel which specific genes account for the heritable tendencies of open angle glaucoma, pseudoexfoliation syndrome, and even angle closure glaucoma. The situation is complex, with mutations in some genes having a large effect on an individual and their family members, and others contributing just a small but important increase in susceptibility.

In our Australian population, primary open angle glaucoma (POAG) is the most common form of the disease. The key to preventing vision loss in glaucoma is early diagnosis, and appropriate treatment which involves topical therapies (eye drops), various forms of laser, or in the most serious cases, surgical procedures to reduce intraocular pressure. A major impediment to early diagnosis is the lack of symptoms in early stage disease. Many patients will not notice the gradual loss of their vision until the disease is in the advanced stage, with irreversible loss of vision.

Even though testing is widely available which can detect early stage disease, there is no universally accepted approach which ensures that a whole population screening approach could be implemented in a cost-effective way. One strategy in place is to encourage family members of those known to be affected to be screened on a regular basis.

The key to preventing vision loss in glaucoma is early diagnosis

What is known about the importance of family history in glaucoma?

• When a close family member is affected with POAG, the family member’s risk is 9.4 fold higher than the rest of the population.
• For these individuals, the lifetime risk is around 22 per cent
• In families with mutations in the Myocilin gene, the lifetime risk is as high as 50 per cent
• In Australia more than half the cases of POAG, have a known positive family history
• Many people affected with POAG don’t pass this information on to their family members
• Even when the information is passed on, many family members ignore it
• Even in families with a strong genetic tendency, some family members are unaware of the situation
• A strategy of systematically examining close relatives of affected cases has been shown to be effective at diagnosing new cases, and also finds even more cases with borderline features (‘glaucoma suspects’)
• The reported family history can turn out to be inaccurate, and those without a known family history are at greater risk of late diagnosis due to lack of awareness.

Further Research
Researchers both in Australia and internationally are making tremendous progress in pinning down the exact genetic causes in both families with severe disease, and in the average glaucoma patient. Through the Australian and New Zealand Registry of Advanced Glaucoma at Flinders University, Myocilin gene testing is available and genetic counselling is being carried out to define those at risk before they develop the disease. These families tend to exhibit high IOP and earlier age of diagnosis and untreated, this leads to blindness.

Family members diagnosed through the genetic testing process are on treatment before any vision is lost, and can expect to retain full vision for life. Similar approaches are now being applied in families affected by rarer forms of dominant normal tension glaucoma. The problem in trying to apply this at the population level is that many disease cases represent the cumulative risk of a number of smaller effect susceptibility genes. Great progress is being made in developing risk calculators based on this information, but it is not yet at a stage for widespread application. These susceptibility tests are currently being evaluated prospectively in an NHMRC funded study of a large number of glaucoma suspects and early manifest glaucoma cases called the PROGRESSA study.

What Can We Do Right Now?
Patients with severe visual field loss who are interested in supporting research about glaucoma can be referred to the ANZRAG (information available at www.anzrag.com). In suitable situations, with appropriate counselling, genetic testing for genes such as Myocilin, Optineurin and TBK1 is applied and this information is used to help other family members. When these tests are negative, samples are used to identify further susceptibility genes.

On a practical level, all practitioners who care for glaucoma patients can make a big contribution by remembering to take a detailed family history of eye disease, and revisiting that history from time to time. Educating affected individuals about the hereditary nature of glaucoma, and encouraging them to suggest that their close family members be screened is very important. The age for this to commence will depend on the age at diagnosis and severity of affected family members, but on average, cases commencing from age 40 on a two-yearly screening strategy is a typical recommendation.

Family Based Screening and Diagnostic Yield
Technology has rapidly evolved such that access to sophisticated tests such as retinal
nerve fibre layer and ganglion cell layer testing has outstripped the understanding of how best to utilise these modalities within community based screening, which has previously focused on clinical examination of the optic disc, measuring IOP and various forms of perimetry. Many questions remain unanswered regarding which tests should be applied, who should have them, if screening is cost-effective and whether there should be funding pathways in place. Glaucoma Australia, in advocating for glaucoma patients and their families, is helping to develop an evidence base, which could inform future strategies to improve access to and quality of screening. This in turn could reduce glaucoma blindness.

The TARRGET Program
In partnership with Flinders University (SA), and the Lions Eye Institute (WA), Glaucoma Australia is supporting the Targeting At Risk Relatives of Glaucoma patients for Early Diagnosis and Treatment study. This pilot program will determine the efficacy of using state-of-the-art screening strategies to examine the first degree relatives of those cases with advanced vision loss registered with the ANZRAG. By pursuing this in these high-risk situations, future strategies to raise knowledge and awareness of the importance of family history in glaucoma are being explored. Most importantly, if an evidence base for the utility of screening in the high risk population can be developed, this can inform future larger programs which could be applied on a national basis.

In 2015, those who care for glaucoma patients know that we will still see new diagnoses of individuals who have already lost most of their vision by the time they are aware of the problem. Given the widespread availability of screening tools, and effective treatments this is an unacceptable tragedy. Australian researchers are working hard to develop ways to make better screening strategies a cost-effective reality.

Professor Jamie Craig is an NHMRC Practitioner Fellow, and member of the Flinders University’s Centre for Ophthalmology, Eye and Vision Research. With a special interest in glaucoma, he and colleagues established the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG), the world’s largest collection of advanced glaucoma cases, in the hope of developing genetic screening tools for people who are most at risk of glaucoma blindness, so that they can be diagnosed and treated before they begin to lose vision. Prof. Craig has been widely published.

Dr. Andrew White

Glaucoma Research Update 2014: The Year in Review
Glaucoma continues to be one of the least well understood eye diseases of all – partly due to the fact that it is an umbrella term for a variety of diseases with a common endpoint and partially due to the complexity of these disease processes. However 2014 was a good year with a number of research breakthroughs – some locally based – that helped provide insights into glaucoma as a disease and as potential avenues for therapy.

In the past few years a number of genetic loci have become implicated in risk for both open and closed angle glaucoma. This year, in a study that was independently replicated, a multinational team lead by
Professor Jamie Craig at Flinders University in Adelaide, identified three new genetic regions associated with increased risk of open angle glaucoma – ABCA1, AFAP1 and GMDS. Their role in the pathogenesis of glaucoma remains unclear though functional studies are underway. There are two major potential outcomes that may stem from these findings: firstly it may be possible to develop genetic testing for people at risk of developing glaucoma to determine whether a susceptibility confers higher risk and thus warrants closer surveillance or earlier treatment. Secondly, functional studies of these genetic loci may reveal targets for new potential treatments for glaucoma patients.¹

A gene associated with anterior chamber depth, ABCC5 was also implicated this year in Genome Wide Association Studies (GWAS) with increased risk of angle closure.²

Potential New Treatments for Glaucoma: Temporary Restoration of Visual Function in Glaucoma
A team led by Professor Bob Casson at the University of Adelaide has been able to temporarily restore visual function in glaucoma patients by application of high dose glucose topically in a double blind, randomised study. In theory this burst of metabolic energy provided by glucose overcomes some of the metabolic dysfunction identified in some models of glaucoma. By itself it may not be a treatment for glaucoma, but it paves the way for other metabolic supplementation therapies that may help or even restore visual function in patients with glaucoma.³

New Drug Shows Promise in Phase II Trial
A variant of latanoprost with a nitric oxide donor molecule, latanoprostene bunod, has been shown to have a better IOP reduction than latanoprost in a randomised Phase II trial of a little over 400 patients in the VOYAGER Study. This builds on other Phase II (CONSTELLATION) and Phase I (KRONOS) studies. The drug is due to undergo Phase III trials and will be jointly marketed by Nicox and Bausch and Lomb under licence, pending further successful trials. The findings from the VOYAGER study were recently published in the British Journal of Ophthalmology.⁴

Long-acting Latanoprost
It is well know that patient adherence to topical glaucoma medications is very poor. However, sustained-release ocular hypotensive agents have been sought for many years with limited success. A group led by Tina Wong, from the Singapore National Eye Center, is developing sustained release latanoprost in nanoparticles to be injected subconjunctivally, ideally leading to a single injection every six months rather than relying on the patient to remember to put eye drops in daily. The latest research in this field published by this group was published in ACS Nano.⁵

Rho Kinase Inhibitors
Rho kinase (ROCK) inhibitors have been under investigation as a new class of glaucoma medication for some time. Recently, one of these AR-13324 (Aerie Pharmaceuticals) was studied in a randomised trial of 224 patients given either AR-13324 or latanoprost. There was a comparable drop in IOP with the main side effect being hyperemia. The findings were published in Ophthalmology.⁶

Ongoing Trials
There are a number of ongoing trials we are eagerly awaiting results on. Two pertaining to Angle Closure (ZAP and EAGLE) looking at the role of prophylactic peripheral iridotomies in China and clear lens extraction for angle closure in the UK respectively are still underway. The Primary Tube vs Trab study (PTVT) looking at efficacy of Seton implants vs trabeculectomy as a primary surgical therapy has just about finished recruiting in the US. The GITS study based in Australia and the LIGHT study based in the UK are looking at the efficacy of Selective Laser Trabeculoplasty as primary therapy long term. A variety of minimally invasive glaucoma drainage devices such as the iStent 2.0, Cypass and Hydrus microstent are underway. These devices may play a role in the surgical management of glaucoma though that is still to be fully determined.

These findings will inform the way forward in terms of glaucoma management for the coming decade. We will have to stay tuned for the outcome.

Doctor Andrew White FRANZCO B.Med.Sci (hons) MBBS PhD, is a clinician scientist ophthalmologist at Westmead Hospital and works as a glaucoma specialist in private practice and at Westmead Hospital. Widely published, 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. He is the current chair of the Glaucoma Australia Expert Advisory Panel, chair of the NSW Government Agency for Clinical Innovation C-Eye-C Project and was the lead author of the RANZCO endorsed guidelines for collaborative management of glaucoma. He is on the Executive of the Australian Society of Ophthalmologists and a member of the RANZCO NSW State Branch Committee.

References:

1. National Genetics 2014 Oct;46(10):1120-5

2. PLoS Genetics 2014 Apr;10(4):e1004352

3. PLoS Genetics PLoS Genet. 2014 Mar 6;10(3):e1004089

4. British Journal of Ophthalmology. Br J Ophthalmol. 2014 Dec 8. [Epub ahead of print]

5. ACS Nano. 2014 Jan 28;8(1):419-29

6. Ophthalmology. 2014 Sep 27. [Epub ahead of print]

Dr. Simon Skalicky

Improving Quality of Life for Patients with Glaucoma
Glaucoma impacts the quality of life (QoL) for over 300,000 Australians and their families. QoL is a reflection of an individual’s general wellbeing: one’s ability to pursue a fulfilled and happy life.^1,2 Although the determinants of QoL are unique for each person and/or culture, good vision is a key influence of QoL
for all. In glaucoma, reduced QoL begins in the earliest stages of disease, and deteriorates proportionally to increasing visual loss from optic nerve damage.^3,4 The negative influence of glaucoma-induced visual loss increases with bilateral involvement.^3-5

Glaucoma impacts activities related to daily function and independence, such as walking, adjusting to different illumination levels, driving, seeing at night, reading, judging distances, walking on stairs and seeing objects coming from the side.^6-10 The influence on these activities is often minimal at first, but gradually increases as optic nerve damage worsens. More advanced glaucoma is associated with increased risk of motor vehicle accidents and injury from falls.¹¹

Numerous other factors may impact visual function and QoL in glaucoma, including other ocular conditions, medical comorbidities, psychological and environmental influences. With poorer vision comes an increasing fear of blindness, social withdrawal and other limitations.^12,13 Depression, associated with chronic disease and disability, is more common in patients with advanced glaucoma, and is associated with reduced QoL.¹⁴ Dry eye syndrome, commonly exacerbated by topical glaucoma medications (especially preserved medications), contributes to the overall burden of disease.¹⁵ Dry eye syndrome can be improved by blepharitis treatment (eyelid hygiene, warmth and massage), topical lubricants (ideally preservative free) and sometimes altering the topical drop regimen. Cataract, frequently found among glaucoma patients,^16-18 is an important determinant of their QoL that is readily treatable by modern cataract surgery.¹⁹

Health-related questionnaires are typically used to quantify glaucoma patients’ QoL. Such questionnaires, also known as patient-reported outcomes (PROs), mostly involve several items that each address a unique visual function. PROs can reflect general health or broad visual function, or can target key attributes, such as visual dysfunction related to glaucoma, health-related anxiety or satisfaction with medical care. PROs are increasingly recognised as key measures of health outcomes, and are commonly used in randomised clinical trials. With the introduction of more psychometrically robust data analysis techniques such as Rasch analysis, PROs have continued to improve and provide more useful metrics of a patient’s holistic health experience related to glaucoma.²⁰

Patient education, counselling, treatment satisfaction, access to advocacy services and support networks can influence QoL related to glaucoma. Increasingly it is recognised that patients who acquire information regarding glaucoma from sources external to their physician have greater treatment satisfaction, improved adherence to and persistence with therapy.²¹ In an effort to improve overall patient understanding from early in the disease course, Glaucoma Australia (GA) has devised a comprehensive patient-focused educational intervention, designed to improve patient knowledge of their condition, autonomy, and adherence to treatment and monitoring regimens. This will hopefully empower patients to make appropriate decisions regarding their health management and translate into improved patient QoL outcomes. However, the impact of GA’s interventions upon patients newly diagnosed with glaucoma has not yet formally been evaluated.

For this reason the Glaucoma Australia Educational Impact Study is being undertaken. This is a randomised clinical trial investigating the health-related impact of mail-out and telephone-based educational interviews to newly diagnosed glaucoma patients, in terms of glaucoma-related comprehension, levels of anxiety, treatment satisfaction and medication regimen adherence. The study will involve newly diagnosed patients with open angle glaucoma who are treated with topical IOP-lowering medications. It is important to perform such a study, as through this we can then identify strengths of Glaucoma Australia’s education service, current limitations and directions of potential growth.

Research into QoL for patients with glaucoma has made substantial progress over several decades, and has provided important insights into the fears and daily challenges of Australians with glaucoma. However, more remains to be learnt. Further work is required to understand better the network of factors that influence QoL in glaucoma. Additionally, we would benefit from continuing refine our methods of QoL assessment. Progress with new and better diagnostic and therapeutic techniques in glaucoma must be matched with carefully conducted studies evaluating the QoL implications of these technologies. Such assessments would be closely linked with health-economic analyses, which are increasingly important as health economic pressures increase. Importantly, we must continue to focus on our patients as individuals, address their real life concerns and understand the impact of glaucoma on their and their families’ lives.

Dr. Simon Skalicky, FRANZCO, BSc (Med), MPhil, MMed, MBBS (Hons 1) is a Visiting Medical Officer at the Royal Victorian Eye and Ear Hospital and Royal Melbourne Hospital. He operates privately at Masada Hospital, St Kilda East and also consults privately at Glaucoma Care practice in Caulfield, Melbourne. He is a Senior Lecturer at the University of Sydney and University of Melbourne and sits on an Expert Advisory Panel for Glaucoma Australia.

Dr. Skalicky recently returned from Cambridge, United Kingdom where he gained subspecialist expertise in the management of glaucoma and challenging cataract surgery. An advocate of evidence-based best practice he is widely published and actively involved in the training of medical students, registrars and fellows.

References:

1. Elliott DB, Pesudovs K, Mallinson T. Vision-related quality of life. Optom Vis Sci. 2007; 84: 656-8.

2. Felce D, Perry, J. 1995; 16(1):51-74. Quality of life: its definition and measurement. Res Dev Disabil 1995; 16: 51-74.

3. McKean-Cowdin R, Varma, R, Wu, J, et al. Severity of visual field loss and health-related quality of life. Am J Ophthalmol. 2007; 143: 1013-23.

4. McKean-Cowdin R, Wang, Y, Wu, J, et al. Impact of visual field loss on health-related quality of life in glaucoma: the Los Angeles Latino Eye Study. Ophthalmology. 2008; 115: 941-8.

5. Varma R, Wu, J, Chong K, et al. Impact of severity and bilaterality of visual impairment on health- related quality of life. Ophthalmology. 2006; 113: 1846-53.

6. Ramulu P, Maul, E, Hochberg, C, et al. Real-world assessment of physical activity in glaucoma using an accelerometer. Ophthalmology. 2012; 119: 1159–66.

7. Nelson P, Aspinall, P, Papasouliotis, O, Worton, B, O’Brien, C. Quality of life in glaucoma and its relationship with visual function. J Glaucoma. 2003; 12: 139-50.

8. Goldberg I, Clement, CI, Chiang, TH, Walt, JG, Lee, LJ, Graham, S, Healey, PR. Assessing quality of life in patients with glaucoma using the Glaucoma Quality of Life-15 (GQL-15) questionnaire. J Glaucoma 2009; 18: 6-12.

9. Wu S, Hennis, A, Nemesure, B, Leske, MC; Barbados Eye Studies Group. Impact of glaucoma, lens opacities, and cataract surgery on visual functioning and related quality of life: the Barbados Eye Studies. Invest Ophthalmol Vis Sci. 2008; 49: 1333-8.

10. Ramulu P. Glaucoma and disability: which tasks are affected, and at what stage of disease? Curr Opin Ophtalmol 2009: 92.

11. Haymes SA, Leblanc RP, Nicolela MT, Chiasson LA and Chauhan BC. Risk of falls and motor vehicle collisions in glaucoma. Investigative ophthalmology & visual science. 2007; 48: 1149-55.

12. Ramulu PY, van Landingham SW, Massof RW, Chan ES, Ferrucci L and Friedman DS. Fear of falling and visual field loss from glaucoma. Ophthalmology. 2012; 119: 1352-8.

13. Janz NK, Wren PA, Guire KE, et al. Fear of blindness in the Collaborative Initial Glaucoma Treatment Study: patterns and correlates over time. Ophthalmology. 2007; 114: 2213-20.

14. 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.

15. Skalicky SE, Goldberg I, McCluskey P. Ocular surface disease and quality of life in patients with glaucoma. Am J Ophthalmol. 2012; 153: 1-9.

16. 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.

17. Lai JS, Tham CC and Chan JC. The clinical outcomes of cataract extraction by phacoemulsification in eyes with primary angle-closure glaucoma (PACG) and co-existing cataract: a prospective case series. J Glaucoma. 2006; 15: 47-52.

18. Patel H, Danesh-Meyer, HV. Incidence and management of cataract after glaucoma surgery. Curr Opin Ophthalmol 2013; 24: 15-20.

19. 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. 2014 (in press).

20. Khadka J, Pesudovs, K, McAlinden, C, Vogel, M, Kernt, M, Hirneiss, C. Reengineering the glaucoma quality of life-15 questionnaire with rasch analysis. Invest Ophthalmol Vis Sci 2011; 52: 6971-7.

21. Friedman DS, Hahn SR, Gelb L, et al. Doctor-patient communication, health-related beliefs, and adherence in glaucoma results from the Glaucoma Adherence and Persistency Study. Ophthalmology. 2008; 115: 1320-7, 7 e1-3.