Glaucoma Management: The Next 15 Years

The current gold standard in glaucoma surgery – trabeculectomy – was developed shortly before man landed on the moon and laser trabeculoplasty was first suggested around a decade later. With these as reference points, it would seem there has been little progress in glaucoma, however glaucoma knowledge, its epidemiology, pathogenesis, and treatments have vastly improved.

a machine that can learn to detect a glaucomatous optic nerve from normal by advanced information processing (applied AI) is possible

Just consider diagnostic elements. Visual field testing has evolved from a manual technique to a highly engineered, highly reproducible, machine based process, and optic disc assessment to exquisitely detailed imaging technology. Variables affecting intraocular pressure (IOP) measurement are much better understood, as is the potential effect of its fluctuation. Though still a major risk factor, IOP is no longer included in the definition of glaucoma.

Yet we are still a long way from the simple pill or procedure to cure glaucoma that was promised in my childhood. It’s clear that progress to a cure, together with flying cars, takes much longer than we would hope. So what can we realistically expect from the next 10–15 years in terms of our knowledge of, and ability to diagnose and manage, glaucoma?

FACING THE ISSUES

Some aspects of the future are clear. Firstly, in a technologically advancing world, vision has become increasingly important. Whether it be information gathering for day to day living, increased productivity in employment, or simply enjoying our leisure, vision based tasks are critical. The human/technology interface is driven by the sense of sight. Though voice recognition technology is improving, our smartphones, iPads, and personal computers all remain vision based.

Secondly, the world’s population is aging. This is significant because across the globe glaucoma prevalence increases with age.

Over the past decade there has been an explosion in new glaucoma surgeries aiming to improve the above deficiencies

Reviews have suggested that prevalence of primary open angle glaucoma (POAG) roughly doubles each decade among populations of European descent and the increase is only slightly less in people of Asian descent. Estimates show that by 2020 there will be 65.5 million people globally with POAG.1 Given that Asia has 60 per cent of the world’s adult and aged population, and that low income countries within this region are predicted to experience rapid increases in life expectancy, the potential explosion in glaucoma cases is concerning. Total glaucoma numbers in Asia, (combining POAG, primary angle closure glaucoma, and secondary glaucoma) are projected to reach over 80 million by 2040.2 This is likely to produce significant strain on health systems in our region but even more importantly, if not identified and adequately treated, the resulting large visually disabled population will have major social and economic costs.

The effect of glaucomatous visual loss in an aged population is significant. As physical mobility declines, glaucoma is associated with an increased risk of falls, depression, decreased social contacts, and loss of independence through driving restriction. Clearly, preservation of vision is critical.

FUTURE DETECTION AND DIAGNOSIS

Artificial Intelligence 

In Australia, as in the rest of the world, there is a large undiagnosed population of glaucoma cases. Early detection and treatment offers the best hope for saving sight into old age, so over the next 10–15 years can we better detect these patients? Population based screening to date has been deemed not cost effective due to time and labour costs. Currently opportunistic screening of patients presenting for other causes, or selective screening of higher risk cases such as family members of glaucoma patients, are the employed techniques. To quote from Alan Turing, one of the pioneers of computer science “What we need is a machine that can learn from experience” to screen on a population basis. Though this quote is from 70 years ago, advances in applied artificial intelligence may make this attainable in the next decade. Already computers use pattern recognition for identification purposes, e.g. retinal scans – why not extend this further?

In broad terms artificial intelligence (AI) may be considered as the ability of a computer to perform tasks commonly associated with intelligent beings, such as the ability to reason, discover meaning, and learn from experience. While building a machine that can think to match a human (strong AI) faces many obstacles, a machine that can learn to detect a glaucomatous optic nerve from normal by advanced information processing (applied AI) is possible.

In machine learning models, a computer is given a task of determining whether a presented data set meets the requirement for a positive or negative (zero or one) response. It requires a training data set to learn from, then a second validation data set to compare its responses against. Having done the comparison, it will refine its algorithms then test again. This can be done indefinitely until a defined end point of accuracy is reached. These processes can be done in a top down (symbolic) or bottom up (connectionist) way. The latter is an attempt to model machine learning on how the human brain works on a neural level. These artificial neural networks involve the input of a stimulus to multiple neurones (processors) at the next level with each single or multiple input having a variable weighting than can be applied. Several layers of neurones may be used. The system is trained to achieve the desired output – either yes or no – from the training data set by altering the weightings at the input level.

AI processing may be of value in the future for both screening and in detecting progression in glaucoma. Since 2015, a number of studies have published on the use of optic disc photographs to determine POAG from normal. Some of these have levels of sensitivity and specificity good enough to suggest potential use in clinical decision making. Further work using optical coherence tomography (OCT) imaging is likely to progress this further. It is not only glaucoma that may benefit from this technology. Similar work has been done with age related macular degeneration and diabetic retinopathy. The possibility of combining glaucoma, diabetic, and macula screening into a single test would revolutionise population based screening, particularly if it was able to be applied in a primary care setting. There are limitations – such as ensuring adequate quality of images, the cost of acquisition, and the impact of the rate of false positives on referral pathways – but it is very exciting to contemplate.

The Genetics of Glaucoma 

Another area that has potential impact on screening is the unfolding understanding of the genetics of glaucoma. Some relatively uncommon single gene mutations have been known for some time, for example those associated with anterior segment dysgenesis or congenital glaucoma. These mutations produce typical phenotypes and thus are of limited value for screening. An exception may be Myocilin, where the phenotype appears normal but genetic identification at an early time point may avoid late presentation with advanced field loss at a young age. For POAG, genome wide association studies from large databases, such as the Australian and New Zealand Register of Advanced Glaucoma and the UK Biobank, have identified multiple loci associated with glaucoma. These loci have a diverse range of cellular effects on cell signalling, the extracellular matrix, and membrane biology, through to mitochondrial metabolism. Though they are a heterogeneous group of genes involved, the field of genetics is progressing at a rate similar to that proposed by Moore’s law3 in computing, that is, a doubling of knowledge every 18 months. This, combined with dramatic decreases in the costs of genetic testing over the past decade, may lead to the very real prospect of genetic screening for glaucoma over the next 10–15 years.

IMAGING

One of the deficiencies of current glaucoma management is the inability to determine the success or failure of treatment in real time. The means used to diagnose disease and detect progression are after the event and only surrogates for the real pathologic process of retinal ganglion cell death. Nerve fibre layer and macular thickness measurements, though closer to the pathology, are still post-mortem events for retinal ganglion cells (RGCs).

Great advances have been made with imaging, however even with things like adaptive optics OCT, RGCs are very difficult to visualise because of their near transparent structure. A hope for the future is the ability to image RGCs, or even better, to measure the number of RGCs currently under stress and at risk of dying. Measurements pre and post treatment would give useful data on a therapy’s success or failure.

An intraocular telemetric pressure sensor would be of great value, especially if it could be inserted in conjunction with commonly performed procedures such as cataract surgery

One development along this line is that of DARC technology (Detection of Apoptosing Retinal Cells). When a RGC is programmed to die, changes occur in its cell membrane. These changes expose phospholipids that have a high affinity for the protein Annexin 5. In animal studies, this protein has been fluorescently labelled, intravenously injected, and shown via imaging with confocal scanning laser ophthalmoscopy, to identify apoptosing RGCs. Results from a Phase II human trial are due to be reported soon. This trial is assessing patients with glaucoma as well as some other diseases such as optic neuritis with the aims of determining the range of apoptosing cells in normal and glaucoma effected eyes, and also whether it is possible to differentiate other diseases from glaucoma.

The benefits of such technology would be to enable the determination of (a) whether a glaucoma suspect is losing RGCs at a rate greater than normal i.e. in diagnosis, and (b) whether a specific therapy is able to decrease the rate of apoptosis in a progressing glaucoma patient. It is unlikely that this technology will become a regular investigation in glaucoma management because it requires an intravenous injection and up to two hours to complete. Nevertheless, it is progress towards real time assessment.

INTRAOCULAR PRESSURE

Intraocular pressure (IOP) remains central to the management of glaucoma and its accurate measurement is very important. IOP fluctuation has been suggested to underlie progression of glaucoma in some patients but to date there has been no satisfactory means to measure IOP through the 24 hour cycle. Attempts via repeated clinic measurement or home self-tonometry can be unreliable in predicting fluctuation. Contact lens based telemetric IOP measurement has been available for a few years but cost, inconvenience and uncertainty of converting its output to a pressure unit have limited its uptake. An intraocular telemetric pressure sensor would be of great value, especially if it could be inserted in conjunction with commonly performed procedures such as cataract surgery. Such devices have been under investigation for the past two decades and appear to be inching closer to clinical use. A recent report on their long term safety in a small number of patients was positive. These devices were inserted anterior to the intraocular lens at the time of cataract surgery. The question posed by the authors is pertinent: are they suitable for everyone and if not, which subset of patients is most likely to be advantaged by their use?

TREATMENT

The mainstay of medical treatment of glaucoma has been the use of one or more classes of topical medication. These agents either decrease aqueous production (beta blockers/alpha agonists/carbonic anhydrase inhibitors), or increase aqueous outflow (prostaglandin analogues/miotics), thus effectively lowering IOP. Major advances in IOP lowering drugs occurred in the 1970s (beta blockers) and 1990s (prostaglandins), so we are overdue for a significant advance.

Drugs targeting the conventional aqueous outflow pathways of trabecular meshwork and Schlemms canal may be candidates for this over the next decade. Several possible classes, such as adenosine receptor agonists, nitric oxide donors, rho kinase inhibitors, and actin polymerisation inhibitors, have been under investigation in Phase II or III trials. Proof of their efficacy, safety, and tolerability would significantly broaden treatment options in the future.

I mentioned previously the substantial increase in the genetic background of glaucoma. The elucidation of these many genes and their functions within the eye allows targeting of some of these functions as therapeutic options. Recently there has been FDA approval of the first gene therapy to treat eye disease. Lebers hereditary optic neuropathy is a blinding disease with an acute or subacute onset caused by point mutations in mitochondrial DNA for which there was no previous definitive treatment.

Gene editing techniques may be applicable in the future in some specific glaucomas, such as Myocilin juvenile onset glaucoma or primary congenital glaucoma, where single genetic mutations exist. Using a viral vector to supply a messenger ribonucleic acid (RNA) guided nuclease (CRISPR/ Cas9) it is possible to produce site specific double stranded breaks in DNA and then either knock out the gene via insertions or deletions, or alternatively integrate repaired DNA sequences.

For the majority of glaucoma there is a heterogeneous aetiology. Here the focus is on gene therapies that enhance survival of RGCs by manipulation of pro and anti-apoptotic pathways within the cell. Investigations into enhancing cell survival pathways have centred on upregulating the neurotrophic factors: brain derived neurotrophic factor (BDNF) and ciliary derived neurotrophic factor (CNTF). On the other side, strategies to inhibit cell death have investigated vectors expressing Caspase inhibitors as these enzymes are known to be a final common pathway in apoptosis. As well, up regulation of proteins associated with mitochondrial integrity have shown promise in animal studies.

While the prospect of gene therapy for neuroprotection in glaucoma appears close, there are some limitations. Firstly, the viral vector must be highly specific for the targeted tissue as off target gene transduction could have significant adverse effects on retinal function. Thankfully, recombinant adeno associated viral vector 2 seems selective for RGCs. Secondly, as glaucoma is a slow disease, prolonged therapeutic gene expression is likely to be required. This extended manipulation of expression will need to be shown to be safe in long term trials.

Adherence is a major issue in glaucoma. Topical medication may be difficult to manipulate, cause tolerability problems due to ocular surface issues, and is inconvenient for patients. Alternative drug delivery systems should improve adherence problems and are likely over the next decade. These may be devices placed in the lacrimal drainage apparatus, subconjunctivally, or intraocularly with systems that allow slow sustained release of medication over several months.

SURGERY

Surgical intervention in glaucoma is typically required when IOP is uncontrolled or there is progression of disease despite maximal medication with or without laser. The primary surgery for the past 50 years, as mentioned at the start of this article, has been drainage of aqueous externally to the subconjunctival space by either trabeculectomy or tube shunt devices. These procedures are effective but complex and time consuming. They involve long recovery times and are subject to various complications. One of these potential long term complications results from the intentional creation of a bleb or elevation of conjunctiva under the upper lid. Over the past decade there has been an explosion in new glaucoma surgeries aiming to improve the above deficiencies.

Trans trabecular surgeries aim to decrease the resistance across the trabecular meshwork and inner wall of Schlemms canal, the major site of outflow obstruction. This is achieved by stenting (iStent/Hydrus) devices or modified trabeculotomy (Trabectome). Draining aqueous internally to the suprachoroidal space has also been developed, but safety concerns with one of these devices has recently lead to its recall. Both these techniques have the advantage of being blebless. Simplifying the process of external drainage of aqueous is the aim of the new Xen and InFocus drainage devices.

While these new interventions have shown benefits of varying degrees in clinical trials, questions regarding their long term efficacy and their place in glaucoma management will certainly become much clearer over the next 10 years. Do they have the potential to replace medication? Is a particular intervention better for a certain type of glaucoma? Do combinations of these surgeries work better together? At what point in management is each most appropriate? Time will give us the answers to most of these questions. A

PROMISING FUTURE

The next 10-15 years will see continued progress on many fronts in the fight against glaucoma blindness. Artificial intelligence may revolutionise screening and decision making in glaucoma care. Genetic therapies may provide real neuroprotection options, and medical and surgical treatments will continue to improve. The holy grail of regenerating the optic nerve however may lie beyond the 10 year horizon. The future in glaucoma is full of promise let’s hope it gets here soon!

Dr Guy D’Mellow is deputy chair of the Australian and New Zealand Glaucoma Society. He graduated in medicine with honours from the University of Queensland and completed his ophthalmic training in Queensland. Following further training in the United Kingdom, he returned to practice in Brisbane.

He is a past examiner for the Royal Australian and New Zealand College of Ophthalmology, a previous Chair of the Therapeutics Committee, and was a Federal councillor.

Dr D’Mellow has a long history of service as a member of the council for Glaucoma Australia and has presented on glaucoma topics at several national and international meetings. He has been involved in philanthropic overseas educational programs in Vietnam, Laos and Cambodia.

He practices as a glaucoma specialist at the Terrace Eye Centre in Brisbane.

References 

1. Kapetanakis vv et al. Global variations and time trends in prevalence of POAG; a systematic review and meta analysis. British Journal of Ophthalmology, 2016 Jan (1) 100 pp 86-93
2. Chan EW et al. Glaucoma in Asia; Regional prevalence variations and future projections British Journal of Ophthalmology, 2016;Jan (1) 100 pp78-85 
3. www.mooreslaw.org
4. Yap T E et al. Real time imaging of retinal ganglion cell apoptosis. Cells, 2018 June 15 
5. Koutsonas A et al. Implantation of a novel telemetric intraocular pressure sensor in patients with glaucoma (ARGOS Study); 1 year results. Invest Ophthalmol Vis Sci 2015 Jan22;56(2) 1063-9