Glaucoma Management: The Next 15 Years

As a child I looked forward with excitement, to the promising advances that technology would bring.  Video wrist watches, flying cars, commercial space travel, all seemed to be in close reach. The future appeared vast and only limited by what humankind could dream up. Lives were going to be drastically improved with labour saving devices, with fewer working hours and much more leisure time. Disease was just another of life’s speed bumps that would be flattened out by technology. I just didn’t think it would take so long!

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.

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. 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. 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. 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

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 (AI)

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? 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 AI 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?

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. 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. 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. 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.

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. 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?

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

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 or increase aqueous outflow, 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 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.

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. For the majority of glaucoma there is a heterogeneous aetiology. Here the focus is on gene therapies that enhance survival of retinal ganglion cells.

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 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 has been 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. 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 devices (iStent/Hydrus) or modified trabeculotomy (Trabectome). Draining aqueous internally has also been developed, but safety concerns with one of these devices (Cypass) has recently lead to its recall. 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? 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!

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