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Glaucoma experts share research in Melbourne

29/07/2019By Lewis Williams PhD
The 2019 World Glaucoma Congress was held in Melbourne from 27-30 March at the Melbourne Convention and Exhibition Centre. In part two of his report, LEWIS WILLIAMS details more of the event’s highlights.

Dispelling 'anti-science'

Melbournian Professor ROBIN BATTERHAM AO was Australia’s chief scientist from 1999 to 2006. He comes from a background in chemical engineering and, in addition to his science background, is also a published organist. For a time he was also the Kernot Professor of Engineering at the University of Melbourne.

His opening remarks revealed that 46% of US citizens support creationism over evolution, and there is no reason to believe that Australians would think significantly differently. He concluded that figures like 46% believing in what amounts to anti-science puts pressure on the scientific method.

Unfortunately, scientists taking extreme positions on their own and other's work, often to counter anti-science extremism, can significantly damage science’s credibility and reputation.

He described science as utilitarian as opposed to a ‘belief system’, and thinks that science education should be compulsory in schools until Year 12.

During his time as chief scientist, he oversaw a doubling of R&D funding to the tune of $2.9 billion. He also believes that Australia is not especially good at balancing basic versus translational funding.

Compounding, if not confounding, that issue is Australia’s poor record of interdisciplinary research. This usually leads to separate funding for entities that could be, or should be, co-operating.

In his opinion, science funding is a balancing act. One driver is the likelihood of commercial returns, which he noted could distort priorities. What is required is a balance between direct commercial benefits versus community benefits at large.

Who says glaucoma is an incurable disease?

Professor KEITH MARTIN, managing director of the Centre for Eye Research Australia (CERA) and president of the World Glaucoma Association, shed light on this vexed question.

To cure glaucoma he proffered that the prevention of damage to, or the repair of, retinal ganglion cells (RGCs) all the way to the brain was a major issue. This is followed by the restoration of all that was ‘lost’ because of the disease.

He noted that insulin could support dendritic tree recovery or regeneration. In mice, it has been shown that high concentrations of Vitamin B3 can significantly decrease the loss of axons. Gene therapy using AAV vectoring of brain-derived neurotrophic factor (BDNF) into RGCs is already showing promise in alleviating RGC loss after optic nerve damage, as well as neuroprotection for up to 6 months.

However, Martin stated: “regeneration of N II was a long way off”. Zymosan (a fungi-derived glucan) either alone or in combination with an appropriate enzyme, has been shown to enhance axonal regeneration. However, the vision restoration proved to be poor.

Even with regeneration, it is usually only the low-level functions that are restored, and certainly not the full complement of capabilities. In Martin’s opinion, ‘protection and regeneration’ are the future, and much of his research is aimed at exactly that.

Glaucoma progression

Professor JONATHAN CROWSTON, professor of ophthalmology at Duke-NUS Medical School Singapore and former CERA director, tackled the subject of Primary open-angle glaucoma disease progression, an art with notoriously poor accuracy.

Overall, 75% of cases progress and the remaining 25% do not progress. Furthermore, it takes a long time to study progress validly, meaning few undertake the task due to it being impractical. He also noted that neuroprotective trials were prohibitively expensive and were unlikely to be undertaken either lightly or without significant support.

Stressed RGCs can lead to cell death and annexin V (also known as annexin A5, a cellular protein) assays permit quantification of the number of dying cells. However, that in turn only allows a rough estimate of the number of residual RGCs. Cells that have already undergone phagocytosis fluoresce.

It is estimated that about 65 RGCs die each day as part of the normal ageing process. Also of interest are RGCs undergoing dendritic pruning involving axonal cytoplasmic and mitochondrial micro-changes. Recovery of RGC function remains largely unknown and its exact nature is still debated.

RGC recovery in rodents has been confirmed in the lab over a period of at least 7 days. Importantly, real-time assessment of RGC health in a lab setting is now possible.

What’s beyond MIGS?

Well-known Canadian eye surgeon and ophthalmology academic Professor IKE AHMED spoke about minimally invasive glaucoma surgery (MIGS) and other anterior chamber drainage approaches to glaucoma therapy.

Significant factors to be considered when selecting a treatment regimen include quality-of-life, cost, and the approach’s ability to prevent blindness. According to Ahmed, the invasiveness of the ab interno MIGS approach “does not matter”, noting that only part of the trabecular meshwork is involved in filtering at any one time.

Despite the number already available, he believes that more devices are still required and that there are some novel examples in the pipeline. He also holds the view that the interest in MIGS is considerable, based on the recent number of publications that focus on the devices. Promoting further interest is the fact that there is a plateau across the purely surgical approaches to glaucoma.

One new approach is the Swiss eyeWatch; an adjustable-flow device featuring a magnetically-coupled, external, adjustable valve. The eyePlate drainage shunt is inserted sub-conjunctivally and is connected to the eyeWatch via a short elastomeric tube. A rigid extension of the eyeWatch component is plumbed into the anterior chamber. Sutured scleral tissue is used to protect the ‘system’ once implanted.

When placed directly over the implant, the eyeWatch Pen surgeon’s tool indicates the current valve setting. It also contains a magnet that is used to adjust the eccentric-cam clamp that impinges upon the eyeWatch’s internal tubing, altering outflow control.

Other devices take a suprachoroidal approach, but he cautioned that any such device needed to be anti-fibrotic to avoid problems in the longer-term. Another device is the Camras Shunt from Camras Vision, now marketed as the Sollevio from Alievio Inc. The shunt targets lower levels of intraocular pressure (IOP), less than 14 mm, and incorporates a micropore antibacterial filter to prevent ingression of micro-organisms into the anterior chamber. Its outlet is located externally, under the upper eyelid.

The iDose (Glaukos) is an intraocular implant that delivers travoprost after a ‘micro-invasive’ surgical procedure. More than half the participants in an early trial showed about a 30% IOP reduction at 12 months compared to baseline results. A much larger clinical trial is underway.

The XEN Gel Stent (Allergan) is a permanent, porcine-gelatine/cross-linked with glutaraldehyde, anterior chamber implant that shunts the anterior chamber to the sub-conjunctival space. A needle ‘introducer’ is used to enter the anterior chamber. It is already available.

In a later presentation, Professor Andrew White from Westmead Hospital (Sydney) reported on his department’s experience with the XEN shunt combined with MMC (mitomycin C used in a large volume/low concentration dose). They found a rapid rehabilitation, with visual acuity back to baselines within seven days. Insertion required minimum manipulation, but care was required to avoid excessive pushing at the time of insertion. As with all tubes, there is a risk of erosion at the insertion site. His study used topical steroids for 4-6 weeks post-insertion to prevent local fibrosis.

Ahmed wrapped up his presentation with a prediction that in the future, microstenting of filtering blebs would be used as a possible glaucoma therapy, or as an adjunct to existing therapy.

The BIG picture

Ophthalmologist, Assistant Professor LUCY SHEN, a glaucoma specialist at Massachusetts Eye and Ear Hospital, gave a brief presentation on imaging, particularly wide-field imaging.

Swept-source optical coherence tomography (OCT) already offers 12 x 9 mm image areas, allowing for a useful analysis of the retinal nerve fibre layer (RNFL). Adaptive optics imaging offers a view of individual cells and nerve fibres, but the process is slow and intense.

Other ocular parameters of interest include Bruch’s membrane opening, minimum rim width, and lamina cribrosa depth, including its deeper layers between 40 and 80 microns further out.

A recurring difficulty involves marrying old and new data due to different instruments and techniques creating incompatibilities. Parameters of interest include changes in RNFL thickness and macula ganglion cell populations, among others.

Another clinical pursuit is reconciling structure and function. OCT-A, for example, uses high-speed OCT to detect retinal features that change over time, especially moving blood. In NAION (Non-arteritic, Anterior Ischaemic Optic Neuropathy), the density of the superficial retinal blood vessels is reduced.

Shen predicted that future OCT devices would be better at characterising the glaucoma patient and their eyes. However, she also noted that artefacts, including optical artefacts, remain an imaging issue.

The 14th Gillies Lecture

Queensland ophthalmologist and academic Professor RAVI THOMAS gave this year’s Gillies Lecture. A born entertainer, he titled his lecture ‘Of Glaucoma, Prevention of Blindness & the Reverend: A personal Khichdi’ (a khichdi is an Indian one-pot lentil and rice dish).

Thomas is the director of glaucoma services at the Queensland Eye Institute and holds academic positions at University of Queensland and Beijing University.

In one study of 118 PACG suspects, 82 progressed to develop the condition after five years. Overtly, there are no differences between those that progressed and those that did not. He noted that PACG progression data cannot be replicated, but it has been shown that the iris volume decreases less in PACG suspects. He posed the question: “Should we screen for it?”

Population attributable risk (PAR%) helps decide if a disease is a public health problem. In his 2012 paper on glaucoma in developing countries, he concluded that PACG is not one, and other more basic issues were much more pressing. He concluded that ultimately, we remain reliant on a clinical examination of each case, not screening programmes.

In POAG cases only, MRI reveals changes in the visual cortex with and without concurrent visual stimulation. On the topic of the effect of combined phaco and intraocular lens implantation on IOP, Thomas summarised most studies as showing small decreases in IOP (1 to 3 mm Hg) with only a 3-4% chance of decreases >5 mm Hg. In cases of PACG resulting in a peripheral iridectomy, he advised against locating them so that they were partially or completely covered by the upper eyelid in normal gaze.

Thomas was also critical of too many blindness prevention studies reporting the number of patients operated on as their main performance indicator without any reference to, or a minimal airing of, the actual outcomes achieved.

Connexin43 in RGC injury

NZ ophthalmologist and academic Professor HELEN DANESH-MEYER from the New Zealand National Eye Centre in Auckland shared some of her cutting edge research.

She dated the discovery of gap junctions to 1969 and described such junctions as electrical synapses that operate bi-directionally and rapidly. Gap junction protein Connexin43 (GJA1) is just one of a family of connexions including 32, 26 and 46, as well as her topic, 43, the most ubiquitously expressed isoform.

In humans, Connexin43 (CX43) is located in the optic nerve head and retina, as well as in astrocytes and the vascular endothelium in the central nervous system, RPE, Müller cells, and microglia. CX43 mutations increase the risk of POAG some 16-18x.

Normally, CX43 hemichannels are unlikely to be open but when injured or in disease, CX43 upregulation and hemichannel opening have been implicated in all aspects of secondary damage. This includes glial cell activation, oedema, and loss of vascular integrity leading to neuronal death. Leaky hemichannels are implicated in several diseases.

In an experimental retinal ischaemic reperfusion model, upregulation of CX43 was confirmed and injury was apparent after 4 hours of ischaemia. Peak damage was observed at about 24 hours.

In human glaucoma, CX43 upregulation has been confirmed in the lamina cribrosa. A concept now being pursued is blocking CX43 or closing hemichannels to stall or prevent the opening up of an inflammatory pathway. Danesh-Meyer believes that CX43 blocking has significant potential, and some of her research is investigating that possibility.

Driving with glaucoma

Optometrist and Queensland University of Technology academic Professor JOANNE WOOD turned her expertise to studying drivers who suffer from glaucoma in real-world situations.

The visual field losses and decreases in contrast sensitivity are the known sequelae of glaucoma. Vision problems are, theoretically at least, netted by regular vision checks that are part of the licence renewal process. Wood posed the question: “Drivers are assessed regularly for vision standards, but is there more?”

Vision loss due to glaucoma is already known to result in an increased crash rate, and up to 25% of those involved in accidents are found to have severe visual field loss. However, when some form of integrated visual field loss estimate and crash rates are compared, they do not correlate.

Data suggests that the crash risk in glaucoma is 6x with moderate to severe field loss, 2x with severe binocular vision impairment, and 1.65x with severe field loss when driving in unfamiliar circumstances.

Factors noted during an assessment include lane keeping, scanning ability, anticipatory skills, and the number of driving instructor interventions needed. There is evidence that some glaucoma cases can partially compensate for their condition.

No visual field measures were associated significantly with driver performance or safety ratings. However, motion sensitivity tested using random dot displays was found to better correlate with driving performance than any other test.

Overall, ‘observation’ was the glaucoma patient’s greatest challenge, especially in situations involving ‘Give Way’ signs and traffic lights.

Experts in the field generally agree that fitness-to-drive should be based on performance, rather than age or diseases. It also needs to be fair. It is known that training can improve results, but there are limits to what can be achieved. Wood finished her presentation with an observation that current drivers licence standards are not actually evidence-based.

Falls, fractures, and physical activity

Wilmer Eye Institute ophthalmologist and glaucoma researcher Dr DAVID FRIEDMAN gave a presentation that showed the effects of glaucoma on activity levels.

He described a 5 dB decrement in central visual fields as “meaningful”, and listed a number of relevant studies of glaucoma patients of which he was a co-author. In his view, mobility is not just about getting about. Rather, it is about getting about ‘safely’. He also has an interest in the related issues of confidence and fear-of-falling.

In the developed world, independence and the ability to drive are almost one and the same. Driving cessation can be related to glaucoma severity and, perhaps more importantly, subsequent depression. Glaucoma cases are up to 4x less likely to drive according to Friedman, and each 5 dB visual field decrement doubles the likelihood of not driving.

Any inactivity attributable to glaucoma increases the likelihood of the patient dying due to inactivity. In bilateral glaucoma, the walking pace can be reduced by as much as 2.4 m per minute. Accelerometers can monitor a patient’s physical activity levels, and data shows that bilateral glaucoma cases are 70% less likely to be active or leave their home.

Severe disease halves the likelihood that patients will undertake excursions. Because of the induced drowsiness resulting from alpha-agonist glaucoma therapy, such cases experience a further reduction to 4.42x less likely. Turning to peripheral visual field losses, Friedman showed that they increased the likelihood of falls more than central field issues. Shockingly, he gave the annualised probability of falls in glaucoma as 44%. Returning to his “meaningful” comment in relation to each 5 dB decrement in visual fields, he gave the falls rate, especially those involving steps, as a 41% increase.

Visual field losses also increase the hip fracture rate in female glaucoma patients, where advanced age is likely to be a contributing factor. Regrettably, there are few papers on the ‘rehabilitation’ of glaucoma patients, especially in view of the fact that ‘disability’ occurs before, or well before, glaucoma ‘blindness’.

OCTA-A: evolution or revolution?

Indian ophthalmologist and glaucoma specialist Dr HARSHA RAO NARAYANA from the Nethralaya Eye Care Hospital presented 10 points about OCT-A.

He noted that OCT-A is scanned in ‘slabs’: the optic nerve slab, the radial peripapillary capillary slab, the choroidal slab, and the foveal superficial layer. In glaucoma, OCT-A:

  • Shows a decreased density of superficial vessels,

  • Shows microvascular dropouts in the choroidal layer along with a global decrease in RNFL thickness, increased axial length, and disc (Drance) haemorrhages,

  • Shows changes before visual fields changes are detectable. A sectoral analysis of blood vessel densities reveal local retinal changes,

  • Might be a better tool for assessing blood vessel density and differentiating glaucoma from non-glaucoma cases,

  • Is not superior in cases of primary angle-closure glaucoma (PACG),

  • Detects choroidal microvascular dropouts that are associated with faster disease progression. Drance haemorrhages and microvascular dropouts are associated, independently with progressive RNFL thinning,

  • Shows that lower baseline vessel density is associated with faster RNFL thinning,

  • Can detect the progressive decrease in the population of capillaries,

  • Might or might not be able to detect disease progression earlier than conventional OCT,

  • Has increased test/retest variability than conventional OCT, which might also apply to reference scans.

Rao does not believe that OCT-A is superior to OCT in the diagnosis of glaucoma and his parting summary was that currently OCT-A is evolutionary but has the potential to be revolutionary.

Anterior segment imaging

Brazilian glaucoma specialist Dr LISANDRO SAKATA gave a wide-ranging lecture on anterior segment imaging.

In angle-closure glaucoma, the aim of therapy is to ameliorate or prevent the adverse outcomes of angle closure, true cases of which are, fortunately, relatively rare.

Despite the advances made in imaging over the last 25 years, Sakata believes that gonioscopy remains the gold standard. Standards using the technique need to be improved as well as maintained. Despite the availability of anterior segment OCT (AS-OCT), gonioscopy still plays an important role.

Regardless, the evaluation and documentation that AS-OCT provides is valuable. While anterior angle imaging has been possible for more than a decade, the angle’s true anatomy may not be shown realistically. Although gonioscopy gives a broad quadrant view of the anterior angle, SS-OCT can provide a 360° view.

However, the current resolution of OCT does not resolve the trabecular meshwork, only the scleral spur. According to Sakata the older time-domain OCT (TD-OCT) is potentially better at detailing the anterior angle, but in up to 20% of cases an image of the scleral spur is captured poorly.

As instrument resolution improves, new anatomical landmarks are disclosed. For example, the Schwalbe’s line to scleral spur transition zone has trabecular meshwork tissue between the two, but the actual anatomy varies by quadrant and between individuals. The relationship between the anterior angle and angle closure as seen in AS-OCT has been studied poorly, but AS-OCT now detects anterior angle closure in more instances than gonioscopy.

Furthermore, if the anterior angle is ‘open’ on AS-OCT, it is now believed that the patient probably has a low risk of angle closure. AS-OCT also confirms what has been known for a long time; phaco opens up the anterior angle, but the actual contribution the crystalline lens makes towards angle closure is not fully understood.

The retinal detachment rate from phaco in younger ages is interesting, as it is higher than in other groups. High myopia, one reason for clear lens extractions, only makes the situation worse.

Sakata suggested doing gonioscopy in dark conditions to observe the bunched-up iris in vivo. To view the trabecular meshwork, scleral indentation might be required.

Resuscitating RGCS

Professor KEITH MARTIN returned to the lectern and posed the question: Are RGCs either healthy or dead?

There is evidence that in humans and other animals, RGCs can exist in an in-between stage where their function is reduced, but they are not dead. Therefore, the possibility exists that they can be rehabilitated.

While it is known that cell injury at the optic nerve head is largely responsible for the functional damage that manifests as POAG, the question that needs to be asked is: Do some cells survive?

While cells that undergo the natural process of apoptosis can be labelled and identified, the detection of ‘sick’ cells was not as easy or straightforward. While the inhibition of apoptosis is a necessity if progress is to be made in tissue preservation, the restoration of function is not necessarily the primary aim. Early damage to RGC axons occurs at the lamina cribrosa, and in very early stages of the disease changes can only be detected there. Early obstruction to transport processes, such as movement of mitochondria along axons, can now be imaged.

Optic nerve transport can be ‘improved’ after 7-10 days of induced ocular hypertension, by which time some debility can be demonstrated all the way back to the brain. Interestingly, exercise has been shown to improve function recovery. However, there is only some supporting evidence, including electrophysiology, for vision recovery in human glaucoma. Predictably, older animals do not recover as well.

Visual field-assessing devices assume a one-tail testing stance, i.e. visual fields only get worse, an aspect that needs to be factored in when analysing results.

Characteristics of aqueous outflow

US-based glaucoma specialist Assistant Professor ALEX HUANG from the Doheny and Stein Eye Institute, School of Medicine, UCLA, revealed his findings on where and how the aqueous outflows from the eye.

He reports that the outflow is segmented. For example it differs in various parts of the outflow architecture. However, this might vary in different disease states. He also suggested that a successful study of aqueous outflow in individuals would be a good guide to where MIGS devices should be implanted/inserted.

For example, if it is possible to visualise where the aqueous flows, or where flow is greatest, that is where a MIGS device should be located for optimum efficacy. He described that pursuit as aqueous angiography, and used the Heidelberg Engineering Spectralis OCT/multimodal imaging platform to demonstrate outflow segmentation. He was also able to show that the outflow is sometimes pulsatile, suggesting the whole system is quite dynamic.

IndoCyanine Green dye injected during cataract surgery showed that the operated eye’s direction of gaze could also affect outflow, further confirming its dynamic nature.

Regardless of a MIGS device’s position Huang believes that there is always some improvement, but ideal positioning gives an optimum result. He also demonstrated that the flow within the trabecular meshwork is also segmented, but more complex than the flow to the collector channels studied earlier.

2019 World Glaucoma Congress



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