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Report

RANZCO NSW Annual Scientific Meeting 2019

02/05/2019By Lewis Williams PhD
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The NSW branch of RANZCO held its 2019 Annual Scientific Meeting on 16 and 17 March. In the first of a two part series, LEWIS WILLIAMS details some of the expertise shared at the event.

The NSW branch of RANZCO held its 2019 Annual Scientific Meeting in Sydney’s Hyatt Regency Hotel during March. The meeting’s theme was ‘Current Waves and Over the Horizon’. The organising committee, headed by ophthalmologist Dr Robert Griffits, organised a successful meeting with 200 delegates in attendance.

The keynote speakers were Professor Ron Adelman, director of the retina and macula service at Yale University’s School of Medicine, Associate Professor Tina Wong, head and senior consultant of the Glaucoma Department at Singapore National Eye Centre, and Associate Professor Lyndell Lim, Principal Research Fellow at CERA, University of Melbourne.

A number of speakers drawn from ophthalmology, urology, oncology, neurology, physiotherapy, rheumatology, and health care management rounded out the line-up.

IOLS in 2019

Sydney ophthalmologist and cataract and refractive surgeon Dr Di Semmonds opened the meeting with an update on Intraocular Lenses (IOLs). She described the ideal IOL as one that provided excellent distance, intermediate, and near vision with enhanced contrast, induced no haloes, caused no posterior capsular opacity (PCOs), offered accuracy of final Rx outcomes, and offered ways to fix any reasonable problem arising.

She gave some details of the small-aperture optics AcuFocus IC-8 IOL. US trials of the IOL, which is based on the optical properties imparted by a pinhole, started in late 2018. The lens incorporates a 3.23 mm diameter ‘iris’ with a 1.36 mm aperture ‘pupil’ that is claimed to provide up to a 3.00 D extended depth of field (EDOF). The one-piece optic is 6 mm in diameter and is made of a hydrophobic material. The product’s information sheet also claims that it ‘compensates to the effects of astigmatism up to 1.50 D’.

According to Semmonds, the B+L Crystalens accommodating IOL, released quite some time ago, failed to provide the range of accommodation needed. Now, there is PowerVision Inc.’s FluidVision IOL, a 2-piece, fluid-filled IOL with a 360 ° haptic that is fitted ‘in the bag’. The device is claimed to offer 3 to 4 D of accommodation by harnessing the eye’s natural environment and normal ciliary muscle activities. The fluid-filled haptics act as a fluid reservoir and when accommodating, the fluid moves into the IOL’s optics. Results were sustained at the 2-year follow-up visit.

Because of its location, concerns were expressed about its potential to induce capsular fibrosis, however early rabbit studies showed ‘remarkably low’ rates overall. Clinical trials in human subjects have already commenced in non-US FDA jurisdictions.



"Semmonds surmised ... The possibility that cataract-prevention technology might become feasible cannot be ruled out."
Di Semmonds, ophthalmologist and cataract and refractive surgeon

The possibility of an ‘electronic’, accommodating IOL was also detailed. While the size of necessary components are within the realms of current electronics, the power source could be a problem because of size, recharging, and probably most importantly, life expectancy. The Elenza Inc.’s Sapphire AutoFocal accommodating IOL is such a device, but the claims of a 50-year battery life using two lithium-ion (Li-ion) batteries are difficult to reconcile.

The only current technology that might go some way towards such a long life is that of supercapacitors, and they have current downsides of lower energy density and larger size. Wireless or inductive recharging is required. Accommodation is achieved without any IOL or component movement, rather, the LCD elements ‘switch’ on to produce an artificial iris, with a reduced-aperture centrally giving an EDOF effect. In the event of device or power failure, the IOL defaults to being a simple monofocal IOL. All of the device’s components are sealed hermetically in a glass wafer, encapsulated in the acrylic IOL.

The Akkolens International’s Lumina accommodating IOL appears to be based on the Alvarez Lens or the slightly thinner Lohmann Lens. These technologies, developed independently in the late 1960s, utilise two elements that move over each other laterally to produce a variable power. Conventional IOL materials are used. The Alvarez Lens was last used in the late 1970s in the revolutionary Hoya/Humphrey Vision Analyser, although few made it to Australia due to its cost and radical differences.

There are other IOL technologies currently under investigation. An example is the Rx Sight light-adjustable IOL, in which spherical and cylindrical power can be altered or bifocality introduced using UV-modulation. By exposing the IOL’s polymer, a collection of silicone macromers, to UV light, changes in shape can be induced for as long as unreacted macromers remain in the IOL. Eventually, the whole lens is irradiated to finalise and fix the IOL’s optical and physical properties.

Theoretically, wavefront-guided shapes can also be made to deliver superior visual outcomes. A similar concept is used in the Perfect Lens’ Perfect Lens IOL, in which a femtosecond laser is used to modulate chemical reactions. Modifications can be made up to weeks later. A novel 2-component IOL is also under investigation in which a permanent base IOL is implanted, followed by a second, replaceable element to offer a full Rx.

IOLs that decrease aberrations are still being sought. Some 15% of IOL recipients experience and report negative dysphotopsias, but that decreases to about 3% over time.

The hydrophilic (25% water) Oculentis Femtis Laser Lens is a 4-haptic (2 large, longitudinal, 2 shorter latitudinal) designed to benefit from the superior capsulorhexis and centration offered by femtosecond lasers in FLACS suites.

Semmonds surmised that although cataract surgery is likely to change and improve over time, the possibility that cataract-prevention technology might become feasible cannot be ruled out. This would lighten much of the current surgical load. Traumatic cataract, or cataract secondary to disease, will probably still be an issue, but mainstream cataract surgical activities would be affected.

During discussion time, the issue of fundus viewing with artificial iris devices, such as the IC-8 IOL in situ, was raised. It was claimed that the fundus can be viewed through the pinhole aperture and around the outside of the artificial iris. The EDOF effect can be useful when examining the eye. However, if a vitrectomy is planned, the IOL must be removed first, and an epiretinal membrane peel can be difficult while the IOL remains in place.

KEYNOTE SPEAKERS

Dr Michael Lawless

Associate Professor Samantha Fraser-Bell

Professor Stuart Graham

Robots and ophthalmology

Sydney ophthalmologist Dr Michael Lawless tackled the subject of the role robots might play in the future of cataract and refractive surgery. He raised the essentially hands-off procedures of trans-epithelial PRK, LASIK, and SMILE as indicators of where ophthalmological surgery could be headed. He admitted that in 2019 corneal lasers were already better than previous versions, but there are still real-world needs, such as screening for possible ectasia cases, before operating.

For the SMILE procedure, he noted the need for increased sophistication on the part of the surgeon, paying special attention to factors like centration and accuracy. While the combination of corneal cross-linking (CXL) and LASIK/SMILE/PRK was useful, he believes that CXL usage needs to be more targeted. He described corneal inlays and multi-focal corneal surgeries as ‘bad ideas’.

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The ianTECH miLOOP crystalline fragmentation device, acquired by Zeiss in 2018, is described as a micro-interventional device for phaco and lensectomy procedures. It uses a thin, elastic Nitinol filament loop to ‘lasso’ the crystalline lens and cleave it on retraction of the loop into its dispensing pen, even when a mature cataract is involved. Because it is capsule and zonule-friendly, it can also be used to assist in the separation of lens cortex from the lens capsule.

Lawless detailed the features of a presbyopic eye as having an enlarged crystalline lens that has stiffened and is of altered viscosity, with a ciliary body that is probably somewhat atrophic. He raised the topic of the UNR844RL drug as a way to reverse some of those features and, to an extent, restore vision. He predicted that in 5 to 10 years drops might make office-based, cataract surgery a same-day, bilateral treatment reality.

One of the leading mainstream surgical robots is the da Vinci product, which has FDA approval for cardiac and colorectal patients. Although somewhat larger than is probably ideal for ocular surgery, in 2017 the da Vinci was used experimentally for pterygium surgery. While successful, it took far too long to complete the surgery and the trial was abandoned. Similarly, a robot has also performed an epiretinal membrane peel, a good test of surgical skill & finesse. While the procedure resulted in less trauma, the time taken was again impractically long.

According to Lawless, a good surgeon can delivery 100 micro accuracy, whereas a robot can achieve an order of magnitude better at 10 microns.

A collaboration between the Jules Stein Eye Institute and the UCLA Department of Mechanical and Aerospace Engineering is working on an ophthalmic surgical robot, called the Intraocular Robotic Interventional Surgical System (IRISS). However, in mid-2018 Dutch medical robotics company PRECEYES Surgical System supplied a University of Oxford team with an ophthalmic robot for use in dissolving blood clots in 3 AMD cases. In theatre, the robot dissected an epiretinal membrane and inner limiting membrane over the macula area, in 6 patients and injected a recombinant tissue plasminogen activator under the retina to displace sight-threatening haemorrhages in the 3 AMD patients. It is perhaps more accurate to describe the surgery performed as robot-assisted surgery.

Other robotic systems in development could be described as semi-autonomous, OCT-guided cataract and vitreoretinal surgery devices. Lawless believes that robots will have a positive impact on patients and ophthalmologists alike, and estimated that in 10 to 20 years’ time ophthalmic robots will have become a routine part of ophthalmic practice.

Emerging therapies in medical retina practice

Associate Professor Samantha Fraser-Bell, a medical retina, and uveitis specialist with appointments at several major Sydney hospitals, spoke about surviving in current practice.

She described current AMD drug therapy as treat and extend, starting with 3x, monthly loading doses before extending the frequency of injections out to 6 weeks. Further extensions out to a cap, usually between 6 and 12 weeks based on what the response is like to earlier treatment, are possible. However, she cautioned not to extend too far as under-treatment must be avoided at all costs. Regardless, she still has reservations about the ‘durability’ of current treatment medications in the eye. To that end, longer-lasting anti-VEGF treatments are being researched, and better treatments are expected.

A partial answer to the dilemma of under-treatment is the so-called Port Delivery System (PDS) by Genentech and Roche, which is currently in clinical trials. The study is two-pronged – ranibizumab for neovascular AMD and faricimab for diabetic macular oedema. The PDS is a refillable, non-biodegradable, ocular implant that releases medications continuously over several months, avoiding the disadvantages of the pulse-dose that results from periodic intravitreal injections. Refilling is done on a PRN basis.

Another drug under investigation is Novartis’ brolucizumab, a single-chain antibody with a smaller size allowing increased molar amounts to be delivered with enhanced durability and reduced injection frequency. Compared with aflibercept, a product already approved, brolucizumab usage resulted in reduced central subfield thickness at the 1 and 2-year clinical trial marks. About 50% of the subjects in the trial could extend injection frequency out to 12 weeks.

Allergan is reported to be investigating the use of DARPins (designed ankyrin repeat proteins): genetically engineered antibodies that mime specific proteins for use in AMD patients. Using the DARPin, abicipar (Abicipar Pergol), two clinical trials are underway that compare abicipar to ranibizumab. Early data suggests an ocular inflammation rate approaching 15% and a reformulation is in the works.

Fraser-Bell also raised the prospect of combination therapies, including the possibilities of combining an anti-VEGF with an anti-angiopoietin-2 to make a bispecific antibody (RG7716) for AMD therapy. A Phase 1 clinical trial commenced in 2017.

In summary, she estimates that there are several promising emerging technologies and eventually, longer lasting therapies are likely.

New strategies in glaucoma neuroprotection

Glaucoma specialist Professor Stuart Graham, Professor of Ophthalmology at the Australian School of Advanced Medicine, Head of Ophthalmology and Visual Science at Macquarie University, and Visiting Professor to the SSI, University of Sydney, presented a lecture on one of his signature topics: neuroprotection of the retina in glaucoma.

While not a new pursuit, previous attempts have not worked adequately. One glaucoma treatment in the pipeline currently is netarsudil (0.02%, market name: Rhopressa, a rho-associated protein kinase [ROCK]). As with most glaucoma trials, the performance of novel entities is compared with the beta-blocker, Timolol.

Another novel approach to glaucoma treatment is the modulation of brain-derived neurotrophic factor (BDNF) using a BDNF agonist, the regulation of BDNF, or gene therapy. Either the upregulation of BDNF or an upregulation of its specific receptors are expected to be useful, but the relevance of animal models to human trials remains unknown. Also, impractically large therapeutic doses would appear to be required.

Alternatively, a 2017 Australian study found that neuroserpin, a serine protease inhibitor and a known neuroprotector, has a regulatory effect on plasmin proteolytic activity in the retina in glaucoma. That study postulated that using antioxidants to inhibit oxidative inactivation of neuroserpin in vivo might have therapeutic potential. An experimental modification of neuroserpin using AAVs (adeno-associated virus vectors) for delivery has been attempted. The processes involved in RGC survival and apoptosis follow complex molecular pathways, and our understanding of them is probably incomplete.

In mice at least, retinoid x receptor (RXR) modulation has been shown to protect against oestrogen receptor (OR) stress responses and be neuroprotective in the central nervous system. Using electrophysiology, an RXR modulator, bexarotene, has been shown to downregulate OR stress markers under glaucomatous conditions protected RGCs in vivo significantly in both acute and chronic glaucoma in the mouse model.

In RGCs, Shp2, a protein-tyrosine phosphatase, undergoes activation/upregulation under glaucomatous stress conditions. Shp-2 regulates the TrkB (tropomyosin receptor kinase B, a receptor for BDNF) receptor activity in the RGCs and the loss or inhibition of Shp2 rescues BDNF/TrkB signalling and restores TrkB activity in retinal cells.

Furthermore, the down regulation of Shp2 is neuroprotective against neural retinal loss in induced experimental glaucoma. Regardless, the actual significance of these findings, especially in humans, remains unknown.

Neuroprotection of RGCs by a novel gene therapy that lasts months is the product of recent research by Professor Keith Martin, the new managing director of CERA in Melbourne. Graham summarised his advice as: treat any elevated IOP, consume adequate dietary omega-3 and vitamin B3 (niacinamide), get adequate exercise, follow a sensible diet, do not smoke, and treat any cardiovascular disease that might be present.

 

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