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Report

The Future of Surgery RANZCO Scientific Meeting 2019

30/05/2019By Lewis Williams PhD
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The NSW branch of RANZCO held its 2019 Annual Scientific Meeting on 16 and 17 March. In Part 2 of his report, LEWIS WILLIAMS details some of the conference’s highlights.

LYNDELL LIM

Melbourne ophthalmologist, Head of Clinical Trials Research at CERA


Associate Professor Lyndell Lim is a Melbourne ophthalmologist, Head of Clinical Trials Research at CERA, and holds positions at the RVEEH and in private practice. She opened with the statement that a case of uveitis cannot be described as anterior until the possibility of posterior uveitis has been completely ruled out. Because the condition can be either unilateral or bilateral, a thorough history and a comprehensive eye examination are mandatory.

Currently, some parts of Australia are in the grips of a syphilis epidemic. Figures from the RVEEH in 2006 found 4.3 cases per 100,000, but numbers had risen to 13.4 per 100,000 by 2016. That is significant because syphilis is nicknamed ‘the great pretender’ for good reason; masquerading as uveitis, or having uveitis as one of its presentations, is one of its many ‘acts’.

However, posterior uveitis and panuveitis are the most common manifestations of ocular syphilis. If an erroneous diagnosis of uveitis is made, treatment of the underlying syphilitic condition is delayed and vision loss can occur.

Things get more difficult when the patient is immunocompromised and of an older age. This makes presentation very complicated, especially if a chronic diseases such as diabetes or one of the blood cancers is a comorbidity. Uveitis can also be associated with autoimmune diseases such as rheumatoid arthritis, or it can be iatrogenic. Herpetic uveitis can result in abnormal iris transillumination appearances due to ischemic necrosis of the iris’ stroma and defects of the iris pigment epithelium. Lim advised her audience to ask their patients if they had been ‘unwell’ lately before digging too deeply with complex investigations and tests.

In her later presentation, Lim spoke of the use of biologics, particularly monoclonal antibodies (MABs), in uveitis, including some of the biologics already US FDA approved for use elsewhere in the body. Inhibition of TNF-alpha, but not intravitreally, and beta cells were mentioned specifically.

 

MINAS CORONEO

Chairman of the Department of Ophthalmology UNSW


Ophthalmic diagnosis: Now and in the future

Professor Minas Coroneo, Chairman of the Department of Ophthalmology UNSW, delivered some insight into where ophthalmic diagnosis is going. He noted that the ocular microbiome only became a topic of significance in 2008, and particular micro-organisms have been shown to reside in limbal epithelial crypts where there is evidence of microbial synergy within the resident population.

Since the advent of the US National Institute of Health’s human microbiome project, it is now accepted that the human body is ‘infested by bugs’. Furthermore, it is now largely accepted that such an arrangement is advantageous and useful to the survival of the host. Surprisingly, the micro-organisms outnumber the number of human cells by a factor of 10:1. The micro-organism population is dominated (90%) by Bacteroides (a genus of Gram-negative, obligate anaerobic bacteria) and Firmicutes (a phylum of bacteria, most, but not all, of which are Gram-positive).

When the microbiome is abnormal for whatever reason, the term ocular dysbiosis is used to describe the situation. A dysbiosis can be due to dry eye disease (DED), failure of the limbus and/or the limbal stem cells residing therein, blepharitis, antibiotic usage, glaucoma drops, conjunctivitis, the presence of Proteobacteria (a Gram-negative phylum of bacteria including known pathogens such as Escherichia, Salmonella, Vibrio, Helicobacter, Yersinia, and Legionellales [typically Legionella and Coxiella] among others), or Firmicutes.

Dysfunction of the human microbiota has been linked to conditions ranging from inflammatory bowel disease to antibiotic-resistant infections. A number of diseases have been shown to correlate with decreased microbiome diversity. For example, one or a few microbes exceed their normal levels and in so doing, dominate their environment. Diversity is sometimes classified into two categories: Alpha, meaning number of different species present in a local habitat, and Beta, the differences between local habitats.

Interestingly, even when the conjunctiva of the anterior ocular surface is ‘disinfected’, some 2% of the DNA of the previous microbial residents can still be detected on the surface. Confounding assays of the micro-organisms present is the fact that about 90% of bacterial species do not culture, making identification and research difficult.

One workaround is to use DNA sequencing techniques to get indirect evidence of what is present. Sequencing reveals that there are many, many more micro-organisms present than first thought. As the significance of the human and ocular microbiomes and dysbiosis of them become better understood, it is reasonable to assume that assaying the ocular microbiome and altering it deliberately in a targeted and beneficial way is likely to become a part of the future practice of ophthalmology.

 

RON ADELMAN

Professor at Yale University’s School of Medicine


Retinal arterial embolism

Professor Ron Adelman from Yale University’s School of Medicine opened his presentation by likening the resolution of an embolus to that involving a foreign body starting with a granulomatous response and moving to a plasmin-mediated dissolution of the clot. If an embolus is outside an artery it is likely to be calcific, whereas a cholesterol embolus is likely to have its origin in atherosclerotic plaque.

He described angiophagy as the process the body uses to clear small clots from blood vessels, essentially a process of microvascular recanalisation that occurs over 1 to 6 days in more than 80% of occluded vessels. Usually, some blood flow is re-established within hours of a blockage.

He also mentioned the alternative processes of translocation (vascular endothelium develops pseudopodia) and extravasation (the leakage of blood, lymph, or other circulating fluids from a blood vessel into the surrounding tissue).

Should a retinal artery occlusion (RAO) be encountered in a patient over 50 years of age, Adelman recommended that giant cell arteritis (GCA) be ruled out early. In cases of central RAO (CRAO), he recommended the patient be referred promptly to a stroke centre. Fibrinolysis does not always work in CRAO cases.

In branch RAO (BRAO) cases, it is less likely to be related to GCA and is more likely to have a more local aetiology. For arterial emboli, he suggested that the eyeball be massaged initially to increase the IOP and then stopped to decrease the IOP, in an attempt to move the embolus along the affected vessel. Even after 90 minutes, some cells will survive if there is some circulation retained.

In animal studies, if adequate circulation is re-established in under 90 to 97 minutes, the ischaemic or anoxic effects of CRAO can be reversed fully. However, the window of time in humans has not been established. The uses of lowered IOP and/or vasodilation to promote downstream embolus movement have been mostly unsuccessful.

 

CON PETSOGLOU

Ophthalmologist at Sydney Eye Hospital


Corneal transplantation in 2040

Ophthalmologist Dr Con Petsoglou, who has positions within USydney (Sydney Eye Hospital), the Lions NSW Eye Bank, and private practice, offered some insight into the future of corneal transplantation. He expressed satisfaction with the current waiting time for transplant tissue in NSW, which is now around 3 months. This is opposed to 21 years ago, a particularly bad time for those wanting a corneal transplant, when it was at least 2 years.

That shortening of waiting times is partly due to a decrease in the number of transplants (penetrating keratoplasty and the more recent lamellar techniques) being undertaken. The advent of corneal cross-linking (CXL) as a treatment for keratoconus (KC) has also decreased the number of KC cases that progress to a transplant by about 40%.

According to him, 2011 was the peak year for transplants, and the availability of CXL has seen a decline in surgery activity ever since. Options for KC cases remain CXL, CLs, IOLs, Kerarings, and laser surgery.

Unexpectedly, transplants for Fuch’s dystrophy have increased by 6x. However, this is because surgeons are treating the condition earlier, not because of an increase in the number of incidence of the condition. A central reason for ‘going early’ is the greater number of endothelial cells still functioning in the diseased cornea. Petsoglu postulated that using the increasingly capable CRISPR technology, Fuch’s dystrophy will become a preventable disease.

He foresaw a role for stem cell (SC) therapy in endothelial cell diseases on the basis that it is known that they can be cultured in vitro. The approach is to take cultured cells, or sheets of cultured cells, and seed the endothelium in vivo through the anterior chamber.

He also saw a future for bioengineered corneas and corneal tissue that he hoped one day will replace donor tissue in most cases. Limbal SCs (LSCs) and corneal endothelial cells can be grown into the shapes required using biological version of basic 3D printing technology, an area of active research at the SSI, Sydney Eye Hospital. Corneal glue, a component of the SSI/SEH iFix bioink project is a product of that research.

To bring his predictions together as a cohesive suite, Petsoglou suggested that eyebanks will morph into ‘bioceutical’ companies. However, placing such the entities in private hands may lead to some serious ethical issues, especially considering that donated tissue is involved. His parting comment was that by 2040, patients would be able to see 6/3 (20/10) with suitable interventions.

 

JACQUELINE BELTZ

Melbourne corneal, cataract, and refractive surgeon


Next generation surgical training

Published Melbourne corneal, cataract, and refractive surgeon Dr Jacqueline Beltz gave a presentation on the future of ophthalmological surgical training, with special reference paid to virtual reality (VR).

Current training programmes result in registrars being involved in more than 40 cataract surgeries by the time they reach the 4th year of their course. There is increasing pressure on surgical training because practicing surgical techniques on live people is no longer acceptable. VR has now been introduced into the Victorian Training Programme, a structured programme involving two wet labs per week in 1st year in which 4 registrars are under the supervision of one specialist fellow. Other activities account for 6 hours per week for 4 months of the year.

The process for a registrar being allowed to enter an operating theatre is strictly merit-based. VR is now a compulsory part of the training programme. Despite what the concept suggests, Beltz believes that VR simulations of most conditions do not need to be ultra-high fidelity for them to be effective. Currently, SEH has one simulator, and since 2018 the RVEEH has two.

To date, simulators have resulted in shorter phacoemulsification times, less ultrasonic power being deployed during phaco, fewer intraoperative complications, and a shorter learning process. The simulation curriculum embedded in the programme consists of four tiers, and a pass is required in each tier before progressing.

Importantly, all information gathered on a trainee is available to the trainers, so no surprises should emerge. As a trainee’s skills improve, their tasks get more complex progressively. The system is designed to provide specific feedback on each trainee and, importantly, trainees also provide feedback to the system. Most procedures within the VR system rated well, and it was uncommon for the help it provided to be rated poorly.

The VR training approach is now being rolled into the 2nd year of the course. Networking of the simulations assists in the organisation of training programmes, and also helps to maintain standards by broadening the number and types of inputs. In 2nd year, trainees are supervised for two sessions per week then undertake surgical training and a lab. Some own time is also spent on the programme.

One downside of VR systems is their high cost and annual fees. Some information about the GENEYE training system, which is the product of collaboration between Alcon, RVEEH, and Beltz, is available at www.geneye.org.au. Provision is made within the system for advanced trainees, fellows, and consultant ophthalmologists. Off-site education days were held in mid-May this year. Beltz’s final observation was that those involved in gaming or playing musical instruments demonstrated advantages during surgical training.

 

JOHN GRIGG

Head of the Discipline of Ophthalmology


Gene therapy for RP

Associate Professor John Grigg, Head of the Discipline of Ophthalmology, Save Sight Institute, Sydney Eye Hospital, University of Sydney and consultant ophthalmologist at the Children’s Hospital Westmead was presenting information on the leading edge of his discipline. He revealed that, generally, inherited retinal disorders are now the most common cause of vision impairment. To date, some 307 retinal dystrophy genes have been identified, but he acknowledged that there was significant genetic overlap between many of those diseases.

LUXTURNA (voretigene neparvovec-rzyl) is marketed by Spark Therapeutics, after it was developed in collaboration with the Children’s Hospital of Philadelphia. It is a gene therapy for patients with inherited retinal disease due to mutations in both copies of the RPE65 gene. After a decade of clinical trails, in 2017 it became the first gene therapy approved for any disease. It is suitable for patients who have sufficient remaining cells in their retina, such as in Leber’s congenital amaurosis (even in adulthood) and retinitis pigmentosa (RP). The biggest barrier to its use is the US$425,000 cost per eye.

RPE65 is an enzyme expressed in the RPE and is responsible for the conversion of all-trans-retinyl esters to 11-cis-retinol during phototransduction. In turn, 11-cis-retinol is then used in visual pigment regeneration in the retinal photoreceptor cells.

Gene replacement therapy is only relevant to cases in which there is loss of viable function. By comparison, LUXTURNA requires an adequate number of functioning retinal cells. Replacement therapy uses a viral Trojan horse, often a small adeno-associated virus (AAV). However, an AAV is a low load carrier. The AAV2 serotype is the original Trojan horse and a target-specific carrier. To be effective, gene therapy requires an accurate genetic diagnosis as well as identification of the patient’s retinal phenotype.

According to Grigg, choroideremia, a progressive vision loss that mainly affects males, will be the next gene therapy ‘cab off the rank’. To be considered successful, a vision-related gene therapy must provide a meaningful clinical outcome and improvements in mobility in various levels of ambient light. Researchers at SEH have created a virtual obstruction course test for such purposes, presenting little chance of physical risk to vision impaired test participants.

Other diseases receiving attention are achromatopsia and cone dystrophies, which share a CNGB3 genetic defect, and X-linked RP.

Stargardt’s Disease (or Stargardt’s macular dystrophy, juvenile macular degeneration, or fundus flamiculatus) is the most common inherited macular dystrophy. Children of Stargardt’s cases have a 1 in 25 chance of inheriting the disease, and there is also a 1 in 50 chance of a child of a carrier inheriting the disease. Those at risk need to be protected from sunlight and avoid ingesting vitamin A. It is also possible that patients with geographic atrophy (GA) that looks slightly atypical have a mild form of Stargardt’s disease.

Therapies under investigation include the use of stem cells to grow retinal organoids. The SCs are often derivatives of skin fibrobalsts converted to iPSC (induced pluripotent SCs). Conventionally retinal gene therapy is delivered intravitreally, but in primates the existence of their retina’s ILM constitutes an problem for any therapy that needs to access the deeper layers of the retina from the vitreous.

NSW offers genetic testing through NSW Health, which also covers the costs incurred. All NSW teaching hospitals have genetic testing facilities.

Further information is available at: www.genetics.edu.au

 

BEN EGGLETON

Physicist and Director of The University of Sydney Nano Institute


Nanoscience for health and medicine

Physicist and Director of The University of Sydney Nano Institute Professor Ben Eggleton gave some insight into the applications of nano technology, including nanorobotics surgery. To set the scene he equated 1 nm to 10 atoms in a row, or 1 billionth of a metre. The word nano therefore implied devices and entities on an atomic scale. The technology is expected to find use across the economy, society, and everyday life via the current multidisciplinary approach to nano-scale science.

Contributing to that push is USyd’s nanoscience hub, which is located well away from ground disturbances such as close-passing trains. The hub also includes a 900 square metre clean room that is electromagnetically shielded. US software giant Microsoft also has a computing facility in the same location.

Tools with nano precision are highly specialised and an integral element of the hub’s manufacturing capability. There is a downside however, and Eggleton described nano particles as potentially dangerous, toxic, or pathological. Given the common use of nanoparticles in everyday products such as make-up and paint for example, the entry of nanoparticles into the environment is responsible at least partially for them starting to appear in the human food chain.

Nano technology also has positive contributions to make to water quality, nanorobots for health, and miniaturisation of computing equipment. Philosophically, all nano activities have to be safe-by-design and not be a contributor to atmospheric carbon dioxide levels.

In a health context, cells are about 10 microns in diameter whereas nano devices are three orders of magnitude smaller, meaning the use of nanorobots in a medical/surgical context is feasible. Furthermore, it is now possible to mount some CMOS logic in nanoscale robots meaning some limited ‘intelligence’ can be incorporated. Currently, silicon chip fabrication technology has a role to play in nanoscale device fabrication. Another challenge is to unlock neural interfaces to be able to interact with it usefully and reliably.

In an ophthalmological context, Eggleton nominated AMD, glaucoma, diabetic retinopathy, and dry eye disease as areas that nanoscale technology could have a role to play. Possible roles include navigating inside the eye, delivery of therapeutic substances in a targeted manner, and the facilitation of selective regrowth within the eye. Challenges include suitable encapsulation of nanoscale devices as there is unlikely to be a universal protective material, how long a device is to be in the body, and perhaps most importantly, where in the body they are located. Especially in a health context, the technology is still in its infancy.

 

ALEXANDRA JOHNSON

Sydney paediatric neurologist


Headaches in children

Sydney paediatric neurologist Dr Alexandra Johnson presented an overview of headaches in children. There are an estimated 4.9 million Australians who suffer from migraines at some time, a problem that costs the Australian economy some $35 billion. Of those, 3-8% are of school age. Migraine, tension, and medicine overuse are significant factors in the aetiology of headaches in children. Chronic daily headaches should lead to suspicion of concussion.

Migraine often begins with prodromal symptoms with or without aura. The condition is often unilateral, although children are more likely to suffer bilaterally. A pulsating or throbbing quality might also be reported. Migraine triggers include decreased water intake, bright lights, exercise, scents/perfumes, and certain foods. Exercise can also aggravate an existing episode and repeated episodes are not uncommon. Other signs include nausea, photophobia, and phonophobia. While a period of sleep will often solve the problems accompanying migraine, a ‘hangover’ of sorts will often be experienced afterwards.

Aura is experienced by more than 90% of migraine sufferers, and types include jagged, fortification spectra, expanding visual fields, and visual obscuration. A child might explain their experience as a ‘blurring’ of vision. Occipital epilepsy and other vascular abnormalities in the head can produce visual ‘snow’. Auras can affect sensory function, speech, and the migraine itself.

An early aetiological theory was that of vascular contraction, but that now seems less likely. An alternative theory of neuronal depolarisation spreading over the brain, first proposed in a PhD thesis in 1949, is considered a possibility.

Regardless, migraine is now generally accepted to be a neurovascular disorder in which the dilation of blood vessels and pain are triggered neurally. Treatments include NSAIDs, paracetamol, triptans, and serotonergics.

Preventative drugs include propranolol, topiramate amitriptyline, and verapamil but some of those can have significant side-effects or are unsuitable for use during pregnancy. Newer agents, including CGRP receptor antagonists, are under clinical investigation as they counter peripheral vasodilation and neurogenic inflammation.

Some migraine variants in children can require MRI investigation, e.g. benign paroxysmal torticollis of infancy, paroxysmal vertigo, and abdominal migraine. Other types of migraine include hemiplegic, (acute) confusional, and vertiginous.

Tension headaches have a lifetime prevalence of 30 to 78%. Some are chronic, daily events while others can be complex, all-day events. Generally, females are more affected than males. Links to mood disorders or anxiety account for 30-67% of cases and often, sleep difficulties are also reported. Sufferers can also withdraw from social interaction.

Moving to the topic of concussion-related headaches, Johnson spoke of concussion/post-concussion syndrome. Red flags to her were sudden, atypical, unusual, progressive occipital headaches than might radiate down the neck while coughing at the same time. She also urged caution when patients are woken during sleep by headaches. Any recent deterioration in school work or developmental aspects should be viewed suspiciously.

Factors that need to be ruled out include tumours, epilepsy, elevated BP, sinusitis, encephalitis, meningitis, idiopathic intracranial hypertension, episodes of vomiting, papilloedema, and N VI palsy. Possible contributions from obesity, side-effects of medications (especially tetracyclines and steroids), and diurnal variations in blood pressure should also be considered. Because CT scanning involves a small amount of radiation, Johnson prefers MRI scanning if needed.

 

DEBORAH JACKSON

Sydney legal practitioner and advisor to the ASO


Electronic Medical Records (EMRS)

Sydney legal practitioner and advisor to the ASO Ms Deborah Jackson delivered a disturbing overview of EMRs, computer system security, and practitioner’s responsibilities in relation to IT. She described cyber attacks as stressful and costly, especially if the privacy of patient records is compromised.

While health care is a common target generally, recent attacks relate to hackable pacemakers and other 500K devices, thereby introducing a new layer of concern. She also mentioned the QBOT (or QAKBOT) malware that replicates and regenerates itself. Other threats of longer standing are viruses, denial-of-service (DoS) attacks, phishing, ransomware, and man-in-the-middle interventions (a 3rd part interposed surreptitiously in normal communications between two unsuspecting parties).

Mitigation is mostly common sense, and includes technical measures such as updating software, backing-up data (preferably keeping at least one copy off-site), instigation of policies and procedures within a practice, social and behavioural measures applied to all involved at all levels, and privacy measures applied on a ‘who needs to know and why’ basis.

Jackson was adamant that no staff ever have social media accounts on practice systems. Importantly, practices needs to develop data-breach contingency plans and learn as much as possible from ‘near misses’ that might have occurred.

Responsibility for compliance with the Privacy Act needs to be given to at least one staff member. Where cloud storage is used, she advised that storage should be in Australia, encrypted in Australia, and backed-up in Australia.

To complicate matters, she believes that patient consent is required for cloud data storage even if it is to be stored in Australia.

All the foregoing is important to a practice/practitioner because ultimately, the storage service provider needs to take responsibility for any breaches.

In relation to professional indemnity insurance, she advised that a special clause be included in any indemnity insurance contract that states that the insurer takes responsibility for any fallout from data breaches and other IT problems relating to EMRs.

The medical defence organisation (currently Avant) needs to be informed of EMR, security and privacy issues arising via an NDB (notifiable data breach).

In summary, Jackson estimated that human error was responsible for 59% of problems starting with such basic mistakes as having devices lost or stolen often after poor or no security measures were undertaken to secure them. Her parting advice was to consider a post hoc step of including a ‘remote shutdown’ feature in all portable devices that might contain sensitive information.

 

More reading:

RANZCO NSW Annual Scientific Meeting 2019

 






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