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Mix of old and new sees ophthalmology updates! Flourish

03/12/2018By Lewis Williams PhD
A unique formula and talented line-up of presenters has seen Ophthalmology Updates! go from strength-to-strength during its short history. In part two of his special report, LEWIS WILLIAMS delves into presentations that cover diverse topics that range from artificial intelligence, to penetrating eye injuries.

Despite being one of the more recent ophthalmic conferences on the Australian circuit, the program at Ophthalmology Updates! has already developed a strong reputation. This year was no exception, as Associate Professor Fung and his team delivered a quality program that continued their record of improving standards with each airing.

As per previous conferences, each presentation followed the well-established pattern of a common condition within a sub-discipline, a ‘frontier’ or novel application/idea within that sub-discipline, and some clinical cases to illustrate the sub-discipline.

Penetrating eye injury

Senior vitreoretinal surgeon Dr John Downie gave a presentation on penetrating eye injuries (PEI – open globe injuries) and a frontier talk about macular holes.

He opened his penetrating injuries lecture with a flowchart, which commenced with the need to establish whether or not the globe’s integrity had been breached and if so the nature of that breach, i.e. a laceration or a rupture. Once the presence of a breach has been established as the nature of the injury, it then needs to be determined whether or not the trauma is a penetrating one (a point of entry but no point of exit) or a perforation. The latter involves points of entry and exit, i.e. whatever the cause, it has gone out ‘the other side’.

Regardless of the injury, the presence or absence of a retained intraocular foreign body(s) (IOFB[s]) is also a vital determination. Figures from Sydney Eye Hospital (SEH), spanning 2010–2015 revealed the following: 80 ruptures, 71 PEIs, 48 IOFBs, and 6 perforating cases.

Interestingly, those cases who were over 60 years of age were generally injured (mostly ruptures) in falls, while those under 60 were usually the result of exposure to inanimate mechanical forces, especially when working with metal. Unsurprisingly, the vast majority of victims were male, especially PEIs (85%), IOFBs (94%), and perforations (100%).

It appears that men are also more prone to falls as well, because 65% of ruptures were also male. In addition to age, personal ocular history also has a role in ruptures because 60% of cases had had previous ocular surgery (cataract and penetrating keratoplasties) and 43% of all rupture cases were a result of a fall. Unfortunately, 54% of rupture cases had their final VA recorded as count fingers.

Initial VA at presentation remained the best indication of the likely final VA. Downie also presented some data from the Royal Victorian Eye and Ear Hospital (RVEEH), which involved 267 cases from 2009–2011. That data showed a different injury profile: PEIs (68%), ruptures (31%), IOFBs (16.5%, half in the posterior segment), perforations (0.7%).

Further data revealed that 37% involved lens capsule breaches, about 35% required a vitrectomy, 18% had a retinal detachment, and 3.7% progressed to endophthalmitis. His preoperative management strategy covered several issues – imaging is required to exclude the presence of an IOFB, antibiotic prophylaxis including tetanus is required, and precautions need to be taken before the patient is transferred lest the condition be exacerbated in transit.

An examination starts with VA determination, an assessment of pupil behaviour and eye movements, followed by an external examination and the best practicable eye examination. Assessments of the integrity of the cranial nerves and the neural system in general were also recommended.

Downie reported that where there is no Relative Afferent Pupillary Defect (RAPD), about 70% of cases will have a final VA better than 6/60. However, when there is an RAPD that figure falls to just 34%. He noted that children can be more challenging because history is less reliable, the examination more difficult and that an examination under a GA might be required.

Generally, globe rupture involves haemorrhages, restricted eye movement, hyphaema, and of course low or no IOP. In such cases, an eye exam may need to be performed under local anaesthetic. Transfer precautions in those cases can require the use of an eye shield, analgesia, and possibly an anti-emetic. Treatment is carried out with extra care to avoid including errant ocular tissue in trauma and/or surgical sites.

RVEEH figures on endophthalmitis show the rate was 6.8% in 2004 and only 3.7% in 2015, due largely to the rigorous use of prophylactic antibiotics. More than 75% of endophthalmitis cases were caused by just three organisms/groups of organisms – Staphylococcus spp. (47%), Bacillus cereus 18%, and Gram– fungi (12%).

Risk factors were predictable – dirty wounds, crystalline lens injury, and repairs delayed by >12 hours. Organism growth is usually along the penetration path and is aided by the vitreous acting as a scaffold for the ‘invaders’. Traction on the peripheral retina adjacent to entry and exit sites can result in a detachment.

Downie listed the advantages of delaying a vitrectomy should one be necessary as better control of inflammation, reduced intraoperative bleeding, and the fact that scleral wounds would usually already be sealed and a PVD might have developed already. He then moved to his frontier presentation, which focused on macular hole (MH).

Downie defined a MH as a full-thickness dehiscence of the neural retina at the fovea that usually affected those in middle age or older. Females outnumber males 3:1 and the population incidence is about 1/1,000.

It can be a result of an anomalous PVD and it can result in decreased VA, visual distortions, and scotomata. However, a PVD is not always involved.

It appears as a hole surrounded by a zone of subretinal fluid (SRF) and an epiretinal membrane might be present. Diagnosis is now usually aided by OCT imaging.

Grading by the most recent (2013) classification, IVTS, starts with vitreo-macular traction (VMT) (1); small, full-thickness MH with VMT (<250 microns) (2); medium, full-thickness MH with VMT (250–400 microns) (3); large, full-thickness MH with VMT >400 microns (4); and any size of full-thickness MH without VMT (5).

About 60% of lesser grade MHs settle spontaneously, while just 11% of mid-grade cases close spontaneously and 74% of such cases progress to more serious stages. With no treatment given, about 75% of cases have a VA worse than 6/60 by year 5.

Apart from PVD and VMT, other causes include blunt trauma (about 50% of those cases close spontaneously by the second month), myopic macular retinoschisis (an increasingly common cause given the expected figures of myopia, especially high myopia), and retinal detachment.

Surgery for MHs involve a vitrectomy and the induction of a PVD, peeling of the retina’s inner limiting membrane (ILM), and the injection of gas (to form a bubble) to support the retina, and the possible use of face-down head positioning. The latter is required less often in cases in which a short acting gas (SF6) is used, the patient is younger, and the MHs are <400 microns in size. Least successful outcomes await those who have large MHs and/or are highly myopic – especially if AL is large or a posterior staphyloma is present.

Downie also spoke of the alternatives to a vitrectomy, namely ocriplasmin or gas injection. Ocriplasmin is a recombinant protease that has the demonstrated ability to cleave fibronectin and laminin at the vitreoretinal interface. Its use has delivered mixed results (it’s also expensive) and according to Downie’s real-world assessment, the MH closure rate is lower than the alternative, along with a greater number of adverse events. In summary, he preferred surgery to ocriplasmin injections.


Adrian Fung

John Downie

Xiaoling Liang

James Wong

AI and ophthalmology

Dr Xiaoling Liang from the Zhongshan Ophthalmic Center at Sun Yat-Sen University in Guangzhou, gave a report on his research centre, which is the largest in China with 1.1 million outpatients, 71,000 surgical interventions, 23,000 cataract surgeries, and 11,000 vitreoretinal surgeries.

The centre’s activities include the usual range of ophthalmic services, along with research involving stem cells, genetic, epigenetic, and gene therapies. Stem cell research is centred on crystalline lens regeneration.

Worldwide, he identified 106 start-ups that are transforming healthcare through AI, a scenario he described as “booming”. Liang nominated the healthcare categories involved in AI as: imaging and diagnostics, remote patient monitoring, core AI companies applying their knowledge to healthcare generally, drug discovery, and cancer research.

He itemised six Chinese AI companies associated with AI research in eyecare. From 2017, the Chinese Government commenced building an AI platform in the country involving four commercial partners – Baidu (autonomous driving), Aliyun (urban brain), Tencent (medical imaging), and iFlyTec (intelligent voice/automatic language translation).

large leaderboard

In the ophthalmic arena, he identified the important aspects of ophthalmic devices as being portable, wearable, multifunctional, and offering multimodal imaging where relevant. A major factor driving the push towards AI can be summed up with just one piece of data – China has 1.8 medical practitioners per 1,000 population according to 2015 figures from the OECD. Like most other large countries, they have the usual maldistribution problem as well. The only OECD countries with worse ratios are South Africa (worst) and Turkey.

AI imaging is targeting cataract, glaucoma, diabetic retinopathy and AMD preventatively, and myopia interventionally. A rare disease consulting network has also been established.

A Chinese AI platform – the multihospital, collaborative management of congenital cataracts – was featured in a 2017 paper in Nature: biomedical engineering. Following the success and US FDA approval of AI detection of mild and moderate NPDR in 2018, China is now developing a DR auto-screener for use in outpatient endocrinology departments using 66,790 images to train its system. Sensitivity and specificity for the system is currently at 92.3% and 93.7%, respectively. Liang’s institute is the reading centre for the project.

The myopia prevention project is based on custom-made, wearable AI devices (attached to spectacle frames) that monitor the wearer’s activities, light levels, working distances, etc. Challenges for any AI project in China include the huge size of databases because of the large population, standardising criteria, data collection, the numerous opportunities on offer in the early stages (difficult to focus on a rational number of aspects rather than all aspects), and the machine deep learning required.

Medical retina

Medical retina specialist Dr James Wong gave a flowing presentation on branch retinal vein occlusion (BRVO) for the common condition and the applications of subthreshold laser for his frontier topic. BRVO is one of three retinal vein occlusions due to a thrombus – central (CRVO), hemi (HRVO), and BRVO. The latter is 3x more common than a CRVO with about 75% of BRVOs involving major branches and 25% involving a macular branch of the vascular tree.

The location of an occlusion is another important factor because 66% of cases are found in the superotemporal retina, 22–43% in the inferotemporal region, and just 0.5–2.6% occur nasally. In Australia, the prevalence in those ≥48 years of age was given as 1.1%, but the country of residence is a factor as China has a 1.3% prevalence in those ≥40 years of age, the USA overall a 0.9% prevalence while Singapore has the lowest (40–80 years) at 0.6%.

Wong gave the 15-year cumulative incidence as 1.8% with no apparent racial or gender predilection, with most cases occurring in the 5th and 6th decades of life. Although the condition is regarded as being multifactorial, three main factors have been identified: retinal vein compression at arterio- venous crossings (the vessels share a common adventitial sheath meaning the vessels are less independent than they appear), degenerative changes in vessel walls, and abnormal haematological factors.

The creation of a thrombus is thought to involve the so-called Virchow’s Triad – vascular endothelial injury, abnormal blood flow in a vessel, and blood hypercoagulability. A thrombus triggers a chain of events – venous obstruction, a subsequent rise in venous pressure on the supply side of the blockage, a resulting overload of the local collateral drainage capacity, macular oedema and ischaemia, and the unrelieved venous pressure, leading ultimately to a vein wall rupture and intraretinal haemorrhage as a direct consequence.

BRVO risk factors and associations are categorised into cardiovascular diseases, coagulation disorders, systemic inflammatory disorders, ocular disorders, and medication/other. In the cardiovascular disease category are all the common ailments – hypertension, diabetes, hypercholesterolaemia, elevated LDL, lipoprotein(a), elevated homocysteine, and hyperuricaemia.

Coagulation disorders include increased haematocrit, factor V Leiden mutation, protein C, protein S and antithrombin III deficiencies, the prothrombin (factor II) gene mutation, antiphospholipid Ab, multiple myeloma, leukaemia, and lymphoma. The systemic inflammatory disorders read like a pathology textbook – Behçet’s disease, polyarteritis nodosa, Wegener’s Granulomatosis, TB, Eales disease, sarcoid, syphilis, lupus, Goodpasture’s syndrome, Giant Cell Arteritis, and CMV/HIV.

Ocular disorders include the usual suspects – glaucoma, elevated IOP, decreased ocular perfusion, optic disc drusen (ODD), hyperopia/short ALs, A-V nipping, Grave’s disease, and orbital tumours. Medications and other were given as the oral contraceptive pill, COX-2 inhibitors, dehydration, smoking, and increased BMI.

Additionally, the hydration issue as a general RVO risk factor was covered at some length by Wong. He noted a rise in cases during Ramadan observers in dry countries such as Saudi Arabia and in young adults undertaking severe physical exercise or using the sauna without taking measures to maintain hydration.

Complications of BRVO include CMO and retinal ischaemia (macular ischaemia, retinal neovascularisation, vitreous haemorrhage). While bilateral BRVOs present in only 5–6% of cases, the eventual risk to the contralateral eye has been put at 10%.

BRVO treatment commences with observation because 50–60% of cases have better than 6/12 vision after 1 year, although 5–15% develop macular oedema over the same period. Some 18–41% of cases with macular oedema improve spontaneously but usually not to 6/12 or better.

For 20% of those with CMO, their condition worsens and a visual impairment results. Systemic treatments such as common anticoagulants like aspirin are ineffective and complex manipulations of blood, such as isovolumic haemodilution, can improve VA somewhat but the complexity of the procedure and the systemic side-effects are a downside.

Peripheral scatter laser treatment helps prevent neovascularisation and vitreous haemorrhage in some cases and macular grid pattern lasering improved vision by an average of two lines in about two-thirds of cases. Peripheral scatter lasering uses 200–500 micron spot sizes for 0.2 seconds at medium power. The treatment area gets no closer than two disc diameters from the fovea.

Macular grid lasering used a small spot size (100 microns) for 0.1 seconds, with even lower power. Studies using intravitreal steroids, e.g. dexamethasone, showed benefits, while the application of anti-VEGF showed similar results when bevacizumab was used but results were better when ranibizumab was used instead. When the latter was used in a longer-term study (4 years with an average of 3.2 injections per year by year), 50% of cases needed ongoing treatment and 50% showed complete resolution of macular oedema.

An aflibercept trial rendered similar results to the ranibizumab trial. Wong concluded that consultants need to be aware of the systemic and ocular associations with BRVO, he finds fundus fluorescein angiography (FFA) to be useful, treatment should not be delayed if the condition isn’t improving, and now he regards anti-VEGF as the first line of treatment.

Wong described photocoagulation as a thermal process in which light energy absorbed by tissue is transformed into local heat, resulting in protein denaturation. In a retinal context, photocoagulation is due to absorption by the three retinal chromophores – melanin (RPE and choroid), haemoglobin (vessels, vascular abnormalities, choriocapillaris), and xanthophylls.

The threshold for visible retinal laser burn depends on the laser’s power, wavelength, and pulse duration. The surgical effects of a retinal laser are the creation of a chorioretinal scar and the prevention of any advancement of retinal detachments or tears.

The medical effects include the inhibition of angiogenesis by the destruction of ischaemic retinal tissue, a reduced VEGF load, a reduced retinal oxygen demand, and the induction of chorioretinal shunts. Macular oedema can be reduced by low energy photocoagulation.

While the mechanism isn’t known with any certainty, theories include increased capillary permeability, an increase in the RPE’s pump mechanism, and by damaging the RPE, the overlying photoreceptors might be helped.

By using short pulse durations, minimal time was given for the local heat generated to diffuse into the surrounding tissue. Subthreshold or short-pulse lasers are classified as micropulse (a train of short pulses with a low duty cycle [9%]) or nanopulse depending on pulse duration. The mechanisms of action of micropulsed lasers include the modification or production of anti-inflammatory cytokines and the induction of heat shock proteins while preserving the functional neurosensory retina.

At the cellular level, the thermal effects are sublethal along with less collateral thermal damage to adjacent structures (neurosensory tissue and the RPE) compared with continuous wave lasers. Micropulsed lasers are useful in macular oedema/diabetic macular oedema (MO/DMO), BRVO, radiation retinopathy, microaneurysms and telangiectasias, and central serous chorioretinopathy.

Nanopulse lasers use even shorter pulse durations (3 nanoseconds) over a 400 micron spot area and are claimed to be capable of inducing retinal rejuvenation. Their roles include drusen and so-called dry macular degeneration. It targets the macular area directly and is claimed to activate repair mechanisms in the retinal layers to slow the ageing process and maintain vision.

The proposed mechanism is photostimulation of the RPE inducing a wound healing response in the adjacent RPE, and selective RPE death, along with preservation of the overlying neurosensory retina. Surprisingly, not only is there drusen regression in the treated eye, there is also drusen regression in the contralateral eye as well as improved macular sensitivity. A rigorous clinical trial is underway currently and it is probable that the method in its current form or an evolved form will become more mainstream in the near term.

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